Maria Luisa Mostacciuolo

Cardiac involvement in becker muscular dystrophy

OBJECTIVES The purpose of this study was to assess the incidence of myocardial involvement and the relation of cardiac disease to the molecular defect at the deoxyribonucleic acid (DNA) or protein level in Becker muscular dystrophy. BACKGROUND Dystrophin gene mutations produce clinical manifestations of disease in the heart and skeletal muscle of patients with Becker muscular dystrophy. METHODS Thirty-one patients underwent electrocardiographic and echocardiographic examination and 24-h Holter monitoring. The diagnosis was established by neurologic examination, dystrophin immunohistochemical assays or Western blot on muscle biopsy, or both, and DNA analysis. RESULTS Electrocardiographic and echocardiographic findings were abnormal in 68% and 62% of the patients, respectively. Right ventricular involvement was detected in 52%. Left ventricular impairment was observed either as an isolated phenomenon (10%) or in association with right ventricular dysfunction (29%). Right ventricular disease was manifested in the teenagers, and an impairment of the left ventricle was observed in older patients. Right ventricular end-diastolic volumes were significantly increased compared with those in a control group. The left ventricular ejection fraction was significantly lower in older patients than in control subjects or younger patients. Life-threatening ventricular arrhythmias were detected in four patients. No correlations were found between skeletal muscle disease, cardiac involvement and dystrophin abnormalities. In our patients, exon 49 deletion was invariably associated with cardiac involvement. Exon 48 deletion was associated with cardiac disease in all but two patients. CONCLUSIONS The cardiac manifestation of Becker muscular dystrophy is characterized by early right ventricular involvement associated or not with left ventricular impairment. Exon 49 deletion is associated with cardiac disease.

Genetic epidemiology of congenital muscular dystrophy in a sample from north-east Italy

Congenital muscular dystrophy (CMD) is a heterogenous disease with autosomic recessive transmission. In an epidemiological study in four provinces of Veneto (region of 2586830 inhabitants in north-east Italy), the recorded incidence rate for the period 1979–1993 was 4.65 x 10−5; the prevalence rate in the year 1993 was 6.8 × 10−6. The incidence and the prevalence rates that we have obtained during the course of our investigation represent the first estimates for CMD in Europe and show that this myopathy is among the most frequent neuromuscular diseases with autosomic recessive transmission.

Facioscapulohumeral muscular dystrophy: epidemiological and molecular study in a north-east Italian population sample

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disease associated with a partial deletion on chromosome 4q35. Few relevant investigations have been reported on its epidemiology and were essentially based on clinical diagnosis, having been performed before recognition of the molecular mutation. We report an epidemiological survey on FSHD patients, in which the diagnosis was obtained by combined clinical and molecular evaluation. The survey concerned the north‐east Italian province of Padova, an area of 871,190 inhabitants (1 January 2004). We identified 40 patients affected by FSHD based on clinical diagnosis. In 33 of them, the EcoRI fragment size in the 4q35 region ranged from 14 to 35 kb. Four other patients belonging to the same family harbored a 38‐kb fragment. In these four cases, the relationship between the borderline deletion with the mild FSHD phenotype was corroborated by additional haplotype reconstruction and segregation analysis. Interestingly, the same mild facial‐sparing clinical pattern was apparent only in one other patient with an EcoRI fragment of 32 kb, suggesting that this unusual FSHD phenotype may be due to very small 4q35 deletions. On the whole, estimating a prevalence rate of 44 × 10−6, our survey confirmed FSHD as one of the most frequent neuromuscular disorders in Western populations.

Different atrophy-hypertrophy transcription pathways in muscles affected by severe and mild spinal muscular atrophy

BackgroundSpinal muscular atrophy (SMA) is a neurodegenerative disorder associated with mutations of the survival motor neuron gene SMN and is characterized by muscle weakness and atrophy caused by degeneration of spinal motor neurons. SMN has a role in neurons but its deficiency may have a direct effect on muscle tissue.MethodsWe applied microarray and quantitative real-time PCR to study at transcriptional level the effects of a defective SMN gene in skeletal muscles affected by the two forms of SMA: the most severe type I and the mild type III.ResultsThe two forms of SMA generated distinct expression signatures: the SMA III muscle transcriptome is close to that found under normal conditions, whereas in SMA I there is strong alteration of gene expression. Genes implicated in signal transduction were up-regulated in SMA III whereas those of energy metabolism and muscle contraction were consistently down-regulated in SMA I. The expression pattern of gene networks involved in atrophy signaling was completed by qRT-PCR, showing that specific pathways are involved, namely IGF/PI3K/Akt, TNF-α/p38 MAPK and Ras/ERK pathways.ConclusionOur study suggests a different picture of atrophy pathways in each of the two forms of SMA. In particular, p38 may be the regulator of protein synthesis in SMA I. The SMA III profile appears as the result of the concurrent presence of atrophic and hypertrophic fibers. This more favorable condition might be due to the over-expression of MTOR that, given its role in the activation of protein synthesis, could lead to compensatory hypertrophy in SMA III muscle fibers.

Genome-wide scan supports the existence of a susceptibility locus for schizophrenia and bipolar disorder on chromosome 15q26.

Schizophrenia (SZ) and bipolar disorder (BPD) are two severe psychiatric diseases with a strong genetic component. In agreement with the ‘continuum theory’, which suggests an overlap between these disorders, the existence of genes that affect simultaneously susceptibility to SZ and BPD has been hypothesized. In this study we performed a 7.5 cM genome scan in a sample of 16 families affected by SZ and BPD, all originating from the same northeast Italian population. Using both parametric and non-parametric analyses we identified linkage peaks on four regions (1p, 1q, 4p and 15q), which were then subjected to a follow-up study with an increased marker density. The strongest linkage was obtained on chromosome 15q26 with a non-parametric linkage of 3.05 for marker D15S1014 (nominal P=0.00197). Interestingly, evidence for linkage with the same marker has been reported previously by an independent study performed on SZ and BPD families from Quebec. In this region, the putative susceptibility gene ST8SIA2 (also known as SIAT8B) was recently associated with SZ in a Japanese sample. However, our allele frequency analyses of the two single-nucleotide polymorphisms (SNPs) with putative functional outcome (rs3759916 and rs3759914) suggest that these polymorphisms are unlikely to be directly involved in SZ in our population. In conclusion, our results support the presence of a gene in 15q26 that influences the susceptibility to both SZ and BPD.

Epidemiology of spinal muscular atrophies in a sample of the Italian population.

In the course of an epidemiological survey in four provinces of Veneto (northeastern Italy) 67 spinal muscular atrophy (SMA) cases (types I, II and III) were recorded. The survey spanned the period 1960-1983 and involved 859,891 consecutive live-born infants in a population of 2,635,800 inhabitants. The overall prevalence at birth for SMA types I, II and III was 7.8/100,000 live births. Type I alone accounted for 4.1/100,000 live births. If the hypothesis that SMA types I, II and III are clinical manifestations of allelic mutations is assumed, the mutation rate would be about 70 x 10(-6) and the frequency of the heterozygotes 1 in 57.

Infancy onset hereditary spastic paraplegia associated with a novel atlastin mutation

Cerebral palsy is the most common cause of spastic paraplegia affecting infants. However, spasticity characterized by progressive gait impairment may also be the first sign of infantile onset hereditary spastic paraplegia (HSP).1 We studied a family with six affected members (figure). Figure. Pedigree of the family with SPG3A . Arrow indicates the index case; blackened and unblackened symbols represent affected and unaffected individuals. Physic map is according to information from the UCSC Genome Browser. Boxes represent the disease-bearing chromosome. The first patient (II-3) had slowly progressive leg spasticity and weakness that started in infancy. She and her second son (III-2) had mild cyanosis at birth, and for that reason their first diagnosis was cerebral palsy. The clinical history is similar for all affected members: normal pregnancy and delivery, motor impairment starting before gait acquisition, and normal cognitive and language development. Clinical characteristics are summarized in table E-1 (see www.neurology.org). All affected members presented delayed motor milestones and gait impairment. There was no sphincteric disturbance. Current neurologic examination revealed severe spastic paraparesis, …

Patterns of deletions of the dystrophin gene in different European populations

The distribution of deletion breakpoints in the dystrophin gene was studied in a series of subjects belonging to different European populations. The data, obtained from the literature or directly from the present study, refer to population samples from France, Finland, Germany, Italy, Netherland, Switzerland, and U.K. (England, Scotland, Wales). In total, 1516 breakpoints were assigned to different introns, 359 in the region encompassing the first 40 exons and 1157 (76%) in the distal part of the gene. Intron 7 appears to be equally involved as the starting or ending breakpoint, whereas intron 44 is involved mostly as a starting breakpoint. Breakpoint distribution by intron seems to differ in different populations, reaching statistical significance in the case of introns 44, 49, and 53. This finding suggests that some intronic sequences might contain preferential breakpoints that might vary in different populations, possibly as a consequence of genetic drift.

Population data on benign and severe forms of X-linked muscular dystrophy

SummaryEpidemiological data on Becker muscular dystrophy (BMD) and Duchenne muscular dystrophy (DMD) from a large sample of the Italian population are reported. For BMD the incidence rate was found to be 5.5x10-5 liveborn males (lbm) and the prevalence rate, 13.1x10-6; the mutation rate was estimated to be about 6.0x10-6. For DMD the incidence and prevalence rates were found to be respectively 26x10-5 lbm and 31.6x10-6. The DMD mutation rate obtained by the Haldane formula was 86.6x10-6 and by the semi-direct method, 65.6x10-6. The results are discussed in the light of possible allelism of BMD and DMD.

Genetic mapping of a susceptibility locus for disc herniation and spastic paraplegia on 6q23.3-q24.1

It has been suggested that a genetic factor(s) or a familial predisposition may contribute to the clinical manifestations of disc herniation; moreover, no genetic linkage between spinal disc herniation and spastic paraplegia has ever been described. A family with consanguineous parents and four of eight sibs affected by multiple disc herniations and spastic paraplegia was clinically and genetically analysed. Surgery caused partial improvement in all of them. After the exclusion of type II collagen and vitamin D receptor genes and the recessive loci for HSPs, a genome wide search was performed with about 500 fluorescent markers. Positive lod score values were obtained for chromosome 6q22.31-q24.1, with evidence of three homozygous intervals. The maximum multipoint lod score of 3.28 was obtained in only one interval, between markers D6S1699 and D6S314. On the whole, a susceptibility locus for disc herniation and autosomal recessive spastic paraplegia was found on chromosome 6q23.3-q24.1. This is the first time that disc herniation and the associated neurological syndrome has been linked to a human chromosomal region.