Abstract
BACKGROUND AND OBJECTIVES: Hereditary cerebellar ataxia (HCA) and hereditary spastic paraplegia (HSP) are rare neurologic disorders that often represent opposite ends of a shared clinical spectrum. Spastic ataxia, defined by the co-occurrence of cerebellar syndrome and overt spasticity, remains comparatively underexplored and is associated with relatively few genetic causes. The aim of this study was to characterize the clinical and genetic features of spastic ataxia in a large HCA cohort and compare them with those of nonspastic HCA. METHODS: A prospective HCA cohort was initiated in 2017, incorporating annual assessments following a structured and standardized protocol. Spastic ataxia was defined as ataxia occurring in conjunction with spasticity grade ≥2 on the Modified Ashworth Scale. Patients meeting this criterion were identified; their clinical and genetic data were analyzed and compared with those of patients with nonspastic forms of HCA. The Movement Disorder Society's nomenclature for genetic disorders was adopted, using dual-prefix notation for combined phenotypes (e.g., HSP/ATX for spastic ataxia), except for entities such as MJD/SCA3 or ARSACS, which are more readily recognized by their original designations. RESULTS: Of 249 patients assessed (164 families), 56 (22.5%; from 46 families) exhibited a spastic ataxia phenotype. Compared with nonspastic HCA, these patients had earlier onset and longer disease duration. Spastic ataxia was significantly associated with autosomal recessive inheritance and conventional (nonrepeat expansion) variants. Thirty-eight probands (80.8%) had a definite genetic diagnosis, involving 22 causal genes. The most frequent diagnoses were ARSACS (17.4%), ATX-SYNE1 (6.5%), ATX-ANO10, HSP/ATX-KIF1C, HSP/ATX-PGN, HSP-ZFYVE26, MxMD-ATP13A2, and ATX/HSP-KCNA2 (4.3% each). A noncerebellar presentation was observed in 30 patients with spastic ataxia (53.6%) while 26 (46.6%) had cerebellar onset. After adjustment for disease duration, patients with spastic ataxia had significantly higher baseline scores on the Scale for the Assessment and Rating of Ataxia, reflecting a greater disease burden. In addition, falls were more frequent in this group. DISCUSSION: Spastic ataxia represented a clinically and genetically distinct subgroup within HCA, marked by recessive inheritance, large genetic heterogeneity, and more severe motor impairment. Greater awareness of its heterogeneous presentations and progressive disability over time is crucial for timely diagnosis, genetic counseling, and development of tailored management strategies for these patients.