Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of rare, neurodegenerative disorders. The most prominent HSP features: spastic paraparesis, mild somatosensory deficits and bladder dysfunction may be accompanied by additional symptoms i.e.: neuropathy, epilepsy, dementia. We aimed to determine subclinical involvement of nonmotor or sensory brain structures in hereditary spastic paraplegias type 3 A (SPG3A) and type 4 (SPG4). Visual evoked potentials (VEPs), brainstem evoked potentials (BAEPs) and electroencephalography (EEG) were performed in 28 SPG4 and 9 SPG3A patients. Disease severity was evaluated with Spastic Paraplegia Rating Scale. The EEG examination revealed abnormalities in 9 SPG4 patients (35%), while it was intact in SPG3A individuals. VEPs indicated mild abnormalities in 38% SPG3A patients: 127.3±7.8ms and 48% SPG4: 122.2±6.4ms. SPG4 patients with DNA microrearrangements in the SPAST gene had statistically significantly longer VEPs latencies (95%CI, 2.78–10.10) and lower amplitudes (95%CI, -5.65 – (-1.45)) than those with single nucleotide variants. BAEPs were distracted accidentally. It appears that visual tracts, which involve shorter axons than in motor-sensory pathways, are also involved in neurodegenerative processes in SPG3A and SPG4. Additionally, in SPG4 abnormal oscillations of neurons indicated by EEG may probably result from impaired axonal transport. The online version contains supplementary material available at 10.1186/s12883-025-04624-4. Our study shows that SPG3A and SPG4 phenotypes are often combined with subclinical nonmotor or sensory brain dysfunctions. The online version contains supplementary material available at 10.1186/s12883-025-04624-4.

Spastic Paraplegia Type 78 (SPG78) is a rare form of hereditary spastic paraplegia (HSP), mainly characterized by late-onset lower-limb spasticity, muscle weakness, and in some cases cerebellar dysfunction and cognitive impairment. Understanding its genetic background is essential to distinguish it from other autosomal recessive types of HSP. A pathogenic variant screening in a Spanish HSP patient was carried out by whole-exome sequencing, followed by a software filtering process and validation of candidate variants by Sanger sequencing. The pathogenicity of the selected variants was evaluated by In Silico predictions and a segregation analysis including the proband and 16 family members. Two variants in the ATP13A2 gene, predicted to have damaging effects by In Silico analyses, were considered potentially pathogenic: NM022089.4:c.649G>A (rs199961048), previously associated with SPG78 but with uncertain clinical significance, and NM_022089.4:c.2097delC, an unreported variant. The segregation analysis revealed that both variants were present in compound heterozygosity in the proband and two affected siblings, while unaffected relatives carried only one or none of the variants. These findings suggest that the two variants are pathogenic when occurring in compound heterozygosity and, therefore, should be included in the genetic spectrum of SPG78 diagnosis.

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 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.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and hereditary spastic paraplegia type 7 (SPG7) represent the most common genotypes of spastic ataxia (SPAX). To date, their magnetic resonance imaging (MRI) features have only been described qualitatively, and a pure neuroradiological differential diagnosis between these two conditions is difficult to achieve. To test the performance of MRI measures to discriminate between ARSACS and SPG7 (as an index of common SPAX disease). In this prospective multicenter study, 3D-T1-weighted images of 59 ARSACS (35.4 ± 10.3 years, M/F = 33/26) and 78 SPG7 (54.8 ± 10.3 years, M/F = 51/27) patients of the PROSPAX Consortium were analyzed, together with 30 controls (45.9 ± 16.9 years, M/F = 15/15). Different linear and surface measures were evaluated. A receiver operating characteristic analysis was performed, calculating area under the curve (AUC) and corresponding diagnostic accuracy parameters. The pons area proved to be the only metric increased exclusively in ARSACS patients (P = 0.02). Other different measures were reduced in ARSACS and SPG7 compared with controls (all with P ≤ 0.005). A cut-off value equal to 1.67 of the pons-to-superior vermis area ratio proved to have the highest AUC (0.98, diagnostic accuracy 93%, sensitivity 97%) in discriminating between ARSACS and SPG7. Evaluation of the pons-to-superior vermis area ratio can discriminate ARSACS from other SPAX patients, as exemplified here by SPG7. Hence, we hereby propose this ratio as the Magnetic Resonance Index for the Assessment and Recognition of patients harboring SACS mutations (MRI-ARSACS), a novel diagnostic tool able to identify ARSACS patients and useful for discriminating ARSACS from other SPAX patients undergoing MRI. © 2024 International Parkinson and Movement Disorder Society.