Clinical and genetic characteristics of pediatric hereditary spastic paraplegia in the Eastern Levant

Hereditary spastic paraplegia (HSP) comprises a heterogeneous group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness primarily of the lower extremities. Data describing pediatric HSP from the Levant region remain limited.

This study characterizes the clinical and genetic spectrum of pediatric HSP patients with an identified variant in an HSP-associated gene evaluated at a tertiary referral center serving the Eastern Levant.

A retrospective descriptive review of pediatric and adolescent patients with a clinical diagnosis of HSP and an identified variant in an HSP-associated gene, evaluated between 2010 and 2024 was conducted. Demographic, clinical, neuroimaging and genetic data were extracted from medical records. Genetic diagnoses were established using next-generation sequencing-based approaches and interpreted according to American College of Medical Genetics and Genomics guidelines. Data were summarized descriptively.

A total of 21 pediatric patients were included. Nineteen patients (90.5%) had an autosomal recessive inheritance, 71.4% were progeny from consanguineous families. Clinically relevant variants were identified across 11 HSP-associated genes, including CYP2U1, SPG11, ARL6IP1, B4GALNT1, DDHD2, RNF170, AMPD2, as well as variants in AP-4 complex genes (AP4B1, AP4M1, AP4S1). Additionally, the autosomal dominant SPAST gene was also featured. Age at symptom onset ranged from infancy to late childhood. Ambulatory status at last follow-up ranged from independent ambulation to dependence on assistive devices or caregiver support. Clinical presentations spanned pure spastic paraplegia and complex phenotypes, the latter being associated with variable combinations of features such as intellectual disability, ataxia or seizures. Brain magnetic resonance imaging findings were variable and encompassed thinning of the corpus callosum and nonspecific white matter abnormalities.

The cases discussed provide a descriptive overview of the clinical and genetic characteristics of pediatric HSP in Lebanon, Syria and Iraq. The relatively high number of CYP2U1 and AP-4 complex variants observed in this referral cohort, together with the predominance of autosomal recessive and complex forms, highlight the value of broad molecular testing in populations with high rates of consanguinity, such as the Eastern Levant.