Two siblings presented with spastic paraplegia and psychomotor retardation with or without seizures with HACE1 variants

Abstract

Rationale: Spastic paraplegia and psychomotor retardation with or without seizures (SPPRS) is a rare autosomal recessive neurodevelopmental disorder caused by biallelic HACE1 variants. Its long-term clinical course and genotype–phenotype spectrum remain incompletely characterized. Patient concerns: Two siblings from a nonconsanguineous Chinese family presented with infantile-onset hypotonia, global developmental delay, markedly delayed motor milestones, gait impairment, language delay, and dysarthria. The older sister experienced recurrent febrile seizures, whereas her younger brother had no seizures. Diagnoses: Whole-exome sequencing followed by Sanger validation identified compound heterozygous HACE1 variants in both siblings: c.1303C > T (p.Gln435Ter), inherited from the father, and c.2158_2159insG (p.Glu720GlyfsTer17), inherited from the mother. Both variants were considered disease-causing after clinical, segregation, database, and ACMG-based assessment. Interventions: Both patients received symptomatic rehabilitation and underwent long-term neurological and developmental follow-up. Outcomes: At the last follow-up, at 25 and 16 years of age, respectively, both siblings could walk independently with a waddling and unstable gait but remained unable to run. Both could understand basic instructions and communicate using short phrases, although dysarthria and substantial cognitive impairment persisted. An updated literature review demonstrated marked clinical heterogeneity among patients with HACE1-associated SPPRS, with hypotonia, developmental impairment, spasticity, speech disturbance, seizures, and structural brain abnormalities occurring at variable frequencies. Lessons: These cases expand the genotypic spectrum of HACE1-associated SPPRS and demonstrate that a relatively mild and gradually improving clinical course may occur. Early molecular diagnosis can facilitate individualized rehabilitation, genetic counseling, and prenatal diagnostic planning.