Definition: Juvenile neuronal ceroid-lipofuscinosis (JNCL, Batten disease, Spielmeyer-Vogt-Sjogren disease, CLN3) is the most common inherited, autosomal recessive, neurodegenerative disorder in man.
Like the other neuronal ceroid-lipofuscinoses, it is characterized by progressive loss of vision, seizures, and loss of cognitive and motor functions, leading to premature demise.
Juvenile neuronal ceroid lipofuscinosis (JNCL), or Batten disease, is one type of the neuronal ceroid lipofuscinoses (NCL), a collection of eight inherited neurodegenerative disease with similar pathological features.
JNCL is the most common inherited neurodegenerative disease in childhood, with an annual incidence from 1/12500 to 1/40000 live births. and 440000 carriers in USA. This disease is an autosomal recessive pattern.
Symptoms typically appear between ages 5 and 8, and include blind, gradual deterioration in motor and cognitive skills, changes in behavior, and progressively severe seizures and ataxia.
Over a period of 10-20 years this process inexorably culminates in persistent vegetative state and death. At this time, clinical interventions are limited to amelioration of symptoms and supportive care. No cure exists, and understanding of the molecular pathogenesis of the disease remains unclear.
Etiology
JNCL is caused by mutations of CLN3, a gene that encodes a hydrophobic transmembrane protein, which localizes to membrane lipid rafts in lysosomes, endosomes, synaptosomes, and cell membrane.
While the primary function of the CLN3 protein (CLN3P) may be debated, its absence affects numerous cellular functions including pH regulation, arginine transport, membrane trafficking, and apoptosis.
germline mutations in CLN3 gene, located on chromosome 16p12.1.
- The CLN3 gene encodes a predicted transmembrane 438 amino acid protein called battenin the function of which remains unknown.
- While 31 different CLN3 mutations have been found, in most cases of JNCL disease, chromosomes carry the inherited defect a 1.02 kb deletion(exon 7 and 8) of genomic DNA, resulting in a truncation of CLN3 such that the resultant protein contains the original 153 N-terminal residues followed by 28 novel amino acids .
- In affected individuals, mutations of CLN3 result in pathologic intracellular inclusions in neurons and other cells including liver, lymphosytes and fibroblasts.
- Lysosomal accumulation of autofluorescent lipids and high concentrations of a mitochondrial protein, ATP synthase subunit C, have been reported. Recent immunofluorescence studies have shown that the predominant intracellular destination of nascent CLN3 is the lysosome .
- Cln3-knockout mice homozygous for a targeted deletion of exons 1?6 in the Cln3 gene have been previously reported to show characteristic accumulation of autofluorescent lipopigments containing mitochondrial ATP synthase subunit c in neural tissue, and selective loss of GABAergic neurons.
References
Rakheja D, Narayan SB, Bennett MJ. Juvenile neuronal ceroid-lipofuscinosis (Batten disease): a brief review and update. Curr Mol Med. 2007 Sep;7(6):603-8. PMID: 17896996