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Devastating Metabolic Brain Disorders of Newborns and Young Infants1 Hyun Jung Yoon, MD Ji Hye Kim, MD Tae Yeon Jeon, MD So-Young Yoo, MD Hong Eo, MD Abbreviation: ADC = apparent diffusion coef ficient, TE = echo time RadioGraphics 2014; 34:1257–1272 Published online 10.1148/rg.345130095 Content Codes: From the Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Ku, Seoul 135-710, Republic of Korea. Presented as an education exhibit at the 2012 RSNA Annual Meeting. Received July 14, 2013; revision requested August 18 and received December 16; final version accepted March 3, 2014. For this journal-based SA-CME activity, the authors, editor, and reviewers have disclosed no relevant relationships. Address correspondence to J.H.K. (e-mail: [email protected]). 1
SA-CME LEARNING OBJECTIVES After completing this journal-based SACME activity, participants will be able to: ■■List metabolic disorders that manifest with acute encephalopathy in newborns and infants. imaging features, clinical manifestations, and biochemical features of devastating metabolic brain disorders in neonates and young infants.
Metabolic disorders of the brain that manifest in the neonatal or early infantile period are usually associated with acute and severe illness and are thus referred to as devastating metabolic disorders. Most of these disorders may be classified as organic acid disorders, amino acid metabolism disorders, primary lactic acidosis, or fatty acid oxidation disorders. Each disorder has distinctive clinical, biochemical, and radiologic features. Early diagnosis is important both for prompt treatment to prevent death or serious sequelae and for genetic counseling. However, diagnosis is often challenging because many findings overlap and may mimic those of more common neonatal conditions, such as hypoxic-ischemic encephalopathy and infection. Ultrasonography (US) may be an initial screening method for the neonatal brain, and magnetic resonance (MR) imaging is the modality of choice for evaluating metabolic brain disorders. Although nonspecific imaging findings are common in early-onset metabolic disorders, characteristic patterns of brain involvement have been described for several disorders. In addition, diffusionweighted images may be used to characterize edema during an acute episode of encephalopathy, and MR spectroscopy depicts changes in metabolites that may help diagnose metabolic disorders and assess response to treatment. Imaging findings, including those of advanced MR imaging techniques, must be closely reviewed. If one of these rare disorders is suspected, the appropriate biochemical test or analysis of the specific gene should be performed to confirm the diagnosis. ©
RSNA, 2014 • radiographics.rsna.org
■■Describe
■■Discuss
the role of diffusion-weighted imaging and MR spectroscopy in diagnosing metabolic disorders. See www.rsna.org/education/search/RG.
Introduction
Although individual metabolic brain disorders are very rare, collectively, they account for a substantial portion of cases of neonatal encephalopathy (1). Metabolic disorders encompass a heterogeneous group of disorders. Most metabolic brain disorders in neonates and infants are inborn errors of metabolism. The brain injury results from the accumulation of endogenous toxic substances or a lack of production of necessary biochemicals (2,3). During the gestational period, the brain is protected from injury because toxic substances are removed and necessary substances supplied by the placenta. Affected neonates are usually asymptomatic at birth. The age of onset ranges from hours to months after birth; patients with more profound enzymatic defects tend to have an earlier clinical onset. In general, early-onset postnatal metabolic brain disorders manifest with acute symptoms of encephalopathy and a life-threatening episode of metabolic decompensation, whereas later-onset disorders have a more manageable clinical course with a better outcome. It is for this reason that early-onset disorders are referred to as “devastating metabolic disorders of the newborn and infant.”
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Classification of Devastating Metabolic Diseases in Newborns and Young Infants Type of Disorder Organic acid disorders
Amino acid metabolism disorders Primary lactic acidosis Fatty acid oxidation disorders
Other metabolic disorders
Diseases Propionic acidemia, methylmalonic acidemia, isovaleric acidemia, Canavan disease, 3-hydroxy-3-methyglutaryl-coenzyme A lyase deficiency, multiple carboxylase deficiency, pyroglutamic aciduria Urea cycle defect (citrullinemia, ornithine transcarbamoylase deficiency, cabamoyl phosphate synthetase deficiency, argininosuccinic aciduria), maple syrup urine disease, nonketotic hyperglycinemia Pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, cytochrome oxidase deficiency, complex succinate dehydrogenase (type II) deficiency Carnitine cycle defects (carnitine–palmitoyle transferase deficiency, carnitine translocase deficiency), mitochondrial β-oxidation disorders (very long-, medium-, and short-chain acyl coenzyme A dehydrogenase deficiency and long- and short-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency), electron transfer flavoprotein dehydrogenase deficiency (glutaric aciduria type II) Zellweger syndrome, neonatal adrenoleukodystrophy Krabbe disease (globoid cell leukodystrophy), Menkes disease (trichopoliodystrophy), D-bifunctional protein deficiency, sulfite oxidase deficiency, galactocemia
Affected neonates and infants are usually in critical condition and require urgent diagnosis and treatment to prevent death or serious sequelae. Early diagnosis is also important for genetic counseling. However, diagnosis is often challenging because metabolic brain disorders are extremely rare and diverse, making it difficult to gain experience dealing with individual diseases. Moreover, clinical manifestations are often nonspecific during the neonatal period and may mimic those of other more common diseases, such as hypoxic-ischemic encephalopathy and infection (4). Biochemical test results may be normal or nonspecific, and genetic analysis often offers little insight unless a specific genetic defect is searched for. Therefore, the diagnostic workup relies heavily on brain imaging. However, the imaging features of neonatal encephalopathy tend to be nonspecific, even in disorders that eventually exhibit characteristic imaging patterns later in life (4). Diagnostic workup may be improved by performing a comprehensive evaluation of magnetic resonance (MR) images to assess the anatomic and functional patterns of brain involvement with advanced MR imaging techniques in combination with appropriate biochemical tests and genetic analyses (5). In this article, we discuss neuroimaging of devastating metabolic brain disorders in newborns and young infants, with a brief review of the clinical and biochemical aspects of individual diseases to help diagnose these conditions.
Classification
The devastating metabolic diseases are classified as intoxication disorders, energy production disorders, disorders of the biosynthesis and breakdown of complex molecules, and neu-
rotransmitter defects (Table) (1,2,4). Intoxication disorders include organic acid and amino acid metabolism disorders. Affected neonates have a variable symptom-free interval after birth because toxic metabolites were metabolized by the mother in utero. Energy production disorders include primary lactic acidosis and fatty acid oxidation disorders. Structures with a high metabolic rate such as the brain, heart, and skeletal muscles are particularly involved. Lysosomal and peroxisomal disorders are disorders of the biosynthesis and breakdown of complex molecules. Although lysosomal and peroxisomal disorders do not typically manifest with neonatal encephalopathy, Zellweger syndrome and neonatal adrenoleukodystrophy have a neonatal onset. Recently, neurotransmitter disorders, such as pyridoxine-dependent epilepsy, are increasingly being recognized as severe metabolic encephalopathy in the neonatal period (1,6).
Clinical Presentations and Laboratory Findings
Typically, patients with organic aciduria, urea cycle defects, or amino acidopathy present with acute symptoms of encephalopathy as a result of accumulated toxic metabolites in the brain tissue. Clinical manifestations include vomiting, poor feeding, stupor, and lethargy and eventually lead to coma and death if left untreated. Abnormal muscle tone and epilepsy may also be present. Moreover, apnea or hyperventilation may result from metabolic acidosis or hyperammonemia (4,7). Typically, fatty acid oxidation disorders manifest with a Reye-like episode, hepatosplenomegaly, and cardiomyopathy and may lead to sudden death. Metabolic toxic injury of the
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Figure 1. Zellweger syndrome in a full-term 3-dayold neonate with seizures. (a) Coronal ultrasonographic (US) image of the brain obtained on the 3rd day of life shows germinolytic cysts in the caudothalamic grooves (arrows). (b) Axial T2weighted MR image shows pachygyria and diffuse excessive high signal intensity in the white matter.
developing brain may cause malformations such as cortical dysplasia (eg, Zellweger syndrome), callosal dysgenesis (eg, nonketotic hyperglycinemia, pyruvate dehydrogenase deficiency, Menkes disease, and Zellweger syndrome), cerebellar dysgenesis (eg, nonketotic hyperglycinemia, Menkes disease, and Zellweger syndrome), and cerebral dysgenesis (eg, glutaric aciduria type II) (Figs 1, 2) (2,8–10). Dysmorphic face may be seen in patients with propionic and methylmalonic acidemias, multiple coenzyme A dehydrogenase deficiency, peroxisomal disorders, and maple syrup urine disease. In addition, characteristic odors, such as “sweaty feet” in glutaric aciduria type II and isovaleric acidemia, “burnt sugar” in maple syrup urine disease, and “cat urine” in multiple carboxylase deficiency, have been described (2). Laboratory test results may reveal combinations of hyperammonemia, organic acidemias, and hypoglycemia during acute encephalopathy in many metabolic disorders (11).
Imaging Considerations for Devastating Metabolic Brain Disorders
US may be an initial screening tool in neonates with acute encephalopathy. During an acute metabolic crisis, diffuse edematous brain lesions that mimic hypoxic ischemic encephalopathy may be seen (Figs 3–5). Moreover, US reliably depicts germinolytic cysts, ventriculomegaly, lenticulostriate vasculopathy, anomalous cortex and callosum, and calcification in diverse neonatal metabolic disorders (Fig 1a) (12). However, US is less sensitive in its depiction of early or subtle brain lesions because its findings
are often nonspecific, and detailed patterns of brain involvement are not reliably seen. Cerebral edema or hemorrhage may also be seen at computed tomography (CT) (Fig 6). However, CT has several limitations, including poor contrast resolution, a result of high water content in the neonatal brain, and the disadvantage of radiation exposure. MR imaging is the modality of choice for evaluating metabolic brain disorders (1,4,13). Characteristic patterns of brain involvement have been described for several metabolic brain disorders: White matter is primarily affected in maple syrup urine disease and nonketotic hyperglycinemia, and deep gray matter lesions are predominantly seen in organic acidemia (Figs 2, 6, 7). Both gray and white matter are involved in primary lactic acidosis, which sometimes mimics hypoxic ischemic encephalopathy (Figs 4, 5). However, in some cases, conventional imaging findings overlap or are nonspecific in neonates with metabolic brain disorders (13). Advanced MR imaging may provide further diagnostic information. Diffusion-weighted imaging sensitively depicts early parenchymal lesions and may help differentiate different types of edema with calculated apparent diffusion coefficients (ADCs). Vasogenic edema is most commonly encountered in patients with acute metabolic decompensation. Excessive vasogenic edema is particularly prominent in urea cycle defects and sulfite oxidase deficiency (Fig 8) (14,15). Cytotoxic edema may be seen in nonischemic conditions, a result of cellular swelling by energy failure, which occurs during metabolic
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Figure 2. Nonketotic hyperglycinemia in a neonate with seizures. (a) Axial T1weighted MR image shows an absence of normal myelination of the posterior limb of the internal capsule. (b) Diffusionweighted MR image shows restricted diffusion in the posterior limb of the internal capsule (arrows). (c) Top pane: T2-weighted MR image shows a hypoplastic cerebellum and a hyperintense central tegmental tract (arrows). Bottom pane: Diffusionweighted MR image shows mildly restricted diffusion in the white matter tracts of the pons and cerebellar white matter (arrows). (d) Sagittal T1-weighted MR image shows a hypo plastic corpus callo sum (arrow). (e) MR spectra (echo time [TE], 135 msec) shows a glycine peak at 3.56 ppm (circle) that is erroneously marked as a myoinositol peak.
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Figure 3. Ornithine transcarbamoylase deficiency in a neonate with tachypnea, decreased activity, and hyperammonemia. (a) Coronal US image obtained on the 4th day of life shows nonspecific diffuse echogenic swelling of the brain. (b, c) Axial T1-weighted (b) and T2-weighted (c) MR images obtained 40 days later show atrophy of the brain, T1 and T2 shortening of deep gray matter (arrows), and diffuse white matter edema. (d) Axial T2-weighted MR image obtained during another episode of acute encephalopathy shows generalized brain edema involving both the cerebral cortex and white matter.
crisis in organic acidemias and energy metabolism disorders (Figs 4, 7) (14,16). In active vacuolating myelinopathy, water is trapped in vacuoles between myelin sheets, resulting in intramyelinic edema, which leads to restricted isotropic water diffusion. Vacuolating myelinopathy may be seen in neonatal maple syrup urine disease, nonketotic hyperglycinemia, and Canavan disease (Fig 2) (1,14,17,18). MR spectroscopy depicts changes in metabolites that may be helpful not only for diagnosis but also for assessing response to treatment in patients with metabolic disorders. Such abnormalities may be nonspecific, with altered normal
constituents (eg, N-acetylaspartate, choline, and creatinine) reflecting a loss of neuronal integrity, myelin breakdown, and impaired energy metabolism (Fig 6). Lactate may also be a nonspecific indicator of metabolic brain disorders. Normally, small amounts of lactate may be present in neonates; however, prolonged lactate elevation is typical of mitochondrial encephalopathy (Fig 4). Several other metabolites that are specifically found in certain disorders are glycine in nonketotic hyperglycinemia, branched chain amino acids (eg, L-leucine, L-isoleucine, and valine) in maple syrup urine disease, and N-acetylaspartate in Canavan disease (Fig 2) (2,4,19,20).
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Figure 4. Pyruvate dehydrogenase deficiency (Leigh syndrome) in a neonate with poor oral intake and lethargy. (a) Coronal US image shows diffuse echogenic swelling of deep gray and white matter. (b) Axial T2-weighted MR image shows markedly swollen basal ganglia and thalami and diffuse white matter edema, which is seen as excessive high signal intensity. (c) Apparent diffusion coefficient (ADC) map shows restricted diffusion in the basal ganglia and thalami. (d) MR spectra (TE, 135 msec) shows a lactate doublet (circle).
Organic Acid Disorders Propionic Acidemia Propionic acidemia is an autosomal recessive disorder caused by a deficiency of propionyl coenzyme A carboxylase (21). The neonatal form manifests with ketoacidosis, hypoglycemia, and hyperammonemia. Severe acidosis may lead to coma and death. Affected infants may present with lethargy, hypotonia, vomiting, seizures, irregular breathing, neutropenia, and thrombocytopenia (4). During an acute metabolic crisis, US and CT depict diffuse brain edema (Fig 6d). At MR imaging, edematous swelling with hyperintensity in the basal ganglia, midbrain, dentate nuclei, and
cerebral cortex may be seen on T2-weighted images. In the acute phase, the involved area of the brain may exhibit restricted diffusion on diffusion-weighted images (3,22). MR spectroscopy depicts nonspecific decreased N-acetylaspartate and myo-inositol and increased glutamate or glutamine and lactate during acute metabolic decompensation (Fig 6c) (3,4,20). At follow-up imaging, lesions become atrophied with delayed myelination.
Methylmalonic Acidemia Methylmalonic acidemia is an autosomal recessive disorder caused by a lack of methlmalonyl coenzyme A mutase. Excess methylmalonyl coenzyme A inhibits other critical metabolic pathways,
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Figure 5. Hypoxic ischemic encephalopathy in a term baby with birth asphyxia. (a) Coronal US image shows diffuse brain swelling. (b) Axial T1-weighted MR image shows loss of normal myelination in the posterior limb of the internal capsule (arrows). (c) ADC map shows restricted diffusion (arrows) in the basal ganglia and thalami. A similar pattern of white matter injury is seen in Krabbe disease, maple syrup urine disease, nonketotic hyperglycinemia, primary lactic acidosis, urea cycle disorders, and X chromosome–linked adrenoleukodystrophy.
such as gluconeogenesis (pyruvate carboxylase), the urea cycle (N-acetylglutamate synthetase), and the hepatic glycine cleavage system in the liver. Inhibition of these pathways leads to ketoacidosis, hyperammonemia, and hyperglycinemia in the first few days of life or early infancy (4,23). MR imaging findings of methylmalonic acidemia are unremarkable or nonspecific in the neonatal period. Mild brain swelling with T2 prolongation of white matter (indicative of vasogenic edema) that spares the myelinated areas of the brain may be seen during an acute metabolic crisis. After the acute phase, diffuse brain atrophy occurs (24). Typical bilateral globus pallidus lesions may appear in later-onset forms of methylmalonic acidemia (2,16).
3-Methyl-Crotonyl-Glycinuria 3-Methyl-crotonyl-glycinuria is an autosomal recessive disorder caused by 3-methylcrotonyl coenzyme A carboxylase deficiency that leads to metabolic acidosis and organic aciduria (25).
There are neonatal or early infantile, late infantile, and juvenile forms according to the onset of disease. Significant phenotypic variations among individuals make clinical diagnosis difficult. Multiple metabolic processes—including fatty acid synthesis, gluconeogenesis, and amino acid catabolism—are impaired, resulting in diverse clinical manifestations according to the involved organs. Patients may present with hypotonia, seizures, vomiting, tachypnea, rashes, and Reyelike symptoms. Biotin (an essential cofactor for methylcrotonyl coenzyme A carboxylase deficiency) supplementation may prevent irreversible brain damage (25). Imaging findings in neonates are not fully described in the literature. In our experience, areas of hyperintensity in the bilateral globi pallidi, thalami, cerebral peduncles, cerebellum, and white matter were seen on T2-weighted MR images. Diffusion-weighted MR images depicted restricted diffusion in the globi pallidi, thalami, and cerebral peduncles, with increased diffusion
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Figure 6. Propionic acidemia in a 4-month-old girl with seizures. (a, b) Axial T2-weighted MR images show swollen basal ganglia, thalami, and cerebral peduncles (arrows in b) and diffusely increased white matter signal intensity. (c) MR spectra (TE, 35 msec) shows a glutamate peak (arrow) and decreased Nacetylaspartate (circle). (d) CT image obtained 3 years later, during another episode of acute encephalopathy, shows diffuse brain edema.
seen in the putamina, white matter, midbrain (except the cerebral peduncles), and cerebellum. Rapid progression of both gray and white matter atrophy associated with subdural hemorrhage was noted at follow-up imaging (Fig 7).
Amino Acid Metabolism Disorders Urea Cycle Defects Urea cycle disorders result from impaired removal of excess nitrogen in the body, which is caused by enzyme defects. Ornithine carba moyltransferase deficiency, carbamoyl phosphate synthetase deficiency, argininosuccinate lyase deficiency, citrullinemia, and hyperargininemia are included in this category of disorders. Defi-
ciency of urea cycle enzymes leads to accumulation of ammonia and other nitrogen compounds, which is directly toxic to brain parenchyma and indirectly promotes synthesis of glutamate, which leads to encephalopathy (Fig 9). Acute encephalopathy may be aggravated by high protein intake or illness. Although many urea cycle defects result from autosomal recessive inborn errors, ornithine carbamoyltransferase deficiency is an X chromosome–linked dominant disorder, and boys are more severely affected (2,4). The timing of onset is closely related to the nature of the molecular defect and the capacity of the body to eliminate nitrogen products; neonatal onset forms of disease are usually associated with more severe disturbances of enzymatic functions (7,26).
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Figure 7. 3-Methyl-crotonyl-glycinuria in a 7-month-old boy who presented with seizures and organic aciduria. (a) Axial T2-weighted MR image shows hyperintense lesions involving the bilateral basal ganglia, thalami, white matter, and medial occipital lobes. (b, c) Serial ADC maps show restricted diffusion in the globi pallidi, thalami, and midbrain and increased diffusion in the putamina, white matter, cerebral peduncles, and cerebellum. (d) T2-weighted MR image obtained 2 months later shows extensive atrophy, ventriculomegaly, and bilateral subdural hemorrhage (arrows).
Imaging findings of urea cycle defects are similar to those of ornithine carbamoyltransferase deficiency, carbamoyl phosphate synthetase deficiency, citrullinemia, and, possibly, hyperargininemia and argininosuccinic aciduria. US and MR imaging depict prominent edema in the brain. Nonmyelinated white matter is more severely affected than myelinated areas (Fig 3). Cortical gray matter and basal ganglia may also be involved in severe cases (Fig 8). Prominent vasogenic edema is typical on diffusion-weighted images, but multifocal restricted diffusion in the
cerebral cortex and basal ganglia was reported in cases of citrullinemia (15,27). In neonates, hyperintensity of the basal ganglia and cortex may be seen on T1-weighted images (Fig 8). Decreased N-acetylaspartate, increased glutamate and glutamine, and a decreased myo-inositol peak are seen at MR spectroscopy (2,4).
Maple Syrup Urine Disease Maple syrup urine disease is an autosomal recessive disorder caused by a defect in the oxidative decarboxylation of the branched-chain
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Figure 8. Citrullinemia in a neonate with seizures. (a, b) Axial T1- (a) and T2weighted (b) MR images show extensive white matter edema, a result of hyperammonemia. Normal myelination of the posterior limb of the internal capsule is absent (arrows in a). The basal ganglia are also edematous with some areas of hyperintensity. (c) ADC map shows the white matter edema, which has increased signal intensity and increased ADC values, findings suggestive of a vasogenic origin, although the posterior internal capsule and deep gray matter demonstrate restricted diffusion.
a-keto acids. As a result of this enzymatic defect, leucine, isoleucine, valine, and their corresponding keto acids accumulate in serum, cerebrospinal fluid, and urine (28). The classic and most severe form of maple syrup urine disease occurs in neonates. Affected neonates typically present with poor feeding, vomiting, seizures, coma, hypoglycemia, and a characteristic odor of maple syrup. MR imaging depicts characteristic edematous lesions with restricted diffusion in the perirolandic white matter, posterior limb of the internal capsules, cerebral peduncles, brainstem, deep cerebellar white matter, and globi pallidi (28–30). These areas are the myelinated or myelinating structures at birth. Generalized edema of the brain may also be seen (18). MR spectroscopy depicts decreased N-acetylaspartate, methyl resonances of branched amino acids at
0.9–1.0 ppm, and lactate in patients with acute metabolic decompensation (20).
Nonketotic Hyperglycinemia Nonketotic hyperglycinemia is an autosomal recessive disorder of glycine metabolism. Defective glycine cleavage causes elevated glycine levels in plasma, urine, and cerebrospinal fluid (3). There are four known clinical phenotypes of nonketotic hyperglycinemia: neonatal, infantile, late-onset, and transient. The neonatal form is the most common and manifests within a few days after birth with severe encephalopathy, hypotonia, lethargy, respiratory failure, myoclonic seizures, and hiccups (31). MR imaging shows white matter edema and delayed myelination. Reduced diffusion may be seen in the frontal cortex, white matter, and corticospinal tracts on diffusion-weighted
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Figure 9. Diagram shows the urea cycle enzymes. ARG = arginase, ASL = argininosuccinate lyase, ASS = argininosuccinate synthase, CO2 = carbon dioxide, CPS = carbamoyl phosphate synthase, H2O = water, NH3 = ammonia, OTC = ornithine carbamoyltransferase.
images and reflects vacuolating myelinopathy, a finding that is also seen in patients with maple syrup urine disease (Fig 2a–2c) (17). MR spectroscopy demonstrates an abnormal glycine peak at 3.56 ppm (Fig 2e). Myo-inositol has a similar chemical shift at short TEs. However, the myoinositol peak disappears on spectra with long TEs because its protons have a short T2 relaxation time. Therefore, spectra should be obtained with a long TE to separate the glycine peak from that of myo-inositol (19). In the later period of the disease, volume loss of the cortex and white matter are common and are associated with hypoplastic corpus callosum (Fig 2d).
Primary Lactic Acidosis
Pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, and mitochondrial complex IV (cytochrome c oxidase) deficiency are the most common causes of severe primary lactic acidosis in neonates. Leigh syndrome is included in this category. Lactic acidosis disorders cause defective oxidative metabolism, which leads to impaired energy production. Patients present with hypotonia, ataxia, ophthalmoplegia, difficulty swallowing, and psychomotor deterioration. Lactic acidosis resulting from disruption of the oxidative phosphorylation process increases glycolysis to compensate for increased energy requirements (4,32). In early-stage primary lactic acidosis, no significant abnormalities or diffuse brain edema is seen at MR imaging. Nonmyelinated white matter is more involved. Typical MR imaging findings include focal high-signal-intensity lesions in the striatum on T2-weighted images, as well as other deep gray matter, periaqueductal areas, white matter, and cerebellar peduncles (Fig 4).
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MR imaging findings may be similar to those of hypoxic ischemic encephalopathy. Primary lactic acidosis may be present if there is no history of perinatal asphyxia; prolonged edematous swelling with restricted diffusion; or lactate peak at MR spectroscopy, even in the normal-appearing parenchyma. Less severe neonatal forms of pyruvate dehydrogenase deficiency may be associated with congenital malformations such as callosal agenesis and migration disorders (1,2). At MR spectroscopy, a prominent lactate doublet at 1.3 ppm is characteristic of lactic acidosis (Fig 4d). However, lactate is not specific to primary lactic acidosis and may be present in other inborn errors (eg, organic acidurias and amino acidopathies) that indirectly disturb oxidative phosphorylation and are associated with hypoxia and impaired glucose metabolism (1,2,4).
Fatty Acid Oxidation Disorders
Fatty acid oxidation disorders include carnitine cycle defects, mitochondrial b-oxidation disorders, and electron transfer flavoprotein dehydrogenase deficiency (glutaric aciduria type II). Most such disorders are autosomal recessive. Fatty acid oxidation disorders are associated with combinations of acidosis, hypoglycemia, hyperammonemia, and lipid accumulation in many organs.
3-Hydroxyacyl–Coenzyme A Dehydrogenase Deficiency Three-hydroxyacyl–coenzyme A dehydrogenase deficiency is associated with HADH gene mutation, in which the ability to convert medium- and short-chain fatty acids to energy is disturbed, especially during prolonged fasting, leading to accumulation of fatty acid in the liver and heart and muscle damage. Symptoms are poor feeding, vomiting, lethargy, hypotonia, and diarrhea. In severe cases, seizures, life-threatening cardiac and respiratory problems, coma, and sudden infant death syndrome may occur. Sometimes, 3-hydroxyacyl–coenzyme A dehydrogenase deficiency is mistaken for Reye syndrome (33). Laboratory test results reveal abnormal liver function, hypoglycemia, and hyperinsulinism. Previous reports have described atrophy and periventricular and parieto-occipital infarction–like lesions at MR imaging, with the latter probably related to perinatal hypoglycemia (4). In our experience, multifocal parenchymal and intraventricular hemorrhage were observed, as well as white matter signal intensity changes (Fig 10).
Multiple Acyl Coenzyme A Dehydrogenase Deficiency Multiple acyl coenzyme A dehydrogenase deficiency (glutaric aciduria type II) is a profound
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Figure 10. Three-hydroxyacyl-coenzyme A dehydrogenase deficiency in a neonate with lethargy, tachypnea, lactic academia, and ketosis. (a) Coronal US image shows multifocal echogenic parenchymal lesions with central liquefaction (arrows). (b) Axial T1-weighted MR image shows multifocal hyperintense lesions in the brain, a finding suggestive of hemorrhage. (c) Gradient echo MR image shows additional areas of low signal intensity in the parenchyma, a finding indicative of hemorrhagic lesions, as well as subependymal and intraventricular hemorrhage.
mitochondrial energy disorder caused by a deficiency of the electron transfer flavoprotein that transports electrons to dehydrogenase in the mitochondria. Laboratory test results reveal metabolic acidosis, organic (glutaric, 2-hydroxyglutaric, isovaleric, isobutyric, ethylmalonic) aciduria, and hypoglycemia without ketosis. The neonatal form may be associated with enlarged liver and kidneys, abnormal external genitalia, rocker bottom feet, abdominal wall defects, and migration anomalies in the brain. Premature birth is common; typically, neonates present with marked hypotonia, stupor, tachypnea, and seizures within a few days of birth. There are two neonatal phenotypes of glutaric aciduria type II. In the first, affected infants usually die within the first few weeks of life because restriction of dietary fat and protein and supplemental riboflavin and carnitine, which are used to treat the disease, are generally not effective. The
second neonatal phenotype is associated with progressive cardiomyopathy and death by the age of 1 year. Underdeveloped frontal and temporal lobes with enlarged sylvian fissures, delayed myelination, and hypoplasia of the corpus callosum are described in the neonatal form of the disease (34,35). At MR spectroscopy, normal N-acetyl aspartate and an increased choline-creatine ratio have been reported and are interpreted as a sign of dysmyelination (36). Glutaric aciduria type II should be distinguished from glutaric acidemia type I, which is characterized by GCDH gene mutation and glutaryl–coenzyme A dehydrogenase deficiency. Glutaric aciduria type I may also manifest during the neonatal and infantile period (within 18 months of age) and is associated with accumulation of glutaric acid or 3-hydroxy glutaric acid, which leads to striatal damage. Patients with glutaric aciduria type I present with acute encephalopathy and
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Figure 11. Krabbe disease in a 3-monthold girl with irritability, fever, and hyperactive reflex. (a) CT image shows subtle high attenuation in the thalami and mild brain atrophy. (b) Axial T2-weighted MR image shows high-signal-intensity lesions involving the periventricular white matter and internal capsules (arrows). (c) Coronal T2-weighted MR image shows cerebellar lesions (arrows).
macrocephaly triggered by febrile illness, dystonic movement, and progressive neurologic deterioration. Imaging findings are characteristic poorly formed operculum and bilateral basal ganglia lesions with restricted diffusion during acute encephalopathy (1,2).
Other Metabolic Disorders
brainstem, cerebellar dentate nuclei, and centrum semiovale are typical of Krabbe disease (Fig 11a). T2-weighted MR imaging shows hyperintensity in the periventricular white matter, thalami, basal ganglia, and dentate nuclei (Fig 11b, 11c) (38,39). MR spectroscopy shows elevated choline, creatine, and myo-inositol associated with moderate N-acetylaspartate (40).
Krabbe Disease
Menkes Disease
Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive neurodegenerative disorder that is characterized by severe myelin loss and the presence of globoid cells in white matter, a result of galactosylceramide b-galactosidase deficiency (37). Affected neonates typically present with flaccidity, irritability, fever, and hyperactive reflex. Krabbe disease usually leads to death within the first few years of life. At CT, highattenuation lesions involving the thalami, posterior limb of the internal capsules, caudate nuclei,
Menkes disease, or trichopoliodystrophy, is an X chromosome–linked recessive disorder that is characterized by a defect in copper transporting protein in the mitochondria and disturbed absorption of copper from the gastrointestinal tract (2). Patients present with hypotonia, hypothermia, and seizures. Laxity of the skin and joints, coarse and sparse hair with broken ends, and hypopigmentation are often observed. MR imaging performed during the early postnatal period may be unremarkable except for the presence of tortuous
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Figure 12. Menkes disease in a 2-monthold boy with hypotonia, seizures, and kinky hair. (a) Axial T2-weighted MR image shows cerebral atrophy, tortuous vessels, and subdural hemorrhage (arrow). (b) MR angiogram shows tortuous and elongated cerebral arteries.
cerebral vessels. Later images typically show a progressive white matter lesion predominantly involving the frontal and temporal areas and progressive brain atrophy with subdural hemorrhage that may mimic injuries related to child abuse (Figs 12a, 13) (41). MR angiography depicts characteristic tortuous cerebral vessels (Fig 12b). Skeletal manifestations include wormian bones, osteopenia, flared metaphysis, and rib fractures (2).
Zellweger Syndrome Zellweger syndrome is an autosomal recessive peroxisomal disorder with disturbed myelination in oligodendrocytes during the neonatal and infantile period. Elevated very long–chain fatty acids in plasma and fibroblasts are characteristic. Dysmorphic facial features and abnormal vision are typical, and other organs may be involved. Cortical dysplasia, hypomyelination, intrahepatic biliary dysgenesis, and polycystic renal disease are also commonly associated. Affected infants present with poor feeding, prolonged jaundice, seizures, and failure to thrive, and they die within the first year of life (2,42). Hypomyelination and cortical malformations (eg, diffuse microgyria with regions of pachygyria) are seen at MR imaging. Subependymal germinolytic cysts in the caudothalamic grooves may be better seen at US (Fig 1) (1). MR spectroscopy depicts increased lipid and decreased N-acetylaspartate levels (20).
Differential Diagnosis
Nonketotic hyperglycinemia, primary lactic acidosis, urea cycle disorders, Krabbe disease, and maple syrup urine disease may have similar MR imaging findings as those of hypoxic ischemic encephalopathy, with selective injury of white and deep gray matter (Figs 2–5, 8, 11). Lack of perinatal asphyxia and a delayed manifestation (several days or weeks after birth) should raise suspicion for the possibility of a metabolic disorder. At neuroimaging, excessive vasogenic edema that predominantly involves nonmyelinated white matter is characteristic of urea cycle disorders, hyperattenuating thalami may be seen at CT in patients with Krabbe disease, and a hypoplastic corpus callosum is typical in patients with nonketotic hyperglycinemia. Proton MR spectroscopy may depict specific metabolites, such as glycine at 3.56 ppm in patients with nonketotic hyper-
glycinemia and branched chain amino acids (Lleucine, L-isoleucine, and valine) at 0.9–1.0 ppm in patients with maple syrup urine disease. In addition, a prominent and prolonged lactate peak is indicative of primary lactic acidosis. Menkes disease, or any metabolic disease with brain atrophy and subdural hemorrhage, may mimic intracranial injuries related to child abuse (Figs 7d, 12a, 13) (41). Findings that may be associated with abusive head trauma include multistage subdural hemorrhage over the convexity, interhemispheric hemorrhages, posterior fossa subdural hemorrhage, hypoxic-ischemic injury, and cerebral edema (43). However, in addition to the subdural hemorrhage associated with progressive brain atrophy, the presence of tortuous vessels at MR imaging and MR angiography may suggest Menkes disease (Fig 12). Several organic acid disorders have similar MR imaging findings as bilirubin encephalopathy (Fig 14). Unconjugated bilirubin deposited in the brain tissue typically involves the globi pal-
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Figure 13. Nonaccidental injury in a 4-month-old girl with seizures. Axial (a) and sagittal (b) T1-weighted MR images show areas of varying signal intensity, a finding indicative of multistage subdural hemorrhage (arrows), with associated extensive parenchymal injury and generalized atrophy. The presence of subdural hemorrhage in a patient of this age should be considered a sign of child abuse until it is proved otherwise. Menkes disease—and any metabolic disease with brain atrophy and subdural hemorrhage—may have similar imaging findings. Figure 14. Bilirubin encephalopathy in a 7-month-old girl with a history of kernicterus. Axial T2-weighted MR image shows the globi pallidi, which are hyperintense. Predominant involvement of the globi pallidi may be seen in several organic acid disorders, hypoxic ischemic encephalopathy, and carbon monoxide poisoning.
be identified. Diffusion-weighted imaging and MR spectroscopy provide functional information and improve the imaging diagnosis. Therefore, the diagnostic approach should include comprehensive MR imaging, as well as assessment of the clinical manifestations and proper screening tests for adequate emergency treatment.
References lidi, subthalamic nuclei, and hippocampus (44). Predominant involvement of bilateral globi pallidi may also be seen in hypoxic ischemic encephalopathy and carbon monoxide poisoning.
Summary
Most inborn errors of metabolism with a neonatal or early infantile onset are categorized as devastating metabolic diseases with potentially severe outcomes. Patients usually present with acute encephalopathy and diverse abnormal laboratory findings. Although nonspecific brain edema, lack of myelination, and atrophy are common imaging findings of neonatal metabolic brain disorders, several specific patterns of brain involvement may
1. Poretti A, Blaser SI, Lequin MH, et al. Neonatal neuroimaging findings in inborn errors of metabolism. J Magn Reson Imaging 2013;37(2):294–312. 2. Barkovich AJ, Patay Z. Metabolic, toxic, and inflammatory brain disorders. In: Barkovich AJ, Raybaud C, eds. Pediatric neuroimaging. Philadelphia, Pa: Lippincott Williams & Wilkins, 2012; 81–239. 3. Cakir B, Teksam M, Kosehan D, Akin K, Koktener A. Inborn errors of metabolism presenting in childhood. J Neuroimaging 2011;21(2):e117–e133. 4. Patay Z. MR imaging workup of inborn errors of metabolism of early postnatal onset. Magn Reson Imaging Clin N Am 2011;19(4):733–759, vii. 5. Barkovich AJ. An approach to MRI of metabolic disorders in children. J Neuroradiol 2007;34(2):75–88. 6. Mercimek-Mahmutoglu S, Horvath GA, CoulterMackie M, et al. Profound neonatal hypoglycemia and lactic acidosis caused by pyridoxine-dependent epilepsy. Pediatrics 2012;129(5):e1368–e1372.
1272 September-October 2014 7. Maestri NE, Clissold D, Brusilow SW. Neonatal onset ornithine transcarbamylase deficiency: a retrospective analysis. J Pediatr 1999;134(3):268–272. 8. Kanaumi T, Takashima S, Hirose S, Kodama T, Iwasaki H. Neuropathology of methylmalonic acidemia in a child. Pediatr Neurol 2006;34(2):156–159. 9. Kolodny EH. Dysmyelinating and demyelinating conditions in infancy. Curr Opin Neurol Neurosurg 1993;6(3):379–386. 10. al-Essa MA, Rashed MS, Bakheet SM, Patay ZJ, Ozand PT. Glutaric aciduria type II: observations in seven patients with neonatal- and late-onset disease. J Perinatol 2000;20(2):120–128. 11. Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics 1998;102(6):E69. 12. Leijser LM, de Vries LS, Rutherford MA, et al. Cranial ultrasound in metabolic disorders presenting in the neonatal period: characteristic features and comparison with MR imaging. AJNR Am J Neuroradiol 2007;28 (7):1223–1231. 13. Khong PL, Lam BC, Tung HK, Wong V, Chan FL, Ooi GC. MRI of neonatal encephalopathy. Clin Radiol 2003;58(11):833–844. 14. Karaarslan E, Arslan A. Diffusion weighted MR imaging in non-infarct lesions of the brain. Eur J Radiol 2008;65(3):402–416. 15. Majoie CB, Mourmans JM, Akkerman EM, Duran M, Poll-The BT. Neonatal citrullinemia: comparison of conventional MR, diffusion-weighted, and diffusion tensor findings. AJNR Am J Neuroradiol 2004;25(1): 32–35. 16. Michel SJ, Given CA 2nd, Robertson WC Jr. Imaging of the brain, including diffusion-weighted imaging in methylmalonic acidemia. Pediatr Radiol 2004;34(7): 580–582. 17. Khong PL, Lam BC, Chung BH, Wong KY, Ooi GC. Diffusion-weighted MR imaging in neonatal nonketotic hyperglycinemia. AJNR Am J Neuroradiol 2003; 24(6):1181–1183. 18. Cavalleri F, Berardi A, Burlina AB, Ferrari F, Mavilla L. Diffusion-weighted MRI of maple syrup urine disease encephalopathy. Neuroradiology 2002;44(6): 499–502. 19. Gabis L, Parton P, Roche P, Lenn N, Tudorica A, Huang W. In vivo 1H magnetic resonance spectroscopic measurement of brain glycine levels in nonketotic hyperglycinemia. J Neuroimaging 2001;11(2):209–211. 20. Cecil KM, Kos RS. Magnetic resonance spectroscopy and metabolic imaging in white matter diseases and pediatric disorders. Top Magn Reson Imaging 2006;17 (4):275–293. 21. Barnes ND, Hull D, Balgobin L, Gompertz D. Biotinresponsive propionicacidaemia. Lancet 1970;2(7666): 244–245. 22. Kandel A, Amatya SK, Yeh EA. Reversible diffusion weighted imaging changes in propionic acidemia. J Child Neurol 2013;28(1):128–131. 23. van der Meer SB, Poggi F, Spada M, et al. Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia. J Pediatr 1994;125(6 Pt 1):903–908. 24. Radmanesh A, Zaman T, Ghanaati H, Molaei S, Robertson RL, Zamani AA. Methylmalonic acidemia: brain imaging findings in 52 children and a review of the literature. Pediatr Radiol 2008;38(10):1054–1061. 25. Leonard JV, Seakins JW, Bartlett K, Hyde J, Wilson J, Clayton B. Inherited disorders of 3-methylcrotonyl CoA carboxylation. Arch Dis Child 1981;56(1): 53–59.
radiographics.rsna.org 26. Takanashi J, Barkovich AJ, Cheng SF, et al. Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders. AJNR Am J Neuroradiol 2003;24(6):1184–1187. 27. Kara B, Albayram S, Tutar O, Altun G, Koçer N, Işlak C. Diffusion-weighted magnetic resonance imaging findings of a patient with neonatal citrullinemia during acute episode. Eur J Paediatr Neurol 2009;13(3): 280–282. 28. Brismar J, Aqeel A, Brismar G, Coates R, Gascon G, Ozand P. Maple syrup urine disease: findings on CT and MR scans of the brain in 10 infants. AJNR Am J Neuroradiol 1990;11(6):1219–1228. 29. Taccone A, Schiaffino MC, Cerone R, Fondelli MP, Romano C. Computed tomography in maple syrup urine disease. Eur J Radiol 1992;14(3):207–212. 30. Kendall BE. Disorders of lysosomes, peroxisomes, and mitochondria. AJNR Am J Neuroradiol 1992;13 (2):621–653. 31. Demirel N, Bas AY, Zenciroglu A, Aydemir C, Kalkanoglu S, Coskun T. Neonatal non-ketotic hyperglycinemia: report of five cases. Pediatr Int 2008;50(1): 121–123. 32. van der Knaap MS, Jakobs C, Valk J. Magnetic resonance imaging in lactic acidosis. J Inherit Metab Dis 1996;19(4):535–547. 33. Bennett MJ, Russell LK, Tokunaga C, et al. Reye-like syndrome resulting from novel missense mutations in mitochondrial medium- and short-chain l-3-hydroxyacyl-CoA dehydrogenase. Mol Genet Metab 2006;89 (1-2):74–79. 34. Mumtaz HA, Gupta V, Singh P, Marwaha RK, Khandelwal N. MR imaging findings of glutaric aciduria type II. Singapore Med J 2010;51(4):e69–e71. 35. Stöckler S, Radner H, Karpf EF, Hauer A, Ebner F. Symmetric hypoplasia of the temporal cerebral lobes in an infant with glutaric aciduria type II (multiple acylcoenzyme A dehydrogenase deficiency). J Pediatr 1994; 124(4):601–604. 36. Firat AK, Karakas HM, Yakinci C. Magnetic resonance spectroscopic characteristics of glutaric aciduria type II. Dev Med Child Neurol 2006;48(10): 847–850. 37. Suzuki K, Suzuki Y. Globoid cell leucodystrophy (Krabbe’s disease): deficiency of galactocerebroside beta-galactosidase. Proc Natl Acad Sci USA 1970;66 (2):302–309. 38. Kwan E, Drace J, Enzmann D. Specific CT findings in Krabbe disease. AJR Am J Roentgenol 1984;143(3): 665–670. 39. Baram TZ, Goldman AM, Percy AK. Krabbe disease: specific MRI and CT findings. Neurology 1986;36(1): 111–115. 40. Farina L, Bizzi A, Finocchiaro G, et al. MR imaging and proton MR spectroscopy in adult Krabbe disease. AJNR Am J Neuroradiol 2000;21(8):1478–1482. 41. Bacopoulou F, Henderson L, Philip SG. Menkes disease mimicking non-accidental injury. Arch Dis Child 2006;91(11):919. 42. Grayer J. Recognition of Zellweger syndrome in infancy. Adv Neonatal Care 2005;5(1):5–13. 43. Kemp AM, Jaspan T, Griffiths J, et al. Neuroimaging: what neuroradiological features distinguish abusive from non-abusive head trauma? A systematic review. Arch Dis Child 2011;96(12):1103–1112. 44. Govaert P, Lequin M, Swarte R, et al. Changes in globus pallidus with (pre)term kernicterus. Pediatrics 2003;112(6 Pt 1):1256–1263.
TM
This journal-based SA-CME activity has been approved for AMA PRA Category 1 Credit . See www.rsna.org/education/search/RG.
Teaching Points
September-October Issue 2014
Devastating Metabolic Brain Disorders of Newborns and Young Infants Hyun Jung Yoon, MD • Ji Hye Kim, MD • Tae Yeon Jeon, MD • So-Young Yoo, MD • Hong Eo, MD RadioGraphics 2014; 34:1257–1272 • Published online 10.1148/rg.345130095 • Content Codes:
Page 1257 In general, early-onset postnatal metabolic brain disorders manifest with acute symptoms of encephalopathy and a life-threatening episode of metabolic decompensation, whereas later-onset disorders have a more manageable clinical course with a better outcome. It is for this reason that early-onset disorders are referred to as “devastating metabolic disorders of the newborn and infant.” Page 1259 Diffusion-weighted imaging sensitively depicts early parenchymal lesions and may help differentiate different types of edema with calculated apparent diffusion coefficients (ADCs). Page 1261 Several other metabolites that are specifically found in certain disorders are glycine in nonketotic hyperglycinemia, branched chain amino acids (eg, L-leucine, L-isoleucine, and valine) in maple syrup urine disease, and N-acetylaspartate in Canavan disease (Fig 2) (2,4,19,20). Page 1270 Nonketotic hyperglycinemia, primary lactic acidosis, urea cycle disorders, Krabbe disease, and maple syrup urine disease may have similar MR imaging findings as those of hypoxic ischemic encephalopathy, with selective injury of white and deep gray matter (Figs 2–5, 8, 11). Page 1270 Menkes disease, or any metabolic disease with brain atrophy and subdural hemorrhage, may mimic intracranial injuries related to child abuse (Figs 7d, 12a, 13) (41).
Devastating Metabolic Brain Disorders of Newborns and Young Infants1 Hyun Jung Yoon, MD Ji Hye Kim, MD Tae Yeon Jeon, MD So-Young Yoo, MD Hong Eo, MD Abbreviation: ADC = apparent diffusion coef ficient, TE = echo time RadioGraphics 2014; 34:1257–1272 Published online 10.1148/rg.345130095 Content Codes: From the Department of Radiology and Center for Imaging Science, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Ilwon-Dong, Kangnam-Ku, Seoul 135-710, Republic of Korea. Presented as an education exhibit at the 2012 RSNA Annual Meeting. Received July 14, 2013; revision requested August 18 and received December 16; final version accepted March 3, 2014. For this journal-based SA-CME activity, the authors, editor, and reviewers have disclosed no relevant relationships. Address correspondence to J.H.K. (e-mail: [email protected]). 1
SA-CME LEARNING OBJECTIVES After completing this journal-based SACME activity, participants will be able to: ■■List metabolic disorders that manifest with acute encephalopathy in newborns and infants. imaging features, clinical manifestations, and biochemical features of devastating metabolic brain disorders in neonates and young infants.
Metabolic disorders of the brain that manifest in the neonatal or early infantile period are usually associated with acute and severe illness and are thus referred to as devastating metabolic disorders. Most of these disorders may be classified as organic acid disorders, amino acid metabolism disorders, primary lactic acidosis, or fatty acid oxidation disorders. Each disorder has distinctive clinical, biochemical, and radiologic features. Early diagnosis is important both for prompt treatment to prevent death or serious sequelae and for genetic counseling. However, diagnosis is often challenging because many findings overlap and may mimic those of more common neonatal conditions, such as hypoxic-ischemic encephalopathy and infection. Ultrasonography (US) may be an initial screening method for the neonatal brain, and magnetic resonance (MR) imaging is the modality of choice for evaluating metabolic brain disorders. Although nonspecific imaging findings are common in early-onset metabolic disorders, characteristic patterns of brain involvement have been described for several disorders. In addition, diffusionweighted images may be used to characterize edema during an acute episode of encephalopathy, and MR spectroscopy depicts changes in metabolites that may help diagnose metabolic disorders and assess response to treatment. Imaging findings, including those of advanced MR imaging techniques, must be closely reviewed. If one of these rare disorders is suspected, the appropriate biochemical test or analysis of the specific gene should be performed to confirm the diagnosis. ©
RSNA, 2014 • radiographics.rsna.org
■■Describe
■■Discuss
the role of diffusion-weighted imaging and MR spectroscopy in diagnosing metabolic disorders. See www.rsna.org/education/search/RG.
Introduction
Although individual metabolic brain disorders are very rare, collectively, they account for a substantial portion of cases of neonatal encephalopathy (1). Metabolic disorders encompass a heterogeneous group of disorders. Most metabolic brain disorders in neonates and infants are inborn errors of metabolism. The brain injury results from the accumulation of endogenous toxic substances or a lack of production of necessary biochemicals (2,3). During the gestational period, the brain is protected from injury because toxic substances are removed and necessary substances supplied by the placenta. Affected neonates are usually asymptomatic at birth. The age of onset ranges from hours to months after birth; patients with more profound enzymatic defects tend to have an earlier clinical onset. In general, early-onset postnatal metabolic brain disorders manifest with acute symptoms of encephalopathy and a life-threatening episode of metabolic decompensation, whereas later-onset disorders have a more manageable clinical course with a better outcome. It is for this reason that early-onset disorders are referred to as “devastating metabolic disorders of the newborn and infant.”
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Classification of Devastating Metabolic Diseases in Newborns and Young Infants Type of Disorder Organic acid disorders
Amino acid metabolism disorders Primary lactic acidosis Fatty acid oxidation disorders
Other metabolic disorders
Diseases Propionic acidemia, methylmalonic acidemia, isovaleric acidemia, Canavan disease, 3-hydroxy-3-methyglutaryl-coenzyme A lyase deficiency, multiple carboxylase deficiency, pyroglutamic aciduria Urea cycle defect (citrullinemia, ornithine transcarbamoylase deficiency, cabamoyl phosphate synthetase deficiency, argininosuccinic aciduria), maple syrup urine disease, nonketotic hyperglycinemia Pyruvate dehydrogenase deficiency, pyruvate carboxylase deficiency, cytochrome oxidase deficiency, complex succinate dehydrogenase (type II) deficiency Carnitine cycle defects (carnitine–palmitoyle transferase deficiency, carnitine translocase deficiency), mitochondrial β-oxidation disorders (very long-, medium-, and short-chain acyl coenzyme A dehydrogenase deficiency and long- and short-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency), electron transfer flavoprotein dehydrogenase deficiency (glutaric aciduria type II) Zellweger syndrome, neonatal adrenoleukodystrophy Krabbe disease (globoid cell leukodystrophy), Menkes disease (trichopoliodystrophy), D-bifunctional protein deficiency, sulfite oxidase deficiency, galactocemia
Affected neonates and infants are usually in critical condition and require urgent diagnosis and treatment to prevent death or serious sequelae. Early diagnosis is also important for genetic counseling. However, diagnosis is often challenging because metabolic brain disorders are extremely rare and diverse, making it difficult to gain experience dealing with individual diseases. Moreover, clinical manifestations are often nonspecific during the neonatal period and may mimic those of other more common diseases, such as hypoxic-ischemic encephalopathy and infection (4). Biochemical test results may be normal or nonspecific, and genetic analysis often offers little insight unless a specific genetic defect is searched for. Therefore, the diagnostic workup relies heavily on brain imaging. However, the imaging features of neonatal encephalopathy tend to be nonspecific, even in disorders that eventually exhibit characteristic imaging patterns later in life (4). Diagnostic workup may be improved by performing a comprehensive evaluation of magnetic resonance (MR) images to assess the anatomic and functional patterns of brain involvement with advanced MR imaging techniques in combination with appropriate biochemical tests and genetic analyses (5). In this article, we discuss neuroimaging of devastating metabolic brain disorders in newborns and young infants, with a brief review of the clinical and biochemical aspects of individual diseases to help diagnose these conditions.
Classification
The devastating metabolic diseases are classified as intoxication disorders, energy production disorders, disorders of the biosynthesis and breakdown of complex molecules, and neu-
rotransmitter defects (Table) (1,2,4). Intoxication disorders include organic acid and amino acid metabolism disorders. Affected neonates have a variable symptom-free interval after birth because toxic metabolites were metabolized by the mother in utero. Energy production disorders include primary lactic acidosis and fatty acid oxidation disorders. Structures with a high metabolic rate such as the brain, heart, and skeletal muscles are particularly involved. Lysosomal and peroxisomal disorders are disorders of the biosynthesis and breakdown of complex molecules. Although lysosomal and peroxisomal disorders do not typically manifest with neonatal encephalopathy, Zellweger syndrome and neonatal adrenoleukodystrophy have a neonatal onset. Recently, neurotransmitter disorders, such as pyridoxine-dependent epilepsy, are increasingly being recognized as severe metabolic encephalopathy in the neonatal period (1,6).
Clinical Presentations and Laboratory Findings
Typically, patients with organic aciduria, urea cycle defects, or amino acidopathy present with acute symptoms of encephalopathy as a result of accumulated toxic metabolites in the brain tissue. Clinical manifestations include vomiting, poor feeding, stupor, and lethargy and eventually lead to coma and death if left untreated. Abnormal muscle tone and epilepsy may also be present. Moreover, apnea or hyperventilation may result from metabolic acidosis or hyperammonemia (4,7). Typically, fatty acid oxidation disorders manifest with a Reye-like episode, hepatosplenomegaly, and cardiomyopathy and may lead to sudden death. Metabolic toxic injury of the
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Figure 1. Zellweger syndrome in a full-term 3-dayold neonate with seizures. (a) Coronal ultrasonographic (US) image of the brain obtained on the 3rd day of life shows germinolytic cysts in the caudothalamic grooves (arrows). (b) Axial T2weighted MR image shows pachygyria and diffuse excessive high signal intensity in the white matter.
developing brain may cause malformations such as cortical dysplasia (eg, Zellweger syndrome), callosal dysgenesis (eg, nonketotic hyperglycinemia, pyruvate dehydrogenase deficiency, Menkes disease, and Zellweger syndrome), cerebellar dysgenesis (eg, nonketotic hyperglycinemia, Menkes disease, and Zellweger syndrome), and cerebral dysgenesis (eg, glutaric aciduria type II) (Figs 1, 2) (2,8–10). Dysmorphic face may be seen in patients with propionic and methylmalonic acidemias, multiple coenzyme A dehydrogenase deficiency, peroxisomal disorders, and maple syrup urine disease. In addition, characteristic odors, such as “sweaty feet” in glutaric aciduria type II and isovaleric acidemia, “burnt sugar” in maple syrup urine disease, and “cat urine” in multiple carboxylase deficiency, have been described (2). Laboratory test results may reveal combinations of hyperammonemia, organic acidemias, and hypoglycemia during acute encephalopathy in many metabolic disorders (11).
Imaging Considerations for Devastating Metabolic Brain Disorders
US may be an initial screening tool in neonates with acute encephalopathy. During an acute metabolic crisis, diffuse edematous brain lesions that mimic hypoxic ischemic encephalopathy may be seen (Figs 3–5). Moreover, US reliably depicts germinolytic cysts, ventriculomegaly, lenticulostriate vasculopathy, anomalous cortex and callosum, and calcification in diverse neonatal metabolic disorders (Fig 1a) (12). However, US is less sensitive in its depiction of early or subtle brain lesions because its findings
are often nonspecific, and detailed patterns of brain involvement are not reliably seen. Cerebral edema or hemorrhage may also be seen at computed tomography (CT) (Fig 6). However, CT has several limitations, including poor contrast resolution, a result of high water content in the neonatal brain, and the disadvantage of radiation exposure. MR imaging is the modality of choice for evaluating metabolic brain disorders (1,4,13). Characteristic patterns of brain involvement have been described for several metabolic brain disorders: White matter is primarily affected in maple syrup urine disease and nonketotic hyperglycinemia, and deep gray matter lesions are predominantly seen in organic acidemia (Figs 2, 6, 7). Both gray and white matter are involved in primary lactic acidosis, which sometimes mimics hypoxic ischemic encephalopathy (Figs 4, 5). However, in some cases, conventional imaging findings overlap or are nonspecific in neonates with metabolic brain disorders (13). Advanced MR imaging may provide further diagnostic information. Diffusion-weighted imaging sensitively depicts early parenchymal lesions and may help differentiate different types of edema with calculated apparent diffusion coefficients (ADCs). Vasogenic edema is most commonly encountered in patients with acute metabolic decompensation. Excessive vasogenic edema is particularly prominent in urea cycle defects and sulfite oxidase deficiency (Fig 8) (14,15). Cytotoxic edema may be seen in nonischemic conditions, a result of cellular swelling by energy failure, which occurs during metabolic
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Figure 2. Nonketotic hyperglycinemia in a neonate with seizures. (a) Axial T1weighted MR image shows an absence of normal myelination of the posterior limb of the internal capsule. (b) Diffusionweighted MR image shows restricted diffusion in the posterior limb of the internal capsule (arrows). (c) Top pane: T2-weighted MR image shows a hypoplastic cerebellum and a hyperintense central tegmental tract (arrows). Bottom pane: Diffusionweighted MR image shows mildly restricted diffusion in the white matter tracts of the pons and cerebellar white matter (arrows). (d) Sagittal T1-weighted MR image shows a hypo plastic corpus callo sum (arrow). (e) MR spectra (echo time [TE], 135 msec) shows a glycine peak at 3.56 ppm (circle) that is erroneously marked as a myoinositol peak.
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Figure 3. Ornithine transcarbamoylase deficiency in a neonate with tachypnea, decreased activity, and hyperammonemia. (a) Coronal US image obtained on the 4th day of life shows nonspecific diffuse echogenic swelling of the brain. (b, c) Axial T1-weighted (b) and T2-weighted (c) MR images obtained 40 days later show atrophy of the brain, T1 and T2 shortening of deep gray matter (arrows), and diffuse white matter edema. (d) Axial T2-weighted MR image obtained during another episode of acute encephalopathy shows generalized brain edema involving both the cerebral cortex and white matter.
crisis in organic acidemias and energy metabolism disorders (Figs 4, 7) (14,16). In active vacuolating myelinopathy, water is trapped in vacuoles between myelin sheets, resulting in intramyelinic edema, which leads to restricted isotropic water diffusion. Vacuolating myelinopathy may be seen in neonatal maple syrup urine disease, nonketotic hyperglycinemia, and Canavan disease (Fig 2) (1,14,17,18). MR spectroscopy depicts changes in metabolites that may be helpful not only for diagnosis but also for assessing response to treatment in patients with metabolic disorders. Such abnormalities may be nonspecific, with altered normal
constituents (eg, N-acetylaspartate, choline, and creatinine) reflecting a loss of neuronal integrity, myelin breakdown, and impaired energy metabolism (Fig 6). Lactate may also be a nonspecific indicator of metabolic brain disorders. Normally, small amounts of lactate may be present in neonates; however, prolonged lactate elevation is typical of mitochondrial encephalopathy (Fig 4). Several other metabolites that are specifically found in certain disorders are glycine in nonketotic hyperglycinemia, branched chain amino acids (eg, L-leucine, L-isoleucine, and valine) in maple syrup urine disease, and N-acetylaspartate in Canavan disease (Fig 2) (2,4,19,20).
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Figure 4. Pyruvate dehydrogenase deficiency (Leigh syndrome) in a neonate with poor oral intake and lethargy. (a) Coronal US image shows diffuse echogenic swelling of deep gray and white matter. (b) Axial T2-weighted MR image shows markedly swollen basal ganglia and thalami and diffuse white matter edema, which is seen as excessive high signal intensity. (c) Apparent diffusion coefficient (ADC) map shows restricted diffusion in the basal ganglia and thalami. (d) MR spectra (TE, 135 msec) shows a lactate doublet (circle).
Organic Acid Disorders Propionic Acidemia Propionic acidemia is an autosomal recessive disorder caused by a deficiency of propionyl coenzyme A carboxylase (21). The neonatal form manifests with ketoacidosis, hypoglycemia, and hyperammonemia. Severe acidosis may lead to coma and death. Affected infants may present with lethargy, hypotonia, vomiting, seizures, irregular breathing, neutropenia, and thrombocytopenia (4). During an acute metabolic crisis, US and CT depict diffuse brain edema (Fig 6d). At MR imaging, edematous swelling with hyperintensity in the basal ganglia, midbrain, dentate nuclei, and
cerebral cortex may be seen on T2-weighted images. In the acute phase, the involved area of the brain may exhibit restricted diffusion on diffusion-weighted images (3,22). MR spectroscopy depicts nonspecific decreased N-acetylaspartate and myo-inositol and increased glutamate or glutamine and lactate during acute metabolic decompensation (Fig 6c) (3,4,20). At follow-up imaging, lesions become atrophied with delayed myelination.
Methylmalonic Acidemia Methylmalonic acidemia is an autosomal recessive disorder caused by a lack of methlmalonyl coenzyme A mutase. Excess methylmalonyl coenzyme A inhibits other critical metabolic pathways,
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Figure 5. Hypoxic ischemic encephalopathy in a term baby with birth asphyxia. (a) Coronal US image shows diffuse brain swelling. (b) Axial T1-weighted MR image shows loss of normal myelination in the posterior limb of the internal capsule (arrows). (c) ADC map shows restricted diffusion (arrows) in the basal ganglia and thalami. A similar pattern of white matter injury is seen in Krabbe disease, maple syrup urine disease, nonketotic hyperglycinemia, primary lactic acidosis, urea cycle disorders, and X chromosome–linked adrenoleukodystrophy.
such as gluconeogenesis (pyruvate carboxylase), the urea cycle (N-acetylglutamate synthetase), and the hepatic glycine cleavage system in the liver. Inhibition of these pathways leads to ketoacidosis, hyperammonemia, and hyperglycinemia in the first few days of life or early infancy (4,23). MR imaging findings of methylmalonic acidemia are unremarkable or nonspecific in the neonatal period. Mild brain swelling with T2 prolongation of white matter (indicative of vasogenic edema) that spares the myelinated areas of the brain may be seen during an acute metabolic crisis. After the acute phase, diffuse brain atrophy occurs (24). Typical bilateral globus pallidus lesions may appear in later-onset forms of methylmalonic acidemia (2,16).
3-Methyl-Crotonyl-Glycinuria 3-Methyl-crotonyl-glycinuria is an autosomal recessive disorder caused by 3-methylcrotonyl coenzyme A carboxylase deficiency that leads to metabolic acidosis and organic aciduria (25).
There are neonatal or early infantile, late infantile, and juvenile forms according to the onset of disease. Significant phenotypic variations among individuals make clinical diagnosis difficult. Multiple metabolic processes—including fatty acid synthesis, gluconeogenesis, and amino acid catabolism—are impaired, resulting in diverse clinical manifestations according to the involved organs. Patients may present with hypotonia, seizures, vomiting, tachypnea, rashes, and Reyelike symptoms. Biotin (an essential cofactor for methylcrotonyl coenzyme A carboxylase deficiency) supplementation may prevent irreversible brain damage (25). Imaging findings in neonates are not fully described in the literature. In our experience, areas of hyperintensity in the bilateral globi pallidi, thalami, cerebral peduncles, cerebellum, and white matter were seen on T2-weighted MR images. Diffusion-weighted MR images depicted restricted diffusion in the globi pallidi, thalami, and cerebral peduncles, with increased diffusion
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Figure 6. Propionic acidemia in a 4-month-old girl with seizures. (a, b) Axial T2-weighted MR images show swollen basal ganglia, thalami, and cerebral peduncles (arrows in b) and diffusely increased white matter signal intensity. (c) MR spectra (TE, 35 msec) shows a glutamate peak (arrow) and decreased Nacetylaspartate (circle). (d) CT image obtained 3 years later, during another episode of acute encephalopathy, shows diffuse brain edema.
seen in the putamina, white matter, midbrain (except the cerebral peduncles), and cerebellum. Rapid progression of both gray and white matter atrophy associated with subdural hemorrhage was noted at follow-up imaging (Fig 7).
Amino Acid Metabolism Disorders Urea Cycle Defects Urea cycle disorders result from impaired removal of excess nitrogen in the body, which is caused by enzyme defects. Ornithine carba moyltransferase deficiency, carbamoyl phosphate synthetase deficiency, argininosuccinate lyase deficiency, citrullinemia, and hyperargininemia are included in this category of disorders. Defi-
ciency of urea cycle enzymes leads to accumulation of ammonia and other nitrogen compounds, which is directly toxic to brain parenchyma and indirectly promotes synthesis of glutamate, which leads to encephalopathy (Fig 9). Acute encephalopathy may be aggravated by high protein intake or illness. Although many urea cycle defects result from autosomal recessive inborn errors, ornithine carbamoyltransferase deficiency is an X chromosome–linked dominant disorder, and boys are more severely affected (2,4). The timing of onset is closely related to the nature of the molecular defect and the capacity of the body to eliminate nitrogen products; neonatal onset forms of disease are usually associated with more severe disturbances of enzymatic functions (7,26).
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Figure 7. 3-Methyl-crotonyl-glycinuria in a 7-month-old boy who presented with seizures and organic aciduria. (a) Axial T2-weighted MR image shows hyperintense lesions involving the bilateral basal ganglia, thalami, white matter, and medial occipital lobes. (b, c) Serial ADC maps show restricted diffusion in the globi pallidi, thalami, and midbrain and increased diffusion in the putamina, white matter, cerebral peduncles, and cerebellum. (d) T2-weighted MR image obtained 2 months later shows extensive atrophy, ventriculomegaly, and bilateral subdural hemorrhage (arrows).
Imaging findings of urea cycle defects are similar to those of ornithine carbamoyltransferase deficiency, carbamoyl phosphate synthetase deficiency, citrullinemia, and, possibly, hyperargininemia and argininosuccinic aciduria. US and MR imaging depict prominent edema in the brain. Nonmyelinated white matter is more severely affected than myelinated areas (Fig 3). Cortical gray matter and basal ganglia may also be involved in severe cases (Fig 8). Prominent vasogenic edema is typical on diffusion-weighted images, but multifocal restricted diffusion in the
cerebral cortex and basal ganglia was reported in cases of citrullinemia (15,27). In neonates, hyperintensity of the basal ganglia and cortex may be seen on T1-weighted images (Fig 8). Decreased N-acetylaspartate, increased glutamate and glutamine, and a decreased myo-inositol peak are seen at MR spectroscopy (2,4).
Maple Syrup Urine Disease Maple syrup urine disease is an autosomal recessive disorder caused by a defect in the oxidative decarboxylation of the branched-chain
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Figure 8. Citrullinemia in a neonate with seizures. (a, b) Axial T1- (a) and T2weighted (b) MR images show extensive white matter edema, a result of hyperammonemia. Normal myelination of the posterior limb of the internal capsule is absent (arrows in a). The basal ganglia are also edematous with some areas of hyperintensity. (c) ADC map shows the white matter edema, which has increased signal intensity and increased ADC values, findings suggestive of a vasogenic origin, although the posterior internal capsule and deep gray matter demonstrate restricted diffusion.
a-keto acids. As a result of this enzymatic defect, leucine, isoleucine, valine, and their corresponding keto acids accumulate in serum, cerebrospinal fluid, and urine (28). The classic and most severe form of maple syrup urine disease occurs in neonates. Affected neonates typically present with poor feeding, vomiting, seizures, coma, hypoglycemia, and a characteristic odor of maple syrup. MR imaging depicts characteristic edematous lesions with restricted diffusion in the perirolandic white matter, posterior limb of the internal capsules, cerebral peduncles, brainstem, deep cerebellar white matter, and globi pallidi (28–30). These areas are the myelinated or myelinating structures at birth. Generalized edema of the brain may also be seen (18). MR spectroscopy depicts decreased N-acetylaspartate, methyl resonances of branched amino acids at
0.9–1.0 ppm, and lactate in patients with acute metabolic decompensation (20).
Nonketotic Hyperglycinemia Nonketotic hyperglycinemia is an autosomal recessive disorder of glycine metabolism. Defective glycine cleavage causes elevated glycine levels in plasma, urine, and cerebrospinal fluid (3). There are four known clinical phenotypes of nonketotic hyperglycinemia: neonatal, infantile, late-onset, and transient. The neonatal form is the most common and manifests within a few days after birth with severe encephalopathy, hypotonia, lethargy, respiratory failure, myoclonic seizures, and hiccups (31). MR imaging shows white matter edema and delayed myelination. Reduced diffusion may be seen in the frontal cortex, white matter, and corticospinal tracts on diffusion-weighted
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Figure 9. Diagram shows the urea cycle enzymes. ARG = arginase, ASL = argininosuccinate lyase, ASS = argininosuccinate synthase, CO2 = carbon dioxide, CPS = carbamoyl phosphate synthase, H2O = water, NH3 = ammonia, OTC = ornithine carbamoyltransferase.
images and reflects vacuolating myelinopathy, a finding that is also seen in patients with maple syrup urine disease (Fig 2a–2c) (17). MR spectroscopy demonstrates an abnormal glycine peak at 3.56 ppm (Fig 2e). Myo-inositol has a similar chemical shift at short TEs. However, the myoinositol peak disappears on spectra with long TEs because its protons have a short T2 relaxation time. Therefore, spectra should be obtained with a long TE to separate the glycine peak from that of myo-inositol (19). In the later period of the disease, volume loss of the cortex and white matter are common and are associated with hypoplastic corpus callosum (Fig 2d).
Primary Lactic Acidosis
Pyruvate carboxylase deficiency, pyruvate dehydrogenase deficiency, and mitochondrial complex IV (cytochrome c oxidase) deficiency are the most common causes of severe primary lactic acidosis in neonates. Leigh syndrome is included in this category. Lactic acidosis disorders cause defective oxidative metabolism, which leads to impaired energy production. Patients present with hypotonia, ataxia, ophthalmoplegia, difficulty swallowing, and psychomotor deterioration. Lactic acidosis resulting from disruption of the oxidative phosphorylation process increases glycolysis to compensate for increased energy requirements (4,32). In early-stage primary lactic acidosis, no significant abnormalities or diffuse brain edema is seen at MR imaging. Nonmyelinated white matter is more involved. Typical MR imaging findings include focal high-signal-intensity lesions in the striatum on T2-weighted images, as well as other deep gray matter, periaqueductal areas, white matter, and cerebellar peduncles (Fig 4).
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MR imaging findings may be similar to those of hypoxic ischemic encephalopathy. Primary lactic acidosis may be present if there is no history of perinatal asphyxia; prolonged edematous swelling with restricted diffusion; or lactate peak at MR spectroscopy, even in the normal-appearing parenchyma. Less severe neonatal forms of pyruvate dehydrogenase deficiency may be associated with congenital malformations such as callosal agenesis and migration disorders (1,2). At MR spectroscopy, a prominent lactate doublet at 1.3 ppm is characteristic of lactic acidosis (Fig 4d). However, lactate is not specific to primary lactic acidosis and may be present in other inborn errors (eg, organic acidurias and amino acidopathies) that indirectly disturb oxidative phosphorylation and are associated with hypoxia and impaired glucose metabolism (1,2,4).
Fatty Acid Oxidation Disorders
Fatty acid oxidation disorders include carnitine cycle defects, mitochondrial b-oxidation disorders, and electron transfer flavoprotein dehydrogenase deficiency (glutaric aciduria type II). Most such disorders are autosomal recessive. Fatty acid oxidation disorders are associated with combinations of acidosis, hypoglycemia, hyperammonemia, and lipid accumulation in many organs.
3-Hydroxyacyl–Coenzyme A Dehydrogenase Deficiency Three-hydroxyacyl–coenzyme A dehydrogenase deficiency is associated with HADH gene mutation, in which the ability to convert medium- and short-chain fatty acids to energy is disturbed, especially during prolonged fasting, leading to accumulation of fatty acid in the liver and heart and muscle damage. Symptoms are poor feeding, vomiting, lethargy, hypotonia, and diarrhea. In severe cases, seizures, life-threatening cardiac and respiratory problems, coma, and sudden infant death syndrome may occur. Sometimes, 3-hydroxyacyl–coenzyme A dehydrogenase deficiency is mistaken for Reye syndrome (33). Laboratory test results reveal abnormal liver function, hypoglycemia, and hyperinsulinism. Previous reports have described atrophy and periventricular and parieto-occipital infarction–like lesions at MR imaging, with the latter probably related to perinatal hypoglycemia (4). In our experience, multifocal parenchymal and intraventricular hemorrhage were observed, as well as white matter signal intensity changes (Fig 10).
Multiple Acyl Coenzyme A Dehydrogenase Deficiency Multiple acyl coenzyme A dehydrogenase deficiency (glutaric aciduria type II) is a profound
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Figure 10. Three-hydroxyacyl-coenzyme A dehydrogenase deficiency in a neonate with lethargy, tachypnea, lactic academia, and ketosis. (a) Coronal US image shows multifocal echogenic parenchymal lesions with central liquefaction (arrows). (b) Axial T1-weighted MR image shows multifocal hyperintense lesions in the brain, a finding suggestive of hemorrhage. (c) Gradient echo MR image shows additional areas of low signal intensity in the parenchyma, a finding indicative of hemorrhagic lesions, as well as subependymal and intraventricular hemorrhage.
mitochondrial energy disorder caused by a deficiency of the electron transfer flavoprotein that transports electrons to dehydrogenase in the mitochondria. Laboratory test results reveal metabolic acidosis, organic (glutaric, 2-hydroxyglutaric, isovaleric, isobutyric, ethylmalonic) aciduria, and hypoglycemia without ketosis. The neonatal form may be associated with enlarged liver and kidneys, abnormal external genitalia, rocker bottom feet, abdominal wall defects, and migration anomalies in the brain. Premature birth is common; typically, neonates present with marked hypotonia, stupor, tachypnea, and seizures within a few days of birth. There are two neonatal phenotypes of glutaric aciduria type II. In the first, affected infants usually die within the first few weeks of life because restriction of dietary fat and protein and supplemental riboflavin and carnitine, which are used to treat the disease, are generally not effective. The
second neonatal phenotype is associated with progressive cardiomyopathy and death by the age of 1 year. Underdeveloped frontal and temporal lobes with enlarged sylvian fissures, delayed myelination, and hypoplasia of the corpus callosum are described in the neonatal form of the disease (34,35). At MR spectroscopy, normal N-acetyl aspartate and an increased choline-creatine ratio have been reported and are interpreted as a sign of dysmyelination (36). Glutaric aciduria type II should be distinguished from glutaric acidemia type I, which is characterized by GCDH gene mutation and glutaryl–coenzyme A dehydrogenase deficiency. Glutaric aciduria type I may also manifest during the neonatal and infantile period (within 18 months of age) and is associated with accumulation of glutaric acid or 3-hydroxy glutaric acid, which leads to striatal damage. Patients with glutaric aciduria type I present with acute encephalopathy and
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Figure 11. Krabbe disease in a 3-monthold girl with irritability, fever, and hyperactive reflex. (a) CT image shows subtle high attenuation in the thalami and mild brain atrophy. (b) Axial T2-weighted MR image shows high-signal-intensity lesions involving the periventricular white matter and internal capsules (arrows). (c) Coronal T2-weighted MR image shows cerebellar lesions (arrows).
macrocephaly triggered by febrile illness, dystonic movement, and progressive neurologic deterioration. Imaging findings are characteristic poorly formed operculum and bilateral basal ganglia lesions with restricted diffusion during acute encephalopathy (1,2).
Other Metabolic Disorders
brainstem, cerebellar dentate nuclei, and centrum semiovale are typical of Krabbe disease (Fig 11a). T2-weighted MR imaging shows hyperintensity in the periventricular white matter, thalami, basal ganglia, and dentate nuclei (Fig 11b, 11c) (38,39). MR spectroscopy shows elevated choline, creatine, and myo-inositol associated with moderate N-acetylaspartate (40).
Krabbe Disease
Menkes Disease
Krabbe disease (globoid cell leukodystrophy) is an autosomal recessive neurodegenerative disorder that is characterized by severe myelin loss and the presence of globoid cells in white matter, a result of galactosylceramide b-galactosidase deficiency (37). Affected neonates typically present with flaccidity, irritability, fever, and hyperactive reflex. Krabbe disease usually leads to death within the first few years of life. At CT, highattenuation lesions involving the thalami, posterior limb of the internal capsules, caudate nuclei,
Menkes disease, or trichopoliodystrophy, is an X chromosome–linked recessive disorder that is characterized by a defect in copper transporting protein in the mitochondria and disturbed absorption of copper from the gastrointestinal tract (2). Patients present with hypotonia, hypothermia, and seizures. Laxity of the skin and joints, coarse and sparse hair with broken ends, and hypopigmentation are often observed. MR imaging performed during the early postnatal period may be unremarkable except for the presence of tortuous
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Figure 12. Menkes disease in a 2-monthold boy with hypotonia, seizures, and kinky hair. (a) Axial T2-weighted MR image shows cerebral atrophy, tortuous vessels, and subdural hemorrhage (arrow). (b) MR angiogram shows tortuous and elongated cerebral arteries.
cerebral vessels. Later images typically show a progressive white matter lesion predominantly involving the frontal and temporal areas and progressive brain atrophy with subdural hemorrhage that may mimic injuries related to child abuse (Figs 12a, 13) (41). MR angiography depicts characteristic tortuous cerebral vessels (Fig 12b). Skeletal manifestations include wormian bones, osteopenia, flared metaphysis, and rib fractures (2).
Zellweger Syndrome Zellweger syndrome is an autosomal recessive peroxisomal disorder with disturbed myelination in oligodendrocytes during the neonatal and infantile period. Elevated very long–chain fatty acids in plasma and fibroblasts are characteristic. Dysmorphic facial features and abnormal vision are typical, and other organs may be involved. Cortical dysplasia, hypomyelination, intrahepatic biliary dysgenesis, and polycystic renal disease are also commonly associated. Affected infants present with poor feeding, prolonged jaundice, seizures, and failure to thrive, and they die within the first year of life (2,42). Hypomyelination and cortical malformations (eg, diffuse microgyria with regions of pachygyria) are seen at MR imaging. Subependymal germinolytic cysts in the caudothalamic grooves may be better seen at US (Fig 1) (1). MR spectroscopy depicts increased lipid and decreased N-acetylaspartate levels (20).
Differential Diagnosis
Nonketotic hyperglycinemia, primary lactic acidosis, urea cycle disorders, Krabbe disease, and maple syrup urine disease may have similar MR imaging findings as those of hypoxic ischemic encephalopathy, with selective injury of white and deep gray matter (Figs 2–5, 8, 11). Lack of perinatal asphyxia and a delayed manifestation (several days or weeks after birth) should raise suspicion for the possibility of a metabolic disorder. At neuroimaging, excessive vasogenic edema that predominantly involves nonmyelinated white matter is characteristic of urea cycle disorders, hyperattenuating thalami may be seen at CT in patients with Krabbe disease, and a hypoplastic corpus callosum is typical in patients with nonketotic hyperglycinemia. Proton MR spectroscopy may depict specific metabolites, such as glycine at 3.56 ppm in patients with nonketotic hyper-
glycinemia and branched chain amino acids (Lleucine, L-isoleucine, and valine) at 0.9–1.0 ppm in patients with maple syrup urine disease. In addition, a prominent and prolonged lactate peak is indicative of primary lactic acidosis. Menkes disease, or any metabolic disease with brain atrophy and subdural hemorrhage, may mimic intracranial injuries related to child abuse (Figs 7d, 12a, 13) (41). Findings that may be associated with abusive head trauma include multistage subdural hemorrhage over the convexity, interhemispheric hemorrhages, posterior fossa subdural hemorrhage, hypoxic-ischemic injury, and cerebral edema (43). However, in addition to the subdural hemorrhage associated with progressive brain atrophy, the presence of tortuous vessels at MR imaging and MR angiography may suggest Menkes disease (Fig 12). Several organic acid disorders have similar MR imaging findings as bilirubin encephalopathy (Fig 14). Unconjugated bilirubin deposited in the brain tissue typically involves the globi pal-
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Figure 13. Nonaccidental injury in a 4-month-old girl with seizures. Axial (a) and sagittal (b) T1-weighted MR images show areas of varying signal intensity, a finding indicative of multistage subdural hemorrhage (arrows), with associated extensive parenchymal injury and generalized atrophy. The presence of subdural hemorrhage in a patient of this age should be considered a sign of child abuse until it is proved otherwise. Menkes disease—and any metabolic disease with brain atrophy and subdural hemorrhage—may have similar imaging findings. Figure 14. Bilirubin encephalopathy in a 7-month-old girl with a history of kernicterus. Axial T2-weighted MR image shows the globi pallidi, which are hyperintense. Predominant involvement of the globi pallidi may be seen in several organic acid disorders, hypoxic ischemic encephalopathy, and carbon monoxide poisoning.
be identified. Diffusion-weighted imaging and MR spectroscopy provide functional information and improve the imaging diagnosis. Therefore, the diagnostic approach should include comprehensive MR imaging, as well as assessment of the clinical manifestations and proper screening tests for adequate emergency treatment.
References lidi, subthalamic nuclei, and hippocampus (44). Predominant involvement of bilateral globi pallidi may also be seen in hypoxic ischemic encephalopathy and carbon monoxide poisoning.
Summary
Most inborn errors of metabolism with a neonatal or early infantile onset are categorized as devastating metabolic diseases with potentially severe outcomes. Patients usually present with acute encephalopathy and diverse abnormal laboratory findings. Although nonspecific brain edema, lack of myelination, and atrophy are common imaging findings of neonatal metabolic brain disorders, several specific patterns of brain involvement may
1. Poretti A, Blaser SI, Lequin MH, et al. Neonatal neuroimaging findings in inborn errors of metabolism. J Magn Reson Imaging 2013;37(2):294–312. 2. Barkovich AJ, Patay Z. Metabolic, toxic, and inflammatory brain disorders. In: Barkovich AJ, Raybaud C, eds. Pediatric neuroimaging. Philadelphia, Pa: Lippincott Williams & Wilkins, 2012; 81–239. 3. Cakir B, Teksam M, Kosehan D, Akin K, Koktener A. Inborn errors of metabolism presenting in childhood. J Neuroimaging 2011;21(2):e117–e133. 4. Patay Z. MR imaging workup of inborn errors of metabolism of early postnatal onset. Magn Reson Imaging Clin N Am 2011;19(4):733–759, vii. 5. Barkovich AJ. An approach to MRI of metabolic disorders in children. J Neuroradiol 2007;34(2):75–88. 6. Mercimek-Mahmutoglu S, Horvath GA, CoulterMackie M, et al. Profound neonatal hypoglycemia and lactic acidosis caused by pyridoxine-dependent epilepsy. Pediatrics 2012;129(5):e1368–e1372.
1272 September-October 2014 7. Maestri NE, Clissold D, Brusilow SW. Neonatal onset ornithine transcarbamylase deficiency: a retrospective analysis. J Pediatr 1999;134(3):268–272. 8. Kanaumi T, Takashima S, Hirose S, Kodama T, Iwasaki H. Neuropathology of methylmalonic acidemia in a child. Pediatr Neurol 2006;34(2):156–159. 9. Kolodny EH. Dysmyelinating and demyelinating conditions in infancy. Curr Opin Neurol Neurosurg 1993;6(3):379–386. 10. al-Essa MA, Rashed MS, Bakheet SM, Patay ZJ, Ozand PT. Glutaric aciduria type II: observations in seven patients with neonatal- and late-onset disease. J Perinatol 2000;20(2):120–128. 11. Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics 1998;102(6):E69. 12. Leijser LM, de Vries LS, Rutherford MA, et al. Cranial ultrasound in metabolic disorders presenting in the neonatal period: characteristic features and comparison with MR imaging. AJNR Am J Neuroradiol 2007;28 (7):1223–1231. 13. Khong PL, Lam BC, Tung HK, Wong V, Chan FL, Ooi GC. MRI of neonatal encephalopathy. Clin Radiol 2003;58(11):833–844. 14. Karaarslan E, Arslan A. Diffusion weighted MR imaging in non-infarct lesions of the brain. Eur J Radiol 2008;65(3):402–416. 15. Majoie CB, Mourmans JM, Akkerman EM, Duran M, Poll-The BT. Neonatal citrullinemia: comparison of conventional MR, diffusion-weighted, and diffusion tensor findings. AJNR Am J Neuroradiol 2004;25(1): 32–35. 16. Michel SJ, Given CA 2nd, Robertson WC Jr. Imaging of the brain, including diffusion-weighted imaging in methylmalonic acidemia. Pediatr Radiol 2004;34(7): 580–582. 17. Khong PL, Lam BC, Chung BH, Wong KY, Ooi GC. Diffusion-weighted MR imaging in neonatal nonketotic hyperglycinemia. AJNR Am J Neuroradiol 2003; 24(6):1181–1183. 18. Cavalleri F, Berardi A, Burlina AB, Ferrari F, Mavilla L. Diffusion-weighted MRI of maple syrup urine disease encephalopathy. Neuroradiology 2002;44(6): 499–502. 19. Gabis L, Parton P, Roche P, Lenn N, Tudorica A, Huang W. In vivo 1H magnetic resonance spectroscopic measurement of brain glycine levels in nonketotic hyperglycinemia. J Neuroimaging 2001;11(2):209–211. 20. Cecil KM, Kos RS. Magnetic resonance spectroscopy and metabolic imaging in white matter diseases and pediatric disorders. Top Magn Reson Imaging 2006;17 (4):275–293. 21. Barnes ND, Hull D, Balgobin L, Gompertz D. Biotinresponsive propionicacidaemia. Lancet 1970;2(7666): 244–245. 22. Kandel A, Amatya SK, Yeh EA. Reversible diffusion weighted imaging changes in propionic acidemia. J Child Neurol 2013;28(1):128–131. 23. van der Meer SB, Poggi F, Spada M, et al. Clinical outcome of long-term management of patients with vitamin B12-unresponsive methylmalonic acidemia. J Pediatr 1994;125(6 Pt 1):903–908. 24. Radmanesh A, Zaman T, Ghanaati H, Molaei S, Robertson RL, Zamani AA. Methylmalonic acidemia: brain imaging findings in 52 children and a review of the literature. Pediatr Radiol 2008;38(10):1054–1061. 25. Leonard JV, Seakins JW, Bartlett K, Hyde J, Wilson J, Clayton B. Inherited disorders of 3-methylcrotonyl CoA carboxylation. Arch Dis Child 1981;56(1): 53–59.
radiographics.rsna.org 26. Takanashi J, Barkovich AJ, Cheng SF, et al. Brain MR imaging in neonatal hyperammonemic encephalopathy resulting from proximal urea cycle disorders. AJNR Am J Neuroradiol 2003;24(6):1184–1187. 27. Kara B, Albayram S, Tutar O, Altun G, Koçer N, Işlak C. Diffusion-weighted magnetic resonance imaging findings of a patient with neonatal citrullinemia during acute episode. Eur J Paediatr Neurol 2009;13(3): 280–282. 28. Brismar J, Aqeel A, Brismar G, Coates R, Gascon G, Ozand P. Maple syrup urine disease: findings on CT and MR scans of the brain in 10 infants. AJNR Am J Neuroradiol 1990;11(6):1219–1228. 29. Taccone A, Schiaffino MC, Cerone R, Fondelli MP, Romano C. Computed tomography in maple syrup urine disease. Eur J Radiol 1992;14(3):207–212. 30. Kendall BE. Disorders of lysosomes, peroxisomes, and mitochondria. AJNR Am J Neuroradiol 1992;13 (2):621–653. 31. Demirel N, Bas AY, Zenciroglu A, Aydemir C, Kalkanoglu S, Coskun T. Neonatal non-ketotic hyperglycinemia: report of five cases. Pediatr Int 2008;50(1): 121–123. 32. van der Knaap MS, Jakobs C, Valk J. Magnetic resonance imaging in lactic acidosis. J Inherit Metab Dis 1996;19(4):535–547. 33. Bennett MJ, Russell LK, Tokunaga C, et al. Reye-like syndrome resulting from novel missense mutations in mitochondrial medium- and short-chain l-3-hydroxyacyl-CoA dehydrogenase. Mol Genet Metab 2006;89 (1-2):74–79. 34. Mumtaz HA, Gupta V, Singh P, Marwaha RK, Khandelwal N. MR imaging findings of glutaric aciduria type II. Singapore Med J 2010;51(4):e69–e71. 35. Stöckler S, Radner H, Karpf EF, Hauer A, Ebner F. Symmetric hypoplasia of the temporal cerebral lobes in an infant with glutaric aciduria type II (multiple acylcoenzyme A dehydrogenase deficiency). J Pediatr 1994; 124(4):601–604. 36. Firat AK, Karakas HM, Yakinci C. Magnetic resonance spectroscopic characteristics of glutaric aciduria type II. Dev Med Child Neurol 2006;48(10): 847–850. 37. Suzuki K, Suzuki Y. Globoid cell leucodystrophy (Krabbe’s disease): deficiency of galactocerebroside beta-galactosidase. Proc Natl Acad Sci USA 1970;66 (2):302–309. 38. Kwan E, Drace J, Enzmann D. Specific CT findings in Krabbe disease. AJR Am J Roentgenol 1984;143(3): 665–670. 39. Baram TZ, Goldman AM, Percy AK. Krabbe disease: specific MRI and CT findings. Neurology 1986;36(1): 111–115. 40. Farina L, Bizzi A, Finocchiaro G, et al. MR imaging and proton MR spectroscopy in adult Krabbe disease. AJNR Am J Neuroradiol 2000;21(8):1478–1482. 41. Bacopoulou F, Henderson L, Philip SG. Menkes disease mimicking non-accidental injury. Arch Dis Child 2006;91(11):919. 42. Grayer J. Recognition of Zellweger syndrome in infancy. Adv Neonatal Care 2005;5(1):5–13. 43. Kemp AM, Jaspan T, Griffiths J, et al. Neuroimaging: what neuroradiological features distinguish abusive from non-abusive head trauma? A systematic review. Arch Dis Child 2011;96(12):1103–1112. 44. Govaert P, Lequin M, Swarte R, et al. Changes in globus pallidus with (pre)term kernicterus. Pediatrics 2003;112(6 Pt 1):1256–1263.
TM
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Teaching Points
September-October Issue 2014
Devastating Metabolic Brain Disorders of Newborns and Young Infants Hyun Jung Yoon, MD • Ji Hye Kim, MD • Tae Yeon Jeon, MD • So-Young Yoo, MD • Hong Eo, MD RadioGraphics 2014; 34:1257–1272 • Published online 10.1148/rg.345130095 • Content Codes:
Page 1257 In general, early-onset postnatal metabolic brain disorders manifest with acute symptoms of encephalopathy and a life-threatening episode of metabolic decompensation, whereas later-onset disorders have a more manageable clinical course with a better outcome. It is for this reason that early-onset disorders are referred to as “devastating metabolic disorders of the newborn and infant.” Page 1259 Diffusion-weighted imaging sensitively depicts early parenchymal lesions and may help differentiate different types of edema with calculated apparent diffusion coefficients (ADCs). Page 1261 Several other metabolites that are specifically found in certain disorders are glycine in nonketotic hyperglycinemia, branched chain amino acids (eg, L-leucine, L-isoleucine, and valine) in maple syrup urine disease, and N-acetylaspartate in Canavan disease (Fig 2) (2,4,19,20). Page 1270 Nonketotic hyperglycinemia, primary lactic acidosis, urea cycle disorders, Krabbe disease, and maple syrup urine disease may have similar MR imaging findings as those of hypoxic ischemic encephalopathy, with selective injury of white and deep gray matter (Figs 2–5, 8, 11). Page 1270 Menkes disease, or any metabolic disease with brain atrophy and subdural hemorrhage, may mimic intracranial injuries related to child abuse (Figs 7d, 12a, 13) (41).
