Neuronal Ceroid Lipofuscinosis Type 6 (CLN6) clinical findings and molecular diagnosis: Costa Rica’s experience

Abstract

Background Commonly known as Batten disease, the neuronal ceroid lipofuscinoses (NCLs) are a genetically heterogeneous group of rare pediatric lysosomal storage disorders characterized by the intracellular accumulation of autofluorescent material (known as lipofuscin), progressive neurodegeneration, and neurological symptoms. In 2002, a disease-causing NCL mutation in the CLN6 gene was identified (c.214G > T) in the Costa Rican population, but the frequency of this mutation among local Batten disease patients remains incompletely characterized, as do clinical and demographic attributes for this rare patient population. Objective To describe the main sociodemographic and clinical characteristics of patients with a clinical diagnosis for Batten Disease treated at the National Children's Hospital in Costa Rica and to characterize via molecular testing their causative mutations. Methods DNA extracted from buccal swabs was used for CLN6 gene sequencing. Participants’ sociodemographic and clinical characteristics were also obtained from their medical records. Results Nine patients with a clinical diagnosis of Batten disease were identified. Genetic sequencing determined the presence of the previously described Costa Rican homozygous mutation in 8 of 9 cases. One patient did not have mutations in the CLN6 gene. In all cases where the Costa Rican CLN6 mutation was present, it was accompanied by a substitution in intron 2. Patients were born in 4 of the 7 Costa Rican provinces, with an average onset of symptoms close to 4 years of age. No parental consanguinity was present in pedigrees. Initial clinical manifestations varied between patients but generally included: gait disturbances, language problems, visual impairment, seizures and psychomotor regression. Cortical and cerebellar atrophy was a constant finding when neuroimaging was performed. Seizure medication was a common element of treatment regimens. Conclusions This investigation supports that the previously characterized c.214G > T mutation is the most common causative NCL mutation in the Costa Rican population. This mutation is geographically widespread among Costa Rican NCL patients and yields a clinical presentation similar to that observed for CLN6 NCL patients in other geographies.

Phenotypic/Genotypic Profile of Children with Neuronal Ceroid Lipofuscinosis in Southern Brazil

“…This finding aligns with a study by Badilla-Porras et al in 2022, which described eight patients with CLN6 carrying the homozygous Costa Rican mutation. [26][27][28][29][30] MFSD8:p.(Tyr121Cysfs à 10) variant was presented in homozygosity and has not been previously reported in the literature. Mutations that lead to loss of function of the MFSD8 gene are classically described with the late infantile phenotype, characterized by seizures, progressive mental and motor deterioration, myoclonus, visual loss, and premature death, already widely described in the literature, with visual loss being a striking feature, presenting a variety of ophthalmological signs ranging from isolated macular degeneration to generalized retinopathy, depending on the genotype found.…”

Cellular Modeling of CLN6 with IPSC-derived Neurons and Glia

“…This cohort had three sibling pairs with five females and four males. There were eight variants: seven of which had been previously reported, along with one novel variant (c.655 +1 G>A; IVS6+1) (Andrade et al, 2012; Badilla-Porras et al, 2022; Berkovic et al, 2019; Chin et al, 2019; White et al, 2018). Four subjects possessed homozygous variants: with two of those being siblings.…”

“…Previous neuroimaging studies of patients clinically-classified with vLINCL reported primary involvement of cortical and subcortical grey matter (Badilla-Porras et al, 2022;Baker et al, 2017;Cannelli et al, 2009;Guerreiro et al, 2013;Jadav et al, 2014;Petersen et al, 1996;Peña et al, 2001;Peña et al, 2004); however confirmed genetic diagnoses were not always established in these subjects, so the data could be representative of a mix of clinically-similar NCLs (Baker et al, 2017;Jadav et al, 2014). Recently, a few genetically-confirmed CLN6 cases were also reported to possess white matter signal abnormalities (WMSAs) (Guerreiro et al, 2013;Biswas et al, 2020;Cannelli et al, 2009;Sun et al, 2018).…”

Rare adult neuronal ceroid lipofuscinosis associated with CLN6 gene mutations: A case report

“…The CLN6 gene is located on chromosome 15q21-23, contains seven exons and encodes a protein with seven transmembrane domains, an N-terminal cytoplasmic domain and a lumen C-terminal. This protein is involved in endoplasmic reticulum-to-Golgi transfer of lysosomal enzymes, causing clinical symptoms[ 10 - 13 ].…”