Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability.
Level 4 - case-series / case-control
Case series of 3 patients with supplementary in vitro functional characterization
PubMed 30388404 · doi:10.1016/j.ajhg.2018.10.004
What was done
Whole-exome sequencing and Sanger sequencing were performed in three unrelated infants presenting with generalized seizures, severe hypomagnesemia, and renal magnesium wasting. Mutant Na+,K+-ATPase alpha 1 subunits (ATP1A1) were functionally characterized using heterologous expression systems.
What was found
Heterozygous de novo mutations in ATP1A1 were identified in all 3 infants. Patients exhibited persistent seizures despite magnesium supplementation and significant intellectual disability. In heterologous systems, mutant subunits showed loss of Na+,K+-ATPase activity and abnormal cation permeabilities causing membrane depolarization. The abstract reports no numerical values or quantitative physiological parameters.
Why it matters
This study defines a novel monogenic disorder linking ATP1A1 mutations to human renal magnesium handling defects and severe refractory neurodevelopmental impairment.
Limits
The clinical sample is limited to 3 infants, restricting assessment of phenotypic variability and long-term outcomes. Functional validation was restricted to heterologous cell models rather than patient-derived tissues or in vivo models. Quantitative biochemical and clinical data are omitted from the abstract.
Cited by
- supports Sodium, potassium, and magnesium electrolytes are essential for the normal physiological function of all cells, particularly neurons.