The case was presented by a research team at King Faisal Specialist Hospital and Research Centre in Riyadh, Saudi Arabia, in a report titled “Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism.”
In developed countries, most cases of severe mental retardation have genetic origin. However, while more than 400 genes have been linked to intellectual disability, the mutations that affect these genes have low prevalence and give rise to indistinguishable outcomes.
Some single-gene disorders, including fragile X syndrome, neurofibromatosis, tuberous sclerosis, Noonan’s syndrome, and Angelman syndrome, are characterized by mental retardation.
In 90 percent of Angelman syndrome cases, the affected gene is UBE3A. Loss of the UBE3A protein in the brain results in severe developmental delay, seizures, uncoordinated muscle movement (ataxia), movement or balance disorder, and absence of speech. More recently, cases of patients with symptoms that resemble those presented by patients with Angelman syndrome have been reported.
In the this report, a team of researchers presented the case of a 23-year-old man who had generalized brain seizures since he was four months old. At early infancy he started to show signs of impaired development, later exhibiting severe developmental delay and severe speech impairment.
After reviewing the family clinical history, the team found that three siblings and four cousins also were similarly affected.
All the individuals were unable to walk when they achieved adolescence, and presented flexed joint deformities of the lower limbs. They presented severe mental retardation, with great difficulty to process commands and speak. They showed no body signs of puberty, were of short stature, had heads smaller than normal, wide-spaced teeth, and the lower mandible positioned forward.
“Their behavioral pattern is best described as frequent episodic smiling and an apparent happy demeanor, with an easily excitable personality and habitual hand flapping movement,” the researchers wrote.
Blood analysis revealed that the patient had low levels of IGF binding protein-3 (suggestive of growth hormone deficiency), testosterone, androgen, and vitamin D. Additional analysis of muscle tissue biopsy revealed that the patient, as well as his siblings, had increased proliferation of mitochondria, the cell’s powerhouse.
Genetic analysis did not reveal any chromosomal rearrangement or genetic alteration that could be linked to Angelman syndrome. Instead, the team identified the substitution of one single DNA letter in VARS2 genetic sequence. The gene encodes an enzyme that is critical for the normal protein production in mitochondria.
Previous case reports had already identified other mutations affecting VARS2, and they all shared some Angelman syndrome-like clinical features, as did the patient and its siblings.
This report not only identified a new genetic mutation associated to a recessive syndrome disorder, but it also underscores the broad spectrum of symptoms and manifestations associated to these genetic disorders.