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.

Pathogenic variants of IBA57 (OMIM ID: 615330) are usually associated with multiple mitochondrial dysfunction syndrome (MMDS) and hereditary spastic paraplegia type 74 (SPG74). Here, we present a novel compound heterozygous IBA57 mutation in a boy with severe global developmental delay, optic atrophy, spastic paraplegia, and focal epileptic seizures. The clinical data of a child diagnosed with MMDS were retrospectively collected. Video electroencephalogram (VEEG), cranial magnetic resonance imaging (MRI), and family whole-exome sequencing (WES) were performed. Suspected mutation sites were further confirmed using Sanger sequencing. The activities of mitochondrial respiratory chain complexes I-IV were determined in peripheral blood mononuclear cells. The phylogenetic conservation of the affected residues was assessed by multiple sequence alignment of IBA57 gene orthologs. Furthermore, we conducted a review of the relevant literature. Whole-exome sequencing identified compound heterozygous variants in the IBA57 gene: c.395_400dup (p.V132_Q133dup) and c.832delC (p.R278Afs*23), inherited from his phenotypically normal father and mother, respectively. Biochemical assays demonstrated selective reduction of complexes I and II activities, with normal complexes III and IV, consistent with impaired 4Fe-4S cluster maturation. Phylogenetic alignment revealed strict conservation of residues V132-Q133 and R278 across vertebrates. These variants had not been previously reported in domestic or international databases. According to the American College of Medical Genetics and Genomics (ACMG) guidelines, the former was classified as a variant of uncertain significance (PM4 + PM2), while the latter was classified as likely pathogenic (PVS1 + PM2). Diseases associated with IBA57 gene variants are autosomal recessive disorders with a broad clinical phenotypic spectrum. Early genetic testing and family screening are beneficial for the diagnosis, treatment, and prognosis of the disease.

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.

Spinocerebellar ataxia 27B (SCA27B) is a common autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. Neuropathological studies have shown that neuronal loss is largely restricted to the cerebellum. Although the repeat locus is highly unstable during intergenerational transmission, it remains unknown whether it exhibits cerebral mosaicism and progressive instability throughout life. We conducted an analysis of the FGF14 GAA•TTC repeat somatic instability across 156 serial blood samples from 69 individuals, fibroblasts, induced pluripotent stem cells and post-mortem brain tissues from six controls and six patients with SCA27B, alongside methylation profiling using targeted long-read sequencing. Peripheral tissues exhibited minimal somatic instability, which did not significantly change over periods of more than 20 years. In post-mortem brains, the GAA•TTC repeat was remarkably stable across all regions, except in the cerebellar hemispheres and vermis. The levels of somatic expansion in the cerebellar hemispheres and vermis were, on average, 3.15 and 2.72 times greater relative to other examined brain regions, respectively. Additionally, levels of somatic expansion in the brain increased with repeat length and tissue expression of FGF14. We found no significant difference in methylation of wild-type and expanded FGF14 alleles in post-mortem cerebellar hemispheres between patients and controls. In conclusion, our study revealed that the FGF14 GAA•TTC repeat exhibits a cerebellar-specific expansion bias, which may explain the pure cerebellar involvement in SCA27B.

Autosomal recessive hereditary spastic paraplegia with thinning of the corpus callosum is a complex hereditary spastic paraplegia. Spastic paraplegia type 11 (SPG11) mutation is the most frequent form of autosomal recessive hereditary spastic paraplegia with thinning of the corpus callosum. The study of SPG11 in China is small scale, and only a few gene mutations have been reported. We report the case of a family with autosomal recessive hereditary spastic paraplegia with thinning of the corpus callosum. We describe a 20-year-old Han female patient with spastic gait and cognitive impairment 2 years ago, whose brain imaging revealed a thinning corpus callosum. Her 14-year-old Han brother had only a spasmodic gait. Detailed history, physical examination, and supplementary examination were performed to rule out the cause of spastic paraplegia. To identify pathogenic mutations, we used target sequence capture sequencing technology to detect hereditary-spastic-paraplegia-related genes in family members in combination with Sanger sequencing. We found two new complex heterozygous mutations in SPG11: c.6738_6739insT and c.5934_5935insTAACCTGGAA. The Glu2247 amino acid codon was changed to a stop codon (p.Glu2247Ter), and the Val1979 amino acid was also changed to a stop codon (p. Val1979Ter). Bioinformatics analysis predicted that these mutations would result in a loss of protein function. In silico analysis of the mutant sequences was performed. We found two novel complex heterozygous mutations, c.6738_6739insT and c.5934_5935insTAACCTGGAA, which enriched the phenotypic spectrum of SPG11 mutations related to hereditary spastic paraplegia and may help to determine the molecular mechanism of hereditary spastic paraplegia with thinning of the corpus callosum.