Early-infantile onset epilepsy and developmental delay caused by bi-allelic GAD1 variants

Abstract

Gamma-aminobutyric acid (GABA) and glutamate are the most abundant amino acid neurotransmitters in the brain. GABA, an inhibitory neurotransmitter, is synthesized by glutamic acid decarboxylase (GAD). Its predominant isoform GAD67, contributes up to ∼90% of base-level GABA in the CNS, and is encoded by the GAD1 gene. Disruption of GAD1 results in an imbalance of inhibitory and excitatory neurotransmitters, and as Gad1−/− mice die neonatally of severe cleft palate, it has not been possible to determine any potential neurological dysfunction. Furthermore, little is known about the consequence of GAD1 disruption in humans. Here we present six affected individuals from six unrelated families, carrying bi-allelic GAD1 variants, presenting with developmental and epileptic encephalopathy, characterized by early-infantile onset epilepsy and hypotonia with additional variable non-CNS manifestations such as skeletal abnormalities, dysmorphic features and cleft palate. Our findings highlight an important role for GAD1 in seizure induction, neuronal and extraneuronal development, and introduce GAD1 as a new gene associated with developmental and epileptic encephalopathy.

GABAergic Gene Regulatory Elements Used in Adeno-Associated Viral Vectors

“…Impairment of GABA synthesis or GABA neuron activity is thought to lead to neurodevelopmental disorders, epilepsy, and psychiatric disorders. For instance, GABA synthesis failure by bi-allelic loss-of-function mutations in the GAD1 gene causes early infantile epilepsy, severe cleft palate, and neonatal death ( 19 , 20 ). In addition, reduced GABAergic neuronal activity, abnormal brain activity, or GABA markers in postmortem studies have been observed in epilepsy ( 21 ), autism ( 22 , 23 ), schizophrenia ( 24 ), Alzheimer's disease ( 25 ), Down's Syndrome ( 26 ), and bipolar disorder ( 27 ).…”

Biallelic Variants in KIF17 Associated with Microphthalmia and Coloboma Spectrum

“…Of note, an association between de novo loss-of-function variants in KIF17 and neurodevelopmental phenotypes, including abnormal behavior and schizophrenia, was previously proposed [ 18 ]. Different genes encoding kinesins and motor proteins have been previously implicated in brain development, and defining the full spectrum of disease-causing molecular pathways will help to diagnose, monitor, and accelerate treatment development in genetic neurodevelopmental conditions with associated cytoskeleton alterations or modulating ionotropic glutamate receptor subunits [ 19 , 20 , 21 , 22 , 23 , 24 ].…”

Prominent and Regressive Brain Developmental Disorders Associated with Nance-Horan Syndrome

“…Despite being in the era of next-generation sequencing (NGS), the etiology and disease mechanisms underlying regressive neurodevelopmental impairment remain undetermined in a certain proportion of cases [ 4 , 5 ]. Defining the full spectrum of disease-causing molecular pathways underlying neurodevelopmental disorders will help to diagnose and monitor developmental trajectories in children affected with these conditions [ 6 , 7 , 8 , 9 , 10 , 11 ]…”