Summary
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.
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.
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.
Diagnosis
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 Clinical Characteristics.)
- Ophthalmologic manifestations (e.g., ectopia lentis)
- Variable course of stochastic regression, sometimes around infection
Suggestive laboratory findings
- Elevated taurine and decreased cystine concentrations on plasma amino acid analysis
- Decreased plasma total homocysteine concentration
- Elevated xanthine and hypoxanthine concentrations on urine pyrimidine analysis
- Decreased plasma uric acid concentration
- Elevated urine levels of S-sulfocysteine and thiosulfate on targeted measurement
Note: Because elevations of these metabolites individually are not entirely specific to molybdenum cofactor deficiency, follow-up testing is required to establish or rule out the diagnosis of molybdenum cofactor deficiency (see Establishing the Diagnosis).
Brain MRI findings
- Acute
- Diffusion restriction and elevated T2-weighted signal throughout the cortical ribbon, subcortical white matter, basal ganglia, midbrain, and to a lesser extent the pons and medulla
- Gyral swelling
- In some affected individuals in the first days of life, imaging features suggestive of prenatal-associated injury
- Chronic
- Atrophy of the cortex, subcortical white matter, basal ganglia, corpus callosum, and/or cerebellum
- High T1-weighted signal in the basal ganglia
- Cavitary leukomalacia
- Ulegyria (mushroom-shaped morphology of gyri resulting from injury and contraction of sulci; also seen in neonatal hypoxic ischemic injury)
- MR spectroscopy
- Lactate doublet
- Glutamine-glutamate (Glx) peak
Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a positive family history does not preclude the diagnosis.
Establishing the Diagnosis
The diagnosis of molybdenum cofactor deficiency is established by identification of biallelic pathogenic (or likely pathogenic) variants in GPHN, MOCS1, MOCS2, or MOCS3 (Table 1), 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. Because of its high sensitivity, molecular genetic testing typically obviates the need for enzymatic testing and thus is the preferred diagnostic test for MoCD.
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include any likely pathogenic variants. (2) Identification of biallelic variants of uncertain significance (or of one known pathogenic variant and one variant of uncertain significance) does not establish or rule out the diagnosis.
Molecular genetic testing approaches can include gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of MoCD has not been considered are more likely to be diagnosed using genomic testing (see Option 2).
Option 1
When the phenotypic and laboratory findings suggest the diagnosis of MoCD, molecular genetic testing typically includes use of a multigene panel.
A neonatal seizure, epilepsy, or neurodegenerative multigene panel that includes GPHN, MOCS1, MOCS2, MOCS3, and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Option 2
When the phenotype is indistinguishable from other inherited disorders characterized by neonatal seizures, epilepsy, or neurodegeneration, comprehensive genomic testing (which does not require the clinician to determine which gene is involved) may be considered. Exome sequencing is most commonly used; genome sequencing is also possible.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
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Table 1.
Molecular Genetic Testing Used in Molybdenum Cofactor Deficiency (MoCD)
Clinical Characteristics
Clinical Description
More than 100 individuals with a molybdenum cofactor deficiency have been identified [Misko et al 2020; Authors, personal observations]. As is the case for many inborn errors of metabolism, 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).
Early-Onset or Severe MoCD
Affected individuals typically present in the first days of life (median1 day; range 1-50 days) with severe encephalopathy, including refractory seizures, opisthotonos, axial hypotonia and appendicular hypertonia, feeding difficulties, and apnea [Misko et al 2020]. Prenatal and birth histories are usually unremarkable, though up to 40% of affected individuals have Apgar scores <7 at one minute with subsequent improvement at five and ten minutes. Lack of a sentinel event in the perinatal period and a delay between birth and the onset of symptoms help distinguish MoCD from neonatal hypoxic ischemic injury. Table 2 lists the most common findings of early-onset MoCD.
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Table 2.
Select Features of Early-Onset or Severe Molybdenum Cofactor Deficiency
Neurologic signs. MoCD primarily affects the central nervous system without involvement of the peripheral nervous system. Affected individuals develop severe psychomotor impairment, spastic quadriplegia, and extrapyramidal rigidity over the first months of life. The severity of cognitive and motor impairment is consistent with the catastrophic degeneration of the cortical and subcortical structures in virtually all affected individuals. Affected individuals may also display nystagmus, myoclonic jerks, or hyperekplexia (excessive startle reaction to loud noises, touch, or movement) with or without concurrent seizures [Macaya et al 2005, Zaki et al 2016]. Manifestations of neonatal hyperekplexia include abnormal responses to auditory, visual, and somatosensory stimuli such as exaggerated startle response and tonic spasms. The tonic spasms may mimic generalized tonic seizures, resulting in apnea without electrographic seizure.
Brain MRI findings. Acute findings in the neonatal period closely resemble those observed in individuals with hypoxic-ischemic injury. Loss of gray and white matter differentiation, gyral swelling, sulci injury (typically assessed by evaluating the depth of the focal lesional injury within the sulci), diffusely elevated T2-weighted signal, and panlobar diffusion restriction are present throughout the forebrain and midbrain, with relative sparing of the brain stem. Prominent lactate doublets and a glutamine/glutamate peak are frequently observed on MR spectroscopy in affected areas. Over the course of several weeks, severe cortical atrophy, cystic leukomalacia, and degeneration of the basal ganglia develop. In contrast to hypoxic-ischemic injury, diffusion restriction is still present in areas of remaining parenchyma through the chronic phase of disease. Progressive thinning of the corpus callosum and cerebellar atrophy also develop with time [Vijayakumar et al 2011]. See also Suggestive Findings, Brain MRI findings.
It is particularly important to distinguish those with MoCD from those with hypoxic ischemic encephalopathy (HIE) because of the potential use of fosdenopterin (NULIBRY®) for treatment of MOCS1-related MoCD (see Management, Targeted Therapies). Radiographic features present in those with MoCD but typically absent in those with HIE include the following:
- Mega cisterna magna or Dandy-Walker malformation
- Hypoplastic/atrophic corpus callosum or cerebellum
- Evidence of prenatal brain degeneration present at the time of birth (cortical atrophy, cystic leukomalacia, or basal ganglia degeneration).
While these features are inconsistently present across all individuals with early-onset or severe MoCD, their presence should suggest MoCD in the right clinical setting. Absence of these findings does not exclude the diagnosis of MoCD.
Seizures and EEG findings. Seizures are the most frequent initial cardinal sign in infants with early-onset MocD. Affected individuals typically develop seizures within two weeks of birth. Seizures are typically refractory to anti-seizure medication, but gradually decrease in frequency over time [Macaya et al 2005, Zaki et al 2016].
- A variety of seizure semiologies have been reported including subtle, clonic, tonic myoclonic, multifocal, and partial migrating.
- A case of epileptic spasms diagnosed at 26 days of life has also been described [Stence et al 2013].Accompanying EEG changes for those with infantile spasms may include burst suppression, multifocal epileptiform discharges, unilateral discharges, generalized or focal slowing, and hypsarrhythmia.
- The diversity of reported semiologies suggests that seizures in those with typical MoCD are secondary to the diffuse cortical degeneration seen on ancillary brain imaging and not specific to the underlying pathophysiology.
Developmental findings. All affected individuals develop severe cognitive impairment and spastic quadriplegia that parallels progressive degeneration of the forebrain and cerebellum. Affected individuals typically demonstrate minimal cognitive function or interaction with their environment. Gross and fine motor development are severely impaired, with most affected individuals unable to maintain head or truncal posture. Affected individuals typically do not develop verbal language and have limited or no receptive language capacity. As the brain stem is relatively preserved, brain stem function typically remains intact.
Respiratory. Apneic episodes during the first days of life have been frequently reported in individuals with typical MoCD. Though the duration and severity of episodes are largely unknown, they are likely consistent with episodes of central apnea secondary to the severe neurodegenerative phenotype. Alternatively, apneic episodes could be a manifestation of seizures. As commonly encountered in other severe neurodegenerative disorders, individuals with severe motor impairments may develop aspiration pneumonia as a consequence of the inability to protect the airway. Aspiration pneumonia may also occur secondary to gastroesophageal reflux disease or pyloric stenosis.
Growth/feeding. Head circumference is typically normal at birth but acquired microcephaly develops as a result of progressive brain degeneration. Dysphagia and aspiration may develop, and a swallow study should be pursued if clinical suspicion arises. Given the progressive neurodegenerative course of MoCD, a gastrostomy tube may be necessary on a permanent basis to prevent aspiration and to support feeding and nutrition.
Although structural malformations of the gastrointestinal tract are not typically seen in association with MoCD, pyloric stenosis has been diagnosed in two individuals with MoCD and in two individuals with isolated sulfite oxidase deficiency, suggesting a possible connection with sulfite intoxication [Parini et al 1997, Tezel et al 2012].
Ophthalmologic findings. Approximately 16% of affected individuals develop ectopia lentis, which presents later in the course of disease (age at identification: median 1 year; range 3 months to 8 years). Other rarer findings may include enophthalmos, microphthalmia, and spherophakia.
Nonspecific dysmorphic features. Affected individuals have dysmorphic facial features that include coarse facial features, bitemporal narrowing, long face, prominent cheeks, widely spaced eyes, enopthalmos, frontal bossing, long palpebral fissures, long philtrum, small nose, and thick vermilion of the upper and lower lips. These features are usually evident in the neonatal period.
Prognosis is poor: about 75% of affected individuals succumb in infancy to secondary complications of their neurologic disability (i.e., pneumonia). Fosdenopterin (NULIBRY®) or recombinant cyclic pyranopterin monophosphate was reported to reduce the risk of death in individuals with MOCS1-related MoCD by 82% compared to untreated, genotype-matched, historical controls (HR = 0.18, 95% CI 0.04, 0.72) (see NULIBRY®, prescribing information; see also Table 6 and Management, Targeted Therapies). Fosdenopterin is the first FDA-approved drug that alters mortality in individuals with MOCS1-related MoCD.
Late-Onset or Mild MoCD
A less severe phenotype with late-onset presentation (1 year; range 4 months to 23 years) and milder symptoms has been recognized (see Table 3).
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Table 3.
Select Features of Late-Onset or Mild Molybdenum Cofactor Deficiency
Neurologic findings. Acute neurologic decompensation in the setting of infection may be the first sign of MoCD and may prompt an evaluation that leads to the diagnosis. 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 [Misko et al 2020]. Headaches have also been observed and anecdotally reported; the nature of these headaches is poorly understood [Authors, personal observation].
Brain imaging. T2-weighted hyperintense or cystic lesions in the globus pallidus, thinning of the corpus callosum, and cerebellar atrophy are frequently reported in milder phenotypic variants, even outside of an inciting event; however, brain MRI may also be normal. Those who experience progressive neurologic symptoms may also show accompanying cerebral atrophy. Similar to what has been described in the early-onset or severe form, atrophy of the corpus callosum and mega cisterna magna may also be present.
Seizures are less common compared to those who have early-onset or severe MoCD. Reported semiologies include tonic-clonic, partial, and atonic. The natural history of seizures and response to anti-seizure medication is poorly understood in those with late-onset or mild MoCD.
Developmental. These individuals may have a history of normal cognitive development or mild developmental delay with hypotonia before first coming to medical attention, which frequently occurs as a result of acute neurologic deterioration.
Growth/feeding. Dysphagia has been reported in a few individuals with late-onset MoCD; a detailed understanding of the onset, duration, and severity of dysphagia is not available.
Ophthalmologic findings. Ectopia lentis may develop. The timing of onset is uncertain; reports have ranged from age six months to eight years at the time of diagnosis.
Prognosis for this form of MoCD is poorly understood. Longitudinal natural history studies are needed to better define outcomes.
Phenotype Correlations by Gene
No clear phenotype correlations have been observed. However, to date the only individuals described with a pathogenic variant in MOCS3 had the late-onset or mild form of MoCD due to partial loss of MOCS3 function.
Nomenclature
Sometimes MoCD is divided into subtypes based on the causative gene. This has become more important now that a targeted treatment is available for one subtype (see Management, Targeted Therapies). The subtypes are denoted as follows: MOCS1-related MoCD is type A, MOCS2-related MoCD is type B, and GPHN-related MoCD is type C. Because of the paucity of known affected individuals with MOCS3-related MoCD, this has not yet been given another subtype designation.
Genotype-Phenotype Correlations
No genotype-phenotype correlations are known to be associated with biallelic pathogenic variants in any gene associated with MoCD.
Prevalence
The global incidence of MoCD is estimated at 1:100,000-1:200,000 live births. Like many other rare diseases, the true incidence remains uncertain, as MoCD is likely underdiagnosed.
Genetically Related (Allelic) Disorders
At present, no phenotypes other than those discussed in this GeneReview are known to be associated with biallelic pathogenic variants in GPHN, MOCS1, MOCS2, or MOCS3.
Differential Diagnosis
Early-Onset or Severe Molybdenum Cofactor Deficiency
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Table 4.
Genes of Interest in the Differential Diagnosis of Early-Onset or Severe Molybdenum Cofactor Deficiency
Late-Onset or Mild Molybdenum Cofactor Deficiency
The differential diagnosis of late onset or mild molybdenum cofactor deficiency includes acquired conditions (e.g., cerebral palsy) and hereditary disorders of basal ganglia and development with extrapyramidal signs and developmental delay including juvenile-onset Huntington disease, early-onset Parkinson disease, Lesch-Nyan disease (see HPRT1 Disorders), progressive supranuclear palsy (OMIM 601104), and Wilson disease.
Management
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 in Table 5 (if not performed as part of the evaluation that led to the diagnosis) are recommended.
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Table 5.
Recommended Evaluations Following Initial Diagnosis of Molybdenum Cofactor Deficiency
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 (see Table 6).
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Table 6.
Targeted Therapies for Molybdenum Cofactor Deficiency
Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended, ideally involving multidisciplinary care by specialists in relevant fields (see Table 7).
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Table 7.
Supportive Treatment of Manifestations in Individuals with Molybdenum Cofactor Deficiency
Developmental Delay / Intellectual Disability Management Issues
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability in the United States. Standard recommendations may vary from country to country.
Ages 0-3 years. Referral to an early intervention program is recommended for access to occupational, physical, speech, and feeding therapy as well as infant mental health services, special educators, and sensory impairment specialists. In the US, early intervention is a federally funded program available in all states that provides in-home services to target individual therapy needs.
Ages 3-5 years. In the US, developmental preschool through the local public school district is recommended. Before placement, an evaluation is made to determine needed services and therapies and an individualized education plan (IEP) is developed for those who qualify based on established motor, language, social, or cognitive delay. The early intervention program typically assists with this transition. Developmental preschool is center based; for children too medically unstable to attend, home-based services are provided.
All ages. Consultation with a developmental pediatrician is recommended to ensure the involvement of appropriate community, state, and educational agencies (US) and to support parents in maximizing quality of life. Some issues to consider:
- IEP services:
- An IEP provides specially designed instruction and related services to children who qualify.
- IEP services will be reviewed annually to determine whether any changes are needed.
- Special education law requires that children participating in an IEP be in the least restrictive environment feasible at school and included in general education as much as possible, when and where appropriate.
- Vision and hearing consultants should be a part of the child's IEP team to support access to academic material.
- PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
- As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
- A 504 plan (Section 504: a US federal statute that prohibits discrimination based on disability) can be considered for those who require accommodations or modifications such as front-of-class seating, assistive technology devices, classroom scribes, extra time between classes, modified assignments, and enlarged text.
- Developmental Disabilities Administration (DDA) enrollment is recommended. DDA is a US public agency that provides services and support to qualified individuals. Eligibility differs by state but is typically determined by diagnosis and/or associated cognitive/adaptive disabilities.
- Families with limited income and resources may also qualify for supplemental security income (SSI) for their child with a disability.
Motor Dysfunction
Gross motor dysfunction
- Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
- Consider use of durable medical equipment and positioning devices as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
- For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox®, anti-parkinsonian medications, or orthopedic procedures.
Fine motor dysfunction. Occupational therapy is recommended for difficulty with fine motor skills that affect adaptive function such as feeding, grooming, dressing, and writing.
Oral motor dysfunction should be assessed at each visit and clinical feeding evaluations and/or radiographic swallowing studies should be obtained for choking/gagging during feeds, poor weight gain, frequent respiratory illnesses, or feeding refusal that is not otherwise explained. Assuming that the child is safe to eat by mouth, feeding therapy (typically from an occupational or speech therapist) is recommended to help improve coordination or sensory-related feeding issues. Feeds can be thickened or chilled for safety. When feeding dysfunction is severe, a nasogastric or gastrostomy tube may be necessary.
Communication issues. Consider evaluation for alternative means of communication (e.g., augmentative and alternative communication [AAC]) for individuals who have expressive language difficulties. An AAC evaluation can be completed by a speech-language pathologist who has expertise in the area. The evaluation will consider cognitive abilities and sensory impairments to determine the most appropriate form of communication. AAC devices can range from low-tech, such as picture exchange communication, to high-tech, such as voice-generating devices. Contrary to popular belief, AAC devices do not hinder verbal development of speech, but rather support optimal speech and language development.
Social/Behavioral Concerns
Children may qualify for and benefit from interventions used in treatment of autism spectrum disorder, including applied behavior analysis (ABA). ABA therapy is targeted to the individual child's behavioral, social, and adaptive strengths and weaknesses and typically performed one on one with a board-certified behavior analyst.
Consultation with a developmental pediatrician may be helpful in guiding parents through appropriate behavior management strategies or providing prescription medications, such as medication used to treat attention-deficit/hyperactivity disorder (ADHD), when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Surveillance
In addition to regular evaluations by a metabolic specialist, the following are recommended.
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Table 8.
Recommended Surveillance for Individuals with Molybdenum Cofactor Deficiency
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 (see Table 6).
Evaluation of Relatives at Risk
For at-risk newborn sibs when prenatal testing was not performed, metabolic treatment should be initiated immediately and continued until such a time as the diagnosis has been excluded. Postnatal diagnostic evaluations can include the following:
- Molecular genetic testing if the pathogenic variants in the family are known
- If the pathogenic variants in the family are not known, measure serum uric acid and urinary: sulfite, s-sulfocysteine, xanthine, hypoxanthine, and uric acid.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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.
Genetic Counseling
Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.
Mode of Inheritance
Molybdenum cofactor deficiency (MoCD) is inherited in an autosomal recessive manner.
Risk to Family Members
Parents of a proband
- The parents of an affected child are obligate heterozygotes (i.e., presumed to be carriers of one GPHN, MOCS1, MOCS2, or MOCS3 pathogenic variant based on family history).
- If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of a proband to confirm that both parents are heterozygous for an MoCD-causing pathogenic variant and to allow reliable recurrence risk assessment. If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, the following possibilities should be considered:
- One of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017].
- Uniparental isodisomy for the parental chromosome with the pathogenic variant resulted in homozygosity for the pathogenic variant in the proband.
- Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Sibs of a proband
- 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.
- Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Offspring of a proband. To date, individuals with MoCD are not known to reproduce.
Other family members. Each sib of the proband's parents is at a 50% risk of being a carrier of an MoCD-causing pathogenic variant.
Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the MoCD-causing pathogenic variants in the family.
Related Genetic Counseling Issues
See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.
Family planning
- The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
- It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are carriers or are at risk of being carriers.
DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].
Prenatal Testing and Preimplantation Genetic Testing
Once the MoCD-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
Resources
GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.
- MedlinePlus
Molecular Genetics
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.
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Table A.
Molybdenum Cofactor Deficiency: Genes and Databases
![Table Icon](/corehtml/pmc/css/bookshelf/2.26/img/table-icon.gif)
Table B.
OMIM Entries for Molybdenum Cofactor Deficiency (View All in OMIM)
Molecular Pathogenesis
The molybdenum cofactor (Moco) is synthesized from guanosine triphosphate (GTP) via a biochemical pathway that can be divided into four steps according to four intermediates: cyclic pyranopterin monophosphate (cPMP; also known previously as precursor Z), MPT, adenylated MPT (MPT-AMP), and Moco. See Figure 1 for an illustration of the pathway and how MOCS1, MOCS2, MOCS3, and GPHN are involved in Moco synthesis.
![Figure 1. . Synthesis of molybdendum cofactor (Moco).](/books/NBK575630/bin/mc-def-Image001.gif)
Figure 1.
Synthesis of molybdendum cofactor (Moco). GTP is converted to cPMP by MOCS1. cPMP is converted to MPT by MOCS2 and MOCS3. The final step is conversion of MPT to Moco by GPHN.
Although four human enzymes are dependent on Moco for catalytic function (sulfite oxidase, the mitochondrial amidoxime reducing component, xanthine oxidase, and aldehyde oxidase), the loss of sulfite oxidase activity alone is necessary and sufficient to give rise to the phenotype of MoCD. Sulfite oxidase catalyzes the oxidation of sulfite to sulfate in the last step of methionine and cysteine catabolism (the sulfur-containing amino acids). In the absence of sulfite oxidase, sulfite accumulates in the blood, urine, and CSF of affected individuals. Because the enzyme is highly expressed in liver and kidney, these organs may be responsible for the generation of sulfite in affected individuals.
Data suggest that sulfite and S sulfocysteine (the reaction product of sulfite and cystine) are the toxic metabolites responsible for neurodegeneration in individuals with MoCD and isolated sulfite oxidase deficiency. Sulfite depletes intracellular ATP in cultured neuronal cell lines and impairs mitochondrial respiration. S sulfocysteine is stereochemically similar to glutamate and activates NMDA receptors [Kumar et al 2017]. The proposed pathomechanisms associated with these metabolites fit well with the brain MRI features which suggest critical energy failure and excitotoxic injury.
Xanthine oxidase requires Moco for the breakdown of nucleotides to uric acid. Aldehyde oxidase requires Moco to catalyze a number of hydroxylation reactions. Mitochondrial amidoxime-reducing component, together with NADH-cytochrome b5 reductase and cytochrome b5, is thought to require Moco for catalyzation detoxification of mutagenic N-hydroxylated bases, although the exact function is as yet unclear.
Mechanism of disease causation. Loss of function
Chapter Notes
Revision History
- 2 February 2023 (pa/ma) Revision: fosdenopterin added as targeted treatment for MOCS1-related MoCD (MoCD type A) (Targeted Therapies)
- 2 December 2021 (ma) Review posted live
- 4 January 2021 (pa) Original submission
References
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Publication Details
Author Information and Affiliations
Massachusetts General Hospital
Harvard Medical School
Boston, Massachusetts
Palm Beach, Florida
Palm Beach, Florida
Department of Chemistry & Center for Molecular Medicine
Cologne University
Cologne, Germany
Palm Beach, Florida
Publication History
Initial Posting: December 2, 2021; Last Revision: February 2, 2023.
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NLM Citation
Misko A, Mahtani K, Abbott J, et al. Molybdenum Cofactor Deficiency. 2021 Dec 2 [Updated 2023 Feb 2]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024.