Objectives

The aim of the study was i) to assess the spectrum of changes over 24 months in ambulant boys affected by Duchenne muscular dystrophy, ii) to establish the difference between the first and the second year results and iii) to identify possible early markers of loss of ambulation.

Methods

One hundred and thirteen patients (age range 4.1–17, mean 8.2) fulfilled the inclusion criteria, 67 of the 113 were on daily and 40 on intermittent steroids, while 6 were not on steroids. All were assessed using the 6 Minute Walk Test (6MWT), the North Star Ambulatory Assessment (NSAA) and timed test.

Results

On the 6MWT there was an average overall decline of −22.7 (SD 81.0) in the first year and of −64.7 (SD 123.1) in the second year. On the NSAA the average overall decline was of −1.86 (SD 4.21) in the first year and of −2.98 (SD 5.19) in the second year. Fourteen children lost ambulation, one in the first year and the other 13 in the second year of the study. A distance of at least 330 meters on the 6MWT, or a NSAA score of 18 at baseline reduced significantly the risk of losing ambulation within 2 years.

Conclusions

These results can be of help at the time of using inclusion criteria for a study in ambulant patients in order to minimize the risk of patients who may lose ambulation within the time of the trial.

Atrial Preference Pacing (APP) is a pacemaker (PM) algorithm that works by increasing the atrial pacing rate to achieve continuous suppression of a spontaneous atrial rhythm and prevent supraventricular tachyarrhythmias. We have previously shown that atrial preference pacing may significantly reduce the number and the duration of AF episodes in myotonic dystrophy type 1 (DM1) patients who are paced for standard indications.

However, the role that APP therapies play in the prevention of AF in a long-term period remains still unclear. Aim of the present prospective study was to evaluate whether this beneficial effect is maintained for 24-months follow-up period.

To this aim, 50 patients with Myotonic Dystrophy type 1 who underwent dual-chamber PM implantation for first- and second- degree atrioventricular block, were consecutively enrolled and followed for 2 years. One month later the stabilization period, after the implantation, they were randomized to APP algorithm programmed OFF or ON for 6 months each, using a cross-over design, and remained in the same program for the second year. The results showed that while the number of AF episodes during active treatment (APP ON phases) was lower than that registered during no treatment (APP OFF phases), no statistically significant difference was found in AF episodes duration between the two phases. Furthermore, during the APP OFF and APP ON phases, the percentage of atrial pacing was 0 and 99%, respectively, while the percentage of ventricular pacing did not show differences statistically significant (11 vs. 9%, P = 0.2). Atrial premature beats were significantly higher during APP OFF phases than during APP ON phases. Lead parameters remained stable over time and there were no lead-related complications. Based on these 24-months follow-up data, we can conclude that, in DM1 patients who underwent dual-chamber PM implantation, APP is an efficacy algorithm for preventing paroxysmal AF even in long term periods.

Duchenne Muscular Dystrophy (DMD) is the most common muscle disease in children. Historically, DMD results in loss of ambulation between ages 7 and 13 years and death in the teens or 20s. In order to determine whether survival has improved over the decades and whether the impact of nocturnal ventilation combined with a better management of cardiac involvement has been able to modify the pattern of survival, we reviewed the notes of 835 DMD patients followed at the Naples Centre of Cardiomyology and Medical Genetics from 1961 to 2006. Patients were divided, by decade of birth, into 3 groups: 1) DMD born between 1961 and 1970; 2) DMD born between 1971 and 1980; 3) DMD born between 1981 and 1990; each group was in turn subdivided into 15 two-year classes, from 14 to 40 years of age. Age and causes of death, type of cardiac treatment and use of a mechanical ventilator were carefully analyzed.

The percentage of survivors in the different decades was statistically compared by chi-square test and Kaplan-Meier survival curves analyses. A significant decade on decade improvement in survival rate was observed at both the age of 20, where it passed from 23.3% of patients in group 1 to 54% of patients in group 2 and to 59,8% in patients in group 3 (p < 0.001) and at the age of 25 where the survival rate passed from 13.5% of patients in group 1 to 31.6% of patients in group 2 and to 49.2% in patients in group 3 (p < 0.001).

The causes of death were both cardiac and respiratory, with a prevalence of the respiratory ones till 1980s. The overall mean age for cardiac deaths was 19.6 years (range 13.4-27.5), with an increasing age in the last 15 years. The overall mean age for respiratory deaths was 17.7 years (range 11.6-27.5) in patients without a ventilator support while increased to 27.9 years (range 23-38.6) in patients who could benefit of mechanical ventilation.

This report documents that DMD should be now considered an adulthood disease as well, and as a consequence more public health interventions are needed to support these patients and their families as they pass from childhood into adult age.

Myotonic dystrophy (Dystrophia Myotonica, DM) is the most frequently inherited neuromuscular disease of adult life. It is a multisystemic disease with major cardiac involvement. Core features of myotonic dystrophy are myotonia, muscle weakness, cataract, respiratory failure and cardiac conduction abnormalities. Classical DM, first described by Steinert and called Steinert's disease or DM1 (Dystrophia Myotonica type 1) has been identified as an autosomal dominant disorder associated with the presence of an abnormal expansion of a CTG trinucleotide repeat in the 3' untranslated region of DMPK gene on chromosome 19. This review will mainly focus on the various aspects of cardiac involvement in DM1 patients and the current role of cardiac pacing in their treatment.

The need for a collaborative approach to complex inherited diseases collectively referred to as laminopathies, encouraged Italian researchers, geneticists, physicians and patients to join in the Italian Network for Laminopathies, in 2009. Here, we highlight the advantages and added value of such a multidisciplinary effort to understand pathogenesis, clinical aspects and try to find a cure for Emery-Dreifuss muscular dystrophy, Mandibuloacral dysplasia, Hutchinson-Gilford Progeria and forms of lamin-linked cardiomyopathy, neuropathy and lipodystrophy.

We report the first case of a heterozygous T78M mutation in the caveolin-3 gene (CAV3) associated with rippling muscle disease and proximal myopathy. The patient displayed also bilateral winged scapula with limited abduction of upper arms and marked asymmetric atrophy of leg muscles shown by magnetic resonance imaging. Immunohistochemistry on the patient’s muscle biopsy demonstrated a reduction of caveolin-3 staining, compatible with the diagnosis of caveolinopathy. Interestingly, consistent with the possible diagnosis of FSHD, the patient carried a 35 kb D4Z4 allele on chromosome 4q35. We discuss the hypothesis that the two genetic mutations may exert a synergistic effect in determining the phenotype observed in this patient.

Cardiomyopathy is an almost universal finding in boys affected by Duchenne muscular dystrophy (DMD). Myocardial changes, as a result of the lack of dystrophin, consist of cell membrane degradation, interstitial inflammation, fatty replacement and fibrosis.

Dystrophinopathic cardiomyopathy generally starts as a preclinical or intermediate stage, with evolution toward advanced stages characterized by ventricle enlargement but also by symptoms and signs of heart failure (dyspnoea, peripheral edema and liver enlargement). However in few patients the dilation could be the first manifestation of the heart involvement.

The ability to detect overt cardiomyopathy increases with age, such that more than 80% of boys older than 18 years will have abnormal systolic function.

Several drugs have been employed with the aim to contrast the evolution of cardiomyopathy toward stages of severe congestive heart failure. A review of cardiac treatment in DMD and personal experience are reported and discussed.

Pompe disease is caused by glycogen accumulation due to a deficiency of the lysosomal acid alpha-glucosidase enzyme by which it is degraded. It is a rare disease, accounting for 1:40.000 births. It is inherited as an autosomal recessive trait so that a couple presents a recurrent risk of 25% to have a child affected, at each pregnancy. The diagnosis could be achieved by biochemical and/ or molecular testing. Carrier detection and prenatal diagnosis are available when the molecular defect is known.

The spinal muscular atrophies (SMAs) include a group of disorders characterized by progressive weakness of the lower motor neurons. Several types of SMAs have been described based on age onset of clinical features: Acute infantile (SMA type I), chronic infantile (SMA type II), chronic juvenile (SMA type III), and adult onset (SMA type IV) forms. The incidence is about 1:6,000 live births with a carrier frequency of 1:40 for the severe form and 1:80 for the juvenile form. The mortality and/or morbidity rates of SMAs are inversely correlated with the age at onset. SMAs are believed to only affect skeletal muscles; however, new data on SMA mice models suggest they may also impact the heart.

Aim of the study was to retrospectively examine the cardiological records of 37 type molecularly confirmed II/III SMA patients, aged 6 to 65 years, in order to evaluate the onset and evolution of the cardiac involvement in these disorders. All patients had a standard ECG and a routine echocardiography. The parameters analysed were the following: Heart rate (HR), PQ interval, PQ segment, Cardiomyopathic Index (ratio QT/PQs), ventricular and supraventricular ectopic beats, pauses ≥ 2,5msec, ventricle diameters, wall and septum thickness, ejection fraction, fiber shortening.

The results showed that HR and the other ECG parameters were within the normal limits except for the Cardiomyopathic Index that was higher than the normal values (2,6-4,2) in 2 patients. Left ventricular systolic function was within the normal limits in all patients. A dilation of the left ventricle without systolic dysfunction was observed in only 2 patients, aged respectively 65 and 63 years; however they were hypertensive and/or affected by coronary artery disease. Data here reported contribute to reassure patients and their clinicians that type II/III SMAs do not present heart dysfunction.

Dysferlin is a 237-kDa transmembrane protein involved in calcium-mediated sarcolemma resealing. Dysferlin gene mutations cause limb-girdle muscular dystrophy (LGMD) 2B, Miyoshi myopathy (MM) and distal myopathy of the anterior tibialis. Considering that a secondary Dysferlin reduction has also been described in other myopathies, our original goal was to identify cases with a Dysferlin deficiency without dysferlin gene mutations. The dysferlin gene is huge, composed of 55 exons that span 233 140 bp of genomic DNA. We performed a thorough mutation analysis in 65 LGMD/MM patients with ≤20% Dysferlin. The screening was exhaustive, as we sequenced both genomic DNA and cDNA. When required, we used other methods, including real-time PCR, long PCR and array CGH. In all patients, we were able to recognize the primary involvement of the dysferlin gene. We identified 38 novel mutation types. Some of these, such as a dysferlin gene duplication, could have been missed by conventional screening strategies. Nonsense-mediated mRNA decay was evident in six cases, in three of which both alleles were only detectable in the genomic DNA but not in the mRNA. Among a wide spectrum of novel gene defects, we found the first example of a ‘nonstop' mutation causing a dysferlinopathy. This study presents the first direct and conclusive evidence that an amount of Dysferlin ≤20% is pathogenic and always caused by primary dysferlin gene mutations. This demonstrates the high specificity of a marked reduction of Dysferlin on western blot and the value of a comprehensive molecular approach for LGMD2B/MM diagnosis.

A 55-year-old man with myotonic dystrophy underwent phacoemulsification with IOL implantation in the right eye.

3 months after surgery, the patient showed a decreased visual acuity and an intraocular pressure (IOP) of 30 mmHg. Slit lamp examination showed a dense fibrosis of the anterior capsule with capsulorexis' shrinkage. Gonioscopy showed a closed angle. After a YAG laser iridotomy no decrease in the IOP was detected; following surgical peeling of the anterior capsule, the slit lamp showed a distended capsular bag. A YAG laser posterior capsulotomy was performed, without decrease in the IOP. Myotonic patients need to be closely followed up after cataract surgery, because in case of CBS development a prompt posterior capsulotomy could avoid more severe complications.