Mitochondrial disorders affecting the nervous system.

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Mitochondrial Disorders Affecting the Nervous System Z. Zolkipli, MB, ChB1,2,4

1 Department of Neurosciences, University of California San Diego,

La Jolla, California 2 Rady Children’s Hospital San Diego, San Diego, California 3 Department of Pediatrics, University of California San Diego, La Jolla, California 4 Metabolic & Mitochondrial Disease Center, University California San Diego, San Diego, California

Address for correspondence Richard H. Haas, MB, BChir, Department of Neurosciences, Division of Pediatric Neurology, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0935 (e-mail: [email protected]).

Semin Neurol 2014;34:321–340.

Abstract Keywords

► mitochondria ► central nervous system ► muscle ► peripheral nerve ► spinal cord ► mitochondrial DNA ► nuclear DNA ► oxidative phosphorylation

Mitochondrial diseases are multiorgan system disorders and the brain is the most commonly affected organ. The high-energy requirement of the brain leaves it vulnerable to energy failure. All components of the neuraxis including muscle, the neuromuscular junction, peripheral nerve, spinal cord, and brain can be affected. Genetic mitochondrial disease can be caused by nuclear gene defects and mitochondrial DNA defects. Mitochondrial medicine is rapidly expanding as exome and mtDNA sequencing is identifying new gene defects on a daily basis. This review will focus on primary genetic mitochondrial diseases that impair energy production and affect the nervous system, pathophysiology of disease, classical phenotypes, diagnosis, and treatment.

Overview and Definitions Mitochondria are indispensable organelles within all cells of the body (apart from mature red blood cells). They are dynamic structures constantly undergoing fusion to form thread-like networks (Mito–Gk thread) and fission to the more recognizable oval structures (chondrion–Gk grain). They are thought to have developed from a symbiotic relationship between bacteria and eukaryotic cells allowing their hosts to tolerate oxygen stress. This review will focus on the neurology of primary genetic mitochondrial disease, although the role of secondary mitochondrial dysfunction is increasingly recognized as a major component of the neurodegenerative disorders. Although ATP production (through oxidative phosphorylation) is a major mitochondrial function, an ever-expanding list of cellular functions have been shown to require mitochondria including the intermediary metabolism of fats,

Issue Theme Neurogenetics; Guest Editor, Ali Fatemi, MD

carbohydrates and proteins, calcium homeostasis, free radical production, apoptosis, intracellular signaling, and innate immunity. Central nervous system (CNS) disorders can arise from failure or compromise of any mitochondrial function, but the most obvious problem resulting in neurologic disease is energy failure as the human brain is 2% of the body weight, but requires 20% of the blood supply and produces an estimated 9 kg of ATP in 24 hours.1 Most brain ATP production occurs through oxidative phosphorylation requiring an intact electron transport chain. Mitochondrial have their own DNA (mtDNA) encoding 13 components of the 97 electron transport chain subunits,2 22 tRNAs, and 2 mRNAs. This is only a small fraction of the > 1200 proteins,3 which make up the mitochondrion but mtDNA mutations are responsible for much human disease. The first human mtDNA diseases were reported in 1988: Leber hereditary optic neuropathy4 and mtDNA deletions as a cause of mitochondrial myopathy.5

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DOI http://dx.doi.org/ 10.1055/s-0034-1386770. ISSN 0271-8235.

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R.H. Haas, MB, BChir1,2,3,4

Mitochondrial Disorders Affecting the Nervous System The genetics of mitochondrial neurologic disease is mixed. mtDNA point mutations are maternally inherited, but may be de novo events. Single mtDNA deletions tend to be sporadic events with a low risk of transmission, but multiple mtDNA deletions and mtDNA depletion are the result of nuclear gene defects inherited in an autosomal recessive or dominant manner.6,7 Epigenetics may play a role in the varied phenotypic expression of mitochondrial disease with mitochondrial-nuclear signaling increasingly recognized.8 Currently recognized adult genetic mitochondrial disease is due to mtDNA mutation 60% of the time,9 but in the pediatric population 80% of mitochondrial disease is due to nuclear gene defects.10 Heteroplasmy (a mixture of wild type and mutant mtDNA), which may vary from cell to cell and tissue to tissue, is a major determinant of the heterogeneity of mitochondrial DNA disease and the percentage of mutant mtDNA may shift often increasing over time resulting in later-onset manifestations of disease when reduced mitochondrial function crosses a threshold for disease expression. This presents important diagnostic problems, mtDNA mutations (particularly deletions) present at a low heteroplasmy percentage may be missed in blood with higher mutation percentage present in affected tissues.11

CNS and Neuromuscular Disease Mitochondrial diseases are typically multiorgan system disorders, but the CNS, muscle, and autonomic and peripheral nerves are frequently involved. Neurologic presentations are the most common manifestations of mitochondrial disease. The high energy requirement of nervous tissue is the likely explanation for its frequent involvement. The common distribution of brain lesions also follows a pattern of high energy need and vulnerability to oxidative injury. Phenotypes vary widely with common molecular defects often identified initially and later expanded as our knowledge base enlarges. Alpers syndrome was the earliest described mitochondrial brain disease (degeneration of the cerebral gray matter in infancy)12 with a rapid fluctuating neurodegenerative course with basal ganglia and cortical lesions often producing occipitally predominant epilepsia partialis continua. Later, hepatic degeneration was described.13 The first biochemical defect identified was complex IV deficiency,14 and later Naviaux et al identified mitochondrial polymerase γ (PolG1) deficiency as the usual underlying molecular defect resulting in mtDNA depletion.15 Subsequently, the Twinkle helicase16 and FARS2 encoding the mitochondrial phenylalanyl-tRNA synthetase17 have also been recognized as rare causes of the Alpers phenotype. Leigh syndrome is the most common pediatric manifestation of genetic mitochondrial disease. This neurodegenerative disease can be viewed as the final common pathway for energy failure in the young brain with clinical manifestations that may include failure to thrive, global developmental delay, ataxia, dystonia, seizures, eye movement abnormalities, and central respiratory failure. Recently, several reviews have described the progressive longitudinal course.18,19 Other neurologic phenotypes to be discussed in detail (all with a Seminars in Neurology

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Haas, Zolkipli variety of genetic causes) include neuropathy ataxia and retinitis pigmentosa (NARP), Kearns-Sayre syndrome, mitochondrial encephalomyopathy with ragged red fibers and stroke-like episodes (MELAS), myoclonic epilepsy with ragged red fibers (MERRF), mitochondrial neurogastrointestinal encephalopathy (MNGIE), Alpers syndrome, and Leber hereditary optic neuropathy (LHON).

Neuropathology Mitochondrial brain disease often affects both gray and white matter.20 Patterns of brain involvement are helpful in defining phenotype, but heterogeneity even with the same molecular defect is common.11,21,22 In Leigh disease, basal ganglia, brainstem nuclei, and white matter damage was first described by Dennis Leigh in 1951.23 This early article contained an excellent description of the typical neuropathology. The neuropathological features of subacute necrotizing encephalomyelopathy (Leigh disease) are very similar to the lesions of Wernicke-Korsakoff syndrome due to alcoholic thiamin deficiency, spongiform white matter degeneration, capillary proliferation, gliosis, and relative preservation of neurons (►Fig. 1). Thiamin is an essential cofactor for the E1 subunit of pyruvate dehydrogenase and deficiency of this enzyme accounts for an estimated 25% of Leigh disease cases.24,25 MELAS has a vascular component not commonly seen in other mitochondrial encephalopathies. In MELAS, vascular endothelial energy failure with heavy succinic dehydrogenase staining indicates mitochondrial proliferation. MELAS patients may have reduced arginine levels. L-arginine or citrulline treatment as a substrate for nitric oxide synthetase (NOS) appears to be an effective acute and chronic treatment.26,27 Patients with stroke-like episodes—often in a posterior nonvascular distribution—usually partially recover as do their symptoms, although after each episode there is some residual cortical injury.28 There is focal hyperperfusion during the acute phase of MELAS stroke with decreased oxygen extraction both acutely and between stroke-like episodes.29

White Matter Disease White matter disease is increasingly recognized and acute or chronic leukoencephalopathy is one common presentation of mitochondrial brain disease.30,31 Acute disseminated encephalomyelitis (ADEM) is a common misdiagnosis early in the course. White matter disease may be patchy or generalized. The vulnerability of oligodendroglia to oxidative injury is the likely substrate. Recently, diffusor tensor imaging abnormalities have been shown in pediatric mitochondrial disease patients even when conventional magnetic resonance imaging (MRI) is normal.32 T2-weighted MRI signal changes are routinely seen in the classical syndromes (MELAS, MERRF, Kearns-Sayre syndrome, and Leigh syndrome).33 Diffuse white matter involvement is a diagnostic feature of MNGIE due to thymidine phosphorylase deficiency,34 and more recently many other defects in mtDNA maintenance have associated leukoencephalopathy.30 Progressive cavitating leukoencephalopathy with periventricular and corpus callosal cysts has been described due to a variety of


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Fig. 1 Leigh syndrome: Subacute necrotizing encephalomyelopathy. (A) Brain slice showing necrotic lesions indicated (B) by arrows on T2-weighted magnetic resonance image (A, subfrontal white matter; B, putamen; C, thalamus).

mitochondrial electron transport chain defects: complex I35,36 and complex II37 (►Fig. 2).

Spinal Cord Involvement Spinal cord involvement is common in Leigh syndrome and was described in Dennis Leigh’s first case.23 An MRI identification of a pattern of extensive dorsal column and lateral corticospinal tract uniform involvement was reported in all eight patients with a syndrome of leukoencephalopathy with brainstem and spinal cord involvement and high lactate (LBSL) associated with a clinical course of progressive spasticity and ataxia.38 This disorder was found on exome sequencing to be caused by autosomal recessive mutations in DARS2, which encodes mitochondrial aspartyl-tRNA synthetase. The phenotype has been expanded by an observational

study of 78 patients, some with milder adult presentations, although the most common presentation was juvenile onset of slowly progressive ataxia, spasticity, and dorsal column dysfunction.39 Axonal neuropathy was documented in five of eight patients with LBSL due to the DARS2 mutation.40 An infantile rapidly progressive fatal phenotype of LBSL is also described.41 Mitochondrial aminoacyl-tRNA synthetases represent a new category of mitochondrial brain disease with a spectrum of presentations from a severe Alpers phenotype17 through LBSL to a milder leukoencephalopathy with ovarian failure.42

Optic Atrophy In relation to optic atrophy, two common causes of earlyonset visual failure are mitochondrial diseases. The visual

Fig. 2 Cavitating leukodystrophy in a 1-year-old girl with encephalopathy following a febrile episode who went on to follow a neurodegenerative course. Complex I deficiency was confirmed in muscle. (A) Fluid-attenuated inversion-recovery axial image showing cystic white matter changes. (B) T1 sagittal image. Arrow points to a cyst in the corpus callosum. Courtesy of Dr. Sakkubai Naidu. Seminars in Neurology

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Fig. 3 Early unilateral R eye involvement in Leber hereditary optic neuropathy due to the mtDNA G11778A mutation. (From: Perez F, Anne O, Debruxelles S, et al. Leber’s optic neuropathy associated with disseminated white matter disease: a case report and review. Clin Neurol Neurosurg 2009;111(1):83–86 with permission.)

system has high energy requirements.43 Autosomal dominant optic atrophy (OPA1) has widespread CNS manifestations in 20% of carriers with bilateral sensorineural deafness, ataxia, myopathy, progressive external ophthalmoplegia (PEO), and peripheral neuropathy.44 Muscle biopsy even in patients with only optic atrophy show cytochrome C oxidasedeficient fibers and multiple mitochondrial DNA deletions.45 OPA1 is an inner mitochondrial membrane protein mutation affecting mitochondrial fusion to the network configuration.46 The earliest optic nerve change is early loss of retinal ganglion cells within the papillomacular bundle.47 This loss of retinal ganglion cells is also the earliest retinal change in LHON . First identified as an mtDNA disease in 1988,4 LHON is caused 90% of the time by one of three pathogenic mtDNA complex I mutations (m.3460G > A, m.11778G > A, and m.14484T > C). Typically young adult males are affected with unilateral vision loss, followed by involvement of the other eye 8 weeks later (►Fig. 3).48 Leber hereditary optic neuropathy may have spinal cord involvement,49 leading to confusion with neuromyelitis optica due to the NMO aquaporin antibody and multiple sclerosis (MS).50 Female carriers of LHON mutations more often have a multiple sclerosis phenotype.51 Although genetic mitochondrial disease may present with an MS phenotype, there is increasing evidence of mitochondrial dysfunction in sporadic MS disease, with white matter astrocytes playing an important role.52,53 Mitochondria are crucial for the innate immunity response and play an important role in apoptosis, in part mediated through purinergic signaling.54 It is hypothesized that pathological permeability transition pore (PTP) opening plays a role in the white matter degeneration in MS.55

Peripheral Neuropathy Peripheral neuropathy is a common manifestation of mitochondrial disease.56 Mechanisms include failure of mitochondrial fusion, mutations affecting 2-oxoglutarate and pyruvate dehydrogenase, and disorders affecting oxidative phosphorylation leading to reduced ATP production and the disorders that result in mtDNA depletion. Mitochondrial neuropathies can be classified into disorders with neuropathy as the only or Seminars in Neurology

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predominant feature, neuropathy as a key feature, and disorders with neuropathy as a minor feature.56 The common mtDNA diseases—MELAS due to tRNAleu(UUR) mutations (commonly m.3243A > G) and neuropathy ataxia and retinitis pigmentosa (NARP) caused by ATPase 6 mutations (most often m.8993T > G)—frequently cause peripheral neuropathy. Nuclear mitochondrial gene defects such as pyruvate dehydrogenase deficiency and disorders of mtDNA maintenance; mitochondrial polymerase (PolG)7 C10ORF2, encoding the Twinkle helicase57 and the rare disorder Navajo neurohepatopathy due to MPV17 mutations58,59 also have peripheral neuropathy as a variable feature. Sensorineural hearing loss is the most common neuropathy in mitochondrial disease. When diabetes mellitus accompanies sensorineural hearing loss, a search for MELAS mutations should be performed.60 Neuropathies are generally axonal in mitochondrial disease, although demyelination can occur, particularly mtDNA maintenance disorders such as PolG, Twinkle, and thymidine phosphorylase deficiency. Neuropathy is the major feature in disorders due to mitochondrial fusion resulting from mitofusin2 (MTF2) mutations that are responsible for Charcot-Marie-Tooth disease CMT2A, CMT5, CMT6, and CMT2K phenotypes. Although mitofusin mutation phenotypes typically have neuropathy as the major feature, type 2A2 may have extensive CNS involvement including optic neuropathy and a MS phenotype with age of onset 1 year to 45 years in an American kindred of Northern European and Cherokee American Indian descent.61

POTS and Autonomic Neuropathy Symptoms of autonomic neuropathy are often reported by patients with mitochondrial disease. These include postural orthostatic tachycardia syndrome (POTS), temperature instability, heat and cold intolerance, tachycardia, and the symptoms of gastrointestinal (GI) dysmotility discussed below.62 Unfortunately, these types of symptoms are difficult to objectively confirm, overlap with psychosomatic disease, and are often downplayed by physicians. It is clear that other neuropathies are common in mitochondrial disease56 and it is very likely that autonomic neuropathy is often overlooked.


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Neuromuscular Junction Disease Neuromuscular junction disease does occur in mitochondrial disease. Patients may have positive titers of acetylcholine receptor antibodies and typically have ophthalmoplegia with ptosis along with fatigability. MUSK antibody positive myasthenia patients have mitochondrial abnormalities on muscle biopsy, including cytochrome oxidase (COX) negative fibers and mitochondrial aggregates.63 Several case reports have reported mitochondrial myopathy patients diagnosed with myasthenia on the basis of fatigability with electrodecremental electromyography (EMG) and some response to anticholinesterase treatment or steroids.64–66 Patients may present in acute crisis with sudden deterioration or weakness.67 Ben Yaou et al reported 12 cases of thymectomy for myasthenic symptoms diagnosed as autoimmune myasthenia in patients later found to have mitochondrial myopathy.68 The authors suggest that in the absence of relevant criteria arguing for myasthenia gravis (significant variability of muscle weakness, positive titer of anti-AChR or anti-MUSK antibodies, decremental EMG response), a muscle biopsy is required before thymectomy to exclude a mitochondrial disease.

Mitochondrial Myopathy Skeletal and cardiac muscle are both frequently involved in mitochondrial disease. There are many excellent reviews of the mitochondrial myopathies.69–71 Ocular myopathy including ptosis and PEO is a common feature of mtDNA deletion disease,70,72 but also occurs in MELAS and mtDNA depletion diseases. The eye muscles are constantly moving, are particularly energy dependent, and have a very high mitochondrial content.73 Along with this comes rapid accumulation of COX negative fibers and mtDNA deletions—even during normal aging—predisposing the ocular muscles to easily manifest mitochondrial disease.74 The classical pathological finding in skeletal muscle is the presence of ragged red fibers most clearly seen on the modified Gomori trichrome stain (►Fig. 4A). COX negative fibers are frequent (►Fig. 4B). These fibers are even more easily identified and quantified as ragged blue fibers, produced by counterstaining of succinic dehydrogenase (SDH) and COX. This pathological marker is predominantly a feature of adult disease and is rarely seen in children. A more common finding is subsarcolemmal mitochondrial proliferation (thought to be an attempt to overcome the mitochondrial

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defect) (►Fig. 4C). In children with mitochondrial muscle symptoms, histochemistry and electron microscopy (EM) are frequently normal, but mitochondrial proliferation that does not reach the level of ragged red fibers may be seen.11 Histochemical features of mitochondrial myopathy include prominent NADH reductase and SDH staining and COX negativity. There may be lipid and or glycogen accumulation. Structural abnormalities of mitochondria including proliferation and creatinine phosphokinase intramitochondrial paracrystalline inclusions may be seen on EM (►Fig. 4C). Paracrystalline inclusions indicate mtDNA abnormality and this diagnostic finding is most often seen in adults with mtDNA point mutations or deletions, and in mtDNA depletion. The most common presentation of mitochondrial muscle disease is exercise intolerance with weakness in more severe cases of skeletal muscle involvement. In pediatric patients, myopathy manifestations include motor developmental delay, hypotonia, exercise intolerance, and less commonly weakness. A retrospective analysis of 113 children with definite mitochondrial disease based on modified Walker criteria found that 60% had predominantly neuromuscular manifestations, 44% had nonspecific encephalomyopathy, but cardiomyopathy was found in 40%—most commonly hypertrophic cardiomyopathy in 58% of patients in the cardiac group, whereas 29% had dilated cardiomyopathy.75 The mortality was much higher in the group with cardiomyopathy, 18% surviving at 16 years of age compared with 95% survival in the group with neuromuscular disease, but no cardiomyopathy.75

Gastrointestinal Dysmotility This common feature of mitochondrial disease is likely a combination of nerve and smooth muscle energy failure. The most severe manifestation that is often fatal occurs in MNGIE, where marked atrophy and fibrosis of the external layer of the muscularis is seen and megamitochondria can be identified in the submucosal and myenteric ganglion cells as well as in smooth muscle cells of the muscularis mucosae and muscularis propria of the entire GI tract.76 Giordano et al reported mtDNA depletion, mitochondrial proliferation, and smooth cell atrophy in the external layer of the muscularis propria, in the stomach, and in the small intestine of MNGIE patients.34 Pseudo-obstruction is a life-threatening complication in mitochondrial encephalomyopathies likely caused

Fig. 4 Mitochondrial myopathy. (A) Ragged red fibers modified Gomori stain. (B) COX negative fiber. (C) Subsarcolemmal mitochondrial accumulation with paracrystalline inclusions on electron microscopy, mtDNA deletion disease. Seminars in Neurology

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Mitochondrial Disorders Affecting the Nervous System by autonomic neuropathy along with smooth muscle myopathy. It may occur acutely in some cases resulting in laparotomy or chronically with intermittent symptoms. A retrospective review of 20 cases noted MELAS, MERRF, and deletion disease as causes.77 The author has seen pseudoobstruction in NARP disease and it is common in MNGIE.78

Classical Phenotypes Leigh Syndrome Leigh syndrome (LS; Online Mendelian Inheritance in Man, OMIM #256000) or subacute necrotizing encephalopathy is a genetically heterogeneous neurodegenerative disorder associated with defects involving mitochondrial oxidative phosphorylation (OXPHOS). Baertling et al have recently proposed a definition based on three of the most commonly described and characteristic aspects: (1) neurodegenerative disease with variable symptoms due to (2) mitochondrial dysfunction caused by a hereditary genetic defect accompanied by (3) bilateral CNS lesions that can be associated with further abnormalities in diagnostic imaging.79 Disease onset is mainly in infancy or early childhood.19,80–95 Prenatal19,96 and late onset in adolescence and adulthood have been described.19,80,97,98 The initial presentation is often triggered by intercurrent illness. The subsequent disease course is stepwise deterioration and psychomotor regression, precipitated by episodic metabolic decompensation commonly triggered by infection, prolonged fasting and any other factors that increase metabolic demands; there may be elevated blood and/or CSF lactate.99 Neurologic features include hypotonia, spasticity, dystonia, ataxia, seizures, developmental delay, developmental regression, ptosis, nystagmus, and poor feeding. In most cases, clinical deterioration leads to death by 3 years of age commonly from central respiratory failure,95,99 although survival into adulthood has been described.82 The clinical presentation can be highly variable, and some patients with Leigh syndrome, can have an atypical course without lactic acidosis or characteristic brain lesions.100 Sofou et al recently reported the largest natural history study of LS to date. This was a retrospective study of 150 patients in Europe followed for a median period of 9.6 years from disease onset. The median age of onset was 7 months and 80% had presented by the age of 2 years.19 The most frequent clinical features at presentation in descending order of frequency were motor and ocular abnormalities, feeding difficulty, seizures and failure to thrive.19 The commonest motor abnormalities were hypotonia, abnormal deep tendon reflexes, and dystonia. The ocular abnormalities most frequently seen were nystagmus, strabismus, visual impairment, optic atrophy, ptosis, and ophthalmoplegia.19 Seizures occurred in 39.2%, respiratory dysfunction (hyperventilation, abnormal breathing pattern, apnea, obstructive or restrictive respiratory disease and central hypoventilation) in 37.7% and cardiac dysfunction (hypertrophic or dilated cardiomyopathy and conduction defects) in 17.7% of patients. Hypertrichosis and peripheral neuropathy, more commonly demyelinating, were found in 41% and 81%, respectively, in a SURF-1 deficient Seminars in Neurology

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Haas, Zolkipli LS patient series, in addition to the most prevalent symptoms of hypotonia and failure to thrive.95 Mild dysmorphic features have also been described.79,95 Sofou et al found that 56.9% of patients experienced at least one acute exacerbation requiring hospitalization in their disease course; intensive care was required in 39.2% of hospitalized patients.19 Acute exacerbations were related to infection (60.8%), respiratory complications (13.5%), strokelike episodes (4.0%), and poor nutrition or hydration (4.0%). Onset of disease before 6 months, failure to thrive, brainstem lesions on MRI scan, and intensive care requirement were significant predictors of poor survival. The median age at death was 2.4 years from respiratory complications (51%), disease progression (18%), or infection (17.6%). The initial description of LS was based on a postmortem diagnosis. The diagnosis has since evolved into a clinical entity characterized by neurodegenerative symptoms and typical radiologic findings, along with biochemical and molecular genetic testing. Lactic acidosis is not always present in LS patients. Of the LS patients in the European cohort with measured lactate levels, 25% had normal (< 2.4 mmol/L) blood and/or CSF lactate levels.19 With the availability of radiologic, biochemical, and molecular analysis techniques, the diagnosis no longer weighs upon postmortem findings.

Leigh Syndrome Mimics Awareness of the conditions that could mimic LS is crucial. Metabolic conditions such as the organic acidurias, propionic academia, methylmalonic academia, and Wilson disease can be excluded by plasma and urine determination. Postinfectious acute necrotizing encephalopathy and bilateral striatal necrosis are other examples. The most significant disorders to exclude would be those amenable to treatment. Biotin-responsive basal ganglia disease (BBGD) is an autosomal recessive disorder caused by mutations in the SLC19A3 gene. 101–103 Biotin-responsive basal ganglia disease typically causes subacute episodes with encephalopathy and subsequent neurologic deterioration that responds to thiamin and biotin treatment. Without treatment, patients have been reported with mild to moderate neurologic deficit, and some deteriorate and die.103 Neuroradiological findings include bilateral signal hyperintensity in the basal ganglia. Biotinidase deficiency has been reported with a Leigh phenotype.104,105 The creatine deficiency syndromes can also present with bilateral basal ganglia hyperintensities and mimic LS,106–108 and in the case of AGAT and GAMT deficiencies, symptoms can be amenable to therapy.109 If there is clinical suspicion for LS, laboratory investigations should include plasma and/or CSF lactate searching for lactic acidosis; plasma amino acids searching for hyperalaninemia and homocitrullinemia, the latter could suggest the presence of mtDNA mutation T8993G; and urine organic acids searching for generalized organic aciduria that may signify renal proximal tubulopathy, 3-methylglutaconic aciduria as a secondary feature in LS, and methylmalonic aciduria (MMA), which is found in a Leigh-like encephalopathy caused by SUCLA2 and SUCLG1 mutations.79


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Typical MRI changes in LS are focal, bilateral, and symmetrical lesions on T2-weighted imaging of the basal ganglia, diencephalon, and/or brainstem (►Fig. 1B). Magnetic resonance spectroscopy may reveal a lactate peak in the brain parenchyma or CSF. Skeletal muscle biopsy may reveal ragged red fibers (RRFs) on a modified Gomori trichrome stain, myofibers that fail to stain with the histochemical reaction for cytochrome c oxidase (COX) or paracrystalline inclusions on EM. Biochemical analysis of skeletal muscle biopsies from the quadriceps femoris may reveal OXPHOS deficiencies. Isolated deficiency of complex I is the most common cause of OXPHOS disease, resulting in variable phenotypes affecting infants and adults and LS is one such phenotype. Isolated complex I deficiency is the most frequently observed biochemical abnormality in LS, accounting for 34% of cases.100 Sofou et al identified abnormal electron transport chain (ETC) activity in 70% of LS patients, the most prevalent being complex I deficiency in 25 of 77 patients (32.5%).19 A muscle biopsy may be avoided if the clinical and biochemical phenotype is suggestive of a particular gene mutation, or if pyruvate dehydrogenase (PDH) deficiency is suspected, for which enzymatic analysis can be performed on fibroblasts from a skin biopsy. A reflexive testing approach to molecular analysis is helpful. Peripheral blood or if available, skeletal muscle should first be screened for mtDNA deletions and common point mutations. If negative, the next step would be mtDNA sequencing, followed by nuclear DNA sequencing or whole exome sequencing. Leigh syndrome can be maternally inherited due to mutations in genes encoded by mitochondrial DNA (mtDNA).99 More often, LS is inherited in a Mendelian manner that includes X-linked forms due to PDH deficiency or autosomal recessive inheritance due to mutations in nuclear genes encoding mitochondrial respiratory chain complex subunits or complex assembly proteins. Mutations causing disturbances in CoQ10 metabolism or dysregulation in mitochondrial RNA/DNA maintenance may also cause LS.110 Genetic etiology was confirmed in 77 of the 150 European LS patients (59.2%): Nuclear DNA mutations were more common than mitochondrial DNA mutations (37.7% and 21.5%, respectively).19 Among the nuclear genes in which pathogenic mutations have been identified are NDUFS1, NDUFS4, NDUFS7, NDUFS8, NDUFV1, SDHA1, SURF1, LRPPRC, GFM1, TACO1, PDSS2, FOXRED1, and BCS1L.110,111

Neuropathy Ataxia and Retinitis Pigmentosa Neurogenic muscle weakness, ataxia, and retinitis pigmentosa (NARP) (OMIM 551500) was first described in a family heteroplasmic for the m.8993T > G mutation in the MT-ATP6 gene.112 Although several mutations throughout MT-ATP6, which encodes subunit 6 of ATPase, have been associated with LS, only mt.8993T > G and mt.8993T > C are established causes of the classical NARP phenotype. Neuropathy ataxia and retinitis pigmentosa is characterized by retinal, central, and peripheral nervous system neurodegeneration.113 The clinical features are a length-dependent sensorimotor axonal polyneuropathy, ataxia, retinitis pigmentosa that manifests clinically as nyctalopia, sensorineural

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hearing loss, seizures, and cognitive deficit. Other described clinical features include short stature, progressive external ophthalmoplegia, cardiac conduction defects and a mild anxiety disorder. Visual symptoms may be the only clinical feature.99 The clinical course of NARP may be stable and slowly progressive over decades. The m.8993T > C and mt.8993T > G mutations are associated with variable disease phenotype within a clinical spectrum ranging from NARP to childhood maternally inherited Leigh syndrome (MILS). Some affected individuals with NARP are often diagnosed after their children have been found to have LS.62 Mitochondrial heteroplasmy may explain some of this phenotypic variability. Greater degrees of mutant heteroplasmy tend to lead to more severe clinical deficits.9,114 In NARP/MILS, the risk of developing severe functional disability as is the case in MILS increases greatly past a threshold of 60% to 70% mutant blood heteroplasmy for the m.8993T > G ATPase 6 mutation and 80% to 90% blood heteroplasmy for the m.8993T> C mutation. 115,116 However, there is both intra- and interfamilial phenotypic variability, even in families with the same mutation and similar levels of heteroplasmy. The disease phenotype is reported to be milder with the m.8993T > C point mutation. The MRI scan in NARP may show pontocerebellar atrophy. The skeletal muscle biopsy may show myopathic changes on histopathology, and any of the abnormalities on histochemistry or EM as outlined above for LS. Analysis of mtDNA targeted to the NARP common point mutations can be performed in peripheral blood and if absent, in skeletal muscle. The absence of deletions in peripheral blood does not exclude the diagnosis, as the pathogenic mutation may be undetectable in mtDNA from leukocytes.

Kearns-Sayre Syndrome and Chronic Progressive External Ophthalmoplegia Kearns–Sayre syndrome (KSS; OMIM #530000) is at the severe end of the spectrum of mitochondrial deletion disease. Kearns–Sayre syndrome is a multisystem disorder defined by the triad of onset before age 20 years, pigmentary retinopathy, and progressive external ophthalmoplegia (PEO). In addition, affected individuals have at least one of the following: cardiac conduction block, CSF protein concentration >100 mg/dL, or cerebellar ataxia. Other clinical features include nystagmus, ataxia, corticospinal dysfunction, kyphoscoliosis, bulbar, and limb girdle muscle weakness. Kearns– Sayre syndrome is also associated with a variety of endocrinopathies such as short stature, gonadal failure, diabetes mellitus, thyroid disease, hyperaldosteronism, hypomagnesaemia, and hypoparathyroidism.117,118 Kearns–Sayre syndrome is usually heralded by ptosis and muscle weakness followed in a few years by PEO. Neurodegeneration with ataxia and dementia is common with spongiform white matter changes typically found.20,31 Multisystemic involvement at presentation is less frequent and is associated with rapid disease progression.119,120 The disease usually progresses to death in young adulthood.121 There are no natural history studies to date. Seminars in Neurology

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Mitochondrial Disorders Affecting the Nervous System Kearns–Sayre syndrome typically causes cardiac conduction defects, progressing to complete heart block manifesting as congestive heart failure, syncope, or sudden death in up to 57% of patients.118 Abnormalities in cardiac conduction might begin with left fascicular block with or without right bundle branch block. Patients with KSS might have an unpredictable progression to complete heart block with an associated mortality of 20%.118 Annual surveillance including an electrocardiogram and echocardiogram is required. If heart block is detected, early intervention with a pacemaker is warranted. The phenotype varies from mild myopathy to KSS syndrome in deletion disease. Progression and symptomatology is correlated with the degree of heteroplasmy and size of the deletion.122 Kearns–Sayre syndrome is due to single, largescale deletions of mtDNA and is almost always sporadic.123 More than 150 mtDNA deletions have been associated with KSS.121 Approximately 90% of individuals with KSS have a large-scale (i.e., 1.1- to 10-kb) mtDNA deletion that is usually present in all tissues; however, mutant mtDNA is often undetectable in blood cells, necessitating examination of muscle.121 A 5 kb “common” deletion is present in approximately one-third of patients.124 Pearson’s marrow-pancreas syndrome (PS), characterized by pancreatic, hepatic, and renal insufficiency with refractory sideroblastic anemia, is diagnosed early in life and usually fatal in infancy. Some of the patients that survive this disease develop KSS.125,126 It is well established that single large mtDNA deletions are generally the cause of KSS, PS, and chronic progressive external ophthalmoplegia (CPEO) syndromes. The diagnosis of KSS is based on clinical features and laboratory investigations. Lactic acidosis may be present. There may be a myopathic appearance on EMG. A nerve conduction study may reveal a neuropathy. The brain MRI may show bilateral basal ganglia lesions, and cerebral or cerebellar atrophy.121 Skeletal muscle biopsy typically shows RRFs with the modified Gomori trichrome stain and hyperactive fibers with the SDH stain. Both RRFs and some nonRRFs fail to stain with the histochemical reaction for COX (►Fig. 4).121 MtDNA deletion may be found in blood by longrange-polymerase chain reaction analysis or Southern blot testing, but muscle is usually required. There may be OXPHOS deficiencies on biochemical analysis. A duplication/deletion mtDNA analysis should be performed on peripheral blood, and if absent, on skeletal muscle to identify mtDNA deletions. The absence of deletions in peripheral blood does not exclude the diagnosis. Chronic progressive external ophthalmoplegia is characterized by slowly progressive, often asymmetric ptosis and limitation of ocular motility in all directions of gaze.127 This condition typically starts in childhood or early adulthood with a bilateral ptosis in up to 90% of patients. The ptosis can be asymmetric at onset.128 Ptosis typically precedes ophthalmoparesis by months to years and may progress to become complete. As the disease progresses, the ptotic eyelids occlude the pupils and interfere with vision; patients may adopt a backward head tilt, accompanied by elevation of the frontalis muscles, to compensate.129 Orbicularis oculi muscles may also become weak in CPEO, resulting in lagophthalmos and Seminars in Neurology

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Haas, Zolkipli ectropion and predisposing patients to exposure keratopathy.129 The ophthalmoparetic process is painless and affects all extraocular muscles symmetrically, and patients do not commonly complain of diplopia until a convergence insufficiency on fixation develops. Visual acuity and papillary function is usually not affected in CPEO. Skeletal muscle weakness is present in most patients with CPEO and may involve the neck, limb, or bulbar musculature, with bifacial weakness the rule.129 Chronic progressive external ophthalmoplegia is the most common manifestation of mitochondrial syndromes associated with the presence of single or multiple deletions in mitochondrial DNA. Patients with CPEO have variable presentations ranging from pure CPEO to a CPEO “plus” syndrome with other accompanying multisystem features of mitochondrial disease,128 commonly KSS. Differential diagnoses include myasthenia gravis, oculopharyngeal muscular dystrophy, and myotonic dystrophy. A skeletal muscle biopsy may show abnormalities on histopathology, histochemistry, and/or EM suggestive of mitochondrial disease. As in the case of KSS, the molecular diagnosis of PEO requires analysis of a muscle biopsy. Chronic progressive external ophthalmoplegia is either due to a point mutation or a single, large-scale mtDNA deletion or multiple mtDNA deletions secondary to a nuclear mutation disrupting mtDNA replication or repair. The nuclear genes that have been implicated in CPEO include TP, which encodes for thymidine phosphorylase, resulting in the autosomal recessive disorder, MNGIE. Mutations in ANT1, Twinkle, POLG1, POLG2, and OPA1 have been implicated in autosomal dominant PEO (adPEO).129 RRM2B mutations have been reported in adult-onset adCPEO130 and arCPEO131 recently, SPG7 mutations have been identified in sporadic adult-onset CPEO with spastic ataxia.132

Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Episodes Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS; OMIM #540000) is an often devastating multisystem syndrome characterized by progressive encephalopathy and stroke-like episodes, leading to disability and early death.133 It causes significant morbidity, with the life-time prevalence of stroke-like episodes approaching 99%.134 The pathophysiology underlying the stroke-like episodes remains questionable. Onset of symptoms is frequently between the ages of 2 and 10 years, some are delayed between 10 and 40 years,135 and 90% have disease onset before 30 years of age.136 In those with disease onset before age 6 years, the most common presenting symptom is developmental delay, in those with onset between 6 and 10 years, it is muscle cramping or pain, and in those with onset within the second and third decades, hearing loss is the commonest presentation.136 The diagnosis is based on diagnostic criteria proposed by Hirano et al in 1992: (1) Stroke-like episodes, typically before age 40 years; (2) encephalopathy with seizures and/or dementia; (3) mitochondrial myopathy, evidenced by lactic acidosis and/or RRF on muscle biopsy; and (4) two of the


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following are required: (a) normal early psychomotor development, (b) recurrent headache, (c) recurrent vomiting.137 Other features of MELAS are exercise intolerance, GI problems, muscle weakness, dementia, short stature, cardiomyopathy, and sensorineural hearing loss.137 Psychiatric manifestations such as hallucinations, depression, and behavior difficulties are also prevalent in MELAS. The cumulative residual effects of the stroke-like episodes gradually impair motor abilities, vision, and cognition, often by adolescence or young adulthood.135 Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes is usually associated with the m.3243A > G mutation in the mtDNA gene MTTL1 encoding mt tRNALeu(UUR). 138 This mutation is predominant in approximately 80% of the patients with MELAS. At least 39 distinct mtDNA mutations have been associated with MELAS, among these are m.3271T > C and m.3252A > G in the MTTL1 gene, and identified with increasing frequency are mutations in ND5 of complex I, the commonest of which is m.13513G > A.135 Population-based studies suggest the m.3243A > G mutation is the most common diseasecausing mtDNA mutation, with a carrier rate of 1 in 400 people.139 It is important to note that m.3243A > G is responsible for several other syndromes aside from MELAS, which include maternally inherited deafness and diabetes (MIDD), progressive external ophthalmoplegia (PEO), and LS. It is also important to note that maternal relatives without a classical MELAS phenotype may suffer from a variety of clinical symptoms involving the central nervous system, muscle, heart, and the endocrine system. In vitro studies in cultured skin fibroblasts have shown that the m.3243A > G mutation impairs mitochondrial respiratory chain and protein synthesis when a certain threshold (85%) of mutant mtDNA is exceeded.140 Because the level of mutant mtDNA varies both among individuals and in different organs and tissues of single individuals, it is thought that the load of mutant mtDNA is in part responsible for the varied clinical expression of mtDNA defects in general and of the M.3243A > G MELAS mutation in particular.140 Of 129 symptomatic patients and asymptomatic carriers (age range 11 months–74 years; 39% male) identified to have m.3243A > G from the MRC Centre for Neuromuscular Diseases Mitochondrial Disease Patient Cohort Study UK, 13 patients (10%) exhibited a classical MELAS phenotype, a lower prevalence compared with previous cohorts; 39 (30%) had MIDD, 8 (6%) MELAS/MIDD, 2 (2%) MELAS/CPEO, and 6 (5%) MIDD/CPEO overlap syndromes.139 Sensorineural hearing loss was evident in 66 patients (51%), and this was an isolated symptom in 4 patients (3%). Diabetes (type I or II) was present in 54 patients (42%). Overall, 36 patients (28%) did not conform to any of the classical syndromes and presented with a diverse phenotypic spectrum that included proximal myopathy (27%), ataxia (24%), migraine (23%), and seizures (18%). Twelve individuals (9%) carrying the mutation were clinically asymptomatic.139 These results highlight the phenotypic variability of the m.3243A > G mutation and the need to identify individuals with this mutation in

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anticipation of future disease expression such as diabetes. Kaufmann et al conducted a cross-sectional study of symptomatic and asymptomatic carriers with controls; carrier relatives carrying the m.3243A > G without the full MELAS phenotype displayed a high prevalence of disease manifestations.141 Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes progresses over years with episodic deterioration related to stroke-like events. In a prospective natural history study of 31 individuals with MELAS (age mean standard deviation [SD], 30 15 years at baseline, range 4–61 years, 48% male) and 54 symptomatic and asymptomatic carrier relatives (age 38 17 years, range 4–76 years, 28% male) harboring the m.3243A > G over a follow-up period of up to 10.6 years, neurologic examination, neuropsychological testing, and daily living scores significantly declined in all affected individuals with MELAS, whereas no significant deterioration occurred in carrier relatives.136 In patients with MELAS, there was a progressive decline in neuropsychological and neurologic findings, worsening MRI abnormalities and progressively increased CNS lactate levels as measured by MRS136 (►Fig. 5). The death rate was more than 17-fold higher in fully symptomatic individuals compared with carrier relatives. The average observed age at death in the affected MELAS group was 34.5 19 years (range 10.2–81.8 years). Of the deaths, 22% occurred in those younger than 18 years and were attributed to MELAS-related medical complications in all patients except for three patients. Seizures, stroke-like episodes, sepsis, and GI pseudo-obstruction were noted during the end-of-life period. In the three patients in whom death was considered sudden and unexpected, two were found to have hypertrophic cardiomyopathy on postmortem, and one had status epilepticus and was on medication for Wolff-Parkinson-White syndrome. The estimated overall median survival time based on fully symptomatic individuals was 16.9 years from onset of focal neurologic disease, for example, seizures or stroke.136 Stroke-like lesions occur in approximately 90% of MELAS patients and correlate with focal neurologic symptoms.138 During stroke-like episodes, the MRI brain scan reveals areas of T2 prolongation, with predominant involvement of the cerebral cortex, predominantly in the occipital and parietal lobes and not confined to vascular territories and sparing of the deep white matter142 (►Fig. 5). An EMG may show myopathy and a nerve conduction study frequently shows neuropathy, and is predominantly axonal and sensory.135 Muscle biopsy often shows RRFs on the modified Gomori trichrome stain, “ragged blue fibers” due to the hyperintense reaction with SDH,135 COX-positive RRFs, and succinate dehydrogenase reactive vessels.143 Electron transport chain activity may be normal, or a deficiency may be detected. Molecular analysis targeted to the common point mutations could first be performed on peripheral blood. If negative, other tissues such as saliva, skin fibroblasts, urinary sediment, or preferably skeletal muscle can be tested. If the common point mutations are absent, the next step would be to proceed with full mtDNA sequencing. Seminars in Neurology

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Fig. 5 Magnetic resonance imaging and magnetic resonance spectroscopy of 12-year-old boy with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) due to m.3243A > G mutation at 90% in blood. (A) T2-weighted magnetic resonance image shows atrophy with ventriculomegaly, caudate nucleus and putaminal bright signal, and bilateral occipital subacute metabolic strokes in a nonvascular distribution, and parietal and left frontal stroke lesions. (B) Magnetic resonance spectroscopy (voxel in posterior paramedian parietal lobe) shows high lactate doublet (1.3 ppm) and a significant decreased N-acetylaspartate (2.0 ppm)/creatine (3.2 ppm) ratio.

Myoclonic Epilepsy with Ragged Red Fibers Myoclonic epilepsy with ragged red fibers (MERRF; OMIM #545000) is a multisystem disorder that was first described in 1980.144 Myoclonic epilepsy with ragged red fibers is characterized by myoclonus, which is often the first symptom, followed by generalized epilepsy, ataxia, weakness, and dementia. Onset is usually in childhood, occurring after normal early development.145 Common findings are hearing loss, short stature, optic atrophy, and cardiomyopathy with Wolff-Parkinson-White (WPW) syndrome. Occasionally pigmentary retinopathy and lipomatosis are observed. Myoclonic epilepsy with ragged red fibers is associated with various mtDNA point mutations, the most frequent being the 8344A > G change in the transfer RNA lysine,146 present in 80% of patients with MERRF. This mutation can also be associated with other phenotypes, such as LS and myopathy with truncal lipomas.147 Three additional mutations, m.8356T > C, m.8363G > A, and m.8361G > A, are present in 10% of affected individuals.145 Mancuso et al conducted a retrospective review of a cohort of patients harboring the 8344A.G mutation who were registered in the database of the Nation-wide Italian Collaborative Network of Mitochondrial Diseases.148 Four of 39 subjects (10.3%) were asymptomatic mutation carriers. The mean age at onset of disease in the 35 symptomatic patients was 30.1 18.4 years (range 0–66; 11/35 with clinical onset before age 16). At the last evaluation, mean age and disease duration were 45.6 15.3 years (range 5–72), and 21.6 6 15.3 years (range 2–59), respectively.148 The CNS features observed in decreasing order of frequency were generalized seizures in 35.3%, cerebellar ataxia (23.5%), myoclonus (23.5%), cognitive involvement (5.9%), and stroke-like episodes (2.9%). In this cohort, myoclonus was a less frequent feature compared with a previous report of 61%.149 In terms of neuromuscular symptoms, muscle weakness was evident in 58.8%, as well as exercise intolerance (44.1%), increased creatine kinase (CK) levels (44.1%), ptosis Seminars in Neurology

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(29.4%), and ophthalmoparesis (5.9%). Other features included cardiomyopathy with arrhythmia (11.8%), arrhythmia (5.9%), peripheral neuropathy (14.7%), swallow impairment (2.9%), respiratory impairment (2.9%), hearing loss (35.3%), and diabetes mellitus (11.8%).148 The authors then conducted a systematic review of the literature and identified 282 previously reported 8344A > G-positive individuals (male/female ratio 0.85; mean age at the last evaluation 34.2 19.1 years).148 In 321 patients with a mean age of 35 years, the clinical picture was characterized by the following signs/symptoms in descending order: myoclonus, muscle weakness, ataxia (35%–45% of patients); generalized seizures, hearing loss (25%–34.9%); cognitive impairment, multiple lipomatosis, neuropathy, exercise intolerance (15%–24.9%); and increased CK levels, ptosis/ophthalmoparesis, optic atrophy, cardiomyopathy, muscle wasting, respiratory impairment, diabetes, muscle pain, tremor, migraine (5%–14.9%).148 Lactic acidosis is frequent in blood and CSF. An MRI scan of the brain often shows atrophy and basal ganglia calcification. A skeletal muscle biopsy may show RRF, hyperactive staining on SDH and COX-negative fibers.145 Electron transport chain activity may be normal.

Leber’s Hereditary Optic Neuropathy Leber’s hereditary optic neuropathy (LHON; OMIM #535000) is characterized by acute, painless loss of central vision, which is bilateral in approximately 25% of cases.150 If unilateral, the contralateral eye is usually affected within 6 to 8 weeks. The majority of carriers become symptomatic in the second and third decades of life, typically young adult males, and over 90% of carriers who will experience visual failure will have onset before the age of 50 years.150 However, visual deterioration can occur at any time during the first to the seventh decade of life; LHON should be part of the differential diagnosis for all cases of bilateral, simultaneous, or sequential optic neuropathy, irrespective of age, and particularly in male patients.150


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The visual loss usually begins with defective color vision and a central scotoma. The loss of visual acuity is profound and levels off below 20/400 within a few months; the visual field defects show large centrocecal absolute scotomas.151 Funduscopy reveals the characteristic signs of circumpapillary telangiectatic microangiopathy, swelling of the retinal nerve fiber layer (RNFL) around the disc and lack of leakage on fluorescein angiography, consistent with pseudoedema.151 The optic disc appears hyperemic initially, though the axonal loss in the papillomacular bundle leads to severe temporal pallor of the optic disc, and in time, optic disc atrophy develops (►Fig. 3). The endpoint of LHON is usually optic atrophy associated with permanent loss of central vision, although there is relative sparing of pupillary light responses.152,153 Loss of visual acuity stabilizes within the first year after onset, leaving the patient, in most cases, legally blind. Microangiopathy and fundus changes such as RNFL swelling may be present in asymptomatic matrilineal relatives.154 Spontaneous recovery of visual acuity may infrequently occur even years after onset, with contraction of the scotoma or reappearance of small islands of vision within it (fenestration).151 The most favorable prognostic factors are young age of onset and the 14484/ND6 mutation.155 Leber’s hereditary optic neuropathy causes significant visual impairment; in the majority of cases, visual recovery is minimal.156 The majority of patients with LHON (90%–95%) harbor one of three primary mtDNA point mutations: m.3460G > A, m.11778G > A, and m.14484T > C, which affect key complex I subunits of the mitochondrial respiratory chain.156 Leber’s hereditary optic neuropathy can be also due to rare pathogenic mtDNA point mutations affecting different subunits of complex I, more commonly the MT-ND6 and MT-ND1 subunit genes.157,158 The mtDNA pathogenic mutations, which are in most cases homoplasmic (100% of the mtDNA molecules are mutated), do not explain at least two features of LHON: the male prevalence and the incomplete penetrance. Not all LHON mutation carriers will experience visual loss during their lifetime. The conversion rate for male carriers is 50% compared with 10% for female carriers. The primary LHON mutation is therefore a prerequisite, but secondary factors are clearly modulating the risk of visual loss.151,159 Their identification has proven challenging, and the evidence favors a complex disease model, with both genetic and environmental factors interacting to precipitate optic nerve dysfunction.159–161 The only strong evidence of a genetic modifier is currently the association of LHON with a European mtDNA background, known as haplogroup J, which increases the penetrance of the m.11778G > A and m.14484T > C LHON mutations.159,162 The differential diagnoses of LHON include LS, MELAS, Friedrich ataxia, and Wolfram syndrome.

mtDNA Depletion Syndromes MtDNA depletion syndromes (MDS) are heterogenous autosomal recessive disorders characterized by a severe reduction in mtDNA content in affected tissues and organs.163 Onset is mainly in infancy leading to an early death. MtDNA depletion

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syndromes are associated with defects in mtDNA maintenance caused by mutations in nuclear genes that function in either mitochondrial deoxyribonucleoside triphosphate (dNTP) synthesis or mtDNA replication. Thymidine kinase 2 (TK2), adenosine diphosphate- (ADP-) forming succinyl CoA ligase β subunit (SUCLA2), guanosine diphosphate (GDP)forming succinyl CoA ligase α subunit (SUCLG1), ribonucleotide reductase M2 B subunit (RRM2B), deoxyguanosine kinase (DGUOK), and thymidine phosphorylase (TYMP) encode proteins that maintain the mitochondrial dNTP pool.163 Mutations in any of these genes result in mtDNA depletion. MtDNA is replicated by the concerted action of DNA polymerase γ (pol γ) encoded by POLG, or its accessory subunit, p55 encoded by POLG2. Pol γ is the only known DNA polymerase to be found in mammalian mitochondria and thus bears the burden of DNA replication and DNA repair functions.6 The mitochondrial helicase, C10orf2 or Twinkle, is a replication factor. Mutations in POLG, POLG2, and C10orf2 (Twinkle) result in insufficient mtDNA synthesis and a reduction of mtDNA content.163 Clinically, MDS are usually classified as one of four forms: a myopathic form associated with mutations in TK2; an encephalomyopathic form associated with mutations in SUCLA2, SUCLG1, or RRM2B; a hepatocerebral form associated with mutations in DGUOK, MPV17, POLG, or C10orf2; and a neurogastrointestinal form associated with mutations in TYMP.164,165

TK2-Related Myopathic MDS Typically, initial development is normal and the majority of affected children present before the age of 2 years with gradual onset of hypotonia, generalized fatigue, proximal muscle weakness, and feeding difficulty, with normal cognitive function.163 Muscle weakness rapidly progresses to respiratory failure and death within a few years of onset. The adult form of TK-2 related myopathy is slowly progressive.166 Rarely, there are encephalomyopathic, hepatomyopathic, or spinal muscular atrophy-like forms of presentation.6 Serum CPK is usually elevated. Electromyography usually shows nonspecific myopathic changes. Histopathological hallmarks for mitochondrial disease such RRF, COX-negative fibers, and SDH hyperstaining may be seen. Electron transport chain activity assays are decreased in multiple complexes, commonly complexes I, I þ III, and IV.163 mtDNA content is severely reduced in muscle.

SUCLA2 and SUCLG1-Related Encephalomyopathic MDS Mutations in the succinyl-CoA synthase gene SUCLA2 cause infants to present with hypotonia typically before the age of 6 months. All affected children develop hypotonia, muscle atrophy, and psychomotor delay. Other features are feeding difficulty, gastroesophageal reflux, sensorineural hearing loss, and epilepsy. Most patients die in childhood.163 SUCLG1 deficiency has a similar phenotype characterized by intrauterine growth retardation, hepatomegaly, hypotonia, respiratory insufficiency due to acidosis, and severe hypothermia.166 In the neonatal form, death ensues within a few days. No adult forms have been reported so far. Lactic acidosis is severe. Hypoglycemia and mild to moderate elevation of Seminars in Neurology

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Mitochondrial Disorders Affecting the Nervous System MMA and methylcitrate may be present. Plasma and urine amino acid determination reveals highly elevated taurine and glycine and moderately elevated lysine and alanine.166 Electromyography may reveal findings suggestive of motor neuron involvement, whereas a brain MRI scan may show cortical atrophy, bilateral basal ganglia involvement, and delayed myelination.163 Electron transport chain assays commonly show combined deficiency of complexes I, III, and IV. Quantitation of mtDNA shows a decreased mtDNA content in muscle.

Haas, Zolkipli hyperintensity of the globus pallidus bilaterally and subtentorial abnormal myelination.171 mtDNA content is reduced in liver and muscle, and electron transport chain activity assays are commonly decreased in complexes I, I þ III, and IV.163 Hepatic dysfunction is progressive in the majority of individuals with both forms of DGUOK-related MDS and is the most common cause of death. For children with the multiorgan form, liver transplantation provides no survival benefit.163

MPV17-Related Hepatocerebral MDS RRM2B-Related Encephalomyopathic MDS Mutations in the nuclear-encoded mitochondrial maintenance gene RRM2B cause mtDNA depletion, and multiple mtDNA deletions. RRM2B-related mtDNA depletion usually manifests as severe multisystem disease (encephalomyopathy with proximal renal tubulopathy) and is often fatal in early life. Inheritance is autosomal recessive. Affected individuals typically present during the first months of life with hypotonia, lactic acidosis, failure to thrive, tubulopathy, microcephaly, psychomotor delay, sensorineural hearing loss, and profound mtDNA depletion in muscle.163 The disease progresses rapidly, leading to death within a few months. Multiple mtDNA deletions cause tissue-specific COX deficiency. Inheritance can be either autosomal recessive, with PEO and multisystem involvement manifesting during early childhood or adulthood,167 or autosomal dominant with tissue specific manifestations such as PEO developing in late adulthood.130,131 RRM2B mutations have been reported to cause a mitochondrial neurogastrointestinal encephalopathy(MNGIE-) like phenotype with mtDNA depletion,168 and a KSS phenotype.167 Lactic acidosis may be present. Muscle biopsy may show RRF and COX-negative fibers. Electron transport chain assays commonly show combined deficiency of complexes I, III, and IV163 or combined I, III, IV, and V.166 In addition to mtDNA depletion, RRM2B mutations also cause multiple mtDNA deletions in adults.169 This mutation is the third most common cause of multiple mtDNA deletions following POLG and C10orf2 (Twinkle).169

DGUOK-Related Hepatocerebral MDS There are two phenotypes of deoxyguanosine kinase (DGUOK) deficiency: multiorgan disease in neonates with isolated hepatic disease later in infancy or childhood, and progressive liver disease is the most common cause of death in both forms.170 The majority of affected individuals have a neonatal-onset multiorgan disease that presents with lactic acidosis and hypoglycemia in the first week of life.163 Within weeks of birth, all infants develop hepatic disease and neurologic dysfunction. Severe myopathy, developmental regression, and typical rotary nystagmus developing into opsoclonus are also seen. Liver involvement may cause neonatal- or infantile-onset liver failure that is generally progressive with ascites, edema, and coagulopathy.163 The majority of affected newborns with the multiorgan form of the disease show elevated serum tyrosine or phenylalanine on newborn screening.163 A brain MRI scan is usually normal in DGUOK deficiency, but some patients show moderate Seminars in Neurology

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The gene MPV17 encodes an inner mitochondrial membrane protein. Mutations cause an infantile-onset disorder, which can present with a spectrum of combined hepatic, neurologic, and metabolic manifestations.163 The phenotype is characterized by recurrent episodes of severe hypoglycemia, hepatopathy evolving toward cirrhosis and liver failure, and growth retardation. Patients present with poor feeding, failure to thrive, diarrhea, and recurrent vomiting.166 Within the first few months of life they develop generalized muscle wasting and hypotonia. Common neurologic phenotypic features include microcephaly, ataxia, developmental delay, muscle weakness, seizures, ischemic stroke, or dystonia. Patients who survive develop polyneuropathy and lesions of the cerebellum and the cerebral cortex.166 In the vast majority of affected individuals, liver disease progresses to liver failure in infancy or childhood, and liver transplant is the only treatment option. Neurologic manifestations include developmental delay, hypotonia, muscle weakness, and motor and sensory peripheral neuropathy. Lactic acidosis and hypoglycemia is present in most cases, which typically presents during the first 6 months of life. A brain MRI may show cortical and subcortical hyperintensities involving the cerebellar white matter.166 Navajo neurohepatopathy is another recognized phenotype.59

C10orf2-Related Hepatocerebral MDS Mutations in C10orf2 (Twinkle mtDNA helicase) have been associated with variable phenotypes, including infantile-onset spinocerebellar ataxia (IOSCA), adPEO, and hepatocerebral MDS.163 Onset is usually in infancy, although adult-onset adPEO has been reported. The neurologic involvement progresses to include hyporeflexia, muscular atrophy, ophthalmoplegia, nystagmus, athetosis, ataxia, epilepsy, sensory neuropathy, sensorineural hearing loss, and psychomotor regression. Prognosis is poor. Mutations in the Twinkle gene most frequently cause multiple mtDNA deletions, but also cause mtDNA depletion, which is more evident in the liver than in skeletal muscle.166

POLG-Related Hepatocerebral MDS Also referred to as Alpers syndrome, Alpers–Huttenlocher syndrome (AHS) presents most frequently during infancy (similar to MCHS) and is fatal.7 Mitochondrial polymerase γ (POLG) deficiency with mtDNA depletion was reported as the cause15 leading to the identification of the first mutations in POLG in two unrelated families.172 Alpers–Huttenlocher syndrome is one of the most severe phenotypic manifestations in


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the spectrum of POLG-related disorders. The hallmark features of AHS include the clinical triad of refractory seizures, developmental regression, hepatopathy, and 2 of 11 other clinical or laboratory findings.173 The typical age of onset is between 2 and 4 years of age, but can range from 3 months to 36 years of age. Children with AHS appear healthy at birth and may develop normally until the onset of their illness.173 Seizures are the first sign of AHS in approximately 50% of affected children,173 with an early predilection of epileptiform discharges over the occipital region of the brain, and generalized discharges as the disease progresses.7 Over time, the seizures become increasingly resistant to anticonvulsant therapy. Valproic acid can precipitate fatal liver failure174 in AHS and should be avoided.174 Migraine headaches are also an early symptom. Early in the disease course areflexia and hypotonia are present and are later followed by spastic paraparesis that evolves over months to years, leading to psychomotor regression.163 Ataxia develops in all persons with AHS, unless the disease process is so rapid that it results in early death or the corticospinal tract involvement precludes the evaluation for ataxia.173 Motor and sensory neuropathy may be present. A rapid and stepwise cognitive deterioration often occurs in the setting of an infectious illness.173 The clinical manifestations may include somnolence, loss of concentration, loss of expressive and receptive language, irritability with loss of normal emotional responses, and memory deficits. Cortical visual loss leading to blindness is common in fully developed AHS, but may not appear for months to years after the onset of other neurologic manifestations.173 Other neurologic features may include stroke and stroke-like episodes, myoclonus, choreoathetosis, parkinsonism, and nystagmus.163 Cerebrospinal fluid protein is generally elevated. A brain MRI scan may show gliosis and generalized brain atrophy. Liver involvement can progress rapidly to end-stage liver failure within a few months.173 Disease progression is variable, with life expectancy from onset of symptoms ranging from 3 months to 12 years.173 Muscle or liver mtDNA depletion (defined as < 35% of agematched normal mtDNA content) can lag behind the onset of disease symptoms.173 With disease progression, all patients will eventually have mtDNA depletion. Therefore, the absence of mtDNA depletion early in the course of disease cannot be used to exclude POLG disease.173

Mitochondrial Neurogastrointestinal Encephalomyopathy Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder first described in 1976.175 Mitochondrial neurogastrointestinal encephalomyopathy is caused by mutations in the nuclear gene TYMP, encoding thymidine phosphorylase (TP).176 Hirano et al defined the diagnostic criteria in 1994: severe gastrointestinal dysmotility; cachexia; ptosis, ophthalmoparesis, or both due to extraocular muscle weakness; peripheral neuropathy; and leukoencephalopathy with TP activity < 10% of the normal control mean.134 Severe biochemical defects of thymine phosphorylase activity lead to marked increases in

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thymidine and deoxyuridine nucleoside levels in blood, urine, and tissues.176–179 These elevated nucleoside levels cause mtDNA instability and ETC dysfunction.180 The condition is relentlessly progressive, and patients usually die at an average age of 37 years. Garone et al reported a cohort of 102 patients with MNGIE (50% female, mean age 32.4 years, age range 11–59 years).180 Ninety-two patients were confirmed to have TYMP mutations. The average age of disease onset was 17.9 years (range 5 months–35 years), but the majority of patients reported the first symptoms in childhood. Surprisingly, among patients with severe thymine phosphorylase deficiency in the buffy coat (< 10% of normal control mean), early onset did not correlate with a short life expectancy.180 Gastrointestinal symptoms were confirmed as the most frequent first feature of the disease as found in 36 of 63 patients (57.1%). These symptoms included diarrhea, abdominal pain, nausea/vomiting, abdominal cramps, weight loss, borborygmi, cachexia, intestinal pseudo-obstruction, bloating, and intestinal invagination. Ocular symptoms such as ptosis and external ophthalmoplegia preceded GI disease in 14 of 63 patients (22.2%). It is not uncommon that the clinical suspicion for a diagnosis of MNGIE is triggered by abdominal imaging that reveals a large and dilated stomach, consistent with pseudo-obstruction, in the context of weight loss and cachexia. This occurred in 9 of 63 patients (14%). Patients presented with peripheral neuropathy manifesting as numbness or foot drop, limb weakness, and paraesthesia or cramps. The neuropathy was predominantly a demyelinating neuropathy. Kaplan–Meier analysis revealed significant mortality between the ages of 20 and 40 years. The average age of death was 35 years (range 15–54 years) and identified causes included pneumonia due to aspiration (eight patients), peritonitis due to intestinal rupture (two patients), suicide (two patients), electrolyte imbalance (two patients), sepsis (one patient), malignant melanoma (one patient), cardiac arrhythmia (one patient), metabolic acidosis (one patient), cardiopulmonary arrest (one patient), and oesophageal varicocele bleeding (one patient).180 The leukoencephalopathy in MNGIE involves the cerebral hemispheres, but basal ganglia, cerebellum, and brainstem are often affected. Typically, patients do not display cognitive manifestations despite the diffuse white matter involvement of the brain, although 20% of patients in this cohort did have mild neurologic symptoms such as cognitive impairment, dementia, seizure, headache, or psychiatric symptoms such as depression. Mitochondrial neurogastrointestinal encephalomyopathy can be diagnosed by demonstrating severely reduced thymine phosphorylase activity in the buffy coat; marked elevations of thymidine, deoxyuridine, or both in plasma or urine; or by detecting TYMP gene mutations in peripheral blood.180 A demyelinating neuropathy may be evident on a nerve conduction study. Muscle biopsy typically reveals mitochondrial alterations such as RRFs, COX-deficient fibers, or decreased activities of mitochondrial OXPHOS activity; however, the skeletal muscle may not show any mitochondrial abnormalities.180 Seminars in Neurology

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Less well-defined mitochondrial phenotype


Reduced mitochondrial enzyme activity (between 20% and 45% of mean control). Elevated citrate synthetase (> 60%)

Mitochondrial accumulation structural abnormality Paracrystalline inclusions on electron microscopy

Basal ganglia, brainstem, cerebellar T2/FLAIR hyper-intensities Stroke-like lesions in a nonvascular distribution. High brain or CSF lactate on MRS.

Metabolic > 2% ragged red fibers > 5% COX negative fibers

Neuroimaging Muscle histology Biochemistry

Very low mitochondrial enzyme activity (typically < 20%)

Gene testing

Proven dominant or recessive nuclear gene mutation or high-level heteroplasmy mtDNA mutation or deletion

Minor

Fig. 6 Elements in the diagnosis of mitochondrial disease. CSF, cerebrospinal fluid; EKG, electrocardiogram; Echo, echocardiogram; ETC, electron transport chain; MRI, magnetic resonance imaging; MRS, magnetic resonance spectroscopy.

Well-defined mitochondrial disease phenotype

The diagnosis of mitochondrial disease requires biochemical, genetic, and clinical evaluation (►Fig. 6). Suggested diagnostic criteria vary somewhat, but all classify patients as definite,

Clinical phenotype

Diagnosis

Major

Coenzyme Q10 (CoQ10) is an essential component of the ETC receiving electrons from complex I, complex II, electron transfer factor (fatty acid oxidation), and other substrates. It has many other functions including acting as both an antioxidant and a pro-oxidant, it is involved in the regulation of apoptosis and is a signaling molecule. Not surprisingly, synthetic defects cause mitochondrial disease and conversely mitochondrial disease causes CoQ10 deficiency.182 Secondary CoQ10 deficiency is much more common than synthetic disease. Phenotypic variation is wide, but CoQ10 deficiency disorders often affect the brain and are particularly important to diagnose as they are treatable.181 Steroid-resistant nephrotic syndrome with ataxia is seen with gene mutations in ADCK3 and ADCK4, which encode the aarF domain containing kinase 4 required for CoQ10 synthesis.183 Other synthetic defects include mutations in COQ2, PDSS1, PDSS2, and COQ4, which cause infantile cytopathies with encephalopathy184 and the COQ6 gene causing nephrotic syndrome with sensorineural deafness. Dominant cerebellar atrophy with ataxia and mitochondrial myopathy is another phenotype of these defects. Secondary CoQ10 deficiency with some response to treatment occurs in Friedreich ataxia.185 Other disorders with secondary deficiency include the mtDNA depletion syndromes186 electron transfer factor dehydrogenase gene defects producing the severe form of glutaric aciduria type II can also cause a late-onset mitochondrial myopathy.187

Criteria

Coenzyme Q10 Deficiency

Elevated plasma and/or CSF lactate or pyruvate. Abnormal lactate/ pyruvate ratio Organic or amino acid elevation suggestive of mitochondrial dysfunction.

Allogeneic hematopoietic stem cell transplantation (AHSCT) offers a permanent cure, but it carries a significantly high mortality risk and is limited by matched donor availability.181

Abbreviations: CSF, cerebrospinal fluid; FLAIR, fluid-attenuated inversion-recovery; MRS, magnetic resonance spectroscopy. Note: Definite mitochondrial disease: two major criteria (one clinical), one major biochemical or molecular defect with one major or minor clinical criterion, one major and two minor criteria (one clinical); probable mitochondrial disease: one major and one minor criterion (one clinical), three or > minor criteria (one clinical); possible mitochondrial disease: one major, two minor criteria (one clinical); unlikely mitochondrial disease: no major or < two minor criteria.

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Likely pathogenic mutation


Table 1 Probability of a diagnosis of mitochondrial disease (after Bernier et al and North American Mitochondrial Disease Consortium [NAMDC] research criteria)

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Treatment Aside from symptom-based management, treatment of mitochondrial disease focuses on maintaining optimal health, using preventive measures to mitigate symptom worsening during times of physiologic stress (such as infection, dehydration, or surgery), and avoiding mitochondrial toxins.194 There are recent reviews on the available supplements and the doses used in mitochondrial disease patients.194,195 These include ubiquinol doses of 2 to 8 mg/kg/d in two divided doses. This form of CoQ10 is a solubilized, bioavailable form and is preferred over ubiquinone. Ubiquinone doses of 5 to 30 mg/kg/d in two divided doses is an available alternative. A recent randomized blinded crossover study using a low dose of 1200 mg of CoQ10 confirms minor benefit in exercise ability and lactate levels.196 Oral levocarnitine (20–50 mg/kg/d in three divided doses), and a B-vitamin complex (B 100) with or without additional riboflavin (300 mg/d) are usually recommended, although the evidence of benefit is largely anecdotal. Creatine monohydrate supplementation has been reported to be beneficial in mitochondrial myopathies.197 Exercise, both isometric and aerobic, has been shown to be beneficial in mitochondrial myopathies and should be advised for patients with mitochondrial myopathy.71,198–200 Dichloroacetate is under study for treatment of PDH deficiency.201,202 EPI-743, a synthetic analog of vitamin E, targets repletion of reduced intracellular glutathione, and has been studied in open-label trials involving small numbers of patients with mitochondrial disease (n ¼ 13), patients with genetically confirmed LS (n ¼ 10), and LHON (n ¼ 5), suggesting either improvement or slowing of disease progression.203

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Copyright of Seminars in Neurology is the property of Thieme Medical Publishing Inc. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.

Mitochondrial dysfunction in central nervous system white matter disorders.

Syndromes affecting the central nervous system.

Hereditary disorders affecting the lacrimal system.

Myopericytoma: A Series of 5 Cases Affecting the Nervous System.

A granulomatous necrotizing arteritis affecting the peripheral nervous system.

Nervous system disorders in dialysis patients.

Mitochondrial retrograde signaling in the Drosophila nervous system and beyond.

Probing disorders of the nervous system using reprogramming approaches.

Paraneoplastic and other autoimmune disorders of the central nervous system.

The role of microbiome in central nervous system disorders.

Review: Central nervous system involvement in mitochondrial disease.

Disorders of the Autonomic Nervous System after Hemispheric Cerebrovascular Disorders: An Update.

Extrasynaptic NMDA receptor involvement in central nervous system disorders.

Targeting Oxidative Stress in Central Nervous System Disorders.

Building global capacity for brain and nervous system disorders research.

Improving and accelerating drug development for nervous system disorders.

Microparticles: a new perspective in central nervous system disorders.

Clinical proton MR spectroscopy in central nervous system disorders.

HCV-related central and peripheral nervous system demyelinating disorders.

Sex and Gender Differences in Central Nervous System-Related Disorders.

Potential involvement of the extracranial venous system in central nervous system disorders and aging.

Respiratory modulation of baroreceptor and chemoreceptor reflexes affecting heart rate through the sympathetic nervous system.

Central Nervous System-Peripheral Immune System Dialogue in Neurological Disorders: Possible Application of Neuroimmunology in Urology.

Novelties in the anatomy of the central nervous system and related disorders.