Neuronal Ceroid Lipofuscinoses 

  • Author: Celia H Chang, MD; Chief Editor: Amy Kao, MD   more...
 
Updated: Sep 17, 2009
 

Background

The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a group of neurodegenerative disorders. They are considered the most common of the neurogenetic storage diseases with a prevalence of 1 in 12,500 in some populations. They are associated with variable yet progressive symptoms including seizures, dementia, visual loss, and/or cerebral atrophy. In 1826, Stengel described the first patients—4 siblings in Norway. Batten made the first clinicopathologic correlation in 1903 and referred to NCL as familial cerebromacular degeneration. Batten was also the first person to differentiate NCL from Tay-Sachs disease in 1914. Vogt, Spielmeyer, Bielschowsky, and Kufs also described older patients with similar symptoms.

In 1939, Klenk discovered increased gangliosides in Tay-Sachs disease but in not juvenile amaurotic idiocy (an early name for NCL). NCL was later so named because of the accumulation of autofluorescent lipopigments resembling ceroid and lipofuscin. In 1959, Koppang described English setters with the same phenotype as patients with NCL. Although NCLs are generally autosomal recessive disorders, in 1971 Boehme also described autosomal dominant inheritance of the same disease in the Parry family of New Jersey. The enzymatic abnormalities were better defined in the 1980s and the molecular genetics have now being described in some variants of NCL. A database of NCL mutations is maintained and can be found here.[1]

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Pathophysiology

The NCLs are almost all characterized by apoptosis and dysregulated sphingolipid metabolism. It is suspected that there are common pathways for many of the variants. Persaud-Sawin et al found that transfecting CLN1 or CLN2 deficient cells with CLN DNA constructs for either CLN1 or CLN2 was somewhat protective against etoposide-induced apoptosis in both cells types. CLN6 and CLN8 constructions resulted in near total correction of growth defects in CLN3 deficient cells and CLN2 DNA constructs were partially effective. CLN2, CLN3, and CLN8 constructs corrected growth for CLN6 deficient cells. CLN2, CLN3, and CLN6 constructs also corrected growth for CLN8 deficient cells.[2]

In CLN1, a lysosomal enzyme, palmitoyl protein thioesterase 1 (PPT1) is deficient. PPT1, which removes fatty acyl groups from cysteine residues on fatty acid modified proteins, remains in the endoplasmic reticulum where it is inactive, causing sapsosins A and D to accumulate in the lysosomes. Mutations have been found in all 9 exons of the CLN1 gene. Although CLN1 usually had onset in infancy, later onset (including in adulthood) has also been described. More than 49 mutations have been described in CLN1.[1] Lyly et al found that glycosylation of N197 and N232, but not N212 is essential for PPT1s activity and intracellular transport. They also found that PPT1 formed oligomers. They believe that mutations cause more glycosylation and complex formation.[3]

Subunit C of the mitochondrial ATP synthase complex accumulates in the lysosomes of patients with some variants of NCL, including CLN2, CLN3, CLN4, CLN5, CLN6, CLN7, and CLN8. Subunit C also accumulates in some animal models of NCL, including the bovine and several canine variants. Subunit C, an extremely hydrophobic 75-amino-acid protein, is encoded by 2 separate genes, P1 and P2.P1 is on chromosome 17 and P2 is on chromosome 12. The mRNA for P2 is the predominant form. Subunit C is part of a transmembrane proton channel located on the inner mitochondrial membrane. Each ATP synthase complex has 10-12 copies of subunit C.

Patients with CLN2 are deficient in a pepstatin-insensitive lysosomal peptidase—tripeptidyl peptidase 1 (TTP1). TTP1 removes tripeptides from the N -terminal of polypeptides. Mutations have been reported in all 13 exons of the CLN2 gene. Some mutations result in a more protracted course. Although onset is usually in late infancy, later onset has been described. More than 58 mutations have been described in CLN2.[1]

The CLN3 gene encodes a 438 amino acid protein that is thought to be a part of the lysosomal membrane. The most common mutation of CLN3 is a 1.02-kb deletion that involves loss of exons 7 and 8. Most patients with the classic phenotype of JNCL are homozygous for the 1.02-kb deletion. Patients who are compound heterozygotes for this deletion may have atypical phenotypes. Munroe reported 2 patients who were compound heterozygotes with visual failure, only one of whom had seizures; both patients were able to hold full-time employment as adults. Wisniewski et al reported similar patients who initially presented with psychiatric or behavioral symptoms but otherwise had a typical course. More than 42 mutations[1] have been described in CLN3. The exact function of CLN3 is unknown, but its expression is highest in secretory/glandular tissues and in gastrointestinal cells. All patients with CLN3 have had visual failure by age 10.

The adult form of NCL (ANCL) is associated with mutations of the CLN4 gene. The CLN4 gene has not been mapped yet.

Mutations in another gene, CLN5 is associated with Finnish variant LINCL (fLINCL). It occurs predominantly in the Finnish population. CLN5 encodes a 407 amino acid transmembrane protein. CLN5 only occurs in vertebrae. The expression of CLN5 increases during cortical neurogenesis. More than 17 mutations have been described in CLN5.[1]

The CLN6 gene is associated with variant LINCL (vLINCL). Disease caused by CLN6 mutations are also referred to as the Czech or Indian variant. The CLN6 gene has been mapped to band 15q21-q23 and encodes a 311 amino acid membrane protein. More than 36 mutations have been described in CLN6.[1] Affected individuals with CLN6 mutations are primarily of Portuguese, Indian, Pakistani, or Czech ancestry.

The CLN7 gene has been assigned to the tLINCL variant. Individuals with the tLINCL variant were thought to originate from Turkey. Siintola et al identified 6 mutations in 5 families, 4 Turkish families and 1 Indian family, in the MFSD8 gene. The authors mapped the locus to 4q28.1-q28.2. The gene encodes a 518 amino acid membrane protein that belongs to the major facilitator superfamily of transporter proteins. MFSD8 localizes mainly to the lysosomal compartment and is ubiquitously expressed.[4] Eight disease-causing mutations have been identified.[1]

CLN8 encodes a 286 amino acid transmembrane protein, which localizes to the endoplasmic reticulum and endoplasmic reticulum-Golgi intermediate complex. The exact function of the CLN8 protein is unknown. More than 11 mutations have been described in CLN8.[1] Some mutations cause vLINCL, but missense mutations (c.70C>G for p.Arg24Gly and c.709G>A for p.Gly237Arg in association with c.70C>G) can also result in progressive epilepsy with mental retardation (PEMR) or Northern epilepsy, which is a protracted disease.

Schulz et al reported that CLN9 produces a protein that may be a regulator of dihydroceramide synthetase. Even though the CLN8 sequence was normal, transfection with CLN8 corrected growth and apoptosis in CLN9 deficient cells.

Two putative disease-causing mutations have also been identified for CLCN6.[1]

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Epidemiology

Frequency

United States

Estimates suggest that approximately 25,000 families in the United States are affected with a form of NCL.

International

CLN1: In the Finnish population, incidence is 1 in 20,000 with a carrier frequency of 1 in 70.

CLN2: Worldwide prevalence is 0.6-0.7 per million inhabitants, with an incidence of 0.46 per 100,000 live births.

CLN3: Worldwide, CLN3 is the second most common form of NCL. Incidence is 7 cases per 100,000 live births in Iceland.

Mortality/Morbidity

Patients with NCL have shortened life expectancy; impact on life span clearly depends on the type of NCL.

Race

The prevalence of NCL is highest in the Scandinavian countries, especially Finland, where the estimated carrier frequency is a little less than 1 in 100 or 1%.

Age

Although the age of onset depends in part upon the type of NCL, molecular genetic discoveries have revealed more clinical overlap than was appreciated previously.

Most cases of CLN1 in the Finnish population have an infantile onset. Only 50% of the CLN1 cases have an infantile onset in the United States. The other cases have late infantile, juvenile, or adult onset.

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Contributor Information and Disclosures
Author

Celia H Chang, MD  Associate Health Sciences Clinical Professor, Department of Neurology, University of California at Davis

Celia H Chang, MD is a member of the following medical societies: American Academy of Neurology and Child Neurology Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Beth A Pletcher, MD  Associate Professor, Co-Director of The Neurofibromatosis Center of New Jersey, Department of Pediatrics, University of Medicine and Dentistry of New Jersey

Beth A Pletcher, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, American Medical Association, and American Society of Human Genetics

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Senior Pharmacy Editor, eMedicine

Disclosure: eMedicine Salary Employment

Kenneth J Mack, MD, PhD  Senior Associate Consultant, Department of Child and Adolescent Neurology, Mayo Clinic

Kenneth J Mack, MD, PhD is a member of the following medical societies: American Academy of Neurology, Child Neurology Society, Phi Beta Kappa, and Society for Neuroscience

Disclosure: Nothing to disclose.

,  Kathy Roarty Placeholder

Disclosure: Nothing to disclose.

Chief Editor

Amy Kao, MD  Assistant Professor, Department of Pediatrics, Division of Pediatric Neurology, Department of Neurology, Oregon Health and Science University; Consulting Staff, Shriners Hospital for Children

Amy Kao, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Pediatrics, American Epilepsy Society, and Child Neurology Society

Disclosure: Nothing to disclose.

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