Neurodevelopmental disorder related to the GABRB2 gene as a differential diagnosis of angelman syndrome: case report

Case presentation: D.H.S., male, 23 months, non-consanguineous parents, born at term, pregnancy and delivery without complications, healthy 7-year-old brother, and no cases of epilepsy or developmental delay in the family. From birth he had difficulty breastfeeding and hypotonia, at 3 months he started episodes of behavioral arrest, and at 9 months episodes of lip cyanosis, hypertonia of the four limbs lasting less than one minute and post-ictal with exacerbation of hypotonia. At the first hospital evaluation, at 18 months, D.H.S. had significant neuropsychomotor delay, global hypotonia, hypopigmentation of the skin and hair, difficulty in eating and sleeping, signs suggestive of autism spectrum disorder, choreoathetosis, dystonia and refractory epilepsy, Angelman Syndrome (AS) was one of the diagnostic hypotheses evaluated. In the diagnostic investigation, the video electroencephalogram showed a generalized electroclinical crisis with a rhythm starting in bilateral central parietal regions and in the midline, clinically classified as generalized tonic-clonic motor onset; what would be considered an atypical pattern in AS, the other tests performed were not elucidative at first for the case. In a genetic evaluation, the variant c.228A>T (p.Glu76Asp) was identified in the GABRB2 gene in heterozygosity; of uncertain meaning, but potentially deleterious, and may be the cause of all symptoms presented by the patient.

Discussion: The GABRB2 gene encodes a subunit of the gamma-aminobutyric acid (GABA) receptor, which is an ion channel involved in inhibitory neurotransmission. Heterozygous pathogenic variants in GABRB2 are associated with epileptic and developmental encephalopathy. Therefore, the clinic presented by the patient, refractory epilepsy, movement disorder and delay in neuromotor development, is consistent with the genetic alteration found. The variant found is of autosomal dominant inheritance, and although it is classified as a variant of uncertain significance (VUS), it is possible to consider that this rare variant is pathogenic.

Final comments: The recent increase in the availability of genetic tests has allowed the diagnosis of diseases that could previously have been clinically misdiagnosed. In the case of the patient reported here, in which the typical facial features of AS would not yet be observed due to age and the clinical picture was compatible, genetic testing was essential for the differential diagnosis.

 

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No conflict of interest has been declared by the author(s).

Publication History

Article published online:
18 September 2023