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1.
Am J Hum Genet ; 104(1): 139-156, 2019 01 03.
Artigo em Inglês | MEDLINE | ID: mdl-30595372

RESUMO

Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic Cα subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(δ) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.


Assuntos
Deficiência Intelectual/genética , Mutação , Proteína Fosfatase 2/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Células HEK293 , Haploinsuficiência/genética , Humanos , Masculino , Ligação Proteica/genética , Subunidades Proteicas/química , Subunidades Proteicas/metabolismo , Síndrome
2.
Mol Genet Metab Rep ; 16: 36-38, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30013935

RESUMO

Propionic acidemia (PA) occurs at a higher incidence within the Amish; however, sensitivity of newborn screening and its impact on long-term clinical outcomes has not been reported in this population. This study reviewed screening data and health records of 20 Wisconsin Amish patients diagnosed with PA. Newborn screening did not identify all cases; however, early detection did offer appreciable long-term protection from neurological sequelae. This is the first report summarizing PA cases within the Amish.

3.
J Pediatr ; 180: 200-205.e8, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27776753

RESUMO

OBJECTIVES: To compare time to evaluation and symptoms at diagnosis of propionic acidemia (PA) by method of ascertainment, and to explore correlations between genotype and biochemical variables. STUDY DESIGN: Clinical symptoms, genotype, and biochemical findings were analyzed retrospectively in 58 individuals with PA enrolled in the Inborn Errors of Metabolism Information System (IBEM-IS) based on the type of initial ascertainment: abnormal newborn screening (NBS), clinical presentation (symptomatic), or family history. RESULTS: The average age at initial evaluation and treatment was significantly younger in patients ascertained via abnormal NBS compared with those referred for clinical symptoms. Furthermore, the majority of individuals ascertained because of abnormal NBS were asymptomatic at diagnosis, compared with a minority of clinical presentations. A notable difference in the frequency of metabolic acidosis at initial presentation was observed between those with abnormal NBS (12.5%; 2 of 16) and those with an abnormal clinical presentation (79%; 19 of 24). The frequency of hyperammonemia was similar in the 2 groups. CONCLUSION: Our data support the continued value of NBS to identify individuals with PA, who are diagnosed and treated earlier than for other modes of ascertainment. There were no statistically significant correlations between genotype and NBS for C3 acylcarnitines. Although expanded use of NBS has allowed for early diagnosis and treatment, long-term outcomes of individuals with PA, especially with respect to mode of ascertainment, remain unclear and would benefit from a longitudinal study.


Assuntos
Triagem Neonatal/métodos , Acidemia Propiônica/diagnóstico , Feminino , Genótipo , Humanos , Lactente , Recém-Nascido , Masculino , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Acidemia Propiônica/genética , Estudos Retrospectivos , Fatores de Tempo
4.
Genet Med ; 19(3): 352-356, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-27513192

RESUMO

PURPOSE: This community project is an initiative through the University of Wisconsin Biochemical Genetics Clinic and the Wisconsin Newborn Screening Program to identify members of the Plain population who are at risk for having children with maple syrup urine disease (MSUD) or propionic acidemia (PA) or who have PA. METHODS: Because of the high prevalence of metabolic conditions in the Plain population and the importance of early intervention, a statewide outreach project was developed to provide targeted variant analysis of the common MSUD and PA pathogenic variants in this population through health-care provider distribution of blood spot testing kits. Awareness was achieved through outreach efforts with the state midwives guild and Plain population meetings. RESULTS: Eighty individuals were tested; diagnosis was confirmed for three adults with PA and one couple was identified as being at risk for having a child with PA. Genetic counseling was provided to those identified. Follow-up diagnostic testing was completed for the at-risk couple's children; none were found to be affected. CONCLUSION: This initiative successfully provided accessible clinical testing for MSUD and PA for a high-risk population. Early identification of at-risk couples sets the foundation for early care of at-risk neonates, thereby improving future clinical outcomes.Genet Med 19 3, 352-356.


Assuntos
Amish/genética , Testes Genéticos/métodos , Doença da Urina de Xarope de Bordo/genética , Acidemia Propiônica/genética , Adolescente , Adulto , Idoso , Erros Inatos do Metabolismo dos Aminoácidos/diagnóstico , Erros Inatos do Metabolismo dos Aminoácidos/genética , Criança , Pré-Escolar , Feminino , Aconselhamento Genético/métodos , Humanos , Recém-Nascido , Masculino , Doença da Urina de Xarope de Bordo/diagnóstico , Doença da Urina de Xarope de Bordo/prevenção & controle , Erros Inatos do Metabolismo/diagnóstico , Erros Inatos do Metabolismo/genética , Pessoa de Meia-Idade , Triagem Neonatal/métodos , Acidemia Propiônica/diagnóstico , Acidemia Propiônica/prevenção & controle , Wisconsin
5.
Am J Hum Genet ; 99(6): 1388-1394, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27889061

RESUMO

Human MITF is, by convention, called the "microphthalmia-associated transcription factor" because of previously published seminal mouse genetic studies; however, mutations in MITF have never been associated with microphthalmia in humans. Here, we describe a syndrome that we term COMMAD, characterized by coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness. COMMAD is associated with biallelic MITF mutant alleles and hence suggests a role for MITF in regulating processes such as optic-fissure closure and bone development or homeostasis, which go beyond what is usually seen in individuals carrying monoallelic MITF mutations.


Assuntos
Albinismo/genética , Alelos , Coloboma/genética , Surdez/genética , Megalencefalia/genética , Fator de Transcrição Associado à Microftalmia/genética , Microftalmia/genética , Osteopetrose/genética , Animais , Pré-Escolar , Feminino , Homozigoto , Humanos , Lactente , Masculino , Linhagem , Síndrome , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
6.
Mol Genet Metab Rep ; 8: 4-7, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28649556

RESUMO

Propionic acidemia (PA) is an inborn error of protein metabolism with a variable clinical presentation ranging from neonatal encephalopathy to seemingly asymptomatic individuals who present with cardiomyopathy or sudden death. PA is recognized in the Amish population, often with an early asymptomatic course and eventual cardiac complications. Thus, Amish women with PA may reach reproductive age without clinical sequelae, but are at increased risk for metabolic decompensation during pregnancy, delivery and postpartum period. We describe the care of an Amish woman with PA during her first pregnancy and delivery.

7.
Mol Genet Metab Rep ; 3: 39-41, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26937394

RESUMO

Very long chain acyl CoA dehydrogenase deficiency (VLCADD) is an inborn error in long chain fatty acid oxidation with significant variability in the severity and timing of its clinical presentation. Neonatal presentations of VLCADD have included hypoglycemia and cardiomyopathy while rhabdomyolysis is usually a later onset complication. We describe a neonate with VLCADD presenting with rhabdomyolysis prior to the return of an abnormal newborn screen. This report suggests that evaluating for rhabdomyolysis, in addition to a cardiac and hepatic work-up, is an important part of the initial evaluation of an infant with an abnormal newborn screen suggesting a diagnosis of VLCADD.

8.
Am J Med Genet A ; 164A(4): 1029-34, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24458799

RESUMO

MECP2 duplication syndrome, originally described in 2005, is an X-linked neurodevelopmental disorder comprising infantile hypotonia, severe to profound intellectual disability, autism or autistic-like features, spasticity, along with a variety of additional features that are not always clinically apparent. The syndrome is due to a duplication (or triplication) of the gene methyl CpG binding protein 2 (MECP2). To date, the disorder has been described almost exclusively in males. Female carriers of the duplication are thought to have no or mild phenotypic features. Recently, a phenotype for females began emerging. We describe a family with ∼290 kb duplication of Xq28 region that includes the MECP2 gene where the proposita and affected family members are female. Twin sisters, presumed identical, presented early with developmental delay, and seizures. Evaluation of the proposita at 25 years of age included microarray comparative genomic hybridization (aCGH) which revealed the MECP2 gene duplication. The same duplication was found in the proposita's sister, who is more severely affected, and the proband's mother who has mild intellectual disability and depression. X-chromosome inactivation studies showed significant skewing in the mother, but was uninformative in the twin sisters. We propose that the MECP2 duplication caused for the phenotype of the proband and her sister. These findings support evidence for varied severity in some females with MECP2 duplications.


Assuntos
Duplicação Gênica , Retardo Mental Ligado ao Cromossomo X/genética , Proteína 2 de Ligação a Metil-CpG/genética , Adulto , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Fenótipo
9.
Hum Mutat ; 35(4): 462-9, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24415674

RESUMO

Guanidinoacetate methyltransferase deficiency (GAMT-D) is an autosomal recessively inherited disorder of creatine biosynthesis. Creatine deficiency on cranial proton magnetic resonance spectroscopy, and elevated guanidinoacetate levels in body fluids are the biomarkers of GAMT-D. In 74 patients, 50 different mutations in the GAMT gene have been identified with missense variants being the most common. Clinical and biochemical features of the patients with missense variants were obtained from their physicians using a questionnaire. In 20 patients, 17 missense variants, 25% had a severe, 55% a moderate, and 20% a mild phenotype. The effect of these variants on GAMT enzyme activity was overexpressed using primary GAMT-D fibroblasts: 17 variants retained no significant activity and are therefore considered pathogenic. Two additional variants, c.22C>A (p.Pro8Thr) and c.79T>C (p.Tyr27His) (the latter detected in control cohorts) are in fact not pathogenic as these alleles restored GAMT enzyme activity, although both were predicted to be possibly damaging by in silico analysis. We report 13 new patients with GAMT-D, six novel mutations and functional analysis of 19 missense variants, all being included in our public LOVD database. Our functional assay is important for the confirmation of the pathogenicity of identified missense variants in the GAMT gene.


Assuntos
Guanidinoacetato N-Metiltransferase/deficiência , Transtornos do Desenvolvimento da Linguagem/genética , Transtornos do Desenvolvimento da Linguagem/patologia , Transtornos dos Movimentos/congênito , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Fibroblastos/enzimologia , Predisposição Genética para Doença , Variação Genética , Guanidinoacetato N-Metiltransferase/genética , Guanidinoacetato N-Metiltransferase/metabolismo , Humanos , Masculino , Transtornos dos Movimentos/genética , Transtornos dos Movimentos/patologia , Mutação de Sentido Incorreto , Inquéritos e Questionários , Adulto Jovem
10.
Spine (Phila Pa 1976) ; 38(5): E293-8, 2013 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-23446706

RESUMO

STUDY DESIGN: A retrospective medical record review of cases with congenital vertebral malformations (CVMs) and controls with normal spine morphology. OBJECTIVE: To determine the relative contribution of maternal environmental factors (MEFs) during pregnancy to CVM development. SUMMARY OF BACKGROUND DATA: CVMs represent defects in formation and segmentation of somites occurring with an estimated incidence of between 0.13 and 0.50 per 1000 live births. CVMs may be associated with various phenotypes and represent significant morbidity due to pain and cosmetic disfigurement. METHODS: A multicenter retrospective medical record review of 229 cases with CVM and 267 controls with normal spine morphology between the ages of 1 and 50 years was performed to obtain the odds ratio (OR) of MEF related to CVM among cases versus controls. An imputation-based analysis was performed in which subjects with no documentation of MEF history were treated as "no maternal exposure." Univariate and multivariate analyses were conducted to calculate the OR. RESULTS: Of the 229 total cases, 104 cases had single or multiple CVMs without additional congenital malformations (group 1) and 125 cases had single or multiple CVMs and additional congenital malformations (group 2). Nineteen percent of total cases had an identified MEF. The OR for MEF history for group 1 was 6.0 (95% confidence interval, 2.4-15.1; P < 0.001) in the univariate analysis. The OR for MEF history in group 2 was 9.1 (95% confidence interval, 3.8-21.6, P < 0.001) in the univariate analysis. The results were confirmed in the multivariate analysis after adjusting for age, sex, and institution. CONCLUSIONS: These results support a hypothesis for an association between these MEFs during pregnancy and CVM and have implications for development of prevention strategies. Further prospective studies are needed to quantify association between CVMs and specific MEF. LEVEL OF EVIDENCE: 4.


Assuntos
Anormalidades Múltiplas/etiologia , Exposição Materna , Efeitos Tardios da Exposição Pré-Natal , Coluna Vertebral/anormalidades , Adolescente , Adulto , Consumo de Bebidas Alcoólicas/efeitos adversos , Criança , Clomifeno/efeitos adversos , Diabetes Mellitus Tipo 1/complicações , Feminino , Febre/complicações , Humanos , Modelos Logísticos , Masculino , Análise Multivariada , Razão de Chances , Gravidez , Gravidez de Gêmeos , Técnicas de Reprodução Assistida/efeitos adversos , Estudos Retrospectivos , Risco Ajustado , Fatores de Risco , Fumar/efeitos adversos , Estados Unidos , Ácido Valproico/efeitos adversos , Adulto Jovem
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