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1.
BMC Med Genet ; 21(1): 22, 2020 02 03.
Artigo em Inglês | MEDLINE | ID: mdl-32013889

RESUMO

BACKGROUND: Methylmalonic acidemia (MMA), which is an autosomal recessive metabolic disorder, is caused by mutations in methylmalonyl-CoA mutase (MUT) gene. As a result, the conversion of methylmalonyl-CoA to succinyl-CoA is impaired in this disorder, leading to a wide range of clinical manifestations varying from no signs or symptoms to severe lethargy and metabolic crisis in newborn infants. Since identification of novel mutations in MUT gene can help discover the exact pathogenesis of MMA and also use these disease-causing mutations in prenatal diagnosis, this study was conducted to uncover the possible mutations in an Iranian couple with a deceased offspring clinically diagnosed as having organic acidemia. Moreover, to prevent the occurrence of the mutation in the next pregnancy, we took the advantage of pre-implantation genetic diagnosis (PGD), which resulted in a successful pregnancy. CASE PRESENTATION: The affected individual was a 15-month-old boy who passed away due to aspiration pneumonia. The child presented at the age of 3 months with lethargy, protracted vomiting, hypotonia, and decreased level of consciousness. To find the mutated gene, Next Generation Sequencing (NGS) was performed as carrier testing for the parents and the results revealed a novel (private) heterozygous missense mutation in MUT gene (c.1055A > G, p.Q352R). After performing PGD on three blastomeres, one was identified as being homozygous wild-type that was followed by successful pregnancy. CONCLUSIONS: Our study identified a novel, deleterious, heterozygous missense mutation in MUT gene in a couple and helps to consider the genetic counselling and prenatal diagnosis more seriously for this family with clinical phenotypes of organic acidemia.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Metilmalonil-CoA Mutase/genética , Diagnóstico Pré-Implantação , Acil Coenzima A/genética , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Criança , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Homozigoto , Humanos , Lactente , Recém-Nascido , Irã (Geográfico) , Masculino , Mutação de Sentido Incorreto/genética , Fenótipo , Gravidez
2.
BMC Neurol ; 20(1): 12, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31918669

RESUMO

BACKGROUND: Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder with heterogeneous phenotypic spectrum resulting from disease-causing variants in the dopa decarboxylase (DDC) gene. Consensus guidelines recommend dopamine agonists, monoamine oxidase inhibitors, and other symptomatic treatments, but most patients have an unrelenting disease course with no response to these therapies. CASE PRESENTATION: We describe 2 African American siblings with AADC deficiency and identify 2 DDC gene variants not previously associated with the disorder. The patients were evaluated for cognitive and neurologic impairments. Diagnosis of AADC deficiency was initially based on evaluation of urine and plasma metabolites, followed by targeted DDC gene sequencing. The first patient, a firstborn African American female, had moderate elevations of vanillactic and vanilpyruvic acids, and slight elevation of N-acetylvanilalanine in urine. The second patient, an African American female and younger sibling of the first patient, had low AADC enzyme activity and elevated 3-O-methyldopa levels in plasma. Genetic testing confirmed that both siblings possessed the same 2 DDC gene variants, which were identified as NM_000790.3: c.48C > A (p.Tyr16Ter) and NM_000790.3: c.116G > C (p.Arg39Pro). CONCLUSIONS: This report describes 2 previously unknown patients with AADC deficiency and confirmed the presence of 2 DDC gene variants not previously associated with this disorder. Further research is needed to identify disease-modifying treatments for this devastating neurometabolic disorder. Gene therapy with a recombinant adeno-associated viral vector serotype 2 carrying the gene for the human AADC protein (AAV2-hAADC) is currently in clinical development.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Descarboxilases de Aminoácido-L-Aromático/deficiência , Afro-Americanos/genética , Descarboxilases de Aminoácido-L-Aromático/genética , Pré-Escolar , Feminino , Variação Genética , Humanos , Lactente , Recém-Nascido , Irmãos
3.
Biochim Biophys Acta Proteins Proteom ; 1868(1): 140269, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31491587

RESUMO

Glutaric Aciduria Type I (GA-I), is an autosomal recessive neurometabolic disease caused by mutations in the GCDH gene that encodes for glutaryl-CoA dehydrogenase (GCDH), a flavoprotein involved in the metabolism of tryptophan, lysine and hydroxylysine. Although over 200 disease mutations have been reported a clear correlation between genotype and phenotype has been difficult to establish. To contribute to a better molecular understanding of GA-I we undertook a detailed molecular study on two GCDH disease-related variants, GCDH-p.Arg227Pro and GCDH-p.Val400Met. Heterozygous patients harbouring these two mutations have increased residual enzymatic activity in relation to homozygous patients with only one of the mutations, suggesting a complementation effect between the two. Combining biochemical, biophysical and structural methods we here establish the effects of these mutations on protein folding, stability and catalytic activity. We show that both variants retain the overall protein fold, but with compromised enzymatic activities. Detailed enzyme kinetic studies reveal that GCDH-p.Arg227Pro has impaired function due to deficient substrate affinity as evidenced by its higher Km, and that the lower activity in GCDH-p.Val400Met results from weaker interactions with its physiological redox partner (electron transfer flavoprotein). Moreover, the GCDH-p.Val400Met variant has a significantly lower thermal stability (ΔTm ≈ 9 °C), and impaired binding of the FAD cofactor in relation to wild-type protein. On these grounds, we provide a rational for the possible interallelic complementation observed in heterozygous patients based on the fact that in GCDH, the low active p.Arg227Pro variant contributes to stabilize the tetramer while the structurally unstable p.Val400Met variant compensates for enzyme activity.


Assuntos
Glutaril-CoA Desidrogenase/genética , 2,6-Dicloroindofenol/química , Erros Inatos do Metabolismo dos Aminoácidos/genética , Encefalopatias Metabólicas/genética , Glutaril-CoA Desidrogenase/química , Glutaril-CoA Desidrogenase/deficiência , Heterozigoto , Humanos , Modelos Moleculares , Mutação , Conformação Proteica , Subunidades Proteicas/química , Subunidades Proteicas/genética
4.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(12): 1158-1162, 2019 Dec 10.
Artigo em Chinês | MEDLINE | ID: mdl-31813137

RESUMO

OBJECTIVE: To report on clinical characteristics and genetic findings in 15 Chinese patients with methylmalonic acidemia (MMA). METHODS: For the 15 MMA patients detected by tandem mass spectrometry, genetic analysis was carried out in twelve pedigrees. Clinical characteristics, genetic finding, treatment and outcomes were retrospectively analyzed. RESULTS: The main features of the patients included poor feeding, recurrent vomiting, lethargy, seizure and development retardation. Blood propionylcarnitine (except for 3 patients), its ratio with acetylcarnitine, and urine methylmalonic acid were increased in all patients. Twelve patients were diagnosed genetically, which included 7 with MUT variants, 4 with MMACHC variants, and 1 with MMAB variant. Nine MUT variants were detected, among which c.1159A>C, 753+1delGinsTGGTTATTA and c.504del were novel. Six known pathogenic MMACHC variants and two novel MMAB variants (c.289_290delGG, c.566G>A) were also detected. Seven patients died of metabolic crises within a year, others had improved effectively following the treatment, but had mild to severe growth delay and/or developmental retardation. CONCLUSION: The clinical manifestation of MMA are complex. Most patients have variants of the MUT and MMACHC genes. High mortality may occur before one year of age.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Alquil e Aril Transferases/genética , China , Humanos , Metilmalonil-CoA Mutase/genética , Oxirredutases/genética , Linhagem , Estudos Retrospectivos
5.
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
6.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(11): 1085-1089, 2019 Nov 10.
Artigo em Chinês | MEDLINE | ID: mdl-31703131

RESUMO

OBJECTIVE: To delineate the clinical and genetic features of two pedigrees affected with aromatic L-amino acid decarboxylase (AADC) deficiency. METHODS: The clinical features, family history and results of genetic testing of 2 patients with AADC deficiency were retrospectively analyzed. RESULTS: Both patients featured hypotension, developmental delay and oculogyric crisis during infancy. Genetic testing confirmed that they have respectively carried c.714+ 4 (IVS6) A to T/c.175(exon2)G TO A compound heterozygous variants and c.714+ 4(IVS6)A to T homozygous variant. CONCLUSION: The clinical manifestation of children with AADC deficiency may include hypotonia, developmental delay and paroxysmal oculogyric crisis. The combination of 3-O-methyldopa testing and variant analysis is not only very useful for early diagnosis, but also important for the evaluation of treatment effect and prognosis of the disease. Discovery of the novel variants has enriched the variant spectrum of AADC deficiency.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Descarboxilases de Aminoácido-L-Aromático/deficiência , Descarboxilases de Aminoácido-L-Aromático/genética , Testes Genéticos , Análise Mutacional de DNA , Humanos , Lactente , Linhagem , Estudos Retrospectivos
7.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(9): 882-885, 2019 Sep 10.
Artigo em Chinês | MEDLINE | ID: mdl-31515781

RESUMO

OBJECTIVE: To screen for potential variants of GCDH gene in 3 patients clinically diagnosed as glutaric aciduria type Ⅰ. METHODS: GCDH gene variants was detected by Sanger sequencing among the three children and their family members. RESULTS: Sanger sequencing showed that patient 1 carried compound heterozygosity variants of c.532G>A (p.Gly178Arg) and c.655G>A (p.Ala219Thr) of the GCDH gene, while his father and mother respectively carried heterozygous c.532G>A(p.Gly178Arg) and c.655G>A (p.Ala219Thr) variants. Patient 2 carried c.532G>A (p.Gly178Arg) and a novel c.1060G>T (p.Gly354Cys) compound heterozygous variant, while his father and mother respectively carried heterozygous c.532G>A (p.Gly178Arg) and c.1060G>T (p.Gly354Cys) variant. Patient 3 carried homozygous c.532G>A (p.Gly178Arg) variant of the GCDH gene, for which both of his parents were heterozygous carriers. CONCLUSION: The GCDH gene variant probably underlie the glutaric aciduria type Ⅰ among the 3 patients. Identifcation of the novel variant has enriched the spectrum of GCDH gene variants.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Encefalopatias Metabólicas/genética , Glutaril-CoA Desidrogenase/deficiência , Feminino , Glutaril-CoA Desidrogenase/genética , Heterozigoto , Humanos , Masculino
8.
Clin Chim Acta ; 498: 116-121, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31442447

RESUMO

BACKGROUND: Isovaleric acidemia (IVA), a rare autosomal recessive disorder in leucine metabolism caused by defected IVD gene, is characterized by episodes of acute metabolic crisis and psychomotor development retardation. This study aimed to determine the clinical, biochemical, and mutation spectrum of patients with IVA from mainland China. METHODS: Eight patients (three boys and five girls) from eight unrelated families were collected, IVD gene mutations and phenotypes were examined. RESULTS: The patients were admitted because of vomiting, feeding difficulty, psychomotor retardation and "dirty sock" odor. Elevated blood isovaleryl (C5)-carnitine and urine isovalerylglycine were detected from all our patients. Fourteen mutations of the IVD gene were detected, eight of them are novel, c.145C>T (p.Q49Ter), c.359G>A (p.R120Q), c.424C>T (p.R142C), c.458T>C (p.L153P), c.466-1G>T, c.676_677insA (p.T226Nfs*13), c.1039G>A (p.A347T) and c.1076A>G (p.D359G). With this study, a total of 34 alleles were studied in the Chinese population. c.1208A>G (p.Y403C), the common mutation in Taiwan, accounts for 9/34 alleles (7 in previous reports and 2 in this study). CONCLUSIONS: We described eight novel mutations detected from eight unrelated Chinese patients and provided evidence to support that the p.Y403C is the hotspot mutation in this population.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Grupo com Ancestrais do Continente Asiático/genética , Isovaleril-CoA Desidrogenase/deficiência , Mutação , Alelos , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Carnitina/sangue , China/epidemiologia , Feminino , Glicina/sangue , Humanos , Recém-Nascido , Isovaleril-CoA Desidrogenase/genética , Masculino , Fenótipo
9.
J Hum Genet ; 64(11): 1137-1140, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31427715

RESUMO

Lysinuric protein intolerance (LPI) is caused by mutations in the SLC7A7 gene at 14q11.2. Its clinical presentation includes failure to thrive, protein intolerance due to a secondary urea cycle defect, interstitial lung disease, renal tubulopathy, and immune disorders. Maternal uniparental disomy 14 (UPD14mat) is the most common cause of Temple syndrome (TS14), which is characterized by severe intrauterine and postnatal growth failure. Here, we describe a severe form of LPI accompanied by TS14 in an 11-month-old girl, which presented as profound failure to thrive and delayed development. LPI was diagnosed by the detection of a homozygous mutation of c.713 C>T (p.Ser238Phe) in SLC7A7, which was eventually found to co-occur with UPD14mat. Despite receiving a protein-restricted diet with citrulline and lysine supplementation, the severe failure to thrive has persisted at follow-up of the patient at 4 years of age.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Sistema y+L de Transporte de Aminoácidos/genética , Dissomia Uniparental/genética , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Pré-Escolar , Cromossomos Humanos Par 14 , Feminino , Homozigoto , Humanos , Lactente , Herança Materna , Mutação , Dissomia Uniparental/patologia
11.
EBioMedicine ; 45: 519-528, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31303505

RESUMO

BACKGROUND: Isolated methylmalonic acidemia/aciduria (MMA) is an ultra-rare, serious, inherited metabolic disorder with significant morbidity and mortality. Exogenously delivered mRNA encoding human methylmalonyl-CoA mutase (hMUT), the enzyme most frequently mutated in MMA, is a potential therapy to produce functional MUT enzyme in liver. METHODS: Two 12-week repeat-dose studies were conducted to evaluate the efficacy and safety of intravenously-administered hMUT mRNA encapsulated in lipid nanoparticles in two murine models of MMA. FINDINGS: In MMA hypomorphic mice, hMUT mRNA treatment resulted in dose-dependent and reproducible biomarker responses after each dose. Enzymatically-active MUT protein was produced in liver in a dose-dependent manner. hMUT mRNA was well-tolerated with no adverse effects, as indicated by the lack of clinical observations, minimal changes in clinical chemistry parameters, and histopathology examination across all tissues. In severe MMA mice, hMUT mRNA led to substantially improved survival and growth and ameliorated biochemical abnormalities, all of which are cardinal clinical manifestations in severely affected patients. INTERPRETATION: These data demonstrate durable functional benefit of hMUT mRNA and support development of this new class of therapy for a devastating, pediatric disorder. FUND: This work was funded by Moderna, Inc.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/terapia , Fígado/metabolismo , Metilmalonil-CoA Mutase/farmacologia , RNA Mensageiro/farmacologia , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Animais , Criança , Modelos Animais de Doenças , Humanos , Lipídeos/genética , Fígado/efeitos dos fármacos , Fígado/patologia , Metilmalonil-CoA Mutase/genética , Camundongos , RNA Mensageiro/genética
12.
J Hum Genet ; 64(9): 849-858, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31213652

RESUMO

Lysinuric protein intolerance (LPI) is caused by dysfunction of the dibasic amino acid membrane transport owing to the functional abnormality of y+L amino acid transporter-1 (y+ LAT-1). LPI is associated with autosomal recessive inheritance and pathological variants in the responsible gene SLC7A7 are also observed. The pathophysiology of this disease had earlier been understood as a transport defect in polarized cells (e.g., intestinal or renal tubular epithelium); however, in recent years, transport defects in non-polarized cells such as lymphocytes and macrophages have also been recognized as important. Although the former can cause death, malnutrition, and urea cycle dysfunction (hyperammonemia), the latter can induce renal, pulmonary, and immune disorders. Furthermore, although therapeutic interventions can prevent hyperammonemic episodes to some extent, progression of pulmonary and renal complications cannot be prevented, thereby influencing prognosis. Such pathological conditions are currently being explored and further investigation would prove beneficial. In this study, we have summarized the basic pathology as revealed in recent years, along with the clinical aspects and genetic features.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Cadeias Leves da Proteína-1 Reguladora de Fusão , Rim , Transportador 1 de Aminoácidos Neutros Grandes , Mutação , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/metabolismo , Erros Inatos do Metabolismo dos Aminoácidos/patologia , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Cadeias Leves da Proteína-1 Reguladora de Fusão/genética , Cadeias Leves da Proteína-1 Reguladora de Fusão/metabolismo , Humanos , Rim/metabolismo , Rim/patologia , Transportador 1 de Aminoácidos Neutros Grandes/genética , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo
13.
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
14.
BMC Med Genet ; 20(1): 88, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31117962

RESUMO

BACKGROUND: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessively-inherited defect of γ-aminobutyric acid (GABA) metabolism. The absence of SSADH, which is encoded by aldehyde dehydrogenase family 5 member A1 (ALDH5A1) gene, leads to the accumulation of GABA and γ-hydroxybutyric acid (GHB). Few cases with SSADH deficiency were reported in China. CASE PRESENTATION: In this study, four Chinese patients were diagnosed with SSADH deficiency in Tianjin Children's Hospital. We conducted a multidimensional analysis with magnetic resonance imaging (MRI) of the head, semi quantitative detection of urine organic acid using gas chromatography-mass spectrometry, and analysis of ALDH5A1 gene mutations. Two of the patients were admitted to the hospital due to convulsions, and all patients were associated with developmental delay. Cerebral MRI showed symmetrical hyperintense signal of bilateral globus pallidus and basal ganglia in patient 1; hyperintensity of bilateral frontal-parietal lobe, widened ventricle and sulci in patient 2; and widened ventricle and sulci in patient 4. Electroencephalogram (EEG) revealed the background activity of epilepsy in patient 1 and the disappearance of sleep spindle in patient 2. Urine organic acid analysis revealed elevated GHB in all the patients. Mutational analysis, which was performed by sequencing the 10 exons and flanking the intronic regions of ALDH5A1 gene for all the patients, revealed mutations at five sites. Two cases had homozygous mutations with c.1529C > T and c.800 T > G respectively, whereas the remaining two had different compound heterozygous mutations including c.527G > A/c.691G > A and c.1344-2delA/c.1529C > T. Although these four mutations have been described previously, the homozygous mutation of c.800 T > G in ALDH5A1 gene is a novel discovery. CONCLUSION: SSADH deficiency is diagnosed based on the elevated GHB and 4, 5DHHA by urinary organic acid analysis. We describe a novel mutation p.V267G (c.800 T > G) located in the NAD binding domain, which is possibly crucial for this disease's severity. Our study expands the mutation spectrum of ALDH5A1 and highlights the importance of molecular genetic evaluation in patients with SSADH deficiency.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Análise Mutacional de DNA/métodos , Deficiências do Desenvolvimento/genética , Mutação , Succinato-Semialdeído Desidrogenase/deficiência , Succinato-Semialdeído Desidrogenase/genética , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico por imagem , Erros Inatos do Metabolismo dos Aminoácidos/etnologia , Grupo com Ancestrais do Continente Asiático/genética , Pré-Escolar , China , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/etnologia , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética/métodos , Masculino , Succinato-Semialdeído Desidrogenase/metabolismo
15.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(6): 602-605, 2019 Jun 10.
Artigo em Chinês | MEDLINE | ID: mdl-31055816

RESUMO

OBJECTIVE: To review the clinical features of a male twin affected with glutaric academia type I (GA-I) and analyze the variations of glutaryl-CoA dehydrogenase (GCDH) gene. METHODS: Clinical data of the pair of twins and their parents were collected. Genomic DNA was extracted from peripheral blood samples, and variants of GCDH genes were detected by capture sequencing using a customized panel. Variants of the twins and their parents were verified by Sanger sequencing. RESULTS: The level of glutaric acyl carnitine (C5DC + C6OH) was 3.26 µmol/L in the male twin. The relative level of glutaric acid in urine was 547.51 by gas chromatography mass spectrometry analysis. Cerebral ultrasonography showed that the patient had subependymal hemorrhage, but no serious clinical manifestation was noted. After treating with special formula milk powder and L-carnitine, the boy showed good growth and development. Two heterozygous variants of the GCDH gene were detected in the patient, among which c.416C>G was suspected to be pathogenic, while c.109_110delCA was unreported. The variants were respectively inherited from his parents. The twin girl only carried the c.416C>G variant. CONCLUSION: GA-I can be diagnosed by mass spectrometry, urine gas chromatographic mass spectrometry, imaging as well as genetic diagnosis. Early diagnosis and intervention is important.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Encefalopatias Metabólicas/genética , Glutaril-CoA Desidrogenase/deficiência , Feminino , Glutaril-CoA Desidrogenase/genética , Humanos , Masculino , Mutação , Fenótipo
16.
Orphanet J Rare Dis ; 14(1): 84, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-31023387

RESUMO

Methylmalonic acidemia/aciduria (MMA) is a genetically heterogeneous group of inherited metabolic disorders biochemically characterized by the accumulation of methylmalonic acid. Isolated MMA is primarily caused by the deficiency of methylmalonyl-CoA mutase (MMA mut; EC 5.4.99.2). A systematic literature review and a meta-analysis were undertaken to assess and compile published epidemiological data on MMA with a focus on the MMA mut subtype (OMIM #251000). Of the 1114 identified records, 227 papers were assessed for eligibility in full text, 48 articles reported on disease epidemiology, and 39 articles were included into the quantitative synthesis. Implementation of newborn screening in various countries has allowed for the estimation of birth prevalence of MMA and its isolated form. Meta-analysis pooled point estimates of MMA (all types) detection rates were 0.79, 1.12, 1.22 and 6.04 per 100,000 newborns in Asia-Pacific, Europe, North America and the Middle East and North Africa (MENA) regions, respectively. The detection rate of isolated MMA was < 1 per 100,000 newborns in all regions with the exception of MENA where it approached 6 per 100,000 newborns. Few studies published data on the epidemiology of MMA mut, therefore no meta-analysis could have been performed on this subtype. Most of the identified papers reported birth prevalence estimates below 1 per 100,000 newborns for MMA mut. The systematic literature review clearly demonstrates that MMA and its subtypes are ultra-rare disorders.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/enzimologia , Erros Inatos do Metabolismo dos Aminoácidos/epidemiologia , Metilmalonil-CoA Mutase/genética , Erros Inatos do Metabolismo dos Aminoácidos/genética , Feminino , Humanos , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/enzimologia , Erros Inatos do Metabolismo/epidemiologia , Erros Inatos do Metabolismo/genética , Metilmalonil-CoA Mutase/deficiência , Triagem Neonatal
17.
N Engl J Med ; 380(15): 1433-1441, 2019 04 11.
Artigo em Inglês | MEDLINE | ID: mdl-30970188

RESUMO

We report an inborn error of metabolism caused by an expansion of a GCA-repeat tract in the 5' untranslated region of the gene encoding glutaminase (GLS) that was identified through detailed clinical and biochemical phenotyping, combined with whole-genome sequencing. The expansion was observed in three unrelated patients who presented with an early-onset delay in overall development, progressive ataxia, and elevated levels of glutamine. In addition to ataxia, one patient also showed cerebellar atrophy. The expansion was associated with a relative deficiency of GLS messenger RNA transcribed from the expanded allele, which probably resulted from repeat-mediated chromatin changes upstream of the GLS repeat. Our discovery underscores the importance of careful examination of regions of the genome that are typically excluded from or poorly captured by exome sequencing.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Ataxia/genética , Deficiências do Desenvolvimento/genética , Glutaminase/deficiência , Glutaminase/genética , Glutamina/metabolismo , Repetições de Microssatélites , Mutação , Atrofia/genética , Cerebelo/patologia , Pré-Escolar , Feminino , Genótipo , Glutamina/análise , Humanos , Masculino , Fenótipo , Reação em Cadeia da Polimerase , Sequenciamento Completo do Genoma
18.
Zhongguo Dang Dai Er Ke Za Zhi ; 21(4): 375-380, 2019 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-31014432

RESUMO

Lysinuric protein intolerance (LPI) is an autosomal recessive disorder caused by SLC7A7 gene mutation and often involves severe lesions in multiple systems. Lung involvement is frequently seen in children with LPI and such children tend to have a poor prognosis. This article summarizes the clinical manifestations and gene mutation characteristics of three children diagnosed with LPI by SLC7A7 gene analysis. All three children had the manifestations of aversion to protein-rich food after weaning, delayed development, anemia, hepatosplenomegaly, and osteoporosis, as well as an increase in orotic acid in urine. In addition, interstitial pneumonia and diffuse pulmonary interstitial lesions were observed in two children. SLC7A7 gene detection showed three pathogenic mutations in these children, namely c.1387delG(p.V463CfsX56), c.1215G>A(p.W405X) and homozygous c.625+1G>A. After a definite diagnosis was made, all three children were given a low-protein diet and oral administration of citrulline [100 mg/(kg.d)], iron protein succinylate [4 mg/(kg.d)], calcium and zinc gluconates oral solution (10 mL/day) and vitamin D (400 IU/day). In addition, patient 3 was given prednisone acetate (5 mg/day). The children had varying degrees of improvement in symptoms and signs. It is hard to distinguish LPI from urea cycle disorder due to the features of amino acid and organic acid metabolism in LPI, and SLC7A7 gene analysis is the basis for a definite diagnosis of LPI.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos , Cadeias Leves da Proteína-1 Reguladora de Fusão/genética , Erros Inatos do Metabolismo dos Aminoácidos/genética , Criança , Citrulina , Humanos , Lisina , Mutação
19.
Orphanet J Rare Dis ; 14(1): 73, 2019 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-30940196

RESUMO

BACKGROUND: Most patients with isolated methylmalonic acidemia (MMA) /propionic acidemia (PA) presenting during the neonatal period with acute metabolic distress are at risk for death and significant neurodevelopmental disability. The nationwide newborn screening for MMA/PA has been in place in Taiwan from January, 2000 and data was collected until December, 2016. RESULTS: During the study period, 3,155,263 newborns were screened. The overall incidence of MMA mutase type cases was 1/121,356 (n = 26), 1 cobalamin B was detected and that for PA cases (n = 4) was 1/788,816. The time of referral is 8.8 days for MMA patients, and 7.5 days for PA patients. The MMA mutase type patients have higher AST, ALT, and NH3 values as well as a lower pH value (p < 0.05). The mean age for liver transplantation (LT) is 402 days (range from 0.6-6.7 yr) with 16 out of 20 cases (80.0%) using living donors. The mean admission length shortened from 90.6 days/year (pre-LT) to 5.3 days/year (at 3rd year post-LT) (p < 0.0005). Similarly, the tube feeding ratio decreased from 67.8 to 0.50% (p < 0.00005). The anxiety level of the caregiver was reduced from 33.4 to 27.2 after LT (p = 0.001) and the DQ/IQ performance of the patients was improved after LT from 50 to 60.1 (p = 0.07). CONCLUSION: MMA/PA patients with LT do survive and have reduced admission time, reduced tube feeding and the caregiver is less anxious.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Transplante de Fígado/normas , Acidemia Propiônica/fisiopatologia , Acidemia Propiônica/terapia , Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/mortalidade , Cuidadores/psicologia , Cuidadores/estatística & dados numéricos , Nutrição Enteral/estatística & dados numéricos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Recém-Nascido , Transplante de Fígado/mortalidade , Masculino , Mutação , Triagem Neonatal , Acidemia Propiônica/genética , Acidemia Propiônica/mortalidade , Taiwan , Resultado do Tratamento
20.
Mol Genet Metab ; 127(1): 12-22, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30952622

RESUMO

Aromatic-l-amino acid decarboxylase (AADC) deficiency is an ultra-rare inherited autosomal recessive disorder characterized by sharply reduced synthesis of dopamine as well as other neurotransmitters. Symptoms, including hypotonia and movement disorders (especially oculogyric crisis and dystonia) as well as autonomic dysfunction and behavioral disorders, vary extensively and typically emerge in the first months of life. However, diagnosis is difficult, requiring analysis of metabolites in cerebrospinal fluid, assessment of plasma AADC activity, and/or DNA sequence analysis, and is frequently delayed for years. New metabolomics techniques promise early diagnosis of AADC deficiency by detection of 3-O-methyl-dopa in serum or dried blood spots. A total of 82 dopa decarboxylase (DDC) variants in the DDC gene leading to AADC deficiency have been identified and catalogued for all known patients (n = 123). Biochemical and bioinformatics studies provided insight into the impact of many variants. c.714+4A>T, p.S250F, p.R347Q, and p.G102S are the most frequent variants (cumulative allele frequency = 57%), and c.[714+4A>T];[714+4A>T], p.[S250F];[S250F], and p.[G102S];[G102S] are the most frequent genotypes (cumulative genotype frequency = 40%). Known or predicted molecular effect was defined for 79 variants. Most patients experience an unrelenting disease course with poor or no response to conventional medical treatments, including dopamine agonists, monoamine oxidase inhibitors, and pyridoxine derivatives. The advent of gene therapy represents a potentially promising new avenue for treatment of patients with AADC deficiency. Clinical studies based on the direct infusion of engineered adeno-associated virus type 2 vectors into the putamen have demonstrated acceptable safety and tolerability and encouraging improvement in motor milestones and cognitive symptoms. The success of gene therapy in AADC deficiency treatment will depend on timely diagnosis to facilitate treatment administration before the onset of neurologic damage.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/genética , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Descarboxilases de Aminoácido-L-Aromático/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Descarboxilases de Aminoácido-L-Aromático/genética , Biologia Computacional , Dopamina/metabolismo , Agonistas de Dopamina/uso terapêutico , Terapia Genética , Humanos , Metabolômica , Neurotransmissores/metabolismo
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