BackgroundSpinocerebellar ataxias comprise a large and heterogeneous group of disorders that may present with isolated ataxia, or ataxia in combination with other neurologic or non-neurologic symptoms. Monoallelic or biallelic GRID2 mutations were recently reported in rare cases with cerebellar syndrome and variable degree of ataxia, ocular symptoms, hypotonia and developmental delay.Case presentationWe report on a consanguineous family with autosomal recessive childhood onset of slowly progressive cerebellar ataxia and delayed psychomotor development in three siblings. MRI of an adult and affected family member revealed slightly widened cerebral and cerebellar sulci, suggesting generalized brain atrophy, and mild cerebellar atrophy. Using whole exome sequencing we identified a novel homozygous missense variant [c.2128C > T, p.(Arg710Trp)] in GRID2 that segregates with the disease. The missense variant is located in a conserved region encoding the extracellular serine-binding domain of the GluD2 protein and predicts a change in conformation of the protein.ConclusionThe widespread supratentorial brain abnormalities, absence of oculomotor symptoms, increased peripheral muscle tone and the novel missense mutation add to the clinical and genetic variability in GRID2 associated cerebellar syndrome. The neuroradiological findings in our family indicate a generalized neurodegenerative process to be taken into account in other families segregating complex clinical features and GRID2 mutations.
Spinocerebellar ataxias (SCA) comprise a heterogeneous group of inherited neurological disorders characterized by a range of symptoms from both cerebellar and extra cerebellar structures. We investigated the cause of autosomal recessive, congenital SCA in six affected family members from a large consanguineous family. Using whole-exome sequencing, we identified a homozygous ITPR1 missense variant [c.5360T>C; p.(L1787P)] segregating in all affected individuals. Heterozygous carriers were asymptomatic despite cerebellar hypoplasia. Variants in the ITPTR1 gene have previously been associated exclusively with autosomal dominant SCA15 and SCA29 with slow or no progression. The L1787 residue is highly conserved and the leucine to proline substitution has a predicted destabilizing effect on the protein structure. Additionally, the L1787P variant is located in a domain separated from previously described and dominant-acting missense variants consistent with a distinct effect on IP3R1 tetramer structure and function. Taken together, we show for the first time that a biallelic ITPR1 missense variant may cause an autosomal recessive and infantile onset SCA29, albeit with subclinical cerebellar hypoplasia in carriers. Our findings add to the genetic complexity of SCA29 and broaden the correlations between ITPR1 variants and their clinical expression.
Polycystic ovary syndrome (PCOS) is a polygenic, endocrine disorder causing ovarian dysfunction. This syndrome encompasses a broad spectrum of phenotypic expression due to heterogeneity. This study aimed to investigate the prevalence and phenotypic factors contributing to the onset of PCOS in Pakistani women. Participating females (n=130) were recruited from different regions of Pakistan explicitly those who were trying to conceive for years. We designed a questionnaire having different subsections comprising questions related to psychological and environmental aspects linked with PCOS. We also analyzed the proportion of women having prior awareness about the genetic basis of the disease. The retrieved data was analyzed through SPSS V.21 by employing descriptive statistics. A Chi-square test was used to establish a correlation between PCOS and associated symptoms. Our findings suggest that factors like obesity, facial and abdomen hair growth, irregular periods, menstrual flow, cramps, and hormonal acne corresponds to PCOS in participating females with a p-value (0.000 < 0.05). Around half of the participants were reported to be experiencing one or other symptom related to PCOS from which hirsutism and anxiety were the most common. Furthermore, our findings indicate that multiple psychological and environmental factors contribute to the onset of the disease with a P-Value (0.000 < 0.05). However, a significantly higher p-value (0.247 > 0.05) for excessive hair loss in participants were observed demonstrating that hair loss is not linked with PCOS. In this survey, 46.5 % of participants responded that they know that PCOS can be inherited. 28.5 % of women responded that they had a family history of PCOS. Adopting a healthy lifestyle and maintaining a healthy weight can minimize the severity of PCOS. This survey evaluates different hypotheses which would facilitate a better understanding of the prevalence and associated symptoms of PCOS in Pakistan thereby enabling researchers to develop better diagnostic, management, and treatment strategies for patients.
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