Phenotype and natural history of variant late infantile ceroid-lipofuscinosis 5
Alessandro Simonati1, Ruth E Williams2, Nardo Nardocci3
1Department of Neuroscience, Biomedicine, Movement - Neurology (Child Neurology and Psychiatry, and Neuropathology), University of Verona, Verona, Italy.
Insights
This study characterizes CLN5 neuronal ceroid lipofuscinosis in children, finding cognitive decline as an early marker. Genetic mutations correlate with disease severity and progression.
Area of Science:
- Pediatric Neurology
- Genetics
- Rare Diseases
Background:
- Neuronal ceroid lipofuscinosis (NCL) are a group of rare, inherited neurodegenerative disorders.
- CLN5 disease is a specific subtype of NCL with poorly understood clinical progression.
Purpose of the Study:
- To define the phenotypic characteristics of children with CLN5 disease.
- To document the natural history and disease progression in a cohort of CLN5 patients.
Main Methods:
- Retrospective analysis of 15 children from the DEM-CHILD International NCL Registry.
- Assessment of functional domains over time, CLN5 gene mutation analysis, and ultrastructural studies.
- In vitro characterization of the pCLN5 gene product in six patients.
Main Results:
- Disease onset ranged from 2 to 7.5 years, with cognitive impairment being the most frequent early symptom.
- Six mutations led to truncated proteins; mixed cytosomes were observed via electron microscopy.
- Disease progression varied between patients and correlated with genetic profiles, with severe mutations linked to faster neurological decline.
Conclusions:
- Cognitive difficulties are early indicators of CLN5 disease.
- Genetic mutations, particularly severe ones, significantly influence the rate of neurological deterioration in CLN5 patients.
Aim:
To characterize the phenotypic profile of a cohort of children affected with CLN5, a rare form of neuronal ceroid-lipofuscinosis (NCL), and to trace the features of the natural history of the disease.
Method:
Records of 15 children (nine males, six females) were obtained from the data sets of the DEM-CHILD International NCL Registry. Disease progression was measured by rating six functional domains at different time points along the disease course. All patients underwent mutation analysis of the CLN5 gene and ultrastructural investigations of peripheral tissues. Expression of the gene product, pCLN5, was characterized in vitro in six patients.
Results:
Disease onset was at 2 to 7 years 6 months of age: impaired learning and cognition were the most common early symptoms. Seizures occurred relatively late (median age 8y) and were the presenting symptoms in two children. Nine mutations were detected in 30 alleles, including six mutations predicting a truncated protein. Mixed cytosomes were observed by electron microscopy. Differences of disease progression were observed in two groups of patients and could be related to their genetic profile.
Interpretation:
Clinical features in a multicentre cohort of patients with CLN5 confirm that cognitive difficulties are early clinical markers of this condition. Severe mutations were associated with a more rapid decline of neurological function.
Related Concept Videos
01:22Lysosomal Hydrolases
01:23Cystic Fibrosis: Pathogenesis
CF is primarily caused by a genetic mutation in a chromosome 7 gene coding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein. The most common gene mutation leading to CF is the ΔF508 mutation,...
01:33Pleiotropy
01:11Genetic Lingo
01:35Pedigree Analysis
01:21Smooth Endoplasmic Reticulum
The ER provides optimal conditions for synthesizing steroid hormones and lipids, such as phospholipids and triglycerides. Traditionally, lipid metabolism was considered to be a smooth ER function. However, there is no direct evidence to prove that rough ER is completely excluded from lipid...