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Abstract 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.

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. [ABSTRACT FROM AUTHOR]

Hereditary spinocerebellar degeneration (SCD) encompasses an expanding list of rare diseases with a broad clinical and genetic heterogeneity, complicating their diagnosis and management in daily clinical practice. Correct diagnosis is a pillar for precision medicine, a branch of medicine that promises to flourish with the progressive improvements in studying the human genome. Discovering the genes causing novel Mendelian phenotypes contributes to precision medicine by diagnosing subsets of patients with previously undiagnosed conditions, guiding the management of these patients and their families, and enabling the discovery of more causes of Mendelian diseases. This new knowledge provides insight into the biological processes involved in health and disease, including the more common complex disorders. This review discusses the evolution of the clinical and genetic approaches used to diagnose hereditary SCD and the potential of new tools for future discoveries.

Hereditary spinocerebellar degeneration (SCD) encompasses an expanding list of rare diseases with a broad clinical and genetic heterogeneity, complicating their diagnosis and management in daily clinical practice. Correct diagnosis is a pillar for precision medicine, a branch of medicine that promises to flourish with the progressive improvements in studying the human genome. Discovering the genes causing novel Mendelian phenotypes contributes to precision medicine by diagnosing subsets of patients with previously undiagnosed conditions, guiding the management of these patients and their families, and enabling the discovery of more causes of Mendelian diseases. This new knowledge provides insight into the biological processes involved in health and disease, including the more common complex disorders. This review discusses the evolution of the clinical and genetic approaches used to diagnose hereditary SCD and the potential of new tools for future discoveries. [ABSTRACT FROM AUTHOR]

Hereditary ataxias (HAs) encompass a diverse and genetically intricate group of rare neurodegenerative disorders, presenting diagnostic challenges. Whole-exome sequencing (WES) has significantly improved diagnostic success. This study aimed to elucidate genetic causes of cerebellar ataxia within a diverse Brazilian cohort. Biological samples were collected from individuals with sporadic or familial cerebellar ataxia, spanning various ages and phenotypes, excluding common SCAs and Friedreich ataxia. RFC1 biallelic AAGGG repeat expansion was screened in all patients. For AAGGG-negative cases, WES targeting 441 ataxia-related genes was performed, followed by ExpansionHunter analysis for repeat expansions, including the recently described GGC-ZFHX3. Variant classification adhered to ClinGen guidelines, yielding definitive or probable diagnoses. The study involved 76 diverse Brazilian families. 16 % received definitive diagnoses, and another 16 % received probable ones. RFC1-related ataxia was predominant, with two definitive cases, followed by KIF1A (one definitive and one probable) and SYNE-1 (two probable). Early-onset cases exhibited higher diagnostic rates. ExpansionHunter improved diagnosis by 4 %.We did not detected GGC-ZFHX3 repeat expansion in this cohort. This study highlights diagnostic complexities in cerebellar ataxia, even with advanced genetic methods. RFC1, KIF1A, and SYNE1 emerged as prevalent mutations. ZFHX3 repeat expansion seem to be rare in Brazilian population. Early-onset cases showed higher diagnostic success. WES coupled with ExpansionHunter holds promise as a primary diagnostic tool, emphasizing the need for broader NGS accessibility in Brazil. • NGS prove valuable in the diagnosis of hereditary ataxias within the Brazilian cohort. • WES and ExpansionHunter yielded a diagnostic rate of 30 %. • The most common pathogenic variants found on WES were SYNE1 and KIF1A. • Within our cohort, AAGGG- RFC1 and GAA- FGF14 ataxia emerged as the most prevalent diagnoses. • GGC -ZFHX3 repeat expansion seem to be rare in Brazilian population. [ABSTRACT FROM AUTHOR]

Genetic testing strategies such as next-generation sequencing (NGS) panels and whole genome sequencing (WGS) can be applied to the hereditary cerebellar ataxias (HCAs), but their exact role in the diagnostic pathway is unclear. We aim to determine the yield from genetic testing strategies and the genetic and phenotypic spectrum of HCA in Australia by analysing real-world data. We performed a retrospective review on 87 HCA cases referred to the Neurogenetics Clinic at the Royal North Shore Hospital, Sydney, Australia. Probands underwent triplet repeat expansion testing; those that tested negative had NGS-targeted panels and WGS testing when available. In our sample, 58.6% were male (51/87), with an average age at onset of 37.1 years. Individuals with sequencing variants had a prolonged duration of illness compared to those with a triplet repeat expansion. The detection rate in probands for routine repeat expansion panels was 13.8% (11/80). NGS-targeted panels yielded a further 11 individuals (11/32, 34.4%), with WGS yielding 1 more diagnosis (1/3, 33.3%). NGS panels and WGS improved the overall diagnostic rate to 28.8% (23/80) in 14 known HCA loci. The genetic findings included novel variants in ANO10, CACNA1A, PRKCG and SPG7. Our findings highlight the genetic heterogeneity of HCAs and support the use of NGS approaches for individuals who were negative on repeat expansion testing. In comparison to repeat disorders, individuals with sequencing variants may have a prolonged duration of illness, consistent with slower progression of disease. [ABSTRACT FROM AUTHOR]

We present here 5 patients with hereditary cerebellar ataxia with peripheral neuropathy and mental retardation as determined by clinical, pathological, and molecular studies. The most characteristic features of this disorder, in contrast to Friedreich’s ataxia, were early onset of ataxic gait, mental retardation, and a marked atrophy of the cerebellum. Sural nerve biopsy showed a reduction of myelinated fibers. The expansion of a GAA triplet repeat within the first intron of the frataxin gene, which causes Friedreich’s ataxia, was not identified in any of the patients. Hereditary cerebellar ataxia with peripheral neuropathy and mental retardation represents a specific clinical entity that so far has only been described in Japan.Copyright © 2000 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

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Thirty-two patients with primary progressive cerebellar ataxia were studied using MRI. This technique is better than CT in demonstrating atrophy of cerebellar structures as well as of brainstem and spinal cord. The differential diagnosis from other diseases particularly with multiple sclerosis is easier. The degree of ataxia correlated well with the degree of atrophy of cerebellum. However we could not see any correlation between the degree of atrophy and the onset and duration of the disease and no certain specific aspects could be demonstrated in the different groups examined. [ABSTRACT FROM AUTHOR]