Hereditary spastic paraplegias (HSP) are rare neurodegenerative disorders marked by spasticity and lower limb weakness. The most common type, SPG4, is usually autosomal dominant and caused by SPAST gene variants, typically presenting as pure HSP. We describe five individuals from three unrelated families who meet the clinical criteria for cerebral palsy and carry biallelic SPAST variants. We aim to increase the clinical and genetic understanding of SPAST-related disorders and explore the underlying abnormal cellular mechanisms. We performed comprehensive phenotyping and genetic analysis. In silico and functional studies were conducted using confocal microscopy on fibroblast cultures derived from carriers of the biallelic SPAST variants, a monoallelic SPAST variant, and a healthy control. Individuals exhibited early-onset complex HSP with a diverse range of encephalopathy severity, spasticity, and neuronoaxonal involvement, occasionally leading to the diagnosis of cerebral palsy. Whole-exome sequencing identified homozygous and compound heterozygous SPAST variants. Functional studies demonstrated reduced spastin and tubulin levels, mitochondrial fragmentation, and abnormal filopodia morphology in patient-derived fibroblasts, supporting the pathogenicity of the variants. We provide the first evidence of biallelic inheritance in SPAST-related disorders, supported by functional analysis, expanding the clinical spectrum to include moderate-to-severe early-onset encephalopathy. Our findings emphasize the importance of genetic diagnosis in cerebral palsy for prognosis, counseling, and personalized therapy. The identified variants reveal the genetic complexity of SPAST-related disease and suggest a threshold effect of spastin levels in phenotypic variation. Cellular mechanisms such as mitochondrial dynamics and membrane morphology may contribute to pathogenesis and warrant further investigation.

SPG7-related hereditary spastic paraplegia (SPG7-HSP) is one of the most common forms of autosomal recessive HSP. There is a growing number of reports of affected individuals found to be heterozygous carriers for the recurrent pathogenic coding variants in SPG7, most notably p.Ala510Val, and this has further led to the suggestion of SPG7-HSP having both recessive and dominant forms. Here, we report a proband with pure HSP initially found to carry a heterozygous pathogenic stop-gain variant in SPG7 (NM_ 003119.4:c.1672 A > T; p.Lys558Ter). Subsequent short-read genome sequencing (GS) identified a second, novel deep intronic variant (NM_003119.4:c.987 + 152G > A) in trans, predicted to activate a cryptic splice donor site. RNA sequencing confirmed inclusion of intronic sequence, resulting in a frameshift and premature stop codon (p.Ser330ValfsTer10). This is only the second report of GS uncovering a pathogenic deep intronic variant in SPG7. Our findings highlight that variants only detectable by GS may be an underappreciated disease mechanism and may account for the missing heritability in instances where only a single coding variant is initially identified. Further, critical review of such reports in the literature found no substantial evidence for true autosomal dominant inheritance in SPG7-HSP. These cases most likely represent undetected second variants, alternative molecular diagnoses, or more complex disease mechanisms that have yet to be understood. We recommend the use of GS in individuals with suspected SPG7-HSP carrying only a single pathogenic variant to ensure a complete and accurate molecular diagnosis.

Autosomal-dominant variants in the CPT1C gene have been associated with hereditary spastic paraplegia type 73 (SPG73), which typically presents with slowly progressive lower limb weakness and spasticity and is therefore considered a pure form of hereditary spastic paraplegia. However, we report two unrelated males with novel CPT1C variants (NM_001199753.2: patient 1: c.2057_2061del (p.Ile686SerfsTer8) and patient 2: c.2020-1G>C (p.?)) who presented with lower limb spasticity at 4 and 3 years old, respectively. Both patients also experienced significant cognitive impairment, seizures, or neurobehavioral symptoms. These cases illustrate a broader and more complex clinical spectrum of SPG73, extending beyond the traditionally recognized pure motor symptoms.

Hereditary spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of neurodegenerative diseases. To date, at least 84 distinct loci (SPGs) and 67 causative genes have been identified. Even though the number of known causative genes is constantly increasing, a substantial portion of patients remains without a molecular diagnosis. Variants in the dynein, cytoplasmic 1, heavy chain 1(DYNC1H1)gene have been reported to cause a range of neurogenetic diseases, including spinal muscular atrophy (SMA), Charcot-Marie-Tooth disease (CMT), and cortical malformations. This study aims to characterize the clinical spectrum of DYNC1H1-related disorders by reporting a rare missense variant (c.13763 C > T, p.Thr4588Met) identified in a Chinese family with autosomal dominant (AD) complex HSP. The affected individuals underwent a comprehensive neurological evaluation, including assessment of clinical features, laboratory testing, brain magnetic resonance imaging (MRI), and electrophysiological studies. The repetition/deletions in the SPAST, ATL1 gene were detected using multiplex ligation-dependent probe analysis (MLPA). Whole-exome sequencing (WES) was performed to identify the disease-causing mutation in the proband, which was subsequently validated by Sanger sequencing in the proband and his parents. In silico analysis was performed to predict the pathogenicity of the identified mutations. A heterozygous missense variant (c.13763 C > T, p.Thr4588Met) in the DYNC1H1 gene was identified, which was classified as likely pathogenic according to ACMG guidelines. The family was affected by autosomal dominant complex HSP, presenting with marked spastic paraplegia and ataxia. In silico analyses (e.g., using PolyPhen-2, PROVEAN, Mutation Taster, and CADD) indicated a deleterious effect on protein function. This study reports a rare DYNC1H1 variant associated with autosomal dominant (AD) complex HSP, expanding the mutational and phenotypic spectrum of DYNC1H1-related disorders.

Hereditary spastic paraplegias (HSPs) comprise a heterogenous spectrum of rare neurogenetic disorders predominantly characterized by progressive spasticity and weakness of the lower extremities. Among autosomal-dominant forms of HSP, molecular defects in the SPAST gene-particularly those associated with the SPG4 subtype-represent the most frequent genetic cause. SPAST encodes spastin, a microtubule-severing ATPase, crucial for cytoskeletal remodeling, neuronal connectivity, and intracellular trafficking. Disruption of spastin function can impair neurite outgrowth and synaptic formation, processes increasingly implicated in neurodevelopmental disorders (NDDs). We conducted a comprehensive clinical, neurological, and dysmorphological evaluation of a 4-year-old male. Standardized neuropsychological assessments were administered. Whole-exome sequencing (WES) was performed to identify underlying genetic causes. EEG and 3T-brain MRI were also acquired. The proband harbored two novel de novo heterozygous missense variants in cis of the SPAST gene, displaying the typical features of early-onset and complex HSP, in addition to global developmental delay and severe autism spectrum disorder (ASD), an underexplored manifestation in this rare genetic disorder. These findings broaden the clinical and mutational spectrum of SPG4, underscoring the importance of considering SPAST gene analysis in patients with ASD in the early years of life and early motor delay, even in the presence of only subtle pyramidal signs. We advocate for comprehensive neuropsychiatric assessment in the diagnostic pathway of early-onset complex HSP presentations and support further investigation into the role of spastin in neuronal connectivity.