Hereditary spastic paraplegias are a diverse group of neurodegenerative diseases, clinically divided into pure and complex types. Spastic paraplegia 48 is caused by pathogenic biallelic variants in the AP5Z1 gene. Our study aims to expand the phenotypic and genotypic spectrum in this very rare syndrome. Case files, detailed anamnesis, radiological imaging, physical examination findings, ophthalmological examination and genetic results were evaluated as part of the clinical assessment. Whole-exome sequencing was performed for the proband. Sanger sequencing and next-generation sequencing were performed for confirmation of the variants and segregation analysis. We identified two disease-causing variants in the AP5Z1 (NM_014855.3) gene, including a pathogenic nonsense variant (c.1322G > A, p.(Trp441Ter)) and a pathogenic frameshift variant (c.857_866del, p.(Leu286ProfsTer25)). Segregation analysis showed compound heterozygosity of the variants. In this report, we present a patient from Turkey with spasticity, who has compound heterozygous variants in the AP5Z1 gene, representing the 17th case described in the literature. This report expands the phenotypic spectrum of the AP5Z1-related spastic paraplegia type 48, which has only rarely been reported in the literature. It underscores the importance of comprehensive genetic testing and variant interpretation in achieving an accurate diagnosis and providing genetic counselling for affected families with spastic paraplegia.

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.

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.

HSP-SPG11 and HSP-ZFYVE26 are autosomal-recessive forms of hereditary spastic paraplegias (HSPs). As therapeutic trials emerge, validated biomarkers are critically needed. To evaluate plasma neurofilament light chain (pNfL) as a biomarker for neurodegeneration and disease progression. We analyzed pNfL levels in 57 patients (36 HSP-SPG11, 21 HSP-ZFYVE26) and matched controls using single-molecule array technology. Longitudinal clinical and biomarker data were collected over 5 years. Baseline pNfL levels were significantly elevated in patients: 33.85 pg/mL (IQR 25.15-47.38) in HSP-SPG11, 46.70 pg/mL (IQR 29.95-54.84) in HSP-ZFYVE26, and 4.90 pg/mL (IQR 3.48-6.90) in controls (P < 0.001). No significant difference was observed between HSP-SPG11 and HSP-ZFYVE26. In matched pair analysis, pNfL showed inverse correlation with age (ρ = -0.463, P < 0.001). Baseline pNfL did not predict future clinical progression. Elevated pNfL reflects early neuroaxonal injury in HSP-SPG11 and HSP-ZFYVE26; however, it could not be used as a surrogate for disease progression. © 2025 International Parkinson and Movement Disorder Society.

Hereditary spastic paraplegias (HSPs) are a genetically heterogeneous group of neurodegenerative disorders clinically characterized by progressive lower limb spasticity with pyramidal weakness. Around a dozen potential molecular mechanisms are recognized. Childhood HSP is a significant diagnostic challenge in clinical practice. Mutations in AP5Z1, which are associated with spastic paraplegia type 48 (SPG48), are extremely rare and seldom described in children.We report the clinical, radiologic, and molecular studies performed in a child harboring novel biallelic mutations in AP5Z1.The child presented a neurodevelopmental disorder with slight lower limb pyramidal signs. Brain magnetic resonance imaging (MRI) showed minimal white matter changes in the frontal horns of the lateral ventricles and a normally shaped corpus callosum. Western blotting in cultured skin fibroblasts indicated reduced protein expression, which confirmed the genetic diagnosis and framed this as a case of protein reduction in a context of impaired autophagy.Our findings expand the spectrum of phenotypes associated with mutations in AP5Z1, highlighting their clinical and pathophysiologic overlap with lysosomal storage disorders. SPG48 should be considered in the differential diagnosis of neurodevelopmental disorders even when pyramidal signs are minimal and brain MRI not fully informative.