Heterogeneity of late-infantile neuronal ceroid lipofuscinosis

Abstract

Purpose: Late-infantile neuronal ceroid lipofuscinosis (LINCL), an autosomal recessively inherited I Y S O S O~~~ storage disorder characterized by autofluorescent inclusions and rapid progression of neurodegeneration, is due to CLN2 gene mutations. However, CLN2 mutation analysis has failed to identify some clinically diagnosed "late-infantile" NCL cases. This study was conducted to further characterize genetic heterogeneity in families affected by LINCL. Methods: DNA mutations in the CLN1, CLN2, and CLN3genes that underlie INCL (infantile NCL).LINCL, and JNCL (juvenile NCL), respectively, were studied with molecular analyses. Results: A total of 252 families affected by childhood NCL were studied. Of 109 families clinically diagnosed a s having LINCL, 3 were determined to have either INCL or JNCL by identification of mutation(s) in CLNl or CLN3. Six families diagnosed initially a s having JNCL were found to have LINCL based on the finding of mutations in the CLN2 gene. In addition, several novel mutations were identified. Conclusions: Clinical and genetic heterogeneity of LINCL was demonstrated in nine LINCL families studied. Genetics in Medicine, 2000:2(6):312-318.

Lysosomal storage disease in the brain: mutations of the β-mannosidase gene identified in autosomal dominant nystagmus

“…The accumulated substrate(s) of the defective enzyme(s) lead to dysfunction in the nervous system, eye, and other systems and ultimately lead to cell death and organspecific clinical manifestations. Most LSDs are inherited in an autosomal-recessive manner, 21 but some, like patients with neuronal ceroid lipofuscinosis 4B and nystagmus 18,22 and the case presented here, present autosomal-dominant inheritance. 23,24 Mutations in MANBA have been previously linked to β-mannosidosis (OMIM 248510), an autosomal-recessive LSD resulting in demyelination of the CNS.…”

A two-dimensional protein fragmentation-proteomic study of neuronal ceroid lipofuscinoses: Identification and characterization of differentially expressed proteins

“…Procedures of PF2D analysis were conducted following the manufacture's protocol (http://www.beckmancoulter.com), as we described earlier [10] with slight modification.…”

“…Similar phenotypes including deregulated cell growth, apoptosis, and abnormal sphingolipid/phospholipids levels, exist in the variant NCLs, have been observed [7], and there are multiple points at which the NCL proteins may associate [8,9]. However, the CLN1, CLN2, and CLN3 encoded proteins may not interact with each other [10]. Despite extensive investigation, the precise biological mechanism underlying the development of the NCLs has remained elusive [11].…”

Myoclonic Epilepsy in Lysosomal Storage Disorders

“…Epilepsy appears later, becoming rapidly intractable and accompanied with cognitive loss, myoclonic jerks and retinopathy. Patient autonomy is completely lost within the age of 6-8 and death occurs within adolescence period (Zhong et al, 2000;Steinfeld et al, 2002;Kohan et al, 2009). Two major distinct phenotypes have been described for classical juvenile phenotype of NCL3 (Batten disease), according to the patient's genotype: a. patients carrying the 1-kb deletion in homozygous, (firstly described in Finland and Northern Europe), and b. patients carrying a compound of 1-kb deletion with other mutations (Munroe et.…”