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

Background To describe the genotype-phenotype dissociation in two Taiwanese patients with molybdenum cofactor deficiency (MoCoD) caused by MOCS2 gene mutations. Patient Description Patient 1 exhibited early-onset neurological symptoms soon after birth, followed by subsequent myoclonic seizures and movement disorder. The brain magnetic resonance imaging (MRI) showed diffuse brain injury with cystic encephalomalacia along with bilateral globus pallidi involvement, hypoplasia of corpus callosum, and cerebellar atrophy. Patient 2 had a mild phenotype with prominent movement disorder after intercurrent illness, and the brain MRI showed selective injury of the bilateral globus pallidi and the cerebellum. Both patients had markedly low levels of plasma uric acid and harbored the same MOCS2 homozygous c.16C > T mutation. Patient 1 showed chronic regression of developmental milestones and died of respiratory failure at the age of 8 years, whereas patient 2 demonstrated improvement in motor function. Conclusion Genotype-phenotype dissociation could be noted in patients with MoCoD due to MOCS2 mutation. Patients with neonatal seizures, developmental delay, movement disorder, and motor regression after an illness, as well as focal or bilateral involvement of the globus pallidi on the neuroimages, should undergo biochemical testing of plasma uric acid. A pronounced plasma uric acid level is a good indicator of MoCoD. Early diagnosis can allow early provision of adequate genetic counseling.

Expanding the Phenotype of Molybdenum Cofactor Deficiency in Neonates: Report of Two Cases

Molybdenum cofactor deficiency (MoCD) is a rare neurometabolic disorder characterized by intractable seizures, progressive microcephaly, tone abnormalities, facial dysmorphism, and feeding difficulties in the neonatal period. We present two different neonatal cases of MoCD with atypical presentations which could have been easily missed. One is a preterm baby admitted with features of sepsis, poor perfusion, and seizures who later developed tone abnormalities and feeding difficulty. The second is a term baby who presented with stridor, respiratory distress, and metabolic acidosis followed by intractable seizures and encephalopathy. Both babies had characteristic radiological and biochemical findings, and genome sequencing identified mutations in MOCS2 and MOCS1 genes, respectively. MoCD presenting as hypoxic-ischemic encephalopathy and cerebral palsy are well described, but its presentation in preterm with “sepsis-like features with drug-responsive seizures” in the early newborn period is not described, and can also cause unnecessary delay in the diagnosis. Its clinical presentation with “stridor, respiratory distress, and metabolic acidosis” is also described for the first time in literature.

Sulfite Alters the Mitochondrial Network in Molybdenum Cofactor Deficiency

Molybdenum cofactor deficiency (MoCD) is an autosomal recessive disorder belonging to the large family of inborn errors in metabolism. Patients typically present with encephalopathy and seizures early after birth and develop severe neurodegeneration within the first few weeks of life. The main pathomechanism underlying MoCD is the loss of function of sulfite oxidase (SO), a molybdenum cofactor (Moco) dependent enzyme located in mitochondrial intermembrane space. SO catalyzes the oxidation of sulfite (SO32–) to sulfate (SO42–) in the terminal reaction of cysteine catabolism, and in the absence of its activity, sulfurous compounds such as SO32–, S-sulfocysteine, and thiosulfate accumulate in patients. Despite growing evidence that these compounds affect neuronal and mitochondrial function, the molecular basis of neuronal dysfunction and cell death in MoCD is still poorly understood. Here we show that mitochondria are severely affected by the loss of SO activity. SO-deficient mouse embryonic fibroblasts display reduced growth rates and impaired ATP production when cultured in galactose, which is an indicator of mitochondrial dysfunction. We also found that mitochondria in SO-deficient cells form a highly interconnected network compared to controls while displaying a slight decrease in motility and unchanged mitochondrial mass. Moreover, we show that the mitochondrial network is directly influenced by SO32–, as a moderate elevation of SO32– lead to the formation of an interconnected mitochondrial network, while high SO32– levels induced fragmentation. Finally, we found a highly interconnected mitochondrial network in MoCD patient-derived fibroblasts, similar to our findings in mouse-derived fibroblasts. We therefore conclude that altered mitochondrial dynamics are an important contributor to the disease phenotype and suggest that MoCD should be included among the mitochondrial disorders.

Asparagine Synthetase Deficiency with Intracranial Hemorrhage Can Mimic Molybdenum Cofactor Deficiency

Here we report a consanguineous Egyptian family with two siblings presented with congenital microcephaly, early-onset epileptic encephalopathy, feeding difficulties, and early lethality. The condition was initially diagnosed as molybdenum cofactor deficiency as the brain imaging for one of them showed brain edema and intracranial hemorrhage in addition to the hypoplastic corpus callosum, vermis hypoplasia, and small-sized pons. Subsequently, whole exome sequencing identified a novel homozygous missense variant in exon 4 of ASNS gene c.397_398GT > CA (p.Val133Gln) confirming the diagnosis of asparagine synthetase deficiency syndrome. No discernible alternative cause for the intracranial hemorrhage was found. Our patient is the second to show asparagine synthetase deficiency and intracranial hemorrhage, thus confirming the involvement of ASNS gene. As such, it is important to consider asparagine synthetase deficiency syndrome in patients with microcephaly, brain edema, and neonatal intracranial hemorrhage.

Delineating the phenotypic spectrum of sulfite oxidase and molybdenum cofactor deficiency

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.