Mutations in the transglutaminase 6 gene (TGM6) are associated with spinocerebellar ataxia type 35 (SCA35), and cases have been reported across diverse ethnic groups. We report the first documented case of SCA35 in Saudi Arabia, together with a focused literature review. A 35-year-old Saudi man presented to a neurology clinic with severe gait instability following nonspecific symptoms, including unintentional weight loss, dysphagia, abdominal pain, and intermittent diplopia. No family history of ataxia or similar neurological disease was noted. The condition progressed with neuropsychiatric manifestations (adjustment disorder, generalized myalgia, fibromyalgia) and upper motor neuron and extrapyramidal signs. He was admitted for further evaluation. A comprehensive diagnostic work-up, including cerebrospinal fluid studies, multiplex polymerase chain reaction, and nerve conduction studies, ruled out celiac disease, Wilson's disease, and demyelinating diseases. Brain and full-spine magnetic resonance imaging showed no cerebellar atrophy or spinal cord abnormalities. Whole-exome sequencing identified a heterozygous splice-site mutation in TGM6 (c.850 + 1G > A), consistent with autosomal dominant SCA35. To our knowledge, this is the first reported case of SCA35 in the Middle East. This case underscores the challenges in diagnosing this condition, as patients may present with atypical features, such as dysphagia. Our findings enhance the current understanding of the epidemiology, clinical manifestations, and genetic landscape of SCA35 to improve the diagnosis and management of this rare disorder.

The gold standard for classification of neurodegenerative diseases is postmortem histopathology; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia-ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann-Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new heterozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.

To investigate whether TGM6 is a specific causative gene for spinocerebellar ataxia type 35 (SCA35). The next-generation sequencing (NGS) data consisted of 47 SCA, 762 non-SCA patients and 2827 normal controls were analyzed. The allele frequencies of low frequent and deleterious TGM6 variants were compared. Functional studies were performed in five widely distributed variants (V314M, R342Q, P347L, V391M, L517W). Two TGM6 detrimental variants were identified in one SCA patient, 14 in non-SCA patients and 43 in normal controls, the allele frequencies of TGM6 variants did not differ among the SCA and other controls. Seven reported pathogenic variants (c.7 + 1G > T, c.331C > T, c.1171G > A, c.1478C > T, c.1528G > C, c.1550 T > G and c.1722_1724delAGA) were identified in patients with various neurologic diseases or normal controls. All the 5 widely distributed variants led to destabilization and significantly reduction of enzymatic activity of TG6 as the reported pathogenic mutations. TGM6 might not be a specific causative gene for SCA35, the relevant clinical consult or diagnostic should be pay more attention.