A Novel CLN6 Variant Associated With Juvenile Neuronal Ceroid Lipofuscinosis in Patients With Absence of Visual Loss as a Presenting Feature

Abstract

The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of autosomal recessive lysosomal storage disorders that are characterized by neurodegeneration, progressive cognitive decline, motor impairment, ataxia, loss of vision, seizures, and premature death. To date, pathogenic variants in more than 13 genes have been associated with NCLs. CLN6 encodes an endoplasmic reticulum non-glycosylated transmembrane protein, which is involved in lysosomal acidification. Mutations in CLN6 cause late-infantile juvenile NCL (JNCL) adult-onset NCL, and Kufs disease. Members from two available families with JNCL were clinically evaluated, and samples were collected from consenting individuals. The molecular investigation was performed by whole-exome sequencing, Sanger sequencing, and family segregation analysis. Furthermore, in silico prediction analysis and structural modeling of the identified CLN6 variants were performed. We report clinical and genetic findings of three patients from two Greek-Cypriot families (families 915 and 926) with JNCL. All patients were males, and the first symptoms appeared at the age of 6 years. The proband of family 926 presented with loss of motor abilities, ataxia, spasticity, seizure, and epilepsy. The proband of family 915 had ataxia, spasticity, dysarthria, dystonia, and intellectual disability. Both probands did not show initial signs of vision and/or hearing loss. Molecular analysis of family 926 revealed two CLN6 biallelic variants: the novel, de novo p.Tyr295Cys and the known p.Arg136His variants. In family 915, both patients were homozygous for the p.Arg136His CLN6 variant. Prediction analysis of the two CLN6 variants characterized them as probably damaging and disease-causing. Structural modeling of the variants predicted that they probably cause protein structural differentiation. In conclusion, we describe two unrelated Cypriot families with JNCL. Both families had variants in the CLN6 gene; however, they presented with slightly different symptoms, and notably none of the patients has loss of vision. In silico prediction and structural analyses indicate that both variants are most likely pathogenic.

Heterozygosity for neuronal ceroid lipofuscinosis predisposes to bipolar disorder

“… 28 Neuronal ceroid lipofuscinosis, which is caused by biallelic variants in the CLN6 gene, usually presents in early to late childhood (1.5 to 8 years of age) and involves slow motor degeneration, ataxia, vision loss, epilepsy, and mental disabilities. 29 Early death by 12-15 years of age is reported. 29 Variants in CLN6 may also lead to a rare adult-onset form of neuronal ceroid lipofuscinosis in which the symptoms present in adulthood, typically between 24 and 38 years of age.…”

“… 29 Early death by 12-15 years of age is reported. 29 Variants in CLN6 may also lead to a rare adult-onset form of neuronal ceroid lipofuscinosis in which the symptoms present in adulthood, typically between 24 and 38 years of age. 30 , 31 The symptomatology includes ataxia, tremor, and cognitive impairment that appear at approximately 41 years of age.…”

Whole exome screening of neurodevelopmental regression disorders in a cohort of Egyptian patients

“…shtml), the PROVEAN ( http://provean.jcvi.org/index.php ), the SIFT ( http://sift.jcvi.org/www/SIFT_enst_submit.html ), and MutationTaster ( http://www.mutationtaster.org/index.html ) prediction tools. According to the previous programs, novel mutations were confirmed to have damaging effect on protein feature with score 1 and cause diseasing with score > 0.99, and novel mutations were confirmed using Gnomad and Novel Taster [ 10 ]. The remained 23 pathogenic mutations were previously reported.…”

“…As rare disease entities, NCLs comprise the most common cause for progressive neurodegenerative disease in children. NCLs are clinically classified into four major types based on the age of onset of the disease: infantile (6–24 months), late infantile (2–4 years), juvenile (5–10 years), and adult-onset (> 18 years) [ 10 ]. Biochemical and genetic studies especially whole exome sequencing (WES) are considered to be the main diagnostic tools of NCLs.…”

CLN6 Variant of Late Infantile Neuronal Ceroid Lipofuscinosis Caused by a Homozygous Mutation: Case Report in Colombia

“…The variant in exon 4 of CLN6 was previously reported in a homozygous state in a Turkish blood family (Karaca et al, 2015). Three patients were recently reported from two unrelated families with biallelic variants in the CLN6 gene, with different clinical characteristics, where two were homozygous for a known CLN6 pathogenic variant (exon 4) while the other case was a heterozygous compound for the well-known novel de novo variant CLN6 (exon 7) [7].…”