Delineating the phenotypic spectrum of sulfite oxidase and molybdenum cofactor deficiency

Albert L Misko, Ye Liang, Joshua B Kohl, Florian Eichler, Albert L Misko, Ye Liang, Joshua B Kohl, Florian Eichler

Abstract

Objective: To define the phenotypic spectrum of isolated sulfite oxidase (ISOD) and molybdenum cofactor deficiency (MoCD), aiming to promote timely diagnosis and assist in future clinical trial design.

Methods: We analyzed clinical, radiographic, biochemical, and genetic data from 146 patients reported in the literature.

Results: We stratified patients into 2 phenotypic subgroups based on clinical and radiographic characteristics. In the first (Class I), patients presented early in life (age 1-50 days) with acute onset of neurologic symptoms and development of diffuse brain injury with cystic leukomalacia. Patients in the second subgroup (Class II) presented later in life (age 30 days-23 years) with prominent movement abnormalities and selective injury of the basal ganglia and cerebellum. A significant difference in survival estimates correlated with milder disease severity among Class II patients. Substantial overlap in sulfur-containing metabolite levels prevented discrimination of subgroups based on diagnostic biomarkers, but genotype-phenotype correlations suggested that residual SUOX activity may contribute to milder phenotypes.

Conclusions: Patients with SUOX and MoCD gravitate toward 1 of 2 distinct clinicoradiographic profiles. Patient stratification may help promote accurate diagnosis, prognostication, and aid in the design of future clinical trials.

Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

Figures

Figure 1. Age at neurologic symptom onset…
Figure 1. Age at neurologic symptom onset and estimated survival distributions for Class I and Class II patients with isolated sulfite oxidase deficiency and molybdenum cofactor deficiency
(A) Age at onset of neurologic symptoms for each patient subgroup. The percentage of patients was calculated separately for Class I and Class II. (B) Survival estimates for Class I and Class II subgroups. A tick mark represents censored patients. The median age of survival for Class I patients was 31 months (C). The median age of survival for Class II was not calculated as survival remained above 50%.
Figure 2. Sulfur-containing metabolite levels reported in…
Figure 2. Sulfur-containing metabolite levels reported in Class I and Class II patients with isolated sulfite oxidase deficiency and MoCD
All sulfur metabolite levels measured in urine (A, B, E, and F) and plasma (C and D) showed substantial overlap between Class I and Class II subgroups. Urine xanthine and plasma uric acid levels in patients with MoCD also showed substantial overlap between Class I and Class II patients (G and H). Horizontal bars represent the median value, and brackets encompass the 25th and 75th quartiles. Solid circles indicate a metabolite value outside of the reported reference range, whereas an open circle indicates a value within the reported reference range. Low sample numbers precluded assessment for a statistically significant difference in median values between subgroups. MoCD = molybdenum cofactor deficiency; SSC = S-sulfocysteine.

References

    1. Johnson JL, Duran M. Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency. In: Beaudet AL, Vogelstein B, Kinzler KW, et al., editors. The Online Metabolic and Molecular Bases of Inherited Disease. New York, NY: The McGraw-Hill Companies, Inc.; 2014. Available at: .
    1. Eichler F, Tan W-H, Shih VE, Grant PE, Krishnamoorthy K. Proton magnetic resonance spectroscopy and diffusion-weighted imaging in isolated sulfite oxidase deficiency. J Child Neurol 2006;21:801–805.
    1. Bakker HD, Abeling NG, ten Houten R, et al. . Molybdenum cofactor deficiency can mimic postanoxic encephalopathy. J Inherit Metab Dis 1993;16:900–901.
    1. Hobson EE, Thomas S, Crofton PM, Murray AD, Dean JCS, Lloyd D. Isolated sulphite oxidase deficiency mimics the features of hypoxic ischaemic encephalopathy. Eur J Pediatr 2005;164:655–659.
    1. Veldman A, Santamaria-Araujo JA, Sollazzo S, et al. . Successful treatment of molybdenum cofactor deficiency type A with cPMP. Pediatrics 2010;125:e1249–e1254.
    1. Kügler S, Hahnewald R, Garrido M, Reiss J. Long-term rescue of a lethal inherited disease by adeno-associated virus-mediated gene transfer in a mouse model of molybdenum-cofactor deficiency. Am J Hum Genet 2007;80:291–297.
    1. Hahnewald R, Wegner W, Reiss J. AAV-mediated gene therapy for metabolic diseases: dosage and reapplication studies in the molybdenum cofactor deficiency model. Genet Vaccines Ther 2009;7:9.
    1. Huijmans JGM, Schot R, de Klerk JBC, et al. . Molybdenum cofactor deficiency: identification of a patient with homozygote mutation in the MOCS3 gene. Am J Med Genet A 2017;173:1601–1606.
    1. Reiss J, Lenz U, Aquaviva-Bourdain C, Joriot-Chekaf S, Mention-Mulliez K, Holder-Espinasse M. A GPHN point mutation leading to molybdenum cofactor deficiency. Clin Genet 2011;80:598–599.
    1. Kohl JB, Mellis A-T, Schwarz G. Homeostatic impact of sulfite and hydrogen sulfide on cysteine catabolism. Br J Pharmacol 2019;176:554–570.
    1. Alkufri F, Harrower T, Rahman Y, et al. . Molybdenum cofactor deficiency presenting with a Parkinsonism-dystonia syndrome. Mov Disord 2013;28:399–400.
    1. Johnson JL, Coyne KE, Rajagopalan KV, et al. . Molybdopterin synthase mutations in a mild case of molybdenum cofactor deficiency. Am J Med Genet 2001;104:169–173.
    1. Bindu PS, Nagappa M, Bharath RD, Taly AB. Isolated sulfite oxidase deficiency. In: GeneReviews®. Seattle: University of Washington, Seattle; 1993–2020.
    1. Vijayakumar K, Gunny R, Grunewald S, et al. . Clinical neuroimaging features and outcome in molybdenum cofactor deficiency. Pediatr Neurol 2011;45:246–252.
    1. Del Rizzo M, Burlina AP, Sass JO, et al. . Metabolic stroke in a late-onset form of isolated sulfite oxidase deficiency. Mol Genet Metab 2013;108:263–266.
    1. Touati G, Rusthoven E, Depondt E, 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.
    1. Bamforth FJ, Johnson JL, Davidson AGF, Wong LTK, Lockitch G, Applegarth DA. Biochemical investigation of a child with molybdenum cofactor deficiency. Clin Biochem 1990;23:537–542.
    1. Sass JO, Gunduz A, Araujo Rodrigues Funayama C, et al. . Functional deficiencies of sulfite oxidase: differential diagnoses in neonates presenting with intractable seizures and cystic encephalomalacia. Brain Dev 2010;32:544–549.
    1. Zaki MS, Selim L, El-Bassyouni HT, et al. . Molybdenum cofactor and isolated sulphite oxidase deficiencies: clinical and molecular spectrum among Egyptian patients. Eur J Paediatr Neurol 2016;20:714–722.
    1. Kisker C, Schindelin H, Pacheco A, et al. . Molecular basis of sulfite oxidase deficiency from the structure of sulfite oxidase. Cell 1997;91:973–983.
    1. Johnson JL, Coyne KE, Garrett RM, et al. . Isolated sulfite oxidase deficiency: identification of 12 novel SUOX mutations in 10 patients. Hum Mutat 2002;20:74.
    1. Karakas E, Kisker C. Structural analysis of missense mutations causing isolated sulfite oxidase deficiency. Dalton Trans 2005:3459–3463.
    1. Rajapakshe A, Tollin G, Enemark JH. Kinetic and thermodynamic effects of mutations of human sulfite oxidase. Chem Biodivers 2012;9:1621–1634.
    1. Feng C, Wilson HL, Tollin G, et al. . The pathogenic human sulfite oxidase mutants G473D and A208D are defective in intramolecular electron transfer. Biochemistry 2005;44:13734–13743.
    1. Rocha S, Ferreira AC, Dias AI, Vieira JP, Sequeira S. Sulfite oxidase deficiency—an unusual late and mild presentation. Brain Dev 2014;36:176–179.
    1. Karakas E, Wilson HL, Graf TN, et al. . Structural insights into sulfite oxidase deficiency. J Biol Chem 2005;280:33506–33515.
    1. 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 USA 1998;95:6394–6398.
    1. Hänzelmann P, Schindelin H. Crystal structure of the S-adenosylmethionine-dependent enzyme MoaA and its implications for molybdenum cofactor deficiency in humans. Proc Natl Acad Sci USA 2004;101:12870–12875.
    1. Wuebbens MM, Liu MT, Rajagopalan K, Schindelin H. Insights into molybdenum cofactor deficiency provided by the crystal structure of the molybdenum cofactor biosynthesis protein MoaC. Structure 2000;8:709–718.
    1. Rudolph MJ, Wuebbens MM, Rajagopalan KV, Schindelin H. Crystal structure of molybdopterin synthase and its evolutionary relationship to ubiquitin activation. Nat Struct Biol 2001;8:42–46.
    1. Daniels JN, Wuebbens MM, Rajagopalan KV, Schindelin H. Crystal structure of a molybdopterin synthase-precursor Z complex: insight into its sulfur transfer mechanism and its role in molybdenum cofactor deficiency. Biochemistry 2008;47:615–626.
    1. Liu MT, Wuebbens MM, Rajagopalan KV, Schindelin H. Crystal structure of the gephyrin-related molybdenum cofactor biosynthesis protein MogA from Escherichia coli. J Biol Chem 2000;275:1814–1822.
    1. Schwarz G, Schrader N, Mendel RR, Hecht HJ, Schindelin H. Crystal structures of human gephyrin and plant Cnx1 G domains: comparative analysis and functional implications. J Mol Biol 2001;312:405–418.
    1. Xiang S, Nichols J, Rajagopalan KV, Schindelin H. The crystal structure of Escherichia coli MoeA and its relationship to the multifunctional protein gephyrin. Structure 2001;9:299–310.
    1. Mayr SJ, Sass JO, Vry J, et al. . A mild case of molybdenum cofactor deficiency defines an alternative route of MOCS1 protein maturation. J Inherit Metab Dis 2018;41:187–196.
    1. Hughes EF, Fairbanks L, Smmonds HA, Robinson RO. Molybdenum cofactor deficiency—phenotypic variability in a family with a late-onset variant. Dev Med Child Neurol 1998;40:57–61.

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