Ceroid Lipofuscinosis, Neuronal, 5

A number sign (#) is used with this entry because neuronal ceroid lipofuscinosis-5 (CLN5) is caused by homozygous or compound heterozygous mutation in the CLN5 gene (608102) on chromosome 13q22.

Description

The neuronal ceroid lipofuscinoses (NCL; CLN) are a clinically and genetically heterogeneous group of neurodegenerative disorders characterized by the intracellular accumulation of autofluorescent lipopigment storage material in different patterns ultrastructurally. The lipopigment patterns observed most often in CLN5 comprise mixed combinations of 'granular,' 'curvilinear,' and 'fingerprint' profiles. The clinical course includes progressive dementia, seizures, and progressive visual failure (Mole et al., 2005).

For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730).

Nomenclature

CLN5 was classically described in Finnish patients with onset between 4 and 7 years of age and is often referred to as the 'Finnish variant of late-infantile NCL' (Finnish vLINCL). With the identification of molecular defects, however, the CLNs are now classified numerically according to the underlying gene defect. CLN5 refers to CLN caused by mutation in the CLN5 gene, regardless of the age at onset.

Clinical Features

Santavuori et al. (1982, 1991) delineated in Finland a variant late infantile neuronal ceroid lipofuscinosis. The disorder was identified in 18 families whose ancestors formed a single cluster on the west coast of Finland. The clinical features included mental retardation, ataxia, and myoclonic epilepsy, and the neurophysiologic (EEG, VEP, and SEP) changes resembled those of the classic late infantile disorder. Compared to the classic form, the age of onset was slightly later (4 to 7 years vs 2 to 4 years) and the survival time longer (13 to 30 years vs 15 years), mimicking the juvenile form (Batten disease). Both curvilinear bodies and fingerprint profiles were demonstrated by electron microscopy of tissues, but no storage material was seen in lymphocytes.

Pineda-Trujillo et al. (2005) reported a consanguineous Colombian family in which 2 sibs had juvenile-onset variant NCL. Both patients presented at age 9 years with visual failure, loss of strength, and tremor of the lower limbs. There was rapid disease progression, with blindness and inability to walk occurring within 1 year of symptom onset. Other features included behavioral changes, loss of language, myoclonus, and seizures. Electron microscopy of skin biopsy of 1 patient showed fingerprint inclusions occasionally associated with lipid droplets, suggestive of a variant NCL. No curvilinear or rectilinear profiles were seen.

Xin et al. (2010) reported 10 unrelated patients with CLN5 from diverse ethnic backgrounds, including non-Finnish Caucasian, French Canadian, Hispanic, Swedish, Chinese, Asian Indian, Egyptian, and Pakistani ancestry. The age at symptom onset was variable, ranging from 4 to 17 years. Seven had a juvenile mean age at onset of 5.6 years, but 2 had adult onset of symptoms at age 17 years. Most presented with motor impairment or regression, 2 presented with seizures, and 2 with visual loss. All developed the classic features of seizures, visual loss, motor difficulty, and cognitive regression within 1 to 8 years. Electron microscopy showed significant variation in inclusion type, such as fingerprint, curvilinear, and granular patterns.

Clinical Variability

Mancini et al. (2015) reported 2 sibs, born of consanguineous Italian parents, with unusually late onset of CLN5. Both patients developed cerebellar ataxia and progressive cognitive impairment in their mid-fifties. Features included unsteady gait, nystagmus, tremor, truncal ataxia, dysmetria, dysdiadochokinesis, and hyperreflexia. One patient had more severe cognitive impairment, especially affecting the visuospatial realm and executive tasks. Brain imaging of 1 patient showed marked cerebellar and cortical atrophy. Studies of patient tissue samples were not reported. Whole-exome sequencing identified a homozygous missense mutation in the CLN5 gene (S312N; 608102.0009) that Mancini et al. (2015) postulated was a hypomorphic allele.

Mapping

Jarvela (1991) demonstrated that the Finnish variant late-infantile form of NCL is not located on chromosome 1p where the CLN1 gene (PPT1; 600722) is situated. Furthermore, the distribution of birthplaces of great-grandparents of affected Finnish patients showed a striking difference: the distribution of the CLN1 ancestry was very wide, suggesting an ancient founder effect; the ancestry of late-infantile variant cases was concentrated in a region of western Finland, suggesting a more recent founder effect.

Williams et al. (1994) performed a linkage study of 11 families with vLINCL containing 13 affected children and 17 healthy sibs. They were able to exclude the CLN5 locus from both CLN1 on 1p and CLN3 (204200) on 16p. Savukoski et al. (1994) mapped the CLN5 locus to 13q21.1-q32 by linkage analysis and demonstrated a high level of linkage disequilibrium between the disease allele and defined alleles for D13S162 and D13S160. Klockars et al. (1996) further refined the map location to a region of about 350 kb between the markers COLAC1 and AC224.

Molecular Genetics

In affected patients with CLN5, Savukoski et al. (1998) identified 3 different mutations in the CLN5 gene (608102.0001-608102.0003).

In 2 Colombian sibs with juvenile-onset CLN5, Pineda-Trujillo et al. (2005) identified a homozygous mutation in the CLN5 gene (608102.0004). The findings indicated that the disease occurs outside of northern Europe.

In 10 of 47 non-Finnish patients with a clinical diagnosis of NCL, Xin et al. (2010) identified 14 mutations in the CLN5 gene, including 11 novel mutations (see, e.g., 608102.0006-608102.0008). Twelve of the 20 disease alleles resulted in premature termination of the protein. The findings suggested that CLN5 mutations may be more common than previously believed, can be found in non-Finnish patients, and can be found in patients with later onset.

In 2 sibs with CLN5, El Haddad et al. (2012) identified a homozygous truncating mutation in the CLN5 gene (Q232X; 608102.0010). The mutation, which was found by homozygosity mapping and candidate gene sequencing, segregated with the disorder in the family. The patients had originally been classified as having CLN9 (609055) by Schulz et al. (2004, 2006), who observed that patient fibroblasts showed decreased dihydroceramide synthase activity (see, e.g., CERS1; 606919). Schulz et al. (2006) found that patient cells showed partial correction of growth defects and apoptosis when transfected with CLN8 (607837) and several human ceramide synthase genes, all of which increase dihydroceramide synthase activity. Schulz et al. (2006) concluded that the protein implicated in CLN9 may be a regulator of dihydroceramide synthase. El Haddad et al. (2012) found that CLN5-null cells had increased growth rates and increased apoptosis compared to controls, and these defects could be corrected by transfection with wildtype CLN5. CLN5-null cells also had decreased levels of sphingolipids downstream of ceramide synthase. CLN5-null patient fibroblasts showed absence of ACTG1 (102560) from CERS1 protein complexes as well as absence of ACTG1-bound proteins, including vimentin (193060) and several histone proteins, which may have explained the cellular phenotype of growth defects. The findings suggested a possible association of CLN8 with CLN5, such as CLN8 and CLN5 acting in a concerted manner to activate ceramide synthesis.

Population Genetics

By haplotype analysis of Finnish patients with CLN5, Varilo et al. (1996) found that a single haplotype formed by flanking markers D13S160 and D13S162 was present in 81% of disease-bearing chromosomes. They detected allele 4 at the marker locus D13S162 in 94% of the disease-bearing chromosomes. To evaluate the age of the CLN5 mutation by virtue of its restricted geographic distribution (in Southern Ostrobothnia), Varilo et al. (1996) used church records to identify the common ancestors for 18 CLN5 families. The pedigrees of the ancestors merged on many occasions, which supported a single founder mutation that happened 20 to 30 generations ago (i.e., approximately 500 years ago) in this isolated population. Linkage disequilibrium was detected with 7 markers covering an extended genetic distance of 11 cM, which further supported the young age of the CLN5 mutation. When the results of genealogic and linkage disequilibrium studies were combined, the authors predicted that the CLN5 locus lies approximately 200 to 400 kb from the closest marker D13S162.

Animal Model

Kopra et al. (2004) developed a mouse model of neuronal ceroid lipofuscinosis-5 by targeted deletion of exon 3 of the mouse Cln5 gene. The Cln5 -/- mice showed loss of vision and accumulation of autofluorescent storage material in CNS and peripheral tissues, without prominent brain atrophy. Electron microscopy of the storage material revealed a mixture of lamellar profiles including fingerprint profiles and curvilinear and rectilinear bodies. Prominent loss of a subset of GABAergic interneurons in several brain areas was also seen. Brain transcript profiling revealed altered expression of several genes involved in neurodegeneration, as well as in defense and immune response, typical of age-associated changes in the CNS. Downregulation of structural components of myelin was detected, consistent with the hypomyelination seen in the human CLN5 patients. Since the Cln5 -/- mice did not exhibit significant brain atrophy, Kopra et al. (2004) suggested that these mice could serve as a model for studying the molecular processes associated with advanced aging.