Bi-allelic GAD1 variants cause a neonatal onset syndromic developmental and epileptic encephalopathy

Abstract

Developmental and epileptic encephalopathies are a heterogeneous group of early-onset epilepsy syndromes dramatically impairing neurodevelopment. Modern genomic technologies have revealed a number of monogenic origins and opened the door to therapeutic hopes. Here we describe a new syndromic developmental and epileptic encephalopathy caused by bi-allelic loss-of-function variants in GAD1, as presented by 11 patients from six independent consanguineous families. Seizure onset occurred in the first 2 months of life in all patients. All 10 patients, from whom early disease history was available, presented with seizure onset in the first month of life, mainly consisting of epileptic spasms or myoclonic seizures. Early EEG showed suppression-burst or pattern of burst attenuation or hypsarrhythmia if only recorded in the post-neonatal period. Eight patients had joint contractures and/or pes equinovarus. Seven patients presented a cleft palate and two also had an omphalocele, reproducing the phenotype of the knockout Gad1-/- mouse model. Four patients died before 4 years of age. GAD1 encodes the glutamate decarboxylase enzyme GAD67, a critical actor of the γ-aminobutyric acid (GABA) metabolism as it catalyses the decarboxylation of glutamic acid to form GABA. Our findings evoke a novel syndrome related to GAD67 deficiency, characterized by the unique association of developmental and epileptic encephalopathies, cleft palate, joint contractures and/or omphalocele.

Keywords: GAD1; arthrogryposis; cleft palate; hypsarrhythmia; omphalocele; suppression-burst.

Figure 1

Pedigrees of the families with GAD1 variants. Pedigrees of Families A–F. In the pedigree, squares = males; circles = females; open symbols = unaffected family members; slash = deceased. Index cases (arrows) and family members who were analysed by next generation sequencing (asterisks) are indicated. WES was performed for Families A, B, E and F and WGS for Families C and D. The grey symbols in the pedigree C indicate adult-onset epilepsy without intellectual disability in two family members. Affected individuals are represented with black shaded symbols. The GAD1 variants identified in each family are indicated.

Figure 2

Clinical features of the patients. (A–G) Case 4 (Patient B-IV:4). (A) Total view of the proband at the age of 9 months, showing multiple contractures at different joints, and corrected omphalocele. (B) Haemangiomas at the right ear and scalp. (C) Dysmorphic facial features of the index patient, at the age of 2 years. Note hypertelorism, downslanting palpebral fissure, broad nasal bridge with anteverted nares, smooth philtrum and thin upper lip vermilion. (D and E) Lateral view of the patient. Note flat facies, microretrognathia and abnormal asymmetric shaped ears. (F) Total view of the proband showing multiple contractures at different joints, right talipes equinovarus (TEV) and corrected omphalocele with incisional hernia. (G) Abnormal external genitalia with hyperplastic clitoris and hypoplasia of both labia majora and minora. (H) Frontal view of Case 7 (Patient D-V:2) showing low set ears, broad nasal bridge, mild hypertelorism and thin upper lip. (I–O) Cases 9 and 10 (Patients E-III:2 and E-III:1). Photographs of Patient E-III:2 at the age of 3.5 months (I and J) and 15 months (K–N). (I, J, M and N) Note facial dysmorphism (high arched eyebrows, up-slanting palpebral fissures, hypertelorism, depressed nasal bridge, anteverted nares, low set ears, microretrognathia, long philtrum, sparse eyebrows and hair). (I–J) Cervical and axillar web. (J) Abdominal distension. (K–N) Flexion contractures of extremities and (L) pes equinovarus deformity. (O) Case 10 (Patient E-III:1). Note prematurity (born at 29 weeks age of gestation), hypertelorism, macrocephaly, narrow thorax and short limbs.

Figure 3

Interictal EEGs. (A) Case 1 (Patient A-III:1). Hypsarrhythmia at the age of 5 months; note random high amplitude slow waves and spikes during sleep with episodes of voltage attenuation. (B and C). Case 2 (Patient A-III:2). (B) Suppression-burst pattern (S-B) persists at the age of 5 weeks (42 weeks age of gestation). Note bursts of high-voltage slow waves intermixed with high amplitude spikes, polyspikes and fast rhythms, lasting ∼4–5 s and alternating with complete suppression lasting ∼4–5 s in wakefulness. Some bursts could terminate with slow waves mixed up with rare sharp waves predominating over central regions. Note also brief and rare bursts of moderate amplitude theta/delta waves. (C) Longer interburst interval (8–10 s) in sleep.

Figure 4

Brain MRI. (A–D) Case 3 (Patient B-IV:4). Sagittal T₁ and T₂ cuts through the midline at the age of 1 month (A) and 2 years (B) showing hypoplastic corpus callosum, mainly body and to a lesser degree its genu, progressive cerebellar and cerebral atrophy and a cervical notch. Axial cuts T₁ (C) and T₂ (D) at the age of 2 years demonstrating mild-to-moderate cortical atrophy predominating on left hemisphere and mildly enlarged lateral ventricles. (E–G) Cases 7 and 8 (Patients D-V:2 and D-V:3). (E) Sagittal MRI image of Case 7 (Patient D-V:2) showing prominent inner liquor spaces without overt brain malformations. (F) Sagittal MRI image of Case 8 (Patient D-V:3) showing prominent inner liquor spaces without apparent brain malformations except a cervical notch causing an impression in the upper cervical spinal cord area. (G) Normal cerebellar size is demonstrated in Case 8 (Patient D-V: 3).