Neuronal ceroid lipofuscinosis in the Russian population: Two novel mutations and the prevalence of heterozygous carriers

Abstract

BackgroundNeuronal ceroid lipofuscinoses (NCLs) are a group of neurodegenerative disorders characterized by an accumulation of lipofuscin in the body's tissues. NCLs are associated with variable age of onset and progressive symptoms including seizures, psychomotor decline, and loss of vision.MethodsWe describe the clinical and molecular characteristics of four Russian patients with NCL (one female and three males, with ages ranging from 4 to 5 years). The clinical features of these patients include cognitive and motor deterioration, seizures, stereotypies, and magnetic resonance imaging signs of brain atrophy. Exome sequencing was performed to identify the genetic variants of patients with NCL. Additionally, we tested 6,396 healthy Russians for NCL alleles.ResultsWe identified five distinct mutations in four NCL‐associated genes of which two mutations are novel. These include a novel homozygous frameshift mutation in the CLN6 gene, a compound heterozygous missense mutation in the KCTD7 gene, and previously known mutations in KCTD7, TPP1, and MFSD8 genes. Furthermore, we estimated the Russian population carrier frequency of pathogenic and likely pathogenic variants in 13 genes associated with different types of NCL.ConclusionOur study expands the spectrum of mutations in lipofuscinosis. This is the first study to describe the molecular basis of NCLs in Russia and has profound and numerous clinical implications for diagnosis, genetic counseling, genotype–phenotype correlations, and prognosis.

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CLN8 Mutations Presenting with a Phenotypic Continuum of Neuronal Ceroid Lipofuscinosis—Literature Review and Case Report

“…The disease’s genetic background continues to unravel. Thus far, more than 430 variants in at least candidate 13 genes ( CLN1 - CLN14 ) are recognized, all autosomal recessive except for the autosomal dominant NCL4, DNAJC5 mutations responsible for the adult onset Parry disease [ 14 , 15 ] NCLs share the common features of cognitive deterioration, movement disorders (including cerebellar ataxia, myoclonus and spasticity), seizures and, in most instances, vision loss due to retina and optic nerve involvement. The exact phenotype, however, depends on the causative gene, mutation and resulting pathology.…”

Whole Exome Sequencing for the Diagnosis of Rare Genetic Neurodevelopmental Disorders Associated with Cerebellar Atrophy

“…Neuronal ceroid lipofuscinosis (NCLs) are a group of clinically and genetically heterogeneous ND lysosomal storage disorders that mostly present by seizures, visual impairment, and a progressive decline in cognitive and motor abilities due to progressive neuronal death [6]. Lysosomal accumulation of auto uorescent lipopigments and proteins in the central nervous system is a key pathological nding of NCLs [7]. This storage process is associated with selective destruction and loss of neurons in brain and retina.…”