Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
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The neuronal ceroid lipofuscinoses (NCLs) consist of eight autosomal recessively inherited storage disorders characterized by lysosomal inclusions of autofluorescent lipofuscins and rapid neurodegenerative progression. The NCLs include eight forms that result from genetic deficiency on genes CLN(1) to CLN(8), respectively: four classic forms with clinical onset at varying ages-infantile (INCL), late-infantile (LINCL), juvenile (JNCL), and adult (ANCL)-and four variants of late-infantile onset-the Finnish variant LINCL (fLINCL), Portuguese variant LINCL (pLINCL), Turkish variant LINCL (tLINCL), and progressive epilepsy with mental retardation (EPMR). The genes CLN(1) and CLN(2) have been characterized to encode lysosomal hydrolytic enzymes, but CLN(3), CLN(5), and CLN(8) encode transmembranous proteins with unknown function. Although clinical and pathological abnormalities have been recognized to be similar in all eight forms, the molecular mechanism explaining NCL pathogenesis remains unclear. In this review, the molecular basis for NCLs and a possible pathogenic mechanism are discussed.
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PMID:Neuronal ceroid lipofuscinoses and possible pathogenic mechanism. 1100 11

The neuronal ceroid lipofuscinoses (NCL) are a large group of autosomal recessive lysosomal storage disorders with both enzymatic deficiency and structural protein dysfunction. Previously, diagnosis of NCL was based on age at onset and clinicopathologic (C-P) findings, classified as 1) infantile (INCL), 2) late infantile (LINCL), 3) juvenile (JNCL), and 4) adult (ANCL). Most patients with NCL have progressive ocular and cerebral dysfunction, including cognitive/motor dysfunction and uncontrolled seizures. After reviewing 319 patients with NCL, the authors found that 64 (20%) did not fit into this classification of NCL. With research progress, four additional forms have been recognized: 5) Finnish, 6) Gypsy/Indian, and 7) Turkish variants of LINCL and 8) northern epilepsy, also known as progressive epilepsy with mental retardation. These eight NCL forms resulted from 100 different mutations on genes CLN1to CLN8 causing different phenotypes (http://www.ucl.ac.uk/ncl). The genes CLN1 and CLN2 encode lysosomal palmitoyl protein thioesterase and tripeptidyl peptidase 1. The function of CLN3, CLN5, and CLN8 gene-encoded products is unknown, although their predicted amino acid sequences suggest they have a transmembrane topology. The diagnosis of NCL is based on C-P findings, enzymatic assay, and molecular genetic testing. Before biochemical and genetic tests are conducted, ultrastructural studies (i.e., blood [buffy coat] or punch biopsies [skin, conjunctiva]) must be performed to confirm the presence and nature of lysosomal storage material (fingerprint or curvilinear profiles or granular osmiophilic deposits). The recognition of variable onset from infancy to middle age supersedes the traditional emphasis on age-related NCL forms.
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PMID:Pheno/genotypic correlations of neuronal ceroid lipofuscinoses. 1154 35

One variant form of late infantile neuronal ceroid lipofuscinosis (LINCL) is found predominantly within the Turkish population (CLN7). Exclusion mapping showed that CLN7 was not an allelic variant of known NCL loci (CLN1, CLN2, CLN3, CLN5 or CLN6). Using the method of homozygosity mapping, a genome-wide search was undertaken and a total of 358 microsatellite markers were typed at an average distance of about 10 cM. A region of shared homozygosity was identified on chromosome 8p23. This telomeric region contained the recently identified CLN8 gene. A missense mutation in CLN8 causes progressive epilepsy with mental retardation (EPMR) or Northern epilepsy, which has so far been reported only from Finland and is now classified as an NCL. The mouse model mnd has been shown to carry a 1 bp insertion in the orthologous Cln8 gene. Statistically significant evidence for linkage was obtained in this region, with LOD scores > 3, assuming either homogeneity or heterogeneity. Flanking recombinants defined a critical region of 14 cM between D8S504 and D8S1458 which encompasses CLN8. This suggests that Turkish variant LINCL, despite having an earlier onset and more severe phenotype, may be an allelic variant of Northern epilepsy. However mutation analysis has not so far identified a disease causing mutation within the coding or non-coding exons of CLN8 in the families. The Turkish variant LINCL disease-causing mutation remains to be delineated.
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PMID:Turkish variant late infantile neuronal ceroid lipofuscinosis (CLN7) may be allelic to CLN8. 1158

The neuronal ceroid lipofuscinoses (NCL) are a large group of autosomal recessive lysosomal storage disorders with both enzymatic deficiency and structural protein dysfunction. Previously, diagnosis of NCL was based on age at onset and clinicopathological (C-P) findings described 4 forms, classified as infantile (INCL) (2), late-infantile (LINCL) (5), juvenile (JNCL) (6), and adult (ANCL) (12). Most patients with NCL have progressive ocular and cerebral dysfunction, including cognitive/motor dysfunction and uncontrolled seizures. After reviewing 520 patients with NCL, we found that about 104 (20%) did not fit this classification of NCL. With further research, 4 additional forms have been recognized: Finnish (13), Gypsy/Indian (14), Turkish (15)--variants of LINCL, and Northern epilepsy (16), also known as progressive epilepsy with mental retardation. These eight NCL forms resulted from 151 different mutations in genes CLN1 to CLN8 causing different phenotypes (http://www.ucl.ac.uk/ncl). The genes CLN1 and CLN2 encode lysosomal palmitoyl protein thioesterase and tripeptidyl peptidase 1. The diagnosis of NCL is based on clinicopathological (C-P) findings, enzymatic assay, and molecular genetic testing. Ultrastructural studies must be performed to confirm the presence and nature of lysosomal storage material (fingerprint or curvilinear profiles, or granular osmiophilic deposits) before doing biochemical testing. Pheno/genotypic correlation studies are discussed.
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PMID:Current state of clinical and morphological features in human NCL. 1499 38

The late-infantile-onset forms of neuronal ceroid lipofuscinosis (LINCL) are the most genetically heterogeneous group among the autosomal recessive neuronal ceroid lipofuscinoses (NCLs), with causative mutations found in CLN1, CLN2, CLN5, CLN6, CLN7 (MFSD8), and CLN8 genes. Homozygous mutations in CLN8 are associated with two distinct phenotypes: progressive epilepsy and mental retardation (EPMR), first identified in Finland; and a variant of late-infantile NCL (v-LINCL) described in a subset of Turkish and Italian patients. The function of the protein encoded by CLN8 is currently unknown. Here we report the identification of an Italian v-LINCL patient with a complete isodisomy of chromosome 8, leading to homozygosity of a maternally-inherited 3-bp deletion in CLN8 gene (c.180_182delGAA, p.Lys61del). Notably, uniparental disomy (UPD) has never been described associated with the NCLs. In addition, we provide evidence of the biological role of CLN8 characterized by expressing in different neuronal cell models the native protein, the protein carrying the mutation identified here, or three additional missense mutations previously described. Our results, validated through a gene silencing approach, indicate that CLN8 plays a role in cell proliferation during neuronal differentiation and in protection against cell death.
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PMID:A novel CLN8 mutation in late-infantile-onset neuronal ceroid lipofuscinosis (LINCL) reveals aspects of CLN8 neurobiological function. 1943 Nov 84

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited lysosomal storage diseases and the prototype of childhood onset neurodegenerative disorders. To date, 10 NCL entities (CLN1-CLN10) are known and characterized by accumulation of autofluorescent storage material, age of onset and clinical symptoms. CLN8 was first identified as the causative gene for a late-onset form with progressive epilepsy and mental retardation in Finnish patients. In addition, CLN8 phenotypes were described in Turkish, Israeli and Italian patients with a more rapid progression of visual loss, epilepsy, ataxia and mental decline. Here, we report the first mutations in German (c.611G>T) and Pakistani (c.709G>A) patients. Our findings confirm previous assumptions that the CLN8 variant can occur in many ethnic groups. So far, large CLN gene deletions are only known for the CLN3 gene. Here, we also describe a novel, large CLN8 gene deletion c.544-2566_590del2613 in a Turkish family with a slightly more severe phenotype. Our data indicate that patients with clinical signs of late infantile NCL and characteristic ultrastructural inclusions should also be screened for CLN8 mutations independent of their ethnic origin.
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PMID:Novel CLN8 mutations confirm the clinical and ethnic diversity of late infantile neuronal ceroid lipofuscinosis. 1980 37

The neuronal ceroid lipofuscinoses (NCLs) are clinically and genetically heterogeneous neurodegenerative disorders. Most are autosomal recessively inherited. Clinical features include a variable age of onset, motor and mental decline, epilepsy, visual loss, and premature death. Mutations in eight genes (PPT1/CLN1, TPP1/CLN2, CLN3, CLN5, CLN6, MFSD8/CLN7, CLN8) have been identified and several more are predicted to exist, including two provisionally named CLN4 and CLN9. Despite excessive in vitro and in vivo studies, the precise functions of the NCL proteins and the disease mechanisms remain elusive. To date 365 NCL-causing mutations are known, with 91 novel disease-causing mutations reported. These are reviewed with an emphasis on their complex correlation to phenotypes. Different mutations within the NCL spectrum can cause variable disease severity. The NCLs exemplify both phenotypic convergence or mimicry and phenotypic divergence. For example, mutations in CLN5, CLN6, MFSD8, or CLN8 can underlie the clinically similar late infantile variant NCL disease. Phenotypic divergence is exemplified by different CLN8 mutations giving rise to two very different diseases, the mild CLN8 disease, EPMR (progressive epilepsy with mental retardation), and the more severe CLN8 disease, late infantile variant. The increase in the genetic understanding of the NCLs has led to improved diagnostic approaches, and the recent proposal of a new nomenclature.
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PMID:Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses. 2199 Jan 11