ABSTRACT
Dystrophinopathies are inherited diseases caused by mutations in the dystrophin (DMD) gene for which testing is mandatory for genetic diagnosis, reproductive choices and eligibility for personalized trials. We genotyped the DMD gene in our Italian cohort of 1902 patients (BMD n = 740, 39%; DMD n =1162, 61%) within a nationwide study involving 11 diagnostic centers in a 10-year window (2008-2017). In DMD patients, we found deletions in 57%, duplications in 11% and small mutations in 32%. In BMD, we found deletions in 78%, duplications in 9% and small mutations in 13%. In BMD, there are a higher number of deletions, and small mutations are more frequent than duplications. Among small mutations that are generally frequent in both phenotypes, 44% of DMD and 36% of BMD are nonsense, thus, eligible for stop codon read-through therapy; 63% of all out-of-frame deletions are eligible for single exon skipping. Patients were also assigned to Italian regions and showed interesting regional differences in mutation distribution. The full genetic characterization in this large, nationwide cohort has allowed us to draw several correlations between DMD/BMD genotype landscapes and mutation frequency, mutation types, mutation locations along the gene, exon/intron architecture, and relevant protein domain, with effects on population genetic characteristics and new personalized therapies.
ABSTRACT
PURPOSE: Jeune syndrome (JS, also described as asphyxiating thoracic dystrophy, ATD) is a rare autosomal recessive skeletal dysplasia characterized by a small, narrow chest and variable limb shortness with a considerable neonatal mortality as a result of respiratory distress. Significant life-threatening cervical spine abnormalities can be typical. METHOD: Here we describe the case of a male infant of Sardinian origin, who developed respiratory distress and feeding difficulties from the first months, correlated with muscle\skeletal dysmorphism prevalent on chest. Nocturnal respiratory sleep alterations were reported from parents. RESULTS: After clinical, genetics, radiographic and cervical MRI investigations, ATD diagnosis with C1 stenosis. A full-night video-polysomnographic study was performed in order to evaluate the sleep apnea condition. The study showed a condition of tachipnea\tachicardia, with several short respiratory events during sleep, both obstructive and central type with apneahypopnea index (AHI) 17/ h, mean duration 3.7 sec with longest 20 sec. CONCLUSION: It can be hypothesized that the combination of altered respiratory and cardiac frequency is related to central type of sleep respiratory disorders consequent to C1 compression, while the obstructive minor component is related to thoracic restrictive disorders. Full night lab-polygraphy is recommended in dysmorphic skeletal disorders like JS.
