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.

A comprehensive study of mutation and phenotypic heterogeneity of childhood mitochondrial leukodystrophies.

OBJECTIVE: Mitochondrial leukodystrophies (MLs) are mainly caused by impairments of the mitochondrial respiratory chains. This study reports the mutation and phenotypic spectrum of a cohort of 41 pediatric patients from 39 distinct families with MLs among 320 patients with a molecular diagnosis of leukodystrophies. METHODS: This study summarizes the clinical, imaging, and molecular data of these patients for five years. RESULTS: The three most common symptoms were neurologic regression (58.5%), pyramidal signs (58.5%), and extrapyramidal signs (43.9%). Because nuclear DNA mutations are responsible for a high percentage of pediatric MLs, whole exome sequencing was performed on all patients. In total, 39 homozygous variants were detected. Additionally, two previously reported mtDNA variants were identified with different levels of heteroplasmy in two patients. Among 41 mutant alleles, 33 (80.4%) were missense, 4 (9.8%) were frameshift (including 3 deletions and one duplication), and 4 (9.8%) were splicing mutations. Oxidative phosphorylation in 27 cases (65.8%) and mtDNA maintenance pathways in 8 patients (19.5%) were the most commonly affected mitochondrial pathways. In total, 5 novel variants in PDSS1, NDUFB9, FXBL4, SURF1, and NDUSF1 were also detected. In silico analyses showed how each novel variant may contribute to ML pathogenesis. CONCLUSIONS: The findings of this study suggest whole-exome sequencing as a strong diagnostic genetic tool to identify the causative variants in pediatric MLs. In comparison between oxidative phosphorylation (OXPHOS) and mtDNA maintenance groups, brain stem and periaqueductal gray matter (PAGM) involvement were more commonly seen in OXPHOS group (P value of 0.002 and 0.009, respectively), and thinning of corpus callosum was observed more frequently in mtDNA maintenance group (P value of 0.042).

An inappropriate decline in ribosome levels drives a diverse set of neurodevelopmental disorders.

Many neurodevelopmental defects are linked to perturbations in genes involved in housekeeping functions, such as those encoding ribosome biogenesis factors. However, how reductions in ribosome biogenesis can result in tissue and developmental specific defects remains a mystery. Here we describe new allelic variants in the ribosome biogenesis factor AIRIM primarily associated with neurodevelopmental disorders. Using human cerebral organoids in combination with proteomic analysis, single-cell transcriptome analysis across multiple developmental stages, and single organoid translatome analysis, we identify a previously unappreciated mechanism linking changes in ribosome levels and the timing of cell fate specification during early brain development. We find ribosome levels decrease during neuroepithelial differentiation, making differentiating cells particularly vulnerable to perturbations in ribosome biogenesis during this time. Reduced ribosome availability more profoundly impacts the translation of specific transcripts, disrupting both survival and cell fate commitment of transitioning neuroepithelia. Enhancing mTOR activity by both genetic and pharmacologic approaches ameliorates the growth and developmental defects associated with intellectual disability linked variants, identifying potential treatment options for specific brain ribosomopathies. This work reveals the cellular and molecular origins of protein synthesis defect-related disorders of human brain development. Highlights: AIRIM variants reduce ribosome levels specifically in neural progenitor cells. Inappropriately low ribosome levels cause a transient delay in radial glia fate commitment.Reduced ribosome levels impair translation of a selected subset of mRNAs.Genetic and pharmacologic activation of mTORC1 suppresses AIRIM-linked phenotypes.