The genetic basis of early-onset hereditary ataxia in Iran: results of a national registry of a heterogeneous population.

BACKGROUND: To investigate the genetics of early-onset progressive cerebellar ataxia in Iran, we conducted a study at the Children's Medical Center (CMC), the primary referral center for pediatric disorders in the country, over a three-year period from 2019 to 2022. In this report, we provide the initial findings from the national registry. METHODS: We selected all early-onset patients with an autosomal recessive mode of inheritance to assess their phenotype, paraclinical tests, and genotypes. The clinical data encompassed clinical features, the Scale for the Assessment and Rating of Ataxia (SARA) scores, Magnetic Resonance Imaging (MRI) results, Electrodiagnostic exams (EDX), and biomarker features. Our genetic investigations included single-gene testing, Whole Exome Sequencing (WES), and Whole Genome Sequencing (WGS). RESULTS: Our study enrolled 162 patients from various geographic regions of our country. Among our subpopulations, we identified known and novel pathogenic variants in 42 genes in 97 families. The overall genetic diagnostic rate was 59.9%. Notably, we observed PLA2G6, ATM, SACS, and SCA variants in 19, 14, 12, and 10 families, respectively. Remarkably, more than 59% of the cases were attributed to pathogenic variants in these genes. CONCLUSIONS: Iran, being at the crossroad of the Middle East, exhibits a highly diverse genetic etiology for autosomal recessive hereditary ataxia. In light of this heterogeneity, the development of preventive strategies and targeted molecular therapeutics becomes crucial. A national guideline for the diagnosis and management of patients with these conditions could significantly aid in advancing healthcare approaches and improving patient outcomes.

Quantification and Correlation Analysis of Bacteroides Species with Diabetes-Related Amino Acids in Individuals with Prediabetes and Type 2 Diabetes Mellitus.

Background: The relationship between gut microbiota and diabetes-related amino acids significantly impacts insulin resistance and obesity. We aimed to quantify two Bacteroidetes species and their correlation with branched-chain amino acids, aromatic amino acids, and glutamate in prediabetes (preDM) and type 2 diabetes mellitus (T2DM). Methods: Fecal samples were collected from 68 participants, including 21 with T2DM, 23 with preDM, and 24 with normal glycemic tolerance (NGT). The abundance of Bacteroides vulgatus and Bacteroides thetaiotaomicron was determined by quantitative real-time polymerase chain reaction. Plasma amino acid measurements were performed using liquid chromatography coupled with tandem mass spectrometry. Results: The quantities of B. vulgatus and B. thetaiotaomicron were reduced in preDM and T2DM than in NGT subjects, but it was not statistically significant. The concentrations of leucine, valine, and tyrosine were significantly higher in preDM and T2DM than in NGT subjects (P < 0.05). A negative correlation was observed between B. thetaiotaomicron abundance and two aromatic amino acids (tyrosine, r = -0.28, P = 0.04; phenylalanine, r = -0.26, P = 0.05). Conclusions: These findings imply that, since gut microbiota varies throughout ethnic groups, further research with many participants will be required to determine the abundance of B. vulgatus and B. thetaiotaomicron in preDM and T2DM and their association with diabetes-related amino acids.