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1.
Eur J Med Genet ; 63(1): 103621, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30682496

RESUMO

Primary coenzyme Q10 deficiency-6 (COQ10D6) is a rare autosomal recessive disorder caused by COQ6 mutations. The main clinical manifestations are infantile progressive nephrotic syndrome (NS) leading to end-stage renal disease and sensorineural deafness. A 7-year-old girl was diagnosed with steroid-resistant NS (SRNS) and an audiological work-up revealed bilateral sensorineural deafness. A renal biopsy demonstrated focal segmental glomerulosclerosis. Despite immunosuppressive therapy, her serum levels of creatinine increased and haemodialysis was indicated within 1 year after the diagnosis. Living-donor kidney transplantation was performed in the eighth month of haemodialysis. A diagnostic custom-designed panel-gene test including 30 genes for NS revealed homozygous c.1058C > A [rs397514479] in exon nine of COQ6. Her older brother, who had sensorineural hearing loss with no renal or neurological involvement, had the same mutation in homozygous form. COQ6 mutations should be considered not only in patients with SRNS with sensorineural hearing loss but also in patients with isolated sensorineural hearing loss with a family history of NS. The reported p.His174 variant of COQ8B was suggested to be a risk factor for secondary CoQ deficiency, while p.Arg174 appeared to improve the condition in a yeast model. Family segregation and the co-occurrence of biallelic p.Arg174 of COQ8B in a brother with hearing loss implied that the interaction of the altered COQ8B with the mutant COQ6 alleviated the symptoms in this family. CoQ10 replacement therapy should be initiated for these patients, as primary CoQ10 deficiency is considered the only known treatable mitochondrial disease.

2.
J Matern Fetal Neonatal Med ; : 1-9, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31204544

RESUMO

Objective: Our aim was to determine the prevalence of maternal and neonatal vitamin B12 (vit-B12) and folate deficiencies, a new cutoff value of serum vit-B12 in newborns using vit-B12-related metabolites and also cutoff values of homocysteine (Hcy), propionyl (C3) carnitine, and methyl malonic acid (MMA) in newborns using a vit-B12 cutoff value of 200 pg/mL. Methods: Healthy pregnant women (without iron deficiency) and 98 healthy, term, singleton babies were included. Blood samples were obtained from women 0-8 h before birth and from cord blood during birth for hemogram and to measure serum vit-B12, folate, and Hcy levels. Maternal and cord blood serum vit-B12 levels were classified as low < 200 pg/mL, marginal 200-300 pg/mL, and normal ≥ 300 pg/mL. Neonatal urine MMA levels were analyzed in mothers with a vit-B12 concentration < 300 pg/mL. C3 carnitine levels of newborns were acquired from extended newborn screening. Receiver operating characteristics curve (ROC) analysis was used for serum vit-B12, urine MMA, C3 carnitine, and Hcy. Results: Of total, 98 pregnant women (28.6 ± 5.5-year-old) and 98 newborn were included. Vit-B12 level was lower than 300 pg/mL in 93% of the pregnant women and 61% of cord blood samples. Folate deficiency was not found in either group. There was statistically significant negative correlation between baby C3 carnitine, cord blood folate (r = -0.265, p = .008) and cord blood vit-B12 (r = -0.220, p = .029). In backward stepwise linear regression analysis, maternal vit-B12 level exerted the most marked effect on cord blood vit-B12 level (adjusted R2 = 0.457). In ROC analysis, the Hcy cutoff value was 4.77 µmol/L (68.4% sensitivity, 58.3% specificity, p = .012) for the detection of vit-B12 deficiency. Conclusion: Vit-B12 deficiency remains an important health issue for pregnant women and newborns. Our study revealed a cutoff value for Hcy for the detection of nutritional vit-B12 deficiency that could be used in practice for newborns.

3.
Nutrients ; 10(12)2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30544518

RESUMO

Children with phenylketonuria (PKU) follow a protein restricted diet with negligible amounts of docosahexaenoic acid (DHA). Low DHA intakes might explain subtle neurological deficits in PKU. We studied whether a DHA supply modified plasma DHA and neurological and intellectual functioning in PKU. In a double-blind multicentric trial, 109 PKU patients were randomized to DHA doses from 0 to 7 mg/kg&day for six months. Before and after supplementation, we determined plasma fatty acid concentrations, latencies of visually evoked potentials, fine and gross motor behavior, and IQ. Fatty acid desaturase genotypes were also determined. DHA supplementation increased plasma glycerophospholipid DHA proportional to dose by 0.4% DHA per 1 mg intake/kg bodyweight. Functional outcomes were not associated with DHA status before and after intervention and remained unchanged by supplementation. Genotypes were associated with plasma arachidonic acid levels and, if considered together with the levels of the precursor alpha-linolenic acid, also with DHA. Functional outcomes and supplementation effects were not significantly associated with genotype. DHA intakes up to 7 mg/kg did not improve neurological functions in PKU children. Nervous tissues may be less prone to low DHA levels after infancy, or higher doses might be required to impact neurological functions. In situations of minimal dietary DHA, endogenous synthesis of DHA from alpha-linolenic acid could relevantly contribute to DHA status.


Assuntos
Cognição/efeitos dos fármacos , Ácidos Docosa-Hexaenoicos/sangue , Ácidos Docosa-Hexaenoicos/uso terapêutico , Destreza Motora/efeitos dos fármacos , Fenilcetonúrias/tratamento farmacológico , Fenilcetonúrias/fisiopatologia , Adolescente , Criança , Ácidos Graxos Dessaturases/genética , Feminino , Humanos , Masculino , Fenilcetonúrias/epidemiologia , Fenilcetonúrias/genética
4.
Mol Genet Metab ; 122(1-2): 67-75, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28689740

RESUMO

2-methylacetoacetyl-coenzyme A thiolase (MAT) deficiency, also known as beta-ketothiolase deficiency, is an inborn error of ketone body utilization and isoleucine catabolism. It is caused by mutations in the ACAT1 gene and may present with metabolic ketoacidosis. In order to obtain a more comprehensive view on this disease, we have collected clinical and biochemical data as well as information on ACAT1 mutations of 32 patients from 12 metabolic centers in five countries. Patients were between 23months and 27years old, more than half of them were offspring of a consanguineous union. 63% of the study participants presented with a metabolic decompensation while most others were identified via newborn screening or family studies. In symptomatic patients, age at manifestation ranged between 5months and 6.8years. Only 7% developed a major mental disability while the vast majority was cognitively normal. More than one third of the identified mutations in ACAT1 are intronic mutations which are expected to disturb splicing. We identified several novel mutations but, in agreement with previous reports, no clear genotype-phenotype correlation could be found. Our study underlines that the prognosis in MAT deficiency is good and MAT deficient individuals may remain asymptomatic, if diagnosed early and preventive measures are applied.


Assuntos
Acetil-CoA C-Aciltransferase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/genética , Ácidos Graxos/metabolismo , Isoleucina/metabolismo , Corpos Cetônicos/metabolismo , Acetil-CoA C-Acetiltransferase/genética , Acetil-CoA C-Aciltransferase/genética , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Criança , Pré-Escolar , Consanguinidade , Feminino , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Masculino , Mutação , Triagem Neonatal , Prognóstico , Estudos Retrospectivos , Adulto Jovem
5.
Mol Genet Metab ; 121(3): 206-215, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28583327

RESUMO

3-Hydroxy-3-methylglutaryl-coenzyme A lyase deficiency (HMGCLD) is a rare inborn error of ketone body synthesis and leucine degradation, caused by mutations in the HMGCL gene. In order to obtain a comprehensive view on this disease, we have collected clinical and biochemical data as well as information on HMGCL mutations of 37 patients (35 families) from metabolic centers in Belgium, Germany, The Netherlands, Switzerland, and Turkey. All patients were symptomatic at some stage with 94% presenting with an acute metabolic decompensation. In 50% of the patients, the disorder manifested neonatally, mostly within the first days of life. Only 8% of patients presented after one year of age. Six patients died prior to data collection. Long-term neurological complications were common. Half of the patients had a normal cognitive development while the remainder showed psychomotor deficits. We identified seven novel HMGCL mutations. In agreement with previous reports, no clear genotype-phenotype correlation could be found. This is the largest cohort of HMGCLD patients reported so far, demonstrating that HMGCLD is a potentially life-threatening disease with variable clinical outcome. Our findings suggest that the clinical course of HMGCLD cannot be predicted accurately from HMGCL genotype. The overall outcome in HMGCLD appears limited, thus rendering early diagnosis and strict avoidance of metabolic crises important.


Assuntos
Acetil-CoA C-Acetiltransferase/deficiência , Erros Inatos do Metabolismo dos Aminoácidos , Adolescente , Adulto , Erros Inatos do Metabolismo dos Aminoácidos/complicações , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/dietoterapia , Erros Inatos do Metabolismo dos Aminoácidos/fisiopatologia , Bélgica , Criança , Pré-Escolar , Ácidos Graxos/metabolismo , Feminino , Estudos de Associação Genética , Alemanha , Humanos , Lactente , Corpos Cetônicos/metabolismo , Leucina/metabolismo , Masculino , Mutação , Países Baixos , Oxo-Ácido-Liases/genética , Avaliação de Resultados da Assistência ao Paciente , Suíça , Turquia , Adulto Jovem
6.
JIMD Rep ; 30: 53-57, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26951141

RESUMO

Mucopolysaccharidosis type VI (MPS VI) is a progressive, chronic, and multisystem lysosomal storage disease. Enzyme replacement therapy (ERT) with the recombinant human arylsulfatase B enzyme (galsulfase [Naglazyme]) is recommended as first-line therapy. It is generally reported as safe and well tolerated. Frequently observed mild to moderate infusion-related reactions which can be easily handled by reducing or interrupting the infusion and/or administering additional antihistamines, antipyretics, and corticosteroids are mostly mediated by non-IgE mechanisms. Here we report two children with MPS VI who experienced IgE-mediated reactions with galsulfase at the second year of the therapy. One child had anaphylaxis and the other had urticarial eruptions. They could receive ERT after successful rapid desensitization. To our knowledge, this is the second report on galsulfase allergy with IgE-mediated reaction. It is important to recognize IgE-mediated reactions since they can be life-threatening and do not respond to the standard therapies. We recommend allergy skin tests in the evaluation of infusion-related reactions unresponsive to standard therapies, so that continuation of ERT will be feasible after successful desensitization.

7.
J Inherit Metab Dis ; 39(1): 115-24, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26025547

RESUMO

BACKGROUND: Severe methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inborn defect disturbing the remethylation of homocysteine to methionine (<200 reported cases). This retrospective study evaluates clinical, biochemical genetic and in vitro enzymatic data in a cohort of 33 patients. METHODS: Clinical, biochemical and treatment data was obtained from physicians by using a questionnaire. MTHFR activity was measured in primary fibroblasts; genomic DNA was extracted from cultured fibroblasts. RESULTS: Thirty-three patients (mean age at follow-up 11.4 years; four deceased; median age at first presentation 5 weeks; 17 females) were included. Patients with very low (<1.5%) mean control values of enzyme activity (n = 14) presented earlier and with a pattern of feeding problems, encephalopathy, muscular hypotonia, neurocognitive impairment, apnoea, hydrocephalus, microcephaly and epilepsy. Patients with higher (>1.7-34.8%) residual enzyme activity had mainly psychiatric symptoms, mental retardation, myelopathy, ataxia and spasticity. Treatment with various combinations of betaine, methionine, folate and cobalamin improved the biochemical and clinical phenotype. During the disease course, patients with very low enzyme activity showed a progression of feeding problems, neurological symptoms, mental retardation, and psychiatric disease while in patients with higher residual enzyme activity, myelopathy, ataxia and spasticity increased. All other symptoms remained stable or improved in both groups upon treatment as did brain imaging in some cases. No clear genotype-phenotype correlation was obvious. DISCUSSION: MTHFR deficiency is a severe disease primarily affecting the central nervous system. Age at presentation and clinical pattern are correlated with residual enzyme activity. Treatment alleviates biochemical abnormalities and clinical symptoms partially.


Assuntos
Homocistinúria/enzimologia , Homocistinúria/genética , Metilenotetra-Hidrofolato Redutase (NADPH2)/deficiência , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Espasticidade Muscular/enzimologia , Espasticidade Muscular/genética , Ataxia/genética , Betaína/uso terapêutico , Criança , Feminino , Ácido Fólico/uso terapêutico , Estudos de Associação Genética/métodos , Homocistinúria/tratamento farmacológico , Humanos , Deficiência Intelectual/genética , Masculino , Metionina/uso terapêutico , Espasticidade Muscular/tratamento farmacológico , Mutação/genética , Fenótipo , Transtornos Psicóticos/tratamento farmacológico , Transtornos Psicóticos/enzimologia , Transtornos Psicóticos/genética , Estudos Retrospectivos , Doenças da Medula Espinal/genética , Vitamina B 12/uso terapêutico
8.
Mol Genet Metab ; 116(3): 163-70, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26260076

RESUMO

The conserved oligomeric Golgi (COG) complex consists of eight subunits and plays a crucial role in Golgi trafficking and positioning of glycosylation enzymes. Mutations in all COG subunits, except subunit 3, have been detected in patients with congenital disorders of glycosylation (CDG) of variable severity. So far, 3 families with a total of 10 individuals with biallelic COG6 mutations have been described, showing a broad clinical spectrum. Here we present 7 additional patients with 4 novel COG6 mutations. In spite of clinical variability, we delineate the core features of COG6-CDG i.e. liver involvement (9/10), microcephaly (8/10), developmental disability (8/10), recurrent infections (7/10), early lethality (6/10), and hypohidrosis predisposing for hyperthermia (6/10) and hyperkeratosis (4/10) as ectodermal signs. Regarding all COG6-related disorders a genotype-phenotype correlation can be discerned ranging from deep intronic mutations found in Shaheen syndrome as the mildest form to loss-of-function mutations leading to early lethal CDG phenotypes. A comparison with other COG deficiencies suggests ectodermal changes to be a hallmark of COG6-related disorders. Our findings aid clinical differentiation of this complex group of disorders and imply subtle functional differences between the COG complex subunits.


Assuntos
Proteínas Adaptadoras de Transporte Vesicular/genética , Defeitos Congênitos da Glicosilação/genética , Defeitos Congênitos da Glicosilação/fisiopatologia , Complexo de Golgi/genética , Adolescente , Criança , Defeitos Congênitos da Glicosilação/complicações , Feminino , Estudos de Associação Genética , Glicosilação , Complexo de Golgi/patologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Microcefalia/etiologia , Dados de Sequência Molecular , Mutação , Fenótipo , Adulto Jovem
9.
Hum Mol Genet ; 24(2): 361-70, 2015 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-25168382

RESUMO

ABCD3 is one of three ATP-binding cassette (ABC) transporters present in the peroxisomal membrane catalyzing ATP-dependent transport of substrates for metabolic pathways localized in peroxisomes. So far, the precise function of ABCD3 is not known. Here, we report the identification of the first patient with a defect of ABCD3. The patient presented with hepatosplenomegaly and severe liver disease and showed a striking accumulation of peroxisomal C27-bile acid intermediates in plasma. Investigation of peroxisomal parameters in skin fibroblasts revealed a reduced number of enlarged import-competent peroxisomes. Peroxisomal beta-oxidation of C26:0 was normal, but beta-oxidation of pristanic acid was reduced. Genetic analysis revealed a homozygous deletion at the DNA level of 1758bp, predicted to result in a truncated ABCD3 protein lacking the C-terminal 24 amino acids (p.Y635NfsX1). Liver disease progressed and the patient required liver transplantation at 4 years of age but expired shortly after transplantation. To corroborate our findings in the patient, we studied a previously generated Abcd3 knockout mouse model. Abcd3-/- mice accumulated the branched chain fatty acid phytanic acid after phytol loading. In addition, analysis of bile acids revealed a reduction of C24 bile acids, whereas C27-bile acid intermediates were significantly increased in liver, bile and intestine of Abcd3-/- mice. Thus, both in the patient and in Abcd3-/- mice, there was evidence of a bile acid biosynthesis defect. In conclusion, our studies show that ABCD3 is involved in transport of branched-chain fatty acids and C27 bile acids into the peroxisome and that this is a crucial step in bile acid biosynthesis.


Assuntos
Transportadores de Cassetes de Ligação de ATP/deficiência , Transportadores de Cassetes de Ligação de ATP/metabolismo , Ácidos e Sais Biliares/biossíntese , Hepatopatias/metabolismo , Peroxissomos/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Ácidos Graxos/metabolismo , Feminino , Humanos , Hepatopatias/genética , Masculino , Camundongos , Camundongos Knockout , Peroxissomos/genética
10.
Orphanet J Rare Dis ; 9: 107, 2014 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-25081276

RESUMO

BACKGROUND: Hepatorenal tyrosinaemia (Tyr 1) is a rare inborn error of tyrosine metabolism. Without treatment, patients are at high risk of developing acute liver failure, renal dysfunction and in the long run hepatocellular carcinoma. The aim of our study was to collect cross-sectional data. METHODS: Via questionnaires we collected retrospective data of 168 patients with Tyr 1 from 21 centres (Europe, Turkey and Israel) about diagnosis, treatment, monitoring and outcome. In a subsequent consensus workshop, we discussed data and clinical implications. RESULTS: Early treatment by NTBC accompanied by diet is essential to prevent serious complications such as liver failure, hepatocellular carcinoma and renal disease. As patients may remain initially asymptomatic or develop uncharacteristic clinical symptoms in the first months of life newborn mass screening using succinylacetone (SA) as a screening parameter in dried blood is mandatory for early diagnosis. NTBC-treatment has to be combined with natural protein restriction supplemented with essential amino acids. NTBC dosage should be reduced to the minimal dose allowing metabolic control, once daily dosing may be an option in older children and adults in order to increase compliance. Metabolic control is judged by SA (below detection limit) in dried blood or urine, plasma tyrosine (<400 µM) and NTBC-levels in the therapeutic range (20-40 µM). Side effects of NTBC are mild and often transient. Indications for liver transplantation are hepatocellular carcinoma or failure to respond to NTBC. Follow-up procedures should include liver and kidney function tests, tumor markers and imaging, ophthalmological examination, blood count, psychomotor and intelligence testing as well as therapeutic monitoring (SA, tyrosine, NTBC in blood). CONCLUSION: Based on the data from 21 centres treating 168 patients we were able to characterize current practice and clinical experience in Tyr 1. This information could form the basis for clinical practice recommendations, however further prospective data are required to underpin some of the recommendations.


Assuntos
Cicloexanonas/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Triagem Neonatal/métodos , Nitrobenzoatos/uso terapêutico , Tirosinemias/diagnóstico , Tirosinemias/terapia , Adolescente , Criança , Pré-Escolar , Estudos Transversais , Cicloexanonas/efeitos adversos , Inibidores Enzimáticos/efeitos adversos , Feminino , Seguimentos , Humanos , Lactente , Recém-Nascido , Falência Hepática/diagnóstico , Falência Hepática/cirurgia , Transplante de Fígado , Masculino , Nitrobenzoatos/efeitos adversos , Doenças Raras/diagnóstico , Doenças Raras/tratamento farmacológico , Insuficiência Renal/diagnóstico , Insuficiência Renal/cirurgia , Estudos Retrospectivos , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
11.
J Inherit Metab Dis ; 37(5): 763-73, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24810368

RESUMO

BACKGROUND: Glutaric aciduria type I (GA-I) is a cerebral organic aciduria caused by inherited deficiency of glutaryl-CoA dehydrogenase and is characterized biochemically by an accumulation of putatively neurotoxic dicarboxylic metabolites. The majority of untreated patients develops a complex movement disorder with predominant dystonia during age 3-36 months. Magnetic resonance imaging (MRI) studies have demonstrated striatal and extrastriatal abnormalities. AIMS/METHODS: The major aim of this study was to elucidate the complex neuroradiological pattern of patients with GA-I and to associate the MRI findings with the severity of predominant neurological symptoms. In 180 patients, detailed information about the neurological presentation and brain region-specific MRI abnormalities were obtained via a standardized questionnaire. RESULTS: Patients with a movement disorder had more often MRI abnormalities in putamen, caudate, cortex, ventricles and external CSF spaces than patients without or with minor neurological symptoms. Putaminal MRI changes and strongly dilated ventricles were identified as the most reliable predictors of a movement disorder. In contrast, abnormalities in globus pallidus were not clearly associated with a movement disorder. Caudate and putamen as well as cortex, ventricles and external CSF spaces clearly collocalized on a two-dimensional map demonstrating statistical similarity and suggesting the same underlying pathomechanism. CONCLUSIONS: This study demonstrates that complex statistical methods are useful to decipher the age-dependent and region-specific MRI patterns of rare neurometabolic diseases and that these methods are helpful to elucidate the clinical relevance of specific MRI findings.


Assuntos
Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/terapia , Encefalopatias Metabólicas/diagnóstico , Encefalopatias Metabólicas/terapia , Glutaril-CoA Desidrogenase/deficiência , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Pesquisas sobre Serviços de Saúde , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/patologia , Exame Neurológico , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
12.
J Inherit Metab Dis ; 37(5): 831-40, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24599607

RESUMO

UNLABELLED: The cblC defect is the most common inborn error of vitamin B12 metabolism. Despite therapeutic measures, the long-term outcome is often unsatisfactory. This retrospective multicentre study evaluates clinical, biochemical and genetic findings in 88 cblC patients. The questionnaire designed for the study evaluates clinical and biochemical features at both initial presentation and during follow up. Also the development of severity scores allows investigation of individual disease load, statistical evaluation of parameters between the different age of presentation groups, as well as a search for correlations between clinical endpoints and potential modifying factors. RESULTS: No major differences were found between neonatal and early onset patients so that these groups were combined as an infantile-onset group representing 88 % of all cases. Hypotonia, lethargy, feeding problems and developmental delay were predominant in this group, while late-onset patients frequently presented with psychiatric/behaviour problems and myelopathy. Plasma total homocysteine was higher and methionine lower in infantile-onset patients. Plasma methionine levels correlated with "overall impression" as judged by treating physicians. Physician's impression of patient's well-being correlated with assessed disease load. We confirmed the association between homozygosity for the c.271dupA mutation and infantile-onset but not between homozygosity for c.394C>T and late-onset. Patients were treated with parenteral hydroxocobalamin, betaine, folate/folinic acid and carnitine resulting in improvement of biochemical abnormalities, non-neurological signs and mortality. However the long-term neurological and ophthalmological outcome is not significantly influenced. In summary the survey points to the need for prospective studies in a large cohort using agreed treatment modalities and monitoring criteria.


Assuntos
Erros Inatos do Metabolismo/genética , Erros Inatos do Metabolismo/metabolismo , Proteínas Proto-Oncogênicas c-cbl/genética , Vitamina B 12/metabolismo , Idade de Início , Encéfalo/patologia , Proteínas de Transporte/genética , Criança , Pré-Escolar , Progressão da Doença , Grupos Étnicos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/terapia , Oxirredutases , Prognóstico , Inquéritos e Questionários
13.
BMC Med Genet ; 15: 10, 2014 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-24433453

RESUMO

BACKGROUND: SRD5A3 is responsible for SRD5A3-CDG, a type of congenital disorder of glycosylation, and mutations have been reported in 15 children. All the mutations are recessive and truncating. CASE PRESENTATION: We present 2 brothers at the age of 38 and 40 years with an initial diagnosis of cerebellar ataxia. We found the candidate disease loci via linkage analysis using data from single nucleotide polymorphism genome scans and homozygous truncating mutation SRD5A3 p.W19X, which was previously reported in 3 unrelated children, by exome sequencing.Clinical investigations included physical and ocular examinations and blood tests. Severe ocular involvement with retinal bone spicule pigmentation and optic atrophy are the most prominent disabling clinical features of the disease. The serum transferrin isoelectric focusing (TIEF) pattern is abnormal in the patient investigated. CONCLUSION: Our patients are older, with later onset and milder clinical phenotypes than all patients with SRD5A3-CDG reported so far. They also have atypical ocular findings and variable phenotypes. Our findings widen the spectrum of phenotypes resulting from SRD5A3 mutations and the clinical variability of SRD5A3-CDG, and suggest screening for SRD5A3 mutations in new patients with at least a few of the clinical symptoms of SRD5A3-CDG.


Assuntos
3-Oxo-5-alfa-Esteroide 4-Desidrogenase/genética , Defeitos Congênitos da Glicosilação/enzimologia , Defeitos Congênitos da Glicosilação/genética , Proteínas de Membrana/genética , Fenótipo , Adulto , Defeitos Congênitos da Glicosilação/patologia , Defeitos Congênitos da Glicosilação/fisiopatologia , Feminino , Humanos , Masculino , Mutação , Polimorfismo de Nucleotídeo Único , Irmãos
14.
Clin Chim Acta ; 430: 28-32, 2014 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-24370386

RESUMO

BACKGROUND: Orotic acid (OA) is the key parameter in the detection of ornithine transcarbamylase deficiency (OTC-D). Inclusion of OA into newborn screening compatibility with existing analytical procedures is necessary. METHODS: OA was eluted from dried blood spots with methanol containing deuterated [1,3-(15)N2] OA as internal standard. Quantification by tandem mass spectrometry was accomplished without chromatographic separation. Samples were measured in MRM mode for the masses m/z 155.1 → 111 for OA and 157.1 → 113 for d2 OA. RESULTS: OA was determined in a wide range of concentrations with high precision, LOD and LOQ being 0.21 and 0.65 µmol/L, respectively. Values correlated well with those obtained after chromatography. Pretreatment of samples with HCl-butanol regularly used for acylcarnitine measurement did not significantly affect quantitative results. Inclusion of the new method into the standard newborn screening procedure did not alter the results for acylcarnitines or amino acids; the total time per analysis, however, was increased from 1.15 to 1.85 min. OA levels of 707 unaffected newborns ranged from 0.28 to 3.73 µmol/L. Five newborns with OTC-D showed concentrations of 89.7-211.1 µmol/L. In newborns with severe citrullinaemia we found values in the range of 4.99-127.7 µmol/L. CONCLUSIONS: This new method can be used as a standalone measurement of OA but it can also easily be implemented into standard newborn screening techniques as a useful supplement. In this case the method allows detection of newborns with OTC deficiency without an extra analytical run.


Assuntos
Teste em Amostras de Sangue Seco , Triagem Neonatal/métodos , Doença da Deficiência de Ornitina Carbomoiltransferase/sangue , Doença da Deficiência de Ornitina Carbomoiltransferase/diagnóstico , Ácido Orótico/sangue , Espectrometria de Massas em Tandem , Humanos , Recém-Nascido , Doença da Deficiência de Ornitina Carbomoiltransferase/metabolismo
15.
Mol Genet Metab ; 102(2): 116-21, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21147011

RESUMO

BACKGROUND: The prevalence of phenylalanine hydroxylase (PAH)-deficient phenylketonuria (PKU) in Turkey is high (1 in 6500 births), but data concerning the genotype distribution and impact of the genotype on tetrahydrobiopterin (BH(4)) therapy are scarce. OBJECTIVE: To characterize the phenotypic and genotypic variability in the Turkish PKU population and to correlate it with physiological response to BH(4) challenge. METHODS: We genotyped 588 hyperphenylalaninemic patients and performed a BH(4) loading test (20mg/kg bw) in 462 patients. Residual PAH activity of mutant proteins was calculated from available in vitro expression data. Data were tabulated in the BIOPKU database (www.biopku.org). RESULTS: Eighty-eight mutations were observed, the most common missense mutations being the splice variant c.1066-11G>A (24.6%). Twenty novel mutations were detected (11 missense, 4 splice-site, and 5 deletion/insertions). Two mutations were observed in 540/588 patients (91.8%) but in 9 patients atypical genotypes with >2 mutations were found (8 with p.R155H in cis with another variant) and in 19 patients mutations were found in BH(4)-metabolizing genes. The most common genotype was c.1066-11G>A/c.1066-11G>A (15.5%). Approximately 22% of patients responded to BH(4) challenge. A substantial in vitro residual activity (average >25% of the wild-type enzyme) was associated with response to BH(4). In homozygous genotypes (n=206), both severity of the phenotype (r=0.83) and residual PAH activity (r=0.85) correlate with BH(4) responsiveness. CONCLUSION: Together with the BH(4) challenge, these data enable the genotype-based classification of BH(4) responsiveness and document importance of residual PAH activity. This first report of a large-scale genotype assessment in a population of Turkish PKU patients also documents a high prevalence (47%) of the severe classic phenotype.


Assuntos
Biopterina/análogos & derivados , Fenótipo , Fenilalanina Hidroxilase/genética , Fenilalanina Hidroxilase/metabolismo , Fenilcetonúrias/enzimologia , Fenilcetonúrias/genética , Alelos , Biopterina/uso terapêutico , Relação Dose-Resposta a Droga , Feminino , Estudos de Associação Genética , Variação Genética , Genótipo , Humanos , Recém-Nascido , Masculino , Mutação , Fenilalanina/sangue , Turquia
16.
Clin Chim Acta ; 412(1-2): 134-8, 2011 Jan 14.
Artigo em Inglês | MEDLINE | ID: mdl-20883679

RESUMO

BACKGROUND: Quantification of nitisinone, 2-(nitro-4-trifluoromethylbenzoyl)1,3-cyclohexanedione (NTBC) has been repeatedly described. Nevertheless monitoring of NTBC has not yet become part of routine therapy surveillance in tyrosinaemia type I (OMIM 276700). We developed a blood spot test to facilitate collection and transport of samples. Furthermore, the test material can be used for determination of other parameters like tyrosine and succinylacetone. METHOD: For quantification of NTBC in blood spots filter paper discs of 3.2mm diameter were extracted with 150 µL methanol containing mesotrione as internal standard (IS). Analysis was done by UPLC-MS/MS on a Xevo mass spectrometer (ESI+), (MRM). Parent ions were 330.05 for NTBC and 340.05 for IS, daughter ions were m/z 217.95 and m/z 125.95 for NTBC, and m/z 227.95 and m/z 103.95 for IS. RESULTS: The calibration curve for NTBC in blood spots was linear from 0.1 µmol/L to 100 µmol/L. Recovery exceeded 73.1%, CV intraday and interday were below 9.6%. Instrumental run time was 2.5 min. Sensitivity of the method was 0.1 µmol/L. NTBC concentrations in plasma were higher than in blood spots by a factor of 1.56 ± 0.13. CONCLUSION: As demonstrated in patients with tyrosinaemia type I quantification of NTBC by UPLC-MS/MS in blood spots is feasible and gives valuable information for monitoring NTBC treatment.


Assuntos
Análise Química do Sangue/métodos , Cicloexanonas/sangue , Nitrobenzoatos/sangue , Manejo de Espécimes/métodos , Tirosinemias/sangue , Cicloexanonas/isolamento & purificação , Cicloexanonas/uso terapêutico , Seguimentos , Humanos , Masculino , Nitrobenzoatos/isolamento & purificação , Nitrobenzoatos/uso terapêutico , Resultado do Tratamento , Tirosinemias/tratamento farmacológico
18.
J Hum Genet ; 54(11): 681-6, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19834502

RESUMO

Glycogen storage disease type III (GSD III) is an autosomal recessive disorder caused by deficiency in the glycogen debranching enzyme (gene symbol: AGL) with two enzyme activities: transferase and glucosidase. A missense mutation causing isolated glucosidase deficiency has never been reported. In this study, we examined 23 patients of Turkish ancestry and identified a novel missense mutation p.R1147G with isolated glucosidase deficiency, along with nine AGL mutations: six nonsense mutations (p.W373X, p.R595X, p.Q667X, p.Q1205X, p.W1327X and p.Q1376X), one deletion (c.1019delA) and two splicing mutation (c.293+2T>G and c.958+1G>A). As p.R1147G impaired glucosidase activity, but maintained transferase activity in vitro, a 12-year-old girl homozygous for p.R1147G was diagnosed with having isolated glucosidase deficiency. Of nine other mutations, p.W1327X and c.1019delA were recurrent, whereas seven mutations were novel. Six patients with p.W1327X were all from two nearby cities on the East Black Sea and shared the same AGL haplotype, indicating a founder effect in Turkish patients. Patients with the same mutations had identical haplotypes. Our results provide the first comprehensive overview of clinical and molecular features of Turkish GSD III patients and the first description of the missense mutation associated with isolated glucosidase deficiency.


Assuntos
Glucosidases/genética , Sistema da Enzima Desramificadora do Glicogênio/genética , Doença de Depósito de Glicogênio Tipo III/genética , Mutação , Adolescente , Adulto , Sequência de Aminoácidos , Criança , Pré-Escolar , Códon sem Sentido , Análise Mutacional de DNA , Feminino , Efeito Fundador , Geografia , Glucosidases/deficiência , Doença de Depósito de Glicogênio Tipo III/enzimologia , Haplótipos , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Polimorfismo de Nucleotídeo Único , Sítios de Splice de RNA/genética , Deleção de Sequência , Turquia , Adulto Jovem
19.
Turk J Pediatr ; 51(2): 97-102, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-19480318

RESUMO

In maple syrup urine disease (MSUD), disease-causing mutations can affect the BCKDHA, BCKDHB or DBT genes encoding for the E1alpha, E1beta and E2 subunits of the multienzyme branched-chain alpha-keto acid dehydrogenase (BCKDH) complex. Here we summarize the MSUD genotypes of a cohort of 32 unrelated Turkish patients in whom both alleles at a single gene locus harbored presumable disease-causing nucleotide changes. The patients had different forms of MSUD, ranging from the severe classical form (26 patients) to severe and mild variants (6 patients). In all except two patients (92%), the mutations occurred homozygously. The mutational spectrum included 27 different sequence variations--12 changes in the BCKDHA, 10 in the BCKDHB, and 5 in the DBT genes. In 37% (12 patients) of a total of 64 alleles, the supposed disease-causing mutations were located in the BCKDHA gene, in 44% (14 patients) in the BCKDHB gene and in 19% (6 patients) in the DBT gene. The mutational profile is heterogeneous, although two mutations occurred three times and five mutations occurred twice. There was no cluster for a single mutation except for c.773G>A (p.Cys258Tyr) in the BCKDHA gene, a hypothetical founder mutation in the Camlidere population.


Assuntos
3-Metil-2-Oxobutanoato Desidrogenase (Lipoamida)/genética , Doença da Urina de Xarope de Bordo/genética , Biologia Molecular , Mutação , Códon sem Sentido , Estudos de Coortes , Consanguinidade , Genótipo , Homozigoto , Humanos , Mutação de Sentido Incorreto , Mutação Puntual , Turquia
20.
Turk J Pediatr ; 49(2): 115-9, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17907509

RESUMO

The aim of this study was to investigate the endothelial dysfunction (ED) and carotid intima-media thickness (IMT) in patients with glycogen storage disease (GSD) types Ia and III. In 22 patients with GSD (13, type Ia; 9, type III) and 18 healthy subjects, endothelial functions of the brachial artery and carotid IMT were evaluated by high-resolution ultrasound. Endothelial-dependent dilatation (EDD) was assessed by establishing reactive hyperemia. EDD and carotid IMTs were compared between the three groups. Mean cholesterol level was slightly higher in GSD type III patients but the difference was not significant. Triglyceride levels and cholesterol to high density lipoprotein (HDL) ratio were significantly higher in GSD type Ia patients. EDD was significantly impaired in GSD type Ia (13% +/- 8%, P = .001) and type III (15% +/- 6%, P = .005) patients when compared with the healthy subjects (22% +/- 4%). The carotid IMT was significantly higher in both GSD type Ia (0.23 +/- 0.03 mm, P =.005) and type III (0.26 +/- 0.05 mm, P = .001) patients when compared with the healthy subjects (0.20 +/- 0.02 mm). Both GSD type Ia and type III patients show significant ED and increased IMT, which are predictors of atherosclerosis.


Assuntos
Aterosclerose/etiologia , Endotélio Vascular/patologia , Doença de Depósito de Glicogênio Tipo III/complicações , Doença de Depósito de Glicogênio Tipo I/complicações , Túnica Média/patologia , Adolescente , Análise de Variância , Aterosclerose/diagnóstico por imagem , Artéria Braquial/diagnóstico por imagem , Artéria Braquial/patologia , Artéria Carótida Primitiva/diagnóstico por imagem , Artéria Carótida Primitiva/patologia , Estudos de Casos e Controles , Distribuição de Qui-Quadrado , Criança , Pré-Escolar , Endotélio Vascular/diagnóstico por imagem , Feminino , Doença de Depósito de Glicogênio Tipo I/patologia , Doença de Depósito de Glicogênio Tipo III/patologia , Humanos , Lactente , Masculino , Valor Preditivo dos Testes , Estatísticas não Paramétricas , Ultrassonografia
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