Journal http://jcn.sagepub.com/ of Child Neurology
A Novel Mutation of ALDH5A1 Gene Associated With Succinic Semialdehyde Dehydrogenase Deficiency Chun-Yen Lin, Wen-Chin Weng and Wang-Tso Lee J Child Neurol published online 22 September 2014 DOI: 10.1177/0883073814544365 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2014/09/17/0883073814544365
Published by: http://www.sagepublications.com
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Brief Communication
A Novel Mutation of ALDH5A1 Gene Associated With Succinic Semialdehyde Dehydrogenase Deficiency
Journal of Child Neurology 1-4 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814544365 jcn.sagepub.com
Chun-Yen Lin, MD1, Wen-Chin Weng, MD1,2, and Wang-Tso Lee, MD, PhD1,2
Abstract Succinic semialdehyde dehydrogenase deficiency is a rare autosomal recessive metabolic disorder affecting g-aminobutyric acid degradation. We described a boy with a severe phenotype of succinic semialdehyde dehydrogenase deficiency and novel mutations of ALDH5A1 gene. He was referred because of developmental delay, focal seizures, and choreoathetosis at 6 months of age. The diagnosis of succinic semialdehyde dehydrogenase deficiency was confirmed by increased level of g-hydroxybutyric acid in urine and novel compound heterozygous mutations in the ALDH5A1 gene. His seizures were successfully controlled. However, the patient showed a slowly progressive clinical course with severe neurologic deficits. A magnetic resonance imaging (MRI) revealed abnormal high intensities in the putamen and globus pallidi on T2-weighted images when he was 6 months old, and more diffuse abnormal signal intensities over bilateral hemispheres were noted when he was 3 years old. Keywords succinic semialdehyde dehydrogenase deficiency, psychomotor retardation, dyskinesia Received March 30, 2014. Received revised June 04, 2014. Accepted for publication July 01, 2014.
Succinic semialdehyde dehydrogenase deficiency (or g-hydroxybutyric aciduria, OMIM 271980; aldehyde dehydrogenase 5A1, ALDH5A1, OMIM 610045) is an autosomal recessively inherited defect in the degradation pathway of g-hydroxybutyric acid (GHB). The absence of succinic semialdehyde dehydrogenase activity will lead to the accumulation of both g-aminobutyric acid (GABA) and g-hydroxybutyric acid in physiological fluids. Succinic semialdehyde dehydrogenase deficiency is a slowly progressive or static encephalopathy with late infantile to early childhood onset, presenting with heterogenic clinical manifestations, such as developmental delay, mental retardation, ataxia, and behavioral problems, etc. Basal ganglia signs such as choreoathetosis, dystonia, and myoclonus have been reported.1-3 Magnetic resonance imaging (MRI) studies usually show symmetric involvement of globus pallidi, dentate nuclei, and occasionally the subthalamic nucleus (pallidodentatoluysian pattern).3-6 Seizures presented in half of patients, and electroencephalography (EEG) shows generalized spike-waves, photosensitivity, background slowing, and sleep spindle asynchrony.1,7-9 Succinic semialdehyde dehydrogenase deficiency has been reported in approximately 450 people until 2011.7 Parental consanguinity has been reported in approximately 40% of all published cases, but no genotype-phenotype correlations have been observed, and there is also no correlation between g-hydroxybutyric acid levels in physiological fluids and the severity of the disease.9
We describe here a first-reported Taiwanese boy with succinic semialdehyde dehydrogenase deficiency who had novel compound heterozygous mutations with deletion and insertion of ALDH5A1 gene. The severe phenotype consisted of global developmental delay and choreoathetosis, and novel neuroimaging abnormalities.
Case Report A 6-month-old boy was seen in the pediatric neurology clinic because of developmental delay and involuntary movements. The patient was born at gestational age of 39 weeks by elective cesarean section to a 36-year-old multigravid mother. His mother received regular perinatal examination with normal results. During the pregnancy, no illicit drug use or substance abuse was reported. Consanguinity was not reported. The labor was smooth without obvious perinatal insults. The birth weight was 2.8 kg (15th to 50th percentile), the body 1 2
Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan Clinical Center of Neuroscience and Behavior, National Taiwan University Hospital, Taipei, Taiwan
Corresponding Author: Wang-Tso Lee, MD, Phd, Department of Pediatrics, National Taiwan University Hospital, 8, Chung-Shan South Road, Taipei 100, Taiwan. Email: [email protected]
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Figure 1. T2-weighted images in the patient with succinic semialdehyde dehydrogenase deficiency. (A) Six months old. Focal signal changes at both globus pallidi and putamen (white arrows) when he did not take vigabatrin. (B) Fourteen months old. Significant signal changes at both basal ganglia (white arrows) and thalami (black arrows with white frame) when he had took vigabatrin (133 mg/kg/d) for 1 month. (C) Three years old. Atrophy of both caudate nuclei and basal ganglia (white arrows) and diffuse hyperintensities over bilateral hemispheres with encephalomalacia changes. The vigabatrin dose was 90 mg/kg/d.
length 51 cm (50th to 75th percentile), and the head circumference was not documented. He passed the oto-acoustic emissions examination. A newborn metabolic screen was normal. There were no relatives with neurologic problems. His parents were both Taiwanese. Poor head control was noticed since the age of 3 months. He cannot roll over at the age of 6 months. Other abnormal findings included episodic involuntary tongue protruding, lower neck muscle tone, involuntary movements, and rigidity. The involuntary movements subsided when he was asleep. He smiled, had cooing voice, but less often looked around. Brain sonography at age 5 months showed prominent frontal horns of both lateral ventricles. On examination, the infant appeared no dysmorphic features. He was irritable with frequent crying, but he did not startle. The body weight was 8 kg (50th percentile), the body height 69 cm (75th to 90th percentile), and the head circumference 41 cm (3rd to10th percentile). There was increased muscle tone, with frequent arching, writhing, and stiffening, but no scissoring or fisting was noted. Head control was poor and tongue thrusting was noted. The anterior fontanel was small. Visual tracking was poor in all directions, without nystagmus. The pupils were reactive, and the funduscopic examination was normal. Plantar reflexes were flexion bilaterally, and the tendon reflexes were brisk but not hyperactive. There was no ankle clonus. This boy was admitted to our pediatric neurology ward at the age of 6 months to further evaluate his developmental delay with choreoathetosis. Urinalysis; complete blood count; levels of serum electrolytes, glucose, and calcium; venous gas analysis; and ammonia and creatine kinase levels were normal, as were tests of liver and renal function. Cerebrospinal fluid evaluations revealed 10 red cells and 2 white cells per cubic millimeter; the level of protein was 33.96 mg/dL and glucose 63 mg/dL. The cerebrospinal fluid neurotransmitters,
including homovanillic acid and 5-hydroxyindoleacetic acid levels, were within normal limits. Urine organic acid analysis revealed an elevated g-hydroxybutyric acid level. Mutation analysis for ALDH5A1 gene was done, which showed compound heterozygous mutations of c.289_309dup (maternal origin)/c.675_680del (paternal origin). Succinic semialdehyde dehydrogenase deficiency was thus diagnosed. EEG on admission revealed mild and diffuse cerebral dysfunction with focal epileptiform discharges over bilateral central areas. Brain MRI revealed focal areas of faintly increased signal intensity on T2-weighted images at both globus pallidi and putamen. MR spectroscopy revealed no remarkable changes of N-acetyl-aspartate/creatine and N-acetyl-aspartate/choline ratios. More diffuse abnormal T2-weighted signal intensities over bilateral basal ganglia and thalami were noted when he was 14 months old. Atrophy of both caudate nuclei and basal ganglia was noted at age 3 years (Figure 1). The patient had been admitted for several times because of pneumonia, urinary tract infection, and dyskinesia episodes. He is now 8 years old under home biphasic positive airway pressure support because of chronic left lung atelectasis and recurrent pneumonia, and he remains bed-ridden, with poor eye fixation and head control. Myoclonic and tonic-clonic seizures were currently controlled with vigabatrin, levetiracetam, oxcarbazepine, and clonazepam.
Discussion In our case, the clinical manifestations of global developmental delay, hypotonia, seizure, and choreoathetosis in combination with the typical MRI findings aroused our suspicion of succinic semialdehyde dehydrogenase deficiency. This is the first case of succinic semialdehyde dehydrogenase deficiency reported from Taiwan. Because of the heterogeneous presentations, multiple
Downloaded from jcn.sagepub.com at The University of Melbourne Libraries on October 14, 2014
Lin et al
3
genotypes and poor genotype-phenotype correlations, succinic semialdehyde dehydrogenase deficiency may be much underdiagnosed. Elevated urine g-hydroxybutyric acid level in gas chromatograph–mass spectrograph was the hallmark for succinic semialdehyde dehydrogenase deficiency, and repeated urine gas chromatographic–mass spectrographic analysis was recommended because of the possibility of pseudo-negative results. Confirmative test consisted of assay of succinic semialdehyde dehydrogenase enzymatic activity in leukocytes and molecular genetic testing of ALDH5A1. Quantitation of ghydroxybutyric acid in dried blood spots for newborn screening had been developed.10 Approximately 50 mutations of the ALDH5A1 gene related to succinic semialdehyde dehydrogenase deficiency were identified until 2012 without definite hotspots.11,12 The mutations in our case had not been reported and either listed in the Leiden open variation database (LOVD)13 and Exom variant server.14 The c.289_309 duplication in exon 1 (NM_170740.1) and c.675_680 deletion in exon 4 are located in the conserved sequence among mammals.15 As a consequence, these mutations are potential to affect succinic semialdehyde dehydrogenase enzymatic activity and resulted in the severe phenotype. A case of Greek origin was also reported to have disease-causing mutations c.278_298dup and c.1145C>T.9 However, no clinical data were available. Elevated succinic semialdehyde dehydrogenase enzymatic activity in the affected individuals was confirmed in cultured leukocytes and possibly made a negative impact on GABA metabolism.16 Succinic semialdehyde dehydrogenase enzymatic activity was not measured in our case, and the effect of both mutations on the enzyme activity was of interest. The pathophysiological mechanism of succinic semialdehyde dehydrogenase deficiency is still under investigation. Both GABA and g-hydroxybutyric acid play important roles. Disturbance in the redox-switch modulation and NADþ-binding of succinic semialdehyde dehydrogenase also contribute to the impairment of enzyme activity.11,17-19 Comparable with affected humans, the viable animal model of ALDH5A1–/– mice showed elevated GABA and g-hydroxybutyric acid level in the brain. Although in a hyperGABAergic status, the paradoxically represented seizure disorders such as absence seizures in humans and mice are both related to excessive g-hydroxybutyric acid– and GABAB-mediated activity; generalized convulsive seizures may be an effect of overusedependent down-regulation of GABAA and GABAB receptor activity,5,17 and the transition from absence seizure to generalized convulsive seizure could be analogous to human epileptic syndromes. Notably, no binding activity or number alteration was noted in g-hydroxybutyric acid receptor and it may be associated with the capacity of g-hydroxybutyric acid to freely traverse the blood-brain barrier.19 To date, no standard treatment was established. The seizures are usually controlled with drugs such as lamotrigine, levetiracetam, and topiramate.7 Vigabatrin is a reasonable therapeutic modality to decrease g-hydroxybutyric acid level through irreversible inhibition of GABA transaminase (GABA-T).
However, vigabatrin-related elevation of GABA levels in this already hyperGABAergic disorder is still concerned. Moreover, GABA-T existing in the periphery (liver, kidney and blood) has different kinetic characteristics from the neural enzyme, and the GABA-T in the periphery could be only partially inactivated by vigabatrin. Therefore, the observed decrease of g-hydroxybutyric acid is no more than the elevation of GABA level in succinic semialdehyde dehydrogenase– deficient patients under vigabatrin treatment.19 The transportation of g-hydroxybutyric acid through the blood-brain barrier could still result in the elevation of intracerebral g-hydroxybutyric acid level. Epileptic children under vigabatrin therapy were found to have transient MRI abnormalities characterized by new-onset and reversible T2-weighted hyperintensities and restricted diffusion in thalami, globus pallidus, dentate nuclei, brainstem, or corpus callosum. Young age and relative high dosage are the risk factors.21 In a retrospective case series of 22 patients, the hyperintensity was transient and maximal 3 to 6 months after the beginning of vigabatrin.22 In our case, the most prominent signal change after vigabatrin treatment was located in the bilateral thalami. However, the brain MRI (when he was 14 months old) was performed just 1 month after starting vigabatrin therapy. Even though the dose of vigabatrin at the time of MRI was high (133 mg/kg/d), the thalamic lesions in our case may still be secondary to vigabatrin toxicity or an unusual presentation of succinic semialdehyde dehydrogenase deficiency with novel mutations. Potential therapeutic modalities were recently reviewed, including L-cycloserine (GABA transaminase inhibitor), SGS-742 (GABAB receptor antagonist), ketogenic diet, NCS382 (g-hydroxybutyric acid receptor antagonist), taurine and other nutrient supplements, and cell-based or gene therapy.19 Both [11C]-flumazenil positron emission tomography (PET) and transcranial magnetic stimulation were performed as outcome measures in clinical trials of succinic semialdehyde dehydrogenase–deficient patients.5,18 In conclusion, succinic semialdehyde dehydrogenase deficiency should be considered in children with mental retardation, developmental delay, and dyskinesia. The therapeutic effect of vigabatrin in children with succinic semialdehyde dehydrogenase deficiency and epilepsy needs further studies, and vigabatrin-related MRI changes should be recognized during treatment. The novel compound heterozygous mutations might also result in the severe phenotype and MRI abnormalities. Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval Informed consent was taken from the parents for publication of the case report.
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References 1. Pearl PL, Gibson KM, Acosta MT, et al. Clinical spectrum of succinic semialdehyde dehydrogenase deficiency. Neurology. 2003;60:1413-1417. 2. Pearl PL, Novotny EJ, Acosta MT, Jakobs C, Gibson KM. Succinic semialdehyde dehydrogenase deficiency in children and adults. Ann Neurol. 2003;54(suppl 6):S73-S80. 3. Bosemani T, Anghelescu C, Boltshauser E, et al. Subthalamic nucleus involvement in children: a neuroimaging patternrecognition approach. Eur J Paediatr Neurol. 2013;pii:S10903798(13)00147-5. 4. Lee WT, Weng WC, Peng SF, Tzen KY. Neuroimaging findings in children with paediatric neurotransmitter diseases. J Inherit Metab Dis. 2009;32:361-370. 5. Pearl PL, Gibson KM, Quezado Z, et al. Decreased GABA-A binding on FMZ-PET in succinic semialdehyde dehydrogenase deficiency. Neurology. 2009;73:423-429. 6. Acosta MT, Munasinghe J, Pearl PL, et al. Cerebellar atrophy in human and murine succinic semialdehyde dehydrogenase deficiency. J Child Neurol. 2010;25:1457-1461. 7. Pearl PL, Shukla L, Theodore WH, Jakobs C, Michael Gibson K. Epilepsy in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism. Brain Dev. 2011;33:796-805. 8. Knerr I, Gibson KM, Murdoch G, et al. Neuropathology in succinic semialdehyde dehydrogenase deficiency. Pediatr Neurol. 2010;42:255-258. 9. Akaboshi S, Hogema BM, Novelletto A, et al. Mutational spectrum of the succinate semialdehyde dehydrogenase (ALDH5A1) gene and functional analysis of 27 novel disease-causing mutations in patients with SSADH deficiency. Hum Mutat. 2003;22: 442-450. 10. Forni S, Pearl PL, Gibson KM, Yu Y, Sweetman L. Quantitation of gamma-hydroxybutyric acid in dried blood spots: feasibility assessment for newborn screening of succinic semialdehyde dehydrogenase (SSADH) deficiency. Mol Genet Metab. 2013; 109:255-259. 11. Kim KJ, Pearl PL, Jensen K, et al. Succinic semialdehyde dehydrogenase: biochemical-molecular-clinical disease mechanisms,
12.
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redox regulation, and functional significance. Antioxid Redox Signal. 2011;15:691-718. Pu¨ttmann L, Stehr H, Garshasbi M, et al. A novel ALDH5A1 mutation is associated with succinic semialdehyde dehydrogenase deficiency and severe intellectual disability in an Iranian family. Am J Med Genet A. 2013;161A:1915-1922. Fokkema IF, Taschner PE, Schaafsma GC, et al. LOVD v.2.0: the next generation in gene variant databases. Hum Mutat. 2011;32: 557-563. Exome Variant Server, NHLBI. Exome Sequencing Project (ESP), Seattle, WA. [updated February 7, 2014]. Available at: http://evs.gs.washington.edu/EVS. Accessed February 20, 2014. Altschul SF, Madden TL, Scha¨ffer AA, et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997;25:3389-3402. Siggberg L, Mustonen A, Schuit R, et al. Familial 6p22.2 duplication associates with mild developmental delay and increased SSADH activity. Am J Med Genet B Neuropsychiatr Genet. 2011;156:448-445. Pearl PL, Gibson KM, Cortez MA, et al. Succinic semialdehyde dehydrogenase deficiency: lessons from mice and men. J Inherit Metab Dis. 2009;32:343-352. Reis J, Cohen LG, Pearl PL, et al. GABAB-ergic motor cortex dysfunction in SSADH deficiency. Neurology. 2012;79:47-54. Vogel KR, Pearl PL, Theodore WH, McCarter RC, Jakobs C, Gibson KM, Thirty years beyond discovery—clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism. J Inherit Metab Dis. 2013;36:401-410. Wheless JW, Carmant L, Bebin M, et al. Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy. Epilepsia. 2009;50:195-205. Pearl PL, Vezina LG, Saneto RP, et al. Cerebral MRI abnormalities associated with vigabatrin therapy. Epilepsia. 2009;50: 184-194. Milh M, Villeneuve N, Chapon F, et al. Transient brain magnetic resonance imaging hyperintensity in basal ganglia and brain stem of epileptic infants treated with vigabatrin. J Child Neurol. 2009; 24:305-315.
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A Novel Mutation of ALDH5A1 Gene Associated With Succinic Semialdehyde Dehydrogenase Deficiency Chun-Yen Lin, Wen-Chin Weng and Wang-Tso Lee J Child Neurol published online 22 September 2014 DOI: 10.1177/0883073814544365 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2014/09/17/0883073814544365
Published by: http://www.sagepublications.com
Additional services and information for Journal of Child Neurology can be found at: Email Alerts: http://jcn.sagepub.com/cgi/alerts Subscriptions: http://jcn.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Sep 22, 2014 What is This?
Downloaded from jcn.sagepub.com at The University of Melbourne Libraries on October 14, 2014
Brief Communication
A Novel Mutation of ALDH5A1 Gene Associated With Succinic Semialdehyde Dehydrogenase Deficiency
Journal of Child Neurology 1-4 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814544365 jcn.sagepub.com
Chun-Yen Lin, MD1, Wen-Chin Weng, MD1,2, and Wang-Tso Lee, MD, PhD1,2
Abstract Succinic semialdehyde dehydrogenase deficiency is a rare autosomal recessive metabolic disorder affecting g-aminobutyric acid degradation. We described a boy with a severe phenotype of succinic semialdehyde dehydrogenase deficiency and novel mutations of ALDH5A1 gene. He was referred because of developmental delay, focal seizures, and choreoathetosis at 6 months of age. The diagnosis of succinic semialdehyde dehydrogenase deficiency was confirmed by increased level of g-hydroxybutyric acid in urine and novel compound heterozygous mutations in the ALDH5A1 gene. His seizures were successfully controlled. However, the patient showed a slowly progressive clinical course with severe neurologic deficits. A magnetic resonance imaging (MRI) revealed abnormal high intensities in the putamen and globus pallidi on T2-weighted images when he was 6 months old, and more diffuse abnormal signal intensities over bilateral hemispheres were noted when he was 3 years old. Keywords succinic semialdehyde dehydrogenase deficiency, psychomotor retardation, dyskinesia Received March 30, 2014. Received revised June 04, 2014. Accepted for publication July 01, 2014.
Succinic semialdehyde dehydrogenase deficiency (or g-hydroxybutyric aciduria, OMIM 271980; aldehyde dehydrogenase 5A1, ALDH5A1, OMIM 610045) is an autosomal recessively inherited defect in the degradation pathway of g-hydroxybutyric acid (GHB). The absence of succinic semialdehyde dehydrogenase activity will lead to the accumulation of both g-aminobutyric acid (GABA) and g-hydroxybutyric acid in physiological fluids. Succinic semialdehyde dehydrogenase deficiency is a slowly progressive or static encephalopathy with late infantile to early childhood onset, presenting with heterogenic clinical manifestations, such as developmental delay, mental retardation, ataxia, and behavioral problems, etc. Basal ganglia signs such as choreoathetosis, dystonia, and myoclonus have been reported.1-3 Magnetic resonance imaging (MRI) studies usually show symmetric involvement of globus pallidi, dentate nuclei, and occasionally the subthalamic nucleus (pallidodentatoluysian pattern).3-6 Seizures presented in half of patients, and electroencephalography (EEG) shows generalized spike-waves, photosensitivity, background slowing, and sleep spindle asynchrony.1,7-9 Succinic semialdehyde dehydrogenase deficiency has been reported in approximately 450 people until 2011.7 Parental consanguinity has been reported in approximately 40% of all published cases, but no genotype-phenotype correlations have been observed, and there is also no correlation between g-hydroxybutyric acid levels in physiological fluids and the severity of the disease.9
We describe here a first-reported Taiwanese boy with succinic semialdehyde dehydrogenase deficiency who had novel compound heterozygous mutations with deletion and insertion of ALDH5A1 gene. The severe phenotype consisted of global developmental delay and choreoathetosis, and novel neuroimaging abnormalities.
Case Report A 6-month-old boy was seen in the pediatric neurology clinic because of developmental delay and involuntary movements. The patient was born at gestational age of 39 weeks by elective cesarean section to a 36-year-old multigravid mother. His mother received regular perinatal examination with normal results. During the pregnancy, no illicit drug use or substance abuse was reported. Consanguinity was not reported. The labor was smooth without obvious perinatal insults. The birth weight was 2.8 kg (15th to 50th percentile), the body 1 2
Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan Clinical Center of Neuroscience and Behavior, National Taiwan University Hospital, Taipei, Taiwan
Corresponding Author: Wang-Tso Lee, MD, Phd, Department of Pediatrics, National Taiwan University Hospital, 8, Chung-Shan South Road, Taipei 100, Taiwan. Email: [email protected]
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Figure 1. T2-weighted images in the patient with succinic semialdehyde dehydrogenase deficiency. (A) Six months old. Focal signal changes at both globus pallidi and putamen (white arrows) when he did not take vigabatrin. (B) Fourteen months old. Significant signal changes at both basal ganglia (white arrows) and thalami (black arrows with white frame) when he had took vigabatrin (133 mg/kg/d) for 1 month. (C) Three years old. Atrophy of both caudate nuclei and basal ganglia (white arrows) and diffuse hyperintensities over bilateral hemispheres with encephalomalacia changes. The vigabatrin dose was 90 mg/kg/d.
length 51 cm (50th to 75th percentile), and the head circumference was not documented. He passed the oto-acoustic emissions examination. A newborn metabolic screen was normal. There were no relatives with neurologic problems. His parents were both Taiwanese. Poor head control was noticed since the age of 3 months. He cannot roll over at the age of 6 months. Other abnormal findings included episodic involuntary tongue protruding, lower neck muscle tone, involuntary movements, and rigidity. The involuntary movements subsided when he was asleep. He smiled, had cooing voice, but less often looked around. Brain sonography at age 5 months showed prominent frontal horns of both lateral ventricles. On examination, the infant appeared no dysmorphic features. He was irritable with frequent crying, but he did not startle. The body weight was 8 kg (50th percentile), the body height 69 cm (75th to 90th percentile), and the head circumference 41 cm (3rd to10th percentile). There was increased muscle tone, with frequent arching, writhing, and stiffening, but no scissoring or fisting was noted. Head control was poor and tongue thrusting was noted. The anterior fontanel was small. Visual tracking was poor in all directions, without nystagmus. The pupils were reactive, and the funduscopic examination was normal. Plantar reflexes were flexion bilaterally, and the tendon reflexes were brisk but not hyperactive. There was no ankle clonus. This boy was admitted to our pediatric neurology ward at the age of 6 months to further evaluate his developmental delay with choreoathetosis. Urinalysis; complete blood count; levels of serum electrolytes, glucose, and calcium; venous gas analysis; and ammonia and creatine kinase levels were normal, as were tests of liver and renal function. Cerebrospinal fluid evaluations revealed 10 red cells and 2 white cells per cubic millimeter; the level of protein was 33.96 mg/dL and glucose 63 mg/dL. The cerebrospinal fluid neurotransmitters,
including homovanillic acid and 5-hydroxyindoleacetic acid levels, were within normal limits. Urine organic acid analysis revealed an elevated g-hydroxybutyric acid level. Mutation analysis for ALDH5A1 gene was done, which showed compound heterozygous mutations of c.289_309dup (maternal origin)/c.675_680del (paternal origin). Succinic semialdehyde dehydrogenase deficiency was thus diagnosed. EEG on admission revealed mild and diffuse cerebral dysfunction with focal epileptiform discharges over bilateral central areas. Brain MRI revealed focal areas of faintly increased signal intensity on T2-weighted images at both globus pallidi and putamen. MR spectroscopy revealed no remarkable changes of N-acetyl-aspartate/creatine and N-acetyl-aspartate/choline ratios. More diffuse abnormal T2-weighted signal intensities over bilateral basal ganglia and thalami were noted when he was 14 months old. Atrophy of both caudate nuclei and basal ganglia was noted at age 3 years (Figure 1). The patient had been admitted for several times because of pneumonia, urinary tract infection, and dyskinesia episodes. He is now 8 years old under home biphasic positive airway pressure support because of chronic left lung atelectasis and recurrent pneumonia, and he remains bed-ridden, with poor eye fixation and head control. Myoclonic and tonic-clonic seizures were currently controlled with vigabatrin, levetiracetam, oxcarbazepine, and clonazepam.
Discussion In our case, the clinical manifestations of global developmental delay, hypotonia, seizure, and choreoathetosis in combination with the typical MRI findings aroused our suspicion of succinic semialdehyde dehydrogenase deficiency. This is the first case of succinic semialdehyde dehydrogenase deficiency reported from Taiwan. Because of the heterogeneous presentations, multiple
Downloaded from jcn.sagepub.com at The University of Melbourne Libraries on October 14, 2014
Lin et al
3
genotypes and poor genotype-phenotype correlations, succinic semialdehyde dehydrogenase deficiency may be much underdiagnosed. Elevated urine g-hydroxybutyric acid level in gas chromatograph–mass spectrograph was the hallmark for succinic semialdehyde dehydrogenase deficiency, and repeated urine gas chromatographic–mass spectrographic analysis was recommended because of the possibility of pseudo-negative results. Confirmative test consisted of assay of succinic semialdehyde dehydrogenase enzymatic activity in leukocytes and molecular genetic testing of ALDH5A1. Quantitation of ghydroxybutyric acid in dried blood spots for newborn screening had been developed.10 Approximately 50 mutations of the ALDH5A1 gene related to succinic semialdehyde dehydrogenase deficiency were identified until 2012 without definite hotspots.11,12 The mutations in our case had not been reported and either listed in the Leiden open variation database (LOVD)13 and Exom variant server.14 The c.289_309 duplication in exon 1 (NM_170740.1) and c.675_680 deletion in exon 4 are located in the conserved sequence among mammals.15 As a consequence, these mutations are potential to affect succinic semialdehyde dehydrogenase enzymatic activity and resulted in the severe phenotype. A case of Greek origin was also reported to have disease-causing mutations c.278_298dup and c.1145C>T.9 However, no clinical data were available. Elevated succinic semialdehyde dehydrogenase enzymatic activity in the affected individuals was confirmed in cultured leukocytes and possibly made a negative impact on GABA metabolism.16 Succinic semialdehyde dehydrogenase enzymatic activity was not measured in our case, and the effect of both mutations on the enzyme activity was of interest. The pathophysiological mechanism of succinic semialdehyde dehydrogenase deficiency is still under investigation. Both GABA and g-hydroxybutyric acid play important roles. Disturbance in the redox-switch modulation and NADþ-binding of succinic semialdehyde dehydrogenase also contribute to the impairment of enzyme activity.11,17-19 Comparable with affected humans, the viable animal model of ALDH5A1–/– mice showed elevated GABA and g-hydroxybutyric acid level in the brain. Although in a hyperGABAergic status, the paradoxically represented seizure disorders such as absence seizures in humans and mice are both related to excessive g-hydroxybutyric acid– and GABAB-mediated activity; generalized convulsive seizures may be an effect of overusedependent down-regulation of GABAA and GABAB receptor activity,5,17 and the transition from absence seizure to generalized convulsive seizure could be analogous to human epileptic syndromes. Notably, no binding activity or number alteration was noted in g-hydroxybutyric acid receptor and it may be associated with the capacity of g-hydroxybutyric acid to freely traverse the blood-brain barrier.19 To date, no standard treatment was established. The seizures are usually controlled with drugs such as lamotrigine, levetiracetam, and topiramate.7 Vigabatrin is a reasonable therapeutic modality to decrease g-hydroxybutyric acid level through irreversible inhibition of GABA transaminase (GABA-T).
However, vigabatrin-related elevation of GABA levels in this already hyperGABAergic disorder is still concerned. Moreover, GABA-T existing in the periphery (liver, kidney and blood) has different kinetic characteristics from the neural enzyme, and the GABA-T in the periphery could be only partially inactivated by vigabatrin. Therefore, the observed decrease of g-hydroxybutyric acid is no more than the elevation of GABA level in succinic semialdehyde dehydrogenase– deficient patients under vigabatrin treatment.19 The transportation of g-hydroxybutyric acid through the blood-brain barrier could still result in the elevation of intracerebral g-hydroxybutyric acid level. Epileptic children under vigabatrin therapy were found to have transient MRI abnormalities characterized by new-onset and reversible T2-weighted hyperintensities and restricted diffusion in thalami, globus pallidus, dentate nuclei, brainstem, or corpus callosum. Young age and relative high dosage are the risk factors.21 In a retrospective case series of 22 patients, the hyperintensity was transient and maximal 3 to 6 months after the beginning of vigabatrin.22 In our case, the most prominent signal change after vigabatrin treatment was located in the bilateral thalami. However, the brain MRI (when he was 14 months old) was performed just 1 month after starting vigabatrin therapy. Even though the dose of vigabatrin at the time of MRI was high (133 mg/kg/d), the thalamic lesions in our case may still be secondary to vigabatrin toxicity or an unusual presentation of succinic semialdehyde dehydrogenase deficiency with novel mutations. Potential therapeutic modalities were recently reviewed, including L-cycloserine (GABA transaminase inhibitor), SGS-742 (GABAB receptor antagonist), ketogenic diet, NCS382 (g-hydroxybutyric acid receptor antagonist), taurine and other nutrient supplements, and cell-based or gene therapy.19 Both [11C]-flumazenil positron emission tomography (PET) and transcranial magnetic stimulation were performed as outcome measures in clinical trials of succinic semialdehyde dehydrogenase–deficient patients.5,18 In conclusion, succinic semialdehyde dehydrogenase deficiency should be considered in children with mental retardation, developmental delay, and dyskinesia. The therapeutic effect of vigabatrin in children with succinic semialdehyde dehydrogenase deficiency and epilepsy needs further studies, and vigabatrin-related MRI changes should be recognized during treatment. The novel compound heterozygous mutations might also result in the severe phenotype and MRI abnormalities. Declaration of Conflicting Interests The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The authors received no financial support for the research, authorship, and/or publication of this article.
Ethical Approval Informed consent was taken from the parents for publication of the case report.
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Journal of Child Neurology
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