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Abstract Background Duchenne and Becker Muscular dystrophies (DMD/BMD) are allelic disorders caused by mutations in the dystrophin gene, which encodes a sarcolemmal protein responsible for muscle integrity. Deletions and duplications account for approximately 75% of mutations in DMD and 85% in BMD. The implementation of techniques allowing complete gene sequencing has focused attention on small point mutations and other mechanisms underlying complex rearrangements. Methods We selected 47 patients (41 families; 35 DMD, 6 BMD) without deletions and duplications in DMD gene (excluded by multiplex ligation-dependent probe amplification and multiplex polymerase chain reaction analysis). This cohort was investigated by systematic direct sequence analysis to study sequence variation. We focused our attention on rare mutational events which were further studied through transcript analysis. Results We identified 40 different nucleotide alterations in DMD gene and their clinical correlates; altogether, 16 mutations were novel. DMD probands carried 9 microinsertions/microdeletions, 19 nonsense mutations, and 7 splice-site mutations. BMD patients carried 2 nonsense mutations, 2 splice-site mutations, 1 missense substitution, and 1 single base insertion. The most frequent stop codon was TGA (n = 10 patients), followed by TAG (n = 7) and TAA (n = 4). We also analyzed the molecular mechanisms of five rare mutational events. They are two frame-shifting mutations in the DMD gene 3'end in BMD and three novel splicing defects: IVS42: c.6118-3C>A, which causes a leaky splice-site; c.9560A>G, which determines a cryptic splice-site activation and c.9564-426 T>G, which creates pseudoexon retention within IVS65. Conclusion The analysis of our patients' sample, carrying point mutations or complex rearrangements in DMD gene, contributes to the knowledge on phenotypic correlations in dystrophinopatic patients and can provide a better understanding of pre-mRNA maturation defects and dystrophin functional domains. These data can have a prognostic relevance and can be useful in directing new therapeutic approaches, which rely on a precise definition of the genetic defects as well as their molecular consequences.

We have been monitoring the respiratory function in 95 DMD patients (aged between 6 and 24 years) who were evaluated once or twice a year in relation to age and clinical conditions, making a total of 429 evaluations. During every evaluation, forced vital capacity, nocturnal oxygen saturation and the abdominal percentage contribution to tidal volume (an index of the action of the diaphragm) were respectively measured with spirometry, pulse oximetry and opto-electronic plethysmography. 46 patients underwent therapy with steroid while the remaining 49 never assumed steroid. No differences ( p = 0.122) were found in forced vital capacity, nocturnal saturation and the action of the diaphragm between the 231 evaluations of the steroid group and the 198 evaluations of the sham group. Steroid therapy seems not to have any effects on the respiratory function decline in DMD patients. [ABSTRACT FROM AUTHOR]

Non progressive cognitive impairment and increased rates psychosocial disorders, ADHD and Autism are reported in DMD patients. Through structured and validated questionnaire (Wechsler scales or Griffiths developmental scale, CBCL, Youth Self Report, Strengths and Difficulties Questionnaire, ADOS and DAWBA) we explored the possible role of cognitive impairment on the neuropsychiatric comorbidity in 32 boys with DMD (4–18 years). Our preliminary analysis shows a mean Full Intelligence Quotient of the whole group of 83.90 ± 16.68, lower in the patients with deletions in the distal portion of the gene (78.28 ± 16.72) than in the ones with proximal deletions (88.52 ± 15.62), with a very high frequency of Autism (about 20%) particularly in children with lower IQ level, and a high frequency of internalizing problems at CBCL, in boys with FIQ within the normal range, suggesting a role of cognitive capabilities in DMD children psychopathology. [ABSTRACT FROM AUTHOR]

Limb girdle muscular dystrophies (LGMD) are genetic heterogeneous disorders characterized by slow but progressive muscular impairment. Despite the recent identification of new genes, about 30% of these LGMDs remain without molecular diagnosis. However clinical-genetic correlations are fundamental for genetic counselling, definition of natural history and insight into pathogenesis. We collected detailed clinical, biochemical, histological and molecular data of 467 Italian LGMD patients, belonging to 8 neuromuscular Italian centres. Detailed data about neuromuscular, cardiological, respiratory involvement as far as molecular analysis and muscle biopsy were collected. Molecular analysis identified mutations in LGMD causative genes in 312 patients; 109 patients (23.1%) are still without a molecular diagnosis and 46 subjects (9.8%) carried heterozygous mutations in genes responsible for autosomal recessive forms. The relative frequency was as follows: 5.8% LGMD1B, 11.2% LGMD1C, 24.3% LGMD2A, 25.6% LGMD2B, 9.6% LGMD2I, 9.9% LGMD2D, 6.4% LGMD2E, 4.2% LGMD2C, 1.9% LGMD2L, 0.3% LGMD2F. Interestingly 1 LGMD patient (0.3%) carried mutations in ISPD and one patient in LAMA2 gene. Onset spans from the first decade to adulthood; LGMD2E being the most precocious (6.2 ± 5.3 years) and LGMD2L the latest (36.6 ± 7.1 years). Creatine-kinase values were generally increased, especially in sarcoglycanopathies, LGMD2B, LGMD1C. Cardiomyopathy was more frequent in LGMD1B (100%), LGMD2E (47%) and LGMD2I (50%) and restrictive pulmonary involvement in LGMD2I (53%) and LGMD2E (47%). About 30% of patients were wheelchair bound. The study of undiagnosed patients will potentially lead to identification of new LGMD causative genes. Overall this study defined the relative frequency of Italian LGMD and improved the knowledge about clinical, morphological and molecular spectrum as far as their natural history as far as the parameters that can better define the clinical evolution of these forms. [ABSTRACT FROM AUTHOR]