Related Experiment Video
Updated: Jan 5, 2026
Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
A novel lethal recognizable polymicrogyric syndrome caused by ATP1A2 homozygous truncating variants
Nicolas Chatron1,2, Sara Cabet3, Eudeline Alix1
1Genetics Department, Hospices Civils de Lyon, Lyon, France.
Abstract:
Polymicrogyria is a heterogeneous malformation of cortical development microscopically defined by an excessive folding of the cortical mantle resulting in small gyri with a fused surface. Polymicrogyria is responsible for a wide range of neurological symptoms (e.g. epilepsy, intellectual disability, motor dysfunction). Most cases have a supposed environmental clastic vascular or infectious origin but progress in genomics has revealed new monogenic entities. We report four cases from two independent families sharing a common recognizable lethal syndromic polymicrogyria of autosomal recessive inheritance. Beyond diffuse polymicrogyria detected prenatally, pathological examination revealed a common pattern associating meningeal arterial calcifications, necrotic and calcified areas in basal ganglia, dentato-olivary dysplasia and severe hypoplasia/agenesis of the pyramidal tracts. In all affected cases, exome sequencing showed a pathogenic homozygous nonsense ATP1A2 variant. This resulted in absence of immunodetectable ATP1A2 protein in two brains analysed. ATP1A2 encodes the alpha-2 isoform of the Na+/K+-ATPase, which is highly expressed in brain tissues and has previously been related to familial hemiplegic migraine (MIM#602481) and alternating hemiplegia of childhood (MIM#104290). Through the description of this genetic entity, we emphasize the possibility of dual mode of transmission for disease-causing genes and provide the key neuropathological features that should prompt geneticists to test for mutations in the ATP1A2 gene.
Insights
A newly identified lethal syndromic polymicrogyria, inherited in an autosomal recessive manner, is caused by mutations in the ATP1A2 gene. This genetic disorder presents with specific neuropathological features, including brain calcifications and developmental abnormalities.
Area of Science:
- Neuroscience
- Genetics
- Developmental Biology
Background:
- Polymicrogyria is a brain malformation characterized by excessive cortical folding, leading to neurological deficits.
- While often attributed to environmental factors, genetic causes are increasingly recognized.
- The ATP1A2 gene, encoding the Na+/K+-ATPase alpha-2 subunit, is known to be involved in neurological disorders.
Purpose of the Study:
- To identify the genetic cause of a lethal syndromic polymicrogyria observed in two families.
- To characterize the neuropathological features associated with this specific form of polymicrogyria.
- To highlight the role of ATP1A2 mutations in a novel syndromic polymicrogyria.
Main Methods:
- Clinical examination and prenatal diagnosis of affected individuals.
- Pathological examination of brain tissue from affected cases.
- Whole exome sequencing to identify genetic variants.
- Immunohistochemical analysis to assess protein expression.
Main Results:
- Four cases from two families presented with a recognizable lethal syndromic polymicrogyria.
- Neuropathological findings included diffuse polymicrogyria, meningeal arterial calcifications, basal ganglia calcifications, dentato-olivary dysplasia, and hypoplastic/absent pyramidal tracts.
- All affected individuals harbored a homozygous nonsense ATP1A2 variant, leading to absent ATP1A2 protein.
- This indicates an autosomal recessive inheritance pattern for this specific ATP1A2-related disorder.
Conclusions:
- A novel autosomal recessive syndromic polymicrogyria is caused by homozygous ATP1A2 mutations.
- Specific neuropathological features are key indicators for ATP1A2 mutation testing in polymicrogyria cases.
- This expands the spectrum of neurological disorders associated with ATP1A2 and highlights potential dual modes of transmission for disease-causing genes.
Related Concept Videos
01:48ATP Synthase: Mechanism
02:41Lethal Alleles
Lucien Cuénot discovered lethal alleles in 1905 while studying the inheritance of coat color in mice. The agouti gene is responsible for the color of the coat in mice. This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow...
01:18ATP Synthase: Structure
01:31Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of...
01:31Translation
Translation Produces the Building Blocks of Life
Proteins are...
01:19Allosteric Proteins-ATCase
Aspartate transcarbamoylase (ATCase) is a cytosolic enzyme that catalyzes the condensation of L-aspartate and carbamoyl phosphate to N-carbamoyl-L-aspartate. This reaction is the first step in pyrimidine biosynthesis. UTP and CTP, the end products of the pyrimidine synthesis...