Molybdenum cofactor deficiency: Review of 12 cases (MoCD and review)

doi:10.1016/j.ejpn.2012.10.003

European Journal of Paediatric Neurology

Volume 17, Issue 1, January 2013, Pages 1-6

https://doi.org/10.1016/j.ejpn.2012.10.003 Get rights and content

Abstract

Molybdenum cofactor deficiency is a rare inborn error of metabolism. The major clinical symptoms are intractable neonatal seizures, progressive encephalopathy, facial dysmorphic features and feeding difficulties. Most of the patients are misdiagnosed as hypoxic ischemic encephalopathy. The majority of patients have mutations in the MOCS1 and MOCS2 genes. Although the therapeutic treatment strategies have not been improved, genetic analysis is essential to elucidate the disease. Here, we report a review of 12 patients with Molybdenum cofactor deficiency reported from Turkey.

Introduction

Molybdenum cofactor deficiency (MoCD) is an autosomal recessive disorder characterized by severe and progressive neurological deterioration, intractable seizures, facial dysmorphism, microcephaly and feeding difficulties.1, 2 MoCD leads to a combined deficiency of molybdenum cofactor dependent enzymes including xanthine dehydrogenase, sulphite oxidase, aldehyde oxidase and mitochondrial amidoxime reducing component.3, 4 MoCD mainly affects the central nervous system and may mimic hypoxic ischemic encephalopathy.² Global cerebral edema, cystic encephalomalacia, cortical and white matter atrophy, focal or bilateral changes within the globi pallidi and subthalamic regions, dysgenesis of corpus callosum and ventriculomegaly have been reported.2, 5 Majority of the mutations that caused the MoCD have been described in the genes of molybdenum cofactor synthesis step 1 (MOCS1) and molybdenum cofactor synthesis step 2 (MOCS 2) with two patients reported in gephrin (GPHN) gene.6, 7, 8 Here, we report a 21 day old girl with MoCD, who was previously misdiagnosed as hypoxic ischemic encephalopathy, in whom a homozygous AG deletion in gene MOCS1 has been identified and review of the clinical, radiologic and genetic properties of the other 11 patients reported from Turkey.

Section snippets

A new case diagnosed with molybdenum cofactor deficiency

The patient was the second child of non-consanguineous parents. She was born after an uneventful pregnancy at 39 weeks of gestation. She had a three year old healthy sister. The weight, height and head circumferences at birth were 3500 g (50–75 p), 52 cm (25 p) and 36 cm (10–25 p), respectively. The APGAR scores were 5 at 1 min and 9 at 5 min. She was hypotonic and developed bradycardia and cyanosis. She was transferred to neonatal care unit and needed mechanical ventilation. On the second day

Review of 12 patients reported from Turkey

Molybdenum cofactor deficiency is a rare inborn error of metabolism that was firstly described by Duran et al. in 1978.⁹ Aldehyde oxidase, xanthine dehydrogenase, sulfite oxidase and mitochondrial amidoxime reducing component recently identified are molybdenum cofactor dependent enzymes and the absence of the cofactor leads to a combined deficiency of these four enzymes.⁶ Patients with MoCD present with intractable seizures and feeding difficulties soon after birth. Patients develop severe

References (22)

K. Vijayakumar et al.
Clinical neuroimaging features and outcome in molybdenum cofactor deficiency
Pediatr Neurol
(2011)
J. Reiss et al.
A mutation in the gene for the neurotransmitter receptor-clustering protein gephyrin causes a novel form of molybdenum cofactor deficiency
Am J Hum Genet
(2001)
S. Arslanoglu et al.
Molybdenum cofactor deficiency associated with Dandy-Walker complex
Brain Dev
(2001)
J.O. Sass et al.
Functional deficiencies of sulfite oxidase: differential diagnoses in neonates presenting with intractable seizures and cystic encephalomalacia
Brain Dev
(2010)
H. Per et al.
Molybdenum cofactor deficiency: clinical features in a Turkish patient
Brain Dev
(2007)
A. Veldman et al.
Successful treatment of molybdenum cofactor deficiency type A with cPMP
Pediatrics
(2010)
G. Schwartz et al.
Molybdenum cofactors, enzymes and pathways
Nature
(2009)
A. Havemeyer et al.
The fourth mammalian molybdenum enzyme mARC: current state of research
Drug Metab Rev
(2011)
N. Carmi-Nawi et al.
Prenatal brain disruption in molybdenum cofactor deficiency
J Child Neurol
(2011)
J. Reis et al.
Mutations in the molybdenum cofactor biosynthetic genes MOCS1-MOCS2 and GEPH
Hum Mutat
(2003)

J. Reiss et al.

A GPHN point mutation leading to molybdenum cofactor deficiency

Clin Genet

(2011)

Cited by (45)

Molybdenum Cofactor Deficiency in the Neonate: Expanding the Phenotype
2024, Pediatric Neurology
The effect of dietary protein restriction in a case of molybdenum cofactor deficiency with MOCS1 mutation
2021, Molecular Genetics and Metabolism Reports
Molybdenum cofactor deficiency (MoCD) is an autosomal recessive inborn error of metabolism that results from mutations in genes involved in molybdenum cofactor (Moco) biosynthesis. MoCD is characterized clinically by intractable seizures and severe, rapidly progressing neurodegeneration leading to death in early childhood in the majority of known cases. We report on a patient with an unusual late disease onset and mild phenotype, characterized by delayed development and a decline triggered by a febrile illness and a subsequent dystonic movement disorder. Magnetic resonance imaging showed abnormal signal intensities of the bilateral basal ganglia. Blood and urine chemistry tests demonstrated remarkably low serum and urinary uric acid levels. A urine sulfite test was positive. Specific diagnostic workup showed elevated levels of xanthine and hypoxanthine in serum with increased urinary sulfocysteine (SSC) levels. Genetic analysis revealed a homozygous missense mutation at c.1510C > T (p.504R > W) in exon 10 of the MOCS1 in isoform 7 (rs1387934803). At age 1 year 4 months, the patient was placed on a low protein diet to reduce cysteine load and accumulation of sulfite and SCC in tissues. At 3 months after introduction of protein restriction, the urine sulfite test became negative and the urine SCC level was decreased. After starting the protein restriction diet, dystonic movement improved, and the patient's course progressed without regression and seizures. Electroencephalogram findings were remarkably improved. This finding demonstrates that the dietary protein restriction suppresses disease progression in mild cases of MoCD and suggests the effectiveness of dietary therapy in MoCD.
Molybdenum cofactor biology, evolution and deficiency
2021, Biochimica et Biophysica Acta - Molecular Cell Research
Citation Excerpt :
Defects in any gene involved in the complex process of Moco biosynthesis result in Moco deficiency (MoCD), a rare recessive inborn error of metabolism first described by Duran and coworkers in 1978 [111]. Since then, more than 200 patients have been reported suffering from MoCD [112] caused by mutations affecting any of the steps in Moco biosynthesis [113]. MoCD is separated into three types (A,B and C) according to which step of the biosynthesis is disrupted [28].
The molybdenum cofactor (Moco) represents an ancient metal‑sulfur cofactor, which participates as catalyst in carbon, nitrogen and sulfur cycles, both on individual and global scale. Given the diversity of biological processes dependent on Moco and their evolutionary age, Moco is traced back to the last universal common ancestor (LUCA), while Moco biosynthetic genes underwent significant changes through evolution and acquired additional functions. In this review, focused on eukaryotic Moco biology, we elucidate the benefits of gene fusions on Moco biosynthesis and beyond. While originally the gene fusions were driven by biosynthetic advantages such as coordinated expression of functionally related proteins and product/substrate channeling, they also served as origin for the development of novel functions. Today, Moco biosynthetic genes are involved in a multitude of cellular processes and loss of the according gene products result in severe disorders, both related to Moco biosynthesis and secondary enzyme functions.
Metabolic crisis after trivial head trauma in late-onset isolated sulfite oxidase deficiency: Report of two new cases and review of published patients
2020, Brain and Development
Isolated sulfite oxidase deficiency (ISOD) is a rare autosomal recessively inherited inborn error of metabolism, caused by mutation in SUOX gene. ISOD has two kind of presentation; early and late-onset. The late-onset form is extremely rare and only 10 cases have been reported.
We report two new cases of late-onset ISOD with biochemical and genetic confirmation. We did a review of the previously published cases of late-onset ISOD.
Together with the presented two cases, 12 cases were available for analysis. The median age at symptom onset and at diagnosis was 8.5 and 23 months respectively. Almost all children had acute regression of milestones followed by slow recovery. The common presenting signs and symptoms were movement disorders, seizures, ectopia lentis and hypertonia. Five children had antecedent events. Trivial trauma precipitating the metabolic crisis was unique to the two cases we report. The most common MRI feature was globus pallidi changes followed by cerebellar white matter changes, vermian hypoplasia and thinned out corpus callosum. Diffusion weighted sequence was performed in 3 children and all had diffusion restriction in the affected area.
Trivial trauma can precipitate metabolic crisis in late-onset ISOD. Low plasma homocysteine and involvement of globus pallidi with diffusion restriction on the MRI are important diagnostic clues. Early diagnosis and intervention with special diet may be effective in preventing long term neurodisability.
The Clinical and Molecular Characteristics of Molybdenum Cofactor Deficiency Due to MOCS2 Mutations
2019, Pediatric Neurology
Citation Excerpt :
Treatment of patients with a MOCS1 mutation by cPMP supplementation has been performed, but currently there is no effective therapy for patients with a MOCS2 gene mutation. Management for patients with MOCS2 mutations largely remains supportive and the prognosis is poor.3,22,23 In conclusion, the occurrence of neonatal seizures and feeding difficulties can be the first clinical signs of molybdenum cofactor deficiency.
We explored the clinical and molecular characteristics of molybdenum cofactor deficiency due to MOCS2 muations.
We summarize the genetic and clinical findings of previously reported patients with a MOCS2 mutation. We also present a new patient with novel neuroradiological findings associated with molybdenum cofactor deficiency due to a novel homozygous variant in the 5′ untranslated region of the MOCS2 gene.
The study population comprised 35 patients with a MOCS2 gene mutation. All reported children had delayed motor milestones. The major initial symptom was seizures in neonatal period. Facial dysmorphism was present in 61% of the patients. Only one patient had ectopia lentis. Agenesis of the corpus callosum and an associated interhemispheric cyst in our case are novel neuroradiological findings.
The occurrence of neonatal seizures and feeding difficulties can be the first clinical signs of molybdenum cofactor deficiency. Although there is no effective therapy for this condition, early diagnosis and genetic analysis of these lethal disorders facilitate adequate genetic counseling.
Molybdenum cofactor deficiency: Neuroimaging findings
2018, Radiology Case Reports
Molybdenum cofactor deficiency is an extremely rare and fatal metabolic disorder that should be considered in the differential diagnosis of hypoxic-ischemic encephalopathy. Magnetic resonance imaging findings are useful in diagnosis. The short-echo-time magnetic resonance spectrum was characterized by a total loss of signal and lipid and lactate peaks. In this case, conventional magnetic resonance imaging and magnetic resonance spectroscopy findings of this extremely rare disease whose pathophysiology was not known were presented.

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Review articleMolybdenum cofactor deficiency: Review of 12 cases (MoCD and review)

Abstract

Introduction

Section snippets

A new case diagnosed with molybdenum cofactor deficiency

Review of 12 patients reported from Turkey

Pediatr Neurol

Am J Hum Genet

Brain Dev

Brain Dev

Brain Dev

Successful treatment of molybdenum cofactor deficiency type A with cPMP

Pediatrics

Molybdenum cofactors, enzymes and pathways

Nature

The fourth mammalian molybdenum enzyme mARC: current state of research

Drug Metab Rev

Prenatal brain disruption in molybdenum cofactor deficiency

J Child Neurol

Mutations in the molybdenum cofactor biosynthetic genes MOCS1-MOCS2 and GEPH

Hum Mutat

A GPHN point mutation leading to molybdenum cofactor deficiency

Clin Genet

Review article
Molybdenum cofactor deficiency: Review of 12 cases (MoCD and review)