Hereditary ataxia (HA) encompasses a diverse group of neurological disorders characterized by significant clinical and genetic heterogeneity. This case series study aims to present a case series of HA from Southwest China, thereby expanding the clinical and genetic understanding of the condition. A comprehensive review of medical records was conducted for patients with progressive ataxia who were evaluated at the Children's Hospital of Chongqing Medical University and Qianjiang Central Hospital. The clinical manifestations, pedigree analysis, neuroimaging, and laboratory evaluations of the probands were systematically examined. Comprehensive genetic testing was conducted on peripheral venous blood samples to investigate HA. The genetic analyses identified spinocerebellar ataxia (SCA) in six families, ataxia-telangiectasia in three families, ataxia with vitamin E deficiency in one family, ATP1A3-associated ataxia in one family, and SPTBN2-associated ataxia in one family. Further subtyping of SCA revealed the presence of SCA types 1, 2, and 3 among the patients. The participants were enrolled an average of 8.5 years after symptom onset, with the age of onset ranging from 1 to 50 years. Gait instability was the most prevalent clinical feature observed in our cohort. We identified 12 families with HA, including four genetic mutations that have not been previously documented. SCA3 was the most frequently inherited dominant ataxia, followed by ataxia-telangiectasia. Whole-exome sequencing has significantly increased the diagnostic yield in patients with suspected genetic ataxia and should be considered for all individuals with negative repeat expansion testing.

Ataxia with Vitamin E Deficiency (AVED) is a rare autosomal recessive genetic disorder, that caused by pathogenic variants in the TTPA gene, which encodes the alpha-tocopherol transfer protein. This study investigates eight patients from three consanguineous Iranian families, using exome sequencing (ES) and Sanger sequencing to identify novel pathogenic variants in the TTPA gene. Two variants were identified: c.219T>A (p.Tyr73*) and c.205-1G>C. the first one (c.219T>A) related to potentially founder effects within regions of homozygosity. Clinical outcomes varied among patients based on vitamin E therapy initiation, with early treatment preventing severe neurological impairment. These findings improve knowledge of TTPA variants, supporting targeted genetic-based therapy. This study emphasizes the importance of genetic screening in consanguineous communities for the early detection and management of Mendelian diseases, with additional implications for managing rare genetic disorders generally.

Hereditary ataxia (HA) is a diverse group of rare inherited neurological disorders characterised by cerebellar impairment and the progressive degeneration of spinocerebellar tracts and the spinal cord. These conditions manifest predominantly as unsteady gait, speech difficulties, dysphagia and motor skill impairment. The complex genetic causes and varied disease mechanisms underlying HA contribute to the multi-systemic symptoms which pose challenges in developing targeted effective treatments. Currently, available options for HA primarily focus on symptomatic management, highlighting a critical need for complementary therapeutic strategies, such as dietary and lifestyle interventions. This review explains recent findings on dietary and nutraceutical interventions, as well as lifestyle modifications such as exercise and rehabilitation programs for HA. It outlines common types of HA, including Friedreich ataxia, spinocerebellar ataxias, ataxia with vitamin E deficiency, ataxia-telangiectasia, and studies on a mixed cohort of patients with HA. The current management options, therapeutic implications of findings from pre-clinical and clinical data and future directions to advance the treatment of HA will also be discussed. The integration of nutraceuticals and rehabilitation programs with current methods of symptomatic management is encouraged for the holistic treatment of HA. These interventions will complement the use of various technological aids with the support of a multidisciplinary health and medical team to improve monitoring of the health status and disease progression of affected individuals; thus facilitating early treatment and an optimised clinical outcome.

Retinopathy with vitamin E deficiency is a familial disease in the English Cocker Spaniel dog breed. Ophthalmic abnormalities observed in retinopathy with vitamin E deficiency-affected English Cocker Spaniel include lipofuscin granule deposition within the tapetal fundus and subsequent retinal degeneration resulting in visual deficits. Affected dogs may also exhibit neurological signs that include ataxia and hindlimb proprioceptive deficits. In all cases, circulating plasma concentrations of α-tocopherol are low. This study sought to investigate the genetic basis of retinopathy with vitamin E deficiency in the English Cocker Spaniel breed. We undertook a genome-wide association study comprising 30 English Cocker Spaniels with normal fundic examinations aged 6 years or older (controls) and 20 diagnosed with retinopathy with vitamin E deficiency (cases) and identified a statistically associated signal on chromosome 29 (Praw = 1.909 × 10-17). Whole genome sequencing of 2 cases identified a 102 bp deletion in exon 1 of the alpha-tocopherol transfer protein gene (TTPA), truncating the protein by 34 amino acids. The c.23_124del variant segregated with retinopathy with vitamin E deficiency in a total of 30 cases and 43 controls. Variants in TTPA are causal for ataxia with vitamin E deficiency in humans which is a phenotypically similar disease to retinopathy with vitamin E deficiency. The identification of the canine variant is extremely significant as the availability of a DNA test will allow for identification of presymptomatic dogs and early therapeutic intervention which may prevent development of retinopathy and improve neurological signs. Breeders can also use the DNA test to efficiently eradicate the disease from this breed.

Retinitis pigmentosa (RP) is a progressive inherited retinal dystrophy, characterized by the degeneration of photoreceptors, presenting as a rod-cone dystrophy. Approximately 20-30% of patients with RP also exhibit extra-ocular manifestations in the context of a syndrome. This manuscript discusses the broad spectrum of syndromes associated with RP, pathogenic mechanisms, clinical manifestations, differential diagnoses, clinical management approaches, and future perspectives. Given the diverse clinical and genetic landscape of syndromic RP, the diagnosis may be challenging. However, an accurate and timely diagnosis is essential for optimal clinical management, prognostication, and potential treatment. Broadly, the syndromes associated with RP can be categorized into ciliopathies, inherited metabolic disorders, mitochondrial disorders, and miscellaneous syndromes. Among the ciliopathies associated with RP, Usher syndrome and Bardet-Biedl syndrome are the most well-known. Less common ciliopathies include Cohen syndrome, Joubert syndrome, cranioectodermal dysplasia, asphyxiating thoracic dystrophy, Mainzer-Saldino syndrome, and RHYNS syndrome. Several inherited metabolic disorders can present with RP, including Zellweger spectrum disorders, adult Refsum disease, α-methylacyl-CoA racemase deficiency, certain mucopolysaccharidoses, ataxia with vitamin E deficiency, abetalipoproteinemia, several neuronal ceroid lipofuscinoses, mevalonic aciduria, PKAN/HARP syndrome, PHARC syndrome, and methylmalonic acidaemia with homocystinuria type cobalamin (cbl) C disease. Due to the mitochondria's essential role in supplying continuous energy to the retina, disruption of mitochondrial function can lead to RP, as seen in Kearns-Sayre syndrome, NARP syndrome, primary coenzyme Q10 deficiency, SSBP1-associated disease, and long chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Lastly, Cockayne syndrome and PERCHING syndrome can present with RP, but they do not fit the abovementioned hierarchy and are thus categorized as miscellaneous. Several first-in-human clinical trials are underway or in preparation for some of these syndromic forms of RP.