Neuronal Ceroid Lipofuscinoses

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. NCLs are associated with variable, yet progressive, symptoms, including seizures, dementia, visual loss, and/or cerebral atrophy. Prenatal diagnosis may be possible in a family with an affected child, depending upon the NCL subtype. (See Epidemiology and Presentation.)

NCL was later so named because of the accumulation of autofluorescent lipopigments resembling ceroid and lipofuscin seen in patients with the condition. Although NCLs are generally autosomal recessive disorders, in 1971 Boehme 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. (See Etiology.) ^{[1, 2, 3]}

Classification

The neuronal ceroid lipofuscinoses (NCLs) originally were defined by their age of onset and clinical symptoms. However, they have since been reclassified on the basis of newer molecular findings, which have provided evidence of far more overlap for the different genetic variants than had previously been suggested by the clinical phenotypes. ^[4] (See Etiology and Presentation.)

Mortality

Patients with NCL have shortened life expectancy. The impact of NCL on life span clearly depends on the type of NCL that a patient has. ^[5]

Patient education

Genetic counseling is essential in the presence of NCL. Families may be referred to a number of support and research groups in the United States, including the following (see Treatment):

• Batten Disease Support and Research Association: 1-800-448-4570 or www.bdsra.org.

• Children's Brain Disease Foundation: 1-415-665-3003

• Institute for Basic Research in Developmental Disabilities: 1-718-494-0600 or 1-718-494-5117

• The National Institute of Neurologic Disorders and Stroke at the National Institutes of Health (NIH)

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 (ceroid lipofuscinosis, neuronal 1)- or CLN2-deficient cells with CLN deoxyribonucleic acid (DNA) constructs for either CLN1 or CLN2 was somewhat protective against etoposide-induced apoptosis in both cell 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. ^[6]

CLN1

In CLN1 NCL, 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 saposins A and D to accumulate in the lysosomes.

Mutations have been found in all 9 exons of the CLN1 gene. Although CLN1 usually has onset in infancy, later onset (including in adulthood) has been described. More than 49 mutations have been described in CLN1. ^{[1, 7]}

Lyly et al found that glycosylation of N197 and N232, but not N212, is essential for PPT1’s activity and intracellular transport. They also found that PPT1 formed oligomers. They believe that mutations cause more glycosylation and complex formation. ^[8]

CLN2

Patients with CLN2 NCL are deficient in a pepstatin-insensitive lysosomal peptidase called 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]

CLN3

The CLN3 gene encodes a 438 ̶ amino acid protein that is thought to be a part of the lysosomal membrane. 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 NCL have visual failure by age 10 years. ^[9]

The most common CLN3 mutation is a 1.02-kb deletion that involves the loss of exons 7 and 8. Most patients with the classic phenotype of juvenile NCL (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 with visual failure who were compound heterozygotes for the 1.02-kb deletion. Only 1 of the patients had seizures, and both 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.

CLN4

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

CLN5

Mutations in gene CLN5 are associated with Finnish variant late-infantile NCL (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 this gene. ^[1]

CLN6

The CLN6 gene is associated with variant LINCL (vLINCL). Disease caused by CLN6 mutations is also referred to as the Czech or Indian variant of NCL. 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.

CLN7

The CLN7 gene has been assigned to the Turkish LINCL (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. ^[10] Eight disease-causing mutations have been identified. ^[1]

CLN8

CLN8 encodes a 286 ̶ amino acid transmembrane protein that 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.

CLN9

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. ^{[11, 12]}

CLCN6

Two putative disease-causing mutations have also been identified for the CLCN6 (chloride channel 6) gene. ^[1]

Subunit C

Subunit C of the mitochondrial adenosine triphosphate (ATP) synthase complex accumulates in the lysosomes of patients with some variants of NCL, including the CLN2, CLN3, CLN4, CLN5, CLN6, CLN7, and CLN8 variants. (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.) 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 messenger ribonucleic acid (mRNA) for P2 is the predominant form.

Occurrence in the United States

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

International occurrence

The prevalence of NCL is highest in the Scandinavian countries, especially Finland. Occurrence of different forms of NCL are as follows:

• CLN1 NCL - In the Finnish population, the incidence is 1 in 20,000 persons, with a carrier frequency of 1 in 70 persons

• CLN2 NCL - The worldwide prevalence is 0.6-0.7 per million inhabitants, with an incidence of 0.46 per 100,000 live births

• CLN3 NCL - Worldwide, CLN3 NCL is the second most common form of NCL; the incidence is 7 cases per 100,000 live births in Iceland

Race- and age-related demographics

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

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