Cardiac assessment of limb-girdle muscular dystrophy 2I patients: an echography, Holter ECG and magnetic resonance imaging study.

Mutations in the FKRP gene may be associated with cardiac involvement. The aim of our study was to assess myocardial involvement in patients with LGMD2I, using physical examination, echocardiography, resting and 24-h ambulatory electrocardiogram and cardiac magnetic resonance imaging, with particular attention to the detection of myocardial morphologic abnormalities. Patients were compared to matched controls. Twenty-three patients were enrolled (men 10--women 13; 32.3+/-9.5 years). Twenty-two had the C826A gene mutation (homozygous 12, heterozygous 10). Nine patients had severe muscle alterations, 10 had milder muscle involvement and 4 had isolated exertional myoglobinuria. When compared to controls, LGMD2I patients had reduced left ventricular ejection fraction (50.8+/-13.9 versus 66.6+/-3.8%, p<0.0001). Sixty percent of patients had reduced left ventricular ejection fraction, including 8% with severe reduced left ventricular ejection fraction <30%. None had significant arrhythmia. Gene mutation and the severity of the muscle disease were not predictive of cardiac involvement. Cardiac magnetic resonance imaging displayed a high prevalence of myocardial functional abnormalities, fatty replacement and fibrosis, among the 13 patients investigated. Reduced contractility and cardiac magnetic resonance imaging morphological abnormalities are highly prevalent in LGMD2I patients suggesting that all patients should be referred for cardiac evaluation.

Skin Biopsy Findings in Patients With CMT1A: Baseline Data From the CLN-PXT3003-01 Study Provide New Insights Into the Pathophysiology of the Disorder.

Charcot-Marie-Tooth disease type 1A (CMT1A), the most common form of Charcot-Marie-Tooth diseases, is a demyelinating neuropathy caused by a deletion encompassing the gene coding for PMP22, a myelin protein of the peripheral nervous system. Although myelinated fibers are mostly involved in CMT1A, some patients experience neuropathic pain. We thus investigated whether unmyelinated fibers are lost in CMT1A. Skin biopsies were taken from the distal portion of the leg of 80 patients with CMT1A as part of the PXT30003-01 study and processed for quantification of intraepidermal nerve fiber density (IENFD). Mean IENFD was significantly lower in CMT1A patients than in healthy controls. Although the data were highly dispersed, IENFD tended to decrease with age and was higher overall in female patients and controls than male patients and controls. This study shows that small nerve fibers are affected in CMT1A and that this correlates with pin sensitivity. The density of epidermal Langerhans cells (LCs) was also significantly reduced in CMT1A patients, suggesting the involvement of LCs in neuropathic pain processes. These findings raise several questions concerning the interactions of Schwann cells and LCs with unmyelinated fibers in CMT1A. Moreover, they suggest that factors other than PMP22 gene dosage are involved in small fiber pathology in CMT1A.

Genetic Mutations and Demographic, Clinical, and Morphological Aspects of Myofibrillar Myopathy in a French Cohort.

BACKGROUND: Protein aggregate myopathies (PAM) represent a group of familial or sporadic neuromuscular conditions with marked clinical and genetic heterogeneity that occur in children and adults. Familial PAM includes myofibrillar myopathies defined by the presence of desmin-positive protein aggregates and degenerative intermyofibrillar network changes. PAM is often caused by dysfunctional genes, such as DES, PLEC 1, CRYAB, FLNC, MYOT, ZASP, BAG3, FHL1, and DNAJB6. OBJECTIVE: To retrospectively analyze genetic mutations and demographic, clinical, and morphological aspects of PAM in a French population. METHODS: Forty-eight PAM patients (29 men, 19 women) were divided into two groups, those with genetically (GIM) and nongenetically identified (NGIM) mutations associated with myofibrillar myopathy. RESULTS: Age of myopathy onset ranged from 13 to 68 years. GIM group mutations (81.25%) included DES (14), ZASP (8), FLNC (4), MYOT (4), BAG3 (1), CRYAB (2), and DNAJB6 (6). The MYOT subgroup displayed a significantly older onset age (p = 0.029). Autosomal dominant inheritance was found in 74.3% of GIM and 44.4% of NGIM subjects. Overall, 22.9% had Maghrebian heritage, 72.9% Caucasian, and 4.2% Asian. The most common clinical sign was distal muscle weakness (66%) followed by simultaneous distal and proximal weakness in 49%. Eleven patients had contractures, one had a rigid spine, and five had respiratory dysfunction. GIM subjects had greater cardiac involvement (51.7%) versus the NGIM group (33.3%). The average serum creatine kinase level was 393 U/L in GIM and 382 U/L in NGIM subjects. Morphological analysis showed significant differences among GIM subgroups, including the number of vacuoles and regenerated fibers (ZASP), group atrophy (ZASP), and rubbed out fibers (MYOT). Ultrastructural findings showed significant differences in intranuclear rods, Z-disc thickness, and intranuclear inclusions between gene mutation subgroups. Paracrystalline inclusions were present in three patients (DNAJB6). The most frequent mutation in was in DES, followed by ZASP. CONCLUSIONS: GIM and NGIM PAM subjects showed similar results, suggesting that any unknown genes, which cause this disease have characteristics similar to those already described. Considering the complexity of clinical, morphological, and genetic data related to PAM, particularly myofibrillar myopathies, physicians should be careful when diagnosing patients with sporadic PAM.

Anti-HMGCR autoantibodies in European patients with autoimmune necrotizing myopathies: inconstant exposure to statin.

Necrotizing autoimmune myopathy (NAM) is a group of acquired myopathies characterized by prominent myofiber necrosis with little or no muscle inflammation. Recently, researchers identified autoantibodies (aAb) against 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) in patients with NAM, especially in statin-exposed patients. Here we report what is to our knowledge the first European cohort of patients with NAM.The serum of 206 patients with suspicion of NAM was tested for detection of anti-HMGCR aAb using an addressable laser bead immunoassay. Forty-five patients were found to be anti-HMGCR positive. Their mean age was 48.9 ± 21.9 years and the group was predominantly female (73.3%). Statin exposure was recorded in 44.4% of patients. Almost all patients had a muscular deficit (97.7%), frequently severe (Medical Research Council [MRC] 5 ≤3 in 75.5%). Subacute onset (<6 mo) was noted for most of them (64.4%). Nevertheless, 3 patients (6.6%) had a slowly progressive course over more than 10 years. Except for weight loss (20%), no extramuscular sign was observed. The mean CK level was high (6941 ± 8802 IU/L) and correlated with muscle strength evaluated by manual muscle testing (r = -0.37, p = 0.03). Similarly, anti-HMGCR aAb titers were correlated with muscular strength (r = -0.31; p = 0.03) and CK level (r = 0.45; p = 0.01). Mean duration of treatment was 34.1 ± 40.8 months, and by the end of the study no patient had been able to stop treatment.This study confirms the observation and description of anti-HMGCR aAb associated with NAM. The majority of patients were statin naive and needed prolonged treatments. Some patients had a dystrophic-like presentation. Anti-HMGR aAb titers correlated with CK levels and muscle strength, suggesting their pathogenic role.

Psychiatric Presentation of Frontotemporal Dementia Associated with Inclusion Body Myopathy due to the VCP Mutation (R155H) in a French Family.

INTRODUCTION: Inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD) is a rare late-onset autosomal dominant disorder due to a mutation of the valosin-containing protein (VCP) gene. CASE REPORT: We report the case of a patient who developed progressive weakness of the limbs in his fifties, until he was confined to a wheelchair. At that time, he developed acute behavioural changes including irritability, severe anxiety and major depression, which led to him being hospitalised in a psychiatric hospital. He also suffered from aphasia and executive function impairment, which helped us to diagnose a behavioural form of frontotemporal dementia (FTD). The diagnosis of IBMPFD due to a mutation in the VCP gene was confirmed by a genetic study of the VCP gene (R155H mutation). DISCUSSION: THE CLINICAL DIAGNOSIS OF IBMPFD IS SUGGESTED BY THE PRESENCE OF AT LEAST ONE OF THREE MAJOR MANIFESTATIONS AS FOLLOWS: inclusion body myopathy (mean onset at 42 years of age), Paget's disease of the bone and FTD (mean onset at 55 years of age). It is mostly the behavioural form of FTD (behavioural changes, executive dysfunction and aphasia). One interesting finding in our report is the predominance of the psychiatric symptoms at the beginning of the behavioural changes, which led to the diagnosis of FTD. The diagnosis of IBMPFD was confirmed by the genetic study: the R155H mutation found on exon 5 domain CDC48 is the most frequent of the 18 known mutations in the VCP gene.