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PubMed2026

Safety and efficacy of recombinant botulinum toxin type A (Eveotox®) in patients with post-stroke upper limb spasticity: Results from a Phase Ib/II clinical trial.

Upper limb spasticity is a common and disabling complication of stroke. Botulinum toxin type A (BoNT-A) is widely used for focal spasticity treatment, but naturally derived products may present limitations related to immunogenicity and manufacturing variability. Recombinant botulinum toxin type A, produced by genetic engineering without complexing proteins, may provide improved product consistency. This Ib/II study evaluated the safety, tolerability, and preliminary efficacy of recombinant botulinum toxin type A in adults with post-stroke upper limb spasticity. This multicenter, seamless Ib/II clinical study included an open-label dose-escalation Ib phase and a randomized, double-blind, placebo-controlled II phase. Adult patients with post-stroke upper limb spasticity received a single intramuscular injection of recombinant botulinum toxin type A or placebo. The primary endpoint in Phase II was the change from baseline in the Modified Ashworth Scale (MAS) score of the primary target muscle group at Week 4. Secondary endpoints included MAS and Tardieu scale changes in individual muscle groups, Disability Assessment Scale (DAS), Physician's Global Assessment (PGA), and immunogenicity. The Ib phase showed improvements in MAS, DAS, and PGA, indicating an early efficacy signal. In Phase II, recombinant botulinum toxin type A produced a significant reduction in MAS score of the primary target muscle group at Week 4 compared with placebo, with effects sustained through Week 12. At Week 4, the PGA score in the Eveotox® group showed a statistically significant improvement compared with the placebo group. While MAS and PGA scores showed significant improvement, DAS functional scores did not differ statistically from the placebo group at week 4. The treatment was generally well tolerated, and low incidence of antibodies were observed. Recombinant botulinum toxin type A was safe and effective in reducing post-stroke upper limb spasticity after a single administration. These results support further Phase III clinical evaluation.

Humans↗
PubMed2026

Treatment of spinal injury muscle spasticity by spinal subpial AAV9-GAD65/VGAT delivery: An efficacy and safety study in rat, pig, and NHP.

The loss in segmental inhibitory GABAergic tone plays the key role in the development of spinal injury-induced muscle spasticity. We use a subpial segment-targeted delivery of adeno-associated virus vector(s) expressing GAD65 (glutamic acid decarboxylase-65) and VGAT (vesicular GABA transporter) transgenes in rats with spinal transection-induced spasticity. In treated animals, a significant suppression in spasticity was seen at 5-8 weeks after treatment. Naive rats, pigs, and non-human primates (NHPs) injected with human equivalent dose of treatment vectors and surviving for 3 weeks to 4.5 years showed normal motor function and pinch-evoked response. A significant increase in the number of VGLUT2 terminals co-expressing GAD65 and VGAT protein in vector-injected segment was seen. This corresponded with the presence of transgene-specific rat Gad2 or human GAD2 and rat Slc32a1 or human SLC32A1 mRNA signal. No spinal toxicity was noted in NHPs at 4.5 years post vector delivery. Analysis of peripheral organs (liver, spleen, and skeletal muscle) showed minimal or no detectable transgenes in pigs and NHPs. These data demonstrate that a single-time-point spinal-segment-targeted subpial delivery of GAD65/VGAT transgenes is effective in suppressing spinal injury-induced spasticity and has a favorable long-term safety profile as defined by normal neurological function and histopathology in naive pigs and NHPs.

Animals↗
PubMed2025

A founder variant in TBCB is associated with global developmental delay, autism spectrum, and spastic paraparesis.

PURPOSE: Hereditary spastic paraparesis (HSP) is a genetically diverse group of Mendelian disorders characterized by length-dependent axonal degeneration. Microtubule dysfunction is a known mechanism in HSP that impairs axonal dynamics. TBCB encodes tubulin-folding cofactor B (TBCB), which, along with TBCE, regulates αβ-heterodimer dynamics and neuronal axonal growth. Here, we describe a new form of complicated HSP caused by a founder variant in TBCB. METHODS: Exome sequencing revealed a homozygous c.589T>A p.(Tyr197Asn) variant in TBCB in a cohort of 10 individuals assembled through genematching tools. Protein function was assessed using Saccharomyces cerevisiae ortholog ALF1, and a CRISPR-Cas9-generated homologous mutant in Drosophila melanogaster. TBCB expression and localization were examined in fibroblasts using western blot and immunofluorescence. RESULTS: Participants displayed late-childhood-onset spastic paraparesis, global developmental delay, and autism spectrum. TBCB protein levels were reduced in affected fibroblasts. The ALF1 mutant in yeast increased benomyl sensitivity, resembling a loss-of-function phenotype. In Drosophila melanogaster, the homologous mutant led to reduced survival and impaired climbing ability. CONCLUSION: We describe a novel neurodevelopmental disorder with spastic paraparesis and a high carrier rate in the Ashkenazi Jewish population. Our results indicate that TBCB has a vital role in the development of central nervous system and potentially in axonal function in humans.

Humans↗
PubMed2026

[Effect of electroacupuncture combined with suspension exercise therapy on lower limb motor function in elderly patients with post-stroke spastic hemiplegia].

OBJECTIVE: To observe the efficacy of electroacupuncture (EA) combined with suspension exercise therapy in elderly patients with post-stroke spastic hemiplegia and its effect on lower limb motor function. METHODS: A total of 120 elderly patients with post-stroke spastic hemiplegia were enrolled. Using a 2&#xd7;2 factorial design, all the patients were assigned to a group A (conventional treatment), a group B (conventional treatment combined with suspension exercise therapy), a group C (conventional treatment combined with EA at Jiaji [EX-B2] and limb acupoints), and a group D(conventional treatment combined with suspension exercise therapy and EA at Jiaji [EX-B2] and limb acupoints), with 30 patients in each group. The main acupoints were bilateral Jiaji (EX-B2) points at the C2-C7, T2-T12, L1-L5, and S1 segments. The adjunct acupoints included Jianyu (LI15), Binao (LI14), Huantiao (GB30), Chengfu (BL36), etc. on the affected side.Continuous wave was applied at a frequency of 100 Hz with a current intensity of 1.5-3.0 mA, and needles were retained for 30 min, once daily for 4 weeks. Before treatment and after 2 and 4 weeks of treatment, the modified Ashworth scale (MAS),Fugl-Meyer assessment (FMA), Berg balance scale (BBS), and Barthel index scores were evaluated in the four groups. Root mean square (RMS) values of surface electromyography (sEMG) of the erector spinae and rectus abdominis muscles on the affected side, as well as balance function indexes, including the mean pressure symmetry index (SI), contact area SI, ellipse area, and displacement distances of the center of pressure in the anteroposterior (AP) and mediolateral (ML) directions, were measured. Clinical efficacy was also compared among the four groups. RESULTS: After 2 and 4 weeks of treatment, MAS scores in all groups were lower than those before treatment (P<0.05), whereas FMA, BBS, and Barthel index scores were higher than those before treatment (P<0.05). After 4 weeks of treatment, MAS scores were lower than those after 2 weeks of treatment (P<0.05), whereas FMA, BBS, and Barthel index scores were higher than those after 2 weeks of treatment (P<0.05) in the four groups. At both 2 and 4 weeks after treatment, group D had lower MAS scores (P<0.05) and higher FMA,BBS, and Barthel index scores (P<0.05) than the other three groups. After 2 and 4 weeks of treatment, RMS values of sEMG of the erector spinae and rectus abdominis muscles on the affected side at all tested angles were higher than those before treatment in all groups (P<0.05), and the values after 4 weeks of treatment were higher than those after 2 weeks of treatment(P<0.05). At both 2 and 4 weeks after treatment, all these indexes in the group D were higher than those in the other three groups (P<0.05). After 2 and 4 weeks of treatment, the mean pressure SI, contact area SI and ellipse area of each group were lower than those before treatment (P<0.05). After 4 weeks of treatment, the mean pressure SI, contact area SI and ellipse area of each group were lower than those after 2 weeks of treatment (P<0.05). After 2 and 4 weeks of treatment, the AP displacement distances of groups A, C and D were lower than those before treatment (P<0.05), and after 4 weeks of treatment, the AP displacement distances of groups A, C and D were lower than those after 2 weeks of treatment (P<0.05);after 2 weeks of treatment, there was no statistically significant difference in AP displacement distance in the group B compared with before treatment (P>0.05), and after 4 weeks of treatment, the AP displacement distance of group B was lower than that before treatment (P<0.05). After 2 weeks of treatment, there was no statistically significant difference in ML displacement distance in group A compared with before treatment (P>0.05); after 4 weeks of treatment, the ML displacement distance of group A was lower than that before treatment (P<0.05). After 2 and 4 weeks of treatment, there was no statistically significant difference in ML displacement distance in the group B compared with that before treatment (P>0.05).After 2 and 4 weeks of treatment, the ML displacement distances of groups C and D were lower than those before treatment(P<0.05), and after 4 weeks of treatment, the ML displacement distances of groups C and D were lower than those after 2 weeks of treatment (P<0.05). At both 2 and 4 weeks after treatment, mean pressure SI, contact area SI, ellipse area, and AP and ML displacement distances in the group D were lower than those in the other three groups (P<0.05). Factorial analysis of variance showed that EA had the strongest main effect on FMA score (F=6.243, P<0.05), suspension exercise therapy had the strongest main effect on BBS score (F=6.292, P<0.05), and the interaction effect was most significant for MAS score (F=5.941, P<0.05), indicating that the combined therapy produced a greater synergistic effect on reducing muscle tone than on the other outcome measures. The total effective rate in the group D was 93.3% (28/30), which was higher than those in the group A (53.3% [16/30]), group B (56.7% [17/30]), and group C (66.7% [20/30], P<0.05). CONCLUSION: EA combined with suspension exercise therapy could effectively promote the recovery of lower limb function in elderly patients with post-stroke spastic hemiplegia, improve motor and balance functions, and enhance activities of daily living.

Humans↗
PubMed2025

Purkinje cell development and degeneration in the spastic Han-Wistar rat model of ataxia.

Hereditary ataxia is a neurodegenerative disorder notable for its early onset, with symptoms appearing in patients as young as two years old. Although affected individuals exhibit severe motor deficits and early mortality rates, the timeline of Purkinje cell loss remains unclear. To address this gap, we used the spastic Han-Wistar rat model, which harbors an unknown homozygous recessive variant that causes Purkinje cell loss. Here, we aimed to determine the onset and temporal progression of Purkinje neuronal loss in the spastic Han-Wistar model. To achieve this, we employed immunohistochemistry, Hematoxylin and Eosin histology, and neuronal density quantification. Behavioral testing demonstrated early-onset, progressive motor impairment in mutant rats, which coincided with a gradual loss of Purkinje cells in the cerebellum. Additionally, guided by pedigree analysis from a previous study indicating autosomal recessive inheritance for this ataxia, we performed whole-genome shotgun sequencing of a parent-offspring trio to identify amino acid-changing mutations consistent with this pattern. We used Sanger sequencing to exclude non-causal candidates. Together, our findings provide new insights into the onset and genetic complexity of ataxia, refining the value of the spastic Han-Wistar rat as a model for investigating mechanisms underlying hereditary ataxia and broader neurodegenerative disorders.

Hereditary ataxia↗
PubMed2025

Genetic analysis of three patients from two unrelated Chinese families with autosomal recessive spastic ataxia of Charlevoix-Saguenay.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare early-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, spasticity, and sensorimotor peripheral neuropathy. This disorder is caused by homozygous or compound heterozygous variants in the sacsin (SACS) gene on chromosome 13q12.12. Three patients with ARSACS from two unrelated Chinese families were recruited for this study. Patient #1 was an 18-year-old male who had been walking unstably for 12 years. Patient #2, the younger sister of Patient #1, was a 5-year-old girl who had been walking unstably for 2 years. Patient #3 was a 19-year-old female who had been walking unstably and a tendency to fall for 17 years. For Patient #1, whole-exome sequencing (WES) identified a hemizygous variant c.8310_8313delAGAT (p.Asp2771fs4*) in SACS (NM_014363.6), with the father being heterozygous, the mother wild-type, and Patient #2 hemizygous, as verified by Sanger sequencing. Additional copy number variant analysis of the WES data indicated that Patient #1 had a heterozygous gross deletion of chr13q12.12 (chr13:23,808,732&#x2009;-&#x2009;24,890,322). Low-coverage whole-genome sequencing results revealed that Patient #2 carried a chr13q12.12 deletion (chr13:23,520,000-24,940,000). Together with Sanger sequencing results, this gross deletion was speculated to have been inherited from the mother, further explaining the hemizygous state of c.8310_8313delAGAT (p.Asp2771fs4*) in Patients #1 and #2. Through WES, Patient #3 was identified as having suspected compound heterozygous variants of c.2881&#xa0;C&#x2009;>&#x2009;T (p.Arg961*) and c.6409&#xa0;C&#x2009;>&#x2009;T (p.Gln2137*), inherited from the father and mother, respectively, as confirmed by Sanger sequencing. This study identified three variants in SACS. The c.8310_8313delAGAT (p.Asp2771fs4*) is novel, whereas c.2881&#xa0;C&#x2009;>&#x2009;T (p.Arg961*) and c.6409&#xa0;C&#x2009;>&#x2009;T (p.Gln2137*) have been reported previously. Moreover, this study highlights the growing trend that ARSACS has become increasingly prevalent worldwide rather than being localized to a specific region or race. As an increasing number of patients with ARSACS are diagnosed, the genetic spectrum of ARSACS will gradually broaden, providing an accurate genetic basis for prenatal diagnosis of mothers in the years ahead, if possible.

Adolescent↗
PubMed2025

Effect of acupuncture on brain microenvironment in rats with post-stroke limb spasticity based on single-cell transcriptome sequencing technology.

OBJECTIVE: To investigate the possible mechanisms by which acupuncture improves post-stroke limb spasticity using single-cell sequencing technology. METHODS: Thirty-two rats were randomly assigned to four groups: Control, Sham, Model, and Acupuncture. The middle cerebral artery occlusion (MCAO) model was established, and the acupuncture groups received acupuncture treatment. After treatment, brain morphological changes and the degree of neurological impairment were assessed. The effect of acupuncture on the proportion of brain cell types in the ischemic penumbra of MCAO rats was analyzed using single-cell transcriptomics, and the expression and enrichment of differentially expressed genes were examined. Finally, selected differential genes were validated by Western blot and quantitative real-time polymerase chain reaction. RESULTS: Triphenyltetrazolium chloride staining showed that the infarct area in MCAO rats was significantly reduced after acupuncture. Garcia scoring, hematoxylin-eosin staining, Nissl staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling demonstrated that acupuncture reduced brain damage. Enzyme-linked immunosorbent assay results showed that acupuncture significantly decreased serum inflammatory factors, including interleukin-1 beta (IL-1&#x3b2;), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-&#x3b1;). Single-cell transcriptome analysis revealed marked changes in cell type proportions between the Acupuncture and Model groups. A total of 207 differential genes were identified, including 157 upregulated and 50 downregulated genes. Analysis of macrophage-specific differential genes in the ischemic penumbra showed enrichment in Gene Ontology terms such as Ras protein signal transduction and regulation of GTPase activity, and Kyoto Encyclopedia of Genes and Genomes pathways including lysosome, axon guidance, and mitogen-activated protein kinase signaling. S100a8 and leukocyte specific transcript 1 (LST1) were identified as key differential genes. CONCLUSION: These findings suggest that the key differential genes S100a8 and LST1 may alleviate post-stroke limb spasticity by regulating the inflammatory response in the ischemic penumbra.

Animals↗
PubMed2026

Genotype-structure-phenotype correlations define divergent natural history in early-onset spastic paraplegia type 4.

Hereditary spastic paraplegia type 4 (SPG4), caused by variants in SPAST, is the most common form of HSP and exhibits a remarkable phenotypic heterogeneity ranging from late-onset pure presentations to severe, early-onset complex disease. Robust genotype-phenotype correlations and detailed natural history data are lacking, limiting clinical trial readiness. We analyzed 206 patients with genetically confirmed SPG4 enrolled across seven international centers, complemented by high-quality literature-derived cases. Deep phenotyping included standardized motor scales, spasticity ratings, developmental milestones, and patient-reported outcomes. We developed an extended essentiality-mapping framework to classify SPAST missense variants by integrating in silico pathogenicity predictions, evolutionary constraint, physicochemical residue connectivity, and variant enrichment within the human spastin hexamer structure. Plasma neurofilament light chain (pNfL) using was quantified using Simoa in 26 patients and 101 controls. We identified 136 distinct SPAST variants, including 10 novel variants. Variant class segregated strongly by inheritance, with de novo cases enriched for missense variants and inherited cases showing a variety of variant classes with enrichment for truncating variants. Longitudinal analysis revealed two latent trajectories: a rapidly progressive severe subgroup enriched for de novo missense variants, and a biphasic moderate subgroup enriched for inherited truncating variants. Patient stratification integrating spastin essentiality mapping (missense variants affecting essential, neutral, or context-dependent residues) with established genetic modifiers (biallelic pathogenic variants or modifier variants in trans) classified patients into predicted severe and moderate subgroups with divergent age at onset and clinical disease progression. The severe subgroup showed early developmental delays, rapid loss of ambulation, and declining quality of life, while the moderate subgroup displayed delayed but accelerating disease progression. pNfL levels were elevated in both subgroups, most pronounced in severe early disease. This study provides the most detailed natural history of SPG4 to date and introduces a biologically informed stratification framework that links variant class and location to divergent clinical trajectories. These data establish clinically meaningful benchmarks and offer a genotype-based framework to improve anticipatory care and optimize trial design for SPG4.

SPAST↗
PubMed2026

A mouse model of autosomal dominant spastic ataxia and myopathy caused by a mutation in Tuba4a.

Hereditary ataxias are a heterogeneous group of neurodegenerative disorders characterized by impaired balance and coordination, often due to cerebellar dysfunction. Despite advances in identifying genetic causes, animal models remain essential for dissecting underlying mechanisms and testing therapeutic strategies. Here we describe a mouse model of spastic ataxia and myopathy caused by a missense mutation in Tuba4a (n.A626C, p.Gln176Pro). In an ENU mutagenesis screen, a male C57BL/6&#xa0;J mouse exhibiting muscle wasting and an intention tremor starting at approximately 4&#xa0;weeks-of-age was identified. The male was bred by in vitro fertilization to BALB/cByJ oocyte donors. Genetic mapping determined dominant inheritance and localized the mutation to Chromosome 1. Genome sequencing revealed single nucleotide polymorphisms (SNPs) in serine threonine kinase 36 (Stk36Y1003N) and alpha-tubulin 4A (Tuba4aQ176P) in the mapping interval. These SNPs were CRISPR-engineered into C57BL/6&#xa0;J mice, which confirmed the Tuba4aQ176P variant as the causative mutation. Mutant mice are normal at 3&#xa0;weeks, except for decrement in muscle response following repetitive nerve stimulation. However, by 30&#xa0;days these mice have overt ataxia, Purkinje neuron degeneration, and extensive skeletal muscle defects, which contribute to a decreased lifespan. Dominant TUBA4A mutations in humans are associated with spastic ataxia type 11 (SPAX11), congenital myopathy type 26 (CMYO26), and frontotemporal dementia/amyotrophic lateral sclerosis type 9 (FTDALS9). Our mice exhibit hallmark features of SPAX11 and CMYO26, but do not show motor neuron degeneration. This specificity makes this model a valuable tool for studying cell-type selective effects of TUBA4A mutations in neurodegeneration and myopathy.

Animals↗
PubMed2026

Proteomic analysis reveals early pathological defects in corticospinal motor neurons of a spastin model of hereditary spastic paraplegia, which are improved by NU-9 treatment.

Upper motor neuron (UMN) degeneration is a characteristic feature of hereditary spastic paraplegia (HSP), a genetically heterogeneous heritable neurodegenerative disorder resulting from mutations in over ninety genes. The mutations in the SPAST gene, which encodes the microtubule-severing protein spastin, are responsible for about 40% of all HSP cases. To date, the cellular and molecular mechanisms linking mutant spastin protein to UMN vulnerability in HSP patients remain unknown and there are no disease modifying therapies. To address this knowledge gap, we isolated pure populations of corticospinal motor neurons (CSMN; a.k.a. UMN in mice) from SPASTC448Y-UeGFP reporter mice at two pre-symptomatic time points and performed bottom-up proteomic analyses to reveal changes in their proteome that informs the underlying causes of their initial vulnerability. We find dynamic changes in their proteome and that limitations with cytoarchitectural integrity and stability of key organelles contribute to their neuronal vulnerability. Since the compound NU-9 was shown to improve similar cellular problems in CSMN that are diseased due to misfolded SOD1 toxicity and TDP-43 pathology, we further investigated its effect on the well-established pathological features of HSP that are recapitulated in the SPASTC448Y mice. We find that NU-9 treatment (100&#xa0;mg/kg, for 100&#xa0;days) significantly prevented degeneration of corticospinal axons, restored the integrity of mitochondria and endoplasmic reticulum, and reduced the presence of electron-dense accumulations in the CSMN of SPASTC448Y mice.

Animals↗
PubMed2024

AAV gene therapy for hereditary spastic paraplegia type 50: a phase 1 trial in a single patient.

There are more than 10,000 individual rare diseases and most are without therapy. Personalized genetic therapy represents one promising approach for their treatment. We present a road map for individualized treatment of an ultra-rare disease by establishing a gene replacement therapy developed for a single patient with hereditary spastic paraplegia type 50 (SPG50). Through a multicenter collaboration, an adeno-associated virus-based gene therapy product carrying the AP4M1 gene was created and successfully administered intrathecally to a 4-year-old patient within 3 years of diagnosis as part of a single-patient phase 1 trial. Primary endpoints were safety and tolerability, and secondary endpoints evaluated efficacy. At 12 months after dosing, the therapy was well tolerated. No serious adverse events were observed, with minor events, including transient neutropenia and Clostridioides difficile gastroenteritis, experienced but resolved. Preliminary efficacy measures suggest a stabilization of the disease course. Longer follow-up is needed to confirm the safety and provide additional insights on the efficacy of the therapy. Overall, this report supports the safety of gene therapy for SPG50 and provides insights into precision therapy development for rare diseases. Clinical trial registration: NCT06069687 .

Humans↗
PubMed1977

[The role of orthopedic surgery in the treatment of spastic patients].

The authors performed 958 operations on spastic patients. Based on this clinical material, they introduce the possibilities and principles of operative treatment. Position of joints in the lower limb, their synergism and compensatory changes in a closed kinetic chain are analysed in the article. These factors must be attended to carefully if one should decide the site and variety of operation to be performed. The authors suggest that patients should be operated on early, in certain cases even preventive operation is necessary. Results are better if children who already can stand and walk are operated on, but in many cases operation itself is needed to enable them to these activities. Results were good in 83,2%, no changes in 3,4%, worse in 4,2 out of the 716 operations evaluated. Operative treatment along with conductive pedagogy and other methods of physiotherapy help these patients to be able to take care of themselves and to become useful members of society.

Age Factors↗
PubMed2026

Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders.

BACKGROUND: Biallelic SPG7 mutations cause one of the most common forms of hereditary spastic paraplegia (HSP). Several reports have suggested that heterozygous SPG7 variants may also play a role in HSP, but also in amyotrophic lateral sclerosis (ALS). However, it remains controversial whether heterozygous SPG7 mutations are pathogenic on their own, or if other mechanisms are at play. We recently provided evidence for non-Mendelian inheritance in spastic paraplegia 7 (SPG7), as heterozygous carriers of SPG7 mutations often also carried mutations in other disease-related genes, including AFG3L2, more frequently than expected by chance. Given that SPG7 and AFG3L2 encode interacting subunits of the mitochondrial m-AAA protease complex, we hypothesized that combined heterozygous mutations in these genes may act synergistically to disrupt mitochondrial function and contribute to disease. In this study, we aimed to examine whether digenic heterozygous mutations in SPG7 and AFG3L2 can lead to a spectrum of neurodegenerative disorders. METHODS: We first analyzed genome and exome sequencing data of 6644 unrelated individuals including 4817 motor neuron disorder (MND) and ataxia patients and 1827 controls. We next analyzed an additional 18,748 exome data from rare disease cohorts to further examine the occurrence of variants in SPG7 and AFG3L2. RESULTS: Among the first 4817 MND and ataxia patients, we identified a total of 6 patients, 4 of whom were unrelated, who carried potentially pathogenic variants in both SPG7 and AFG3L2, in contrast to none in 1827 unrelated controls. Further analysis of the 18,748 additional patients with rare disease, as well as a comprehensive literature review, identified 6 more patients, 5 of whom were unrelated, who had digenic mutations in SPG7 and AFG3L2. In the two families we identified, digenic mutations in SPG7 and AFG3L2 perfectly segregated with the disease. The 12 patients reported here exhibited predominant signs of motor neuron and cerebellar involvement. CONCLUSIONS: Our findings demonstrate that digenic inheritance of concurrent heterozygous mutations in SPG7 and AFG3L2 may cause motor neuron and cerebellar disorders. Screening of the entire SPG7 and AFG3L2 genes in genetically undiagnosed cases of MND and spastic ataxia may help to increase the diagnostic yield.

Humans↗
PubMed2024

Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations.

PURPOSE: Biallelic HPDL variants have been identified as the cause of a progressive childhood-onset movement disorder, with a broad clinical spectrum from severe neurodevelopmental disorder to juvenile-onset pure hereditary spastic paraplegia type 83. This study aims at delineating the geno- and phenotypic spectra of patients with HPDL-related disease, quantitatively modeling the natural history, and uncovering genotype-phenotype associations. METHODS: A cross-sectional analysis of 90 published and 1 novel case was performed, using a Human-Phenotype-Ontology-based approach. Unsupervised phenotypic clustering was used alongside in silico analyses to identify distinct patient subgroups. RESULTS: The study models the natural history of the HPDL-related disease in a global cohort, clarifying the molecular and phenotypic spectrum and identifying 3 distinct subgroups characterized by differences in onset, clinical trajectories, and survival. It establishes genotype-phenotype associations, showing that the presence of moderately pathogenic missense variants in 1 allele leads to a milder, spastic paraplegic phenotype with later disease onset, whereas biallelic, highly pathogenic missense or truncating variants are associated with a more severe phenotype and reduced life span. CONCLUSION: Quantitative and unbiased natural history modeling in HPDL-related disease reveals significant genotype-phenotype associations, providing a foundation for variant interpretation, anticipatory guidance, and choice of outcome measures in future prospective and functional studies.

Humans↗
PubMed2026

Beyond Rett syndrome: a case series expanding the neurological spectrum associated with pathogenic MECP2 variants.

BACKGROUND: Although pathogenic variants in MECP2 are classically associated with Rett syndrome (RTT), increasing evidence suggests that they can underlie a broader spectrum of neurological phenotypes. Clinical manifestations may vary according to sex, variant type, residual protein function, and pattern of X-chromosome inactivation. METHODS: We describe five unrelated individuals carrying pathogenic MECP2 variants identified through multiplex ligation-dependent probe amplification, chromosomal microarray analysis, and next-generation sequencing. Clinical, neuroradiological, neurophysiological, and molecular findings were retrospectively reviewed. RESULTS: Two unrelated girls carrying large de novo Xq28 deletions encompassing the entire MECP2 locus presented with mild neurodevelopmental impairment and epilepsy, but no developmental regression or classic RTT features. Both girls showed borderline cognitive functioning and normal brain MRI. A 9-year-old boy carrying a maternally inherited MECP2 frameshift variant presented with intellectual disability, autism spectrum disorder, and focal epilepsy, whereas carriers in his family exhibited milder neuropsychiatric manifestations. A 44-year-old man carrying a MECP2 missense variant presented with an early-onset spastic-ataxic syndrome, peripheral neuropathy, and cerebellar dysfunction, while a 16-year-old girl patient carrying a distinct de novo MECP2 missense variant displayed isolated mild motor incoordination and subtle cerebellar signs with preserved cognitive functioning. CONCLUSIONS: Our findings expand the evidence that pathogenic MECP2 variants can produce neurological phenotypes distinct from classic RTT, including mild neurodevelopmental impairment without regression, and predominantly cerebellar or spastic-ataxic manifestations associated with limited cognitive involvement. Allelic heterogeneity seems to correlate with clinical phenotypes, at least in our small cohort. In conjunction with established diagnostic criteria, these observations support testing MECP2 in a selection of atypical neurodevelopmental and movement disorder presentations.

Humans↗