Acute Infantile Encephalopathy as Presentation of Succinic Semialdehyde Dehydrogenase Deficiency

Acute Infantile Encephalopathy as Presentation of Succinic Semialdehyde Dehydrogenase Deficiency

Accepted Manuscript Acute Infantile Encephalopathy as Presentation of Succinic Semialdehyde Dehydrogenase Deficiency William A. Zeiger, MD, PhD, Lisa ...

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Accepted Manuscript Acute Infantile Encephalopathy as Presentation of Succinic Semialdehyde Dehydrogenase Deficiency William A. Zeiger, MD, PhD, Lisa R. Sun, MD, Thangamadhan Bosemani, MBBS, Phillip L. Pearl, MD, Carl E. Stafstrom, MD, PhD PII:

S0887-8994(15)30034-5

DOI:

10.1016/j.pediatrneurol.2015.10.009

Reference:

PNU 8768

To appear in:

Pediatric Neurology

Received Date: 5 July 2015 Revised Date:

21 October 2015

Accepted Date: 21 October 2015

Please cite this article as: Zeiger WA, Sun LR, Bosemani T, Pearl PL, Stafstrom CE, Acute Infantile Encephalopathy as Presentation of Succinic Semialdehyde Dehydrogenase Deficiency, Pediatric Neurology (2015), doi: 10.1016/j.pediatrneurol.2015.10.009. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Revised Final 10/5/15

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Acute Infantile Encephalopathy as Presentation of Succinic Semialdehyde Dehydrogenase Deficiency Running title: Acute onset of SSADHD

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William A. Zeiger*a MD, PhD, Lisa R. Sun*b MD, Thangamadhan Bosemanic MBBS, Phillip L. Pearl MDd, Carl E. Stafstromb MD, PhD a Department of Neurology, Johns Hopkins Hospital, Baltimore, Maryland b Division of Pediatric Neurology, Johns Hopkins Hospital, Baltimore, Maryland c Section of Pediatric Neuroradiology, Johns Hopkins Hospital, Baltimore, Maryland d Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts E-mail Addresses: [email protected], [email protected], [email protected], [email protected], [email protected]

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Corresponding Author: Carl E. Stafstrom MD, PhD Division of Pediatric Neurology Johns Hopkins Hospital Rubenstein Building 2157 200 N Wolfe St Baltimore, MD 21287 Phone: 410-955-4259

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* These authors contributed equally responsible to the work described in this paper. Word Count: 1287

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Abstract Background: Succinic semialdehyde dehydrogenase deficiency is a rare neurologic disorder resulting from impaired gamma-amino butyric acid metabolism. The syndrome typically presents as a static encephalopathy with developmental delays, hypotonia, and seizures.

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Methods: A 6-month-old previously healthy girl developed acute choreoathetosis and severe hypotonia in the setting of influenza A infection. In our database of 112 patients with succinic semialdehyde dehydrogenase deficiency, one additional patient was identified who presented with an acute illness (encephalopathy associated with bronchiolitis at 5 months of age).

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Results: Urine organic acid and cerebrospinal fluid analyses confirmed elevated 4hydroxybutyric acid in both cases, verified by enzymatic quantification in lymphocytes in the second patient. Brain magnetic resonance imaging scans in both cases showed bilateral symmetric T2 hyperintensities of globus pallidi. The lesions demonstrated restricted diffusion, consistent with acute symptom onset.

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Conclusions: In contrast to most organic acidopathies, succinic semialdehyde dehydrogenase deficiency typically presents with nonprogressive global developmental delays. Here we report that succinic semialdehyde dehydrogenase deficiency can present fulminantly in the setting of febrile illness as well as in the more common statis fashion, thereby broadening the spectrum of onset patterns in this disorder.

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Keywords: succinic semialdehyde dehydrogenase deficiency (SSADHD); gamma-amino butyric acid (GABA); ALDH5A1; gamma-hydroxybutyric acid (GHB); chorea; hypotonia

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Introduction

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Succinic semialdehyde dehydrogenase deficiency (SSADHD; OMIM#271980) is a rare neurologic disorder resulting from a defect in gamma-amino butyric acid (GABA) metabolism. SSADHD was first characterized in a child with developmental delay, hypotonia, ataxia, and elevated urinary gamma-hydroxybutyric acid (GHB) and succinic semialdehyde (1). Hundreds of similarly affected children have since been identified with the same biochemical alterations in GABA metabolism. Mutations in the ALDH5A1 gene dramatically reduce SSADH activity (2), leading to an accumulation of succinic semialdehyde, which is then metabolized to GHB (3). Individuals with SSADHD present with symptoms of widely varying severity; the diagnosis has been made as early as infancy and as late as adulthood, with a mean age of symptom onset of about 1year. Manifesting signs typically include gradually worsening development delay and hypotonia, behavioral disturbances, ataxia, and seizures (4). Approximately 10% of cases have early extrapyramidal manifestations (5).

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Diagnosis is facilitated by clinical history, urine organic acid analysis, and CSF testing for GHB and GABA, with confirmation via enzymatic quantification in lymphocytes or sequencing of the ALDH5A1 gene (6). Metabolite screening for the biomarker GHB is feasible (7). Characteristic MRI findings include bilateral symmetric T2 hyperintensities of globus pallidi, subthalamic nuclei, cerebellar dentate nuclei, and subcortical white matter (8). There is no specific therapy other than supportive management.

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The index case is a 6-month-old previously healthy girl who developed acute hypotonia and choreoathetosis. She presented with two days of fussiness, lethargy, poor head control, and abnormal movements. Pregnancy was uncomplicated; delivery at term was uneventful. She had appropriate growth and typical development. The child was in her usual state of health except for a transient fever (38.0ºC) the previous week that resolved with acetaminophen. Four days later, she became irritable with decreased oral intake, loss of head control, flailing extremity movements, tongue thrusting, and decreased arousability. Physical examination revealed a nondysmorphic, inconsolable, hypotonic infant with constant, asynchronous, large amplitude choreoathetosis of all extremities. Weight was 7.1 kg (38th percentile) and head circumference was 44.5 cm (95th percentile). Blood glucose, electrolytes, urinalysis, and urine toxicology were normal. She tested positive for influenza A and was treated with oseltamivir. Brain MRI scan revealed bilateral symmetric T2 hyperintensities of the globus pallidi and subthalamic nuclei (Fig. 1). An additional focus of T2 hyperintensity was seen in the subcortical white matter of the right parietal lobe. All of these lesions demonstrated diffusion restriction. Single voxel proton MR spectroscopy of the left frontal lobe and left thalamus (areas without T2 hyperintensity) 3

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showed prominent signal intensity in the ‘Glx’ region, consistent with increased levels of GABA and GHB (Fig 2). Urine organic acid analysis detected markedly increased levels of GHB, erythro- and threo-4,5-dihydroxyhexanoic lactones, 3,4-dihydroxybutanoic acid, 3-hydroxy-hex4-enoic acid, and 5-hydroxy-hex-2-enoic acid. Concordantly, CSF GHB was increased at 538.15 µmol/L (reference < 3). The diagnosis of SSADHD was made. The child’s clinical status improved gradually. At follow up 2 months later, there was mild residual choreoathetosis but persistent hypotonia, decreased head control, and impaired fine motor coordination. The child has a sister, now 12 years old, who presented at age 4 years with developmental delays, autistic behaviors and seizures, and was diagnosed with SSADHD; another sister and a brother have normal development.

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The unusual presentation of the index case led to a review of our database of 112 confirmed SSADHD patients for other instances of this atypical presentation. The database is a registry that includes age of presentation and diagnosis, symptoms and developmental status at presentation and at periodic follow-ups, and results of laboratory, imaging, and neurophysiologic testing. The database is maintained at Boston Children’s Hospital, whose Institutional Review Board approved this study.

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Patients in the SSADHD database ranged from 1.7 to 63years (mean 17 years, median 14.9 years). Mean ages at symptom onset and diagnosis were 1.1 years (median 6 months) and 4.3 years (median 2.5 years), respectively. An additional patient was identified who was diagnosed with SSADHD following an acute febrile illness associated with bronchiolitis. This child presented at 5 months of age with fever, tachypnea, acute hypotonia, and coma. Brain MRI showed bilateral symmetric pallidal hyperintensities; urine organic acids revealed increased excretion of 4-hydroxybutyric acid. SSADHD was confirmed by demonstration of negligible enzymatic activity in extracted lymphocytes. The remainder of patients in the database presented with a static neurodevelopmental disorder characterized by delayed acquisition of motor and language developmental milestones, hypotonia, nonprogressive ataxia including fine motor incoordination, and hyporeflexia. Discussion

An acute, fulminant presentation with encephalopathy and an extrapyramidal syndrome characterizes some organic acidopathies but is distinctly unusual in SSADHD. Prominent dyskinetic and extrapyramidal features, including chorea, athetosis, dystonia, and myoclonus, have been noted in a small number of SSADHD patients (approximately 10%) (5). Rahbeeni et al (9) reported movement disorders in 5 patients from 3 families, with one patient presenting at 4 days old with subcortical myoclonus, myoclonic seizures, and severe hypotonia. The other patients presented with developmental delays between 13 months and 12 years. Our database confirms that the typical presentation is developmental delay with hypotonia. MRI scans of the 4

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presently reported cases demonstrate restricted diffusion corresponding to the T2 hyperintense lesions, suggesting an acute to sub-acute time frame for the onset of injury. Other disorders in which symmetric deep gray matter lesions may be seen include Leigh syndrome, glutaric aciduria, proprionic academia, Wilson disease, and mitochondrial encephalomyopathy lactic acid and stroke-like episodes; the presentations of the patients reported here are not consistent with those disorders.

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The pathogenesis of acute symptoms in metabolic encephalopathies may be related to accumulation of toxic intermediates or energy failure in the setting of a systemic crisis (10). SSADHD has been described as lacking these intermittent episodic exacerbations (3). In the murine model (Aldh5a1-/-), total deficiency of SSADH results in early fatality preceded by status epilepticus (7). Rescue and prolonged survival was achieved with the amino acid taurine, as well as experimental GABA(B) and GHB receptor antagonists (11). These findings led to a clinical trial of taurine in SSADHD, which did not show benefit on primary outcome measures (12). A clinical trial of the experimental GABA(B) receptor antagonist SGS-742 is in progress. The diversity of human phenotypes in SSADHD suggests that additional mechanisms determine symptom onset. Recent studies have demonstrated GABA-dependent impairments in mitochondrial degradation and elevated reactive oxygen species in the brains of SSADHdeficient mice, implicating oxidative stress as well as defects in autophagy, mediated by dysregulation of the mTOR pathway (13-14). Intriguingly, our index patient presented with acute symptoms in the context of influenza A infection. RNA viruses, including influenza, are known to induce oxidative stress and impaired homeostasis (15). We speculate that influenza A induced a state of metabolic or oxidative stress that triggered the initial manifestations of SSADHD.

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Our cases expand the spectrum of SSADHD presentations to include acute as well as slowly progressive onset. Therefore, SSADHD, like many other metabolic disorders, can present acutely in the setting of intercurrent illness. It is also noteworthy that SSADHD presented acutely in our index patient and gradually in her older sister, suggesting that within the same family, there can be different phenotypes with regard to disease onset.

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References

6.

7.

8.

9. 10. 11. 12. 13.

14.

15.

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Jakobs C, Bojasch M, Monch E, et al. Urinary excretion of gamma-hydroxybutyric acid in a patient with neurological abnormalities. The probability of a new inborn error of metabolism. Clin Chim Acta 1981;111:169-178. 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;22:442450. Kim KJ, Pearl PL, Jensen K, et al. Succinic semialdehyde dehydrogenase: biochemicalmolecular-clinical disease mechanisms, redox regulation, and functional significance. Antioxid Redox Signal 2011;15:691-718. Parviz M, VogelK, Gibson KM, Pearl PL. Disorders of GABA metabolism: SSADH and GABA-transaminase deficiencies. J Pediatr Epilepsy 2014;3: 217-227. Pearl PL, Acosta MT, Wallis DD, et al. Dyskinetic features of succinate semialdehyde dehydrogenase deficiency, a GABA degradative defect. In: Paediatric Movement Disorders: Progress in Understanding. Fernandez-Alvarez E, Arzimanoglu A, Tolosa E (eds). John Libbey Eurotext, 2005:203-212. Pearl PL, Parviz M, Vogel K, et al. Inherited Disorders of Gamma-aminobutyric acid metabolism and advances in ALDH5A1 mutation identification. Dev Med Child Neurol 2015;57(7):611-617. doi: 10.1111/dmcn.12668. Forni S, Pearl PL, Gibson KM, et al. Quantification of gamma-hydroxybutyric acid in dried blood spots: Feasibility assessment for newborn screening of succinic semialdehyde dehydrogenase (SSADH) deficiency. Mol Genet Metab 2013;109(3):255-259. Bosemani T, Anghelescu C, Boltshauser E, et al. Subthalamic nucleus involvement in children: a neuroimaging pattern-recognition approach. Eur J Paediatr Neurol 2014;18:249-256. Rahbeeni Z, Ozand PT, Rashed M, et al. 4-Hydroxybutyric aciduria. Brain Dev 1994; 16 (suppl):64-71. Kolker S, Sauer SW, Hoffmann GF, et al. Pathogenesis of CNS involvement in disorders of amino and organic acid metabolism. J Inherit Metab Dis 2008;31:194-204. Hogema BM, Gupta M, Senephansiri H, et al. Pharmacologic rescue of lethal seizures in mice deficient in succinate semialdehyde dehydrogenase. Nat Genet 2001;29:212-216. Pearl PL, Schreiber J, Theodore WH, et al. Taurine trial in succinic semialdehyde dehydrogenase deficiency and elevated CNS GABA. Neurology 2014;82:940-944. Lakhani R, Vogel KR, Till A, et al. Defects in GABA metabolism affect selective autophagy pathways and are alleviated by mTOR inhibition. EMBO Mol Med 2014;6:551-566. Sauer SW, Kolker S, Hoffmann GF, et al. Enzymatic and metabolic evidence for a region specific mitochondrial dysfunction in brains of murine succinic semialdehyde dehydrogenase deficiency (Aldh5a1-/- mice). Neurochem Int 2007;50:653-659. Reshi ML, Su YC, Hong JR. RNA viruses: ROS-mediated cell death. Int J Cell Biol 2014: 467452.

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Funding: None. Conflicting interests: None. Details of contribution of each author: WZ, LS, PP, and CS conceived and designed the study, collated information, and drafted the article. TB interpreted the neuroradiological studies. All authors revised the manuscript critically and approved the final version.

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FIGURE LEGENDS

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Figure 1 Axial trace of diffusion map (A) demonstrates diffusion restriction in the bilateral globus pallidi. (B) Coronal reformat of axial trace shows diffusion restriction in bilateral globus pallidi (arrows) and subthalamic nuclei (arrowheads). (C) Axial T2-weighted image demonstrates hyperintensity in bilateral globus pallidi (arrows).

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Figure 2 Proton MR spectroscopy (1H-MRS) spectra of right frontal white matter demonstrates prominent signal between 2.2 and 2.4 ppm (arrow) corresponding to the glx peak, including GABA and 4hydroxybutyrate (GHB).

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