RESUMO
Charcot-Marie-Tooth type 4 (CMT4) is an autosomal recessive severe form of neuropathy with genetic heterogeneity. CMT4B1 is caused by mutations in the myotubularin-related 2 (MTMR2) gene and as a member of the myotubularin family, the MTMR2 protein is crucial for the modulation of membrane trafficking. To enable future clinical trials, we performed a detailed review of the published cases with MTMR2 mutations and describe four novel cases identified through whole-exome sequencing (WES). The four unrelated families harbor novel homozygous mutations in MTMR2 (NM_016156, Family 1: c.1490dupC; p.Phe498IlefsTer2; Family 2: c.1479+1G>A; Family 3: c.1090C>T; p.Arg364Ter; Family 4: c.883C>T; p.Arg295Ter) and present with CMT4B1-related severe early-onset motor and sensory neuropathy, generalized muscle atrophy, facial and bulbar weakness, and pes cavus deformity. The clinical description of the new mutations reported here overlap with previously reported CMT4B1 phenotypes caused by mutations in the phosphatase domain of MTMR2, suggesting that nonsense MTMR2 mutations, which are predicted to result in loss or disruption of the phosphatase domain, are associated with a severe phenotype and loss of independent ambulation by the early twenties. Whereas the few reported missense mutations and also those truncating mutations occurring at the C-terminus after the phosphatase domain cause a rather mild phenotype and patients were still ambulatory above the age 30 years. Charcot-Marie-Tooth neuropathy and Centronuclear Myopathy causing mutations have been shown to occur in proteins involved in membrane remodeling and trafficking pathway mediated by phosphoinositides. Earlier studies have showing the rescue of MTM1 myopathy by MTMR2 overexpression, emphasize the importance of maintaining the phosphoinositides equilibrium and highlight a potential compensatory mechanism amongst members of this pathway. This proved that the regulation of expression of these proteins involved in the membrane remodeling pathway may compensate each other's loss- or gain-of-function mutations by restoring the phosphoinositides equilibrium. This provides a potential therapeutic strategy for neuromuscular diseases resulting from mutations in the membrane remodeling pathway.
RESUMO
AIM: To prevent possible chronic kidney diseases in healthy school- age children by screening for hematuria and proteinuria using a urine strip. METHODS: The incidence of hematuria and proteinuria was determined in 1848 healthy school-age children aged 7 to 14 years by urine screening in the eastern region of Turkey in 2008. Cases with persistent hematuria and/or proteinuria were referred to a pediatric nephrologist, and further examinations were carried out. RESULTS: Isolated hematuria, isolated proteinuria, and combined hematuria-proteinuria were found in 92 (4.9%), 16 (0.8%) and 10 (0.5%) patients, respectively. In addition, 11.9% (11/92) of cases of isolated hematuria and 40% (4/10) of cases of combined hematuria- proteinuria were observed to have persisted. Persistent hematuria and persistent hematuria-proteinuria were found in 11 (0.5%) and 4 (0.2%) patients, respectively. In these cases, underlying causes were found: renal stone disease, hypercalciuria, urinary tract infection, vesicoureteral reflux, atrophic kidney, and IgA nephropathy. CONCLUSION: According to this study, cases with persistent hematuria should be examined especially in terms of renal stones, hypercalciuria, and urinary tract infection.
