Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 58258004; ORPHA: 168491, 79262, 79263, 79264; DO: 0110721;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p34.2 | Ceroid lipofuscinosis, neuronal, 1 | 256730 | Autosomal recessive | 3 | PPT1 | 600722 |
A number sign (#) is used with this entry because neuronal ceroid lipofuscinosis-1 (CLN1) is caused by homozygous or compound heterozygous mutation in the gene encoding palmitoyl-protein thioesterase-1 (PPT1; 600722) on chromosome 1p34.
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 pattern seen most often in CLN1 is referred to as granular osmiophilic deposits (GROD). The patterns most often observed in CLN2 and CLN3 are 'curvilinear' and 'fingerprint' profiles, respectively. CLN4, CLN5, CLN6, CLN7, and CLN8 show mixed combinations of granular, curvilinear, fingerprint, and rectilinear profiles. The clinical course includes progressive dementia, seizures, and progressive visual failure (Mole et al., 2005).
Zeman and Dyken (1969) referred to these conditions as the 'neuronal ceroid lipofuscinoses.' Goebel (1995) provided a comprehensive review of the NCLs and noted that they are possibly the most common group of neurodegenerative diseases in children.
Mole et al. (2005) provided a detailed clinical and genetic review of the neuronal ceroid lipofuscinoses.
Genetic Heterogeneity of Neuronal Ceroid Lipofuscinosis
See also CLN2 (204500), caused by mutation in the TPP1 gene (607998) on chromosome 11p15; CLN3 (204200), caused by mutation in the CLN3 gene (607042) on 16p12; CLN4 (162350), caused by mutation in the DNAJC5 gene (611203) on 20q13; CLN5 (256731), caused by mutation in the CLN5 gene (608102) on 13q22; CLN6A (601780) and CLN6B (204300), both caused by mutation in the CLN6 gene (606725) on 15q21; CLN7 (610951), caused by mutation in the MFSD8 gene (611124) on 4q28; CLN8 (600143) and the Northern epilepsy variant of CLN8 (610003), both caused by mutation in the CLN8 gene (607837) on 8p23; CLN10 (610127), caused by mutation in the CTSD gene (116840) on 11p15; CLN11 (614706), caused by mutation in the GRN gene (138945) on 17q21; CLN13 (615362), caused by mutation in the CTSF gene (603539) on 11q13; and CLN14 (611726), caused by mutation in the KCTD7 gene (611725) on 7q11.
CLN9 (609055) has not been molecularly characterized.
A disorder that was formerly designated neuronal ceroid lipofuscinosis-12 (CLN12) is now considered to be a variable form of Kufor-Rakeb syndrome (KRS; 606693).
The CLNs were originally classified broadly by age at onset: CLN1 as the infantile-onset form, or the infantile-onset Finnish form, having first been described in that population; CLN2 as the late infantile-onset form; CLN3 as the juvenile-onset form; and CLN4 as the adult-onset form. With the identification of molecular defects, however, the CLNs are now classified numerically according to the underlying gene defect. CLN1 refers to CLN caused by mutation in the PPT1 gene, regardless of the age at onset (Mole et al., 2005).
Classic Infantile-Onset CLN1
Hagberg et al. (1968) described 'progressive encephalopathy' in a child of unrelated Finnish parents. The disorder was characterized by mental retardation, loss of speech, minor motor seizures, regression of motor development, and ataxia. Histologically, the brain showed total derangement of cortical cytoarchitecture, severe degeneration of white matter, and deposits of granular material suggesting free fatty acids and unsaturated fatty acids. Biochemical studies showed a disturbance of linoleic acid metabolism.
Santavuori et al. (1973) and Haltia et al. (1973) characterized the distinctive clinical and morphologic features of infantile-onset CLN1, respectively. Morphologic findings included severe neuronal destruction with massive accumulations of phagocytes, often binucleated, and unusually hypertrophic fibrillary astrocytes in the cerebral cortex. The fatty acid pattern of serum lecithin showed an increase of arachidonic acid and corresponding decrease of linoleic acid.
Santavuori et al. (1974) reported that infantile-onset CLN is clinically homogeneous in the Finnish population. After normal development, visual failure, speech and motor deterioration, and seizures appeared between the ages of 6 and 24 months. Most patients had no cortical activity demonstrable by EEG by age 3 years. At least 55 cases of the same abnormality were identified in Finland (Hagberg, 1974). Age at onset ranged from 8 to 18 months with rapid psychomotor deterioration, ataxia, and muscular hypotonia. Other features included microcephaly and myoclonic jerks; convulsions were less common. Affected individuals were blind by age 2 years with optic atrophy and macular and retinal changes but no pigment aggregation. Both the ERG and the EEG showed early extinction.
Baumann and Markesbery (1982) stated that about 60 cases of 'Santavuori disease' had been reported. They described the first American cases: 3 cases in 2 unrelated families. A brother and sister were from Appalachian Kentucky. Features were early developmental deterioration, retinal blindness, microcephaly, and seizures. Baumann and Markesbery (1982) found characteristic inclusion material in circulating leukocytes. This material was electron microscopically identical to that in brain tissues and was apparently unique to Santavuori disease.
Vanhanen et al. (1995) reviewed the MRI appearance of the brain in 21 patients with infantile neuronal ceroid lipofuscinosis and compared them to 46 neurologically normal controls. MRI abnormalities were detectable before clinical symptoms and changed with the progression of the disease. In the early stage there was generalized cerebral atrophy, thalamic hypointensity to the white matter and to the basal ganglia, and thin periventricular high-signal rims from 13 months onward on T2-weighted images. They noted a pathognomonic appearance in patients older than 4 years of age, and found that the signal intensity of the gray matter on T2-weighted images was less than that of the white matter, or reverse of the normal appearance.
Late Infantile- and Juvenile-Onset CLN1
Becker et al. (1979) described the child of a consanguineous German couple who developed onset of mental and visual disturbances at age 3 years, followed by ataxia and myoclonic jerks. The chemical changes were those of the infantile form, but the electron microscopy of muscle and skin and the clinical course were more consistent with classically described later-onset forms of CLN (e.g., CLN2 or CLN3).
Philippart et al. (1995) and Hofman and Taschner (1995) described a variant of juvenile-onset CLN in which electron microscopy demonstrated intracellular fine granular osmiophilic deposits (GROD) characteristic of the infantile subtype. Curvilinear and fingerprint bodies, characteristic of other forms of CLN were not identified. Learning disabilities began between ages 6 and 10 years, but visual failure was delayed until age 10 to 14 years. Linkage analysis of 1 family excluded markers on chromosome 16p12 associated with CLN3.
Mitchison et al. (1998) reported 11 patients with juvenile-onset of CLN with GROD, including those reported by Philippart et al. (1995) and Hofman and Taschner (1995). Deterioration of intellect began between ages 7 and 13 years, deterioration of motor function between ages 7 and 15 years, deterioration of vision between ages 6 and 14 years, and onset of EEG changes and epilepsy between ages 7 and 17 years. Vacuolated lymphocytes were not detected in 11 of 16 patients. The tissues in which granular osmiophilic deposits were observed included skin, conjunctiva, rectum, and blood.
Wisniewski et al. (1998) reported 5 patients from 3 unrelated families with late infantile-onset CLN1 with GROD. PPT1 activity was less than 10% of normal values, suggesting a variant form of CLN1.
Das et al. (1998) found excellent correlation between absence of PPT1 activity and GROD histology among 32 unrelated individuals with CLN. All 23 patients with pure GROD and 6 (67%) of 9 patients with GROD mixed with curvilinear or fingerprint inclusions had decreased PPT1 activity. Fourteen patients had infantile onset before 24 months of age, 5 had late-infantile onset between ages 2 and 4, and 13 had juvenile onset after age 5 years. The 3 patients with normal PPT1 activity all had juvenile-onset CLN; 1 of these patients was subsequently found to have mutations in the CLN3 gene (607042). Twenty-eight patients with CLN without GROD histology all had normal PPT1 activity. The patients included the 3 probands reported by Wisniewski et al. (1998).
Adult-Onset CLN1
Van Diggelen et al. (2001) reported 2 sisters with adult-onset neuronal CLN1 confirmed by the finding of compound heterozygous mutations in the PPT1 gene (600722.0006; 600722.0009). Onset in both patients was in the thirties, with symptoms of depression progressing to cognitive decline, cerebellar ataxia, parkinsonism, and decreased verbal fluency in their fifties. Both patients showed generalized brain atrophy on MRI. Enzyme analysis showed severe PPT deficiency.
Ramadan et al. (2007) reported a 24-year-old woman who presented with psychiatric features, including low mood, irritability, lack of interest, bizarre behavior, and academic decline. She deteriorated over the next 18 months, developing tunnel vision, retinitis pigmentosa, visual hallucinations, and further cognitive decline. Brain MRI showed marked generalized cerebral and cerebellar atrophy. Skin and rectal mucosal biopsies showed a storage disease with autofluorescent granular osmiophilic deposits, and biochemical studies showed decreased PPT1 activity. Genetic analysis identified compound heterozygosity for 2 mutations in the PPT1 gene (600722.0006; 600722.0010). Ramadan et al. (2007) emphasized the late onset in this patient and noted the similarities to the sisters reported by Van Diggelen et al. (2001).
By linkage analysis in Finnish families with infantile-onset CLN1, Jokiaho et al. (1990) excluded linkage to chromosome 16, where the gene for Batten disease (CLN3) had been mapped.
In studies of 15 Finnish families with infantile-onset CLN1, Jarvela et al. (1991) demonstrated linkage to chromosome 1p (maximum lod scores of 3.38 for D1S57, 3.56 for D1S7, and 3.56 for D1S79). Jarvela (1991) presented a map of the birthplaces of great-grandparents of 35 patients with CLN1. The wide distribution of this ancestry suggested a very old founder effect. On the basis of further linkage studies, Jarvela et al. (1991) mapped the CLN1 gene to chromosome 1p32.
Hellsten et al. (1993) observed linkage disequilibrium between CLN1 and a newly discovered, highly polymorphic marker. Incorporation of the observed linkage disequilibrium into multipoint linkage analysis significantly increased the informativeness of the limited family material and facilitated refined assignment of the CLN1 locus. Hellsten et al. (1995) constructed a pulsed field gel electrophoresis (PFGE) map of 4 Mb in the region of the CLN1 gene. They established the order of several loci at 1p32 by combining data obtained from analysis of a chromosome 1 somatic cell hybrid panel, PFGE, and interphase fluorescence in situ hybridization. They found that a 1-Mb contig contained MYCL1, the HY-TM1 marker closely linked to CLN1, RLF (180610), and COL9A2 (120260). Within the contig, they identified 5 CpG islands, in addition to those associated with the earlier cloned genes.
Voznyi et al. (1999) reported a new fluorimetric assay for PPT activity based on the fluorochrome 4-methylumbelliferone. PPT1 activity was detectable in fibroblasts, leukocytes, lymphoblasts, amniotic fluid cells, and chorionic villi, but was deficient in tissues from CLN1 patients.
Prenatal Diagnosis
De Vries et al. (1999) reported prenatal diagnosis of CLN1 by chorionic villi sampling. PPT1 activity was deficient and molecular analysis identified a homozygous mutation in the PPT1 gene (600722.0008). The pregnancy was terminated and the PPT deficiency was confirmed in cultured chorionic villi cells as well as in cultured fetal skin fibroblasts.
By positional candidate gene methods, Vesa et al. (1995) identified a homozygous mutation (R122W; 600722.0001) in the PPT1 gene in patients with infantile-onset CLN1 from 40 of 42 Finnish families. The findings were consistent with a founder effect.
Mitchison et al. (1998) identified homozygosity or compound heterozygosity for mutations in the PPT1 gene (600722.0002-600722.0006) in 11 patients with juvenile-onset CLN1 with the ultrastructural findings of granular osmiophilic deposits.
Das et al. (1998) identified 19 different mutations in the PPT1 gene in 57 of 58 mutated alleles from 29 patient-derived cell lines. The R151X mutation (600722.0006) accounted for 40% of the alleles, and the T75P mutation (600722.0002) accounted for 13% of the alleles. Fifty percent of patients had infantile onset, 17% had late-infantile onset, and 33% had juvenile onset.
Kim et al. (2006) noted that apoptosis is 1 of the major causes of neurodegeneration in INCL. In a follow-up to studies in a mouse model of CLN1 that showed activation of the endoplasmic reticulum stress response (Zhang et al., 2006), Kim et al. (2006) studied signals of apoptosis in brain samples from a patient with CLN1. Brain tissue showed increased levels of mitochondrial superoxide dismutase-2 (SOD2; 147460), caspase-9 (CASP9; 602234), caspase-3 (CASP3; 600636), and cleaved PARP1 (173870) compared to control brain samples. These findings were consistent with rapid neuronal death by apoptosis. Studies of Ppt1-null mice revealed similar patterns, and studies of cultured neurospheres indicated that ER stress caused elevated levels of reactive oxygen species (ROS). Kim et al. (2006) proposed that the rapid progression of neurodegeneration in human INCL is likely to be caused by ER stress-mediated caspase-12 (CASP12; 608633) activation as well as by elevated ROS production, which stimulates SOD2 production and destabilization of calcium homeostasis. Together these abnormalities mediate activation of CASP9, CASP3, and cleavage of PARP, which is indicative of apoptosis.
CLN1 is most common in populations of Finnish descent, with an incidence of 1:20,000 and a carrier frequency of 1 in 70 (summary by Miller et al., 2015).
Gupta et al. (2001) engineered disruptions in the Ppt1 and Ppt2 (603298) genes to create knockout mice that were deficient in either enzyme. Both lines of mice were viable and fertile; however, both lines developed spasticity (a 'clasping' phenotype) at a median age of 21 weeks and 29 weeks, respectively. Motor abnormalities progressed in the Ppt1 knockout mice, leading to death by 10 months of age. In contrast, most Ppt2 mice were alive at 12 months. Myoclonic jerking and seizures were prominent in the Ppt1 mice. Autofluorescent storage material was striking throughout the brains of both strains of mice. Neuronal loss and apoptosis were particularly prominent in Ppt1-deficient brains. These studies provided a mouse model for infantile neuronal ceroid lipofuscinosis and further suggested that PPT2 serves a role in the brain that is not carried out by PPT1.
Zhang et al. (2006) reported that the brains of Ppt1-null mice accumulated autofluorescent material, abnormalities of the neuronal endoplasmic reticulum (ER), and showed progressive neuronal apoptosis that correlated with neurologic motor impairment. There was an abnormal accumulation of palmitoylated GAP43 (162060) in the ER. Increased levels of this and other S-acylated proteins coincided with activation of the unfolded protein response, characterized by increased phosphorylation of EIF2A (609234) and activation of CASP12, which ultimately leads to cellular apoptosis. Zhang et al. (2006) concluded that PPT1 deficiency leads to neurodegeneration by activation of the unfolded protein response as a result of abnormal accumulation of palmitoylated proteins.
Neural communication relies on repeated cycles of exo- and endocytosis of synaptic vesicles containing neurotransmitters at the plasma membranes of nerve terminals. In the mouse brain, Kim et al. (2008) found that Ppt1 localized in the synaptosomes and synaptic vesicles of the presynaptic compartment under physiologic conditions. Ppt1 deficiency resulted in abnormal and persistent membrane retention of palmitoylated synaptic vesicle-associated proteins, including VAMP2 (185881), SNAP25 (600322), syntaxin-1 (STX1A; 186590), SYTI (185605), and GAD65 (138275) in brain tissue from both human patients with neuronal lipofuscinosis and Ppt1-deficient mice. Since these S-acylated proteins must undergo depalmitoylation to detach from the membrane, which is required for recycling, Ppt1 deficiency may cause these proteins to remain membrane bound. Kim et al. (2008) proposed a mechanism by which PPT1 deficiency leads to the disruption of synaptic vesicle recycling, prevents the regeneration of fresh vesicles, and results in a progressive decline in the total pool size, which ultimately impairs neurotransmission.
Miller et al. (2015) generated a transgenic mouse model homozygous for the common R151X PPT1 mutation (600722.0006). The phenotype of the mutant mice recapitulated that observed in humans, including impaired motor function, decreased exploratory behavior, accumulation of autofluorescent material in the brain, and widespread astrogliosis and microglial activation throughout the brain. PPT1 enzyme activity in homozygous mice was 1.7 to 3.1% of controls. Administration of the read-through compound ataluren (PTC124) increased PPT1 enzyme activity and protein level in mutant mice in a proof-of-principle study.
Oppenheimer and Andrews (1959) reported 2 patients with 'ceroid storage disease': a 4-year-old white male from West Virginia who died from liver failure and had ceroid deposits of liver, spleen and intestinal mucosa, and a white 22-month-old female who at autopsy had ceroid limited largely to hepatic macrophages. The sister and 2 brothers reported by Nelson et al. (1961) may have had the same condition. The isolated case reported by Jonas (1966) may have had the same or a related condition.
Ryan et al. (1970) provided a detailed report of a boy with 'lipofuscin storage disease.' Menkes (1982) reviewed this paper and suggested, mainly on clinical grounds because the electron microscopy was unsatisfactory, that the correct diagnosis was the Finnish or Santavuori type of infantile neuronal ceroid lipofuscinosis.
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