Maria Antonietta Maioli

MUSCLE IMAGING ANALOGIES IN A COHORT OF PATIENTS WITH DIFFERENT CLINICAL PHENOTYPES CAUSED BY LMNA GENE MUTATIONS

Laminopathies are a heterogeneous group of LMNA‐gene‐mutation–related clinical disorders associated with alterations of cardiac and skeletal muscle and peripheral nerves, metabolic defects, and premature aging. Leg muscle imaging investigations were performed in a cohort of patients with LMNA gene alterations who were suffering from Emery–Dreifuss muscular dystrophy, limb‐girdle muscular dystrophy type 1B, isolated cardiac disorders or a phenotype of cardiac disorders, and lipodystrophy, including one individual with peripheral neuropathy. Leg muscle imaging revealed varying degrees of alteration in the soleus and medial head of gastrocnemius in each subject. This study demonstrates that LMNA‐gene‐mutated patients devoid of any clinically detectable skeletal muscle involvement have the same pattern of leg muscle involvement as patients with overt skeletal muscle compromise. This finding suggests the presence of a continuum of skeletal muscle involvement among phenotypes of LMNA‐gene‐mutation–related skeletalmyopathy and cardiomyopathy. Muscle Nerve, 2010

Muscle MRI findings in patients with an apparently exclusive cardiac phenotype due to a novel LMNA gene mutation

The case of a family in which several members displayed conduction defects inherited as a dominant trait is reported. The proband was a young woman with a 1st degree atrio-ventricular block and high serum creatine kinase. Several members of the family featured cardiologic symptoms. All adult family members were clinically evaluated and blood tests including serum creatine-kinase levels, standard and Holter ECG, echocardiogram and muscle MRI were performed. LMNA gene analysis was carried out and a novel missense mutation consisting in substitution of exon 4 c.799 T/C, p.Tyr267His was revealed. The mutation was present in seven family members, five of whom displayed cardiac defects alone with no involvement of the skeletal muscle. In all mutated individuals muscle MRI featured a pattern of skeletal muscle involvement similar to that observed in autosomal dominant Emery Dreifuss muscular dystrophy, suggesting that even patients bearing a LMNA gene mutation associated to an apparently selective cardiac phenotype may present subclinical skeletal muscle involvement.

Influence of treatments in multiple sclerosis disability: A cohort study

Background and objective: A critical aspect of multiple sclerosis (MS) treatments is understanding the effect of disease-modifying drugs (DMDs) on the long-term risk of disability and whether the effect is related to disability at start of treatment. Methods: We performed an observational study on 3060 MS patients. The effect of therapy on progression to Expanded Disability Status Scale (EDSS) 3.0 and 6.0 from onset was analysed in treated vs untreated (UTP) patients using Cox regression analysis adjusted for propensity score and immortal time bias. Results: Compared to UTP, the risks of EDSS 3.0 were 94% and 73% lower in immunomodulant (IMTP-) and immunosuppressant (ISTP-) treated patients, respectively, while the risk of EDSS 6.0 was 86% lower in IMTP. The risk of EDSS 6.0 was, respectively, 91% and 75% lower in 1275 IMTP before and 114 after EDSS 3.0 than in 539 UTP; the risk was higher in IMTP starting therapy after EDSS 3.0 than before (HR = 4.42). Conclusions: DMDs delayed long-term disability in MS patients treated either in the early or, to a lesser extent, in the later phase of the disease. Thus, the window of therapeutic opportunity is relatively extended, assuming that early is better than late treatment, but late is better than never.

Clinical and molecular characterization of limb-girdle muscular dystrophy due to LAMA2 mutations

In this study we describe the clinical and molecular characteristics of limb‐girdle muscular dystrophy (LGMD) due to LAMA2 mutations.

Evolution of the phenotype in a family with an LMNA gene mutation presenting with isolated cardiac involvement

The aim of this study is to report the evolution of a phenotype in members of a single family carrying the heterozygous exon 1 c.178 C/G, p.Arg 60 Gly LMNA gene mutation. All mutated family members underwent neurological and cardiological assessments for a period ranging from 10 to 20 years. At onset, 4 affected adult members presented a phenotype that required pacemaker implantation. Three subjects underwent cardiac transplantation leading to long‐term survival in 2 of them. One of the 3 longest surviving relatives manifested late lipodystrophy, and the other 2 had lipodystrophy, insulin‐resistant diabetes, and distal peripheral neuropathy. The findings demonstrate that the exon 1 c.178 C/G, p.Arg 60 Gly LMNA gene mutation is associated with a novel phenotype featuring cardiac involvement followed by late lipodystrophy, diabetes, and peripheral axonal neuropathy. Muscle Nerve, 2010

Cardiac and muscle imaging findings in a family with X-linked Emery-Dreifuss muscular dystrophy

The following is a report on a large family with 5 males affected by the X-linked recessive form of Emery-Dreifuss muscular dystrophy with mutation in the STA gene. A detailed longitudinal cardiological evaluation and muscle imaging studies allowed for the assessment of intrafamilial variability of cardiac and muscle involvement. Long term cardiological follow up in the 5 affected males and in 7 female carriers revealed different degrees of severity, ranging from tachycardia-bradycardia syndrome and variable biatrial and left ventricle dilatation, to an episode of isolated symptomatic sustained ventricular tachycardia requiring a device implantation. Muscle imaging in the affected males showed involvement of the soleus and medial head of gastrocnemius on leg muscles and variable involvement on thigh muscles that have not been previously reported. In some cases, imaging showed clear signs of muscle involvement even when no overt signs of weakness could be detected during clinical examination.

Late-onset polyglucosan body myopathy in five patients with a homozygous mutation in GYG1.

Five Sardinian patients presented in their 5th or 6th decade with progressive limb girdle muscle weakness but their muscle biopsies showed vacuolar myopathy. The more or less abundant subsarcolemmal and intermyofibrillar vacuoles showed intense, partially α-amylase resistant, PAS-positive deposits consistent with polyglucosan. The recent description of late-onset polyglucosan myopathy has prompted us to find new genetic defects in the gene (GYG1) encoding glycogenin-1, the crucial primer enzyme of glycogen synthesis in muscle. We found a single homozygous intronic mutation harbored by five patients, who, except for two siblings, appear to be unrelated but all five live in central or south Sardinian villages.

Cardiac involvement in patients with lamin A/C gene mutations: a cohort observation.

Introduction: LMNA gene mutations are associated with cardiac and skeletal muscle alterations. Methods: A cohort of 21 mutated individuals was assessed with clinical and instrumental investigations over the years. Results: The median observation period was 6 years. Cardiac compromise was detected in 16 patients. Bradyarrhythmias were the most frequent manifestations, followed by supraventricular arrhythmias. Two individuals suffered from nonsustained and 1 from sustained ventricular tachyarrhythmias. Dilated cardiomyopathy was detected in 3 patients. Evaluation of the frequencies of the clinical expressions showed a high probability of suffering from analogue heart compromise in study subjects bearing the same LMNA gene mutation. Conclusions: Cardiac involvement represents a very common phenotypic expression of LMNA gene mutation. Subjects sharing common genetic background seem to suffer from analogue pattern of cardiac manifestation. Muscle Nerve 46: 187–192, 2012

Aberrant splicing in the LMNA gene caused by a novel mutation on the polypyrimidine tract of intron 5

Introduction: Familial dilated cardiomyopathy with conduction system defects variably associated with skeletal muscle abnormalities is frequently caused by LMNA gene mutations. Methods: A family affected by cardiac abnormalities, either isolated or variably associated with skeletal muscle compromise, was identified. LMNA gene analysis was applied to all family members. Results: A novel intron 5 (c.937‐11 C>G) mutation was identified. mRNA transcription analysis was subsequently performed, and cDNA was obtained from mutated patients. It displayed an aberrant splice product featuring the insertion of 40 nucleotides from intron 5, leading to a frameshift. Computational predictions identified a cryptic splice site 40 bp upstream from the canonical site; this alternative splicing event was elicited by intronic mutation, which seems to interfere with the polypyrimidine tract of the canonical site. Conclusions: We have described the first mutation on the LMNA gene interfering with the polypyrimidine tract. Our findings underline the importance of including introns in the search for mutations. Muscle Nerve, 2011

Partial lipodystrophy associated with muscular dystrophy of unknown genetic origin

Overlapping syndromes characterized by the concomitant presence of abnormal fat distribution and muscular dystrophy have been reported in association with mutations either in the LMNA or PTRF genes. LMNA mutations may cause partial lipodystrophy and muscular dystrophy, whereas PTRF mutations result in generalized lipodystrophy with muscular dystrophy. We report 2 siblings who presented with abnormal fat distribution, muscular dystrophy, and metabolism alterations. Mutations in known genes responsible for nuclear envelopathies and lipodystrophies were ruled out, as was Madelung disease. Patient 1 is the third child from healthy, consanguineous parents. She complained of menstrual irregularity since youth. At age 33 years she developed abnormal subcutaneous fat distribution with accumulation in the neck, abdomen, and axillae, and she had progressive reduction of subcutaneous fat in the legs. She was diagnosed with diabetes 10 years later. At age 50 years, physical examination showed abnormal fat accumulation in the neck, abdomen, clavicular regions, axillae, labia majora, back, and below the triceps. There was also reduction of subcutaneous fat in the legs. She had mild proximal muscle weakness (MRC 4) affecting both shoulder and hip girdle muscles. Her brother, patient 2, was evaluated at age 49 years. He had fat distribution abnormalities, with increased subcutaneous adipose tissue of the abdomen and the axillae and a reduction of subcutaneous fat in the legs. Muscle strength was normal. Blood analyses showed high creatine kinase in both patients and elevated triglycerides and cholesterol levels in patient 1. Cardiovascular investigations revealed no abnormality in either subject. Muscle biopsy from patient 1 showed dystrophic changes with normal immunohistochemical labeling of the proteins responsible for most common muscular dystrophies; trichrome and oxidative stains did not show any evidence of mitochondrial disease. Multiplex Western blot analysis of muscle was normal. In cultured skin fibroblasts and pre-adipocytes, lamin A/C, prelamin A, emerin, and SUN1 were expressed normally (Fig. 1). Magetic resonance imaging (MRI) of patient 1 disclosed fat accumulation in the cervical, dorsal, and abdominal regions; hepatic steatosis; predominant posterior thigh muscle increased T2 signal; and increased T2 signal of tibialis anterior and posterior, extensor digitorum longus, and soleus muscles. MRI of patient 2 showed inhomogeneous subcutaneous fat distribution with fat predominance in the anterior abdomen, and posterior leg muscle increased T2 signal. Lower limb subcutaneous fat was reduced on MRI in both patients (Fig. 1). Karyotype analysis of patient 1 revealed normal chromosome numbers and absence of gross structural changes; direct sequencing of the coding regions and 100–150 bp of exon–intron junctions of PTRF1, LMNA, ZMPSTE24, BANF, STA, PPARG, PLIN, CAV1, LMNB2, CIDEC, AKT2, AGPAT2, and BSCL2 genes excluded pathogenic mutations. Multiplex ligation probe amplification analysis also excluded LMNA deletions/duplications. Respiratory chain enzyme dose and sequencing of whole mitochondrial DNA were normal. Single-nucleotide polymorphism (SNP) array analysis excluded copy number variations of pathogenic relevance shared between the siblings. Given the parental consanguinity and the discordant genders, the likely mode of inheritance is autosomal recessive. We speculate that this complex phenotype is due to either a new causative gene or is a new phenotype of an already described form of myopathy. Further studies are in progress to identify the underlying disease-causing gene.