‘Alternative’ genetic cause for Rett found in case of Swedish girl
Variant in GABBR2 identified after standard genetic testing proved negative
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A girl in Sweden who was diagnosed with Rett syndrome at age 7 despite testing negative for standard gene mutations was found to have an “alternative genetic cause” for the rare disease: a change in the DNA sequence of the GABBR2 gene.
The researchers say this child’s case shows that mutations in GABBR2 can cause symptoms of classic Rett and, as such, should be considered when symptoms are present but genetic testing for MECP2 mutations is negative. MECP2 is the gene most commonly associated with Rett.
“We describe a girl fulfilling the clinical diagnostic criteria for classic [Rett] in whom standard genetic testing … was normal,” the researchers wrote, noting that a more extensive analysis found the so-called alternative cause “that was confirmed.” The team noted that the girl had all the typical features of Rett, with “developmental stagnation, regression, and characteristic neurological symptoms.”
According to the scientists, “these findings … highlight the importance of considering GABBR2 in the genetic evaluation of MECP2-negative patients with … clinical [signs of Rett].”
The child’s case was described in “A Heterozygous Variant in the GABBR2 Gene in a Girl With Clinical Classic Rett Syndrome,” which was published as a report in the journal Molecular Genetics & Genomic Medicine.
In classic Rett, children develop normally in infancy, but then progression typically stalls. That’s usually followed by a loss of skills already learned, a subsequent stage of stabilization, and a later phase of motor function deterioration. For most youngsters, motor impairments worsen over time and communication does not improve. Children with atypical Rett, meanwhile, show many features of the disease but do not meet all criteria for classic Rett.
Most cases of classic Rett are caused by mutations in MECP2, which helps control gene activity in nerve cells in the brain. However, other genes may be involved.
This report describes a girl with typical features of classic Rett: She developed normally at first, but by 6 months she had difficulty eating and her motor development was delayed. She also had problems grasping objects and had delayed head control.
Just before turning 1, she could smile and make sounds but had little direct eye contact. According to the researchers, she could not sit independently and had frequent episodes of screaming. She also needed a feeding tube and had lower than normal pain sensitivity.
During her second year, she lost hand and communication skills, while teeth grinding, called bruxism, developed. By age 3, she had developed behaviors such as self-biting and self-hitting and was diagnosed with autism.
At age 7, a specialist found that she met the diagnostic criteria for classic Rett. However, genetic testing found no disease-causing mutation in MECP2.
Whole-exome sequencing, which covers the protein-coding parts of genes, revealed a variant in GABBR2. This gene provides instructions for making part of the GABA-B receptor, which helps nerve cells control their activity using GABA, a chemical messenger that generally reduces nerve cells’ ability to receive, create, or send messages.
The identified mutation, called p.Ala567Thr, was a de novo variant because it was not present in either parent but rather arose anew in the child. It was heterozygous, meaning only one of the two copies of the gene had the change.
“This was the only clinically relevant de novo variant,” the researchers wrote.
As the genetic testing strategy [used in Rett] increasingly shifts toward broader sequencing approaches, [this] … GABBR2 … variant may prove to be more common than currently recognized.
The researchers reported that, by the time the girl reached age 15, behavioral challenges had become a major concern. She experienced repeated cycles of about two weeks of better behavior followed by two weeks of increased agitation, screaming, and self-injury. During better periods, she could attend special school up to five days a week; during difficult periods, she attended no more than two days a week.
Several medications — including clonidine, aripiprazole, melatonin, promethazine, and risperidone — were tried to manage behavior and sleep. Risperidone, an antipsychotic medication, appeared to help the most, but its benefit lasted only a few hours, the team noted.
According to the researchers, this case adds to the evidence that changes in GABBR2 can sometimes produce classic Rett symptoms.
“As the genetic testing strategy increasingly shifts toward broader sequencing approaches, the recurrent GABBR2 (p.Ala567Thr) variant may prove to be more common than currently recognized,” the team wrote.
The exact biological mechanism are still not fully understood, but the finding suggests that disrupted GABA-B receptor signaling may contribute to classic Rett-like features.
“Since cost and access still influence diagnostic strategies, we believe GABBR2 should be included if a less comprehensive testing approach is chosen,” the researchers concluded.
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