Cln

Global

aINCL = infantile NCL; LINCL=late-infantile NCL; JNCL=juvenile NCL; ANCL=adult NCL. bGROD = granular osmiophilic deposit; CV = curvilinear; FP=fingerprint; RL=rectilinear. cGene is not yet identified. Progressive epilepsy with mental retardation.

aINCL = infantile NCL; LINCL=late-infantile NCL; JNCL=juvenile NCL; ANCL=adult NCL. bGROD = granular osmiophilic deposit; CV = curvilinear; FP=fingerprint; RL=rectilinear. cGene is not yet identified. Progressive epilepsy with mental retardation.

procedure for making the initial differential diagnosis from other neurological disorders.[7] Whenever possible, EM should be carried out at the initial medical center for a patient believed to have an NCL. If the EM results are positive for lipopigment inclusions, further genetic characterization should be pursued. If the initial EM findings are negative, then the EM study should be repeated with different tissues every 3-6 months.

Deficiency of PPT1 or TPP1 has been determined in various tissues such as lymphocytes, lymphoblasts, fibroblasts, brain, and amniotic cells, and chorionic villi in NCL1[14,15] or NCL2.[16,17] Testing the activities of PPT1 or TPP1 may help to identify or exclude NCL1 or NCL2 patients. Testing of enzymatic activity is the choice method for carriers, for whom the information of familial DNA mutation is not available. However, if the familial mutations have been identified, molecular testing of the mutation(s) would be preferred to determine the carrier status.

Molecular testing of NCLs consists of two phases: clinically based testing for common mutations, and research-based testing for rare or novel mutations. Conducting molecular analyses of CLNi-3 genes will allow identification of the majority of NCL patients/families, which account for > 85-90% of clinically recognized NCL cases in the general population with mixed ethnic backgrounds. Five common mutations in CLN1-3 genes, which are c.223A !G (Y109D) and c.451 C ! T (R151X) in CLN IVS5-1G !C (splicing error) and c.636 C ! T (R280X) in CLN2, and deletion of a 1.02-kb genomic fragment involving exons 7 and 8 in CLN3, have been characterized.1-18-1 Testing for these mutations may provide a sensitivity ranging from 66% for NCLj, to 75% for NCL2, to 78% for NCL3, among clinically referred cases.[5,19] Mutation of the 2-bp deletion in exon 4 of the CLN5 gene accounts for 90% of NCL5 cases,[20] and the mutation c.70C!G (R24G) in CLN8 was seen in all NCL8 cases.[21] No single mutation in the CLN6 gene could be characterized as common in the heterozygous population, but the mutation c.214G! T (E72X) in exon 3 has been found in 91% of NCL6 families from Costa Rica.[22-24] A total of 144 ''private'' or ''familial'' mutations identified in CLNi_3, CLN5 6, and CLN8 genes can be detected in research laboratories. NCL patients with a specific ethnic background (Fig. 1b) may present with one of the NCL variants encoded by the CLN5 6 or CLN8 gene. Therefore, mutation screening should be extended to these genes.

Molecular technology involved in the genetic analysis of common mutations (Table 2) for NCL1-3, NCL6, and NCL8 includes the amplification refractory mutation system (ARMS) and allele-specific primer extension (ASPE).[18,25] DNA sequencing of polymerase chain reaction (PCR)-amplified genomic fragments (PCR

M utatlon an alyses in CLN,

GROD or GROD-containing

M utatlon an alyses in CLN,

GROD or GROD-containing

Finnish or Northern European

Mutation analyses in CLNS

Not Detected

Mutation analyses in CLNa

Ethnic

background

Getting Started With Dumbbells

Getting Started With Dumbbells

The use of dumbbells gives you a much more comprehensive strengthening effect because the workout engages your stabilizer muscles, in addition to the muscle you may be pin-pointing. Without all of the belts and artificial stabilizers of a machine, you also engage your core muscles, which are your body's natural stabilizers.

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