Delineating the phenotypic spectrum of sulfite oxidase and molybdenum cofactor deficiency

Abstract

ObjectiveTo 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.MethodsWe analyzed clinical, radiographic, biochemical, and genetic data from 146 patients reported in the literature.ResultsWe 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.ConclusionsPatients 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.

Postmortem whole-genome sequencing on a dried blood spot identifies a novel homozygous SUOX variant causing isolated sulfite oxidase deficiency

“…Other clinical features of ISOD include ectopia lentis and increased urinary excretion of thiosulfate, sulfite, and S-sulfocysteine (Edwards et al 1999). In a recent review of 47 cases, MRI abnormalities like herein were identified in all cases (Eichler et al 2006;Bindu et al 2017;Claerhout et al 2018;Misko et al 2020). There is currently no effective treatment for ISOD.…”

Genotype-Phenotype Dissociation in Two Taiwanese Children with Molybdenum Cofactor Deficiency Caused by MOCS2 Mutation

“…10 Recently published articles have reviewed MoCoD patients reported in the literature and delineated the phenotypic spectrum: a narrow phenotypic spectrum across patients in the early-onset form with severe neurological impairment and a pattern of global injury susceptibility of the forebrain and cerebellum may be driven mainly by genotype; a wider phenotypic spectrum in patients with the late-onset form ranged from static neurologic symptoms to progressive neurological involvement with periodic decompensation in function, even in adulthood, and the pattern of selective injury susceptibility of the basal ganglia and cerebellum may be driven by a complex interaction of genotype, external environment triggers, and developmental context. 5,8 In addition, the residual enzymatic activity of sulfite oxidase might contribute to the phenotypes. 5 One of the limitations of this study was the lack of available data on sulfite oxidase activity, so it was not possible to draw definitive conclusions from our results.…”

“…5,8 In addition, the residual enzymatic activity of sulfite oxidase might contribute to the phenotypes. 5 One of the limitations of this study was the lack of available data on sulfite oxidase activity, so it was not possible to draw definitive conclusions from our results. Further studies are needed to investigate the correlations among phenotype, genotype, sulfite oxidase activity, and environmental triggers in patients with MoCoD.…”

“…3,4 Patients with MoCoD gravitate toward one of two distinct clinicoradiographic profiles: classical (early onset, age 1-50 days) and atypical (late onset, age 30 days to 23 years) forms. 5 Patients with early-onset MoCoD typically manifest with symptoms shortly after birth with a severe and often fatal disease course. The most commonly noted initial clinical features are feeding difficulty, irritable cry, neonatal seizures, and abnormal tone; later in the disease course, the clinical features comprise microcephaly, craniofacial dysmorphic features, intractable epilepsy, spastic tetraplegia, profound psychomotor impairment, and lens dislocation.…”

Fosdenopterin: a First-in-class Synthetic Cyclic Pyranopterin Monophosphate for the Treatment of Molybdenum Cofactor Deficiency Type A

“…17 Clinically, ISOD and MoCD present with the same symptoms and complications caused by sulphite accumulation, except those patients with MoCD can, in addition, develop nephrolithiasis due to impaired XOR activity. 18 MoCD and ISOD are ultra-rare diseases, with published reports of fewer than 200 patients with MoCD [19][20][21] and fewer than 100 with ISOD. 22 (MoCD-B), caused by MOCS2 variants 23 or, rarely, MOCS3 mutations.…”