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1.
Arch Biochem Biophys ; 696: 108646, 2020 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-33098870

RESUMO

Organic acidurias (OADs) are inherited disorders of amino acid metabolism biochemically characterized by accumulation of short-chain carboxylic acids in tissues and biological fluids of the affected patients and clinically by predominant neurological manifestations. Some of these disorders are amenable to treatment, which significantly decreases mortality and morbidity, but it is still ineffective to prevent long-term neurologic and systemic complications. Although pathogenesis of OADs is still poorly established, recent human and animal data, such as lactic acidosis, mitochondrial morphological alterations, decreased activities of respiratory chain complexes and altered parameters of oxidative stress, found in tissues from patients and from genetic mice models with these diseases indicate that disruption of critical mitochondrial functions and oxidative stress play an important role in their pathophysiology. Furthermore, organic acids that accumulate in the most prevalent OADs were shown to compromise bioenergetics, by decreasing ATP synthesis, mitochondrial membrane potential, reducing equivalent content and calcium retention capacity, besides inducing mitochondrial swelling, reactive oxygen and nitrogen species generation and apoptosis. It is therefore presumed that secondary mitochondrial dysfunction and oxidative stress caused by major metabolites accumulating in OADs contribute to tissue damage in these pathologies.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Mitocôndrias/metabolismo , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/fisiopatologia , Estresse Oxidativo/fisiologia , Animais , Encéfalo/metabolismo , Ácidos Carboxílicos/metabolismo , Humanos
2.
Neurology ; 95(23): e3129-e3137, 2020 12 08.
Artigo em Inglês | MEDLINE | ID: mdl-32943488

RESUMO

OBJECTIVE: To analyze the clinical characteristics of patients with hydrocephalus secondary to cobalamin C (cblC) deficiency and to discuss the optimal strategies for assessing and treating such patients by performing clinical and laboratory studies in 70 patients. METHODS: A total of 1,211 patients were clinically diagnosed with methylmalonic acidemia (MMA) from 1998 to 2019. Among them, cblC deficiency was confirmed in 70 patients with hydrocephalus by brain imaging and biochemical and genetic analysis. RESULTS: Of the 70 patients, 67 (95.7%) had early-onset MMA and homocystinuria. The patients typically had high blood propionylcarnitine and total homocysteine, low methionine, and methylmalonic aciduria. Signs of intracranial hypertension were relatively rare. We measured ventricular dilatation early in the disease by cranial ultrasound and MRI and/or CT. Eighteen different MMACHC mutations, including 4 novel mutations (c.427C>T, c.568insT, c.599G>A, and c.615C>A), were identified biallelically in all 70 patients. c.609G>A was the most frequent mutation, followed by c.658_660del, c.217C>T, and c.567dupT. Three cases were diagnosed by postmortem study. Metabolic therapy, including cobalamin injections supplemented with oral l-carnitine and betaine, was administered in the remaining 67 cases. A ventriculoperitoneal shunt was performed in 36 cases. During the follow-up, psychomotor development, nystagmus, impaired vision, and sunset eyes improved gradually. CONCLUSION: Hydrocephalus is a severe condition with several different causes. In this study, ventriculomegaly was found in 70 patients with cblC deficiency. Early diagnosis, etiologic treatment, and prompt surgical intervention are crucial to improve the prognosis of patients.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Hidrocefalia , Derivação Ventriculoperitoneal , Deficiência de Vitamina B 12 , Vitamina B 12/administração & dosagem , Complexo Vitamínico B/administração & dosagem , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Criança , Pré-Escolar , Feminino , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/etiologia , Hidrocefalia/cirurgia , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Oxirredutases/genética , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Ultrassonografia , Deficiência de Vitamina B 12/complicações , Deficiência de Vitamina B 12/tratamento farmacológico , Deficiência de Vitamina B 12/genética
3.
BMC Med Genet ; 21(1): 183, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32957924

RESUMO

BACKGROUND: Disorders of the metabolism and absorption of vitamin B12 can lead to decrease in activity of methionine synthetase and methylmalonate coenzyme A mutase (MMUT), which results in increased levels of methylmalonic acid and homocysteine in blood and urine. Often, combined methylmalonic acidemia (MMA) and homocysteinemia is misdiagnosed due to a lack of specific symptoms. The clinical manifestations are diverse, but proteinuria as the initial presentation is rare. CASE PRESENTATION: Two cases of MMA with homocysteinemia in children are reported. Proteinuria were a primary presenting symptom, followed by anemia and neurologic symptoms (frequent convulsions and unstable walking, respectively). Screening of amino acids and acyl carnitine in serum showed that the propionyl carnitine:acetylcarnitine ratio increased. Profiling of urinary organic acids by gas chromatography-mass spectrometry revealed high levels of methylmalonic acid. Homocysteine content in blood was increased. Comprehensive genetic analyses of peripheral blood-derived DNA demonstrated heterozygous variants of methylmalonic aciduria type C and homocystinuria (MMACHC) and amnionless (AMN) genes in our two patients, respectively. After active treatment, the clinical manifestations in Case 1 were relieved and urinary protein ceased to be observed; Case 2 had persistent proteinuria and was lost to follow-up. CONCLUSIONS: Analyses of the organic acids in blood and urine suggested MMA combined with homocysteinemia. In such diseases, reports of renal damage are uncommon and proteinuria as the initial presentation is rare. Molecular analysis indicated two different genetic causes. Although the pathologic mechanisms were related to vitamin B12, the severity and prognosis of renal lesions were different. Therefore, gene detection provides new insights into inherited metabolic diseases.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Hiper-Homocisteinemia/complicações , Proteinúria/diagnóstico , Adolescente , Erros Inatos do Metabolismo dos Aminoácidos/genética , Aminoácidos/sangue , Sequência de Bases , Carnitina/análogos & derivados , Carnitina/sangue , Pré-Escolar , DNA/sangue , DNA/genética , Cromatografia Gasosa-Espectrometria de Massas , Homocisteína/sangue , Humanos , Hiper-Homocisteinemia/genética , Masculino , Ácido Metilmalônico/urina , Proteinúria/etiologia
4.
BMC Psychiatry ; 20(1): 395, 2020 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-32758201

RESUMO

BACKGROUND: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare neurometabolic disorder resulting in a heterogeneous clinical phenotype. Adolescent and adult patients with SSADH deficiency may present with OCD symptoms. There is minimal literature regarding the pathological basis of OCD symptoms and their management amongst SSADH deficiency patients. CASE PRESENTATION: A 26-year-old woman with SSADH deficiency experienced obsessional slowness and hesitancy in her activities of daily living, with motor rituals and stereotypies of her hands and face. Neuroimaging revealed T2 hyperintensities of the globi pallidi bilaterally. Commencement of the serotonergic escitalopram moderately improved her OCD symptoms. The addition of the dopaminergic pramipexole hydrochloride yielded further improvement, following unsuccessful trial of other adjuncts: risperidone, methylphenidate and mirtazapine. CONCLUSIONS: Pallidal pathology may explain the manifestation of OCD symptoms amongst individuals with SSADH deficiency. Serotonergic and concomitant dopaminergic therapy may be a viable treatment regimen for SSADH deficiency patients presenting with OCD symptoms.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Transtorno Obsessivo-Compulsivo , Atividades Cotidianas , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Criança , Deficiências do Desenvolvimento , Feminino , Humanos , Transtorno Obsessivo-Compulsivo/complicações , Transtorno Obsessivo-Compulsivo/diagnóstico , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Succinato-Semialdeído Desidrogenase/deficiência
6.
Brain Dev ; 42(4): 357-362, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31937422

RESUMO

PURPOSE: We report on one patient with methylmalonic acidemia (MMA) who presented with symmetrical hemorrhage of the caudate nucleus accompanied by severe ventricular dilatation, follow-up magnetic resonance imaging (MRI) findings from one year later, and the clinical manifestations, neuropsychological scores, genetic test results, urine and blood laboratory results and evolution of the disorder. MATERIALS AND METHODS: This study describes the recent and remote neuropathologic findings, reviews the literature, and discusses the possible pathogenetic mechanisms of these central nervous system lesions. RESULTS: Patients with MMA may have signs of basal ganglia hemorrhage during acute onset, and the hemorrhage may disappear after treatment. During the treatment, both laboratory examination indexes and neuropsychological scores improved. There was a correlation between the evolution of bilateral basal ganglia hemorrhage using MRI(magnetic resonance imaging) and neurological damage recovery in this infant with MMA. CONCLUSION: There was a correlation between the evolution of the bilateral basal ganglia hemorrhage using MR imaging and neurological damage recovery in an infant with MMA. We recommend performing conventional MR and diffusion-weighted imaging (DWI) examinations in patients with MMA who present with neurological symptoms.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Hemorragia dos Gânglios da Base/diagnóstico por imagem , Hemorragia dos Gânglios da Base/patologia , Hemorragia dos Gânglios da Base/complicações , Hemorragia dos Gânglios da Base/tratamento farmacológico , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Recuperação de Função Fisiológica , Resultado do Tratamento
7.
Amino Acids ; 52(3): 371-385, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31902007

RESUMO

The aim of this study was to investigate the effect of the chronic administration of methionine (Met) and/or its metabolite, methionine sulfoxide (MetO), on the behavior and neurochemical parameters of young rats. Rats were treated with saline (control), Met (0.2-0.4 g/kg), MetO (0.05-0.1 g/kg), and/or a combination of Met + MetO, subcutaneously twice a day from postnatal day 6 (P6) to P28. The results showed that Met, MetO, and Met + MetO impaired short-term and spatial memories (P < 0.05), reduced rearing and grooming (P < 0.05), but did not alter locomotor activity (P > 0.05). Acetylcholinesterase activity was increased in the cerebral cortex, hippocampus, and striatum following Met and/or MetO (P < 0.05) treatment, while Na+, K+-ATPase activity was reduced in the hippocampus (P < 0.05). There was an increase in the level of thiobarbituric acid reactive substances (TBARS) in the cerebral cortex in Met-, MetO-, and Met + MetO-treated rats (P < 0.05). Met and/or MetO treatment reduced superoxide dismutase, catalase, and glutathione peroxidase activity, total thiol content, and nitrite levels, and increased reactive oxygen species and TBARS levels in the hippocampus and striatum (P < 0.05). Hippocampal brain-derived neurotrophic factor was reduced by MetO and Met + MetO compared with the control group. The number of NeuN-positive cells was decreased in the CA3 in Met + MetO group and in the dentate gyrus in the Met, MetO, and Met + MetO groups compared to control group (P < 0.05). Taken together, these findings further increase our understanding of changes in the brain in hypermethioninemia by elucidating behavioral alterations, biological mechanisms, and the vulnerability of brain function to high concentrations of Met and MetO.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Glicina N-Metiltransferase/deficiência , Hipocampo/patologia , Transtornos da Memória/etiologia , Transtornos da Memória/patologia , Metionina/análogos & derivados , Espécies Reativas de Oxigênio/metabolismo , Acetilcolinesterase/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/induzido quimicamente , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Animais , Catalase/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Feminino , Glutationa Peroxidase/deficiência , Glicina N-Metiltransferase/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Masculino , Transtornos da Memória/metabolismo , Memória de Curto Prazo/efeitos dos fármacos , Metionina/metabolismo , Metionina/toxicidade , Ratos , Ratos Wistar , Memória Espacial/efeitos dos fármacos , Superóxido Dismutase/deficiência , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo
8.
Int J Dev Neurosci ; 80(1): 42-49, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31910296

RESUMO

Glutaric acidemia type I (GA1) is caused by severe deficiency of glutaryl-CoA dehydrogenase activity, resulting in an accumulation of glutaric acid and glutarylcarnitine (C5DC) in the organism. Patients affected by GA1 are asymptomatic in the neonate period but usually manifest chronically progressive neurodegeneration apart from severe encephalopathic crises associated with acute striatum necrosis. Neurological manifestations like dyskinesia, dystonia, hypotonia, muscle stiffness, and spasticity are present. Treatment is based on protein/lysine restriction and l-carnitine supplementation. In this work, we evaluated markers of neurodegeneration and inflammation, namely BDNF (brain-derived neurotrophic factor), NCAM (neuronal adhesion molecule), PDGF-AA (platelet-derived growth factor), and cathepsin-d in plasma of six treated GA1 patients. We first found marked increases of plasma C5DC concentrations in GA1 patients, as well as increased levels of the markers BDNF and cathepsin-d as compared to those of age-matched healthy children. Furthermore, C5DC concentrations were highly correlated with the levels of cathepsin-d. These results may demonstrate that brain tissue degeneration is present in GA1 patients and that there is a relationship between increased metabolites concentrations with this process. To the best of our knowledge, this is so far the first study showing altered peripheral parameters of neurodegeneration and inflammation in GA1 patients.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/sangue , Encefalopatias Metabólicas/sangue , Fator Neurotrófico Derivado do Encéfalo/sangue , Catepsina D/sangue , Glutaril-CoA Desidrogenase/deficiência , Degeneração Neural/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Biomarcadores/sangue , Encefalopatias Metabólicas/complicações , Criança , Pré-Escolar , Feminino , Glutaril-CoA Desidrogenase/sangue , Humanos , Lactente , Recém-Nascido , Masculino , Degeneração Neural/sangue , Degeneração Neural/etiologia , Moléculas de Adesão de Célula Nervosa/sangue , Fator de Crescimento Derivado de Plaquetas/metabolismo
9.
Iran Biomed J ; 24(3): 201-5, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31952437

RESUMO

Background: Glutaric acidemia (GAI) and mucopolysaccharidosis type IIIB (MPSIIIB) are two rare genetic disorders caused by pathogenic variants in two different genes. Here, we report a coexistence of these two different rare disorders in an individual. Methods: A four-year-old Iranian boy born to first-cousin parents suspected to have MPSIIIB and/or GAI was investigated in this study. Targeted genomic enrichment and next-generation sequencing were used to examine genes related to MPS and GA. Sanger sequencing was performed to confirm the results. Results: Two homozygous likely pathogenic variants in α-N-acetylglucosaminidase (NAGLU) and GCDH genes were found and confirmed in the proband. Conclusion: A combination of specific features of two different diseases in a patient has been reported here. More studies on this case and similar cases can provide more information about the effect of simultaneous pathogenic variants in different genes.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Encefalopatias Metabólicas/complicações , Glutaril-CoA Desidrogenase/deficiência , Mucopolissacaridose III/complicações , Sequência de Bases , Pré-Escolar , Feminino , Humanos , Masculino , Linhagem
10.
Mol Genet Metab ; 129(1): 20-25, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31813752

RESUMO

The long-term consequences and need for therapy in children with short-chain acyl-CoA dehydrogenase deficiency (SCADD) or isobutyryl-CoA dehydrogenase deficiency (IBDD) identified via newborn screening (NBS) remains controversial. Initial clinical descriptions were severe; however, while most cases identified through NBS have remained asymptomatic, clinical concerns have been raised in these populations. It is not clear whether these children are asymptomatic because of the success of NBS, or because the normal clinical course of these disorders is relatively benign. To evaluate these possibilities in our program, we evaluated the clinical outcomes of children with SCADD or IBDD identified by the Georgia NBS compared to the health status of a healthy age-matched control group. We also assessed parental anxiety during a phone interview both subjectively and objectively using the Pediatric Inventory for Parents (PIP), a validated measure of illness-related parental stress. The general health of 52 SCADD and nine IBDD cases from 2007 to 2016 were compared to the general health of unaffected control children obtained through the Centers for Disease Control and Prevention (CDC) parent listserv. We also collected statements from parents who participated in a phone survey regarding events they experienced during and after their diagnostic process. Overall, the children with SCADD and IBDD had no major health problems. There was no significant difference in cognitive development (p = .207). We identified a slightly higher incidence of reported neonatal hypoglycemia in the SCADD group; two of these occurred in the context of maternal diabetes. All interviewed parents reported extreme anxiety during the diagnostic period and current feelings of uncertainty about their child's future. PIP scores for all six caregivers who responded to that portion of the survey were consistent with some degree of parental stress. The greatest reported stressor was the unknown long-term impact of the illness. All children with SCADD and IBDD had no significant long-term sequelae. The phone interviews revealed substantial parental anxiety about the identification and follow-up of SCADD and IBDD. Based on our findings, the anxiety parents experience may be unwarranted given that we see no disease-associated morbidity or mortality in these children. Consideration should be given to the removal of these conditions from NBS panels, or if that is not possible, clinicians could educate parents on the benign nature of these diagnoses and release them from follow-up without treatment.


Assuntos
Acil-CoA Desidrogenase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Ansiedade/etiologia , Erros Inatos do Metabolismo Lipídico/diagnóstico , Triagem Neonatal/psicologia , Pais/psicologia , Acil-CoA Desidrogenase/genética , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/genética , Ansiedade/epidemiologia , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Variação Genética , Georgia/epidemiologia , Humanos , Lactente , Recém-Nascido , Erros Inatos do Metabolismo Lipídico/complicações , Erros Inatos do Metabolismo Lipídico/genética , Masculino , Inquéritos e Questionários
11.
BMC Neurol ; 19(1): 345, 2019 Dec 29.
Artigo em Inglês | MEDLINE | ID: mdl-31884946

RESUMO

BACKGROUND: Hyperprolinemia type 2 (HPII) is a rare autosomal recessive disorder of the proline metabolism, that affects the ALDH4A1 gene. So far only four different pathogenic mutations are known. The manifestation is mostly in neonatal age, in early infancy or early childhood. CASE PRESENTATION: The 64-years female patient had a long history of abdominal pain, and episode of an acute neuritis. Ten years later she was admitted into the neurological intensive-care-unit with acute abdominal pain, multiple generalized epileptic seizures, a vertical gaze palsy accompanied by extensive lactic acidosis in serum 26.0 mmol/l (reference: 0.55-2.2 mmol/l) and CSF 12.01 mmol/l (reference: 1.12-2.47 mmol/l). Due to repeated epileptic seizures and secondary complications a long-term sedation with a ventilation therapy over 20 days was administered. A diagnostic work-up revealed up to 400-times increased prolin-level in urine CSF and blood. Furthermore, a low vitamin-B6 serum value was found, consistent with a HPII causing secondary pyridoxine deficiency and seizures. The ALDH4A1 gene sequencing confirmed two previously unknown compound heterozygous variants (ALDH4A1 gene (NM_003748.3) Intron 1: c.62 + 1G > A - heterozygous and ALDH4A1 gene (NM_003748.3) Exon 5 c.349G > C, p.(Asp117His) - heterozygous). Under high-dose vitamin-B6 therapy no further seizures occurred. CONCLUSION: We describe two novel ALDH4A1-variants in an adult patient with hyperprolinemia type II causing secondary pyridoxine deficiency and seizures. Severe and potentially life-threatening course of this treatable disease emphasizes the importance of diagnostic vigilance and thorough laboratory work-up including gene analysis even in cases with atypical late manifestation.


Assuntos
1-Pirrolina-5-Carboxilato Desidrogenase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/genética , 1-Pirrolina-5-Carboxilato Desidrogenase/genética , Acidose Láctica/etiologia , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Feminino , Humanos , Mutação , Estado Epiléptico/etiologia
12.
Eur J Paediatr Neurol ; 23(5): 755-759, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31679561

RESUMO

3-Hydroxyisobutyryl-CoA hydrolase (HIBCH) deficiency is a recently described disease resulting from mutations in HIBCH with no effective treatment. Here, we report a female Chinese patient presenting with exercise-induced dystonia and bilateral symmetrical hyperintensities of the globus pallidus on brain MRI associated with novel HIBCH mutations (c.1027C>G;p. H343D and c.383T>A;p.V128D). After treatment for 1 year with a low-valine diet, both clinical symptoms and brain lesions improved substantially. We propose that HIBCH deficiency should be considered in the differential diagnosis for patients with exercise-induced dystonia, particularly if bilateral symmetrical lesions in the globus pallidus are present. A low-valine diet is a potentially promising treatment for HIBCH deficiency.


Assuntos
Anormalidades Múltiplas/dietoterapia , Erros Inatos do Metabolismo dos Aminoácidos/dietoterapia , Distúrbios Distônicos/dietoterapia , Exercício Físico , Tioléster Hidrolases/deficiência , Anormalidades Múltiplas/diagnóstico por imagem , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico por imagem , Criança , Distúrbios Distônicos/complicações , Feminino , Globo Pálido/diagnóstico por imagem , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imagem por Ressonância Magnética , Mutação de Sentido Incorreto , Tioléster Hidrolases/genética , Resultado do Tratamento
13.
J Pediatr Endocrinol Metab ; 32(10): 1181-1185, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31473688

RESUMO

Mitochondrial acyl-CoA dehydrogenase 9 (ACAD9) deficiency is one of the common causes of respiratory chain complex I deficiency, which is characterized by cardiomyopathy, lactic acidemia, and muscle weakness. Infantile cardiomyopathy is the most common phenotype and is usually lethal by the age of 5 years. Riboflavin treatment is known to be effective in ~65% of the patients; however, the remaining are unresponsive to riboflavin and are in need of additional treatment measures. In this report, we describe a patient with ACAD9 deficiency who developed progressive cardiomyopathy at 8 months of age. As the patient's left ventricular ejection fraction (LVEF) kept decreasing to 45.4% at 1 year 8 months, sodium pyruvate treatment was introduced together with a beta-blocker and coenzyme Q10. This resulted in a steady improvement, with full and sustained normalization of cardiac function without riboflavin. The therapy, therefore, might be a useful addition for the treatment of ACAD9 deficiency.


Assuntos
Acidose/tratamento farmacológico , Acil-CoA Desidrogenase/deficiência , Acil-CoA Desidrogenases/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/tratamento farmacológico , Cardiomiopatias/tratamento farmacológico , Cardiomiopatia Hipertrófica/tratamento farmacológico , Carvedilol/administração & dosagem , Doenças Mitocondriais/tratamento farmacológico , Debilidade Muscular/tratamento farmacológico , Piruvatos/administração & dosagem , Ubiquinona/análogos & derivados , Acidose/complicações , Acidose/patologia , Antagonistas Adrenérgicos beta/administração & dosagem , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Cardiomiopatias/complicações , Cardiomiopatias/patologia , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/patologia , Quimioterapia Combinada , Feminino , Humanos , Recém-Nascido , Doenças Mitocondriais/complicações , Doenças Mitocondriais/patologia , Debilidade Muscular/complicações , Debilidade Muscular/patologia , Prognóstico , Ubiquinona/administração & dosagem , Vitaminas/administração & dosagem
14.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(9): 870-873, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31515778

RESUMO

OBJECTIVE: To assess the value of dry blood spot tandem mass spectrometry for the diagnosis of autism spectrum disorder (ASD). METHODS: Peripheral blood samples of 277 autistic children were collected. Their amino acid and carnitine profiles were detected by liquid chromatography tandem mass spectrometry. Urine samples of suspected patients were collected for verification by gas chromatography mass spectrometry. Blood samples were also taken for genetic testing. RESULTS: Of the 277 children with ASD, 19 (6.9%) were suspected to be with inborn error of metabolism (IEM), which included 6 cases with amino acidemia, 9 with organic acidemia and 4 with fatty acidemia. Three cases of phenylketonuria, one case of homocysteinemia, one case of propionemia, one case of methylmalonic acidemia, one case of glutaric acidemia, one case of isovaleric acidemia, one case of argininemia, one case of citrullinemia I and four cases of primary carnitine deficiency were confirmed by genetic testing, which yielded an overall diagnostic rate of 5.1% (14/277). CONCLUSION: Our result has provided further evidence for the co-occurrence of ASD and IEM. Tandem mass spectrometry has a great value for the diagnosis and treatment of ASD in childhood.


Assuntos
Transtorno do Espectro Autista/diagnóstico , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Transtorno do Espectro Autista/complicações , Criança , Teste em Amostras de Sangue Seco , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Erros Inatos do Metabolismo/complicações , Espectrometria de Massas em Tandem
15.
Hemodial Int ; 23(4): E115-E119, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476111

RESUMO

Several metabolic disorders are related to rhabdomyolysis, but their association with methylmalonic acidemia (MMA) and propionic acidemia (PA) is unclear. Eleven patients with MMA and four patients with PA were treated and/or followed up in Kumamoto University Hospital between January 2009 and December 2018. Three patients with MMA and one patient with PA developed rhabdomyolysis at 1-2 weeks after onset of metabolic crisis. Cases 1 and 4 initially developed rhabdomyolysis after withdrawal from continuous hemodiafiltration (CHDF), and cases 2 and 3 developed rhabdomyolysis at the time of onset and had recurrent rhabdomyolysis during the recovery phase after withdrawal from CHDF. Mitochondrial dysfunction is associated with rhabdomyolysis. The rhabdomyolysis in patients with MMA and PA may have been attributed to a defect in energy production because of a secondary mitochondrial disorder. Therefore, physicians should closely follow patients with MMA and PA, especially after withdrawal of hemodialysis therapy, and provide supportive care for their mitochondrial function.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Acidemia Propiônica/complicações , Diálise Renal/métodos , Rabdomiólise/etiologia , Rabdomiólise/fisiopatologia , Feminino , Humanos , Recém-Nascido , Masculino
16.
Ophthalmic Genet ; 40(4): 313-322, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31269850

RESUMO

Background: Classical MMA, caused by methylmalonyl-CoA mutase deficiency, may result in late-onset dysfunction in several organ systems. To date, 10 cases of optic neuropathy have been reported. The prevalence of optic neuropathy in visually asymptomatic patients has not been determined. This study sought to identify overt and subclinical optic neuropathy in a cohort with classical MMA. Methods and Materials: Neuroophthalmic examinations were performed on 21 patients identified with classical MMA, older than 10years. Diagnosis of optic neuropathy was determined by a combination of visual acuity, optic nerve appearance and electrodiagnostic tests. Tabulated data were analyzed for association of variables using SAS software. Significance was set at p < .05. Results: Two-thirds were Saudi nationals and one third, Syrian. Age range was 11-29years. Eleven (52.4%) patients had optic neuropathy. Nine (81.8%) of these were bilateral, seven (57.9% to 63.6%) reported decreased vision and four (33.1% to 36.4%) were asymptomatic. Two patients had catastrophic vision loss, following acute metabolic crises. Sixteen patients had chronic renal impairment while three had renal hypertension. Seventeen patients had short stature and eight, chronic pancreatitis. Methylmalonic acid levels ranged from 82 to 3,324µmol/L (Normal<1µmol/L). There was a significant association between optic neuropathy and female gender (p = .011) and none with age, nationality, renal impairment, pancreatitis or specific genotype. Conclusion: Optic neuropathy was a frequent finding in classical MMA. It was often bilateral and some cases were sub-clinical, lacking visual symptoms. These findings have important management implications. Full ophthalmic evaluations should be performed early and regularly in patients with MMA, even when patients are asymptomatic.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Doenças do Nervo Óptico/patologia , Adolescente , Adulto , Criança , Feminino , Seguimentos , Humanos , Masculino , Doenças do Nervo Óptico/etiologia , Prognóstico , Acuidade Visual , Adulto Jovem
17.
J Inherit Metab Dis ; 42(5): 793-802, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31260114

RESUMO

Methylmalonic aciduria (MMA) is an inherited metabolic disease caused by methylmalonyl-CoA mutase deficiency. Early-onset disease usually presents with a neonatal acute metabolic acidosis, rapidly causing lethargy, coma, and death if untreated. Late-onset patients have a better prognosis but develop common long-term complications, including neurological deterioration, chronic kidney disease, pancreatitis, optic neuropathy, and chronic liver disease. Of note, oncogenesis has been reported anecdotally in organic acidurias. Here, we present three novel and two previously published cases of MMA patients who developed malignant liver neoplasms. All five patients were affected by a severe, early-onset form of isolated MMA (4 mut0 , 1 cblB subtype). Different types of liver neoplasms, that is, hepatoblastoma and hepatocellular carcinoma, were diagnosed at ages ranging from infancy to adulthood. We discuss pathophysiological hypotheses involved in MMA-related oncogenesis such as mitochondrial dysfunction, impairment of tricarboxylic acid cycle, oxidative stress, and effects of oncometabolites. Based on the intriguing occurrence of liver abnormalities, including neoplasms, we recommend close biochemical and imaging monitoring of liver disease in routine follow-up of MMA patients.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/patologia , Fígado/patologia , Acidose Láctica/complicações , Adulto , Idade de Início , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Encefalopatias Metabólicas Congênitas/complicações , Criança , Feminino , Humanos , Lactente , Recém-Nascido , Fígado/diagnóstico por imagem , Masculino , Erros Inatos do Metabolismo/complicações , Metilmalonil-CoA Mutase/deficiência , Tomografia Computadorizada por Raios X , Ultrassonografia , Adulto Jovem
18.
J Neurol ; 266(10): 2434-2439, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31203424

RESUMO

Combined homocysteinemia with methylmalonic aciduria (MMA/HCY) are genetic disorders of intracellular cobalamin (cbl) transport and processing that cause downstream deficiencies in methylcobalamin and adenosylcobalamin. Untreated disease is characterized biochemically by methylmalonic aciduria and hyperhomocysteinemia, while the clinical features are variable. When spastic paraplegia (SP) dominates, it is difficult to differentiate from hereditary spastic paraplegia (HSP). Clinical, biochemical and imaging features were reviewed in eight patients with MMA/HCY that mimicked HSP. Seven males and one female were enrolled. The median onset age was 13 years old (range 7-26 years old). The median time delay of diagnosis was 20.5 months (range 2-60 months). Spastic gait was the first symptom in four patients, while the other four patients presented with chronic emotional abnormalities or cognitive impairment. The main clinical manifestation was SP, and other neurological symptoms included cognitive impairment (5/8), spastic dysuria (3/8), personality change and depression (3/8), ataxia (2/8), seizures (2/8), limb numbness (2/8), and developmental delay (2/8). When patients were diagnosed, the mean serum homocysteine level, the methylmalonic acid level in urine, the serum propionylcarnitine (C3) level and the ratios of C3-to-acetylcarnitine (C2) and free carnitine (C0) were all dramatically elevated. Cranial MRIs showed nothing remarkable except mild brain atrophy. All spinal MRIs were normal except for case 8. Definite compound heterozygous mutations in MMACHC were detected in five cases. Follow-up indicated partial improvement in all the patients after intramuscular cbl, oral betaine and folate, supporting the diagnosis of MMA/HCY. Our data highlight the need for extensive investigation of intracellular cbl transport and processing, when spastic paraparesis is a prominent component of the clinical picture. Testing for urine methylmalonic acid and serum homocysteine levels is a simple but critical approach in suspected cases. Genetic testing, especially for MMACHC gene mutations, is needed. Raising awareness of this disorder could result in the timely initiation of targeted treatment, which may significantly improve patient outcomes.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Hiper-Homocisteinemia/diagnóstico , Paraplegia/diagnóstico , Paraplegia Espástica Hereditária/diagnóstico , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/genética , Criança , Feminino , Humanos , Hiper-Homocisteinemia/complicações , Hiper-Homocisteinemia/genética , Masculino , Paraplegia/etiologia , Estudos Retrospectivos , Adulto Jovem
19.
J Inherit Metab Dis ; 42(5): 730-744, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31119747

RESUMO

Over the last decades, advances in clinical care for patients suffering from propionic acidemia (PA) and isolated methylmalonic acidemia (MMA) have resulted in improved survival. These advances were possible thanks to new pathophysiological insights. However, patients may still suffer from devastating complications which largely determine the unsatisfying overall outcome. To optimize our treatment strategies, better insight in the pathophysiology of complications is needed. Here, we perform a systematic data-analysis of cohort studies and case-reports on PA and MMA. For each of the prevalent and rare complications, we summarize the current hypotheses and evidence for the underlying pathophysiology of that complication. A common hypothesis on pathophysiology of many of these complications is that mitochondrial impairment plays a major role. Assuming that complications in which mitochondrial impairment may play a role are overrepresented in monogenic mitochondrial diseases and, conversely, that complications in which mitochondrial impairment does not play a role are underrepresented in mitochondrial disease, we studied the occurrence of the complications in PA and MMA in mitochondrial and other monogenic diseases, using data provided by the Human Phenotype Ontology. Lastly, we combined this with evidence from literature to draw conclusions on the possible role of mitochondrial impairment in each complication. Altogether, this review provides a comprehensive overview on what we, to date, do and do not understand about pathophysiology of complications occurring in PA and MMA and about the role of mitochondrial impairment herein.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Mitocôndrias/patologia , Doenças Mitocondriais/etiologia , Acidemia Propiônica/complicações , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Animais , Humanos , Doenças Mitocondriais/fisiopatologia , Acidemia Propiônica/fisiopatologia
20.
J Neural Transm (Vienna) ; 126(6): 739-757, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31076915

RESUMO

Status dystonicus (SD) is a rare and potentially life-threatening condition requiring intensive care management. Deep brain stimulation (DBS) has emerged as an effective treatment for SD refractory to medical management, but its application in this field is still limited. Here, we report the long-term outcome of four pediatric patients treated with DBS at the University Hospital of Padua, Italy, for SD refractory to medications. In addition, we present the results of a systematic literature review aimed at identifying published cases of SD treated with DBS, with focus on motor outcome. In our cohort, two children were affected by methylmalonic acidemia and suffered acute basal ganglia lesions, while the other two carried a pathogenic mutation in GNAO1 gene. DBS target was subthalamic nucleus (STN) in one case and globus pallidus internus (GPi) in three. All patients experienced SD resolution within 8-19 days after surgery. Mean post-operative follow-up was 5 years. We identified in the literature 53 additional SD cases treated with DBS (median age at DBS implantation: 12 years) with reported positive outcome in 51 and resolution of SD in a mean of 17 days after surgery. Our findings indicate that DBS is an effective treatment for SD refractory to medications, even in patients with acute basal ganglia lesions; STN can be an appropriate target when GPi is damaged. Moreover, data from long-term follow-up show that SD recurrences can be significantly reduced in frequency or abolished after DBS implantation.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/complicações , Doenças dos Gânglios da Base/complicações , Estimulação Encefálica Profunda , Distonia/etiologia , Distonia/terapia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP , Globo Pálido , Núcleo Subtalâmico , Adolescente , Doenças dos Gânglios da Base/genética , Doenças dos Gânglios da Base/patologia , Criança , Feminino , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Humanos , Mutação
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