Clinical Guidance
PI4KA-related disorder is a clinically variable disorder characterized by neurologic dysfunction, gastrointestinal manifestations (intestinal atresia, inflammatory bowel disease), and immunodeficiency. Onset is typically antenatal or in early childhood. Four overlapping clinical phenotypes have been described: • Hypomyelinating leukodystrophy with pyramidal features including lower limb spasticity, developmental delay, and intellectual disability, with or without inflammatory bowel disease. The most common presentation; neurologic features typically present in infancy or early childhood. • Severe antenatal-onset neurologic disorder with arthrogryposis and structural brain anomalies (e.g., perisylvian polymicrogyria, cerebellar hypoplasia) • Multiple intestinal atresia presenting shortly after birth, with or without immunodeficiency • Rarely, later-onset pure hereditary spastic paraplegia To date, 24 individuals have been identified with PI4KA pathogenic variants . The following description of the phenotypic features associated with this condition is based on these reports. Table 2. PI4KA-Related Disorder: Frequency of Select Features
Feature | Proportion ofPersons w/Feature1 | Comment |
|---|
manifestations | Limb spasticity | 16/16 |
Developmental delay | 14/16 | — |
Intellectual disability | 15/16 | — |
Seizures | 10/16 | — |
Ataxia | 10/16 | — |
Nystagmus | 8/16 | Brain MRI |
findings | Hypomyelinating leukodystrophy/delayed myelination | 12/16 |
Cerebellar hypoplasia/ atrophy | 12/19 | — |
Dysplastic/thin corpus callosum | 11/19 | — |
Perisylvian polymicrogyria | 4/19 | — |
Multiple intestinal atresia | 5/24 | — |
Inflammatory bowel disease | 4/24 | — |
Immunodeficiency | 6/21 | 1. Affected persons who died before a specific clinical sign would become apparent are not included in the table. Limb spasticity. All individuals with molecularly confirmed PI4KA-related disorder reported to date who survived beyond age one month developed or presented with limb spasticity. |
Source: GeneReviews — "PI4KA-Related Disorder"
