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Two dozen new mutations in the CLN6 have been identified in nearly 100 people, mostly from the Middle East and North Africa, with CLN6 Batten disease, according to a study.

These findings “confirm the genetics and ethnicity [variability] of CLN6 disease,” and should “raise awareness of CLN6 disease and reduce the time from first symptoms to diagnosis for patients and their loved ones worldwide,” the researchers wrote.

The data comes from “one of the largest [groups] to date of genetically diagnosed CLN6 patients screened in a single center,” according to the scientists.

As such, the results broaden the spectrum of illnesses associated with the disease. CLN6 mutations and identify those that are more common in these underrepresented populations, the team said.

The study, “Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single centerwas published in the journal Orphanet Journal of Rare Diseases.

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Batten disease, also known as neuronal ceroid lipofuscinoses (NCL), comprises a group of neurodegenerative conditions characterized by the toxic buildup of waste molecules in body cells. It primarily affects brain cells and leads to nerve cell damage and death.

To date, Batten has been associated with different mutations in more than 13 genes. Those in the CLN6 have been associated with late-infantile (onset at 2-4 years) and juvenile (onset at 5-10 years) Batten, as well as the very rare adult form of the disease.

Common manifestations of CLN6 Batten disease include loss of coordination (ataxia), seizures, visual disturbances, and developmental regression.

“Because these are shared by other neurological diseases, the identification of CLN6 genetic variants are imperative for early diagnosis,” the researchers wrote.

Now, a team from Centogene GmbH, a leader in the genetic diagnosis of rare diseases, has described the demographic, clinical and genetic data of 97 people genetically diagnosed with CLN6 disease at their center between 2010 and 2020.

Patients came from 20 countries – most often those from the Middle East (59%) and North Africa (32%). Most (87%) were unrelated individuals, but 12 (13%) included familial cases.

The majority of patients (86, or 89%) had late infantile Batten. Eight people (8%) had juvenile Batten, the most common form of the disease, and three (3%) had adult-onset disease. Of those who emerged as adults, two had been diagnosed with Kufs disease type A and one with progressive myoclonic epilepsy onset in adolescence.

Median age of onset ranged from less than one month to 15 years, and time from disease onset to referral ranged from less than one month to 8.3 years. The median age at the time of referral was 5.8 years for patients in late childhood, 9.8 years for patients with juvenile onset, and 22.5 to 33.2 years for the three individuals at early adult.

Clinical symptoms, provided for 86 patients, were consistent with previous reports. The most common were developmental regression (53%), seizures (43%), ataxia (33%) and intellectual disability (30%). Additionally, after the nervous and musculoskeletal systems, the eye was the third most affected organ, with varying reports of symptoms.

Genetic testing identified 45 CLN6 genetic mutations, 42% of which were classified as causing or probably causing the disease. Genetic variants with a higher probability of resulting in a defective CLN6 protein were found in 21% of cases and accounted for 33% of all mutations.

A total of 24 of these mutations (53.3%) had not been previously reported. One was classified as causing the disease, seven as probably causing the disease, and 16 as variants of uncertain significance.

Notably, some mutations appeared to be associated with specific disease forms and geographic regions.

The most common and probably disease-causing variant – c.794_796del (p.S265del) – was found exclusively in both copies of the CLN6 gene in 30 patients with Batten with late infantile onset.

The c.83G>A (p.R28K) mutation was exclusively present in three of the eight unrelated juvenile patients and “may be characteristic of this pattern of disease onset,” the researchers wrote.

Furthermore, the most frequent new variant – c.257A > G (p.H86R) – was detected in five of 23 unrelated Egyptian patients, but not in patients from other countries. The c.794 796del (p.S265del) mutation was present in 22 (38.6%) of the 57 patients from the Middle East and in seven (22.6%) of the 31 patients from North Africa.

Cases with newly discovered mutations most often came from Egypt and Iran, where these variants were present in more than half of the patients.

“Our study significantly increases the number of published clinical cases and the mutational spectrum of diseases associated with the disease. CLN6 variants, especially for the Middle East and North Africa regions,” the researchers wrote.

These geographic regions were “underrepresented in the previous dataset compared to Europe and North America,” they added.

“Including CLN6 in genetic diagnosis is recommended for people with developmental regression, seizures, ataxia, intellectual disability and [eye] symptoms,” the team concluded.