Alternative titles; symbols
SNOMEDCT: 61663001; ICD10CM: E75.4; ORPHA: 79264; DO: 0110731;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p12.1 | Ceroid lipofuscinosis, neuronal, 3 | 204200 | Autosomal recessive | 3 | CLN3 | 607042 |
A number sign (#) is used with this entry because neuronal ceroid lipofuscinosis-3 (CLN3) is caused by homozygous or compound heterozygous mutation in the CLN3 gene (607042) on chromosome 16p12.
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 clinical course includes progressive dementia, seizures, and progressive visual failure (Mole et al., 2005).
The hallmark of CLN3 is the ultrastructural pattern of lipopigment with a 'fingerprint' profile, which can have 3 different appearances: pure within a lysosomal residual body; in conjunction with curvilinear or rectilinear profiles; and as a small component within large membrane-bound lysosomal vacuoles. The combination of fingerprint profiles within lysosomal vacuoles is a regular feature of blood lymphocytes from patients with CLN3 (Mole et al., 2005).
For a general phenotypic description and a discussion of genetic heterogeneity of CLN, see CLN1 (256730).
The CLNs were originally classified broadly according to age at onset, with CLN3 as the juvenile-onset form (JNCL), with onset between 4 and 10 years of age. With the identification of molecular defects, however, the CLNs are now classified numerically according to the underlying gene defect. CLN3 refers to CLN caused by mutation in the CLN3 gene, regardless of the age at onset.
JNCL has also been called Batten disease, Vogt-Spielmeyer disease, and Spielmeyer-Sjogren disease. Mole et al. (1999) used 'Batten disease' as a generic designation for the NCLs, which they defined as a group of neurodegenerative disorders characterized by the accumulation of an autofluorescent lipopigment in many cell types.
Batten (1903, 1914) described juvenile-onset of a familial form of 'cerebral degeneration with macular changes.'
Spalton et al. (1980) reviewed 26 patients with Batten disease. Children presented with rapid progressive visual loss at age 6 to 7 years, early mental deterioration, and seizures. Macular degeneration was a consistent early feature, and peripheral retinal changes became more marked as the disease progressed.
Wisniewski et al. (1992) reviewed the clinical and pathologic features of 163 patients with juvenile-onset CLN. The disorder was characterized by onset at 4 to 10 years of age of gradual visual loss with macular degeneration, optic atrophy, and/or retinitis pigmentosa. Other features included seizures and gradual mental and motor dysfunction. Ultrastructural examination of neuronal and nonneuronal tissues showed fingerprint inclusions. The youngest age at death was 16 years, and the oldest living patient was 40 years old but had been in a vegetative state for 21 years.
In a review of 57 patients with CLN3, Boustany (1992) concluded that the first symptom was insidious onset of retinitis pigmentosa between ages 4 and 6 years, which was often not identified before age 7 or 8 years. Visual decline was followed by progressive cognitive decline, and most patients developed seizures by age 10 years. Other motor symptoms included myoclonus, parkinsonism, and a severe dysarthria resulting in mutism in their twenties. Most patients developed behavioral problems with angry outbursts, physical violence, and features of depression.
Taschner et al. (1995) reported a Moroccan child, born of consanguineous parents, with Batten disease. He had a typical clinical history of failing vision at the age of 9 years, leading to a diagnosis of tapetoretinal degeneration with normal neurologic examinations and scanning studies at that time. He became forgetful shortly after the start of visual deterioration and had, from the age of 11 years, generalized seizures that were well controlled by valproic acid. More than 1% of lymphocytes were vacuolated, most of which contained storage material in a 'fingerprint' pattern. At the age of 19 years, he developed parkinsonism without tremor. Molecular genetic studies identified a small homozygous deletion in the CLN3 gene (607042.0003).
The International Batten Disease Consortium (1995) reported a Finnish patient with Batten disease confirmed by identification of compound heterozygosity for 2 deletions in the CLN3 gene (607042.0001; 607042.0002). After a normal birth and early childhood, he developed failing vision at age 6.5 years. Electroretinogram was abolished, and visual evoked potential was abnormal with delayed latency. Slight motor clumsiness and muscular hypotonia were found. Vacuolated lymphocytes were positive on repeated examinations. From age 11, he had generalized epileptic seizures that were well controlled by sodium valproate-clonazepam. An MRI at age 16 showed slight central, cortical, and cerebellar atrophy. The patient was still able to walk independently, but jumping had become difficult.
Wisniewski et al. (1998) reported 2 sibs with a protracted form of juvenile-onset CLN3: the sister died at age 51 of aspiration pneumonia and the brother was living at age 39. The sister developed progressive visual loss at 5 years of age and became totally blind at age 13. From 45 years of age, she had progressive impairment of coordination, memory loss, problems with naming and calculation, and episodes of confusion. A general examination at age 48 was normal. Neurologic examination showed disorientation for time and space, impairment of short- and long-term memory, dysarthria, oromandibular dystonia, and naming deficit. A pendular nystagmus was present. The optic fundi showed optic nerve atrophy, pigmentary retinal degeneration, and spicules. The brother began to lose vision at age 5 years, leading to blindness at the age of 12. The main finding on examination was blindness secondary to optic atrophy and pigmentary retinal degeneration. Both were compound heterozygous for 2 mutations in the CLN3 gene (607042.0001; 607042.0005).
Cortese et al. (2014) reported 2 adult Italian brothers, born in a consanguineous family, with a protracted form of CLN3 confirmed by genetic analysis (G165E; 607042.0007). Both sibs presented at age 7 years with visual loss, which rapidly progressed to total blindness due to retinitis pigmentosa. Psychomotor development was normal. At ages 36 and 29 years, respectively, both developed well-controlled generalized seizures and severe concentric hypertrophic cardiomyopathy requiring pacemakers. Brain imaging showed mild cerebral and cerebellar vermian atrophy. Both sibs later showed mild cognitive impairment, but there was no evidence of muscle impairment except for mildly increased serum creatine kinase. Muscle biopsy showed autophagic vacuoles with glycogen and myelin-like debris, as well as autofluorescence. Electron-dense material formed structures similar to curvilinear bodies. Lymphocytes showed cytoplasmic vacuolization.
Nielsen et al. (2015) studied the ophthalmologic features in all 35 patients with JNCL born in Denmark between 1971 and 2003. During the study period (1996-2012), cataracts were detected in 5 patients at the average age of 20.1 + 1.6 years (mean, +2 SD). All 5 patients had the common 1.02-kb deletion in the CLN3 gene (607042.0001). Two of the 5 patients developed acute glaucoma, and 1 patient underwent prophylactic cataract surgery. Nielsen et al. (2015) concluded that presenile cataract formation and secondary acute glaucoma are complications of JNCL for which patients over the age of 16 years should be screened routinely.
Pathologic Features
The major pathologic features of Batten disease are (1) severe widespread neuronal degeneration resulting in retinal atrophy and in massive loss of brain substance, the average brain weight being about 600 gm, and (2) accumulation of lipofuscin in neuronal perikaryon (Zeman and Donahue, 1963; Gonatas et al., 1963).
Vacuolation of the lymphocytes is a well-established feature in the homozygote (McKusick, 1963). Although Rayner (1963) claimed that about 1% of lymphocytes are vacuolated in heterozygotes, Burrig et al. (1982) concluded that cytoplasmic vacuoles and inclusions occur only in homozygotes. Strouth et al. (1966) reported characteristic leukocyte abnormalities in juvenile-onset CLN.
Armstrong et al. (1974) reported deficiency of leukocyte peroxidase in patients with the CLN2 (204500) and CLN3; however, Farrell and Sumi (1977) were unable to confirm the reported deficiency of leukocyte peroxidase.
Dayan and Trickey (1970) found large amounts of lipofuscin in the thyroid of patients with Batten disease. Farrell and Sumi (1977) identified fingerprint profiles, curvilinear bodies, and rectilinear bodies in skin biopsies from patients with CLN3. Baumann and Markesbery (1978) identified numerous fingerprint profiles ultrastructurally within vacuolated lymphocytes from 4 patients with Batten disease.
In a 7-year-old child with juvenile-onset CLN3, Brod et al. (1987) detected vacuolated peripheral blood lymphocytes and characteristic ultrastructural fingerprint profiles. The patient's mother, who was presumably heterozygous, also demonstrated vacuolated lymphocytes with membranous formations and osmiophilic granular bodies. Kimura and Goebel (1988) examined lymphocytes from 10 patients with juvenile-onset CLN3 and found that vacuolated lymphocytes varied from 34 to 67% in specimens. In addition, the percentage of vacuolated lymphocytes increased with duration of illness up to age 11.
Dawson et al. (1989) reported decreased levels of cathepsin H (116820) and phospholipase A1 in a subset of patients with juvenile-onset CLN.
Subunit C of the Fo region of the ATP synthase complex of the inner mitochondrial membrane is found in high concentrations in lysosomes in late infantile CLN2 and juvenile CLN3. Kominami et al. (1995) found marked delay of degradation of subunit C in patient fibroblasts with no significant differences between control and patient cells with regard to degradation of cytochrome oxidase subunit IV. Furthermore, accumulation of labeled subunit C in the mitochondrial fraction was detected before lysosomal appearance of the radiolabeled subunit, suggesting to the authors a specific failure in the degradation of subunit C after its normal inclusion in mitochondria and its consequent accumulation in lysosomes. Jolly (1995) reported that subunit C represents more than 50% of the accumulated metabolites in the ovine form of CLN and also accumulates significantly in late infantile and juvenile forms of human CLN and several other animal forms. The author suggested that the extreme hydrophobicity and lipophilicity of subunit C may be partially responsible.
Ramirez-Montealegre and Pearce (2005) reported that lysosomes from juvenile Batten disease lymphoblast cell lines demonstrated defective transport of arginine. Furthermore, a depletion of arginine in these cells was noted. Lysosomal arginine transport in normal lysosomes is ATP-, vacuolar ATPase (see 606939)-, and cationic-dependent. Both arginine and lysine are transported by the same transport system, designated system c. However, lysosomes from juvenile Batten disease lymphoblasts were only defective for arginine transport. An antibody to CLN3 was able to block lysosomal arginine transport, and transient expression of CLN3 in JNCL cells restored lysosomal arginine transport. Ramirez-Montealegre and Pearce (2005) suggested that the CLN3 defect in juvenile Batten disease may affect how intracellular levels of arginine are regulated or distributed throughout the cell.
The transmission pattern of CLN3 in the families reported by the International Batten Disease Consortium (1995) was consistent with autosomal recessive inheritance.
Bessman and Baldwin (1962) found imidazole amino aciduria in 5 patients and some of their immediate relatives in 3 unrelated families. They suggested that the finding might be useful for detection of heterozygotes and for identifying heterogeneity in this category of disease. Danes and Bearn (1968) showed that both homozygotes and heterozygotes can be identified on the basis of metachromasia in skin fibroblasts in cell culture.
By polyacrylamide gel electrophoresis (PAGE), LaBadie and Pullarkat (1990) demonstrated low molecular weight peptides in the urine from patients with Batten disease and suggested that these might be specific biochemical markers for this disorder.
Goebel (1996) reviewed the neuronal ceroid lipofuscinoses and noted that correct diagnosis of disease type requires ultrastructural examination of a patient's cells. CLN3 is characterized by fingerprint profiles, with or without curvilinear profiles.
Jarvela et al. (1996) developed a rapid diagnostic solid-phase minisequencing test to detect the common 1.02-kb deletion in the CLN3 gene (607042.0001). Taschner et al. (1997) described an allele-specific PCR method for detection of the deletion in the CLN3 gene associated with Batten disease.
Marshall et al. (2005) developed a multimodal clinical rating instrument, the Unified Batten Disease Rating Scale (UBDRS), to assess motor, behavioral, and functional capabilities of patients with juvenile-onset CLN3.
Prenatal Diagnosis
Munroe et al. (1996) used PCR to identify the intragenic microsatellite marker D16S298 to make the prenatal diagnosis of Batten disease on the basis of a chorionic villus sample. The Finnish woman sought counseling because of a son with Batten disease. Allele 6 at the D16S298 marker is present in 96% of Finnish Batten disease patients. Both the fetus and the affected son carried the same high-risk genotype, 6/6, and both were homozygous for the 1-kb deletion. The pregnancy was terminated, and the diagnosis was confirmed by electron microscopy of fetal cells.
To study the efficacy of dopaminergic medication for extrapyramidal symptoms in juvenile-onset CLN3, Aberg et al. (2001) treated 10 patients with levodopa and 6 patients with selegiline and found a favorable response to levodopa, as measured by scoring on the motor part of the Unified Parkinson Disease Rating Scale. Six of 10 patients treated with levodopa showed decreased symptoms at 1 year, and 4 showed increased symptoms, although 3 of these showed decreased symptoms at 6 months. Patients treated with selegiline and those untreated showed no significant difference at 1 year.
Eiberg et al. (1989) found linkage between haptoglobin (HP; 140100) and Batten disease on chromosome 16q22 (maximum lod score of 3.00). Gardiner et al. (1990) confirmed the mapping of Batten disease to chromosome 16 (maximum lod score of 6.05 at marker D16S148).
By linkage studies in a larger group of families, Callen et al. (1991) concluded that the most likely location for CLN3 is the interval between D16S67 and D16S148. Physical mapping of these markers by mouse/human hybrid cell analysis and fluorescence in situ hybridization positioned them at 16p12.3-p12.1 and 16p12.1-p11.2, respectively. Callen et al. (1991) concluded that CLN3 is in a 2-cM interval on 16p12. Mitchison et al. (1993) reported the findings in 70 CLN3 families. Crossovers in 3 maternal meioses allowed localization of CLN3 to the interval between D16S297 and D16S57. Haplotype analysis suggested that most CLN3 chromosomes arose from a single founder mutation.
Using highly informative dinucleotide repeat markers, Lerner et al. (1994) refined the localization of CLN3 to 16p12.1. They found that one haplotype, D16S298/D16S299, was highly overrepresented, accounting for 54% of CLN3 chromosomes as compared with 8% of control chromosomes. They conclusively excluded the CLN2 (204500) locus from this region.
By haplotype and linkage disequilibrium mapping in 111 affected families, including 27 Finnish families, Mitchison et al. (1995) predicted that the CLN3 gene lies 8.8 kb (range 6.3 to 13.8 kb) from D16S298 and 165.4 kb (range 132.4 to 218.1 kb) from D16S299. Enrichment of certain alleles indicated that the same major mutation is responsible for Batten disease in Finland as in most other European countries.
The International Batten Disease Consortium (1995) demonstrated that the mutation responsible for 73% of Batten disease chromosomes was a 1.02-kb deletion in the CLN3 gene (607042.0001). In Finland, 90% of patients with Batten disease carry the 1.02-kb deletion (Jarvela et al., 1996).
In a Moroccan child with Batten disease, Taschner et al. (1995) found homozygosity for a small deletion in the CLN3 gene (607042.0003).
Munroe et al. (1997) identified homozygosity for the common 1.02-kb CLN3 deletion in 139 (74%) of 188 unrelated patients with Batten disease; 41 were compound heterozygous for the deletion and another CLN3 mutation. By SSCP analysis and direct sequencing, Munroe et al. (1997) found 19 novel mutations in the CLN3 gene, bringing the total number of known disease-associated mutations in CLN3 to 23.
Mole et al. (1999) tabulated the mutations that had been identified in the various CLNs; they reported 25 mutations and 2 polymorphisms associated with CLN3.
Kitzmuller et al. (2008) demonstrated that the common 1.02-kb deletion retains residual function. Overexpression of the mutant CLN3 transcripts consistently caused lysosomes to decrease in size. Studies in mouse cell models and yeast confirmed that the corresponding mutant transcripts retained significant function. The majority of the mutant 1.02-kb deletion CLN3 protein was retained within the endoplasmic reticulum. Kitzmuller et al. (2008) concluded that the common mutant CLN3 protein retains significant function and that JNCL is a mutation-specific disease phenotype. The residual function likely explains why this form of CLN shows later onset and less severe clinical manifestations compared to other forms of CLN.
In West Germany, Claussen et al. (1992) estimated the frequency of juvenile-onset CLN3 to be 0.71 per 100,000 live births and of CLN2 to be 0.46 per 100,000 live births. The estimates were based on a novel method applicable to other autosomal recessive disorders. For 10 years, 1968 through 1977, the slope of registration of new cases was a steep, nearly straight line. The authors presumed that this represented a period of efficient registration of new cases.
CLN3 is especially enriched in Finland with an incidence of 1:21,000 live births and a carrier frequency of 1 in 70 (Mitchison et al., 1995).
Tuck-Muller et al. (1995) observed a balanced translocation between chromosomes 10 and 18, t(10;18)(q22.1;q21.1), in a girl with typical Batten disease beginning at 5 years of age. The intracellular cytosomes were predominantly fingerprint in type. Translocation was not observed in the patient's mother or sister. The father was unavailable for analysis. Although Tuck-Muller et al. (1995) stated that the translocation may be unrelated to the disease, the findings raised the possibility of genetic heterogeneity in this form of CLN.
A model of Batten disease in sheep was discussed by Jolly et al. (1992) and a model in the dog by Koppang (1992) and Taylor and Farrow (1992).
A yeast model for the study of Batten disease was created by Pearce and Sherman (1998). They had previously cloned the Saccharomyces cerevisiae homolog of the CLN3 gene, designated BTN1. The amino acid structure of the yeast and human proteins had been shown to be 39% identical and 59% similar. They reported that BTN1-delta deletion yeast strains were more resistant to a chemical denoted ANP, a phenotype that could be complemented in yeast by the human CLN3 gene. Furthermore, the severity of Batten disease in humans and the degree of ANP resistance in yeast were related when the equivalent amino acid replacements in the CLN3 and the BTN1 proteins were compared. These results indicated that yeast can be used as a model for the study of Batten disease.
Chattopadhyay et al. (2002) reported neutralizing autoantibodies to glutamic acid decarboxylase (GAD2; 138275) in Cln3-knockout mice serum that associates with brain tissue but is not present in sera or brain of normal mice. A concomitant elevation of glutamate in the brain of Cln3-knockout mice colocalized with presynaptic markers. An autoantibody to GAD2 was present in sera of all 20 individuals tested with Batten disease, and postmortem brain tissue from 1 patient showed decreased reactivity to an anti-GAD antibody. The authors proposed that an autoimmune response to GAD2 may contribute to a preferential loss of GABAergic neurons associated with Batten disease.
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