Mutations in the CLN6 The gene – which has been linked to different forms of Batten disease – may lead to the development of an atypical form of juvenile Batten that does not cause vision loss, according to a study reporting the cases of three patients from two Greek Cypriot families .
In particular, a new de novo (non-hereditary) causing diseases CLN6 mutation was identified in one of the patients, likely marking the first of such reports. de novo mutations are those that, instead of being inherited, first appear in a person.
These results, showing a link between CLN6 mutations and atypical forms of juvenile Batten, further support the variability of Batten forms and symptoms caused by mutations in this gene. The researchers noted that mutations in more than a dozen genes have been linked to the disease.
The study, “A novel CLN6 Variant associated with juvenile neuronal ceroid lipofuscinosis in patients without visual loss as a presenting featurewas published in the journal Frontiers in genetics.
Batten disease, the most common group of pediatric neurodegenerative disorders, is characterized by loss of vision – due to retinal damage – along with progressive cognitive decline, motor impairment, loss of coordination (ataxia) and seizures. It should be noted that the retina is the light-sensitive inner lining of the eye that contains photoreceptors that convert light into electrical signals.
The disease is divided into four main types based on the age of onset of symptoms: infantile (6 to 24 months), late infantile (2 to 4 years), juvenile (5 to 10 years) and adult (18 and more) .
To date, scientists have linked Batten to different mutations in more than 13 genes. Those in the CLN6 have been linked to late-infantile and juvenile Batten, and the very rare adult form of the disease.
Now, a team of researchers in Cyprus has described the cases of three male patients from two unrelated Greek Cypriot families who presented with an atypical form of juvenile Batten disease caused by CLN6 mutations that did not result in vision loss.
The first patient, who was followed until the age of 28, showed cognitive decline at age 6 and mild walking ataxia. These symptoms progressed over time and four years later he experienced his first attack. The seizures worsened during his teenage years and continue to occur on occasion.
He also developed severe motor disabilities, spasticity, meaning stiff or tense muscles, and difficulty swallowing and speaking.
The other two boys, brothers born to consanguineous parents (biologically related to each other), developed their first symptoms at 6 and 7 years old. Their main clinical features were walking ataxia, spasticity, speech difficulties, involuntary spasms and intellectual disability. .
At these ages, the boys had no history of seizures, one of the main symptoms of CLN6-Associate Batten, the team noted. The family was then lost sight of.
Notably, none of the three patients had initial signs of visual problems, contrary to what is usually seen in pediatric forms of Batten.
However, at age 18, the first patient showed reduced visual acuity and signs of retinal damage.
Genetic testing revealed that the first patient carried a previously reported mutation, called p.Arg136His, in one of the CLN6 copies of genes, and a new one, de novo mutation, called p.Tyr295Cys, in the other.
“To our knowledge, this is the first report of a de novo variant in CLN6“, wrote the researchers.
The siblings were found to have the p.Arg136His mutation in both copies of the CLN6 uncomfortable. The presence of two p.Arg136His mutations was previously reported in a consanguineous Turkish family, whose Batten disease was not associated with seizures.
To better understand the effects of CLN6 mutations on protein structure and function, the researchers then performed predictions and structural analyses.
They found that the p.Arg136His and p.Tyr295Cys mutations resulted in a change in an amino acid, the building blocks of proteins, which was believed to promote structural changes in the resulting CLN6 protein. Both mutations were considered likely responsible for the disease.
“Protein structural analysis has shown a possible explanation for how these variants may affect CLN6 protein binding activity and function and therefore cause disease,” the researchers concluded.