BACKGROUND The most frequently mutated gene in hereditary spastic paraplegia (HSP) is SPAST. Only symptomatic treatment is available for this disease. Fampridine has been successfully used to treat gait disturbances in some patients with HSP. A positive effect of fampridine has not been previously reported in HSP4 caused by the c.683-2A>C variant in the SPAST gene. CASE REPORT We report the case of a 63-year-old woman with hypogeusia and hyposmia for several years, pollakiuria, gait disturbances, reduced walking speed, occasional dysphagia, constipation and delayed defecation, occasional memory problems, right-sided hearing loss, and exercise-induced myalgia and muscle cramps. Genetic testing revealed the c.683-2A>C variant in SPAST. Her 69-year-old sister also had pollakiuria since her youth, and since the age of 50 had frequent stumbling, unsteadiness, spasticity, and positional vertigo. At age 62, our patient began taking fampridine (4-aminopyridine) and has since experienced significant relief. Fampridine led to an improvement in spasticity, gait disorders, and walking speed, as documented by the 6-meter walk test, spastic paraplegia rating scale, and multidimensional self-esteem scale. CONCLUSIONS This case shows that HSP4 can progress slowly over a period of 7 years and can present with typical phenotypic characteristics of the disease as it progresses. The rate of progression can vary among affected family members, and people with HSP4 can still work even in old age and do not necessarily need antispastic drugs. This case also provides preliminary evidence that fampridine may be a viable symptomatic treatment option for patients with HSP4, including those with the mutation c.683-2A>C. It justifies further prospective, controlled studies in a larger SPAST-HSP population.

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.

Autosomal dominant spastic paraplegia type 4 (SPG4, SPAST gene) is commonly described as a pure phenotype, with progressive spastic weakness of the lower limbs. Some cognitive disorders have been reported but remain difficult to characterize. Brain flurodesoxyglucose (18F-FDG) PET is a sensitive biomarker of glycolytic metabolism and shows loss of neuronal activity. Our objective was to describe the cognitive impairment of SPG4 patients, supported by brain 18F-FDG PET, to characterize the cognitive pattern and its localization. Twenty subjects from the Grand Est region, with a pathogenic variant in the SPAST gene, were included. Each patient had to undergo a neuropsychological assessment, a brain 18F-FDG PET scan, and a SPATAX-EuroSpa clinical assessment, including the Spastic Paraplegia Rating Scale (SPRS). Brain 18F-FDG PET was analyzed semiquantitatively after comparison with age and sex-matched control subjects. The study population was 65% (13/20) female, with an average age of 50 years (19-75 years). The median SPRS was 15/52 (12-45). Forty-six percent (7/15) of patients had a deficient Montreal Cognitive Assessment (MoCA) score (score <26) without any severe impairment (score <10). Assessments with a pathological score of <1.65 standard deviations or at the 5th percentile included verbal episodic memory in 16-item Free and Cued Recall Test (16-FCRT; 63%, 10/16), facial emotion recognition (56%, 9/16), and executive functions (Trail Making Test A and B; 47%, 7/15; the Stroop; 47%, 7/15; digit span of Weschler Adult Intelligence Scale 4; 38%, 6/16). Compared with those of control subjects, 18-FDG PET images of the brains of SPG4 subjects revealed frontotemporal and precuneus hypometabolism, principally in the prefrontal cortex, which was mainly mesial (P voxel value <0.001, corrected for the size of the familywise error (FWE) cluster, k = 1464). Frontal hypometabolism was correlated with age at onset (k = -0.475, P = 0.046) and the time to perform the Trail Making Test B test (k = -0.597, P = 0.019). Here, we describe a mild cognitive disorder clinically in SPG4 patients, associated with an hypometabolism on 18F-FDG PET imaging, which mainly corresponded to frontotemporal localization. Mild cognitive dysfunction should be screened in SPG4, as it can have a significant impact on socioprofessional life. Brain 18F-FDG PET, combined with neuropsychological assessment appears to be a good screening and follow-up examination for cognitive disorders.

患儿，男，7岁8月龄，因“步态异常4年余”就诊，患儿1岁前运动发育同正常同龄儿，1岁2月龄会独站，1岁6月龄独走，走路不稳，容易摔倒。3岁起逐渐出现双下肢运动功能倒退，走路踮脚，摇摆步态，呈缓慢加重。体格检查示双下肢肌力4级，肌张力增高，伴共济失调体征，深腱反射减弱，锥体束征阳性。头颅磁共振成像显示双侧侧脑室后角旁及双侧内囊后肢T2加权像及液体衰减反转恢复序列高信号。肌电图示下运动单位病变。基因检测示ENTPD1基因纯合变异c.523G>C。患儿确诊常染色体隐性遗传性痉挛性截瘫64型。.

With treatment trials on the horizon, this study aimed to identify candidate digital-motor gait outcomes for autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), capturable by wearable sensors with multicenter validity, and ideally also ecological validity during free walking outside laboratory settings. Cross-sectional multicenter study (four centers), with gait assessments in 36 subjects (18 ARSACS patients; 18 controls) using three body-worn sensors (Opal, APDM) in laboratory settings and free walking in public spaces. Sensor gait measures were analyzed for discriminative validity from controls, and for convergent (ie, clinical and patient relevance) validity by correlations with SPRSmobility (primary outcome) and Scale for the Assessment and Rating of Ataxia (SARA), Spastic Paraplegia Rating Scale (SPRS), and activities of daily living subscore of the Friedreich Ataxia Rating Scale (FARS-ADL) (exploratory outcomes). Of 30 hypothesis-based digital gait measures, 14 measures discriminated ARSACS patients from controls with large effect sizes (|Cliff's δ| > 0.8) in laboratory settings, with strongest discrimination by measures of spatiotemporal variability Lateral Step Deviation (δ = 0.98), SPcmp (δ = 0.94), and Swing CV (δ = 0.93). Large correlations with the SPRSmobility were observed for Swing CV (Spearman's ρ = 0.84), Speed (ρ = -0.63), and Harmonic Ratio V (ρ = -0.62). During supervised free walking in a public space, 11/30 gait measures discriminated ARSACS from controls with large effect sizes. Large correlations with SPRSmobility were here observed for Swing CV (ρ = 0.78) and Speed (ρ = -0.69), without reductions in effect sizes compared with laboratory settings. We identified a promising set of digital-motor candidate gait outcomes for ARSACS, applicable in multicenter settings, correlating with patient-relevant health aspects, and with high validity also outside laboratory settings, thus simulating real-life walking with higher ecological validity. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.