Limb-girdle Weakness Research Articles

OD12 - Detection of TRIM32 variants associated with LGMD2H in a large cohort of patients with unexplained limb-girdle weakness

OD12 - Detection of TRIM32 variants associated with LGMD2H in a large cohort of patients with unexplained limb-girdle weakness

OD11 - The MYO-SEQ project: application of exome sequencing technologies to 1000 patients affected by limb-girdle weakness of unknown origin

OD11 - The MYO-SEQ project: application of exome sequencing technologies to 1000 patients affected by limb-girdle weakness of unknown origin

Phenotypic Variability of Dystrophinopathy Symptomatic Female Carriers

Dystrophinopathies are X-linked muscular dystrophies characterized by pathogenic mutations in the dystrophin gene. Symptomatic dystrophinopathy female carriers may present with limb-girdle weakness. The diagnosis may be challenging in the absence of affected male relatives. We aimed to describe the phenotypic variability in a series of molecular-confirmed female dystrophinopathy patients. This is a retrospective analysis of medical records from 1997 to 2015. Ten female dystrophinopathy patients were selected, two with unusual phenotypes: one with early joint contractures muscular dystrophy and the other with very late onset myopathy. Muscle imaging studies demonstrated predominant asymmetric fat replacement. Muscle biopsy immunohistochemistry demonstrated clear mosaic pattern in two cases and only subtle reduction of dystrophin intensity in three. Adequate diagnosis is fundamental for genetic counseling and cardiologic follow-up. Female patients with dystrophinopathy may present unusual phenotypes such as early contractures and very late onset myopathy.

Clinical, electrophysiological and pathological evaluation of limb girdle weakness

Clinical, electrophysiological and pathological evaluation of limb girdle weakness

P.59 - Screening for late onset Pompe disease – Single center experience

Late onset Pompe disease (LOPD, OMIM# 32300) is an autosomal recessive disorder caused by mutations of GAA gene encoding acid maltase. LOPD can present with a variety of neuromuscular phenotypes, from limb-girdle weakness to asymptomatic CK-emia. Several diagnostic approaches were proposed. Search for decreased GAA activity can be done either when other known causes of neuromuscular symptoms were excluded, or it can be the first screening step in a predefined population. Material and methods: a cohort of patients older than 5 y. with limb-girdle weakness or persistently elevated CK (more than 1.5× ULN). Enzyme activity from a dry blood spot (DBS) was estimated, followed by confirmatory testing if GAA levels were significantly reduced. 178 patients were tested (mean age 29.5 years, SD 19, range 5–78), 40% were women. Decreased GAA activity was detected in eight patients at first screening. It led to diagnosis of LOPD in 4 patients (2.2%), including two siblings of a boy originally tested for persistent CK-emia. DBS is useful for LOPD screening in patients with isolated CK-emia or limb-girdle weakness. LOPD ratio in our screened cohort is similar as in previously reported populations.

P.192 - Autoimmune myopathy with cardiac involvement associated with antimitochondrial antibodies

Antimitochondrial antibodies (AMA) are associated with primary biliary cirrhosis (PBC). They act against autoantigens situated in the inner membrane of mitochondria. AMA M2, directed against the proteins of the 2–oxo acid dehydrogenase family, is the subtype most frequently associated with hepatic disease. The relation of AMA M2 with inflammatory myopathies has recently been reported by Hashimoto et al, who described 24 patients among 212 patients with seronegative inflammatory myopathy associated with AMA antibodies. We aim to describe a series of patients suffering from immunomediated myopathy (IMM) associated with AMA. We identified 8 patients with IMM. We determined serum CK levels and excluded other specific myositis antibodies. We performed a complete cardiological examination in all patients focused on the presence of arrhythmias. The patients were 7 females and 1 male. Age at onset varied from 31 to 71 years, and diagnosis delay ranged from 1 to 10 years. All patients presented with subacute progressing limb girdle weakness. 6 patients suffered cardiac involvement at onset with supraventricular arrhythmias; 3 of them eventually developed a dilated cardiomyopathy. One patient presented hypercapnic respiratory failure. Three patients presented PBC. Serum CK levels were elevated. Muscle biopsy revealed muscle fiber necrosis in 6 patients. Only in one were perivascular inflammatory infiltrates observed. MHC class I was up-regulated in 6 patients. All patients received immunomodulatory therapy. Muscle weakness improved with steroid treatment but cardiac involvement didn't respond. AMA must be determined in patients suffering with autoimmune myopathy, especially when cardiac manifestations are present. A detailed cardiological examination may be performed in patients with limb girdle weakness associated with AMA. Arrhythmias and dilated cardiomyopathy often fail to respond to conventional immunomodulatory therapy.

P.64 - Application of exome sequencing technologies: A case study of patients with unexplained limb-girdle muscle weakness harbouring GAA mutations

P.64 - Application of exome sequencing technologies: A case study of patients with unexplained limb-girdle muscle weakness harbouring GAA mutations

P.349 - Myofibrillar myopathies with autophagic vacuoles: Report of a case series

The presence of autophagic vacuoles containing lysosomal, autophagosomal and sarcolemmal membrane components depicts autophagic vacuolar myopathies as a spectrum of disorders unified by distinctive myopathologic features. While not being classified as autophagic vacuolar myopathies, also muscle disorders including myopathies with rimmed vacuoles, inclusion body myopathies and myofibrillar myopathies (MFM) have autophagic pathology. Here, we present the diagnostic algorithm which led us to the diagnosis of MFM in four unrelated patients with autophagic vacuolar myopathies. Patient 1 is a 39-year-old male, that came to our attention at the age of 35 for hyperCKemia (5× normal value) and a mild exercise intolerance; his clinical conditions have worsened in the last years of follow up, with the appearance of a progressive limb girdle weakness resembling a LGMD-like phenotype. Patient 2 is a 74-year-old woman with a 7-year history of a progressive axial and pelvic girdle weakness, in association with a moderate increase of blood CK (4× normal value). Patients 3 and 4 are respectively 19-year-old and 37-year-old males that present an asymptomatic hyperckemia (5× normal value), without muscle weakness. None of them is affected by cardiomyopathy. Their family history is inconsistent for neuromuscular diseases. The ultrastructural studies of the muscle biopsies have showed myofibrillar myopathy features, including progressive myofibrillar degeneration commencing at the Z-disk, accumulation of degraded filamentous material and entrapment of dislocated membranous organelles in autophagic vacuoles.

P.243 - The MYO-SEQ project: Application of exome sequencing technologies to 1000 patients affected by limb-girdle weakness of unknown origin

P.243 - The MYO-SEQ project: Application of exome sequencing technologies to 1000 patients affected by limb-girdle weakness of unknown origin

The frequency of late-onset Pompe disease in pediatric patients with limb-girdle muscle weakness and nonspecific hyperCKemia: A multicenter study

The aim of this multicenter study was to screen for late-onset Pompe disease in high-risk children with limb-girdle muscle weakness and nonspecific hyperCKemia using the dried blood spot (DBS) test. Seventy-two children from four pediatric neurology departments in Turkey were enrolled in the study: 37 with limb-girdle muscle weakness and 35 with nonspecific hyperCKemia. Acid α-glucosidase (GAA) activity was measured on DBS by tandem mass spectrometry. Six patients tested positively for Pompe disease. In three patients, one with the limb-girdle muscle weakness and two with nonspecific hyperCKemia, this was confirmed by genetic analysis. The overall frequency of late-onset Pompe disease in the study population was 4.2%. The c.1784C>T mutation found in one patient is a new mutation whereas the c.1655T>C mutation detected in the other two patients is not novel. In conclusion, Pompe disease should be suspected in patients with limb-girdle muscle weakness and nonspecific hyperCKemia. The DBS test is a safe and reliable method of diagnosis but must be confirmed by genetic analysis. In patients with a positive DBS test and negative genetic analysis, tissue assay of GAA should be considered.

Limb-girdle congenital myasthenic syndrome in a Chinese family with novel mutations in MUSK gene and literature review

ObjectivesTo describe the clinical and genetic features of a Chinese congenital myasthenic syndromes (CMS) patient with two novel missense mutations in muscle specific receptor tyrosine kinase (MUSK) gene and review 15 MUSK-related CMS patients from 8 countries. MethodsThe patient was a 30-year-old man with chronic progressively proximal limb weakness for 22 years and diagnosed as muscular dystrophy before. Serum creatine kinase (CK) was normal. Repetitive nerve stimulation (RNS) test showed decrements at low rate stimulation. Weakness became worse after conventional doses of pyridostigmine. Mild multiple atrophy of thigh and leg muscle was observed in MRI. Open muscle biopsy and genetic analysis were performed. One hundred healthy individuals were set for control. ResultsMuscle biopsy showed mild variation in fiber size. Two missense mutations in MUSK gene (p.P650T and p.I795S) were identified in the patient. The mutation of p.I795S was identified in his father and p.P650T in his mother. Both of them were not detected among the healthy controls and predicted to be damaging or disease causing by prediction tools. ConclusionIn this study, we identified a limb-girdle CMS (LG-CMS) patient carrying two novel heterozygous missense mutations in MUSK gene. CMS related genes should be analyzed in patients with limb-girdle weakness, normal CK, decrement of CMAP at RNS and mild change in muscle biopsy or MRI.

Childhood Pompe disease: clinical spectrum and genotype in 31 patients.

BackgroundAs little information is available on children with non-classic presentations of Pompe disease, we wished to gain knowledge of specific clinical characteristics and genotypes. We included all patients younger than 18 years, who had been evaluated at the Pompe Center in Rotterdam, the Netherlands, between 1975 and 2012, excluding those with the classic-infantile form. None were treated with enzyme replacement therapy at the time of evaluation. We collected information on first symptoms, diagnosis, use of a wheelchair and/or respirator, and enzyme and mutation analysis and assessed muscle strength, pulmonary function, and cardiac parameters.ResultsThirty-one patients participated. Median age at symptom onset was 2.6 years (range 0.5–13y) and at diagnosis 4.0 years. Most first problems were delayed motor development and problems related to limb-girdle weakness. Fatigue, persistent diarrhea and problems in raising the head in supine position were other first complaints. Ten patients were asymptomatic at time of diagnosis. Five of them developed symptoms before inclusion in this study. Over 50 % of all patients had low or absent reflexes, a myopathic face, and scoliosis; 29 % were underweight. Muscle strength of the neck flexors, hip extensors, hip flexors, and shoulder abductors were most frequently reduced. Pulmonary function was decreased in over 48 % of the patients; 2 patients had cardiac hypertrophy. Patients with mutations other than the c.-32–13T > G were overall more severely affected, while 18 out of the 21 patients (86 %) with the c.-32–13T > G/‘null’ genotype were male.ConclusionsOur study shows that Pompe disease can present with severe mobility and respiratory problems during childhood. Pompe disease should be considered in the differential diagnosis of children with less familiar signs such as disproportional weakness of the neck flexors, unexplained fatigue, persistent diarrhea and unexplained high CK/ASAT/ALAT. Disease presentation appears to be different from adult patients. The majority of affected children with GAA genotype c.-32–13T > G/‘null’ appeared to be male.

Prevalence of Pompe disease in 3,076 patients with hyperCKemia and limb-girdle muscular weakness.

We prospectively screened a large European cohort of patients presenting with hyperCKemia and/or limb-girdle muscular weakness (LGMW) for acid α-glucosidase (GAA) deficiency by dried blood spot (DBS) investigation. DBS were collected from 3,076 consecutive adult patients from 7 German and British neuromuscular centers. All specimens were investigated for GAA deficiency by fluorometry. Samples with reduced enzyme activity were subsequently investigated for GAA gene mutations. Of 3,076 patients with DBS samples, 232 patients (7.6%) showed low GAA enzyme activity. Of these 232 patients, 55 (24%) presented with isolated hyperCKemia and 176 (76%) with hyperCKemia and LGMW. With both features present, 94% of the patients showed a low enzymatic activity. Mutational analysis found GAA gene mutations in 74 patients (2.4%); herein 70 patients were heterozygote for the common GAA gene splice-site mutation c.-32-13T>G. The most common clinical presentation in the confirmed Pompe cohort was a limb-girdle phenotype (85.3%) combined with ventilatory insufficiency (61%). Isolated hyperCKemia was found in 12%, while 2.7 had hyperCKemia and ventilatory insufficiency only. In a large cohort of unselected adult patients with hyperCKemia and/or LGMW, we found a prevalence of late-onset Pompe disease of 2.4%. Therefore, targeted screening of such a population should be encouraged in clinical practice.

Clinical features of the myasthenic syndrome arising from mutations in GMPPB

BackgroundCongenital myasthenic syndrome (CMS) due to mutations in GMPPB has recently been reported confirming the importance of glycosylation for the integrity of neuromuscular transmission.MethodsReview of case notes of patients with...

Analysis of the Specific Immune Response in Skeletal Muscle in LGMD2I Patients

Background/Purpose: Limb-girdle muscular dystrophy 2I (LGMD2I) is one of the most frequently encountered muscular dystrophies worldwide. Caused by mutations in the fukutin-related protein (FKRP) gene, it leads to a typical clinical limb girdle weakness and reduced or absent sarcolemmal staining of α- dystroglycan in skeletal muscle fibers. Inflammatory infiltrates have been detected on biopsies before, but a detailed characterization is lacking so far. Hence, we analyzed biopsy specimens from three university hospital institutions of genetically confirmed LGMD2I patients, focusing on markers of adaptive immunity and fibrosis.

Intranuclear Aggregates Precede Clinical Onset in Oculopharyngeal Muscular Dystrophy.

Oculopharyngeal muscular dystrophy (OPMD) has long been characterized by a combination of bilateral ptosis and dysphagia and subsequent limb girdle weakness. The role of the typical intranuclear inclusion in the pathophysiology is unresolved. The aim of this study was to describe the clinical and histopathological features of oculopharyngeal muscular dystrophy (OPMD). We examined this in a Dutch cohort including presymptomatic Ala-expanded-PABPN1 carriers and late symptomatic patients. We performed a prospective, observational study in OPMD patients and adult children of genetically confirmed OPMD patients. The study includes a structured history, a detailed neurological examination, muscle histology and biochemical analysis. Forty patients and 18 adult children participated in this study, among whom were six presymptomatic mutation carriers. One patient died during the study and had given permission to autopsy. In addition to the characteristic OPMD symptoms including ptosis and dysphagia, other symptoms such as limb girdle and axial weakness, and external ophthalmoplegia were frequently observed. Intranuclear aggregates were observed in the biopsies of presymptomatic carriers. Biochemical analysis of the biopsies of the presymptomatic carriers showed no mitochondrial dysfunction. The autopsy showed that muscle weakness correlated with histopathological findings in five different muscles in an individual patient. The main findings of this nationwide study are the presence of intranuclear aggregates before clinical onset and the absence of mitochondrial changes in Ala-expanded-PABPN1 carriers. This indicates that the expression of Ala-expanded-PABPN1 causes the formation of nuclear aggregates before the onset of muscle weakness. Normal results of biochemical analysis in presymptomatic carriers suggest that possible mitochondrial dysfunction occurs later. Furthermore we confirmed that limb girdle weakness occurs frequently in Dutch OPMD patients. This study thus expands the OPMD research towards characterization of presymptomatic carriers.

Clinical spectrum of valosin containing protein (VCP)-opathy.

Valosin containing protein (VCP) mutations cause a rare disorder characterized by hereditary inclusion body myopathy, Paget disease of bone (PDB), and frontotemporal dementia (FTD) with variable penetrance. VCP mutations have also been linked to amyotrophic lateral sclerosis and Charcot-Marie-Tooth disease type 2. Review of clinical, serological, electrophysiological, and myopathological findings of 6 VCP-opathy patients from 4 unrelated families. Patients manifested muscle weakness between ages 40 and 53 years and developed predominant asymmetric limb girdle weakness. One patient had distal weakness at onset and co-existing peripheral neuropathy. Another patient had PDB, 1 had mild cognitive deficits, and 1 had FTD. All patients had myopathic and neurogenic electromyographic findings with predominant neurogenic changes in 2. Rimmed vacuoles were infrequent, while neurogenic changes were prominent in muscle biopsies. VCP-opathy is a multifaceted disorder in which myopathy and peripheral neuropathy can coexist. The electrophysiological and pathological neurogenic changes raise the possibility of coexisting motor neuron involvement. Muscle Nerve, 2015 Muscle Nerve 54: 94-99, 2016 Muscle Nerve 54: 94-99, 2016.

Long-term follow-up in patients with congenital myasthenic syndrome due to RAPSN mutations

Rapsyn (RAPSN) mutations are a common cause of postsynaptic congenital myasthenic syndromes. We present a comprehensive description of the clinical and molecular findings of ten patients with CMS due to mutations in RAPSN, mostly with a long-term follow-up. Two patients were homozygous and eight were heterozygous for the common p.Asn88Lys mutation. In three of the heterozygous patients we have identified three novel mutations (c.869T > C; p.Leu290Pro, c.1185delG; p.Thr396Profs*12, and c.358delC; p.Gln120Serfs*8). In our cohort, the RAPSN mutations lead to a relatively homogeneous phenotype, characterized by fluctuating ptosis, occasional bulbar symptoms, neck muscle weakness, and mild proximal muscle weakness with exacerbations precipitated by minor infections. Interestingly, episodic exacerbations continue to occur during adulthood. These were characterized by proximal limb girdle weakness and ptosis, and not so much by respiratory insufficiency after age 6. All patients presented during neonatal period and responded to cholinergic agonists. In most of the affected patients, additional use of 3,4-diaminopyridine resulted in significant clinical benefit. The disease course is stable except for intermittent worsening.

Sporadic late onset nemaline myopathy with monoclonal gammopathy: Hematopoietic stem cells therapy

Sporadic late onset nemaline myopathy (SLONM) is a rare acquired form of myopathy. The disease progression is fast and the prognosis is poor when associated with monoclonal gammopathy of undetermined significance (MGUS), which happens in half of the cases. The pathogenetic link with MGUS has not been elucidated at present. We report the case of a 38-year-old female patient, who presented with progressive proximal limb girdle and axial muscle weakness, atrophy of limb girdle muscles, myalgia and respiratory weakness due to SLONM with MGUS. This patient is the ninth case described who, except one, responded favourably to autologous stem cell transplantation. We highlight the importance of an early diagnosis of this rapidly progressive, often fatal, acquired myopathy, since it can be treated.

Congenital Myasthenic Syndromes with Predominant Limb Girdle Weakness.

Congenital myasthenic syndromes are a heterogeneous group of genetically determined disorders characterized by impaired neuromuscular transmission. They usually present from birth to childhood and are characterised by exercise induced weakness and fatigability. Genotype-phenotype correlations are difficult. However, in some patients particular phenotypic aspects may point towards a specific genetic defect.The absence of ptosis and ophthalmoparesis in patients with limb-girdle weakness makes the diagnosis of a neuromuscular transmission defect particularly challenging (LG-CMS). This is illustrated by a well-documented case published by Walton in 1956. The diagnosis of LG-CMS is secured by demonstrating a neuromuscular transmission defect with single fibre EMG or repetitive nerve stimulation, in the absence of auto-antibodies. Ultimately, a genetic test is required to identify the underlying cause and assure counselling and optimization of treatment. LG-CMS are inherited in autosomal recessive traits, and are often associated with mutations in DOK7 and GFPT1, and less frequently with mutations in COLQ, ALG2, ALG14 and DPAGT.Genetic characterization of CMS is of the upmost importance when choosing the adequate treatment. Some of the currently used drugs can either ameliorate or aggravate the symptoms depending on the underlying genetic defect. The drug most frequently used for the treatment of CMS is pyridostigmine an acetylcholinesterase inhibitor. However, pyridostigmine is not effective or is even detrimental in DOK7- and COLQ-related LG-CMS, while beta-adrenergic agonists (ephedrine, salbutamol) show some sustained benefit. Standard clinical trials may be difficult, but standardized follow-up of patients and international collaboration may help to improve the standards of care of these conditions.