To explore the genetic basis for a Chinese pedigree affected with Hereditary spastic paraplegia type 3A (SPG3A) and the genotype-phenotype correlation. A three-generation pedigree presented at Huantai Maternal and Child Health Care Hospital in March 2021 was selected as the study subject. Whole-exome sequencing (WES) and pedigree analysis was carried out. Candidate variant was validated by Sanger sequencing of the members from the pedigree. Haplotype analysis was used to trace the origin of the variant, and pathogenicity was rated based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). This study was approved by the Medical Ethics Committee of the Hospital (Ethics No.: 2025-12). A c.1024C>T (p.Pro342Ser) variant of the ATL1 was identified in the four affected members, including the proband, but none of the three unaffected relatives. Haplotype analysis suggested that the variant was derived from the proband's mother and has co-segregated with the disease phenotype. Based on the guidelines of the ACMG, it was classified as likely pathogenic. The ATL1 c.1024C>T (p.Pro342Ser) variant probably underlay the pathogenesis in this pedigree. Above finding has enriched the mutational spectrum of ATL1 and phenotypic spectrum of SPG3A in the Chinese population, and enabled genetic counseling for this pedigree.

Current clinical scales that track disease progression are more tailored to spasticity or ataxia, with limited sensitivity to change. The aim was to develop a sensitive and valid scale specifically geared towards optimized sensitivity to change and adapted to patients presenting with both spasticity and ataxia. Longitudinal data from 127 spastic paraplegia type 7 (SPG7) and 112 autosomal recessive spastic ataxia Charlevoix-Saguenay (ARSACS) patients were collected within the multicenter PROSPAX study. Sensitivity to change over 2 years of 30 items from the Scale for the Rating and Assessment of Ataxias (SARA), Spastic Paraplegia Rating Scale (SPRS), and the Activities of Daily Living subscale of the Friedreich's Ataxia Rating Scale (FARS-ADL) was evaluated. Items that demonstrated the highest sensitivity to change were used to build the Spastic Ataxia Composite scale (SPAXCOM). With seven items, the SPAXCOM showed an effect size of 0.71, higher than reference scales (SARA: 0.43, SPRS: 0.42, FARS-ADL: 0.27). The SPAXCOM had a similar sensitivity to change for both genotypes and was more sensitive in participants with a SARA lower than 10 and within the intermediate disease stage (FARS-Disease Staging: 2-3.5). The SPAXCOM showed a high correlation with disease duration (r = 0.67 [0.60; 0.72]) and disease stage (r = 0.86 [0.83; 0.89]). Perception of improvement, stagnation, and worsening were associated with a mean yearly SPAXCOM change of 0.44 (-0.14; 1.01), 0.61 (0.19; 1.03), and 1.22 (0.96; 1.49), respectively. The SPAXCOM is more sensitive to change and homogeneous across genotypes than the reference scales, allowing a reduction of the required sample size in future clinical trials. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

An increasing number of cases of comorbid hereditary spastic paraplegia (HSP) and multiple sclerosis (MS) have been described. We report a patient with the SPG3A form of HSP and features of relapsing-remitting MS (RRMS). We took this opportunity to review the current literature of co-occurring MS and HSP. The patient underwent clinical, laboratory and neuroimaging evaluations. We performed a literature search for cases of HSP and MS. The 2017 McDonalds Criteria for MS were retrospectively applied to the selected cases. A 34-year-old woman, presenting a molecular diagnosis of SPG3A, complained subacute sensory-motor symptoms. Spinal MRI disclosed T2-hyperintense lesions at C2, T6 and T4 level, the latter presenting contrast-enhancement. CSF analysis showed oligoclonal bands. She was treated with intravenous high-dose steroids, with symptom resolution. The literature review yielded 13 papers reporting 20 possible cases of MS and HSP. Nine patients (5 M, median age 34) met the 2017 McDonald criteria. Five (25%) received a diagnosis of RRMS and four (20%) of primary progressive MS. Brain MRI showed multiple WM lesions, mostly periventricular. Six of seven cases (85.7%) had spinal cord involvement. Oligoclonal bands were found in 6/8 (75%) patients. Seven patients (77.7%) improved/stabilized on immunotherapy. This is the first description on the association between SPG3A type of HSP and MS. This report adds to the other reported cases of co-occurring HSPs and MS. Although it remains unclear if this association is casual or causal, clinicians should be aware that an HSP diagnosis does not always exclude a concomitant MS.

Spastic paraplegia type 11 (SPG11) is the most frequent autosomal recessive HSP. Studies on SPG11 patients' fibroblasts, post-mortem brains, and mouse models revealed endolysosomal system dysfunction and lipid accumulation, especially gangliosides. We report a patient with early clinical findings mimicking a GM2-gangliosidosis. A clinical, biochemical, and metabolic characterization was performed. Electron microscopy analysis was completed on rectal mucosa and skin biopsy specimens. A NGS panel of genes associated to neuronal ceroid lipofuscinosis and HSP was analyzed. The patient presented with worsening walking difficulty and psychomotor slowdown since childhood; to exclude a neurometabolic storage disease, skin and rectal biopsies were performed: enteric neurons showed lipofuscin-like intracellular inclusions, thus suggesting a possible GM2-gangliosidosis. However, further analysis did not allow to confirm such hypothesis. In adulthood we detected flaccid paraplegia, nystagmus, axonal motor neuropathy, carpus callosum atrophy, and colon atony. Surprisingly, the NGS panel detected two already reported SPG11 mutations in compound heterozygosity. We describe for the first time pathological hallmarks of SPG11 in enteric neuron from a rectal mucosa biopsy. The report illustrates the possible overlap between SPG11 and GM2-gangliosidosis, especially in the first disease phases and helps to improve our knowledge about SPG11 physiopathology.

In spastic paraplegia type 5, spinal cord atrophy and white matter signal abnormalities in the brain are the main MR imaging alterations. However, the specific mechanism remains unclear. We explored the microstructural changes occurring in spastic paraplegia type 5 and assessed the relation between MR imaging and clinical data. Seventeen patients with spastic paraplegia type 5 and 17 healthy controls were scanned with DTI and T1 mapping on a 3T MR imaging scanner. Fractional anisotropy, mean diffusivity, radial diffusivity, axial diffusivity, and T1 values were obtained using Tract-Based Spatial Statistics and the Spinal Cord Toolbox. Neurofilament light and myelin basic protein in the CSF were measured. The differences in MR imaging and biochemical data between patients with spastic paraplegia type 5 and healthy controls were compared using the Student t test. A widespread reduction of fractional anisotropy values and an elevation of mean diffusivity, T1, and radial diffusivity values were found in most cervical, T4, and T5 spinal cords; corona radiata; optic radiations; and internal capsules in spastic paraplegia type 5. A variation in axial diffusivity values was shown only in C2, C6, and the corona radiata but not in the gray matter. The levels of neurofilament light and myelin basic protein were higher in those with spastic paraplegia type 5 than in healthy controls (myelin basic protein, 3507 [SD, 2291] versus 127 [SD, 219]  pg/mL; neurofilament light, 617 [SD, 207] versus 265 [SD, 187]  pg/mL; P < .001). No correlation was found between the clinical data and MR imaging-derived measures. Multiparametric MR imaging and biochemical indicators demonstrated that demyelination (mainly) and axonal loss led to the white matter integrity loss without gray matter injury in spastic paraplegia type 5.