From spastic paraplegia to infantile neurodegenerative disorder: Expanding the phenotypic spectrum associated with biallelic SPAST variants

• DOI: 10.1111/ene.70025
• Publication Date: 2024-12-28T06:59:12Z
• Authors: Manon Degoutin; Chloé Angelini; Claire Bar; Wahiba Amer El Kh...; Christine Barnerias; Razika Boulariah‐...; Mehrdad A. Estiar; Claire Ewenczyk; Ziv Gan‐Or; Didier Lacombe; Claire Lefeuvre; Purvi Majethia; Mouna Messaoud‐Kh...; Dhanya Lakshmi Na...; Guy A. Rouleau; Oksana Suchowersky; Anju Shukla; Marine Guillaud‐B...; Giovanni Stevanin; Cyril Goizet
• Keywords: 0303 health sciences; 03 medical and health sciences; Spastic paraplegia; SPAST; Original Article; Neurodegenerative disorder; [SDV.GEN] Life Sciences [q-bio]/Genetics; Homozygous; SPG4

AbstractPurposeHeterozygous pathogenic variants in SPAST are known to cause Hereditary Spastic Paraplegia 4 (SPG4), the most common form of HSP, characterized by progressive bilateral lower limbs spasticity with frequent sphincter disorders. However, there are very few descriptions in the literature of patients carrying biallelic variants in SPAST.MethodsTargeted Sanger sequencing, panel sequencing and exome sequencing were used to identify the genetic causes in 9 patients from 6 unrelated families with symptoms of HSP or infantile neurodegenerative disorder.ResultsWe describe 5 patients with pure HSP with a variable age of onset, mostly in infancy, and 4 patients with profound intellectual disability and progressively worsening tetrapyramidal syndrome. The patients' parents, heterozygous carriers of pathogenic SPAST variants, included both asymptomatic carriers and patients with classic forms of SPG4.ConclusionBiallelic variants of SPAST may explain cases of hereditary spastic paraplegia with autosomal recessive inheritance. Furthermore, some biallelic variants may also cause psychomotor regression with an infantile neurodegenerative disorder, associated with a tetrapyramidal syndrome, a new phenotype associated with the SPAST gene.