Molybdenum cofactor deficiency presenting with a parkinsonism‐dystonia syndrome

Alkufri, Fadi; Harrower, Tim; Rahman, Yusof; Hughes, Elaine; Mundy, Helen; Knibb, Jonathan A.; Moriarty, John; Connor, Steve; Samuel, Michael

doi:10.1002/mds.25276

Cited by 19 publications

(21 citation statements)

References 5 publications

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“…1,6,5 Clinical phenotype is expanding with recognition of lens dislocation as forme fruste of neurologic manifestations, neonatal hyperekplexia with startle and flexor spasms leading to apnea without any electrographic seizure, and adult-onset progressive parkinsonism-dystonia syndrome. 7 The majority of the affected individuals die of the illness within the first few days or weeks of life. 6 Late-onset, milder phenotype with survival into adult life and neurologically asymptomatic patients detected during sibling screening are also reported.…”

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confidence: 99%

Child Neurology: Molybdenum cofactor deficiency

et al. 2015

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Molybdenum cofactor deficiency (MoCD) is a rare inherited metabolic disorder characterized by neonatal onset intractable seizures, severe psychomotor retardation, dysmorphic facies, and dislocated ocular lenses.1 A characteristic biochemical profile permits early diagnosis. Although more than 100 genetically characterized patients have been reported, this number is discrepant with the actual prevalence as MoCD is often mistaken for hypoxic-ischemic encephalopathy (HIE) secondary to perinatal asphyxia. It is important to recognize MoCD to provide appropriate genetic counseling and prenatal diagnosis.2 Effective pharmacotherapies that overcome the primary biochemical defect are also in the pipeline. We present a child with biochemically and genetically confirmed MoCD and discuss the clinical, imaging, biochemical, and genetic profile of this disorder.CASE REPORT A 4-year-old boy from the south Indian state of Kerala presented with developmental delay and seizures. He was the only child of consanguineous parents (first cousins). He was born at term following an uneventful antenatal period with a birthweight of 3.25 kg, cried immediately at birth, and did not have features of birth asphyxia. He developed generalized seizures on the fifth day of life. The seizures remained refractory to multiple anticonvulsants at optimal dosages. He also developed episodes of intermittent sudden flexion of trunk and limbs once in 1-2 minutes. The frequency of these episodes was reduced with time and occurred in response to sound only. Since 6 months of age, he developed progressive stiffness with intermittent posturing of neck and trunk. There was no history of neurologic illness in the family.On examination, he was irritable and poorly nourished with intermittent stridor. He had microcephaly with head circumference of 46 cm, bilaterally dislocated lenses, and could not fix or track light. He had exaggerated startle to sound. There was severe spasticity, cervical dystonia, and opisthotonus. Investigations showed normal hemogram, renal and hepatic function tests, serum vitamin B 12 , folic acid, and biotidinase levels. Cytogenetic study showed normal male karyotype. Screening for amino-acidemias, organic acidemias, and disorders of fatty acid oxidation by tandem mass spectrometry drew negative results. Urine analysis for abnormal metabolites, glycosaminoglycans, total mucopolysaccharides, and organic acids was normal. Lactate (32.9 mg/dL; ref 4.5-20 mg/dL) and ammonia (67.7 mg/dL; ref 11-35 mg/dL) were mildly elevated. Mild laryngomalacia was detected on bronchoscopic examination. Brain MRI done at fourth month of life showed severe diffuse cerebral atrophy, areas of T2 shortening in bilateral basal ganglia suggestive of intracranial haemorrhage, and pontine hypoplasia with enlargement of the prepontine cistern ( figure, A-D). EEG showed recurrent multifocal epileptiform discharges.Serum homocysteine was markedly reduced (0.9 mmol/L; ref 4-12 mmol/L), and uric acid was undetectable. Examination of purine metabolites in urine showed the

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confidence: 99%

Child Neurology: Molybdenum cofactor deficiency

et al. 2015

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“…A late‐onset form has also been reported in literature in 13 patients (Alkufri et al, ; Arenas et al, ; Graf et al, ; Hughes et al, ; Huijmans et al, ; Johnson et al, , ; Mayr et al, ; Megahed et al, ; Mize et al, ; Shih et al, ; Vijayakumar et al, ; Zaki et al, ). Table below compares the clinical, genetic, neurological, and neuroradiological findings of those with our patient.…”

Section: Discussionmentioning

confidence: 78%

“…The classical form manifests in the neonatal period with severe encephalopathy, including intractable seizures, MRI changes that resemble hypoxic‐ischemic injury, microcephaly, and early death (Mechler et al, ). In the literature, an atypical phenotype with late‐onset has been recognized and to date only 13 patients are reported (Alkufri et al, ; Arenas et al, ; Graf, Oleinik, Jack, Weiss, & Johnson, ; Hughes, Fairbanks, Simmonds, & Robinson, ; Huijmans et al, ; Johnson et al, ; Johnson, Wuebbens, Mandell, & Shih, ; Mayr et al, ; Megahed et al, ; Mize, Johnson, & Rajagopalan, ; Shih et al, ; Vijayakumar et al, ; Zaki et al, ).…”

Section: Introductionmentioning

confidence: 99%

Mild phenotype in Molybdenum cofactor deficiency: A new patient and review of the literature

Scelsa

Gasperini

Righini

et al. 2019

Molec Gen & Gen Med

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Background Molybdenum cofactor deficiency (MoCD) is a rare autosomal‐recessive disorder that results in the combined deficiency of molybdenum‐dependent enzymes. Four different genes are involved in Molybdenum cofactor biosynthesis: MOCS1, MOCS2, MOCS3, and GEPH. The classical form manifests in the neonatal period with severe encephalopathy, including intractable seizures, MRI changes that resemble hypoxic‐ischemic injury, microcephaly, and early death. To date, an atypical phenotype with late‐onset has been reported in the literature in 13 patients. Methods We describe a late‐onset and a relatively mild phenotype in a patient with MOCS2 homozygous mutation. Results Pyramidal and extrapyramidal signs are recognized in those patients, often exacerbated by intercurrent illness. Expressive language is usually compromised. Neurological deterioration is possible even in adulthood, probably due to accumulation of sulfite with time. Conclusion Sulfite inhibition of mitochondrial metabolism could be responsible for the ischemic lesions described in patients with MoCD or alternatively could predispose the brain to suffer an ischemic damage through the action of other insults, for instance intercurrent illness. It is possible that sulfite accumulation together with other external triggers, can lead to neurological deterioration even in adulthood. The role of other factors involved in clinical expression should be investigated to establish the reason for phenotypic variability in patients with the same mutation.

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“…Alkufri et al [6] reported an adult with progressive apathy, slowness of movements, tremor and generalized parkinsonism was reported by and diagnosed as MOCOD.…”

Section: Discussionmentioning

confidence: 99%

“…Patients typically present with neonatal seizure, severe neurodevelopmental delay, epileptic encephalopathy, lens dislocation, feeding difficulties and dysmorphias [3]. Movement disorders have been rarely reported as presenting complaint of MOCOD [4][5][6].…”

Section: Introductionmentioning

confidence: 99%

Status Dystonicus: A Rare Presentation of Molybdenum Cofactor Deficiency

et al. 2017

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Molybdenum cofactor deficiency (MOCOD) is a severe inborn error of metabolism. It is characterized by neonatal presentation of intractable seizures, feeding difficulties, severe developmental delay, microcephaly with brain atrophy and coarse facial features. Movement disorders have been rarely reported as presenting complaint of MOCOD. We report a previously healthy 10 months old boy presenting with acute onset status dystonicus. A novel homozygote IVS1-1G>A (c.251-1G>A) mutation was determined and he was diagnosed as MOCOD. MOCOD must be considered in the differential diagnosis of movement disorders.

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Molybdenum cofactor deficiency presenting with a parkinsonism‐dystonia syndrome

Cited by 19 publications

References 5 publications

Child Neurology: Molybdenum cofactor deficiency

Child Neurology: Molybdenum cofactor deficiency

Mild phenotype in Molybdenum cofactor deficiency: A new patient and review of the literature

Status Dystonicus: A Rare Presentation of Molybdenum Cofactor Deficiency

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