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1.
BMC Med Genet ; 21(1): 235, 2020 11 26.
Artigo em Inglês | MEDLINE | ID: mdl-33243190

RESUMO

BACKGROUND: Cerebral folate deficiency (CFD) is a neurological disease, hallmarked by remarkable low concentrations of 5-methyltetrahydrofolic acid (5-MTHF) in cerebrospinal fluid (CSF). The primary causes of CFD include the presence of folate receptor (FR) autoantibodies, defects of FR encoding gene FOLR1, mitochondrial diseases and congenital abnormalities in folate metabolism. CASE PRESENTATION: Here we first present a Chinese male CFD patient whose seizure onset at 2 years old with convulsive status epilepticus. Magnetic Resonance Imaging (MRI) revealed the development of encephalomalacia, laminar necrosis in multiple lobes of the brain and cerebellar atrophy. Whole Exome Sequencing (WES) uncovered a homozygous missense variant of c.524G > T (p.C175F) in FOLR1 gene. Further laboratory tests demonstrated the extremely low level of 5-MTHF in the CSF from this patient, which was attributed to cerebral folate transport deficiency. Following the intravenous and oral treatment of calcium folinate, the concentrations of 5-MTHF in CSF were recovered to the normal range and seizure symptoms were relieved as well. CONCLUSIONS: One novel variation of FOLR1 was firstly identified from a Chinese male patient with tonic-clonic seizures, developmental delay, and ataxia. The WES and laboratory results elucidated the etiology of the symptoms. Clinical outcomes were improved by early diagnosis and proper treatment.


Assuntos
Encefalomalacia/genética , Receptor 1 de Folato/genética , Deficiência de Ácido Fólico/genética , Convulsões/genética , Estado Epiléptico/genética , Idade de Início , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Criança , Encefalomalacia/líquido cefalorraquidiano , Encefalomalacia/diagnóstico por imagem , Encefalomalacia/tratamento farmacológico , Receptor 1 de Folato/deficiência , Deficiência de Ácido Fólico/líquido cefalorraquidiano , Deficiência de Ácido Fólico/diagnóstico por imagem , Deficiência de Ácido Fólico/tratamento farmacológico , Homozigoto , Humanos , Leucovorina/uso terapêutico , Imageamento por Ressonância Magnética , Masculino , Convulsões/líquido cefalorraquidiano , Convulsões/diagnóstico por imagem , Convulsões/tratamento farmacológico , Estado Epiléptico/líquido cefalorraquidiano , Estado Epiléptico/diagnóstico por imagem , Estado Epiléptico/tratamento farmacológico , Tetra-Hidrofolatos/líquido cefalorraquidiano , Sequenciamento do Exoma
2.
Pediatr Neurol ; 99: 55-59, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31201073

RESUMO

BACKGROUND: We explored the clinical and molecular characteristics of molybdenum cofactor deficiency due to MOCS2 muations. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Erros Inatos do Metabolismo dos Metais/genética , Sulfurtransferases/deficiência , Regiões 5' não Traduzidas/genética , Agenesia do Corpo Caloso/diagnóstico por imagem , Agenesia do Corpo Caloso/genética , Cisterna Magna/diagnóstico por imagem , Cisterna Magna/patologia , Bases de Dados Factuais , Encefalomalacia/diagnóstico por imagem , Encefalomalacia/genética , Face/anormalidades , Transtornos de Alimentação na Infância/genética , Feminino , Heterogeneidade Genética , Homozigoto , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Masculino , Transtornos dos Movimentos/congênito , Transtornos dos Movimentos/genética , Neuroimagem , Fenótipo , Convulsões/congênito , Sulfurtransferases/genética , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
3.
Brain Dev ; 32(7): 544-9, 2010 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-19793632

RESUMO

Sulfite oxidase is a mitochondrial enzyme encoded by the SUOX gene and essential for the detoxification of sulfite which results mainly from the catabolism of sulfur-containing amino acids. Decreased activity of this enzyme can either be due to mutations in the SUOX gene or secondary to defects in the synthesis of its cofactor, the molybdenum cofactor. Defects in the synthesis of the molybdenum cofactor are caused by mutations in one of the genes MOCS1, MOCS2, MOCS3 and GEPH and result in combined deficiencies of the enzymes sulfite oxidase, xanthine dehydrogenase and aldehyde oxidase. Although present in many ethnic groups, isolated sulfite oxidase deficiency and molybdenum cofactor deficiency are rare inborn errors of metabolism, which makes awareness of key clinical and laboratory features of affected individuals crucial for early diagnosis. We report clinical, radiologic, biochemical and genetic data on a Brazilian and on a Turkish child with sulfite oxidase deficiency due to the isolated defect and impaired synthesis of the molybdenum cofactor, respectively. Both patients presented with early onset seizures and neurological deterioration. They showed no sulfite oxidase activity in fibroblasts and were homozygous for the mutations c.1136A>G in the SUOX gene and c.667insCGA in the MOCS1 gene, respectively. Widely available routine laboratory tests such as assessment of total homocysteine and uric acid are indicated in children with a clinical presentation resembling that of hypoxic ischemic encephalopathy and may help in obtaining a tentative diagnosis locally, which requires confirmation by specialized laboratories.


Assuntos
Coenzimas/deficiência , Encefalomalacia/enzimologia , Encefalomalacia/patologia , Doenças do Recém-Nascido/enzimologia , Doenças do Recém-Nascido/etiologia , Metaloproteínas/deficiência , Convulsões/etiologia , Sulfito Oxidase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/genética , Brasil , Coenzimas/genética , Análise Mutacional de DNA , Diagnóstico Diferencial , Encefalomalacia/etiologia , Encefalomalacia/genética , Feminino , Humanos , Recém-Nascido , Doenças do Recém-Nascido/genética , Doenças do Recém-Nascido/patologia , Metaloproteínas/genética , Cofatores de Molibdênio , Pteridinas , Convulsões/complicações , Sulfito Oxidase/genética , Turquia
4.
J Child Neurol ; 23(6): 695-8, 2008 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-18539994

RESUMO

Methylenetetrahydrofolate reductase catalyzes the formation of 5-methyltetrahydrofolate from 5,10-methylentetrahydrofolate and produces folate for the methylation of homocysteine to methionine. Due to insufficient conversion of homocysteine to methionine, plasma homocysteine levels increase in methylenetetrahydrofolate reductase deficiency. Homocysteine is an amino acid that contains a neurotoxic sulfur molecule and can induce neuronal apoptosis. Methylenetetrahydrofolate reductase deficiency is 1 of the etiological factors that causes neurological symptoms and signs in the newborn and childhood period. Here, we report a premature baby with prenatal onset diffuse multicystic encephalomalacia and cerebellar atrophy due to homozygous methylenetetrahydrofolate reductase mutation.


Assuntos
Análise Mutacional de DNA , Encefalomalacia/genética , Doenças do Prematuro/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Dissinergia Cerebelar Mioclônica/genética , Encéfalo/patologia , Hemorragia Cerebral/genética , Hemorragia Cerebral/patologia , Ecoencefalografia , Encefalomalacia/diagnóstico , Humanos , Recém-Nascido , Doenças do Prematuro/diagnóstico , Imageamento por Ressonância Magnética , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Dissinergia Cerebelar Mioclônica/diagnóstico , Tomografia Computadorizada por Raios X
5.
Am J Vet Res ; 62(3): 343-9, 2001 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-11277198

RESUMO

OBJECTIVE: To investigate the possibility that excessive maternal iron (overload) may contribute to development of congenital leukoencephalomalacia in captive black rhinoceroses. SAMPLE POPULATION: Tissue specimens and serum samples from 18 rhinoceroses in 2 kindreds harboring 4 (possibly 5) affected female calves. PROCEDURE: Fresh and archival sera and necropsy tissue specimens were evaluated to determine the nature and extent of iron overload in captive and wild black rhinoceroses as well as other rhinoceros species. RESULTS: Quantitative serum and tissue assays of iron and iron analytes, corroborated by histopathologic findings, indicated that these kindreds carried the greatest body burdens of iron yet found among captive black rhinoceroses. Fourteen of 18 rhinoceroses had the highest serum ferritin concentrations measured among 64 black rhinoceroses in captivity in the United States. Dams of affected calves had serum ferritin concentrations 2 orders of magnitude higher than clinically normal humans, equids, or free-ranging rhinoceroses. A neonatal serum sample from 1 affected female calf had a high ferritin concentration (approx 100-fold increase), but a male sibling of another affected female did not, suggesting a possible sex disparity in fetal response to maternal iron overload. Morphologic hallmarks of hemochromatosis were prominent in dams and grandams of affected calves. CONCLUSIONS AND CLINICAL RELEVANCE: Excessive maternal iron may affect female fetuses more than males, possibly inducing leukoencephalomalacia by catalyzing production of highly toxic hydroxyl free radicals during crucial periods of in utero development. Reduction of maternal iron overload may decrease the probability of developing leukoencephalomalacia and some other disorders commonly affecting rhinoceroses in captivity.


Assuntos
Encefalomalacia/veterinária , Sobrecarga de Ferro/veterinária , Perissodáctilos/metabolismo , Animais , Encefalomalacia/congênito , Encefalomalacia/etiologia , Encefalomalacia/genética , Feminino , Ferritinas/sangue , Haptoglobinas/metabolismo , Histocitoquímica/veterinária , Ferro/sangue , Ferro/metabolismo , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/genética , Sobrecarga de Ferro/patologia , Fígado/metabolismo , Masculino , Linhagem , Perissodáctilos/sangue , Perissodáctilos/genética , Gravidez , Complicações na Gravidez/sangue , Complicações na Gravidez/metabolismo , Transferrina/metabolismo
6.
An Esp Pediatr ; 32(2): 163-6, 1990 Feb.
Artigo em Espanhol | MEDLINE | ID: mdl-2189324

RESUMO

Multicystic encephalomalacia (ME) is a rare entity in the pediatric age. In ME brain tissue in substituted by cavities of variable size. ME has different etiologies being asphyxia and circulatory alterations the most important factors. In monozygotic twins there is an increased incidence of structural anomalies than dizygotic twins. We present four twin patients with ME. Three of them had a prenatal dead sibling. The fourth pair of twins had a twin-twin transfusion. We want to stress the utility of brain echography in early diagnosis of ME.


Assuntos
Encefalopatias/genética , Cistos/congênito , Doenças em Gêmeos , Encefalomalacia/congênito , Encefalopatias/congênito , Encefalopatias/diagnóstico , Cistos/complicações , Cistos/diagnóstico , Cistos/genética , Encefalomalacia/complicações , Encefalomalacia/diagnóstico , Encefalomalacia/genética , Feminino , Humanos , Recém-Nascido , Tomografia Computadorizada por Raios X , Ultrassonografia
8.
Hum Genet ; 62(1): 52-9, 1982.
Artigo em Inglês | MEDLINE | ID: mdl-6891369

RESUMO

Two male half siblings developed rapid progression of neurologic symptoms at 11/2 and 21/2 years of age. Neither boy had a metabolic acidosis. Characteristic features of subacute necrotizing encephalomyelopathy, the neuropathologic basis of Leigh's syndrome, were demonstrated at autopsy. X-linkage of the disorder was considered because the boys had different fathers. An X-linked form of Leigh's syndrome was supported by a review of the literature, which showed an unexplained male/female ratio in Leigh's syndrome of 1.83/1, and a significant excess of male-male siblings. An X-linked form of Leigh's syndrome would explain the excess of males, and may account for some of the clinical and biochemical heterogeneity.


Assuntos
Encefalomalacia/genética , Ligação Genética , Cromossomos Sexuais , Cromossomo X , Encéfalo/patologia , Pré-Escolar , Encefalomalacia/patologia , Feminino , Genes Recessivos , Humanos , Lactente , Masculino , Necrose , Linhagem , Fenótipo , Síndrome
10.
Arch Dis Child ; 55(10): 789-94, 1980 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-7436444

RESUMO

Erythrocyte transketolase activity and the effect of adding thiamine pyrophosphate (% thiamine pyrophosphate effect) were measured in 111 subjects suspected to suffer from Leigh's disease (subacute necrotising encephalomyelopathy). From clinical evidence these subjects were divided into five groups: (1) necropsy-proved cases of subacute necrotising encephalomyelopathy, (2) cases positive for urinary thiamine pyrophosphate: adenosine triphosphate phosphotransferase inhibitor, (3) clinically likely cases of subacute necrotising encephalomyelopathy (patients still alive, or on whom no necropsy was performed), (4) cases diagnosed as diseases other than subacute necrotising encephalomyelopathy (control group), (5) cases for which no diagnosis had been made. Comparison of erythrocyte transketolase activities with and without added thiamine pyrophosphate and of the % thiamine pyrophosphate effect for each group compared with the control group showed no statistically significant differences from normal values for any of these parameters. Similarly, there were no differences between the two sexes in transketolase activity, and no correlation between transketolase activity and age. These results indicate that erythrocyte transketolase activity is not altered in subacute necrotising encephalomyelopathy and is unlikely to be of value for the diagnosis of Leigh's disease.


Assuntos
Tronco Encefálico , Encefalomalacia/enzimologia , Eritrócitos/enzimologia , Transcetolase/sangue , Criança , Encefalomalacia/sangue , Encefalomalacia/genética , Feminino , Humanos , Masculino , Síndrome , Tiamina Pirofosfato , Transcetolase/antagonistas & inibidores
11.
Ann Neurol ; 7(4): 304-10, 1980 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-6246834

RESUMO

The large family of a 21-year-old man who died of Leigh disease was investigated for evidence of neurological abnormalities and presence of the adenosine triphosphate-thiamine diphosphate phosphoryltransferase inhibitor factor. Of 217 persons (seven generations) included in the pedigree, 68 were examined neurologically and biochemically. Fourteen (20%), 5 of whom had abnormal neurological findings, were found to excrete the inhibitor factor. Clinical manifestations varied from severe neurological affliction to subtle deficits. A chronic relapsing course was frequently encountered, with exacerbations occurring in association with apparent metabolic stress. Parental consanguinity was identified in the propositus as well as in other family members with neurological abnormalities. Males and females were affected, and no vertical transmission of the trait was found. These multigenerational data suggest that Leigh disease in adults is inherited in an autosomal recessive manner and has variable degrees of expression with a wide spectrum of neurological manifestations.


Assuntos
Tronco Encefálico , Encefalomalacia/genética , Inibidores Enzimáticos/urina , Fosfotransferases (Aceptor do Grupo Fosfato) , Fosfotransferases/antagonistas & inibidores , Adulto , Criança , Aberrações Cromossômicas , Transtornos Cromossômicos , Consanguinidade , Encefalomalacia/epidemiologia , Encefalomalacia/urina , Feminino , Genes Recessivos , Grécia , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Síndrome
12.
An Esp Pediatr ; 11(3): 247-52, 1978 Mar.
Artigo em Espanhol | MEDLINE | ID: mdl-666130

RESUMO

A 6-month-old girl with familiar history of two dead sisters few months old, was admitted to the Hospital with a neurological process. After her admission progressively worsened until her death. The patient had clinical manifestation of proximal tubular acidosis. Levels of lactic and piruvic acid were normal. Necropsic study was compatible with the diagnoses of subacute necrotizing encephalomielopathy of Leigh syndrome.


Assuntos
Acidose Tubular Renal/genética , Encefalomalacia/genética , Acidose Tubular Renal/patologia , Tronco Encefálico/patologia , Diagnóstico Diferencial , Encefalomalacia/patologia , Feminino , Humanos , Lactente , Síndrome
15.
Monatsschr Kinderheilkd (1902) ; 123(2): 84-90, 1975 Feb.
Artigo em Alemão | MEDLINE | ID: mdl-1121308

RESUMO

The characteristic neuropathological features of subacute necrotizing encephalomyelopathy (Leigh), their histology and distribution are described. Clinical findings are unspecific. Impairment of feeding. vomitus, respiratory abnormality, retardation of psychomotor development, familial incidence and onset in early childhood are prominent symptoms. Atactic and athetoid movements, optic atrophy, oculomotor abnormalities are observed in most cases. An enzyme inhibitor excreted in the urine seems to be related to an inborn error of thiamine dependent metabolism in brain tissue. Treatment with thiamine derivatives may have a beneficial effect on the clinical course.


Assuntos
Tronco Encefálico , Fatores Etários , Ataxia/complicações , Atetose/complicações , Autopsia , Criança , Pré-Escolar , Coreia/complicações , Encefalomalacia/complicações , Encefalomalacia/diagnóstico , Encefalomalacia/tratamento farmacológico , Encefalomalacia/genética , Encefalomalacia/patologia , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/patologia , Atrofia Óptica/complicações , Transtornos Psicomotores/diagnóstico , Transtornos Psicomotores/tratamento farmacológico , Transtornos Psicomotores/patologia , Tiamina/uso terapêutico , Vômito
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