Molybdenum cofactor deficiencies (MoCD) are a group of inborn errors of metabolism that result in impaired synthesis of molybdenum cofactor, crucial for the function of three oxidases (sulfite oxidase, xanthine oxidase and aldehyde oxidase). Most patients present with severe neonatal-onset epileptic encephalopathy, hypotonia, poor feeding and apnoea, with death typically occurring within the first three years of life. Whilst there is now an emerging therapy for MoCD Type A (cPMP/fosdenopterin), this treatment is not effective for MoCD Type B and there is no treatment for isolated sulfite oxidase deficiency (ISOD). Liver directed gene delivery is a potential alternative therapy for sulfite intoxication disorders. We report an attempt to use hepatocyte transplantation as a treatment option for MoCD Type B, in an infant with a strong family history of neonatal-onset disease and early mortality. Six transfusions of hepatocytes were given between Day 1 and Day 18 of life, totalling around 1 × 109 cells with immunosuppressive cover. Concomitantly dietary protein restriction was maintained at 2 g/kg, including 0.7 g/kg of methionine- and cyst(e)ine-free amino acid mixture. The aim was to utilize hepatocyte transplantation as a bridge to liver transplantation. Whilst there was evidence of biochemical stabilization with reduction in concentrations of sulfite and S-sulfocysteine and a moderate increase in urate levels compared to the sibling, the treatment was not able to prevent acute brain injury from sulfite toxicity which was evident in neuroimaging at 35 h of age. This correlated clinically with ongoing seizures as well as minimal developmental progress.

Molybdenum cofactor deficiency (MoCD) classically presents shortly after birth, with neurological symptoms ascribed to postnatal toxicity of accumulating sulphite. Case reports suggest that cerebral damage associated with MoCD may have a prenatal onset. A meta-analysis of case reports was performed on individuals with genetically proven MoCD retrieved through a systematic review and in-house search. Cases were categorized as classical or late-onset, based on the time of onset of symptoms. Available cerebral images were scored for the presence of restricted diffusion, pathological signal, subcortical cysts, and atrophy. Estimated onset of each event and the minimal number of events needed to explain the observed imaging abnormalities were deduced by combining age at imaging, type of imaging abnormality, and known natural evolution of the imaging abnormalities. Of a total of 30 retrieved cases, 21 were classical. Prenatal origin of damage was possible in all classical cases and certain in 11 of 21 (52%). Multiple events were deduced in 5/21 classical cases based on imaging data alone and in 11 of 21 cases when presuming that a postnatal onset of symptoms signifies a recent event. Multiple, but postnatal, events were also described in 3 of 9 late-onset cases. Prenatal onset of cerebral damage in patients with classical MoCD is more frequently encountered than anticipated. It may have been overlooked by the overwhelming postnatal symptoms erroneously pointing to a single culprit. This insight is important when counseling for prognosis, particularly in the context of considering the timing and anticipated prospects of therapeutic intervention.

Sulfite intoxication is the hallmark of four ultrarare disorders that are caused by impaired sulfite oxidase activity due to genetic defects in the synthesis of the molybdenum cofactor or of the apoenzyme sulfite oxidase. Delays on the diagnosis of these disorders are common and have been caused by their unspecific presentation of acute neonatal encephalopathy with high early mortality, followed by the evolution of dystonic cerebral palsy and also by the lack of easily available and reliable diagnostic tests. There is significant variation in survival and in the quality of symptomatic management of affected children. One of the four disorders, molybdenum cofactor deficiency type A (MoCD-A) has recently become amenable to causal treatment with synthetic cPMP (fosdenopterin). The evidence base for the rational use of cPMP is very limited. This prompted the formulation of these clinical guidelines to facilitate diagnosis and support the management of patients. The guidelines were developed by experts in diagnosis and treatment of sulfite intoxication disorders. It reflects expert consensus opinion and evidence from a systematic literature search.

Molybdenum cofactor deficiency type A has successfully been treated in a small number of children with daily intravenous administration of cyclic pyranopterin monophosphate. Pharmacodynamic data for this novel treatment have not been published and alternative dosing intervals have not been explored. We monitored pharmacodynamic biomarkers of sulfite oxidase and xanthine oxidoreductase activity in three patients with MoCD-A for a period of 2 to 9 months after discontinuation of cPMP substitution. We found that the clinical and metabolic effects were sustained for longer than expected, over 7 days at least. Our data implicate a biological half-life of the molybdenum cofactor dependent enzyme activities of approximately 3 days and suggest the possibility that less frequent than once daily dosing intervals could be a safe alternative to current practice.

Molybdenum cofactor deficiency is a rare and fatal genetic disorder. Due to recurrence in the family, the etiological diagnosis could have impacted family planning and alertness to future offspring. Molybdenum cofactor deficiency (MoCD) is a rare and fatal genetic disorder that impairs molybdenum-dependent enzymes, resulting in conspicuous elevated urine sulfite levels and lowered serum uric acid levels. The disorder may be early-onset, causing high fatality in neonates due to secondary complications, or late-onset, manifesting in the first 2 years of life. Severe seizures, progressive neurological degeneration, motor abnormalities, and feeding difficulties are hallmarks of MoCD. Due to the similarity of clinical findings with those of sulfite oxidase deficiency and its neurological findings with hypoxic-ischemic encephalopathy, determining the true etiology remains challenging in MoCD patients. This case report presents a neonate in the first week of life with early onset refractory seizures, motor abnormalities, hypoactivity, and poor feeding behavior. Administering anti-epileptic drugs did not improve the patient's condition, who started decompensating further. Nevertheless, a thorough screening for metabolic disorders revealed low serum uric acid and high sulfite levels in the urine, indicating potential MoCD. A whole exome sequencing (WES) was thus consulted for confirmatory diagnosis. Unfortunately, the patient's WES results were received after his demise, revealing MoCD caused by a novel variant of the MoCS2 gene that has not yet been reported to the best of our knowledge. This case emphasizes the need to disseminate crucial information regarding MoCD and its etiologies for prompt molecular diagnosis to reduce morbidity and mortality.