RESUMO
Inherited peripheral neuropathies are a genetically heterogeneous group of disorders characterized by distal muscle weakness and sensory loss. Mutations in genes encoding aminoacyl-tRNA synthetases have been implicated in peripheral neuropathies, suggesting that these tRNA charging enzymes are uniquely important for the peripheral nerve. Recently, a mutation in histidyl-tRNA synthetase (HARS) was identified in a single patient with a late-onset, sensory-predominant peripheral neuropathy; however, the genetic evidence was lacking, making the significance of the finding unclear. Here, we present clinical, genetic, and functional data that implicate HARS mutations in inherited peripheral neuropathies. The associated phenotypic spectrum is broad and encompasses axonal and demyelinating motor and sensory neuropathies, including four young patients presenting with pure motor axonal neuropathy. Genome-wide linkage studies in combination with whole-exome and conventional sequencing revealed four distinct and previously unreported heterozygous HARS mutations segregating with autosomal dominant peripheral neuropathy in four unrelated families (p.Thr132Ile, p.Pro134His, p.Asp175Glu and p.Asp364Tyr). All mutations cause a loss of function in yeast complementation assays, and p.Asp364Tyr is dominantly neurotoxic in a Caenorhabditis elegans model. This study demonstrates the role of HARS mutations in peripheral neuropathy and expands the genetic and clinical spectrum of aminoacyl-tRNA synthetase-related human disease.
Assuntos
Ligação Genética/genética , Neuropatias Hereditárias Sensoriais e Autônomas/genética , Histidina-tRNA Ligase/genética , Mutação/genética , Doenças do Sistema Nervoso Periférico/genética , Doença de Charcot-Marie-Tooth/genética , Feminino , Humanos , Masculino , LinhagemRESUMO
BACKGROUND: In patients with gestational diabetes, breastfeeding decreases the lifetime risk of Type 2 diabetes by half. Lactation consultation has been shown to increase breastfeeding rates in the general population but has not been assessed in a gestational diabetes population. RESEARCH AIMS: To determine if (1) a postpartum International Board Certified Lactation Consultant (IBCLC) consultation during delivery hospitalization improved inclusive (any) or exclusive breastfeeding rates at hospital discharge and 3 months postpartum in participants with GDM; and if (2) obstetrical providers' acknowledgement of maternal feeding preference affected the rates of IBCLC consultation for patients. METHODS: This was a retrospective, comparative, secondary analysis of a prospective cohort (N = 517) study of women gestational diabetes. Participants who received a IBCLC consultation (n = 386; 74.5%) were compared to those who did not (n = 131; 25.5%). Baseline demographics, antepartum characteristics, neonatal information, mode of infant feeding at hospital discharge and 3 months postpartum, and IBCLC consultation during postpartum hospitalization were measured. RESULTS: After adjusting for baseline differences, participants who received an IBCLC consultation were more likely to report any breastfeeding at postpartum discharge (aOR 4.87; 95% CI [2.67, 8.86]) and at 3 months postpartum (aOR 5.39; 95% CI [2.61, 11.16]) compared to participants who did not. However, there was no difference in exclusive breastfeeding rates between those who did and did not receive IBCLC consultation. CONCLUSION: Inpatient IBCLC consultation during the immediate postpartum period was associated with improved rates of any breastfeeding in participants with GDM.
Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Gestacional , Aleitamento Materno , Consultores , Feminino , Humanos , Lactente , Recém-Nascido , Lactação , Mães , Gravidez , Estudos Prospectivos , Encaminhamento e Consulta , Estudos RetrospectivosRESUMO
Mutations in FGD1 cause Aarskog-Scott syndrome (AAS), an X-linked condition characterized by abnormal facial, skeletal, and genital development due to abnormal embryonic morphogenesis and skeletal formation. Here we report a novel FGD1 mutation in a family with atypical features of AAS, specifically bilateral upper and lower limb congenital joint contractures and cardiac abnormalities. The male proband and his affected maternal uncle are hemizygous for the novel FGD1 mutation p.Arg921X. This variant is the most carboxy-terminal FGD1 mutation identified in a family with AAS and is predicted to truncate the FGD1 protein at the second to last amino acid of the carboxy-terminal pleckstrin homology (PH) domain. Our study emphasizes the importance of the 3' peptide sequence in the structure and/or function of the FGD1 protein and further demonstrates the need to screen patients with X-linked congenital joint contractures for FGD1 mutations.