Childhood onset hereditary spastic paraplegia

Gene: INPP4A

Green List (high evidence)

Comment on list classification: There is sufficient evidence available (10 patients from 9 families and functional studies) for the promotion of this gene to green rating in the next GMS update.

Created: 14 Aug 2025, 9 a.m. | Last Modified: 14 Aug 2025, 9 a.m.

Panel Version: 8.8

PMID:39315527 (2025) reported 30 patients from 17 unrelated families with biallelic INPP4A variants and a clinically variable neurodevelopmental disorder. The clinical features include global developmental delay, severe-profound intellectual disability, microcephaly, limb weakness, cerebellar signs, and short stature. A more severe presentation associated with biallelic INPP4A variants downstream of exon 4 has additional features of (ponto)cerebellar hypoplasia, reduced cerebral volume, peripheral spasticity, contractures, intractable seizures, and cortical visual impairment. Nine patients from eight families were reported with spasticity, of which six had LoF variants downstream of exon 4 and the remaining three had missense variants. Although age of onset was not provided for these patients, the age of last examination for eight of nine patients were below 16.

There is also functional evidence available in support of the disease association. Preliminary fibroblast cell lines from an affected individual showed disruption of endocytic pathways as the likely mechanism of disease. All mouse models displayed a phenotype mirroring human INPP4A-related neurodevelopmental disorder.

PMID:40772914 (2025) reported a 34-month old female patient with the same biallelic variant that was reported in family 7 from PMID:39315527 (c.981del/ p.Asp328Ilefs*4) and with INPP4A-related disorder. This patient had spasticity.
Sources: Literature

Created: 14 Aug 2025, 8:54 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
neurodevelopmental disorder, MONDO:0700092

Publications

• 39315527
• 40748307
• 40772914