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.

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.

Mutations of the alsin protein have been linked to infantile-onset ascending hereditary spastic paraplegia (IAHSP), a rare neurodegenerative disease. More precisely, the pathological R1611W mutation has been identified in the Vacuolar Protein Sorting 9 (VPS9) domain, which acts as a guanine nucleotide exchange factor (GEF) for Rab5. This mutation results in the expression of tryptophan instead of arginine that alters the oligomeric state of alsin and its GEF functions. Insights into the conformational structure of the wild-type or mutant VPS9 domain may help elucidate the mechanisms involved in the onset of the disease. In this study, we combined in vitro and in silico approaches to elucidate the structure and understand the effects of the R1611W mutation on the isolated VPS9 domain of alsin. This mutation induces conformational changes that alter the local structure of the protein and its ability to oligomerize. This study lays the groundwork for understanding how R1611W alters the VPS9 domain function.

Autosomal recessive spastic paraplegia type 35 (SPG35), associated with the FA2H gene, is characterized by onset in childhood (usually at 3-5 years) and a «complicated» phenotype: signs associated with spastic paraparesis and MRI changes. We describe a very rare case of late-onset SPG35 with differences in sisters aged 47 and 45 in a non-inbred Russian family. Spastic paraparesis in the older sister manifested at the age of 40 and in the younger sister-at the age of 25; cognitive-personal disorders manifested at the age of 42 and 40, respectively, and rapidly progressed; both developed dysarthria. MRI in both sisters showed periventricular leukopathy (more pronounced in the older one), atrophic changes in the cortex and cerebellum (more pronounced in the younger one) and hypointensity in the area of pale globes, and thinning of the corpus callosum (only in the younger sister). Whole genome sequencing (WGS) followed by family Sanger sequencing for the sisters showed the previously described missense variants c.232G>A, p.Glu78Lys and c.137G>A, p.Gly46Asp in the FA2H gene in a compound-heterozygous state; the mother had a heterozygous variant of p.Glu78Lys (the father died, there are no other siblings). This article is a literature review on the late-onset SPG35. Аутосомно-рецессивная спастическая параплегия 35-го типа (SPG35), связанная с геном FA2H, характеризуется началом в детстве (чаще в 3—5 лет) и «осложненным» фенотипом: признаками, сопутствующими спастическому парапарезу, в частности, изменениями на МРТ. Описан очень редкий случай поздней SPG35 с различиями у сестер 47 и 45 лет в неинбредной русской семье. Спастический парапарез у старшей сестры манифестировал в 40 лет, у младшей — в 25 лет, когнитивно-личностные расстройства — в 42 года и 40 лет соответственно и быстро прогрессировали; у обеих развилась дизартрия. При МРТ у обеих сестер выявлены перивентрикулярная лейкопатия (больше выраженная у старшей), атрофические изменения коры и мозжечка (больше у младшей) и гипоинтенсивность в области бледных шаров, только у младшей сестры — истончение мозолистого тела. При полногеномном секвенировании WGS с последующим семейным секвенированием по Сэнгеру в гене FA2H у сестер найдены ранее описанные миссенс-варианты c.232G>A, p.Glu78Lys и c.137G>A, p.Gly46Asp в компаунд-гетерозиготном состоянии, у матери — гетерозиготный вариант p.Glu78Lys (отец умер, других сибсов нет). Представлен обзор литературы о поздней SPG35.

Hereditary spastic paraparesis (HSP) is a group of central nervous system diseases primarily affecting the spinal upper motor neurons, with different inheritance patterns and phenotypes. SPG18 is a rare, early-onset, complicated HSP, first reported as linked to biallelic ERLIN2 mutations. Recent cases of late-onset, pure HSP with monoallelic ERLIN2 variants prompt inquiries into the zygosity of such genetic conditions. The observed relationship between phenotype and mode of inheritance suggests a potential dominant negative effect of mutated ERLIN2 protein, potentially resulting in a milder phenotype. This speculation suggests that a wider range of HSP genes could be linked to various inheritance patterns. With documented cases of HSP loci exhibiting both dominant and recessive patterns, this study emphasizes that the concept of zygosity is no longer a limiting factor in the establishment of molecular diagnoses for HSP. Recent cases have demonstrated phenoconversion in SPG18, from HSP to an amyotrophic lateral sclerosis (ALS)-like syndrome. This report highlights two cases out of five exhibiting HSP-ALS phenoconversion, discussing an observed prevalence in autosomal dominant SPG18. Additionally, the study emphasizes the relatively high incidence of the c.502G>A variant in monoallelic SPG18 cases. This mutation appears to be particularly common in cases of HSPALS phenoconversion, indicating its potential role as a hotspot for a distinctive SPG18 phenotype with an ALS-like syndrome. Clinicians need to be aware that patients with HSP may show ALS signs and symptoms. On the other hand, HSP panels must be included in genetic testing methods for instances of familial ALS.