Clinical and genetic characterization of a cohort of 97 CLN6 patients tested at a single center

Abstract

Background Ceroid lipofuscinoses neuronal 6 (CLN6) disease belongs to the neuronal ceroid lipofuscinoses (NCLs), complex and genetically heterogeneous disorders with wide geographical and phenotypic variation. The first clinical signs usually appear between 18 months and 8 years, but examples of later-onset have also been reported. Common manifestations include ataxia, seizures, vision impairment, and developmental regression. Because these are shared by other neurological diseases, identification of CLN6 genetic variants is imperative for early diagnosis. Results We present one of the largest cohorts to date of genetically diagnosed CLN6 patients screened at a single center. In total 97 subjects, originating from 20 countries were screened between 2010 and 2020. They comprised 86 late-infantile, eight juvenile, and three adult-onset cases (two patients with Kufs disease type A, and one with teenage progressive myoclonic epilepsy). The male to female ratio was 1.06: 1.00. The age at referral was between six months and 33 years. The time from disease onset to referral ranged from less than 1 month to 8.3 years. The clinical phenotype consisted of a combination of symptoms, as reported before. We characterized a total of 45 distinct variants defining 45 distinct genotypes. Twenty-four were novel variants, some with distinct geographic associations. Remarkably, c.257A > G (p.H86R) was present in five out of 23 unrelated Egyptian individuals but in no patients from other countries. The most common genotype was homozygosity for the c.794_796del in-frame deletion. It was present in about one-third of CLN6 patients (28 unrelated cases, and 2 familial cases), all with late-infantile onset. Variants with a high likelihood of causing loss of CLN6 function were found in 21% of cases and made up 33% of all distinct variants. Forty-four percent of variants were classified as pathogenic or likely pathogenic. Conclusions Our study significantly expands the number of published clinical cases and the mutational spectrum of disease-associated CLN6 variants, especially for the Middle Eastern and North African regions. We confirm previous observations regarding the most prevalent symptoms and recommend including CLN6 in the genetic diagnosis of patients presenting with early-onset abnormalities of the nervous system, musculoskeletal system, and eye.

Cellular Modeling of CLN6 with IPSC-derived Neurons and Glia

“…We evaluated each subjects’ previous neuroimaging to and found WMSAs were present on each subjects’ brain MRI, whether those neuroimaging studies were performed early or late in their disease course (Fig 1). WMSAs were predominantly present in the periventricular and occipital regions and were similar to previous case reports (Biswas et al, 2020; Cannelli et al, 2009; Guerreiro et al, 2013; Jadav et al, 2014; Katz et al, 2020; Rus et al, 2022; Sawiak et al, 2015; Sun et al, 2018; White et al, 2018). Brief summaries of each subject’s genotype, phenotype and white matter findings are presented in the Supplementary Information.…”

“…Currently, no effective therapeutic interventions have been developed for CLN6A. The CLN6A subtype typically presents with delayed language development, cognitive regression, and motor decline (Canafoglia et al, 2015;Rus et al, 2022).…”

“…Clinically, CLN6-related phenotypes are categorized into two major subtypes: a severe childhood form, CLN6A (or variant late-infantile (vLINCL); OMIM 601780)(Cárcel-Trullols et al, 2015; Haltia and Goebel, 2013; Rus et al, 2022; Tuermer et al, 2021) and an adult-onset disease, CLN6B (or Kufs type; OMIM 204300). Currently, no effective therapeutic interventions have been developed for CLN6A.…”

“…Currently, no effective therapeutic interventions have been developed for CLN6A. The CLN6A subtype typically presents with delayed language development, cognitive regression, and motor decline (Canafoglia et al, 2015; Rus et al, 2022). 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).…”

The involvement of Purkinje cells in progressive myoclonic epilepsy: Focus on neuronal ceroid lipofuscinosis

“…In CLN6 mouse model brains, expression of Zip7 in PCs was altered, being shown to be higher than in control brains. Seizures are a typical symptom of CLN6 disease ( Canafoglia et al, 2015 ; Berkovic et al, 2019 ), especially in the adult form ( Rus et al, 2022 ), in which patchy loss of PCs has been observed ( Robertson et al, 2008 ). However, in the abovementioned mouse model, only PC involvement in motor symptoms was evaluated; the possible involvement of these cells in epileptic status in this model thus needs to be further evaluated.…”