ABSTRACT
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.
Subject(s)
Developmental Disabilities , Metal Metabolism, Inborn Errors , Humans , Developmental Disabilities/etiology , Developmental Disabilities/diagnosis , Metal Metabolism, Inborn Errors/complications , Metal Metabolism, Inborn Errors/diagnosis , MolybdoferredoxinABSTRACT
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.
Subject(s)
Metal Metabolism, Inborn Errors , Sulfite Oxidase , Humans , Infant, Newborn , Amino Acid Metabolism, Inborn Errors/diagnosis , Amino Acid Metabolism, Inborn Errors/therapy , Amino Acid Metabolism, Inborn Errors/genetics , Coenzymes/deficiency , Consensus , Metal Metabolism, Inborn Errors/diagnosis , Metal Metabolism, Inborn Errors/therapy , Metalloproteins/deficiency , Molybdenum Cofactors , Pteridines , Sulfite Oxidase/deficiency , Sulfite Oxidase/geneticsABSTRACT
Molybdenum cofactor deficiency (MoCD) includes three ultrarare autosomal recessive inborn errors of metabolism (MoCD type A [MoCD-A], MoCD-B, and MoCD-C) that cause sulfite intoxication disorders. This natural history study analyzed retrospective data for 58 living or deceased patients (MoCD-A, n = 41; MoCD-B, n = 17). MoCD genotype, survival, neuroimaging, and medical history were assessed retrospectively. Prospective biomarker data were collected for 21 living MoCD patients. The primary endpoint was survival to 1 year of age in MoCD-A patients. Of the 58 MoCD patients, 49 (MoCD-A, n = 36; MoCD-B, n = 13) had first presenting symptoms by Day 28 (neonatal onset; median: 2 and 4 days, respectively). One-year survival rates were 77.4% (overall), 71.8% (neonatal onset MoCD-A), and 76.9% (neonatal onset MoCD-B); median ages at death were 2.4, 2.4, and 2.2 years, respectively. The most common presenting symptoms in the overall population were seizures (60.3%) and feeding difficulties (53.4%). Sequelae included profound developmental delay, truncal hypotonia, limb hypertonia that evolved to spastic quadriplegia or diplegia, dysmorphic features, and acquired microcephaly. In MoCD-A and MoCD-B, plasma and urinary xanthine and S-sulfocysteine concentrations were high; urate remained below the normal reference range. MOCS1 mutation homozygosity was common. Six novel mutations were identified. MoCD is a severe neurodegenerative disorder that often manifests during the neonatal period with intractable seizures and feeding difficulties, with rapidly progressive significant neurologic disabilities and high 1-year mortality rates. Delineation of MoCD natural history supports evaluations of emerging replacement therapy with cPMP for MoCD-A, which may modify disease course for affected individuals.
Subject(s)
Metal Metabolism, Inborn Errors , Metalloproteins , Coenzymes , Humans , Infant, Newborn , Metal Metabolism, Inborn Errors/diagnosis , Prospective Studies , Pteridines , Retrospective Studies , Seizures/complicationsABSTRACT
Objective: To explore the phenotypes and genotypes of molybdenum cofactor deficiency type B (MoCD-B) manifested as Leigh-like syndrome. Methods: The clinical data, laboratory tests, neuroimaging and gene results of one patient diagnosed as MoCD-B at Beijing Children's Hospital and Hebei Children's Hospital in December 2018 were collected. Related literature was searched and reviewed at Wanfang Data Knowledge Service Platform, China National Knowledge Infrastructure and PubMed (up to September 2020) by using terms "MOCS2" "molybdenum cofactor deficiency" "Leigh-like syndrome,MOCS2" "molybdenum cofactor deficiency, Leigh-like syndrome". The phenotypes and genotypes of MoCD-B were summarized. Results: A 7 months and 14 days old boy with the chief complaint of "cough for 6 days, abnormal posture for 4 days and fever for 2 days" was admitted to Hebei Children' Hospital on December 2018. His abnormal posture presented as opisthotonos accompanied with dysphagia, without seizures. His previous psychomotor development was described as normal. He was born at term after an uneventful pregnancy to non-consanguineous parents. Blood test showed a slightly increased lactic acid and a significantly decreased uric acid. Urine metabolism test showed an obviously increased xanthine and hypoxanthine. Brain magnetic resonance imaging showed hyperintense signal on T2 weighted image and fluid attenuated inversion recovery in bilateral globus pallidus and pedunculus cerebri. The patient was diagnosed with Leigh-like syndrome. No obvious improvement was achieved after cocktail therapy and symptomatic treatment. The whole exome sequencing showed that the patient carried a homozygous variant of MOCS2 gene, c.19G>T(p.Val7Phe), which was a previously reported pathogenic site in the literature and could cause MoCD-B. His parents carried a heterozygous variant respectively. A total of 41 MoCD-B cases with MOCS2 gene variants were collected through literature review and our study, among which 30 cases had full medical records. The onset ages of 23 (77%) cases were in neonate, manifesting with severe encephalopathy, including neonatal-onset intractable seizures, developmental delay, laboratory abnormalities included very low levels of serum and urinary uric acid, increased urinary levels of xanthine and hypoxanthine. Cranial imaging showed cerebral atrophy, cystic encephalomalacia, etc. The onset ages of 7 patients varied from 5 months to 23 years. Four cases had normal psychomotor development before disease onset. Neurological disorders appeared acutely or exacerbated after external triggers and all of them had basal ganglia involvement. Among the 30 cases, 3 cases had a relatively milder phenotype with the ability of brief communication and walking without or with support. Conclusions: Molybdenum cofactor deficiency is a rare disease. Most cases had severe phenotypes and poor outcomes, but some cases may have mild phenotype. MoCD-B caused by MOCS2 gene variants may manifest as Leigh-like syndrome with a normal psychomotor development before the trigger of infection strike. Hypouricemia, xanthinuria and hypoxanthinuria can be indicators of the disease. The presence of MOCS2 gene variants would confirm a final diagnosis.
Subject(s)
Metal Metabolism, Inborn Errors , Child , Child, Preschool , China , Homozygote , Humans , Infant , Infant, Newborn , Male , Metal Metabolism, Inborn Errors/diagnosis , Metal Metabolism, Inborn Errors/genetics , PhenotypeABSTRACT
Molybdenum cofactor is essential for the activity of multiple enzymes including xanthine dehydrogenase. Molybdenum cofactor deficiencies are rare inborn errors of metabolism. Clinically, they present with intractable seizures, axial hypotonia, and hyperekplexia. They further develop cerebral atrophy, microcephaly, global developmental delay and ectopia lentis. We report a 5-year-old female with clinically, biochemically and genetically confirmed molybdenum cofactor deficiency type B due to compound heterozygous pathogenic variants in the molybdenum cofactor synthesis 2 gene found on whole exome sequencing. The xanthine stones were a key clue towards diagnosis. No mutation was detected in XDH gene. Implementation of a low-purine diet, urine alkalization and hydration lead to a near complete decrease in stone burden. The patient received pyridoxine supplementation with improvement in energy levels and attentiveness. Despite reports of high mortality at a young age, our patient was 9 years old at the time of this writing. Molybdenum cofactor deficiencies should be considered in neonates with early-onset seizures, hypotonia, and feeding difficulties. Screening with serum uric acid levels and empiric treatment may be considered while awaiting genetic results.
Subject(s)
Metal Metabolism, Inborn Errors/diagnosis , Purine-Pyrimidine Metabolism, Inborn Errors/etiology , Child , Humans , Metal Metabolism, Inborn Errors/complicationsABSTRACT
Neonatal encephalopathy with seizures is a presentation in which rapid whole-genome sequencing (rWGS) has shown clinical utility and improved outcomes. We report a neonate who presented on the third day of life with seizures refractory to antiepileptic medications and neurologic and computerized tomographic findings consistent with severe generalized brain swelling. rWGS revealed compound heterozygous variants in the molybdenum cofactor synthesis gene, type 1A (MOCS1 c.*7 + 5G > A and c.377G > A); a provisional diagnosis of molybdenum cofactor deficiency on day of life 4. An emergency investigational new drug application for intravenous replacement of the MOCS1 product, cyclic pyranopterin monophosphate, was considered, but felt unsuitable in light of the severity of disease and delay in the start of treatment. The patient died on day of life 9 despite having a precise molecular diagnosis within the first week of life. This case illustrates that an rWGS-based molecular diagnosis within the first week of life may be insufficient to improve outcomes. However, it did inform clinical decision-making with regard to resuscitation and predicted long-term outcome. We suggest that to achieve optimal reductions in morbidity and mortality, rWGS must be implemented within a comprehensive rapid precision medicine system (CRPM). Akin to newborn screening (NBS), CRPM will have onboarding, diagnosis, and precision medicine implementation components developed in response to patient and parental needs. Education of health-care providers in a learning model in which ongoing data analyses informs system improvement will be essential for optimal effectiveness of CRPM.
Subject(s)
Delivery of Health Care , Infant Mortality , Metal Metabolism, Inborn Errors/diagnosis , Metal Metabolism, Inborn Errors/mortality , Precision Medicine , Alleles , Clinical Decision-Making , Disease Management , Disease Susceptibility , Genotype , Humans , Infant , Infant, Newborn , Male , Metal Metabolism, Inborn Errors/etiology , Phenotype , Polymorphism, Single Nucleotide , Precision Medicine/methods , Whole Genome SequencingABSTRACT
This preliminary study summarizes the genotypes of 42 Labrador Retrievers and Labrador Retriever-Golden Retriever crosses and phenotypes a subset of ten of these dogs that are homozygous mutant, heterozygous, or homozygous normal for mutations in the ATP7A and ATP7B genes that have been associated with the development of copper toxicosis in Labrador Retrievers. The purpose of this study is to evaluate whether there is a correlation between ATP7A and ATP7B genotypes and clinical evidence of hepatic pathology in young, asymptomatic Labrador Retrievers. We evaluated serum ALT levels, hepatic copper concentrations, and hepatic histopathology from ten offspring where both parents had a least one copy of the ATP7B mutation. Five were homozygous mutant, four were heterozygous, and one was homozygous normal for comparison. None had increased serum ALT activity. All dogs homozygous for the ATP7B mutation had elevated hepatic copper concentrations compared to dogs heterozygous for the ATP7B mutation regardless of sex or presence of an ATP7A mutation with the mean hepatic copper concentration being 1464 ppm (reference range 100-330 ppm). Mean hepatic copper concentration in homozygous normal and heterozygous dogs was 328 ppm. In this preliminary analysis, we found that dogs that carry two copies of the ATP7B mutation have abnormally elevated hepatic copper levels despite having normal serum ALT activity. Our findings support the hypothesis that the ATP7B DNA test can predict defects in hepatic copper metabolism. Veterinarians can test for the ATP7B gene mutation to identify Labrador Retrievers at risk for copper toxicosis so that they can take steps to prevent development of copper-associated chronic hepatitis in their patients.
Subject(s)
Copper-Transporting ATPases/genetics , Copper/blood , Copper/toxicity , Dog Diseases/genetics , Liver Cirrhosis/diagnosis , Liver Cirrhosis/veterinary , Metal Metabolism, Inborn Errors/diagnosis , Metal Metabolism, Inborn Errors/veterinary , Alanine Transaminase/blood , Animals , Dogs , Female , Genetic Predisposition to Disease/genetics , Genotype , Hepatolenticular Degeneration/complications , Hepatolenticular Degeneration/genetics , Humans , Male , Rhodanine/metabolismABSTRACT
In spite of the efforts and interventions by the Government of Pakistan and The World Health Organization, the neonatal mortality in Pakistan has declined by only 0.9% as compared to the global average decline of 2.1% between 2000 and 2010. This has resulted in failure to achieve the global Millennium Development Goal 4. Hypoxic-ischaemic encephalopathy, still birth, sepsis, pneumonia, diarrhoea and birth defects are commonly attributed as leading causes of neonatal mortality in Pakistan. Inherited metabolic disorders often present at the time of birth or the first few days of life. The clinical presentation of the inherited metabolic disorders including hypotonia, seizure and lactic acidosis overlap with clinical features of hypoxic-ischaemic encephalopathy and sepsis. Thus, these disorders are often either missed or wrongly diagnosed as hypoxicischaemic encephalopathy or sepsis unless the physicians actively investigate for the underlying inherited metabolic disorders. We present 4 neonates who had received the diagnosis of hypoxic-ischaemic encephalopathy and eventually were diagnosed to have various inherited metabolic disorders. Neonates with sepsis and hypoxic-ischaemic encephalopathy-like clinical presentation should be evaluated for inherited metabolic disorders.
Subject(s)
Hyperglycinemia, Nonketotic/diagnosis , Hypoxia-Ischemia, Brain/diagnosis , Metal Metabolism, Inborn Errors/diagnosis , Pyruvate Carboxylase Deficiency Disease/diagnosis , Zellweger Syndrome/diagnosis , Brain/diagnostic imaging , Diagnosis, Differential , Female , Humans , Infant , Infant, Newborn , Magnetic Resonance Imaging , Male , Pakistan , Radiography , Tertiary Care CentersABSTRACT
Copper deficiency (hypocupremia) or toxicosis (hypercupremia) may cause disorders of central and peripheral nervous systems. Hypocupremia causes myeloneuropathy resembling vitamin B12 deficiency. However, the clinical manifestations, particularly peripheral neuropathy (PN), of hypercupremia have not been adequately evaluated. To compare clinical, laboratory and electrodiagnositc features of PN between patients with hypocupremia and hypercupremia, we retrospectively reviewed the charts of patients with abnormal copper levels. Subjects with zinc abnormalities were excluded. Five hypocupremia (Male/Femaleâ¯=â¯4/1; age: 54.6⯱â¯17.1â¯years; copperâ¯=â¯55.0⯱â¯8.5⯵g/dL [normalâ¯=â¯72-175]; zincâ¯=â¯74.4⯱â¯15.5⯵g/dL [normalâ¯=â¯60-130]) and 3 hypercupremia (M/Fâ¯=â¯1/2; age: 57.0⯱â¯8.2â¯years; copperâ¯=â¯215.0⯱â¯10.8⯵g/dL; zincâ¯=â¯72.3⯱â¯14.6⯵g/dL) were studied. The notable clinical findings included ambulatory difficulty in hypocupremia (2/5); paresthesia in both hypocupremia (3/5) and hypercupremia (2/3) but pain was only seen in (3/3) hypercupremia patients. Tendon reflexes were decreased in hypocupremia (3/5) and hypercupremia (1/3) but hyperreflexias in hypocupremia (2/5) only. Preexisting comorbidity such as diarrhea were observed in (2/3) hypercupremia but not in hypocupremia patients. Laboratory findings showed vitamin D deficiency (16.4⯱â¯5.6â¯ng/mL) in (2/2) hypercupremia but normal (40.4⯱â¯4.7â¯ng/mL) in (2/2) hypocupremia. Neurophysiologic studies showed evidence of neuropathy in (3/5) hypocupremia only. Different patterns of clinical, neurological examination and electrophysiologic findings between hypocupremia and hypercupremia suggest different underlying pathophysiologies.
Subject(s)
Copper/blood , Copper/deficiency , Copper/toxicity , Electrodiagnosis/methods , Liver Cirrhosis/blood , Metal Metabolism, Inborn Errors/blood , Peripheral Nervous System Diseases/blood , Adult , Aged , Female , Humans , Liver Cirrhosis/diagnosis , Liver Cirrhosis/physiopathology , Male , Metal Metabolism, Inborn Errors/diagnosis , Metal Metabolism, Inborn Errors/physiopathology , Middle Aged , Peripheral Nervous System Diseases/diagnosis , Peripheral Nervous System Diseases/physiopathology , Retrospective StudiesABSTRACT
Seizures in the neonatal period are practically always a symptom of an underlying illness. Quick diagnosis and treatment can be crucial to the outcome. A few aetiological factors account for most of the seizures. However, a significant number is caused by rare conditions such as metabolic or genetic disorders, and arriving at the right diagnosis can be challenging. Previous studies indicate, that a standardized algorithm clearly improves the diagnostic success. This article presents an overview of aetiological factors and an algorithm for a standardized work-up.
Subject(s)
Algorithms , Seizures/diagnosis , Cerebral Infarction/complications , Cerebral Infarction/diagnosis , Humans , Hypoglycemia/complications , Hypoglycemia/diagnosis , Hypoxia-Ischemia, Brain/complications , Hypoxia-Ischemia, Brain/diagnosis , Infant, Newborn , Intracranial Hemorrhages/complications , Intracranial Hemorrhages/diagnosis , Metal Metabolism, Inborn Errors/complications , Metal Metabolism, Inborn Errors/diagnosis , Point-of-Care Testing , Seizures/etiology , Seizures/genetics , Seizures/therapyABSTRACT
BACKGROUND: Zinc deficiency-like (ZDL) syndrome is an inherited defect of Fleckvieh calves, with striking similarity to bovine hereditary zinc deficiency (BHZD). However, the causative mutation in a phospholipase D4 encoding gene (PLD4) shows no connection to zinc metabolism. OBJECTIVES: To describe clinical signs, laboratory variables, and pathological findings of ZDL syndrome and their utility to differentiate ZDL from BHZD and infectious diseases with similar phenotype. ANIMALS: Nine hospitalized calves with crusting dermatitis and confirmed mutation in PLD4 and medical records from 25 calves with crusting dermatitis or suspected zinc deficiency. METHODS: Prospective and retrospective case series. RESULTS: The 9 calves (age: 5-53 weeks) displayed a moderate to severe crusting dermatitis mainly on the head, ventrum, and joints. Respiratory and digestive tract inflammations were frequently observed. Zinc supplementation did not lead to remission of clinical signs in 4 calves. Laboratory variables revealed slight anemia in 8 calves, hypoalbuminemia in 6 calves, but reduced serum zinc concentrations in only 3 calves. Mucosal erosions/ulcerations were present in 7 calves and thymus atrophy or reduced thymic weights in 8 calves. Histologically, skin lesions were indistinguishable from BHZD. Retrospective analysis of medical records revealed the presence of this phenotype since 1988 and pedigree analysis revealed a common ancestor of several affected calves. CONCLUSIONS AND CLINICAL IMPORTANCE: ZDL syndrome should be suspected in Fleckvieh calves with crusting dermatitis together with diarrhea or respiratory tract inflammations without response to oral zinc supplementation. Definite diagnosis requires molecular genetic confirmation of the PLD4 mutation.
Subject(s)
Cattle Diseases/pathology , Zinc/blood , Animals , Cattle , Cattle Diseases/diagnosis , Cattle Diseases/genetics , Dermatitis/diagnosis , Dermatitis/genetics , Dermatitis/veterinary , Female , Male , Metal Metabolism, Inborn Errors/diagnosis , Metal Metabolism, Inborn Errors/genetics , Prospective Studies , Retrospective Studies , Syndrome , Zinc/therapeutic useABSTRACT
Molybdenum cofactor deficiency is an autosomal recessive inborn error of metabolism, which results from mutations in genes involved in Moco biosynthesis. Moco serves as a cofactor of several enzymes, including sulfite oxidase. MoCD is clinically characterized by intractable seizures and severe, rapidly progressing neurodegeneration leading to death in early childhood in the majority of known cases. Here we report a patient with an unusual late disease onset and mild phenotype, characterized by a lack of seizures, normal early development, a decline triggered by febrile illness and a subsequent dystonic movement disorder. Genetic analysis revealed a homozygous c.1338delG MOCS1 mutation causing a frameshift (p.S442fs) with a premature termination of the MOCS1AB translation product at position 477 lacking the entire MOCS1B domain. Surprisingly, urine analysis detected trace amounts (1% of control) of the Moco degradation product urothione, suggesting a residual Moco synthesis in the patient, which was consistent with the mild clinical presentation. Therefore, we performed bioinformatic analysis of the patient's mutated MOCS1 transcript and found a potential Kozak-sequence downstream of the mutation site providing the possibility of an independent expression of a MOCS1B protein. Following the expression of the patient's MOCS1 cDNA in HEK293 cells we detected two proteins: a truncated MOCS1AB protein and a 22.4 kDa protein representing MOCS1B. Functional studies of both proteins confirmed activity of MOCS1B, but not of the truncated MOCS1AB. This finding demonstrates an unusual mechanism of translation re-initiation in the MOCS1 transcript, which results in trace amounts of functional MOCS1B protein being sufficient to partially protect the patient from the most severe symptoms of MoCD.
Subject(s)
Coenzymes/metabolism , Metal Metabolism, Inborn Errors/metabolism , Metalloproteins/metabolism , Nuclear Proteins/metabolism , Peptide Fragments/metabolism , Pteridines/metabolism , Age of Onset , Carbon-Carbon Lyases , Child , Child, Preschool , Diet, Protein-Restricted , Frameshift Mutation , Genetic Predisposition to Disease , HEK293 Cells , Humans , Magnetic Resonance Imaging , Male , Metal Metabolism, Inborn Errors/diagnosis , Metal Metabolism, Inborn Errors/diet therapy , Metal Metabolism, Inborn Errors/genetics , Molybdenum Cofactors , Nuclear Proteins/genetics , Peptide Fragments/genetics , PhenotypeABSTRACT
A child, 2 years with the 'hypercalprotectinaemia with hyperzincaemia' clinical syndrome, presented with atypical symptoms and signs, notably persistent fever of approximately 38°C, thrombocythaemia of > 700 × 109 /l and a predominance of persistent intestinal symptoms. In an effort to find a cure by identifying the dysregulated pathways we analysed whole-genome mRNA expression by the Affymetrix HG U133 Plus 2·0 array in blood on three occasions 3-5 months apart. Major up-regulation was demonstrated for the Janus kinase/signal transducer and activators of transcription (JAK/STAT) pathway including, in particular, CD177, S100A8, S100A9 and S100A12, accounting for the thrombocytosis; a large number of interleukins, their receptors and activators, accounting for the febrile apathic state; and the high mobility group box 1 (HMBG1) gene, possibly accounting for part of the intestinal symptoms. These results show that gene expression array technology may assist the clinician in the diagnostic work-up of individual patients with suspected syndromal states of unknown origin, and the expression data can guide the selection of optimal treatment directed at the identified target pathways.
Subject(s)
Blood Proteins/genetics , Leukocyte L1 Antigen Complex/metabolism , Metal Metabolism, Inborn Errors/diagnosis , Child, Preschool , Clinical Decision-Making , Female , Fever , Gastrointestinal Diseases , Genome-Wide Association Study , Humans , Leukocyte L1 Antigen Complex/genetics , Metal Metabolism, Inborn Errors/genetics , Microarray Analysis , Pathology, Molecular , Signal Transduction , Thrombocytosis , Whole Genome SequencingABSTRACT
OBJECTIVES: Hyperzincaemia/hypercalprotectinemia (Hz/Hc) syndrome is a recently described condition caused by a specific de novo mutation (E250K) affecting PSTPIP1 gene. It has a phenotype distinct from classical pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) syndrome that includes severe systemic and cutaneous inflammation, hepatosplenomegaly, arthritis without sequelae, pancytopenia and failure to thrive. METHODS: We describe an 8-year-old boy who presented recurrent right knee swelling mimicking septic arthritis and persistent bone marrow involvement, without cutaneous involvement. RESULTS: Molecular analysis of the PSTPIP1 gene revealed the presence of a heterozygous E250K mutation. No growth failure was detected nor in the patient neither in his mother, carrying the same variant. Blood zinc and calprotectin MRP8/14 concentrations of the patient were found to be markedly increased. Therapy with anakinra was started with rapid disappearance of clinical symptoms and normalization of CRP levels in 24 hours, but persistence of bone marrow involvement. CONCLUSIONS: The patient described has a milder phenotype, with no skin features, minor episodes of arthritis with no sequelae and normal growth. Compared to the patients with de novo mutations described in the literature, familial cases seem to have a milder phenotype. Our case further confirms the lack of efficacy of anakinra on bone marrow involvement.
Subject(s)
Acne Vulgaris/genetics , Adaptor Proteins, Signal Transducing/genetics , Arthritis, Infectious/genetics , Cytoskeletal Proteins/genetics , Metal Metabolism, Inborn Errors/genetics , Mutation/genetics , Pyoderma Gangrenosum/genetics , ATP-Binding Cassette Transporters/blood , Acne Vulgaris/blood , Acne Vulgaris/diagnosis , Acne Vulgaris/drug therapy , Antirheumatic Agents/therapeutic use , Arthritis, Infectious/blood , Arthritis, Infectious/diagnosis , Arthritis, Infectious/drug therapy , Biomarkers/blood , C-Reactive Protein/metabolism , Calgranulin B/blood , Child , DNA Mutational Analysis , Genetic Predisposition to Disease , Heterozygote , Humans , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Male , Metal Metabolism, Inborn Errors/blood , Metal Metabolism, Inborn Errors/diagnosis , Metal Metabolism, Inborn Errors/drug therapy , Phenotype , Predictive Value of Tests , Pyoderma Gangrenosum/blood , Pyoderma Gangrenosum/diagnosis , Pyoderma Gangrenosum/drug therapy , Risk Factors , Treatment Outcome , Zinc/bloodABSTRACT
BACKGROUND: Molybdenum cofactor deficiency (MoCD) is characterised by early, rapidly progressive postnatal encephalopathy and intractable seizures, leading to severe disability and early death. Previous treatment attempts have been unsuccessful. After a pioneering single treatment we now report the outcome of the complete first cohort of patients receiving substitution treatment with cyclic pyranopterin monophosphate (cPMP), a biosynthetic precursor of the cofactor. METHODS: In this observational prospective cohort study, newborn babies with clinical and biochemical evidence of MoCD were admitted to a compassionate-use programme at the request of their treating physicians. Intravenous cPMP (80-320 µg/kg per day) was started in neonates diagnosed with MoCD (type A and type B) following a standardised protocol. We prospectively monitored safety and efficacy in all patients exposed to cPMP. FINDINGS: Between June 6, 2008, and Jan 9, 2013, intravenous cPMP was started in 16 neonates diagnosed with MoCD (11 type A and five type B) and continued in eight type A patients for up to 5 years. We observed no drug-related serious adverse events after more than 6000 doses. The disease biomarkers urinary S-sulphocysteine, xanthine, and urate returned to almost normal concentrations in all type A patients within 2 days, and remained normal for up to 5 years on continued cPMP substitution. Eight patients with type A disease rapidly improved under treatment and convulsions were either completely suppressed or substantially reduced. Three patients treated early remain seizure free and show near-normal long-term development. We detected no biochemical or clinical response in patients with type B disease. INTERPRETATION: cPMP substitution is the first effective therapy for patients with MoCD type A and has a favourable safety profile. Restoration of molybdenum cofactor-dependent enzyme activities results in a greatly improved neurodevelopmental outcome when started sufficiently early. The possibility of MoCD type A needs to be urgently explored in every encephalopathic neonate to avoid any delay in appropriate cPMP substitution, and to maximise treatment benefit. FUNDING: German Ministry of Education and Research; Orphatec/Colbourne Pharmaceuticals.