Limb-girdle Syndrome Research Articles

Late Onset Pompe Disease with Novel Mutations and Atypical Phenotypes.

Late onset Pompe disease (LOPD) is rare and generally manifests predominantly as progressive limb girdle muscle weakness. It is linked to the pathogenic mutations in GAA gene, which leads to glycogen accumulation in various tissues. We describe the unusual clinical, biochemical, histopathological and genetic characteristics of 5 cases of LOPD. The first case had progressive anterior horn cell like disease (AHCD) that evolved later to classical limb girdle syndrome and respiratory failure, the second patient had rigid spine syndrome with gastrointestinal manifestations, the third had limb girdle weakness superimposed with episodic prolonged worsening and respiratory failure, the fourth had large fibre sensory neuropathy without primary muscle involvement and the fifth presented with classical limb girdle muscle weakness. Two homozygous missense mutations c.1461C > A (p.Phe487Leu) and c.1082C > T (p.Pro361Leu) in the GAA gene were identified in case 1 and 2 respectively. Case 3 was compound heterozygous with inframe c.1935_1940del (p.Val646_Cys647del) and an intronic splice effecting variant c.-32-13T > G. Compound heterozygous missense variants c.971C > T (p.Pro324Leu) and c.794G > A (p.Ser265Asn) were identified in case 4. Case 5 had a frameshift insertion c.1396dupG (p.Val466GlyfsTer40) and a synonymous splice affecting variant c.546G > T(p.Thr182=). We are describing for the first time from India on LOPD with unusual phenotypes identified. A high degree of clinical suspicion and diagnosing rare phenotypes of Pompe disease is imperative to consider early initiation of Enzyme Replacement Therapy (ERT).

A Novel Multisystem Proteinopathy Caused by a Missense ANXA11 Variant.

Protein misfolding plays a central role not only in amyotrophic lateral sclerosis (ALS), but also in other conditions, such as frontotemporal dementia (FTD), inclusion body myopathy (hIBM) or Paget's disease of bone. The concept of multisystem proteinopathies (MSP) was created to account for those rare families that segregate at least 2 out of these 4 conditions in the same pedigree. The calcium-dependent phospholipid-binding protein annexin A11 was recently associated to ALS in European pedigrees. Herein, we describe in detail 3 Brazilian families presenting hIBM (isolated or in combination with ALS/FTD) caused by the novel p.D40Y change in the gene encoding annexin A11 (ANXA11). We collected clinical, genetic, pathological and skeletal muscle imaging from 11 affected subjects. Neuroimaging was also obtained from 8 patients and 8 matched controls. Clinico-radiological phenotype of this novel hIBM reveals a slowly progressive predominant limb-girdle syndrome, but with frequent axial (ptosis/dropped head) and distal (medial gastrocnemius) involvement as well. Muscle pathology identified numerous rimmed vacuoles with positive annexin A11, TDP-43 and p62 inclusions, but no inflammation. Central nervous system was also involved: two patients had FTD, but diffusion tensor imaging uncovered multiple areas of cerebral white matter damage in the whole group (including the corticospinal tracts and frontal subcortical regions). These findings expand the phenotypic spectrum related to ANXA11. This gene should be considered the cause of a novel multisystem proteinopathy (MSP type 6), rather than just ALS. ANN NEUROL 2021;90:239-252.

Collagen VI-related limb-girdle syndrome caused by frequent mutation in COL6A3 gene with conflicting reports of pathogenicity

Recently the scientific community has started to view Bethlem myopathy 1 and Ullrich congenital muscular dystrophy as two extremes of a collagen VI-related myopathy spectrum rather than two separate entities, as both are caused by mutations in one of the collagen VI genes. Here we report three individuals in two families who are homozygous for a COL6A3 mutation (c.7447A> G; p.Lys2483Glu), and compare their clinical features with seven previously published cases. Individuals carrying homozygous or compound heterozygous c.7447A> G, (p.Lys2483Glu) mutation exhibit mild phenotype without loss of ambulation, similar to the cases described previously as Collagen VI-related limb-girdle syndrome. The phenotype could arise due to an aberrant assembly of Von Willebrand factor A domains. Based on these data, we propose that c.7447A> G, (p.Lys2483Glu) is a common pathogenic mutation.

Reevaluating Muscle Biopsies in the Diagnosis of Pompe Disease: A Corroborative Report

Previous reports suggest that although a diagnostic muscle biopsy can confirm the presence of Pompe disease, the absence of a definitive biopsy result does not rule out the diagnosis. In this study, we reviewed patients with a limb-girdle syndrome who demonstrated nonspecific abnormalities of muscle, without evidence of the classical changes of acid maltase deficiency. These patients were rescreened for Pompe disease using dried blood spot (DBS) testing. Twenty-seven patients provided blood samples for the DBS test. Four patients underwent subsequent genetic testing. Genetic analysis demonstrated that one patient tested positive for Pompe disease and one patient had one copy of a pathogenic variant. In conclusion, the ability of a diagnostic muscle biopsy to definitively rule out the presence of Pompe disease is limited. There is a role for a screening DBS in all patients presenting with a limb-girdle syndrome without a clear diagnosis.

P.17.12 POLG mitochondrial myopathy presenting as a limb girdle syndrome

Polymerase gamma 1 (POLG1) mutations are an increasingly recognized cause of autosomal dominant and recessive complex neurological phenotypes. We describe a 70year old man and his sister who presented with a limb-girdle distribution of muscle weakness. Our patient had elevated serum CPK up to 600U/L in his 50's without evidence of muscle weakness until 60years of age, when the limb-girdle pattern of muscle weakness became evident. Muscle biopsy age 64 showed non-specific myopathic changes and LGMD genetic panel (Athena) was normal for FKRP, CAPN3, SGCA, LMNA, and CAV3 genes. Immunostaining revealed no evidence of a primary dystrophinopathy, dysferlinopathy, sarcoglycanopathy or merosinopathy. At age 70, he displayed 4/5 muscle weakness in his limb-girdle muscles, with normal strength of the forearm and hand muscles. Severe foot dorsiflexion weakness with absent deep tendon reflexes and a steppage gait was notable. There were no ocular findings. The serum CK was 891U/L (normal<204). A second muscle biopsy at age 70 showed 40% cytochrome oxidase (COX) negative fibers. There were no vacuoles or inclusion bodies. Electron transport chain (ETC) assay in muscle demonstrated very low COX activity at 0.06 COX/CS ratio (normal 0.27–1.15). Muscle coenzyme Q10 (CoQ10) levels were reduced at 0.06μg/mg protein (0.14–0.29). Muscle mtDNA sequencing was normal. However, nuclear gene sequencing revealed a mutation in POLG1 Arg443Cys predicted to be pathogenic. His sister, who also presented with late onset limb-girdle weakness and no ocular findings had the same mutation. His exercise intolerance responded to CoQ10 supplementation, l-carnitine and high dose B vitamins. This case illustrates the importance of considering the diagnosis of a mitochondrial disorder such as POLG in patients with limb girdle syndrome. In addition, decreased muscle CoQ10 levels have not been described in the POLG spectrum, and supplementation appears helpful.

Enzyme Histochemical Assessment of Mitochondrial Functions in Patients with Myopathic form of Limb-Girdle Syndrome

Isolated mitochondrial myopathy is characterized by slowly progressive limb-girdle muscle weakness and resembles other muscle disorders like muscular dystrophy or inflammatory myopathy on clinical grounds. Identification of abnormal mitochondria in the muscle tissue is required for the diagnosis of isolated mitochondrial myopathy. Therefore, this study was done with aim to identify patients with isolated mitochondrial myopathy among those with limb-girdle muscle syndromes of undefined cause. Forty-eight consecutive patients with limb-girdle muscle disease from 2008 to 2010 were screened for Duchenne/Becker muscular dystrophy gene deletion, metabolic myopathy, and drug-induced and endocrine causes. Twenty patients without an identifiable cause were subjected to muscle biopsy for hematoxylin and eosin staining and enzyme histochemistry. Clinical, biochemical, and electrophysiological features in all these patients with limb-girdle muscle disease were nonspecific, and no conclusion regarding the underlying cause could be drawn from these investigations. On hematoxylin and eosin staining, 12 patients were diagnosed as muscular dystrophy, inflammatory myopathy with characteristic appearance of polymyositis was diagnosed in 4 patients, and 3 patients had normal muscle histology. After enzyme histochemistry, one patient was identified having mitochondrial myopathy. A brief case summary of the only patient diagnosed as isolated mitochondrial myopathy in our study is presented.

Myopathy

Published with permission from Bjorn Oskarsson, MD This brief review touches on 5 relatively new things that ought to be useful for neurologists in general practices. The chosen topics include common conditions, techniques that are rapidly growing in utilization, and new developments that mandate new paradigms of treatment. Furthermore, all topics have had important developments in the last 5 years. The first section discusses the very common myalgias, myopathies, and rare rhabdomyolysis occurring with statin use. Next, the recently established necrotizing myopathy associated with statins is described. The third topic is muscle imaging with MRI and ultrasound, which are techniques used in conjunction with neuromuscular examination, EMG, and muscle biopsies, all of which remain the mainstay of diagnostic studies for muscle disease. The fourth topic reviewed is the myositis-specific autoantibodies and their relationship to the inflammatory myopathies. Finally, enzyme replacement therapy for Pompe disease is reviewed. This is the first limb-girdle syndrome for which we have a specific treatment and this has increased the importance of firmly establishing the underlying diagnosis in patients with these phenotypes. Before proceeding, it should be acknowledged that the review will not cover other interesting developments in the field of muscle diseases, particularly the muscular dystrophies and mitochondrial muscle diseases, where huge steps in our understanding of these conditions have been made. Also, while the term myositis is often used interchangeably with myopathy in both clinical practice and in the literature, in this review the term myositis will be used exclusively for the inflammatory myopathies. It is important to be aware that the term often is used to refer to all myopathies, inflammatory or not, and that it can not be taken to imply an inflammatory etiology. Statin drugs are being used more and more frequently, with up to 29.7 million people using them in …

Diagnostic criteria for late‐onset (childhood and adult) pompe disease

The diagnosis of late-onset (childhood and adult) Pompe disease can often be challenging, as it is a rare disease and the heterogeneous clinical presentation can mimic the presentation of other neuromuscular disorders. The objective was to develop a consensus-based algorithm for the diagnosis of late-onset Pompe disease. A systematic literature search was conducted, and an expert panel composed of neuromuscular specialists and individuals with expertise in Pompe disease reviewed the literature and convened for consensus development. An algorithm for the diagnosis of late-onset Pompe disease was created. Patients presenting with either a limb-girdle syndrome or dyspnea secondary to diaphragm weakness should undergo further testing, including evaluations of muscle strength, motor function, and pulmonary function. A blood-based acid alpha-glucosidase (GAA) enzyme activity assay is the recommended tool to screen for GAA enzyme deficiency. The diagnosis should be confirmed by a second test: either a second GAA enzyme activity assay in another tissue or GAA gene sequencing.

Shank sign in myotonic dystrophy type-1 (DM-1)

This study aimed to examine the specific shape of the shoulders and arms as a result of selective changes in muscle bulk, which could be diagnostic of myotonic dystrophy type-1 (DM-1). Thirty-two DM-1 patients from 18 families were asked to abduct their arms to about 90° with elbows flexed to 90° in such a manner that the hands were directed upwards. Examination from behind revealed a normal appearance of the shoulder girdle and proximal upper arm musculature, and sudden tapering thereafter, due to wasting of biceps, triceps and forearm muscles. The upper limbs looked like the shanks of an animal. ‘Shank sign’ was visible in 25 (78%) patients with DM-1 but not in any with DM-2 or other common muscular dystrophies such as Becker’s dystrophy, limb-girdle syndrome or facioscapulohumeral dystrophy. Patients with positive signs included nine with very mild myotonia, suggesting its clinical utility in difficult cases.

Avascular necroses inducing limb-girdle syndrome

Disuse myopathy can be caused by many disorders. However, disuse myopathy with symmetrical weakness of the proximal muscles in the four limbs is rare. Here we report a 45-year-old man who presented with the appearance of myopathy similar to the clinical picture of limb-girdle syndrome with symmetrical weakness of proximal muscles in four limbs. A battery of intensive investigations confirmed that the patient had symmetric disuse myopathy induced by multiple avascular necroses of hip and shoulder joints. After the patient had received bilateral total hip replacement operations he had remarkable improvement in his muscle power in both lower limbs. This report highlights that some myopathies can be reversed if their underlying causes are correctable.

Response to high-intensity eccentric muscle contractions in persons with myopathic disease.

Although the response to intense eccentric muscle contractions is well described in normal subjects, concern exists about possible untoward effects in persons with myopathic diseases. We investigated 14 subjects with slowly progressive muscular dystrophies including myotonic muscular dystrophy (n = 9), facioscapulohumeral dystrophy (n = 2), limb-girdle syndrome (n = 2), and Becker muscular dystrophy (n = 1). Control subjects consisted of 18 able-bodied persons. Subjects performed two sets of eight maximal-effort eccentric repetitions of the elbow flexors, with measurement of maximal concentric strength, serum creatine kinase, resting and flexed arm angle, arm circumference, and soreness at days 0, 3, and 7. Although the myopathic group had less initial strength, both groups demonstrated a similar response to the protocol over 7 days. Both groups had a significant rise in serum creatine kinase, which was still elevated at 7 days (P < 0.05). The control group demonstrated a slightly greater injury response in terms of soreness, resting and flexed arm angles, and arm swelling. Both groups of subjects appeared to respond similarly to an acute bout of eccentric contractions. However, the potential long-term effects of this type of exercise in persons with myopathic diseases remains unknown.

The clinical and histopathological spectrum of limb girdle syndrome in Egypt

The clinical and histopathological spectrum of limb girdle syndrome in Egypt

Employment profiles in neuromuscular diseases.

Consumer and rehabilitation provider factors that might limit employment opportunities for 154 individuals with six slowly progressive neuromuscular diseases (NMD) were investigated. The NMDs were spinal muscular atrophy (SMA), hereditary motor sensory neuropathy (HMSN), Becker's muscular dystrophy (BMD), facioscapulohumeral muscular dystrophy (FSHD), myotonic muscular dystrophy (MMD), and limb-girdle syndrome (LGS). Forty percent were employed in the competitive labor market at the time of the study, 50% had been employed in the past, and 10% had never been employed. The major consumer barrier to employment was education. Other important factors were type of occupation, intellectual capacity, psychosocial adjustment, and the belief by most individuals that their physical disability was the only or major barrier to obtaining a job. Psychological characteristics were associated with level of unemployment. However, physical impairment and disability were not associated with level of unemployment. There also were differences among the types of NMDs. Compared with the SMA, HMSN, BMD, and FSHD groups, the MMD and LGS groups had significantly higher levels of unemployment, lower educational levels, and fewer employed professional, management, and technical workers. Nonphysical impairment factors such as a low percentage of college graduates, impaired intellectual function in some individuals, and poor psychological adjustment were correlated with higher unemployment levels in the MMD group. Unemployment in the LGS group was correlated with a failure to complete high school. Major provider barriers to employment were the low level of referrals to Department of Rehabilitation by physicians and the low percentage of acceptance into the State Department of Rehabilitation. The low rate of acceptance was primarily attributable to the low number of referrals compounded by a lack of counselor experience with individuals with NMD. Both consumer and provider barriers may contribute to the lack of interest in obtaining a job.

Autosomal dominant limb girdle myopathy with ragged-red fibers and cardiomyopathy A pedigree study by in vivo 31P-MR spectroscopy indicating a multisystem mitochondrial defect

We describe a late-onset autosomal dominant limb girdle myopathy, associated with dilated cardiomyopathy and mental deterioration. In two affected members of the pedigree with histochemical (ragged-red and cytocrome c oxidase — negative fibers) and ultrastructural abnormalities of muscle mitochondria, in vivo muscle phosphorus MR spectroscopy disclosed a slow rate of phosphocreatine resynthesis after exercise. Brain phosphorus MR spectroscopy revealed a defect of the energy metabolism in the two patients and in a third asymptomatic member, as shown by a significantly low phosphocreatine, increased ADP and decreased phosphorylation potential. Molecular analysis of muscle mitochondrial DNA failed to reveal any known mutation, including multiple deletions of the mtDNA which have been associated with some autosomal dominant mitochondrial diseases. The multisystem clinical involvement, the presence of ragged-red fibers and the alterations revealed by in vivo brain and muscle 31P-MRS suggest that this limb-girdle syndrome represents an unusual phenotype of mitochondrial cytopathy.

Profiles of neuromuscular diseases. Limb-girdle syndromes.

Sixty-six individuals with Limb-Girdle Syndrome (LGS) were evaluated over a 10-yr period and classified into three types: 19 severe autosomal recessive muscular dystrophy of childhood (ARMDC), alternatively referred to by some as SCARMD, 18 autosomal dominant late onset (ADLO), and 29 pelvifemoral (PF) individuals. ARMDC subjects showed the greatest weakness, 2.5 +/- 1.0, mean Manual Muscle Test (MMT) grade for all muscles combined, and the only significant progression of loss of strength, -0.59 MMT unit decline per decade. Strength loss in ADLO and PF types was about the same, 3.7 +/- 0.7 and 4.0 +/- 0.7 grades, respectively. Quantitative strength measurements in ADLO and PF types were more sensitive than MMTs, showing losses of 30-40% strength in muscle groups with MMT grades of 4 or higher. All three types showed greater proximal and lower extremity weakness but usually no difference between flexor and extensor strength. There was a high percentage (44%) of mild very slowly progressive scoliosis in ARMDC, but spine deformity was unusual in ADLO and PF (11%) LGS. Contractures were few, slowly progressive, and usually mild in severity in all types, although more frequent in ARMDC. There also was a low frequency of severe restrictive lung disease in all types (10%) but a high percentage of electrocardiogram abnormalities (62-73%). The most common electrocardiogram abnormalities were increased R/S ratio in V1 and infranodal conduction defects. Intellectual and cognitive functions were within normal limits. Mobility and extremity function reflected the strength differences between the ARMDC and other types of LGS. Eight-five percent of ARMDC individuals relied on a wheelchair for all or part of their mobility, and all were unable to complete timed motor performance tests within the 99th percentile range for controls.

Profiles of neuromuscular diseases. Design of the protocol.

The purpose of this 10-yr investigation was to develop comprehensive impairment and disability profiles of the clinical characteristics of seven neuromuscular diseases: spinal muscular atrophy, hereditary motor sensory neuropathy, Duchenne muscular dystrophy, Becker's muscular dystrophy, facioscapulohumeral muscular dystrophy, limb-girdle syndrome, and myotonic dystrophy. Based on the World Health Organization's classification of disablement, as applied to neuromuscular diseases, impairment was evaluated by measurements of strength, range of motion, spine deformity, cardiac and pulmonary function, and intellectual capacity. Disability was evaluated by measures of mobility and upper extremity function, cardiopulmonary adaptations, cardiac and pulmonary complications, and psychosocial adjustment.

Electromyographic and muscle biopsy findings in limb girdle syndrome

Electromyographic and muscle biopsy findings in limb girdle syndrome

Electromyographic and muscle biopsy findings in limb girdle syndrome

Electromyographic and muscle biopsy findings in limb girdle syndrome

Myotonic dystrophy and limb girdle muscular dystrophy in one family

A family is reported in which a 29-year-old woman showed the clinical features of myotonic dystrophy while her 26-year-old brother presented with the clinical picture of limb girdle syndrome. In the affected female, direct genetic testing for the specific myotonic dystrophy mutation on chromosome 19 revealed abnormal expansion of a repeat unit containing the three nucleotides cytosine, thymine, and guanine (CTG)-typical for myotonic dystrophy-while her diseased brother displayed two normal alleles. This supports the hypothesis of the extremely rare occurrence of two clinically and genetically different myopathies in one family. Genetic analysis of six other family members showed that the father of the diseased siblings as well as all of his three brothers and sisters had a pathological CTG repeat expansion, and that the other two family members tested had a normal allelic pattern. The number of CTG repeats in the diseased women was approximately tenfold higher than in her asymptomatic relatives who revealed an abnormal allelic pattern. The increase in CTG repeats with transmission to a subsequent generation in this family was paralleled by a dramatic increase in the severity of myotonic dystrophy.

Limb-girdle syndrome: a genetic study of 22 large Brazilian families comparison with X-linked Duchenne and Becker dystrophies

The differential clinical diagnosis between the X-linked muscular dystrophies (DMD and BMD) and autosomal recessive limb-girdle muscular dystrophy (LGMD), which is extremely important for genetic counseling, may be very difficult. The aim of the present report is to describe clinical and laboratory findings in patients from large families, with AR inheritance, in an attempt to characterize better cases which have been diagnosed as LGMD compared with the X-linked forms. The main features analysed are: age of onset and of confinement to a wheelcchair, reproductive performance, serum enzymes (CK and PK) and dystrophin assessment (through immunohistochemistry and Western blot). Twenty-two families, with 62 affected patients diagnosed as limb-girdle muscular dystrophy, were included in this report. In 19 families, the patients had a milder clinical course, while in the remaining 3, the progression of the disease was continuous and clinically similar to X-linked DMD (“DMD-like”). A high consanguinity rate was observed among the parents of the affected patients (77%). No major clinical difference was observed between the X-linked and the AR forms. However, muscle dystrophin was found qualitatively and quantitatively normal in the autosomal forms but absent or abnormal in the X-linked ones. The reproductive performance was significantly higher for male than female patients. In addition, a surprising finding was the significantly greater fitness estimated for male LGMD cases as compared with Becker patients of comparable age studied in our center. The implications of such findings are discussed.