Novel mutation in spectrin-like repeat 1 of dystrophin central domain causes protein misfolding and mild Becker muscular dystrophy.

Mutations in the dystrophin gene without disruption of the reading frame often lead to Becker muscular dystrophy, but a genotype/phenotype correlation is difficult to establish. Amino acid substitutions may disrupt binding capacities of dystrophin and have a major impact on the functionality of this protein. We have identified two brothers (ages 8 and 10 years) with very mild proximal weakness, recurrent abdominal pain, and moderately elevated serum creatine kinase levels. Gene sequencing revealed a novel mutation in exon 11 of the dystrophin gene (c.1280T>C) leading to a L427P amino acid substitution in repeat 1 of the central rod domain. Immunostaining of skeletal muscle showed weak staining of the dystrophin region encoded by exons 7 and 8 corresponding to the end of the actin-binding domain 1 and the N-terminal part of hinge 1. Spectrofluorescence and circular dichroism analysis of the domain repeat 1-2 (R1-2) revealed partial misfolding of the L427P mutated protein as well as a reduced refolding rate after denaturation. Based on computational homology models of the wild-type and mutated R1-2, a molecular dynamics study showed an alteration in the flexibility of the structure, which also strongly affects the conformational space available in the N-terminal region of the fragment. Our results suggest that this missense mutation hinders the dynamic properties of the entire N-terminal region of dystrophin.

Prevalence of congenital myopathies in a representative pediatric united states population.

The prevalence of congenital myopathies in the United States has not been examined. To address this, we determined the point prevalence of congenital myopathies in a well-defined pediatric population from Southeastern Michigan. The overall point prevalence was 1:26,000. Mutations in RYR1 were the most common cause of congenital myopathies at 1:90,000. Our data broadly agrees with estimates from previous European studies and provides the first estimate of the prevalence of congenital myopathies in the United States. Ann Neurol 2011;70:662-665.

Exome sequencing of a pedigree with Tourette syndrome or chronic tic disorder.

Ten members of a 3-generation pedigree with 7 showing Tourette syndrome/chronic tic phenotype (TS-CTD) were evaluated with whole exome sequencing. We identified 3 novel, nonsynonymous single nucleotide variants in the MRPL3, DNAJC13, and OFCC1 genes that segregated with chronic tic phenotype. These variants were not present in 100 control subjects or in dbSNP/1000 Genomes databases. A novel variant in the 5' untranslated region of the OFCC1 gene was found in 2 TS-CTD patients from a different pedigree. Further studies will clarify the importance of variants in MRPL3, DNAJC13, and OFCC1 genes in TS.

Heck's disease: diagnosis and susceptibility.

Focal epithelial hyperplasia, or Heck's disease, is an uncommon proliferation of oral mucosa that presents primarily in Native Central and South American populations. It presents as asymptomatic papules or nodules on the oral mucosa, gingiva, tongue, and lips. In the majority of cases, human papilloma virus 13 or 32 is detected. Factors that determine disease susceptibility are unclear, but genetics, and having the human lymphocytic antigen-DR4 (DRB1*0404) allele in particular, are thought to play a major role in disease vulnerability. We report another case of focal epithelial hyperplasia, hypothesize on disease susceptibility, and review the current understanding of this uncommon disorder.

Nephrogenic systemic fibrosis: is gadolinium the missing piece to the puzzle?

New medical disorders arise infrequently, but nephrogenic systemic fibrosis (NSF) is one such entity. It exclusively affects patients with renal failure, resulting in debilitating progressive fibrosis of the skin and systemic organs. Although much work has been done elucidating the histopathologic changes, a trigger has not been detected. Recently, case reports have implicated gadolinium (Gd) contrast agents as a potential etiology, prompting a health advisory from the US Food and Drug Administration (FDA) in June 2006. We discuss the literature regarding the effects of Gd on tissue and its potential relationship to the known histopathologic characteristics of NSF.

Nephrogenic systemic fibrosis: risk factors and incidence estimation.

PURPOSE: To retrospectively review data in 13 patients with biopsy-confirmed nephrogenic systemic fibrosis (NSF), assess the associated risk factors, and report the incidence of NSF at the authors' institution. MATERIALS AND METHODS: This HIPAA-compliant study had institutional review board approval; informed consent was waived. Statistical analysis was performed for all available clinical and laboratory data in patients with biopsy-confirmed NSF. The data from the patients with NSF were compared with data from a control population of patients with renal insufficiency but who did not develop NSF. RESULTS: There were eight male and five female patients, aged 17-69 years, with a diagnosis of NSF. Within 6 months of diagnosis, all 13 patients had been exposed to gadodiamide and one had been exposed to gadobenate dimeglumine in addition to gadodiamide. At the time of contrast material-enhanced magnetic resonance (MR) imaging, all 13 patients had renal insufficiency (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m(2)) and were hospitalized for a proinflammatory event (major surgery, infection, or vascular event). The group with NSF had significantly decreased eGFR (P = .01), more proinflammatory events (P < .001), and more contrast-enhanced MR examinations per patient (P = .002) than did the control group. CONCLUSION: A combination of factors, including altered kidney function, inflammatory burden, and exposure to gadolinium-based contrast agents may all play a role in development of NSF. Alternative imaging should be considered in patients with these factors. If use of a gadolinium-based agent is clinically indicated, the referring physician and patient should be informed of the potential risk of developing NSF.

Clinical use of evidence-based medicine--clinical questions: Acetylcysteine, a new treatment for an old foe?

This is a small, good quality, randomized controlled trial that shows a modest slowing in the deterioration of VC and DLco with the addition of high dose N-acetylcysteine to standard therapy in IPF. Overall the study should be interpreted with caution given its high drop out rate, which may have biased the results towards a more dramatic slowing of the disease progression. There were no differences in dyspnea score or functional status. There was no increase in the adverse events in the N-acetylcysteine group and the medication is inexpensive. Given only modest effects of N-acetylcysteine on VC and DLco, no change in functional scores, and the flaws of the study we would hesitate to use N-acetylcysteine as standard therapy in all patients with IPF.