Hereditary spastic paraplegia, childhood onset

Gene: ATP1A3

Green List (high evidence)

Comment on list classification: There are nine unrelated cases reported with the same recurrent heterozygous variant and functional evidence available in support of the association of this gene with a novel disorder with spasticity and ID/ DD. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 13 Aug 2026, 8:42 a.m. | Last Modified: 13 Aug 2026, 8:42 a.m.

Panel Version: 9.11

PMID: 37043503 (2023) reported the identification of a novel recurrent heterozygous variant in ATP1A3 gene (c.2324C>T/ p.Pro775Leu) in nine unrelated patients with progressive or non-progressive spasticity and developmental delay/intellectual disability (DD/ID). None of the patients met diagnostic criteria for already reported ATP1A3-related disorders or were suspected of having an ATP1A3-related disorder prior to genetic testing.

Functional electrophysiology in Xenopus oocytes and an ouabain-complementation survival assay demonstrated that p.Pro775Leu causes loss of normal ion-pump function plus a novel inward Na+/H+ "leak" current, a distinct pathogenic mechanism from classical ATP1A3 variants. This variant is absent in gnomAD v4.1.1.

Monoallelic variants in this gene have already been associated with other phenotypes in OMIM (MIMs #128235, #601338, #614820 & #619606), but not with this milder phenotype of spasticity and DD/ ID (last accessed 12 August 2026).

Episodic hemiplegia and quadriplegia have been reported as clinical presentations of Alternating hemiplegia of childhood 2 (AHC2, MIM #614820), and quadriparesis as a clinical feature of Developmental and epileptic encephalopathy 99 (DEE99, MIM #619606). Both these disorders are of infantile or early-childhood onset. However, spastic paraplegia/ parapresis or quadriplegia/ quadriparesis have not been reported as features of the other two disorders – Dystonia-12 (MIM #128235) and CAPOS syndrome (MIM #601338), and Dystonia-12 has its onset in adolescence or early adulthood.

Created: 13 Aug 2026, 8:40 a.m. | Last Modified: 13 Aug 2026, 8:40 a.m.

Panel Version: 9.8

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Alternating hemiplegia of childhood 2, OMIM:614820; alternating hemiplegia of childhood 2, MONDO:0013900; Developmental and epileptic encephalopathy 99, OMIM:619606; developmental and epileptic encephalopathy 99, MONDO:0030473; Spasticity, HP:0001257; intellectual disability, MONDO:0001071

Publications

• 37043503

Green List (high evidence)

Recurrent de novo pathogenic variant reported in nine individuals with childhood onset of phenotypes resembling complex hereditary spastic paraplegia or idiopathic spastic cerebral palsy.
Sources: Literature

Created: 9 Aug 2026, 7:16 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
spasticity; developmental delay; intellectual disability

Publications

• PMID: 37043503