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Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients
Brain & Development xxx (2019) xxx–xxx www.elsevier.com/locate/braindev
Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients Indar Kumar Sharawat a, Lokesh Saini b,⇑, Bhanudeep Singanamala b Arushi Gahlot Saini b, Jitendra Kumar Sahu b, Savita Verma Attri c, Naveen Sankhyan b a Pediatric Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, Rishikesh, Uttarakhand 249201, India Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India c Pediatric Biochemistry Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India b
Received 27 September 2019; received in revised form 25 October 2019; accepted 18 November 2019
Abstract Background: Isolated sulfite oxidase deficiency (ISOD) is a rare autosomal recessively inherited inborn error of metabolism, caused by mutation in SUOX gene. ISOD has two kind of presentation; early and late-onset. The late-onset form is extremely rare and only 10 cases have been reported. Methods: We report two new cases of late-onset ISOD with biochemical and genetic confirmation. We did a review of the previously published cases of late-onset ISOD. Results: Together with the presented two cases, 12 cases were available for analysis. The median age at symptom onset and at diagnosis was 8.5 and 23 months respectively. Almost all children had acute regression of milestones followed by slow recovery. The common presenting signs and symptoms were movement disorders, seizures, ectopia lentis and hypertonia. Five children had antecedent events. Trivial trauma precipitating the metabolic crisis was unique to the two cases we report. The most common MRI feature was globus pallidi changes followed by cerebellar white matter changes, vermian hypoplasia and thinned out corpus callosum. Diffusion weighted sequence was performed in 3 children and all had diffusion restriction in the affected area. Conclusion: Trivial trauma can precipitate metabolic crisis in late-onset ISOD. Low plasma homocysteine and involvement of globus pallidi with diffusion restriction on the MRI are important diagnostic clues. Early diagnosis and intervention with special diet may be effective in preventing long term neurodisability. Ó 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Isolated sulfite oxidase deficiency; Metabolic crisis; Trivial trauma; Diffusion restriction; Molybdenum cofactor deficiency; Late-onset
1. Introduction
⇑ Corresponding author at: Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India. E-mail address: [email protected] (L. Saini).
Sulfite oxidase deficiency is a rare autosomal recessively inherited inborn error of metabolism. Sulfite oxidase a mitochondrial enzyme, encoded by the SUOX gene and it is responsible for the oxidative degradation of potentially toxic sulfites to relatively non-toxic sulfates in the metabolic pathway of sulfur-containing
https://doi.org/10.1016/j.braindev.2019.11.003 0387-7604/Ó 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003
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amino acids [1,2]. It can occur as an isolated enzyme defect (ISOD, OMIM 272300) due to mutations of the SUOX gene or as a part of deficiency of group of enzymes that share the common molybdenum-pterin co-factor (OMIM 252150) [3]. The molybdenum cofactor is essential for the function of three enzymes namely xanthine oxidase, sulfite oxidase and aldehyde oxidase. Both of these defects have similar clinical manifestations and two types of manifestations, early and late. The early onset type presents in early infancy with intractable seizures, axial hypotonia, limb hypertonicity, dislocation of lens and severe psychomotor delay mimicking hypoxic-ischemic encephalopathy. Biochemically, an increased urinary excretion of sulphate, thiosulphate, taurine and S-sulphocysteine and low plasma cysteine and total homocysteine are detectable. The late onset form is extremely rare and may lack suggestive symptoms and may present with predominant dystonia, seizures and developmental regression [4]. The biochemical finding of low plasma uric acid, and high urine xanthine and hypoxanthine are found in molybdenum cofactor deficiency, while normal plasma uric acid, urine xanthine, and hypoxanthine levels are seen in isolated sulfite oxidase deficiency (ISOD). Elevated urinary levels of S-sulfocysteine, thiosulfate, sulfite and taurine with nearly undetectable levels of plasma total homocysteine and cystine are the biochemical hallmarks of isolated form [5,6]. In addition, urinary urothione, a breakdown product of the molybdenum cofactor, is absent in molybdenum cofactor deficiency but present in ISOD [7]. Here we present two genetically proven cases of lateonset ISOD and a review of the previously published cases of late-onset ISOD. Institutional Ethical Committee’s approval and the Informed Consent taken from the guardians of both the patients. 2. Case presentation 2.1. Case: 1 A 10-month-old boy presented with acute onset loss of the milestones for the past one month. He had developed normally till 9-months of age and was able to sit without support, crawl, speak monosyllable words and had stranger anxiety. At nine months of age, he had an accidental fall from the bed (2 feet height) and developed 3 episodes of vacant staring, lasting for 3–5 min over a period of 40 min without gaining consciousness in between. Thereafter, he was observed to have lost head control, he stopped visual fixation and following and was no longer to recognized mother. There was a history of intermittent twisting of limbs which was more during crying. There was no prior history of regression, recurrent fever, rash, vomiting, or any abnormal body odor. He was the first born to a non-consanguineous
couple and had an uncomplicated perinatal period. There was no family history of similar illness or any other neurological disorders. On examination, he had normal head circumference (44.5 cm), intermittent generalized dystonia, choreic movements of limbs, hypotonia, and exaggerated muscle stretch reflexes. On ophthalmic assessment, the fundii and lens were normal. Investigations revealed normal blood counts, electrolytes, blood sugar, blood pH, lactate, ammonia, vitamin B12, and creatine kinase levels. Urinary sulfites were positive by dipstick. His urinary S-sulfocysteine (142.5 mM/mM creatine; normal: 0.28–18.8 mM/mM creatine) and taurine (271. 5 mM/mM creatine; normal 8–150 mM/mM creatine) levels were markedly elevated along with normal urinary excretion of xanthines, hypoxanthine, and uric acid. His plasma homocysteine (0.6 mmol/L; normal: 3.3–11.3 mmol/L) and cystine levels (0.4 mM/mM creatine; normal: 4–15 mM/mM creatine) were decreased and uric acid level (3.6 mg/dL; normal: 3.4–7 mg/dL) was normal. The magnetic resonance imaging (MRI) of the brain (Fig. 1) showed symmetrical T2-weighted hyperintense signal changes in bilateral globus pallidi and dentate nuclei of the cerebellum with diffusion restriction. A next-generation sequencing showed a novel homozygous, missense variation in exon 6 of the SUOX gene (c.1382A > T/p.As p461Val) confirming the diagnosis of late-onset sulphite oxidase deficiency. Both the parents were carriers for the same variation on SANGER sequencing. The pathogenicity of variant was confirmed by in silico (PolyPhen-2) prediction. Parents were counseled about the nature of the disease and offered prenatal diagnosis. The infant was treated with antiepileptics, low protein diet, antidystonic medications, and other supportive management. On last follow up, he was 16 months old and had gained a few milestones. He had residual axial and appendicular hypotonia and was able to sit with support, visually fixate and follow, identify family members and able to speak 1 to 2 words. 2.2. Case: 2 A 24-month old boy, born to non-consanguineous parents, presented with acute-onset loss of milestones for the past 20 days. Prior to the illness, he was able to run, stands on tiptoes, kick a ball, knew the names of familiar people, was able to combine 2 to 3-words in to a sentence, and follow two-step instructions. Twenty days prior, he had a fall (about from 3-feet height) while playing and a trivial head contact. Soon, he had an episode of generalized tonic seizures which was lasted for 10 min and the child slept after the episode. He woke up after 2 h and was observed to have no head control or ability to sit. He cried but was unable to speak anything, nor could he recognize his parents
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003
I.K. Sharawat et al. / Brain & Development xxx (2019) xxx–xxx
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Fig. 1. Magnetic resonance images of the brain of case-1. T2-weighted (a) and fluid attenuated inversion recovery (b) axial section showing symmetrical hyperintense signal changes in bilateral globus pallidi (arrow). Diffusion weighted (c, e) axial sequences and corresponding apparent diffusion coefficient (ADC) map (d, f) showed intense diffusion restriction in bilateral globus pallidi and dentate nuclei of the cerebellum.
and was unable to communicate needs. There was no significant past history. There was no history of fever, vomiting, abnormal body odor, rash and bleeding from any site. The family history was unremarkable. On, examination, he had normocephaly (47.8 cm), normal fundii, inability to sit or roll over, absence of meaningful vocalization, intermittent appendicular and axial dystonia, and generalized hypotonia. On investigations, blood gases, electrolytes, serum uric acid, ammonia, lactate and vitamin B12 levels were normal. The cerebrospinal cell count and biochemistry were normal. Urinary sulfites were positive by dipstick. The urinary S-sulfocysteine (178.3 mM/mM creatine; normal: 0.28–18.8 mM/mM creatine) and taurine (192. 5 mM/mM creatine; normal 8–150 mM/mM creatine) levels were elevated. The urinary excretion of xanthines, hypoxanthine, and uric acid were normal. The plasma homocysteine (1.49 mmol/L; normal: 3.3–11.3 mmol/L) and cystine levels (1.2 mM/mM creatine; normal: 4– 15 mM/mM creatine) were decreased. An MRI of the brain showed T2-weighted hyperintense signal changes in globus pallidi and dentate nuclei of the cerebellum (Fig. 2). The Diffusion-weighted sequences showed restricted diffusion. Next-generation sequencing showed a pathogenic homozygous novel missense variant in exon 4 of the SUOX gene (c.1382A > T; p.Asp461Val),
confirming the diagnosis of late-onset sulphite oxidase deficiency. The pathogenicity was confirmed by in silico (PolyPhen-2) prediction. Both the parents were carriers for the same variation on SANGER sequencing. The infant was treated with antiepileptics, low protein diet, antidystonic medications, and other supportive management. At the last follow up, the child was 30-months old and had started walking with support, could speak 1 to 2 words, and could identify the family members and had residual mild hypotonia and dystonia. 3. Search strategy and analysis of literature Citations were identified through PubMed, Web of science and Google scholar searches using the search terms (including variations), ‘‘isolated sulfite oxidase deficiency”, and ‘‘late-onset sulfite oxidase deficiency”, combined with study filters for case reports, case series and original research. The identified reports were screened manually for patients fulfilling inclusion criteria (late-onset ISOD). Additional articles were identified from the reference lists of identified papers. Only papers published in English were reviewed. Ten previously published cases were identified in the literature [3,4,8–13]. Together with presented two new cases, 12 cases were thus available for analysis (Tables 1, 2).
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003
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Fig. 2. Magnetic resonance images of the brain of case-2. T2-weighted (a) axial section showing symmetrical hyperintense signal changes in bilateral globus pallidi. Diffusion weighted (b, c) axial sequences and corresponding ADC map (d) showed intense diffusion restriction in bilateral globus pallidi and dentate nuclei of the cerebellum.
4. Results The median age at symptom onset was 8.5 months (range: 3–23) and at diagnosis was 23 months (range: 8–72). Two children died at two and four year of age. Parental consanguinity was present in five. Five (41.6%) patients had preexisting development delay. Almost all children had acute regression of milestone followed by slow recovery; however, 6 (50%) children had persistent regression. Antecedent events were present in 5 children (otitis media: 1; nonspecific febrile illness: 2 and trivial trauma: 2). Common associated signs and symptoms were movement disorders (8), seizures (7), ectopia lentis (6), hypertonia (4), feeding difficulty (4), microcephaly (3), behavioral changes (3), macrocephaly (1), nystagmus (1) and stroke (1). Initial
hypotonia was present in 9 (75%) children and 2 had an episodic presentation. Dysmorphic facial features and demyelinating polyneuropathy was present in one child each. An MRI of the brain was performed in 9 (75%) patients (Table 2). The most common MRI feature was globus pallidi changes (77.7%) followed by cerebellar white matter changes (33.3%), vermian hypoplasia (33.3%) and thinned out corpus callosum (22.2%). Diffusion weighted sequence was performed in 3 patients and all had diffusion restriction in the affected area. 5. Discussion We report here two cases of isolated sulfite oxidase deficiency with biochemical and genetic confirmation.
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003
Case 1 Authors/year
Vander Kei-van Moorsel LM, 1990 Age at diagnosis 12 (months) Sex M Age of onset 11 (months) Death (month) – Parental Yes consanguity Precipitating Febrile illness factor Developmental No delay Regression No Feeding difficulty No Stroke No Seizure Yes Choreo-athetoid Yes movements Dystonia No Ataxia Yes Microcephaly Yes Ectopia lentis No Nystagmus No Hypertonia No Hypotonia Yes Behavioural No changes Episodic No symptoms Confirmation Biochemical Mutation
Not done
Case 2
Case 3
Case 4
Case 5
Case 6
Case 7
Case 8
Case 9
Barbot C, 1995 72
Goh A, 1997 24
Goh A, 1997 18
Garrett RM, 1998 60
Touati G, 2000 22
Touati G, 2000 8
Chan KY, 2002 42
Del Rizzo M, Rocha S, 2014 Present case 2013 12 51 10
Case 10
Case 11
Case 12
24
F 3
F 6
M 6
F 5
M 15
F 8
F 5
F 12
F 12
M 9
M 23
– Yes
24 No
48 No
– Yes
– No
– Yes
– Yes
– No
– No
– No
– No
Otitis media No
No
No
No
No
Yes (global) No
No
No No No No Yes
Yes Yes No Yes No
Yes Yes No No No No Yes No No
Present case
No
No
Trivial trauma Trivial trauma
Yes (global) No
Febrile illness Yes (motor) No
Yes (global)
Yes (motor)
No
No
Yes Yes No Yes No
Yes Yes No Yes Yes
No No No No Yes
No No No No No
Yes Yes No Yes No
No No Yes No No
No No No No Yes
Yes No No Yes Yes
Yes No No Yes Yes
No No Yes No No Yes Yes No
No No Nm Yes No Yes No No
Yes Yes Nm Yes Nm Yes Yes Yes
No No No No No No No Yes
No Yes No Yes No No Yes No
No No Yes Yes Nm Yes No No
No No No Yes Yes No Yes No
No Yes No Yes No No Yes Yes
Yes Yes No No No No Yes No
No Yes No No No No Yes No
No
No
No
Yes
No
No
No
Yes
No
No
Biochemical and Genetic c.182 T > C (p.Leu61Pro)
Biochemical and Genetic c.1382A > T
Biochemical and Genetic c.1382A > T
Biochemical Not Biochemical Biochemical Biochemical Biochemical Biochemical Biochemical mentioned and Genetic Not done Not done Note done G479A Not done Not done Not done c.427C > A (p.His143Asn)
I.K. Sharawat et al. / Brain & Development xxx (2019) xxx–xxx 5
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003
Table 1 Clinical characteristics of children with late-onset isolated sulfite oxidase deficiency.
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Authors/year MRI features Globus Pallidi changes Thin corpus callosum Diffusion restriction Cerebral atrophy Ectasia of cerebral arteries Cerebellar white matter changes Basal ganglia calcification Vermian hypoplasia Cerebellar atrophy Enlarged cistern magna
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
Case 7
Case 8
Case 9
Case 10
Case 11
Case 12
Vander Kei-van Moorsel LM, 1990 Not done
Barbot C, 1995
Goh A, 1997
Goh A, 1997
Garrett RM, 1998
Touati G, 2000 Not done
Touati G, 2000 Not done
Chan KY, 2002
Del Rizzo M, 2013
Rocha S, 2014
Present case
Present case
Yes
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
Nm
No
Yes
No
No
Nm
Nm
Nm
Nm
Nm
Yes
Nm
Yes
Yes
No No
Yes No
No No
No No
Yes No
Yes No
No Yes
No No
No No
No
No
No
No
Yes
No
No
Yes
Yes
No
No
No
Yes
No
No
No
No
No
Yes
No
Yes
Yes
No
No
No
No
No
No Yes
Yes No
No Yes
Yes No
No No
No No
No No
No Yes
No No
I.K. Sharawat et al. / Brain & Development xxx (2019) xxx–xxx
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003
Table 2 Neuroimaging characteristics of children with late-onset isolated sulfite oxidase deficiency.
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The clinical setting to suspect sulphite oxidase deficiency is quite challenging; but fortunately, simple and widely available screening biochemical tests such as the low serum homocysteine level help in deciding whether expensive confirmatory tests are worthwhile. Clinicoradiologically the disorder can be considered as a cause of Leighs syndrome. Till date, only 10 cases of late-onset ISOD have been reported in the literature. Common presenting features are seizures, developmental regression/ delay, movement disorder, and progressive neurological signs of predominantly extrapyramidal at onset and pyramidal signs later. The myriad of possibilities with this constellation of clinical features is bewildering; and the single clinching clinical feature is ectopia lentis was picked up at around 2 years age in 3 out of the 6 cases, and the earliest diagnosis done was at 18 months of age, thus demonstrating the challenge in suspecting the disease. Trivial trauma has been associated with precipitation of basal ganglia stroke in infants with mineralizing angiopathy, seizures in megalencephalic leukoencephalopathy with subcortical cysts (MLC), and neuroregression and unexplained coma in vanishing white matter disease (VWM) [14]. It has also been associated with severe neurological deterioration, fatal cerebral edema and coma occurring after a lucid interval (‘‘delayed cerebral edema”) in channelopathies, especially CACNA1A. However, it is not reported with ISOD. Both of our children had preceding history of trivial head trauma. The pathophysiology underlying the acute deterioration in some disorders following trivial head trauma is still uncertain. Different hypothesis have been proposed for different disorders. Mineralizing angiopathy leads to macroscopic abnormality resulting in abnormal vasculature and predisposition to vasospasm and stroke while VWM, MLC and CACNA1A possibility operate at molecular or cellular level. In VWM, stressful conditions such as heat stress and head injury, lead to activation of specific kinases that phosphorylate the a-subunit of eIF2 and phosphorylated form is a competitive inhibitor of eIF2B which is already defective in this disorder [15]. In MLC, the transitory coma may be related to microscopic injuries upon large group of loosely myelinated axons in the brainstem which don’t imply a definite structural damage [16,17]. The pathogenesis underlying acute deterioration in ISOD with trivial trauma is also not known. The accumulation of glutamate due to inhibition of glutamate dehydrogenase by sulfites is thought to be responsible for neuronal damage. Trauma like any other stress, involves a metabolic cascade terminating at excitotoxic injury. The metabolic defect expressed itself as developmental delay with seizures and choreo-athetoid movements at 8 months in the first reported of this group by van der Klei-van Moorsel et al in 1990 [8]. This patient did not have an ectopia lentis; and an abnormal urine amino
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acid profile led to the diagnosis. The second in this series were 2 unrelated patients reported by Touati et al [4]. One of them was a 15-month-old who developed extrapyramidal symptoms after recovering from an episode of otitis media, the diagnostic clue again being an abnormal urine amino acidogram. Their second case was a 10-month-old girl admitted with motor developmental delay, extrapyramidal features, ataxia and ectopia lentis-clinical suspicion was already present before biochemical confirmation. They successfully tried dietary therapy containing low protein from natural sources (daily methionine intake 130–150 mg) and a synthetic amino acid mixture (50 g per day) without cystine and methionine. Del Rizzo et al [12] in 2013 reported a unique presentation of a 1 year old developmentally delayed girl with acute onset left hemiplegia. She had ectopia lentis on examination. Her MRI revealed bilateral asymmetric globus pallidi signal changes with diffusion restriction; and this case was aptly termed as a ‘metabolic stroke’ secondary to an ‘energy crisis’ mechanism that mimics a hypoxic- ischemic like state. They supported this theory with experimental data from animal studies showing defective ATP synthesis due to inhibition of glutamate dehydrogenase enzyme by high sulphite content in brain cells [18]. Globus pallidi diffusion weighted changes secondary to cytotoxic edema and metabolic derangement were unknown before this report. Both our cases too had diffusion restriction in globus pallidi and cerebellar white matter. Although, cerebellar white matter changes have been previously reported by Chan KY and colleagues [11], but diffusion restriction was novel finding in our cases. 6. Conclusions The classical or early onset form of ISOD is devastating and untreatable disease while the late-onset form is generally a milder condition. The neuroradiological and clinical features of the late-onset form are quite protean and non-specific and trivial trauma can precipitate acute metabolic crisis. Most characteristic features are acute onset movement disorder sometimes preceded by febrile illness or minor trauma, seizures and ectopia lentis. Low plasma homocysteine and involvement of globus pallidi with diffusion restriction on the MRI are important diagnostic clues. Early diagnosis and intervention with special diet may be effective in preventing long term neurodisability. Early diagnosis is also an important tool for preventing recurrence and prognostication. Funding/support None declared.
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003
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Disclaimers Nil. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.braindev.2019.11. 003. References [1] Sass JO, Gunduz A, Araujo Rodrigues Funayama C, Korkmaz B, Dantas Pinto KG, Tuysuz B, et al. Functional deficiencies of sulfite oxidase: differential diagnoses in neonates presenting with intractable seizures and cystic encephalomalacia. Brain Dev 2010;32:544–9. [2] Zaki MS, Selim L, El-Bassyouni HT, Issa MY, Mahmoud I, Ismail S, et al. Molybdenum cofactor and isolated sulphite oxidase deficiencies: clinical and molecular spectrum among Egyptian patients. Eur J Paediatr Neurol 2016;20:714–22. [3] Barbot C, Martins E, Vilarinho L, Dorche C, Cardoso ML. A mild form of infantile isolated sulphite oxidase deficiency. Neuropediatrics 1995;26:322–4. [4] Touati G, Rusthoven E, Depondt E, Dorche C, Duran M, Heron B, et al. Dietary therapy in two patients with a mild form of sulphite oxidase deficiency. evidence for clinical and biological improvement. J Inherit Metab Dis 2000;23:45–53. [5] Bayram E, Topcu Y, Karakaya P, Yis U, Cakmakci H, Ichida K, et al. Molybdenum cofactor deficiency: review of 12 cases (MoCD and review). Eur J Paediatr Neurol 2013;17:1–6. [6] Schwarz G, Mendel RR. Molybdenum cofactor biosynthesis and molybdenum enzymes. Annu Rev Plant Biol 2006;57:623–47. [7] Claerhout H, Witters P, Re´gal L, Jansen K, Van Hoestenberghe M-R, Breckpot J, et al. Isolated sulfite oxidase deficiency. J Inherit Metab Dis 2018;41:101–8.
[8] van der Klei-van Moorsel JM, Smit LM, Brockstedt M, Jakobs C, Dorche C, Duran M. Infantile isolated sulphite oxidase deficiency: report of a case with negative sulphite test and normal sulphate excretion. Eur J Pediatr 1991;150:196–7. [9] Goh A, Lim KW. Sulphite oxidase deficiency–a report of two siblings. Singapore Med J 1997;38:391–4. [10] Garrett RM, Johnson JL, Graf TN, Feigenbaum A, Rajagopalan KV. Human sulfite oxidase R160Q: Identification of the mutation in a sulfite oxidase-deficient patient and expression and characterization of the mutant enzyme. Proc Natl Acad Sci U S A 1998;95:6394–8. [11] Chan KY, Li CK, Lai CK, Ng SF, Chan AYW. Infantile isolated sulphite oxidase deficiency in a Chinese family: a rare neurodegenerative disorder. Hong Kong Med J 2002;8:279–82. [12] Del Rizzo M, Burlina AP, Sass JO, Beermann F, Zanco C, Cazzorla C, et al. Metabolic stroke in a late-onset form of isolated sulfite oxidase deficiency. Mol Genet Metab 2013;108:263–6. [13] Rocha S, Ferreira AC, Dias AI, Vieira JP, Sequeira S. Sulfite oxidase deficiency–an unusual late and mild presentation. Brain Dev 2014;36:176–9. [14] Kieslich M, Fiedler A, Heller C, Kreuz W, Jacobi G. Minor head injury as cause and co-factor in the aetiology of stroke in childhood: a report of eight cases. J Neurol Neurosurg Psychiatry 2002;73:13–6. [15] van der Knaap MS, Pronk JC, Scheper GC. Vanishing white matter disease. Lancet Neurol 2006;5:413–23. [16] Bugiani M, Moroni I, Bizzi A, Nardocci N, Bettecken T, Ga¨rtner J, et al. Consciousness disturbances in megalencephalic leukoencephalopathy with subcortical cysts. Neuropediatrics 2003;34:211–4. [17] Sharawat IK, Suthar R. Girl with progressive head enlargement and gait disturbance: clinico-radiological clues. Pediatr Neurol 2019;97:80–1. [18] Zhang X, Vincent AS, Halliwell B, Wong KP. A mechanism of sulfite neurotoxicity: direct inhibition of glutamate dehydrogenase. J Biol Chem 2004;279:43035–45.
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003
Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients Indar Kumar Sharawat a, Lokesh Saini b,⇑, Bhanudeep Singanamala b Arushi Gahlot Saini b, Jitendra Kumar Sahu b, Savita Verma Attri c, Naveen Sankhyan b a Pediatric Neurology Division, Department of Pediatrics, All India Institute of Medical Sciences, Rishikesh, Uttarakhand 249201, India Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India c Pediatric Biochemistry Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Chandigarh 160012, India b
Received 27 September 2019; received in revised form 25 October 2019; accepted 18 November 2019
Abstract Background: Isolated sulfite oxidase deficiency (ISOD) is a rare autosomal recessively inherited inborn error of metabolism, caused by mutation in SUOX gene. ISOD has two kind of presentation; early and late-onset. The late-onset form is extremely rare and only 10 cases have been reported. Methods: We report two new cases of late-onset ISOD with biochemical and genetic confirmation. We did a review of the previously published cases of late-onset ISOD. Results: Together with the presented two cases, 12 cases were available for analysis. The median age at symptom onset and at diagnosis was 8.5 and 23 months respectively. Almost all children had acute regression of milestones followed by slow recovery. The common presenting signs and symptoms were movement disorders, seizures, ectopia lentis and hypertonia. Five children had antecedent events. Trivial trauma precipitating the metabolic crisis was unique to the two cases we report. The most common MRI feature was globus pallidi changes followed by cerebellar white matter changes, vermian hypoplasia and thinned out corpus callosum. Diffusion weighted sequence was performed in 3 children and all had diffusion restriction in the affected area. Conclusion: Trivial trauma can precipitate metabolic crisis in late-onset ISOD. Low plasma homocysteine and involvement of globus pallidi with diffusion restriction on the MRI are important diagnostic clues. Early diagnosis and intervention with special diet may be effective in preventing long term neurodisability. Ó 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Isolated sulfite oxidase deficiency; Metabolic crisis; Trivial trauma; Diffusion restriction; Molybdenum cofactor deficiency; Late-onset
1. Introduction
⇑ Corresponding author at: Pediatric Neurology Unit, Department of Pediatrics, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh 160012, India. E-mail address: [email protected] (L. Saini).
Sulfite oxidase deficiency is a rare autosomal recessively inherited inborn error of metabolism. Sulfite oxidase a mitochondrial enzyme, encoded by the SUOX gene and it is responsible for the oxidative degradation of potentially toxic sulfites to relatively non-toxic sulfates in the metabolic pathway of sulfur-containing
https://doi.org/10.1016/j.braindev.2019.11.003 0387-7604/Ó 2019 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003
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amino acids [1,2]. It can occur as an isolated enzyme defect (ISOD, OMIM 272300) due to mutations of the SUOX gene or as a part of deficiency of group of enzymes that share the common molybdenum-pterin co-factor (OMIM 252150) [3]. The molybdenum cofactor is essential for the function of three enzymes namely xanthine oxidase, sulfite oxidase and aldehyde oxidase. Both of these defects have similar clinical manifestations and two types of manifestations, early and late. The early onset type presents in early infancy with intractable seizures, axial hypotonia, limb hypertonicity, dislocation of lens and severe psychomotor delay mimicking hypoxic-ischemic encephalopathy. Biochemically, an increased urinary excretion of sulphate, thiosulphate, taurine and S-sulphocysteine and low plasma cysteine and total homocysteine are detectable. The late onset form is extremely rare and may lack suggestive symptoms and may present with predominant dystonia, seizures and developmental regression [4]. The biochemical finding of low plasma uric acid, and high urine xanthine and hypoxanthine are found in molybdenum cofactor deficiency, while normal plasma uric acid, urine xanthine, and hypoxanthine levels are seen in isolated sulfite oxidase deficiency (ISOD). Elevated urinary levels of S-sulfocysteine, thiosulfate, sulfite and taurine with nearly undetectable levels of plasma total homocysteine and cystine are the biochemical hallmarks of isolated form [5,6]. In addition, urinary urothione, a breakdown product of the molybdenum cofactor, is absent in molybdenum cofactor deficiency but present in ISOD [7]. Here we present two genetically proven cases of lateonset ISOD and a review of the previously published cases of late-onset ISOD. Institutional Ethical Committee’s approval and the Informed Consent taken from the guardians of both the patients. 2. Case presentation 2.1. Case: 1 A 10-month-old boy presented with acute onset loss of the milestones for the past one month. He had developed normally till 9-months of age and was able to sit without support, crawl, speak monosyllable words and had stranger anxiety. At nine months of age, he had an accidental fall from the bed (2 feet height) and developed 3 episodes of vacant staring, lasting for 3–5 min over a period of 40 min without gaining consciousness in between. Thereafter, he was observed to have lost head control, he stopped visual fixation and following and was no longer to recognized mother. There was a history of intermittent twisting of limbs which was more during crying. There was no prior history of regression, recurrent fever, rash, vomiting, or any abnormal body odor. He was the first born to a non-consanguineous
couple and had an uncomplicated perinatal period. There was no family history of similar illness or any other neurological disorders. On examination, he had normal head circumference (44.5 cm), intermittent generalized dystonia, choreic movements of limbs, hypotonia, and exaggerated muscle stretch reflexes. On ophthalmic assessment, the fundii and lens were normal. Investigations revealed normal blood counts, electrolytes, blood sugar, blood pH, lactate, ammonia, vitamin B12, and creatine kinase levels. Urinary sulfites were positive by dipstick. His urinary S-sulfocysteine (142.5 mM/mM creatine; normal: 0.28–18.8 mM/mM creatine) and taurine (271. 5 mM/mM creatine; normal 8–150 mM/mM creatine) levels were markedly elevated along with normal urinary excretion of xanthines, hypoxanthine, and uric acid. His plasma homocysteine (0.6 mmol/L; normal: 3.3–11.3 mmol/L) and cystine levels (0.4 mM/mM creatine; normal: 4–15 mM/mM creatine) were decreased and uric acid level (3.6 mg/dL; normal: 3.4–7 mg/dL) was normal. The magnetic resonance imaging (MRI) of the brain (Fig. 1) showed symmetrical T2-weighted hyperintense signal changes in bilateral globus pallidi and dentate nuclei of the cerebellum with diffusion restriction. A next-generation sequencing showed a novel homozygous, missense variation in exon 6 of the SUOX gene (c.1382A > T/p.As p461Val) confirming the diagnosis of late-onset sulphite oxidase deficiency. Both the parents were carriers for the same variation on SANGER sequencing. The pathogenicity of variant was confirmed by in silico (PolyPhen-2) prediction. Parents were counseled about the nature of the disease and offered prenatal diagnosis. The infant was treated with antiepileptics, low protein diet, antidystonic medications, and other supportive management. On last follow up, he was 16 months old and had gained a few milestones. He had residual axial and appendicular hypotonia and was able to sit with support, visually fixate and follow, identify family members and able to speak 1 to 2 words. 2.2. Case: 2 A 24-month old boy, born to non-consanguineous parents, presented with acute-onset loss of milestones for the past 20 days. Prior to the illness, he was able to run, stands on tiptoes, kick a ball, knew the names of familiar people, was able to combine 2 to 3-words in to a sentence, and follow two-step instructions. Twenty days prior, he had a fall (about from 3-feet height) while playing and a trivial head contact. Soon, he had an episode of generalized tonic seizures which was lasted for 10 min and the child slept after the episode. He woke up after 2 h and was observed to have no head control or ability to sit. He cried but was unable to speak anything, nor could he recognize his parents
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003
I.K. Sharawat et al. / Brain & Development xxx (2019) xxx–xxx
3
Fig. 1. Magnetic resonance images of the brain of case-1. T2-weighted (a) and fluid attenuated inversion recovery (b) axial section showing symmetrical hyperintense signal changes in bilateral globus pallidi (arrow). Diffusion weighted (c, e) axial sequences and corresponding apparent diffusion coefficient (ADC) map (d, f) showed intense diffusion restriction in bilateral globus pallidi and dentate nuclei of the cerebellum.
and was unable to communicate needs. There was no significant past history. There was no history of fever, vomiting, abnormal body odor, rash and bleeding from any site. The family history was unremarkable. On, examination, he had normocephaly (47.8 cm), normal fundii, inability to sit or roll over, absence of meaningful vocalization, intermittent appendicular and axial dystonia, and generalized hypotonia. On investigations, blood gases, electrolytes, serum uric acid, ammonia, lactate and vitamin B12 levels were normal. The cerebrospinal cell count and biochemistry were normal. Urinary sulfites were positive by dipstick. The urinary S-sulfocysteine (178.3 mM/mM creatine; normal: 0.28–18.8 mM/mM creatine) and taurine (192. 5 mM/mM creatine; normal 8–150 mM/mM creatine) levels were elevated. The urinary excretion of xanthines, hypoxanthine, and uric acid were normal. The plasma homocysteine (1.49 mmol/L; normal: 3.3–11.3 mmol/L) and cystine levels (1.2 mM/mM creatine; normal: 4– 15 mM/mM creatine) were decreased. An MRI of the brain showed T2-weighted hyperintense signal changes in globus pallidi and dentate nuclei of the cerebellum (Fig. 2). The Diffusion-weighted sequences showed restricted diffusion. Next-generation sequencing showed a pathogenic homozygous novel missense variant in exon 4 of the SUOX gene (c.1382A > T; p.Asp461Val),
confirming the diagnosis of late-onset sulphite oxidase deficiency. The pathogenicity was confirmed by in silico (PolyPhen-2) prediction. Both the parents were carriers for the same variation on SANGER sequencing. The infant was treated with antiepileptics, low protein diet, antidystonic medications, and other supportive management. At the last follow up, the child was 30-months old and had started walking with support, could speak 1 to 2 words, and could identify the family members and had residual mild hypotonia and dystonia. 3. Search strategy and analysis of literature Citations were identified through PubMed, Web of science and Google scholar searches using the search terms (including variations), ‘‘isolated sulfite oxidase deficiency”, and ‘‘late-onset sulfite oxidase deficiency”, combined with study filters for case reports, case series and original research. The identified reports were screened manually for patients fulfilling inclusion criteria (late-onset ISOD). Additional articles were identified from the reference lists of identified papers. Only papers published in English were reviewed. Ten previously published cases were identified in the literature [3,4,8–13]. Together with presented two new cases, 12 cases were thus available for analysis (Tables 1, 2).
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003
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Fig. 2. Magnetic resonance images of the brain of case-2. T2-weighted (a) axial section showing symmetrical hyperintense signal changes in bilateral globus pallidi. Diffusion weighted (b, c) axial sequences and corresponding ADC map (d) showed intense diffusion restriction in bilateral globus pallidi and dentate nuclei of the cerebellum.
4. Results The median age at symptom onset was 8.5 months (range: 3–23) and at diagnosis was 23 months (range: 8–72). Two children died at two and four year of age. Parental consanguinity was present in five. Five (41.6%) patients had preexisting development delay. Almost all children had acute regression of milestone followed by slow recovery; however, 6 (50%) children had persistent regression. Antecedent events were present in 5 children (otitis media: 1; nonspecific febrile illness: 2 and trivial trauma: 2). Common associated signs and symptoms were movement disorders (8), seizures (7), ectopia lentis (6), hypertonia (4), feeding difficulty (4), microcephaly (3), behavioral changes (3), macrocephaly (1), nystagmus (1) and stroke (1). Initial
hypotonia was present in 9 (75%) children and 2 had an episodic presentation. Dysmorphic facial features and demyelinating polyneuropathy was present in one child each. An MRI of the brain was performed in 9 (75%) patients (Table 2). The most common MRI feature was globus pallidi changes (77.7%) followed by cerebellar white matter changes (33.3%), vermian hypoplasia (33.3%) and thinned out corpus callosum (22.2%). Diffusion weighted sequence was performed in 3 patients and all had diffusion restriction in the affected area. 5. Discussion We report here two cases of isolated sulfite oxidase deficiency with biochemical and genetic confirmation.
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003
Case 1 Authors/year
Vander Kei-van Moorsel LM, 1990 Age at diagnosis 12 (months) Sex M Age of onset 11 (months) Death (month) – Parental Yes consanguity Precipitating Febrile illness factor Developmental No delay Regression No Feeding difficulty No Stroke No Seizure Yes Choreo-athetoid Yes movements Dystonia No Ataxia Yes Microcephaly Yes Ectopia lentis No Nystagmus No Hypertonia No Hypotonia Yes Behavioural No changes Episodic No symptoms Confirmation Biochemical Mutation
Not done
Case 2
Case 3
Case 4
Case 5
Case 6
Case 7
Case 8
Case 9
Barbot C, 1995 72
Goh A, 1997 24
Goh A, 1997 18
Garrett RM, 1998 60
Touati G, 2000 22
Touati G, 2000 8
Chan KY, 2002 42
Del Rizzo M, Rocha S, 2014 Present case 2013 12 51 10
Case 10
Case 11
Case 12
24
F 3
F 6
M 6
F 5
M 15
F 8
F 5
F 12
F 12
M 9
M 23
– Yes
24 No
48 No
– Yes
– No
– Yes
– Yes
– No
– No
– No
– No
Otitis media No
No
No
No
No
Yes (global) No
No
No No No No Yes
Yes Yes No Yes No
Yes Yes No No No No Yes No No
Present case
No
No
Trivial trauma Trivial trauma
Yes (global) No
Febrile illness Yes (motor) No
Yes (global)
Yes (motor)
No
No
Yes Yes No Yes No
Yes Yes No Yes Yes
No No No No Yes
No No No No No
Yes Yes No Yes No
No No Yes No No
No No No No Yes
Yes No No Yes Yes
Yes No No Yes Yes
No No Yes No No Yes Yes No
No No Nm Yes No Yes No No
Yes Yes Nm Yes Nm Yes Yes Yes
No No No No No No No Yes
No Yes No Yes No No Yes No
No No Yes Yes Nm Yes No No
No No No Yes Yes No Yes No
No Yes No Yes No No Yes Yes
Yes Yes No No No No Yes No
No Yes No No No No Yes No
No
No
No
Yes
No
No
No
Yes
No
No
Biochemical and Genetic c.182 T > C (p.Leu61Pro)
Biochemical and Genetic c.1382A > T
Biochemical and Genetic c.1382A > T
Biochemical Not Biochemical Biochemical Biochemical Biochemical Biochemical Biochemical mentioned and Genetic Not done Not done Note done G479A Not done Not done Not done c.427C > A (p.His143Asn)
I.K. Sharawat et al. / Brain & Development xxx (2019) xxx–xxx 5
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003
Table 1 Clinical characteristics of children with late-onset isolated sulfite oxidase deficiency.
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Authors/year MRI features Globus Pallidi changes Thin corpus callosum Diffusion restriction Cerebral atrophy Ectasia of cerebral arteries Cerebellar white matter changes Basal ganglia calcification Vermian hypoplasia Cerebellar atrophy Enlarged cistern magna
Case 1
Case 2
Case 3
Case 4
Case 5
Case 6
Case 7
Case 8
Case 9
Case 10
Case 11
Case 12
Vander Kei-van Moorsel LM, 1990 Not done
Barbot C, 1995
Goh A, 1997
Goh A, 1997
Garrett RM, 1998
Touati G, 2000 Not done
Touati G, 2000 Not done
Chan KY, 2002
Del Rizzo M, 2013
Rocha S, 2014
Present case
Present case
Yes
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
Nm
No
Yes
No
No
Nm
Nm
Nm
Nm
Nm
Yes
Nm
Yes
Yes
No No
Yes No
No No
No No
Yes No
Yes No
No Yes
No No
No No
No
No
No
No
Yes
No
No
Yes
Yes
No
No
No
Yes
No
No
No
No
No
Yes
No
Yes
Yes
No
No
No
No
No
No Yes
Yes No
No Yes
Yes No
No No
No No
No No
No Yes
No No
I.K. Sharawat et al. / Brain & Development xxx (2019) xxx–xxx
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003
Table 2 Neuroimaging characteristics of children with late-onset isolated sulfite oxidase deficiency.
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The clinical setting to suspect sulphite oxidase deficiency is quite challenging; but fortunately, simple and widely available screening biochemical tests such as the low serum homocysteine level help in deciding whether expensive confirmatory tests are worthwhile. Clinicoradiologically the disorder can be considered as a cause of Leighs syndrome. Till date, only 10 cases of late-onset ISOD have been reported in the literature. Common presenting features are seizures, developmental regression/ delay, movement disorder, and progressive neurological signs of predominantly extrapyramidal at onset and pyramidal signs later. The myriad of possibilities with this constellation of clinical features is bewildering; and the single clinching clinical feature is ectopia lentis was picked up at around 2 years age in 3 out of the 6 cases, and the earliest diagnosis done was at 18 months of age, thus demonstrating the challenge in suspecting the disease. Trivial trauma has been associated with precipitation of basal ganglia stroke in infants with mineralizing angiopathy, seizures in megalencephalic leukoencephalopathy with subcortical cysts (MLC), and neuroregression and unexplained coma in vanishing white matter disease (VWM) [14]. It has also been associated with severe neurological deterioration, fatal cerebral edema and coma occurring after a lucid interval (‘‘delayed cerebral edema”) in channelopathies, especially CACNA1A. However, it is not reported with ISOD. Both of our children had preceding history of trivial head trauma. The pathophysiology underlying the acute deterioration in some disorders following trivial head trauma is still uncertain. Different hypothesis have been proposed for different disorders. Mineralizing angiopathy leads to macroscopic abnormality resulting in abnormal vasculature and predisposition to vasospasm and stroke while VWM, MLC and CACNA1A possibility operate at molecular or cellular level. In VWM, stressful conditions such as heat stress and head injury, lead to activation of specific kinases that phosphorylate the a-subunit of eIF2 and phosphorylated form is a competitive inhibitor of eIF2B which is already defective in this disorder [15]. In MLC, the transitory coma may be related to microscopic injuries upon large group of loosely myelinated axons in the brainstem which don’t imply a definite structural damage [16,17]. The pathogenesis underlying acute deterioration in ISOD with trivial trauma is also not known. The accumulation of glutamate due to inhibition of glutamate dehydrogenase by sulfites is thought to be responsible for neuronal damage. Trauma like any other stress, involves a metabolic cascade terminating at excitotoxic injury. The metabolic defect expressed itself as developmental delay with seizures and choreo-athetoid movements at 8 months in the first reported of this group by van der Klei-van Moorsel et al in 1990 [8]. This patient did not have an ectopia lentis; and an abnormal urine amino
7
acid profile led to the diagnosis. The second in this series were 2 unrelated patients reported by Touati et al [4]. One of them was a 15-month-old who developed extrapyramidal symptoms after recovering from an episode of otitis media, the diagnostic clue again being an abnormal urine amino acidogram. Their second case was a 10-month-old girl admitted with motor developmental delay, extrapyramidal features, ataxia and ectopia lentis-clinical suspicion was already present before biochemical confirmation. They successfully tried dietary therapy containing low protein from natural sources (daily methionine intake 130–150 mg) and a synthetic amino acid mixture (50 g per day) without cystine and methionine. Del Rizzo et al [12] in 2013 reported a unique presentation of a 1 year old developmentally delayed girl with acute onset left hemiplegia. She had ectopia lentis on examination. Her MRI revealed bilateral asymmetric globus pallidi signal changes with diffusion restriction; and this case was aptly termed as a ‘metabolic stroke’ secondary to an ‘energy crisis’ mechanism that mimics a hypoxic- ischemic like state. They supported this theory with experimental data from animal studies showing defective ATP synthesis due to inhibition of glutamate dehydrogenase enzyme by high sulphite content in brain cells [18]. Globus pallidi diffusion weighted changes secondary to cytotoxic edema and metabolic derangement were unknown before this report. Both our cases too had diffusion restriction in globus pallidi and cerebellar white matter. Although, cerebellar white matter changes have been previously reported by Chan KY and colleagues [11], but diffusion restriction was novel finding in our cases. 6. Conclusions The classical or early onset form of ISOD is devastating and untreatable disease while the late-onset form is generally a milder condition. The neuroradiological and clinical features of the late-onset form are quite protean and non-specific and trivial trauma can precipitate acute metabolic crisis. Most characteristic features are acute onset movement disorder sometimes preceded by febrile illness or minor trauma, seizures and ectopia lentis. Low plasma homocysteine and involvement of globus pallidi with diffusion restriction on the MRI are important diagnostic clues. Early diagnosis and intervention with special diet may be effective in preventing long term neurodisability. Early diagnosis is also an important tool for preventing recurrence and prognostication. Funding/support None declared.
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003
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Disclaimers Nil. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.braindev.2019.11. 003. References [1] Sass JO, Gunduz A, Araujo Rodrigues Funayama C, Korkmaz B, Dantas Pinto KG, Tuysuz B, et al. Functional deficiencies of sulfite oxidase: differential diagnoses in neonates presenting with intractable seizures and cystic encephalomalacia. Brain Dev 2010;32:544–9. [2] Zaki MS, Selim L, El-Bassyouni HT, Issa MY, Mahmoud I, Ismail S, et al. Molybdenum cofactor and isolated sulphite oxidase deficiencies: clinical and molecular spectrum among Egyptian patients. Eur J Paediatr Neurol 2016;20:714–22. [3] Barbot C, Martins E, Vilarinho L, Dorche C, Cardoso ML. A mild form of infantile isolated sulphite oxidase deficiency. Neuropediatrics 1995;26:322–4. [4] Touati G, Rusthoven E, Depondt E, Dorche C, Duran M, Heron B, et al. Dietary therapy in two patients with a mild form of sulphite oxidase deficiency. evidence for clinical and biological improvement. J Inherit Metab Dis 2000;23:45–53. [5] Bayram E, Topcu Y, Karakaya P, Yis U, Cakmakci H, Ichida K, et al. Molybdenum cofactor deficiency: review of 12 cases (MoCD and review). Eur J Paediatr Neurol 2013;17:1–6. [6] Schwarz G, Mendel RR. Molybdenum cofactor biosynthesis and molybdenum enzymes. Annu Rev Plant Biol 2006;57:623–47. [7] Claerhout H, Witters P, Re´gal L, Jansen K, Van Hoestenberghe M-R, Breckpot J, et al. Isolated sulfite oxidase deficiency. J Inherit Metab Dis 2018;41:101–8.
[8] van der Klei-van Moorsel JM, Smit LM, Brockstedt M, Jakobs C, Dorche C, Duran M. Infantile isolated sulphite oxidase deficiency: report of a case with negative sulphite test and normal sulphate excretion. Eur J Pediatr 1991;150:196–7. [9] Goh A, Lim KW. Sulphite oxidase deficiency–a report of two siblings. Singapore Med J 1997;38:391–4. [10] Garrett RM, Johnson JL, Graf TN, Feigenbaum A, Rajagopalan KV. Human sulfite oxidase R160Q: Identification of the mutation in a sulfite oxidase-deficient patient and expression and characterization of the mutant enzyme. Proc Natl Acad Sci U S A 1998;95:6394–8. [11] Chan KY, Li CK, Lai CK, Ng SF, Chan AYW. Infantile isolated sulphite oxidase deficiency in a Chinese family: a rare neurodegenerative disorder. Hong Kong Med J 2002;8:279–82. [12] Del Rizzo M, Burlina AP, Sass JO, Beermann F, Zanco C, Cazzorla C, et al. Metabolic stroke in a late-onset form of isolated sulfite oxidase deficiency. Mol Genet Metab 2013;108:263–6. [13] Rocha S, Ferreira AC, Dias AI, Vieira JP, Sequeira S. Sulfite oxidase deficiency–an unusual late and mild presentation. Brain Dev 2014;36:176–9. [14] Kieslich M, Fiedler A, Heller C, Kreuz W, Jacobi G. Minor head injury as cause and co-factor in the aetiology of stroke in childhood: a report of eight cases. J Neurol Neurosurg Psychiatry 2002;73:13–6. [15] van der Knaap MS, Pronk JC, Scheper GC. Vanishing white matter disease. Lancet Neurol 2006;5:413–23. [16] Bugiani M, Moroni I, Bizzi A, Nardocci N, Bettecken T, Ga¨rtner J, et al. Consciousness disturbances in megalencephalic leukoencephalopathy with subcortical cysts. Neuropediatrics 2003;34:211–4. [17] Sharawat IK, Suthar R. Girl with progressive head enlargement and gait disturbance: clinico-radiological clues. Pediatr Neurol 2019;97:80–1. [18] Zhang X, Vincent AS, Halliwell B, Wong KP. A mechanism of sulfite neurotoxicity: direct inhibition of glutamate dehydrogenase. J Biol Chem 2004;279:43035–45.
Please cite this article in press as: Sharawat IK et al. Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients. Brain Dev (2019), https://doi.org/10.1016/j.braindev.2019.11.003