Clinical Guidance

No genotype-phenotype correlations are known to be associated with biallelic pathogenic variants in any gene associated with MoCD.

Source: GeneReviews — "Molybdenum Cofactor Deficiency"

Diagnostic Criteria

Formal clinical diagnostic criteria for molybdenum cofactor deficiency have not been established.

Suggestive Findings

Molybdenum cofactor deficiency (MoCD) typically manifests in the neonatal period and should be suspected in individuals with the following clinical, supportive laboratory, brain MRI, and family history findings.

Clinical findings

• Acute encephalopathy

• Intractable seizures

• Poor feeding

• Hyperekplexia (excessive startle reaction to loud noises, touch, or movement)

• Apnea

• Pyramidal and extrapyramidal dysfunction

• Severe developmental delay / intellectual disability

• Acquired microcephaly

• Nonspecific craniofacial dysmorphic features (See .)

• Ophthalmologic manifestations (e.g., ectopia lentis)

• Variable course of stochastic regression, sometimes around infection

Source: GeneReviews — "Molybdenum Cofactor Deficiency"

Differential Diagnosis

Early-Onset or Severe Molybdenum Cofactor Deficiency

Table 4.

Genes of Interest in the Differential Diagnosis of Early-Onset or Severe Molybdenum Cofactor Deficiency

Gene(s) | Disorder | MOI | Clinicoradiographic Findings | Laboratory Findings/ Comment

SUOX | Isolated sulfite oxidase deficiency (ISOD) | AR | Identical to MoCD | • plasma taurine

• urinary thiosulfate S-sulfocysteine

• plasma levels of total homocysteine cystine

Unlike MoCD, serum uric acid levels are normal in ISOD as are urine xanthine hypoxanthine levels.

ALDH7A1

| Pyridoxine-dependent epilepsy (PDE) | AR | • Neonates w/pyridoxine-responsive seizures refractory to ASM encephalopathy

• Thinning of corpus callosum mega cisterna magna on brain MRI

Source: GeneReviews — "Molybdenum Cofactor Deficiency"

Management Guidelines

When molybdenum cofactor deficiency (MoCD) is suspected during the diagnostic evaluation (i.e., due to laboratory findings consistent with the condition), metabolic treatment should be initiated immediately. If laboratory findings and/or clinical presentation are highly suggestive, treatment should be initiated prior to the availability of confirmatory genetic testing. No consensus clinical treatment guidelines have been published. Evaluations Following Initial Diagnosis To establish the extent of disease and needs in an individual diagnosed with MoCD, the evaluations summarized (if not performed as part of the evaluation that led to the diagnosis) are recommended. Table 5. Recommended Evaluations Following Initial Diagnosis of Molybdenum Cofactor Deficiency Evaluation | Comment Consultation w/metabolic physician / biochemical geneticist1 | Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended). Consultation w/neurologist | To evaluate manage seizures Consultation w/gastroenterologist, nutritionist, feeding team | To evaluate: • Aspiration risk nutritional status; • Gastrostomy tube placement in those w/dysphagia /or aspiration risk. Polysomnogram | To assess for central apnea in those w/apnea after a long-term EEG excludes seizures as the primary cause. Consultation w/ophthalmologist | To assess for vision, abnormal ocular movement, strabismus Consultation w/psychologist /or social worker | To ensure understanding of the diagnosis assess parental / affected person's coping skills resources Consultation w/PT, OT, speech therapist | To aid in developmental deficiencies Developmental assessment | Consider referral to developmental pediatrician. Genetic counseling2 | To inform affected persons families re nature, MOI, implications of molybdenum cofactor deficiency in order to facilitate medical personal decision making MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist 1. After a new diagnosis of molybdenum cofactor deficiency in an infant, the closest hospital and local pediatrician should also be informed. 2. Medical geneticist, certified genetic counselor, certified advanced genetic nurse Treatment of Manifestations Targeted Therapies In GeneReviews, a targeted therapy is one that addresses the specific underlying mechanism of disease causation (regardless of whether the therapy is significantly efficacious for one or more manifestation of the genetic condition); would otherwise not be considered without knowledge of the underlying genetic cause of the condition; or could lead to a cure. —ED There is no cure for MoCD. However, targeted therapies for individuals with all subtypes of MoCD and specifically for MOCS1-related MoCD (MoCD type A) are available . Table 6. Targeted Therapies for Molybdenum Cofactor Deficiency

Source: GeneReviews — "Molybdenum Cofactor Deficiency"

Clinical Guidance

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 .

Source: GeneReviews — "Molybdenum Cofactor Deficiency"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Source: GeneReviews — "Molybdenum Cofactor Deficiency"

Surveillance Guidelines

In addition to regular evaluations by a metabolic specialist, the following are recommended. Table 8. Recommended Surveillance for Individuals with Molybdenum Cofactor Deficiency

Source: GeneReviews — "Molybdenum Cofactor Deficiency"