Sulfite oxidase deficiency – An unusual late and mild presentation

doi:10.1016/j.braindev.2013.01.013

Brain and Development

Volume 36, Issue 2, February 2014, Pages 176-179

https://doi.org/10.1016/j.braindev.2013.01.013 Get rights and content

Abstract

Introduction: Sulfite oxidase deficiency (SOD) is an autosomal recessive inherited disease usually presenting in the neonatal period with severe neurological symptoms including seizures, often refractory to anticonvulsant therapy, and a rapidly progressive encephalopathy resembling neonatal hypoxic ischemia, with premature death. Most patients develop dislocated ocular lenses. Later or milder presentations of SOD are being reported with increasing frequency. These presentations include neurological regression with loss of previously acquired milestones or movement disorders. Case report: We report a four years old girl presenting with intermittent ataxia and uncoordinated limb movements. A similar episode of ataxia had occurred previously, one year before, with complete neurologic recovery and normal developmental milestones. Bilateral lens dislocation had been recently diagnosed. Cranial MRI demonstrated bilateral globus pallidus enhancement. Low homocysteine was found in plasma and Sulfitest^R was positive. Further investigations led to confirmation of isolated sulfite oxidase deficiency with no enzyme activity detected on skin fibroblasts culture. Discussion: This case illustrates the clinical variability of SOD and it is not only atypical but also seems to be the mildest form described so far. The association of ectopia lentis with a movement disorder, even without psychomotor regression, should prompt us to look for this diagnosis.

Introduction

Sulfite oxidase is an enzyme in the terminal pathway of sulfur aminoacid degradation. Isolated sulfite oxidase deficiency (SOD) or deficiency of molybdenum, its cofactor (MoCoD), are autosomal recessive inherited diseases, usually with neonatal onset presenting with seizures often refractory to anticonvulsant therapy, axial hypotonia and limb hypertonicity and a rapidly progressive encephalopathy leading to a state resembling that of neonatal hypoxic ischemia. Most patients develop microcephaly, feeding difficulties and dislocated ocular lenses. A few patients present with a milder late onset form of the disease with dystonia and developmental regression [1], [2], [3].

Biochemical features of the isolated form include increased urinary excretion of sulfite, thiosulfate, taurine and S-sulfocysteine and low plasma cystine and homocysteine. Urinary excretion of xanthine and hypoxanthine is normal, and so is uric acid, unlike the combined deficiency of sulfite and xanthine oxidase seen in MoCoD (Fig. 1) [1], [2], [3].

The pathogenesis of neurotoxicity is not completely understood but could comprise the accumulation of glutamate, an excitotoxic neurotransmitter, due to the combined inhibition of glutamate dehydrogenase (GDH) and possibly alfa-ketoglutarate dehydrogenase by sulfites [4].

We report the mildest presentation form described so far, with normal psychomotor development and recurrent episodes of ataxia.

Section snippets

Case report

This four-year-old girl was the second born, after a full term pregnancy and a normal delivery. Her birth weight was 3350 g, and the Apgar score was 9 and 10, at one and five minutes, respectively. The neonatal course was uneventful. The family history was unremarkable and there was no consanguinity.

Growth, including head circumference, and psychomotor development were normal, except for a mild delay of walking at 18 months. At 12 months of age, she presented with acute hypotonia, lasting a few

Discussion

Since its first description in 1967, several cases of SOD have been reported, mostly with neonatal onset showing tone abnormalities and refractory seizures mimicking hypoxic-ischemic encephalopathy, with a fatal course within few years [1], [2], [3], [4]. Rare milder and later presentations have been described [5], [6], [7], characterized by a prominent movement disorder, usually with seizures and psychomotor regression or delay.

The quantification of plasma total homocysteine has been

Acknowledgements

The authors thank Dr. Carla Conceição, from the Department of Neuroradiology of Hospital de Dona Estefânia, for her comments on magnetic resonance imaging, and Drs Christine Vianey and Cécile Acquaviva, from the Service de Maladies Héréditaires du Métabolisme et Dépistage Neonatal in Lyon for the enzymatic and molecular studies.

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Sulfite oxidase deficiency (SOD) and related disorders, especially molybdenum cofactor deficiency (MoCD), are a group of rare and severe neurometabolic disorders caused by gene mutations that affect the sulfur-containing amino acid catabolic pathway. These disorders are characterized by distinctive neuroimaging features such as diffuse cerebral atrophy, multicystic encephalomalacia, and ventriculomegaly in early infancy. These features are essential for early diagnosis and treatment. Moreover, the genetics of these disorders are complex but have been increasingly elucidated in the era of molecular medicine. Therefore, we reviewed 28 articles (published from January 1967 until October 2021) on SOD and MoCD, focusing on their neuroimaging and genetic aspects. We highlighted the differences between SOD and MoCD and other conditions that may mimic them, such as common neonatal hypoxic-ischemic encephalopathy and uncommon neonatal metabolic disorder (Leigh syndrome). We also summarized the current knowledge on the genetic mechanisms and the manifestation of seizure disorders of SOD and MoCD. In conclusion, if clinical, neuroimaging, and neuropathological findings suggest a possible SOD or related disorder; extensive molecular diagnostics should be performed to confirm the diagnosis.
Whole exome sequencing identified a homozygous novel mutation in SUOX gene causes extremely rare autosomal recessive isolated sulfite oxidase deficiency
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Till now, only 32 germline variants of SUOX have been identified to be associated with ISOD. Among 32 reported variants, 20 variants are missense, 4 variants are nonsense, 6 variants are deletion which result into frameshift and one duplication [4,9–20,27–31]. One deletion leads to loss of the wild type stop codon and followed by formation of a prolonged protein (Table 2) [13].
Isolated sulfite oxidase deficiency (ISOD) is a rare type of life-threatening neurometabolic disorders characterized by neonatal intractable seizures and severe developmental delay with an autosomal recessive mode of inheritance. Germline mutation in SUOX gene causes ISOD. Till date, only 32 mutations of SUOX gene have been identified and reported to be associated with ISOD.
Here, we investigated a 5-days old Chinese female child, presented with intermittent tremor or seizures of limbs, neonatal encephalopathy, subarachnoid cyst and haemorrhage, dysplasia of corpus callosum, neonatal convulsion, hyperlactatemia, severe metabolic acidosis, hyperglycemia, and hyperkalemia.
Whole exome sequencing identified a novel homozygous transition (c.1227G > A) in exon 6 of the SUOX gene in the proband. This novel homozygous variant leads to the formation of a truncated sulfite oxidase (p.Trp409*) of 408 amino acids. This variant causes partial loss of the dimerization domain of sulfite oxidase. Hence, it is a loss-of-function variant. Proband’s father and mother is carrying this novel variant in a heterozygous state. This variant was not found in 200 ethnically matched normal healthy control individuals.
Our study not only expanded the mutational spectrum of SUOX gene associated with ISOD, but also strongly suggested the significance of whole exome sequencing for identifying candidate genes and novel disease-causing variants.
Mechanisms of the protective effects of nitrate and nitrite in cardiovascular and metabolic diseases
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Electron withdrawal from XOR or AO by nitrite may not only serve to form NO but also to inhibit ROS generation [59]. SO is mainly found in eukaryotes and has a dioxo Mo-center at the active site, involved in oxidation of sulfite to sulfate [60]. Nitrite reduction activity of SO was found to be sulfite-dependent [33] and sensitive to pH changes.
Within the body, NO is produced by nitric oxide synthases via converting _l-arginine to citrulline. Additionally, NO is also produced via the NOS-independent nitrate-nitrite-NO pathway. Unlike the classical pathway, the nitrate-nitrite-NO pathway is oxygen independent and viewed as a back-up function to ensure NO generation during ischaemia/hypoxia. Dietary nitrate and nitrite have emerged as substrates for endogenous NO generation and other bioactive nitrogen oxides with promising protective effects on cardiovascular and metabolic function. In brief, inorganic nitrate and nitrite can decrease blood pressure, protect against ischaemia-reperfusion injury, enhance endothelial function, inhibit platelet aggregation, modulate mitochondrial function and improve features of the metabolic syndrome. However, many questions regarding the specific mechanisms of these protective effects on cardiovascular and metabolic diseases remain unclear. In this review, we focus on nitrate/nitrite bioactivation, as well as the potential mechanisms for nitrate/nitrite-mediated effects on cardiovascular and metabolic diseases. Understanding how dietary nitrate and nitrite induce beneficial effect on cardiovascular and metabolic diseases could open up novel therapeutic opportunities in clinical practice.
Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients
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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).
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.
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.
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.
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.
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This chapter is a revision of the previous edition's chapter by Raymond Y. Wang, William R. Wilcox, and Stephen D. Cederbaum, Chapter 92, Amino Acid Metabolism, pp 2564–2605 © 2013, Elsevier Ltd. (Wang et al., 2013). The inborn errors of amino acid metabolism are a family of genetic conditions in which an enzyme deficiency results in the accumulation of a ninhydrin-positive amino acid or a proximal metabolite. They are conceptually identical to disorders caused by enzyme defects that result in the accumulation of the organic acid intermediates (see Chapter 8). The current chapter strives to highlight the clinical, biochemical, molecular, and pathologic features of defects in aromatic amino acid processing and related neurotransmitter metabolism disorders, disorders of glycine metabolism, defects in the processing of sulfur-containing amino acids, disorders of branched-chain amino acid metabolism, proline metabolism, urea cycle disorders, and defects of serine synthesis. As our understanding of the dynamics of amino acid metabolism grows, simplistic notions of metabolic pathways solely as conduits for elimination of excess substrate have been abandoned. We now realize that most, if not all, of these reactions are highly regulated and integrated into the total fabric of metabolic homeostasis in which amino acids play an important role. Nevertheless, such considerations are largely beyond the scope of this concise overview and are covered in more detail in the work by Valle and colleagues, 2014, the standard reference work on these and other inborn errors of metabolism and one that explores the physiologic interactions more fully. Much of the current information on the molecular aspects of these disorders can be accessed through the Online Mendelian Inheritance in Man database (OMIM; http://www.ncbi.nlm.nih.gov/omim).
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Case reportSulfite oxidase deficiency – An unusual late and mild presentation

Abstract

Introduction

Section snippets

Case report

Discussion

Acknowledgements

Brain Dev

J Biol Chem

Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency

Isolated sulfite oxidase deficiency: a case report with a novel mutation and review of the literature

Pediatrics

Sulfite oxidase deficiency. Biochemical and clinical investigations of a hereditary metabolic disorder in sulfur metabolism

N Engl J Med

Case report
Sulfite oxidase deficiency – An unusual late and mild presentation