Spinocerebellar ataxia, autosomal recessive type 23 (SCAR23) is an ultra-rare inherited disorder caused by biallelic Loss-of-Function (LoF) variants in TDP2, a nuclear enzyme involved in DNA double-strand breaks repair. To date, only 12 cases with homozygous variants and complex neurological phenotypes have been reported. We describe a 20-year-old male presenting with cerebellar ataxia, drug-resistant epilepsy, mild intellectual disability, and recurring craniofacial traits observed in SCAR23. Additional findings included polycythemia and a pituitary hamartoma. Clinical exome sequencing (CES) identified two novel TDP2 nonsense variants. In silico and structural analyses indicated that both variants affect highly conserved residues in the catalytic domain. Longitudinal video-oculography confirmed downbeat nystagmus (DBN), while static stabilometry captured subtle postural changes over 12 months not detected by routine clinical examination, highlighting the utility of quantitative digital assessments. This case expands the genotypic spectrum of SCAR23 and highlights recurring facial traits that may aid recognition. The coexisting SHOX deletion (i.e., Leri-Weill syndrome) was considered unrelated to the neurological phenotype. Digital assessments provided objective measures of motor function over time. Our findings broaden the clinical and molecular characterization of SCAR23 and illustrate the potential of digital biomarkers for longitudinal monitoring. Despite the lack of functional validation and the inherent limitations of a single-case report, these observations provide valuable insights for future research in this ultra-rare disorder.

Marinesco-Sjögren syndrome (MSS) is a rare autosomal recessive neuromuscular disorder marked by ataxia, muscle weakness, cataracts, and often intellectual and skeletal abnormalities. It is commonly caused by loss-of-function variants in the SIL1 gene, which impair binding immunoglobulin protein (BiP) function, leading to protein misfolding and activation of the unfolded protein response. In a 2-year-old patient with typical MSS symptoms, we identified a previously unreported c.1024G>A (p.E342K) variant in SIL1 via whole-exome sequencing. The pathogenicity of this Sil1 variant was supported by evidence of structural changes revealed through in silico predictions, circular dichroism, and native gel electrophoresis. Patient-derived fibroblasts exhibited reduced Sil1 protein levels, likely due to misfolding and degradation, which was partially rescued by proteasome inhibition. Proteomics revealed a profile similar to known MSS cases and a distinctive MSS transcriptional signature. Ultrastructural analysis confirmed typical MSS features, such as autophagic vacuoles and lipid droplets. Although the p.E342K phenotype appears milder than the reference pathogenic variant R111X, our findings support the reclassification of this novel variant as pathogenic, in accordance with the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) 2015 guidelines and the refinements proposed by the Clinical Genome Resource Sequence Variant Interpretation (ClinGen SVI) recommendations. Furthermore, the overall evidence also provides important insights into the genotype-phenotype correlation and the underlying pathogenic mechanism of the p.E342K variant.

Cerebellar ataxias are a group of disorders characterized by clumsy movements because of defective muscle control. In affected individuals, muscular impairment might have an impact on activities like walking, balance, hand coordination, speech, and feeding, as well as eye movements. The development of symptoms typically takes place during the span of adolescence, and it has the potential to cause distress for individuals in many areas of their lives, including professional and interpersonal relationships. Although skeletal muscle is understudied in ataxias, its examination may provide hitherto unexplored details in this family of disorders. Observing muscle involvement can assist in diagnosing conditions where genetic tests alone are inconclusive. Furthermore, it helps determine the stage of progression of a pathology that might otherwise be challenging to assess. In this study, we reviewed the main scientific literature reporting on skeletal muscle examination in autosomal recessive cerebellar ataxias (ARCAs), with a focus on the rare Marinesco-Sjögren syndrome. (MSS). Our aim was to highlight the similarities in muscle alterations observed in ARCA patients while also considering data gathered from preclinical models. Analyzing the similarities among these disorders could enhance our understanding of the unidentified mechanisms underlying the phenotypic evolution of some less common conditions.

Spastic ataxic syndrome is a combination of cerebellar ataxia with spasticity and other pyramidal features. Common causes of spastic ataxic syndrome include spinocerebellar ataxia (SCA) 1, SCA2, autosomal recessive ataxia of Charlevoix-Saguenay, Friedreich ataxia, and hereditary spastic paraplegia type-7. We report a 32-year-old female who presented with unsteadiness of gait, incoordination, and tremulousness of both hands for 10 years with microphthalmia, microdontia, dental caries, and syndactyly. Magnetic resonance imaging of the brain showed T2 fluid-attenuated inversion recovery hyper intensities in periventricular and lobar white matter and internal capsule. Thus, we report a genetically confirmed oculodentodigital dysplasia (ODDD), an autosomal dominant disorder, in an Indian patient who presented with spastic ataxic syndrome, a rarity that has not been reported so far.

Over the years, a diverse range of animal models has been established and employed in both basic and translational research, elucidating the intricate molecular mechanisms that drive cerebellar ataxias. However, many preclinical models remain insufficiently characterised, hindering our understanding of the diseases and the development of effective therapeutic approaches. The present study provides a comprehensive phenotypic and molecular characterisation of the woozy (Sil1wz) mouse model of Marinesco-Sjögren Syndrome (MSS), a rare autosomal recessive cerebellar ataxia characterised by cerebellar dysfunction, congenital cataracts, and progressive myopathy. Disease progression was monitored from 5 to 26 weeks using a series of motor assessments, including the accelerating rotarod, beam walking, pole test, and inverted grid test. These evaluations revealed progressive cerebellar ataxia in Sil1wz mice, with symptoms emerging around the ninth week of age. A clear sex-related difference was observed in the motor tests, with female Sil1wz mice outperforming their male counterparts across all assessments. Histological analysis revealed significant muscular atrophy in glycolytic muscles (gastrocnemius and quadriceps) but not in oxidative muscles (soleus) of 26-week-old Sil1wz mice. Molecular analyses confirmed the upregulation of unfolded protein response markers (BiP and pEIF2α) and proteolysis-associated proteins (Rab11 and LC3-II) in glycolytic but not oxidative muscles. Cognitive assessment using nesting behaviour showed deficits in Sil1wz mice at 14 weeks, assuming similarities with mental retardation shown by MSS patients. Our findings established a comprehensive timeline of disease progression in this MSS model and highlighted the differential vulnerability of glycolytic versus oxidative muscles and cerebellar regions. These insights pave the way for the development of therapeutic strategies for MSS and related cerebellar ataxias. AFG3L2-related neurologic disorders comprise four phenotypes. Spinocerebellar ataxia type 28 (SCA28), the most common phenotype, is characterized by young adult onset (26.5 ± 17.2 years); the onset range is from birth to 74 years of a cerebellar syndrome manifesting initially as very slowly progressive gait and limb ataxia resulting in incoordination and balance problems. Less frequently, ptosis/ophthalmoplegia, dysarthria, or upper-limb incoordination may occur as the initial finding. Pyramidal syndrome (increased and brisk reflexes, extensor plantar reflex, and spasticity) is commonly observed in individuals with longer disease duration. Although cognitive impairment, spasticity, and ophthalmologic signs can occur with disease progression, most individuals remain ambulatory and fully independent throughout their lives. Spastic ataxia type 5 (SPAX5), reported in 14 individuals to date, ranges from severe neurodegeneration with microcephaly, poor weight gain, developmental delay, developmental regression around age nine months, and death as early as age 2.5 years. Milder presentations range from onset in infancy to an early-onset complex cerebellar ataxia with myoclonic epilepsy. AFG3L2-related autosomal recessive spinocerebellar ataxia (AFG3L2-SCAR), reported in two individuals to date, is a late-onset ataxia with a clinical phenotype closely resembling that of SCA28. Optic atrophy type 12 (OPA12) manifests as decreased visual acuity (variable but frequently ranging from 0.2/10 to 2/10), photophobia, and impaired color vision. Ophthalmologic findings are optic nerve pallor and highly reduced retinal nerve fiber layer on optical coherence tomography. Although affected individuals do not present with ataxia, some may exhibit sensorineural hearing loss, neurodevelopmental disorders, dystonia, and spasticity. The diagnoses of SCA28 and OPA12 are established in a proband with suggestive findings and a heterozygous pathogenic variant in AFG3L2 identified by molecular genetic testing. The diagnoses of SPAX5 and AFG3L2-SCAR are established in a proband with suggestive findings and biallelic pathogenic variants in AFG3L2 identified by molecular genetic testing. Treatment of manifestations: Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields including neurologists (to address pharmacologic treatment of myoclonic epilepsy, spasticity, movement disorders); occupational therapists (to optimize activities of daily living and home safety); physiatrists and physical therapists (to help maintain independence and mobility); nutritionists and feeding therapy programs (to assess the risks of aspiration and need for gastrostomy tube placement for those with dysphagia); speech-language therapists (to address communication for individuals who have expressive language difficulties), ophthalmologists (to consider surgery for ptosis); low vision clinics (for those with optic atrophy); and social workers and psychologists (depending on any cognitive or psychologic manifestations). Surveillance: Routinely scheduled follow-up appointments with treating clinicians are recommended to monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations. Agents/circumstances to avoid: Alcohol consumption and sedatives such as benzodiazepines that may worsen gait ataxia and coordination. Carbamazepine and phenytoin may exacerbate myoclonus in SPAX5. SCA28 and OPA12 are inherited in an autosomal dominant manner. AFG3L2-SCAR and SPAX5 are inherited in an autosomal recessive manner. Autosomal dominant inheritance: Most individuals diagnosed with SCA28, and some individuals diagnosed with OPA12, have an affected parent. Some individuals diagnosed with an autosomal dominant AFG3L2-related neurologic disorder have the disorder as the result of a de novo pathogenic variant. Each child of an individual with an autosomal dominant AFG3L2-related neurologic disorder has a 50% risk of inheriting the pathogenic variant. If the reproductive partner of an individual with an autosomal dominant AFG3L2-related neurologic disorder also has an AFG3L2 pathogenic variant, offspring are at risk of inheriting biallelic pathogenic variants and having an autosomal recessive AFG3L2-related neurologic disorder. Once the AFG3L2 pathogenic variant has been identified in an affected family member, predictive testing for at-risk relatives and prenatal/preimplantation genetic testing are possible. Autosomal recessive inheritance: The parents of a child with an autosomal recessive AFG3L2-related neurologic disorder are presumed to be heterozygous for an AFG3L2 pathogenic variant. If both parents are known to be heterozygous for an AFG3L2 pathogenic variant, each sib of an affected individual has at conception a 25% chance of inheriting biallelic pathogenic variants and being affected, a 50% chance of being heterozygous, and a 25% chance of inheriting neither of the familial AFG3L2 pathogenic variants. Heterozygous family members of an individual with an autosomal recessive AFG3L2-related neurologic disorder are typically asymptomatic and the risk of developing an AFG3L2-related neurologic disorder appears to be low. Once the AFG3L2 pathogenic variants has been identified in an affected family member, carrier testing for at-risk relatives and prenatal/preimplantation genetic testing are possible.