The study also represents the second-ever publication describing CLN5 disease in people in Pakistan, hinting at a more worldwide distribution of the condition than previously thought.
The results, “Novel likely disease-causing CLN5 variants identified in Pakistani patients with neuronal ceroid lipofuscinosis,” were published in the Journal of the Neurological Sciences.
Late infantile Batten disease refers to Batten disease in which symptoms manifest in childhood, usually ages 2 to 8. CLN5 disease is a form of late infantile Batten disease that is caused by mutations in the gene CLN5.
The disease originally was identified in northern European populations in the late 1990s. Since then, research has revealed that this disease also is present elsewhere in the world.
The new study describes two Pakistani families that were found to be affected by CLN5 disease. In both families, the parents were consanguineous (biologically related to each other).
In one family, the two oldest children were affected: a 10-year-old girl and a 7-year-old boy. Both children experienced a similar progression of symptoms, including memory loss, difficulty moving, loss of vision, and speech impairment, which started to emerge at 6–7 years of age and progressed over time.
Genetic testing in this family revealed that the affected children had a mutation in CLN5 that had not been reported previously. This mutation was termed c.477T>C or p.Cys159Arg, referring respectively to the change at the DNA and protein level.
The children were homozygous for this mutation — that is, the mutation was present in both of their copies of the CLN5 gene (one copy from each biological parent). Their unaffected siblings, and their parents, were determined to be heterozygous; they had one mutated copy of CLN5, and one wild-type copy.
The disease is inherited in an autosomal recessive matter, which means that a person will develop the disease only if they have two mutant versions of CLN5. People with only one copy are said to be “carriers.” That means they aren’t themselves affected, but risk passing the mutated gene to their biological children, who could develop the disease if they also inherit a second mutant gene from the other biological parent.
In the second family, a 10-year-old boy began experiencing seizures at age 6. Over time, the seizures worsened, and the boy also experienced memory loss, vision impairment, and decreased motor abilities.
Genetic testing revealed the boy to be homozygous for a never-before-reported mutation referred to as c.925_926del or p.Leu309AlafsTer4. His parents were both heterozygous carriers.
Computer modeling of both these newly described mutations suggested that both mutations significantly hindered the function of the protein encoded by CLN5. This is consistent with these mutations causing CLN5 disease.
“In the two Pakistani families, we identified two novel homozygous variants in CLN5,” wrote the authors of the study, noting that, “Our subjects are also the second CLN5 cases in the Pakistani population,” following a previous report published in 2009.
This suggests that CLN5 disease might be more widespread throughout the world than previously appreciated.
“To date, most cases of CLN5 disease have been described in Finnish and [northern] European countries as well as in Italy and China,” the authors wrote. “Our findings indicate that CLN5 pathogenic variants are also present in the South Asian Punjab area, resulting in a more worldwide distribution of CLN5 disease.”
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