Recent Insight into the Genetic Basis, Clinical Features, and Diagnostic Methods for Neuronal Ceroid Lipofuscinosis

Abstract

Neuronal ceroid lipofuscinoses (NCLs) are a group of rare, inherited, neurodegenerative lysosomal storage disorders that affect children and adults. They are traditionally grouped together, based on shared clinical symptoms and pathological ground. To date, 13 autosomal recessive gene variants, as well as one autosomal dominant gene variant, of NCL have been described. These genes encode a variety of proteins, whose functions have not been fully defined; most are lysosomal enzymes, transmembrane proteins of the lysosome, or other organelles. Common symptoms of NCLs include the progressive loss of vision, mental and motor deterioration, epileptic seizures, premature death, and, in rare adult-onset cases, dementia. Depending on the mutation, these symptoms can vary, with respect to the severity and onset of symptoms by age. Currently, all forms of NCL are fatal, and no curative treatments are available. Herein, we provide an overview to summarize the current knowledge regarding the pathophysiology, genetics, and clinical manifestation of these conditions, as well as the approach to diagnosis.

Two compound heterozygous variants in the CLN8 gene are responsible for neuronal cereidolipofuscinoses disorder in a child: a case report

“…Microscopic analysis of ultrastructural patterns of cellular deposits helps categorize patients into possible NCL subtypes, as lipopigment morphotypes generally strongly correlate with genotype ( 2 ). Skin biopsy (punch) was performed and fixed in a mixture of 2.5% glutaraldehyde, 2% formaldehyde, 0.1 M sodium cacodylate buffer, pH 7.4, 2 hs at room temperature.…”

“…Neuronal Ceroid Lipofuscinosis (NCL) disorders are the most common neurodegenerative diseases in childhood, and are reported as the leading cause of childhood dementia worldwide ( 1 , 2 ). The higher prevalence of selected forms of NCL in restricted geographic areas is historical and might reflect early progress in molecular diagnosis in some countries ( 3 ).…”

Intravitreal enzyme replacement for inherited retinal diseases

“…CLN2 (OMIM # 204500) is caused by bi-allelic mutations in the CLN2 gene on chromosome 11p15 [18]. The most common initial symptoms of individuals affected by CNL2 are: language delay and seizures progressive deterioration in cognitive and motor functions, worsening vision from ages 2-4, and premature death by the second decade of life [19].…”

Progressive Visual Loss Is Not Always Accompanied by Neurodegenerative Disorder in Juvenile Neuronal Ceroid Lipofuscinosis: A Case Report

“…Type 3, the classic and most common form, is caused by homozygous or compound heterozygous pathogenic variants in the CLN3 gene that encodes a lysosomal transmembrane protein. This yields in unbalanced cellular homeostasis and increased neuronal loss, as the physiological protein is predicted to be a pH regulator and modulator of vesicular transport and fusion 1 . Clinical symptoms mostly present between 5 – 10 years of age and manifest as progressive vision loss and, rarely, seizures.…”

“…Clinical symptoms mostly present between 5 – 10 years of age and manifest as progressive vision loss and, rarely, seizures. Cognitive and behavioural impairment is thought to appear a few years after the onset of visual impairment 1 . This is, however, not always the case.…”