Treatment of molybdenum cofactor deficiency (MoCD) Type A with cyclic pyranopterin monophosphate (cPMP): a plain language summary

Background: Molybdenum cofactor deficiency (MoCD) is a rare autosomal recessive inborn error of metabolism causing deficiency in molybdenum-dependent enzymes, leading to accumulation of toxic metabolites such as sulfite, resulting in severe neurological damage. We describe a neonate with MoCD type B. Clinical Description: A term neonate, the third child of third-degree consanguineous parents, presented with seizures and encephalopathy shortly after birth. There were two prior sibling deaths due to neonatal seizures. The neonate had hypotonia and exaggerated startle response (hyperekplexia) but no facial dysmorphism. Management and Outcome: Biochemical testing showed undetectable serum uric acid. Brain magnetic resonance imaging revealed findings classical of MoCD with cystic encephalomalacia and lactate peaks on magnetic resonance spectroscopy. Whole-exome sequencing confirmed a homozygous pathogenic variant in the MOCS2 gene. Conclusion: In neonates presenting with refractory seizures and encephalopathy soon after birth, without perinatal asphyxia, MoCD should be suspected, especially in the context of consanguinity or sibling deaths. Low uric acid and suggestive neuroimaging, guide the diagnosis, confirmed by genetic testing. Treatment remains supportive.

Molybdenum Cofactor Deficiency (MoCD) is an autosomal recessive inherited congenital metabolic disease with rare and serious clinical findings. Clinically, neurological findings such as lethargy, hypotonia, and seizures are observed. Clinical findings may be seen immediately or days after birth. It is necessary to distinguish it quickly from hypoxic-ischemic encephalopathy (HIE), which may present with neurological findings immediately after birth and require urgent treatment. Here, we present our patient who had HIE-like clinical findings immediately after birth and was quickly diagnosed with MoCD by laboratory and brain magnetic resonance (MRI). During the follow-up of our patient, the diagnosis was confirmed with the Molybdenum cofactor synthesis 2 (MOCS2) Type B (c.226G>A, (p.G76R) (p.Gly76Arg) mutation, which was genetically identified in a small number of cases. Additionally, our case is the first case in which MoCD was accompanied by a cleft palate. Our aim in presenting the case is to emphasize the importance of distinguishing the conditions that cause neonatal encephalopathy immediately after birth and not to give therapeutic hypothermia treatment inappropriately due to an incorrect diagnosis of hypoxic-ischemic encephalopathy.

ABSTRACTMolybdenum cofactor deficiency (MoCD) is a rare differential diagnosis of neonatal hypoxic ischemic encephalopathy (HIE) with considerable variation in presentation and treatment outcomes. The temporospatial evolution of brain MRI appearances has not been well described. We systematically evaluated 35 MRI brain scans of 13 patients with neonatal MoCD (7 type A, 6 type B) to characterize brain abnormalities arising from exposure to toxicity related to sulfite accumulation and to evaluate changes in response to cPMP treatment in 6 children with MoCD type A. All cases showed evidence of chronic toxicity with developmental disruption. We identified a disease‐specific pattern of acute and chronic brain injury, distinct from HIE. White matter edema, as the earliest sign of sulfite‐related toxicity, indicates a reversible disease stage. The presence of restricted diffusion in the context of MoCD signifies irreversible brain injury and a poor neurological prognosis, irrespective of subsequent biochemical correction upon cPMP treatment. This is the largest neuroimaging study of children with MoCD and the first longitudinal study to examine MR imaging changes in MoCD type A under cPMP substitution. Neuroimaging can identify diagnostic and prognostic features with relevance for treatment decisions and for the evaluation of the effectiveness of treatment attempts.

Metformin restores mitochondrial bioenergetics and redox homeostasis through modulation of mitochondrial biogenesis and dynamics in patient derived cultured fibroblasts and an animal model of molybdenum cofactor deficiency.

Early postnatal hepatocyte transplantation in a child with molybdenum cofactor deficiency type B.

A bstract Molybdenum cofactor deficiency (MoCD) is an inborn error of metabolism characterized by refractory seizures, global developmental delay with psychomotor retardation, and lens dislocation. It may mimic hypoxic-ischemic encephalopathy (HIE) in the neonatal period with seizures and encephalopathy. Later, spastic quadriparesis, microcephaly, and recurrent seizures with imaging features of multi-cystic encephalomalacia masquerading as HIE sequelae. Knowledge about this condition is essential to confirm the diagnosis in the index case and for genetic counseling. A 5-month-old baby presented with recurrent flexor spasms and developmental delay. Examination revealed spastic quadriparesis, microcephaly, and visual difficulty. The child had seizures since the second postnatal day and was on three antiseizure medications. A previous sibling had a similar illness and died at 10 months of age. Magnetic resonance imaging of the brain showed multi-cystic encephalomalacia. Serum calcium, magnesium, lactate, and ammonia were normal. Tandem mass spectrometry was negative. Serum uric acid was low, and urine sulfites were elevated suggestive of MoCD. Genetic testing confirmed the diagnosis. The child was treated with oral steroids for epileptic spasms, antiseizure medications in addition to physiotherapy, occupational therapy and speech therapy. A high index of suspicion is necessary to identify MoCD which may mimic HIE.

ABSTRACTMolybdenum cofactor deficiency (MoCD) Type A is an ultrarare disorder causing neurodegeneration and early death. Cyclic pyranopterin monophosphate (cPMP), a molybdenum cofactor precursor, is a therapeutic option for patients with MoCD Type A. In this study, efficacy in patients with MoCD Type A treated with recombinant cPMP (rcPMP) and/or fosdenopterin, a synthetic form of cPMP, from one retrospective and two prospective open‐label studies (N = 14), was compared with a retrospective/prospective natural history study (untreated; N = 37). Safety was evaluated in treated patients. Patients treated with fosdenopterin/rcPMP had significantly reduced risk of premature/early death versus untreated patients (Cox proportional hazards 5.1; 95% CI 1.32–19.36; p = 0.01). MoCD disease biomarkers of urinary S‐sulfocysteine and xanthine returned to near‐normal from baseline to last visit in treated patients but remained abnormal in untreated patients. At 12 months, in treated patients, 43% could sit unassisted, 44% were ambulatory, and 57% could feed orally. Initiating fosdenopterin/rcPMP treatment ≤ 14 days after birth appeared to result in better clinical outcomes than initiating > 14 days after birth. Most patients (13/14) had a treatment‐emergent adverse event; most were unrelated to fosdenopterin/rcPMP, were mild to moderate in severity, and none led to treatment discontinuation. These results demonstrate that patients with MoCD Type A who received fosdenopterin/rcPMP versus untreated patients were more likely to survive. Some treated patients were able to feed orally and achieve developmental milestones including walking. Fosdenopterin/rcPMP was generally well‐tolerated. Improved outcomes in patients treated early support the importance of identifying MoCD in neonates and initiating treatment as soon as possible.

Xanthinurias are rare inherited disorders of purine metabolism. Xanthinuria type III is caused by molybdenum cofactor deficiency (MoCD) due to pathogenic variants in MOCS1, MOCS2, MOCS3, or GEPH genes. Here, we described five Roma patients from four unrelated families with hypouricemia, accumulation of xanthine/hypoxanthine, deficiency of xanthine oxidase activity, variable age of diagnosis, and only asymptomatic or mild clinical course. Whole exome sequencing was performed on all probands, aged 3 to 43 years, due to lack of genetic confirmation for xanthinuria types I and II. The causality of the putative pathogenic variant was confirmed by analysis of sulfite and related metabolites and in vitro functional characterization of metal-binding pterin (MPT) synthesis and protein complex formation. Considering the rarity of the condition and recessive inheritance, 34 candidate variants were identified after filtering out allele frequency threshold in non-Finnish Europeans. An ultra-rare MOCS2 variant rs776441627 in two overlapping reading frames (c.244A > T (NM_176806.4; p.Ile82Phe) = c.57A > T (NM_004531.5; p.Leu19Phe)) segregated with the disease in all five patients (four homozygotes, one compound heterozygote). The variant has an allele frequency of 3.6% in a Roma population control group. Functional characterization revealed the significantly decreased MPT synthesis activity and confirmed the causality of rs776441627 in MoCD.Conclusion: The rs776441627 is a functional variant for MoCD with a mild to asymptomatic clinical phenotype and fully penetrant biochemical phenotype. Hypouricemia should be considered in the differential diagnostic algorithm of pediatric and adult patients with neurological symptoms, and MOCS2 should be considered in gene panels for xanthinuria screening.What is Known:• Xanthinuria type III is caused by molybdenum cofactor deficiency (MoCD) due to pathogenic variants in MOCS1, MOCS2, MOCS3, or GEPH genes.• The majority of patients with xanthinuria III present with classical early-onset MoCD due to autosomal recessive variants in the MOCS1 gene, manifesting severe progressive neurological complications during the first postnatal days.• To date, approximately 40 patients with MoCD due to pathogenic MOCS2 variants have been reported; most were diagnosed during the neonatal period with intractable seizures and feeding disorders.What is New:• A novel ultra-rare variant, rs776441627, located in two overlapping reading frames of the MOCS2, was identified in five Roma patients presenting a mild to asymptomatic clinical MoCD phenotype and a fully penetrant biochemical phenotype.• Functional studies of p.Ile82Phe (small MOCS2A subunit) and p.Leu19Phe (large MOCS2B subunit) demonstrate a strong reduction in molydopterin synthase complex formation and activity, consistent with the changes in biomarkers of MoCD observed in affected individuals.• The rs776441627 variant shows significantly elevated frequency among the Roma population, highlighting the importance of considering ethnic background in the differential diagnosis of MoCD.• Hypouricemia may provide an initial, generally available biochemical key marker indicator of molybdenum cofactor deficiency.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00431-025-06335-x.

P076: Molybdenum cofactor deficiency: Results of rapid S-sulfocysteine analysis and genome sequencing still not rapid enough

Molybdenum cofactor deficiency (MOCOD) is a rare autosomal recessive disorder associated with a high mortality rate. We report a genetically confirmed MOCOD case of a Sri Lankan infant girl born to a consanguineous family, who presented with refractory neonatal seizures, respiratory distress, and the appearance of global cerebral ischemia on the CT brain. Biochemical investigations revealed hypouricemia, hypouricosuria, and increased urinary xanthine. Genetic analysis revealed a homozygous novel pathogenic variant in the MOCS1 gene, consistent with MOCOD.

We investigated neonatal seizures in three probands admitted to the neonatal intensive care units and their affected family members. Whole exome sequencing (WES) was performed along with confirmation by Sanger sequencing and segregation analysis. Copy number variant (CNV) analysis was also conducted. Neuroimaging, electroencephalography, and metabolic analysis revealed clinical phenotypes. Bi-allelic variants c.1025T>C and c.1150G>A in MOCS1 were found in twin girls with molybdenum cofactor deficiency. The c.1025T>C variant was novel. A c.877C>T variant in KCNQ2 co-segregated with seizures in a family. A de novo 6.25 Mb duplication on 2q24.3 encompassing SCN1A, SCN2A, and SCN3A was identified in a proband who demonstrated normal development without seizures on follow-up. WES facilitated the molecular diagnosis of neonatal seizures in the study participants. Variants in the KCNQ2 and MOCS1 genes were classified as likely pathogenic based on our findings. The individual with a duplication of the sodium channel gene cluster on 2q24.3 exhibited additional phenotypes. Our investigation expanded the genotype-phenotype spectrum.

cPMP rescue of a neonate with severe molybdenum cofactor deficiency after serendipitous early diagnosis, and characterisation of a novel MOCS1 variant

Pharmacodynamic profiling in three patients with molybdenum cofactor deficiency type A reveals prolonged biological effects after withdrawal of cyclic pyranopterin monophosphate

ALDH7A1 deficiency is an epileptic encephalopathy whose seizures respond to treatment with supraphysiological doses of pyridoxine. It arises as a result of damaging variants in ALDH7A1, a gene in the lysine catabolism pathway. α‐Aminoadipic semialdehyde (α‐AASA) and Δ1‐piperideine‐6‐carboxylate (P6C), which accumulate because of the block in the lysine pathway, are diagnostic biomarkers for this disorder. Recently, it has been reported that 6‐oxo‐pipecolic acid (6‐oxo‐PIP) also accumulates in the urine, CSF and plasma of ALDH7A1‐deficient individuals and that, given its improved stability, it may be a more suitable biomarker for this disorder. This study measured 6‐oxo‐PIP in urine from a cohort of 30 patients where α‐AASA was elevated and showed that it was above the normal range in all those above 6 months of age. However, 6‐oxo‐PIP levels were within the normal range in 33% of the patients below 6 months of age. Levels increased with age and correlated with a decrease in α‐AASA levels. Longitudinal analysis of urine samples from ALDH7A1‐deficient patients who were on a lysine restricted diet whilst receiving supraphysiological doses of pyridoxine showed that levels of 6‐oxo‐PIP remained elevated whilst α‐AASA decreased. Similar to α‐AASA, we found that elevated urinary excretion of 6‐oxo‐PIP can also occur in individuals with molybdenum cofactor deficiency. This study demonstrates that urinary 6‐oxo‐PIP may not be a suitable biomarker for ALDH7A1 deficiency in neonates. However, further studies are needed to understand the biochemistry leading to its accumulation and its potential long‐term side effects.

The authors declare no conflict of interest.

Molybdenum cofactor deficiency classically presents in neonates with intractable seizures; however, milder cases generally present before age 2 years with developmental delays and may go undiagnosed. Early diagnosis, and safe, US Food and Drug Administration-approved substrate replacement are critical to preserve neurologic function. This article discusses 2 children who presented with late-onset molybdenum cofactor deficiency type A.

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.

PurposeMolybdenum 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. MethodsA 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. ResultsOf 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. ConclusionPrenatal 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.

INTRODUCTION: Classical xanthinuria is an autosomal recessive hereditary disease which manifests as a result of deficiency of xanthine dehydrogenase which converts hypoxanthine, and xanthine into uric acid. Molybdenum cofactor deficiency, an inherited form of xanthinuria, causes hyperreflexia, microcephaly, and other central nervous system symptoms in newborns. Molybdenum cofactor deficiency, an inherited form of xanthinuria, causes hyperreflexia, microcephaly, and other central nervous system symptoms in newborns. The function of three different enzymes (xanthine dehydrogenase, aldehyde oxidase, and sulfite oxidase) depends on a molybdenum-containing cofactor that is congenitally defective in this disorder. CASE REPORT: A full term female baby born to a G3P1L1A1 mother via normal vaginal delivery was referred from outside hospital on day of life 10 in view of one episode of convulsion on day 3 of life. Baby was screened for inborn errors of metabolism which revealed increased excretion of Xanthine in urine. MRI of brain was done which showed extensive areas of diffusion restriction involving bilateral cerebral hemispheres, bilateral corticospinal tracts and corpus callosum suggestive of Acute hypoxic ischaemic encephalopathy. DISCUSSION: Because of enzymatic deficiency, xanthine dehydrogenase cannot be converted into uric acid which leads to increase in blood levels, and urinary excretion of hypoxanthine, and xanthine. Since these substances have a lower solubility in urine, they accumulate in the urinary system leading to formation of stones. Reduced or undetectable serum uric acid levels associated with MoCD are a result of the deficiency of xanthine dehydrogenase. Most of the patients with classical xanthinuria are asymptomatic, and in 30% of the cases urolithiasis develops. CONCLUSION: Refractory seizures, encephalopathy, and the absence of radiologic signs of HIE a positive family history of perinatal asphyxia, and refractory seizures are contributors in newborn fatalities that demonstrate a significant tendency to develop xanthinuria. A thorough research regarding its prevalence and prognosis should be done. Keywords: xanthinuria, autosomal recessive hereditary disease, newborn