CLN6 Mutations May Lead to Batten Without Vision Loss, 3 Cases Show
Mutations in the CLN6 gene — which have been associated with 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.
Notably, a new, de novo (non-inherited) disease-causing 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, appear for the first time in a person.
These findings, highlighting 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 associated with the disease.
The study, “A Novel CLN6 Variant Associated With Juvenile Neuronal Ceroid Lipofuscinosis in Patients With Absence of Visual Loss as a Presenting Feature,” was published in the journal Frontiers in Genetics.
Batten disease, the most common group of pediatric neurodegenerative disorders, is characterized by vision loss — due to damage to the retina — as well as progressive cognitive decline, motor impairment, loss of coordination (ataxia), and seizures. Of note, the retina is the light-sensitive inside lining of the eye that contains photoreceptors that transform light into electrical signals.
To date, scientists have linked Batten to different mutations in more than 13 genes. Those in the CLN6 gene have been linked to late-infantile and juvenile Batten, and to the very rare adult form of the disease.
Now, a team of researchers in Cyprus described the cases of three male patients from two unrelated Greek-Cypriot families who showed an atypical form of juvenile Batten disease caused by CLN6 mutations that did not lead to vision loss.
The first patient, who was followed until he was 28 years old, showed cognitive decline at age 6 and mild ataxia when walking. Those symptoms progressed over time and four years later, he experienced his first seizure. Seizures worsened during his adolescence and continue to occur on occasion.
He also developed severe motor disabilities, spasticity, which is stiff or tight muscles, and swallowing and speech difficulties.
The two other boys, brothers who were born of consanguineous parents (biologically related to each other), developed their first symptoms at ages 6 and 7. Their main clinical characteristics included ataxia when walking, spasticity, speech difficulties, involuntary spasms, and intellectual disability.
At those ages, the boys had no history of seizures, one of the main symptoms of CLN6-associated Batten, the team noted. The family was subsequently lost to follow-up.
Notably, none of the three patients had initial evidence of visual problems, contrasting with what is typically seen in pediatric forms of Batten.
However, at 18, the first patient showed reduced visual acuity and signs of retina damage.
Genetic testing revealed that the first patient carried a previously reported mutation, called p.Arg136His, in one of the CLN6 gene copies, and a new, de novo mutation, called p.Tyr295Cys, in the other.
“To our knowledge, this is the first report of a de novo variant in CLN6,” the researchers wrote.
The siblings were found to have the p.Arg136His mutation in both copies of the CLN6 gene. 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 the identified CLN6 mutations on protein structure and function, the researchers then conducted prediction and structural analyses.
They found that both p.Arg136His and p.Tyr295Cys mutations resulted in a change in one amino acid, the build blocks of proteins, which was considered to promote structural changes in the resulting CLN6 protein. Both mutations were deemed likely disease-causative.
“Protein structural analysis displayed a possible explanation of how these variants may affect the binding activity and the function of the CLN6 protein and consequently cause the disease,” the researchers concluded.