2021 Dec 2 [updated 2023 Feb 2]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023.
CLINICAL CHARACTERISTICS: Molybdenum cofactor deficiency (MoCD) represents a spectrum, with some individuals experiencing significant signs and symptoms in the neonatal period and early infancy (termed early-onset or severe MoCD) and others developing signs and symptoms in childhood or adulthood (termed late-onset or mild MoCD). Individuals with early-onset MoCD typically present in the first days of life with severe encephalopathy, including refractory seizures, opisthotonos, axial and appendicular hypotonia, feeding difficulties, and apnea. Head imaging may demonstrate loss of gray and white matter differentiation, gyral swelling, sulci injury (typically assessed by evaluating the depth of focal lesional injury within the sulci), diffusely elevated T2-weighted signal, and panlobar diffusion restriction throughout the forebrain and midbrain with relative sparring of the brain stem. Prognosis for early-onset MoCD is poor, with about 75% succumbing in infancy to secondary complications of their neurologic disability (i.e., pneumonia).
Late-onset MoCD is typically characterized by milder symptoms, such as acute neurologic decompensation in the setting of infection. Episodes vary in nature but commonly consist of altered mental status, dystonia, choreoathetosis, ataxia, nystagmus, and fluctuating hypotonia and hypertonia. These features may improve after resolution of the inciting infection or progress in a gradual or stochastic manner over the lifetime. Brain imaging may be normal or may demonstrate T2-weighted hyperintense or cystic lesions in the globus pallidus, thinning of the corpus callosum, and cerebellar atrophy.
DIAGNOSIS/TESTING: The diagnosis of molybdenum cofactor deficiency is established by identification of biallelic pathogenic variants in GPHN, MOCS1, MOCS2, or MOCS3, or when unavailable, of significantly reduced activity of the enzyme sulfite oxidase in cultured fibroblasts. However, due to low expression of sulfite oxidase in fibroblasts, differentiation between total and partial loss of enzyme activity is difficult to discern.
MANAGEMENT: Treatment – targeted therapies: In those with MOCS1-related MoCD (MoCD type A), fosdenopterin (NULIBRY®) daily infusion through an indwelling catheter (dose based on weight and age; each vial contains 9.5 mg) may be considered, but must be initiated in a very short window after symptom manifestation to achieve maximum benefit. Affected individuals (all subtypes) are often placed on a cysteine-restricted diet, which typically includes low protein intake with restriction of whole natural protein.
Treatment – supportive care: Feeding therapy and consideration of gastrostomy tube placement in those with concerns about aspiration and/or persistent feeding issues. Thiamine supplementation (1.2 mg/day for infants; 50 mg/1x/day to 100 mg/2x/day for children/adolescents) for those with thiamine deficiency. Magnesium supplementation and standardized migraine prophylactics for those with headaches. Standard treatment for seizures, developmental delay / intellectual disability, spasticity/dystonia, and ectopia lentis.
Surveillance: Routine measurement of essential amino acids in those on a low-cysteine low-protein diet. Assessment for new or progressive neurologic manifestations, measurement of growth parameters and head circumference, monitoring of developmental milestones, and assessment of mobility and self-help skills at each visit. At least annual ophthalmology evaluations. Neuropsychological testing and standardized quality-of-life assessments as clinically indicated.
Agents/circumstances to avoid: Valproate should be avoided if possible, as sulfite intoxication impairs mitochondrial function in vitro. For individuals on fosdenopterin (NULIBRY®), direct sunlight and artificial UV light exposure (i.e., UVA or UVB phototherapy) should be avoided.
Evaluation of relatives at risk: For at-risk newborn sibs in whom prenatal testing was not performed, metabolic treatment should be initiated immediately and continued until such a time as the diagnosis has been excluded through molecular genetic testing or by measurement of serum uric acid and urinary: sulfite, s-sulfocysteine, xanthine, hypoxanthine, and uric acid.
GENETIC COUNSELING: Molybdenum cofactor deficiency (MoCD) is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an MoCD-causing pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the MoCD-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk, and preimplantation genetic testing are possible.