RESUMO
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.
Assuntos
Deficiências do Desenvolvimento , Erros Inatos do Metabolismo dos Metais , Humanos , Deficiências do Desenvolvimento/etiologia , Deficiências do Desenvolvimento/diagnóstico , Erros Inatos do Metabolismo dos Metais/complicações , Erros Inatos do Metabolismo dos Metais/diagnóstico , MolibdoferredoxinaRESUMO
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.
Assuntos
Erros Inatos do Metabolismo dos Metais/diagnóstico , Erros Inatos do Metabolismo da Purina-Pirimidina/etiologia , Criança , Humanos , Erros Inatos do Metabolismo dos Metais/complicaçõesRESUMO
Molybdenum cofactor deficiency (MoCD) is a rare autosomal recessive metabolic disease with severe neurological symptoms. Most disease-causing mutations are found in the MOCS1 gene, corresponding to MoCD type A (MoCD-A). There have been few reports describing the long-term detailed neurological features with MoCD-A because most patients do not survive childhood. We describe the clinical, radiologic, biochemical, and genetic data of two patients (female siblings aged 26 and 22 years) with MoCD-A. Both patients presented with feeding difficulties, neurological deterioration, and persistent generalized muscle contraction which can be easily confused with status dystonicus. Biochemical tests revealed low serum uric acid, elevated urinary sulfocysteine, and xanthine. Brain magnetic resonance imaging (MRI) revealed distinctive abnormalities in the bilateral caudate nucleus, putamen, globus pallidus, and cerebral white matter adjacent to the cortex. The thalamus was relatively unaffected. Genetic testing identified a novel homozygous variant in the MOCS1 gene (c.949C > T p.Arg317Cys). Biochemical results supported the hypothesis that this genetic variant is a pathological mutation. When there are symptoms of persistent generalized muscle contraction and characteristic MRI findings, MoCD should be considered as a differential diagnosis.
Assuntos
Erros Inatos do Metabolismo dos Metais/diagnóstico por imagem , Erros Inatos do Metabolismo dos Metais/genética , Contração Muscular/genética , Irmãos , Adulto , Feminino , Humanos , Erros Inatos do Metabolismo dos Metais/complicações , Adulto JovemRESUMO
Neutropenia in pediatric patients can be due to a variety of disorders. We describe two patients who underwent extensive evaluation over many years for arthralgias and moderate neutropenia of unclear etiology. Genetic testing identified a pathogenic variant in PSTPIP1 (proline-serine-threonine phosphatase-interacting protein 1) in both patients. Markedly elevated inflammatory markers and zinc levels confirmed the rare diagnosis of PSTPIP1-associated myeloid-related proteinemia inflammatory (PAMI) syndrome, tailoring treatment. Neutropenia is common in patients with PAMI syndrome. Unique mutations seen in PAMI syndrome may account for the specific phenotypic features of this disorder.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Artralgia/patologia , Proteínas do Citoesqueleto/genética , Inflamação/complicações , Erros Inatos do Metabolismo dos Metais/complicações , Mutação , Neutropenia/patologia , Artralgia/etiologia , Artralgia/genética , Criança , Feminino , Humanos , Neutropenia/etiologia , Neutropenia/genética , Fenótipo , Prognóstico , SíndromeRESUMO
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.
Assuntos
Algoritmos , Convulsões/diagnóstico , Infarto Cerebral/complicações , Infarto Cerebral/diagnóstico , Humanos , Hipoglicemia/complicações , Hipoglicemia/diagnóstico , Hipóxia-Isquemia Encefálica/complicações , Hipóxia-Isquemia Encefálica/diagnóstico , Recém-Nascido , Hemorragias Intracranianas/complicações , Hemorragias Intracranianas/diagnóstico , Erros Inatos do Metabolismo dos Metais/complicações , Erros Inatos do Metabolismo dos Metais/diagnóstico , Testes Imediatos , Convulsões/etiologia , Convulsões/genética , Convulsões/terapiaRESUMO
We describe the clinical presentation and 17 years follow up of a boy, born to consanguineous parents and presenting with intellectual disability (ID), autism, "marfanoid" dysmorphic features, and moderate abnormalities of sulfite metabolism compatible with molybdenum cofactor deficiency, but normal sulfite oxidase activity in cultured skin fibroblasts. Genomic exome analysis revealed a homozygous MOCS3 missense mutation, leading to a p.Ala257Thr substitution in the highly conserved ubiquitin-like-domain of the protein. MOCS3 is the third protein, besides MOCS1 and MOCS2, involved in the biosynthesis of the molybdenum cofactor and has a dual ubiquitin-like function in tRNA thiolation. It is plausible that the phenotype results from deficiency of this dual function, not only from defective synthesis of molybdenum cofactor, which would explain similarities and differences from the MOCS1 and MOCS2-related disorders. This observation should encourage testing of additional ID patients with mild abnormalities of sulfite metabolism for MOCS3 mutations.
Assuntos
Transtorno Autístico/genética , Deficiência Intelectual/genética , Erros Inatos do Metabolismo dos Metais/genética , Nucleotidiltransferases/genética , Sulfurtransferases/genética , Adolescente , Transtorno Autístico/complicações , Transtorno Autístico/fisiopatologia , Expressão Gênica , Homozigoto , Humanos , Deficiência Intelectual/complicações , Deficiência Intelectual/fisiopatologia , Masculino , Erros Inatos do Metabolismo dos Metais/complicações , Erros Inatos do Metabolismo dos Metais/fisiopatologia , Mutação de Sentido Incorreto , FenótipoRESUMO
The aim of this study was to investigate the histopathological features of dental pulp in acute zinc (Zn) intoxication and to identify possible physiopathological mechanisms of the lesions. Twelve adult male Wistar rats were divided into two groups, the control one and the exposed group. Each animal from the experimental group received a single dose of zinc chloride (ZnCl2) by intraperitoneal injection. Blood samples were collected from exposed animals at 2, 4, and 6 hours after the injection and plasma Zn concentrations were determined by spectrophotometry. After six hours of observation, the animals were sacrificed and two teeth from every rat were removed. Twelve teeth were processed by standard histological technique using Hematoxylin-Eosin (HE) and Szekely trichrome stainings, and the other twelve were subjected to Schliff cutting-grinding technique. The experimental group showed increased plasma zinc concentration (0.46±0.06 mg÷L) after two hours and then slightly decreasing values in the next four hours. Undecalcified teeth did not showed any changing into the dentin or enamel structures, but decalcified teeth revealed numerous deposits into the dental pulp, which consisted of red acellular superposed sediments that could be made up of zinc with some plasma protein, or there could be an unknown compound which precipitated under the influence of zinc cation (Zn2+). We can presume that the dental pulp may be an elective place for zinc accretion and so it must be considered a potential target for this metal.
Assuntos
Esmalte Dentário/patologia , Erros Inatos do Metabolismo dos Metais/complicações , Zinco/toxicidade , Animais , Masculino , Ratos , Ratos WistarRESUMO
Neonatal seizure incidence is approximately 3.5/1000 live births. Inborn metabolic diseases account for approximately 1-4% of neonatal seizure cases. Among them, the catabolism anomaly of sulfite to sulfate caused by sulfite oxidase or cofactor molybdenum deficiency (MoCD) is a rare metabolic disorder in which neurological damage is similar to that found in neonatal asphyxia. We report the case of a newborn child with a MoCD. Born of related parents, this child had intrauterine growth retardation predominating on size diagnosed in the third trimester of pregnancy. After an uneventful birth, he presented convulsions at the 12th hour of life, confirmed by an electroencephalogram. Anticonvulsants and adjuvant treatments were ineffective; the child then required intubation at day 5 of life. The initial biological assessment found an elevated blood lactate level and the chromatography of amino acids showed a significant decrease of cystine and the abnormal presence of sulfocysteine, suggestive of a lack of sulfite oxidase activity. The uric acid level measured secondarily was low, suggesting a MoCD. Brain MRI was performed at day 5 for diffuse ischemic injury of different ages. After limiting acute care, the child died at day 14 of life. The genetic study of the child found a homozygous mutation c.564+1G>A in the MOCS2 gene, confirming the diagnosis of MoCD, present in the heterozygous state in both parents. Investigations in a logical sequence quickly suggested the MoCD diagnosis in presence of a low plasma concentration of cysteine, the abnormal presence of sulfocysteine, and low uric acid levels. The diagnosis of sulfite oxidase deficiency was made. Until now, no treatment has proven effective but a new treatment appears to be effective in cases with a MOCS1 mutation.
Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/etiologia , Encefalopatias/etiologia , Erros Inatos do Metabolismo dos Metais/complicações , Sulfito Oxidase/deficiência , Humanos , Recém-Nascido , Masculino , Índice de Gravidade de DoençaRESUMO
BACKGROUND: SLC30A10 mutations cause an autosomal recessive disorder, characterized by hypermanganesaemia, polycythemia, early-onset dystonia, paraparesis, or late-onset parkinsonism, and chronic liver disease. This is the first identified inborn error of Mn metabolism in humans, reported in 10 families thus far. METHODS: Methods for this study consisted of clinical examination, neuroimaging studies (MRI), serum dosages, and SLC30A10 genetic analysis. RESULTS: We describe early disease manifestations (including videos) in 5 previously unreported Indian children, carrying novel homozygous SLC30A10 mutations. Gait and speech disturbances, falls, dystonias, and central hypotonia were the presenting neurological features, starting within the first 5 years of life. All children also had severe hypermanganesemia, polycythemia, variable degree of liver disease, and marked brain MRI T1 hyperintensities. CONCLUSIONS: Our findings expand the mutational and clinical spectra of this recently recognized disorder. An early diagnosis is warranted, because treatment with manganese-chelating agents, iron supplementation, or their combination might improve symptoms and prevent progression of this otherwise potentially fatal disease. © 2015 International Parkinson and Movement Disorder Society.
Assuntos
Proteínas de Transporte de Cátions/genética , Distonia/genética , Distonia/fisiopatologia , Manganês/metabolismo , Erros Inatos do Metabolismo dos Metais/genética , Erros Inatos do Metabolismo dos Metais/fisiopatologia , Adolescente , Pré-Escolar , Consanguinidade , Distonia/sangue , Distonia/etiologia , Feminino , Humanos , Masculino , Erros Inatos do Metabolismo dos Metais/sangue , Erros Inatos do Metabolismo dos Metais/complicações , Mutação , Linhagem , Fenótipo , Transportador 8 de ZincoRESUMO
As our understanding of iron metabolism improves through the more accurate description of iron metabolism actors, new causes of iron overload are identified. We, here, report 16 cases of hereditary hypotransferrinemia related to 4 previously undescribed TF (transferrin) mutations (p.Val221Gly, p.Arg609Trp, p.Glu370Lys, p.Tyr533X and p.Cys421Arg). We show that, besides increasing serum transferrin saturation without iron overload, hypotransferrinemia, when associated to mutations in HFE or HAMP or to acquired factors, can lead to clinically relevant iron burden. These cases emphasize the usefulness of serum transferrin determination in the diagnostic evaluation of iron overload and the importance for clinicians to be aware of this syndrome.
Assuntos
Hepcidinas/genética , Antígenos de Histocompatibilidade Classe I/genética , Sobrecarga de Ferro/genética , Ferro/metabolismo , Proteínas de Membrana/genética , Erros Inatos do Metabolismo dos Metais/genética , Mutação , Transferrina/deficiência , Transferrina/genética , Adulto , Idoso , Análise Mutacional de DNA , Feminino , Expressão Gênica , Genótipo , Proteína da Hemocromatose , Hepcidinas/metabolismo , Heterozigoto , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Sobrecarga de Ferro/sangue , Sobrecarga de Ferro/etiologia , Sobrecarga de Ferro/patologia , Masculino , Proteínas de Membrana/metabolismo , Erros Inatos do Metabolismo dos Metais/sangue , Erros Inatos do Metabolismo dos Metais/complicações , Erros Inatos do Metabolismo dos Metais/patologia , Pessoa de Meia-Idade , Linhagem , Transferrina/metabolismoAssuntos
Distonia/etiologia , Erros Inatos do Metabolismo dos Metais/complicações , Transtornos Parkinsonianos/etiologia , Adolescente , Encéfalo/patologia , Distonia/complicações , Feminino , Humanos , Imageamento por Ressonância Magnética , Molibdoferredoxina , Transtornos Parkinsonianos/complicaçõesRESUMO
Molybdenum cofactor deficiency (MoCD) is a lethal autosomal recessive inborn error of metabolism with devastating neurologic manifestations. Currently, experimental treatment with cyclic pyranopterin monophosphate (cPMP) is available for patients with MoCD type A caused by a mutation in the MOCS-1 gene. Here we report the first case of an infant, prenatally diagnosed with MoCD type A, whom we started on treatment with cPMP 4 hours after birth. The most reliable method to evaluate neurologic functioning in early infancy is to assess the quality of general movements (GMs) and fidgety movements (FMs). After a brief period of seizures and cramped-synchronized GMs on the first day, our patient showed no further clinical signs of neurologic deterioration. Her quality of GMs was normal by the end of the first week. Rapid improvement of GM quality together with normal FMs at 3 months is highly predictive of normal neurologic outcome. We demonstrated that a daily cPMP dose of even 80 µg/kg in the first 12 days reduced the effects of neurodegenerative damage even when seizures and cramped-synchronized GMs were already present. We strongly recommend starting cPMP treatment as soon as possible after birth in infants diagnosed with MoCD type A.
Assuntos
Erros Inatos do Metabolismo dos Metais/tratamento farmacológico , Compostos Organofosforados/uso terapêutico , Pterinas/uso terapêutico , Discinesias/diagnóstico , Discinesias/etiologia , Eletroencefalografia , Feminino , Humanos , Recém-Nascido , Erros Inatos do Metabolismo dos Metais/complicações , Erros Inatos do Metabolismo dos Metais/diagnóstico , Molibdoferredoxina , Gravidez , Diagnóstico Pré-Natal , Convulsões/diagnóstico , Convulsões/etiologia , Gravação em VídeoRESUMO
Movement disorders, especially dystonia, are a frequent manifestation of neurometabolic diseases. Proper characterization and classification of movement disorders is crucial but may be challenging in this setting. The diagnostic work-up should be focused first on treatable disease. Mixed movement disorders, marked orofacial involvement and associated neurological and extra-neurological features should prompt the clinician to consider the possibility of an underlying neurometabolic disorder. The diagnostic approach is based on the abrupt, paroxysmal or insidious nature of onset of the movement disorders, the clinical picture including neurological and systemic signs and symptoms, and the presence or absence of abnormalities on the brain MRI. In addition to specific treatment for the metabolic disease, when available, symptomatic treatment of the movement disorders can be proposed, remembering that these patients are particularly vulnerability to iatrogenesis.
Assuntos
Doenças Metabólicas/complicações , Transtornos dos Movimentos/etiologia , Doenças do Sistema Nervoso/complicações , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Monoaminas Biogênicas/metabolismo , Erros Inatos do Metabolismo dos Carboidratos/complicações , Estimulação Encefálica Profunda , Metabolismo Energético/fisiologia , Humanos , Síndrome de Lesch-Nyhan/complicações , Doenças por Armazenamento dos Lisossomos/complicações , Imageamento por Ressonância Magnética , Doenças Metabólicas/diagnóstico , Erros Inatos do Metabolismo dos Metais/complicações , Transtornos dos Movimentos/diagnóstico , Doenças do Sistema Nervoso/diagnósticoRESUMO
Genetic disorders of copper metabolism, including Menkes kinky hair disease (MD), occipital horn syndrome (OHS) and Wilson's disease (WD) are reviewed with a focus on the neurological aspects. MD and OHS are X-linked recessive disorders characterized by a copper deficiency. Typical features of MD, such as neurologic disturbances, connective tissue disorders and hair abnormalities, can be explained by the abnormally low activity of copper-dependent enzymes. The current standard-of-care for treatment of MD is parenteral administration of copper-histidine. When the treatment is initiated in newborn babies, neurologic degeneration can be prevented, but delayed treatment is considerably less effective. Moreover, copper-histidine treatment does not improve connective tissue disorders. Novel treatments targeting neurologic and connective tissue disorders need to be developed. OHS is the mildest form of MD and is characterized by connective tissue abnormalities. Although formal trials have not been conducted for OHS, OHS patients are typically treated in a similar manner to MD. WD is an autosomal recessive disorder characterized by the toxic effects of chronic exposure to high levels of copper. Although the hepatic and nervous systems are typically most severely affected, initial symptoms are variable, making an early diagnosis difficult. Because early treatments are often critical, especially in patients with neurologic disorders, medical education efforts for an early diagnosis should target primary care physicians. Chelating agents and zinc are effective for the treatment of WD, but neurologic symptoms become temporarily worse just after treatment with chelating agents. Neurologic worsening in patients treated with tetrathiomolybdate has been reported to be lower than rates of neurologic worsening when treating with other chelating agents.
Assuntos
Cobre/fisiologia , Erros Inatos do Metabolismo dos Metais/patologia , Erros Inatos do Metabolismo dos Metais/terapia , Doenças do Sistema Nervoso/terapia , Criança , Cobre/metabolismo , Degeneração Hepatolenticular/complicações , Degeneração Hepatolenticular/genética , Degeneração Hepatolenticular/fisiopatologia , Degeneração Hepatolenticular/terapia , Homeostase/fisiologia , Humanos , Síndrome dos Cabelos Torcidos/complicações , Síndrome dos Cabelos Torcidos/genética , Síndrome dos Cabelos Torcidos/fisiopatologia , Síndrome dos Cabelos Torcidos/terapia , Erros Inatos do Metabolismo dos Metais/complicações , Erros Inatos do Metabolismo dos Metais/psicologia , Doenças do Sistema Nervoso/etiologiaRESUMO
OBJECTIVE: To present the case of a term newborn with rapid progression of signs of neurodegenerative disease. RESULTS: In a case of a term newborn with numerous dysmorphic features, with seizure activity from the 3rd day of life, hypertonia and serious changes on brain parenchyma were presented. Diagnosis of molybdenum cofactor deficiency was confirmed by the decreased level of uric acid, 31 µmol/l, in serum, increased excretion of thiosulfate and S-sulfocysteine in urine, taurine (1729.3 µmol/mmol crea; normal range 30-300 µmol/mmol crea) and xanthine (276.9 µmol/mmol crea; normal range < 25 µmol/mmol crea) in urine. Sulfite oxidase activity on skin fibroblasts in culture was not detectable. The patient died at the age of 28 days of life. CONCLUSION: Deficiency of molybdenum cofactor leads to accumulation of toxic metabolites (levels of sulfite), which causes disturbances of neurotransmitters even before delivery. Therapy is symptomatic, no effective therapy is available. Seizures are difficult to suppress. This case report is about the first patient in Slovakia.