Genotype-phenotype correlations in pediatric patients with myotonic dystrophy type 1 / 소아과

PURPOSE: Myotonic dystrophy, also known as dystrophia myotonica (DM), is an autosomal dominant disorder with 2 genetically distinct forms. DM type 1 (DM1) is the more common form and is caused by abnormal expansion of cytosine/thymine/guanine (CTG) repeats in the DM protein kinase (DMPK) gene. Our study aimed to determine whether the age of onset is correlated with CTG repeat length in a population of pediatric patients with DM1. METHODS: We retrospectively identified 30 pediatric patients with DM1 that underwent DMPK testing, of which the clinical data of 17 was sufficient. The cohort was divided into 2 subgroups based on the clinical phenotype (congenital-onset vs. late-onset) and number of CTG repeats ( < 1,000 vs. ≥1,000). RESULTS: We found no significant difference between the age of onset and CTG repeat length in our pediatric patient population. Based on clinical subgrouping, we found that the congenital-onset subgroup was statistically different with respect to several variables, including prematurity, rate of admission to neonatal intensive care unit, need for respiratory support at birth, hypotonia, dysphagia, ventilator dependence, and functional status on last visit, compared to the late-onset subgroup. Based on genetic subgrouping, we found a single variable (poor feeding in neonate) that was significantly different in the large CTG subgroup than that in the small CTG subgroup. CONCLUSION: Clinical variables exhibiting statistically significant differences between the subgroups should be focused on prognosis and designing tailored management approaches for the patients; our findings will contribute to achieve this important goal for treating patients with DM1.

Association of CTG repeat polymorphism in carnosine dipeptidase 1 (CNDP1) gene with diabetic nephropathy in north Indians.

Background & objectives: CNDP1 gene, present on chromosome 18q22.3-23, encodes carnosinase, the rate-limiting enzyme in hydrolysis of carnosine to β-alanine and L-histidine. Linkage of CTG trinucleotide (leucine) repeat polymorphism in CNDP1 gene with diabetic nephropathy has been observed in several populations. However, this association is conflicting and population-dependent. We investigated this association in type 2 diabetes mellitus (T2DM) patients with and without nephropathy in north India. Methods: A total of 564 individuals [199 T2DM without nephropathy (DM), 185 T2DM with nephropathy (DN) and 180 healthy individuals (HC)] were enrolled. CNDP1 CTG repeat analysis was done by direct sequencing of a 377 base pair fragment in exon 2. Results: The most frequent leucine (L) repeats were 5L-5L, 6L-5L and 6L-6L. 5L-5L genotype frequency was reduced in DN (24.3%) as compared to DM (34.7%, P=0.035) and HC (38.4%, P=0.005). Similarly, 5L allele frequency was lower in DN (46.8%) as compared to DM (57.3%, P=0.004) and HC (60.5%, P<0.001). The genotype and allelic frequencies were similar in DM and HC groups. No gender specific difference was observed in the genotype or allelic frequencies between groups. Interpretation & conclusions: Compared to healthy individuals and those with diabetes but no kidney disease, patients with diabetic nephropathy exhibited lower frequencies of 5L-5L genotype and 5L allele of CNDP1 gene, suggesting that this allele might confer protection against development of kidney disease in this population.

A Case of Congenital Myotonic Dystrophy Diagnosed by Molecular Genetics

Congenital myotonic dystrophy is a progressive degenerative disease of the neuromuscular system, usually inherited in an autosomal dominant fashion. Affected infant presents with varying degrees of respiratory failure, often necessitating immediate and prolonged ventilatory assistance. An expression of a CTG (cystosine-thymine-guanine) repeat in the 3'-unsaturated region of a protein kinase gene contributes to the development of myotonic dystrophy. We experienced a case of congenital myotonic dystrophy in a male neonate with respiratory difficulty, hypotonia and difficulty in sucking and swallowing. His mother had mild manifestations of adult type myotonic dystrophy. PCR analysis revealed that CTG repeats in the myotonic dystrophy gene of the neonate and the mother were about 800 and 100 respectively.

A Case of Familial Spinocerebellar Ataxia Type 8

Spinocerebellar ataxia type 8 (SCA8), originally described in a family characterized by pure cerebellar ataxia, is caused by the expansion of combined CTA/CTG repeats on chromosome 13q21. We experienced a 26-year-old man who presented with a 10-years history of slowly progressive gait ataxia, dysarthria and blepharospasm. We performed genetic studies for SCA1, 2, 3, 6, 7 and 8, and detected CTA/CTG repeat expansion in the SCA8 gene. We now report the first Korean familial case of SCA8 confirmed by genetic study.

Clinical Significance of CTG Repeat Expansion in Korean Myotonic Dystrophy Patients

BACKGROUND: Myotonic dystrophy is the most common type of muscular dystrophy affecting adults, associated with the expansion of triplet repeat DNA sequences. A hallmark of the inherited disease with trinucleotide repeat DNA expansion is the clinical and genetic anticipation. The copy numbers of the CTG repeat are known to be related to the severity and the onset age of clinical symptoms. METHODS: The copy numbers of the CTG repeats were determined using PCR amplification and Southern blotting. The clinical manisfestations of 34 patients from 14 families who had the CTG repeat expansion were evaluated based on the muscular disability rating scale and the electrophysiological study. RESULTS: There was a significant positive correlation between the clinical scores and the size of the amplification of trinucleotide repeat, and a negative correlation with the age of onset. In 9 patients with copy numbers of CTG repeats between 61 and 100, 8 cases were asymptomatic and myotonic discharges were not seen in 71% of patients. Larger expanded bands, earlier onset, and worse symptoms were evident with each successive generation. CONCLUSIONS: Molecular genetic analysis with CTG repeat expansion might be useful in the detection and the genetic counseling of myotonic dystrophy patients.

The CTG Repeat Polymorphisms of Myotonic Dystrophy (DM) Gene in Korean Population

Myotonic dystrophy(DM) is caused by the expansion of CTG trinucleotide repeat near the 3' end of the gene encoding for a member of protein kinase gene family (DMPK). The normal range of the CTG repeat was determined in 178 nomal individuals (141 unrelated individuals and 37 of 9 families) by polymerase chain reaction (PCR), polyacrylamide gel electrophoresis and silver staining method. And the expansion of the CTG repeats in a DM family was analyzed with Southern analysis. In normal population, the range of CTG repeat is between 5 and 34 and 19 different alleles were obserbed in that range, and (CTG)11-14 alleles were predominant. 4 members of an affected family showed the 0.5 - 2.0 kb size expansion of CTG repeats. In this study we could predict the incidence of DM in Korea as 1 in 20,000 and we could establish the diagnostic procedure for myotonic dystrophy.