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We describe the clinical presentation and 17 years follow up of a boy, born to consanguineous parents and presenting with intellectual disability (ID), autism, 'marfanoid' dysmorphic features, and moderate abnormalities of sulfite metabolism compatible with molybdenum cofactor deficiency, but normal sulfite oxidase activity in cultured skin fibroblasts. Genomic exome analysis revealed a homozygous MOCS3 missense mutation, leading to a p.Ala257Thr substitution in the highly conserved ubiquitin-like-domain of the protein. MOCS3 is the third protein, besides MOCS1 and MOCS2, involved in the biosynthesis of the molybdenum cofactor and has a dual ubiquitin-like function in tRNA thiolation. It is plausible that the phenotype results from deficiency of this dual function, not only from defective synthesis of molybdenum cofactor, which would explain similarities and differences from the MOCS1 and MOCS2-related disorders. This observation should encourage testing of additional ID patients with mild abnormalities of sulfite metabolism for MOCS3 mutations. [ABSTRACT FROM AUTHOR]

The peroxisome biogenesis disorders (PBDs) with generalized peroxisomal dysfunction include Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), and infantile Refsum disease (IRD). There is clinical, biochemical, and genetic overlap among the three phenotypes, also known as Zellweger spectrum disorders. Clinical distinctions between the phenotypes are not sharply defined. Only limited sources are available to serve as a background for prognosis in PBD, especially in case of prolonged survival. We delineated the natural history of 31 PBD patients (age 1.2-24 years) through systematic clinical and biochemical investigations. We excluded classical ZS from our study, and included all patients with a biochemically confirmed generalized peroxisomal disorder over 1 year of age, irrespective of the previously diagnosed phenotype. The initial clinical suspicion, age at diagnosis, growth, development, neurological symptoms, organ involvements, and survival are summarized. Common to all patients were cognitive and motor dysfunction, retinopathy, sensorineural hearing impairment, and hepatic involvement. Many patients showed postnatal growth failure, 10 patients displayed hyperoxaluria of whom 4 had renal stones. Motor skills ranged from sitting with support to normal gait. Speech development ranged from non-verbal expression to grammatical speech and comprehensive reading. The neurodevelopmental course was variable with stable course, rapid decline with leukodystrophy, spinocerebellar syndrome, and slow decline over a wide range of faculties as outcome profiles. At the molecular level, 21 patients had mutations in the PEX1 gene. The two most common PEX1 mutations were the G843D (c.2528G-->A) missense and the c.2097insT frameshift mutation. Patients having the G843D/G843D or the G843D/c.2097insT genotypes were compared. Patients homozygous for G843D generally had a better developmental outcome. However, one patient who was homozygous for the "mild" G843D mutation had an early lethal disease, whereas two other patients had a phenotype overlapping with the G843D/c.2097insT group. This indicates that next to the PEX1 genotype other yet unknown factors determine the ultimate phenotype., (Copyright 2004 Wiley-Liss, Inc.)