Search Results (112)

We present a family of five siblings who came to our attention with a clinical and radiological diagnosis of familial hypomyelinating leukodystrophy. Despite brain white matter abnormalities being present in all siblings, the clinical phenotype was variable: the three brothers presented with a clear-cut late-onset spastic paraplegia, whereas the two sisters displayed only mild pyramidal signs. Molecular analysis revealed a single relevant variant shared by all affected siblings, namely the likely pathogenic variant c.659C>T (p.Ser220Phe) in the GJA1 gene. Variants in this gene are generally associated with oculodentodigital dysplasia (ODDD), an autosomal dominant condition characterized by distinctive facial features and anomalies of the eyes, teeth, and digits. Neurological features are reported in about 30% of cases. In this family, ODDD manifested as a predominantly neurological phenotype. Although a clear explanation for this uncommon presentation is lacking, shared genetic modifiers, the effect of the specific variant, and a possible patient-population bias may have contributed. This case highlights the wide phenotypic spectrum of CX43-related disorders and suggests the importance of testing the GJA1 gene in individuals with atypical presentations, including predominant or isolated neurological phenotypes such as late-onset spastic paraplegia. MRI findings may also provide a useful diagnostic clue when ODDD is suspected. Full article

Oligodendrocytes (OLs) are the myelinating cells of the central nervous system (CNS). The PLP1 gene, predominantly expressed in OLs, encodes proteolipid protein (PLP), a major structural component of CNS myelin that also regulates oligodendrocyte precursor cell (OPC) proliferation, differentiation, and maturation. Pelizaeus–Merzbacher disease (PMD) is a rare X-linked leukodystrophy caused by PLP1 mutations and characterized by defective myelination. Clinical manifestations range from severe connatal PMD to classic PMD and the milder spastic paraplegia type 2 (SPG2), reflecting substantial phenotypic heterogeneity. Beyond disrupting myelin structure, PLP1 mutations impair oligodendrocyte development and function. Increasing evidence indicates that PMD is fundamentally a proteostasis disorder, in which misfolded PLP accumulates within the endoplasmic reticulum (ER), overwhelms ER quality control mechanisms, and triggers chronic unfolded protein response (UPR) activation. Persistent ER stress and maladaptive UPR signaling ultimately promote oligodendrocyte dysfunction and degeneration. Using PMD as a representative model, this review summarizes the relationships between PLP1 mutations and disease phenotypes and discusses the cellular mechanisms by which ER stress and UPR signaling contribute to oligodendrocyte pathology. Full article

Mitofusin-2 (MFN2) variants are a well-established cause of Charcot–Marie–Tooth disease type 2A, although central nervous system involvement has increasingly been recognized in a subset of affected patients. We report a 51-year-old woman carrying a likely pathogenic MFN2 variant (c.2119C>T, p.Arg707Trp) who developed rapidly progressive spastic paraplegia and became wheelchair-dependent within several months. Neurological examination demonstrated severe pyramidal tract signs with preserved sensory function. Nerve conduction studies were suggestive of distal motor axonal involvement, while transcranial magnetic stimulation and somatosensory evoked potentials indicated corticospinal and central sensory pathway dysfunction in the lower extremities. Brain magnetic resonance imaging revealed extensive bilateral confluent periventricular and deep white matter hyperintensities. Comprehensive investigations excluded inflammatory, vascular, metabolic, infectious, neoplastic, and common genetic causes of hereditary spastic paraplegia. Targeted next-generation sequencing identified a heterozygous likely pathogenic MFN2 p.Arg707Trp variant. Although central nervous system manifestations have previously been described in MFN2-related disease, this phenotype is unusual because of the combination of late-onset rapidly progressive spastic paraplegia, and extensive cerebral white matter abnormalities associated with the p.Arg707Trp variant. This case further expands the recognized phenotypic spectrum of MFN2-related disease and highlights that MFN2 variants should be considered in the differential diagnosis of selected patients with late-onset progressive spastic paraplegia accompanied by cerebral white matter abnormalities and distal motor axonal neuropathy. Full article

Background: Spinal cord injury (SCI) patients face many difficulties in life, affecting their quality of life. This study evaluated the health-related quality of life (HRQoL) of patients with spinal cord injury in Saudi Arabia and additionally identified the key determinants associated with lower scores. Methods: This cross-sectional study recruited 50 SCI patients from an outpatient clinic of a tertiary care rehabilitation center during the last quarter of 2024. The WHOQOL-BREF questionnaire was used to assess the HRQoL across overall, physical, psychological, social, and environmental domains. The scale of scores was transformed to 0–100 using the formula. Descriptive statistics were used to present categorical variables in terms of frequencies and percentages, and continuous data as means and standard deviations. Inferential statistics were used to determine the relationship between the various dependent and independent variables. Results: Of the total sample of 50 SCI patients, 84% were caused by motor vehicle accidents, and 74% were at the paraplegia level. The mean age was 35 ± 10.46 years, the average time since the injury was 6.3 ± 6.0 years, and the mean number of admissions of the study patients was 3.2 ± 1.6. The overall HRQoL score was 75.5 ± 24.5, and the general health score was 66.5 ± 31.0. Among all the WHOQOL-BREF domains, the psychological domain achieved the highest score (71.7 ± 17.5), while the physical health domain scored the lowest (55.9 ± 18.8). Presence of neuropathic pain was significantly associated with lower scores across overall quality of life (p = 0.033), physical health (p = 0.022), and psychological health (p = 0.044). A notable correlation was identified between poor environmental health and the presence of spasticity (p = 0.042). Depression was significant (p = 0.047) in patients with low physical health scores. Conclusion: Neuropathic pain, spasticity, and depressive symptoms were the strongest determinants of lower HRQoL, indicating the importance of targeted multidisciplinary management. Full article

Background: Spasticity is a common and disabling feature of several neuromotor disorders. Repetitive transcranial magnetic stimulation (rTMS) has been proposed as a non-invasive approach to modulate corticospinal excitability and reduce spasticity, although its clinical effectiveness remains debated. This systematic review evaluated the efficacy and safety of rTMS in reducing spasticity in stroke and other neuromotor conditions. Methods: A systematic search of PubMed, Scopus, and Cochrane Library was conducted up to June 2025 in accordance with PRISMA 2020 guidelines. Eligible studies were randomized controlled trials (RCTs) comparing rTMS with sham stimulation or conventional therapy and assessing spasticity using validated scales, primarily the Modified Ashworth Scale. Included populations comprised patients with stroke, spinal cord injury, multiple sclerosis, cerebral palsy, and hereditary spastic paraplegia. Risk of bias was assessed using the RoB 2.0 tool, and certainty of evidence was evaluated with GRADE. Results: Twenty-six RCTs were included, mainly involving stroke patients. Most studies reported a significant reduction in spasticity with rTMS compared with control interventions. Low-frequency stimulation was commonly used after stroke, while excitatory protocols predominated in other conditions. Benefits generally persisted for up to 12 weeks. Evidence quality was moderate, and no serious adverse events were reported. Conclusions: rTMS appears to be a safe and promising adjunctive treatment for spasticity across neuromotor disorders. However, protocol heterogeneity and small sample sizes limit definitive clinical recommendations, highlighting the need for standardized, larger-scale studies. Full article

Customized foot orthoses are widely used to manage plantar pressure and improve structural support in children with hereditary spastic paraparesis. However, the combined biomechanical effects of insole design parameters remain insufficiently quantified. This study employed a patient-specific three-dimensional finite element model to evaluate the influence of four design factors (arch height, heel cup depth, insole thickness, and material type, namely ethylene-vinyl acetate [EVA], thermoplastic polyurethane [TPU], and rubber) on four biomechanical metrics: plantar pressure distribution, von Mises stress, strain, and total deformation. Nine orthotic configurations, defined by a Taguchi L9 orthogonal array, were simulated under a vertical ground reaction force equal to 1.1× body weight. The configuration with an arch height of 42 mm, heel cup depth of 20 mm, thickness of 10 mm, and EVA material achieved the lowest peak plantar pressure (0.087 MPa). Arch height was the dominant factor for plantar pressure (79.4% of variance), deformation (68.1%), and strain (48.2%), while heel cup depth was most influential for stress (40.2%). Material type contributed minimally to plantar pressure and deformation but had a greater effect on stress (11.6%) and strain (15.0%). Thickness played a secondary role, particularly in deformation (19.9%) and strain (22.3%). These findings demonstrate the feasibility of using finite element modeling combined with the Taguchi method to systematically evaluate and optimize orthotic design parameters. Specifically, the study demonstrates that optimized personalized insoles can substantially reduce peak plantar pressure and improve load distribution in a pediatric patient with HSP, pes planovalgus, and flexed-knee gait, providing a potentially effective noninvasive intervention to prevent secondary complications and improve gait mechanics. Full article

Objectives: Alexander disease (AxD) is a rare neurodegenerative disorder that represents a group of leukodystrophies with severe disability and premature death, mostly with an infancy/childhood onset. In rare cases of late-onset phenotypes, symptoms are often milder and difficult to diagnose. We present a diagnostic journey of a teenage male patient with a progressive gait disorder starting at the age of 13 years, with a final diagnosis of Alexander disease. Early in the course of the disease, the boy exhibited distinctive cognitive involvement and neuropsychological deterioration characterized by selective impairment of visual and long-term auditory memory, along with a decline in IQ but preserved reasoning abilities. Methods: The patient underwent an extensive neurological diagnostic workup, which included magnetic resonance imaging (MRI) of the brain, spine, and abdomen, as well as electrophysiological, metabolic, and biochemical tests. Numerous specialist consultations were conducted, including genetic, cardiology, ophthalmology, pulmonology, oncohematology, psychological, and speech–language pathology consultations. In addition, a focused literature review was performed using PubMed, Scopus, Web of Science, and Google Scholar with the search terms “Alexander disease,” “GFAP gene,” “late-onset,” “spastic paraplegia” and “GFAP variant p/Gly18Val”. Results: Whole exome sequencing revealed an extremely rare missense GFAP heterozygous variant NM_002055.5: c.54G>T (p/Gly18Val), confirming the diagnosis of AxD. Conclusions: The presented case highlights the importance of whole-exome sequencing in the diagnosis of unexplained otherwise neurological symptoms, such as progressive spastic paraplegia. Full article

Mutations in the human patatin-like lysophospholipase domain containing the 6 gene PNPLA6 encode an evolutionarily conserved (lyso)phospholipase, leading to the development of a complex hereditary spastic paraplegia 39 (SPG 39) and a number of rare severe syndromes in humans. Diseases disrupt the functioning of the nervous and reproductive systems and the gastrointestinal tract. The study aims to investigate the role of the Drosophila melanogaster swiss cheese gene, an ortholog of the human PNPLA6 gene, in gut function. We showed that the swiss cheese gene knockout leads to changes in the morphology of the midgut, disruption of the septate junction structure and the intestinal barrier permeability, and a decrease in the lipid droplet number in enterocytes. As a result of such disturbances, intestinal stem cells (ISCs) proliferation is activated, and the gut microbiome is altered. Ectopic expression of human PNPLA6 leads to the recovery of the intestinal barrier in the fly gut. The example of Drosophila demonstrates the important role of evolutionarily conserved (lyso)phospholipase in intestinal homeostasis. Full article

Background: Neurodegenerative diseases, including spastic paraplegia type 11 (SPG11), are complex disorders characterized by progressive neurological decline and significant metabolic disturbances. Spatacsin, the protein encoded by the SPG11 gene, plays a critical role in autophagy and lysosomal homeostasis, which are essential for neuronal health. Its impairment leads to defective cellular clearance and neurodegeneration. Recently, personalized and precision nutrition have emerged as promising approaches to enhance clinical outcomes by tailoring dietary interventions to individual genetic, metabolic, and phenotypic profiles. Objectives: This mini scoping review aimed to synthesize current evidence on the application of personalized and precision nutrition in SPG11 and to explore how insights from related neurodegenerative diseases could inform the development of future dietary and metabolic interventions for this rare disorder. Methods: Following PRISMA-ScR guidelines, a scoping review was conducted using PubMed, Scopus, and Web of Science databases (2020–2024). Eligible studies included investigations addressing nutritional, genomic, or metabolic interventions in neurodegenerative diseases. Of 30 screened papers, nine met the inclusion criteria, primarily focusing on nutritional and metabolic interventions related to neurodegenerative and neuromuscular conditions. Results: To date, no dietary intervention trials have been conducted specifically for SPG11. However, evidence from studies on related neurodegenerative diseases suggests that antioxidant, mitochondrial-supportive, and microbiota-targeted dietary approaches may beneficially influence key pathological processes such as oxidative stress, lipid dysregulation, and autophagy—core mechanisms that are also central to SPG11 pathophysiology. Conclusions: Although current evidence remains preliminary, personalized nutrition is a promising supplementary strategy for managing neurodegenerative diseases, including SPG11. Future research should incorporate systems-based approaches that combine dietary, metabolic, and neuroimaging assessments, with sex and comorbidity-stratified analyses, multi-omics profiling, and predictive modeling. These frameworks could help design safe, effective, and personalized nutritional interventions aimed at enhancing metabolic resilience and slowing disease progression in SPG11. Full article

The gene SPG7 codes for the protein paraplegin, a subunit of the m-AAA protease in the inner mitochondrial membrane involved in protein quality control. SPG7 was initially identified as causing autosomal recessive hereditary spastic paraplegia (HSP), with a pure (insidiously progressive bilateral leg weakness and spasticity) and complex (with additional neurologic features including cerebellar signs and optic atrophy) forms. Now identified as one of the most common causes of HSP, SPG7-associated disease has been linked to additional neuro-ophthalmologic features, including isolated dominant optic atrophy, cerebellar eye signs (various forms of nystagmus, dysmetric saccades), progressive external ophthalmoplegia (PEO), and supranuclear vertical palsy. This review describes in detail the various neuro-ophthalmologic presentations of SPG7-associated disease, illustrating the role of mitochondrial dysfunction in the pathophysiology of these different entities. Knowledge of the different manifestations of SPG7-associated disease is crucial for both neurologists and ophthalmologists, and SPG7 should be considered in the work-up of patients presenting with entities such as optic atrophy, PEO, and cerebellar eye signs. Full article

Using Medline and Scopus as search engines, we identified reports of 10 clinical studies (published up to 1 September 2025) on botulinum neurotoxin therapy for hereditary spastic paraplegia (HSP). Nine studies were conducted in adults and one in children. Only one of the ten studies was double-blind and placebo-controlled. The search strategy included only articles published in English and articles providing basic information such as the type of the study, type and dose of the toxin and results of the treatment. Articles not in English, case reports and review articles were excluded. A total of 258 patients were included across all studies. The injected toxin in the open-label studies was botulinumtoxin-A (Botox or Dysport or Xeomin), whereas in the blinded study, the investigators used Prosigne. All open-label studies, which used FDA approved botulinumtoxin-A neurotoxins, demonstrated a degree of motor and non-motor improvement, whereas treatment with Prosigne did not improve patients’ function. The possible reasons for this discrepancy between the blinded study and the open-label studies are discussed. We found no studies on the effect of BoNTs on bladder dysfunction in HSP. There is a need for double-blind, placebo-controlled studies assessing the efficacy of FDA-approved botulinum neurotoxins in children and adults affected by hereditary spastic paraparesis. Such studies should also investigate the effect(s) of early botulinum neurotoxin therapy in this disorder. The novelty of this review is that it represents a comprehensive and critical literature review on this subject, with no other studies of this kind published previously. It also includes data not present in previous reviews of this subject. Full article

Background: Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders marked by progressive corticospinal tract dysfunction and wide phenotypic variability. Their genetic heterogeneity has so far limited the identification of biomarkers that are broadly applicable across different subtypes. Objective: We aim to define a balanced review on the use of biomarkers in HSP. Methods: This review focuses on fluid biomarkers already available in clinical or research settings—primarily validated in other neurodegenerative diseases—and assesses their potential translation to the HSP context. Biomarkers such as neurofilament light chain, brain-derived tau, glial fibrillary acidic protein, and soluble TREM2 reflect key converging mechanisms of neurodegeneration, including axonal damage, neuronal loss, and glial activation. These shared downstream pathways represent promising targets for disease monitoring in HSP, independently of the underlying genetic mutation. Results: An integrative framework of fluid biomarkers could assist in defining disease progression and stratify patients in both clinical and research settings. Moreover, recent advances in ultrasensitive assays and remote sampling technologies, such as dried blood spot collection, offer concrete opportunities for minimally invasive, longitudinal monitoring. When combined with harmonized multicenter protocols and digital infrastructure, these tools could support scalable and patient-centered models of care. Conclusions: The integration of already available biomarkers into the HSP field may accelerate clinical translation and offer a feasible strategy to overcome the challenges posed by genetic and clinical heterogeneity. Full article

Background: Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by progressive lower-limb spasticity and weakness. SPAST mutations are the most common cause of autosomal dominant HSP (SPG4). However, many pathogenic SPAST variants are unique and genetic data from underrepresented communities remain limited. Methods: Whole-exome sequencing (WES) was performed on the index patient with HSP. Variant annotation tools included Ensembl VEP, LOFTEE, CADD, SIFT, PolyPhen-2, MutationTaster, and SpliceAI. Variant interpretation followed ACMG/AMP guidelines. Clinical evaluation and family history supported phenotypic correlation and segregation. Results: A novel heterozygous frameshift variant in SPAST (c.339delG; p.Glu114Serfs*47) was identified. The variant was predicted to cause nonsense-mediated decay, resulting in loss of the microtubule-interacting and AAA ATPase domains of spastin. It was absent from population databases (gnomAD, TOPMed, 1000 Genomes) and public variant repositories (ClinVar, HGMD). The variant segregated with disease in two affected siblings and could be classified as likely pathogenic. Conclusions: This novel SPAST frameshift variant expands the mutational spectrum of SPG4-HSP and highlights the importance of including isolated or minority communities in genomic research to improve variant interpretation. Full article

Spastic paraplegia 80 (SPG80), caused by mutations in ubiquitin-associated protein 1 (UBAP1), is a pure form of juvenile-onset hereditary spastic paraplegia (HSP) and leads to progressive motor dysfunction. Despite recent advances in the molecular analyses of HSP, disease-modifying therapy has not been established for HSP including SPG80. In the present study, we evaluated the therapeutic potential of 4-phenylbutyric acid (4-PBA), a chemical chaperone and histone deacetylase inhibitor, in Ubap1 knock-in (KI) mice expressing a disease-associated truncated UBAP1 variant. We found that 4-PBA administration significantly improved the motor performance of KI mice in the rotarod and beam walk tests, with maximal benefits achieved when given during pre- or early-symptomatic stages. Partial efficacy was also observed when treatment began after symptom onset in KI mice. Furthermore, 4-PBA attenuated spinal microglial activation and partially restored microglial morphology, although astrocytic reactivity remained unchanged. These findings support 4-PBA as a candidate therapeutic compound for SPG80 and highlight the potential of proteostasis-targeted interventions in HSPs. Full article

Objective: The classification of hereditary spastic paraplegia (HSP) is based on genetics, and the number of genetic loci continues to increase with new genetic descriptions. Additionally, the number of new variants in known mutations continues to increase. In this paper, we aim to report our experience with genetically confirmed HSPs. Methods: We retrospectively evaluated 10 consecutive children with genetically confirmed HSPs. Results: In this study, we identified six novel mutations, including spastic paraplegia 11 (SPG11), glucosylceramidase beta 2 (GBA2), chromosome 19 open reading frame 12 (C19orf12), 1 in each of the Cytochrome P450 family 7 subfamily B member 1 (CYP7B1) genes, and two different mutations in the intropomyosin-receptor kinase fused gene (TFG) gene. We also identified different clinical phenotypes associated with known mutations. Conclusions: Heterozygous mutations with GBA2 and SPG11 mutation-related HSP are reported for the first time, expanding the known inheritance patterns. We report a novel homozygous chromosome 19 open reading frame 12 (C19orf12) mutation resulting in iron accumulation in the brain, broadening the genetic variants and clinical findings. We determine the first Turkish patients with carnitine palmitoyltransferase IC (CPT1C) and TFG gene mutation-related pure HSP. A pure form of HSP with two novel TFG gene mutations is also identified for the first time. We report the first Turkish patient with kinase D-interacting substrate of 220 kDa (KIDINS220) gene, broadening the clinical spectrum of KIDINS220 variant-related disorders to encompass certain HSPs. Moreover, a novel variant in the oxysterol7-hydroxylase (CYP7B1) gene is reported, expanding the genetic variants and clinical findings relating to SPG5. Full article