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

Heterozygous 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 ca...

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Published in:European journal of neurology 2025-01, Vol.32 (1), p.e70025
Main Authors: Degoutin, Manon, Angelini, Chloé, Bar, Claire, El Khedoud, Wahiba Amer, Barnerias, Christine, Boulariah-Hadjou, Razika, Estiar, Mehrdad A, Ewenczyk, Claire, Gan-Or, Ziv, Lacombe, Didier, Lefeuvre, Claire, Majethia, Purvi, Messaoud-Khelifi, Mouna, Narayanan, Dhanya Lakshmi, Rouleau, Guy A, Suchowersky, Oksana, Shukla, Anju, Guillaud-Bataille, Marine, Stevanin, Giovanni, Goizet, Cyril
Format: Article
Language:English
Subjects:
Adolescent
Adult
Child
Child, Preschool
Female
Humans
Infant
Intellectual Disability - genetics
Male
Mutation
Neurodegenerative Diseases - complications
Neurodegenerative Diseases - genetics
Original
Paraplegia
Pedigree
Phenotype
Spastic Paraplegia, Hereditary - genetics
Spastin - genetics
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Summary:Heterozygous 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. Targeted 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. We 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. Biallelic 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.
ISSN:1468-1331
1351-5101
1468-1331
DOI:10.1111/ene.70025