Hereditary spastic paraplegia (HSP) refers to a group of genetic neurodegenerative diseases marked by gradually worsening spasticity and hyperreflexia in the lower extremities. This study aimed to describe the clinical and genetic characteristics of Korean patients with spastic paraplegia. We retrospectively reviewed medical records of 69 patients with spastic paraplegia from 54 unrelated families between 2002 and 2024. Genetic, clinical, electrophysiological, and radiological features were comprehensively analyzed. Causative genes were identified in 34 (63%) of 54 unrelated families; SPAST, detected in 26 families, was the most prevalent. Seven novel pathogenic variants were identified. Clinically, the median age of symptom onset was 25 years [14.0-37.0]. Out of 69 patients with spastic paraplegia, 51 (74%) presented with the pure form of spastic paraplegia, which included all patients with SPG4. Spastic gait was a universal feature in all patients. Urinary dysfunction was present in 42 (61%) patients. Additional neurologic manifestations included peripheral neuropathy 9 (13%), cognitive impairment 5 (7%), upper limb weakness 4 (6%), dysarthria 4 (6%), dysphagia 3 (4%), ataxia 3 (4%), and scoliosis 1 (3%). Brain MRI findings demonstrated a thin corpus callosum in two patients with SPG11; all patients with SPG4 had normal findings. Spine MRI revealed spinal cord atrophy in 16 (27%) patients, including 6 (21%) patients with SPG4. The study comprehensively reviewed genetic and clinical spectra of spastic paraplegia in Korean patients, emphasizing the predominance of SPAST as the causative gene and underscoring the genetic and phenotypic heterogeneity of spastic paraplegia.

Neurodegenerative upper motor neuron (UMN) syndromes ranging from primary lateral sclerosis (PLS) to pure and complicated types of hereditary spastic paraplegia (HSP) remain challenging to differentiate clinically, especially in the early stages of disease. As they share the hallmark of spastic paraparesis, easily accessible biomarkers are warranted to facilitate an early diagnosis. We examined serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein (sGFAP) as diagnostic biomarkers to differentiate PLS from HSP, represented by two paradigmatic subtypes: SPG4, the most common type of pure HSP, and adrenomyeloneuropathy (AMN), a common complicated form of HSP. In addition to sNfL and sGFAP raw levels, we used age-adjusted z-scores to account for age-related biomarker level increases. In our cohort of 18 PLS patients, 18 AMN patients, 25 SPG4 patients and 60 controls, sNfL z-scores were higher in PLS than in SPG4 (p < 0.001), AMN (p = 0.03), and controls (p < 0.001). Furthermore, sNfL z-scores allowed distinguishing PLS from SPG4 (AUC 0.82, 95% CI 0.67-0.98) and-slightly less accurate-from AMN (AUC 0.77, 95% CI 0.60-0.95). sGFAP z-scores did not differ significantly between groups. Our study suggests that serum NfL, but not GFAP, is a potential diagnostic biomarker in degenerative UMN diseases and may help to differentiate PLS from pure and complicated forms of HSP. Our results indicate that axonal degeneration-the source of NfL release-is predominant over astrocytic pathology-the source of GFAP release-in PLS, AMN, and SPG4.

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.

Spastic paraplegia type 5 (SPG5) is a rare neurodegenerative disease diagnosed primarily through genetic testing.We identified a specific spinal cord sign on conventional MR imaging to help narrow the scope of genetic screening. In 25 patients with SPG5 and 21 healthy controls (HCs), the spinal cord cross sign was evaluated on T2*-weighted imaging. The morphological and signal characteristics of the dorsal column (DC), ventral funiculi (VF), dorsal horn (DH), ventral horn (VH), and intermediate zone (IMZ) were assessed. Differences in fractional anisotropy (FA) values within specific regions between HC and SPG5 were tested using Student's t-test. Spearman correlation was used to evaluate associations between cross-sign scores, FA values, and clinical indicators. The cross sign was detected in the cervical spinal cord of all SPG5 patients. The occurrence of T2 hyperintensity in the DC, VF and IMZ was 100%,100% and 88%,respectively. Bilateral VH morphology was normal in 14.4% of cases, blurred in 49.6%, and absent in 36%.Bilateral DH morphology was normal in 13.6%, blurred in 56%, and absent in 30.4%. FA values were reduced in these spinal cord regions. Cross-sign scores were negatively correlated with FA values in both grey (r = -0.70~-0.37) and white matter (r = -0.78~-0.70). Cross-sign scores were positively correlated with Spastic Paraplegia Rating Scale (r = 0.57) and disease duration (r = 0.42). The spinal cord cross sign was a potential imaging marker for SPG5. Cross-sign scores were associated with disease duration and severity in SPG5 patients. A Registered Cohort Study on Spastic Paraplegia,NCT04006418 Registered 1 July 2019, https://clinicaltrials.gov/study/NCT04006418 .

With targeted treatment trials on the horizon, identification of sensitive and valid outcome measures becomes a priority for >100 spastic ataxias. While digital-motor measures, assessed using wearable sensors, are considered prime outcome candidates for spastic ataxias, genotype-specific validation studies are lacking. We here aimed to identify candidate digital-motor outcomes for spastic paraplegia type 7 (SPG7)-one of the most common spastic ataxias-that (1) reflect patient-relevant health aspects, even in mild, trial-relevant disease stages; (2) are suitable for a multicenter setting; and (3) assess mobility also during uninstructed walking simulating real life. This cross-sectional multicenter study (7 centers, 6 countries) analyzed defined laboratory-based walking and uninstructed "supervised free walking" in patients with SPG7 and healthy controls using 3 wearable sensors (Opal APDM). For the extracted digital gait measures, we assessed effect sizes for the discrimination of patients and controls (Cliff δ) and Spearman correlations with measures of functional mobility and overall disease severity (Spastic Paraplegia Rating Scale [SPRS], including mobility subscore SPRSmobility; Scale for the Assessment and Rating of Ataxia [SARA]) and the activities of daily living subscore of the Friedreich Ataxia Rating Scale (FARS-ADL). Gait was analyzed in 65 patients with SPG7 and 50 healthy controls. Among 30 hypothesis-based gait measures, 18 demonstrated at least moderate effect size (δ > 0.5) in discriminating patients from controls and 17 even in mild disease stages (SPRSmobility ≤ 9, n = 41). Spatiotemporal variability measures such as spatial variability measure SPcmp (ρ = 0.67, p < 0.0001) and stride time CV (ρ = 0.67, p < 0.0001) showed the largest correlations with functional mobility (SPRSmobility)-as with overall disease severity (SPRS, SARA) and activities of daily living (FARS-ADL). The correlations of variability measures with SPRSmobility could be confirmed in mild disease stages (e.g., SPcmp: ρ = 0.50, p < 0.0001) and in "supervised free walking" (e.g., stride time CV: ρ = -0.57, p < 0.0001). We here identified trial-ready digital-motor candidate outcomes for the spastic ataxia SPG7 with proven multicenter applicability, ability to discriminate patients from controls, and correlation with measures of patient-relevant health aspects-even in mild disease stages. If validated longitudinally, these sensor outcomes might inform future natural history and treatment trials in SPG7 and other spastic ataxias.