Proximal Limb Muscle Weakness Research Articles

Rapidly worsening bulbar symptoms in a patient with spinobulbar muscular atrophy

X-linked spinobulbar muscular atrophy (Kennedy’s disease) affects muscles and motor neurons, manifesting as weakness and wasting of bulbar, facial, and proximal limb muscles due to loss of anterior horn cells in the brain and spinal cord. We present the case of a patient with X-linked spinobulbar muscular atrophy with rapidly worsening bulbar symptoms caused by laryngopharyngeal irritation associated with a viral upper respiratory tract infection, seasonal allergies and laryngopharyngeal reflux, who dramatically improved with multimodality therapy.

Long-Term Follow-Up in Infantile-Onset Lambert-Eaton Myasthenic Syndrome

Lambert-Eaton myasthenic syndrome is a neuromuscular junction disorder characterized by proximal limb muscle weakness, fatigability, decreased deep-tendon reflexes, and autonomic symptoms. There are 2 forms of Lambert-Eaton myasthenic syndrome: one most frequently associated with small-cell lung cancer (P-Lambert-Eaton myasthenic syndrome) and the other that is a pure autoimmune form (NP-Lambert-Eaton myasthenic syndrome). Lambert-Eaton myasthenic syndrome is a very rare disorder in children younger than age 12 years. Herein, we report a 25-year-old man with NP-Lambert-Eaton myasthenic syndrome, which onset was at the age of 10 years. To date, this is the most long-term follow-up of NP-Lambert-Eaton myasthenic syndrome in childhood. In our patient, the only symptomatic treatment with 3,4-diaminopyridine phosphate has been sufficient to guarantee him a good quality of life. Our data remind physicians to keep in mind the diagnosis of Lambert-Eaton myasthenic syndrome in children with a proximal myopathic pattern and they confirm the specificity of compound muscle action potential incremental pattern after brief maximal effort in Lambert-Eaton myasthenic syndrome.

Compound heterozygous mutations of the TNXB gene cause primary myopathy

Complete deficiency of the extracellular matrix glycoprotein tenascin-X (TNX) leads to recessive forms of Ehlers-Danlos syndrome, clinically characterized by hyperextensible skin, easy bruising and joint hypermobility. Clinical and pathological studies, immunoassay, and molecular analyses were combined to study a patient suffering from progressive muscle weakness. Clinical features included axial and proximal limb muscle weakness, subclinical heart involvement, minimal skin hyperextensibility, no joint abnormalities, and a history of easy bruising. Skeletal muscle biopsy disclosed striking muscle consistency and the abnormal presence of myotendinous junctions in the muscle belly. TNX immunostaining was markedly reduced in muscle and skin, and serum TNX levels were undetectable. Compound heterozygous mutations were identified: a previously reported 30kb deletion and a non-synonymous novel missense mutation in the TNXB gene. This study identifies a TNX-deficient patient presenting with a primary muscle disorder, thus expanding the phenotypic spectrum of TNX-related abnormalities. Biopsy findings provide evidence that TNX deficiency leads to muscle softness and to mislocalization of myotendinous junctions.

Limb-girdle Muscular Dystrophy Type 2A with Mutation in CAPN3: The First Report in Taiwan

The autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by mutations in the calpain 3 (CAPN3) gene, and it is characterized by selective atrophy and weakness of proximal limb and girdle muscles. We report a 33-year-old woman with initial presentations of exercise intolerance and running difficulty at age 15 years. At presentation, waddling gait, positive Gowers' sign, and marked muscle atrophy in pelvic and leg muscles were noted. Muscle computed tomography (CT) imaging demonstrated symmetric involvement of the posterior thigh muscles with relative sparing of vastus lateralis, sartorius, and gracilis. Muscle biopsy revealed a dystrophic change and many lobulated fibers on NADH-tetrazolium reductase staining. Genetic analysis of the CAPN3 gene identified a novel homozygous mutation of c2047_2050 del4, p.Lys683fs mutation, confirming the first LGMD2A patient in Taiwan.

Oxime and atropine failure to prevent intermediate syndrome development in acute organophosphate poisoning

Intermediate syndrome (IMS) was described a few decades ago, however, there is still a controversy regard ing its exact etiology, risk factors, diagnostic parameters and required therapy. Considering that acute poisonings are treated in different types of medical institutions this serious complication of organophosphate insecticide (OPI) poison ing is frequently overlooked. The aim of this paper was to present a case of IMS in organophosphate poisoning, which, we believe, provides additional data on the use of oxime or atropine. After a well-resolved cholinergic crisis, the patient developed clinical presentation of IMS within the first 72 h from deliberate malathion ingestion. The signs of IMS were weakness of proximal limb muscles and muscles innervated by motor cranial nerves, followed by the weakness of respiratory muscles and serious respiratory insufficiency. Malathion and its active metabolite were confirmed by ana lytical procedure (liquid chromatography-mass spectrometry). Pralidoxime methylsulphate, adiministered as a continuous in fusion until day 8 (total dose 38.4 g), and atropine until the day 10 (total dose 922 mg) did not prevent the development of IMS, hence the mechanical ventilation that was stopped after 27 h had to be continued until the day 10. Continuous pralidoxime methylsulphate infusion with atro pine did not prevent the development of IMS, most likely due to the delayed treatment and insufficient oxime dose but also because of chemical structure and lipophilicity of ingested OPI. A prolonged intensive care monitoring and respiratory care are the key management for the intermediate syndrome.

運動ニューロン疾患の臨床像を呈し，<i>VCP</i>遺伝子変異が明らかになったinclusion body myopathy with Paget’s disease of bone and frontotemporal dementia（IBMPFD）の1例

Inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) is caused by mutations in the valosin-containing protein (VCP) gene. Varied clinical features caused by VCP mutations have been reported: these clinical phenotypes include distal myopathy, frontotemporal dementia and amyotrophic lateral sclerosis. We report a 49-year-old woman with 3-year history of progressive proximal limb muscle weakness. Family history was notable for her father with motor neuron disease and an elder brother with a myopathy involving tibialis anterior and quadriceps. Neurological examinations showed proximal muscle atrophy, especially severe atrophy of paravertebral muscles, right-dominant scapular winging, bilateral pyramidal signs and hyperreflexia. Serum CK level was normal and EMG showed chronic neurogenic changes. Muscle imaging (CT) showed adipose tissue replacement of paravertebral muscles and right serratus anterior, and marked atrophy of bilateral trapezius and vastus intermedius muscles. Her lumbar spine X-ray showed an osteosclerotic change in the vertebral body, where an increased uptake of Tc99m was also observed in bone scintigraphy. Although brain MRI was normal, neuropsychological examination showed a mild attention deficit with cognitive impairment. A muscle biopsy specimen revealed scattered fibers with rimmed vacuoles. These findings prompted us to analyze a mutation in the VCP gene. Genomic sequencing of all exons of the gene showed a heterozygous missense mutation in exon 5 (c.1315G>C; p.Ala439Pro).

Ultrastructural changes in LGMD1F

A large Italo-Spanish kindred with autosomal-dominant inheritance has been reported with proximal limb and axial muscle weakness. Clinical, histological and genetic features have been described. A limb girdle muscular dystrophy 1F (LGMD1F) disease locus at chromosome 7q32.1-32.2 has been previously identified. We report a muscle pathological study of two patients (mother and daughter) from this family. Muscle morphologic findings showed increased fiber size variability, fiber atrophy, and acid-phosphatase-positive vacuoles. Immunofluorescence against desmin, myotilin, p62 and LC3 showed accumulation of myofibrils, ubiquitin binding protein aggregates and autophagosomes. The ultrastructural study confirmed autophagosomal vacuoles. Many alterations of myofibrillar component were detected, such as prominent disarray, rod-like structures with granular aspect, and occasionally, cytoplasmic bodies. Our ultrastructural data and muscle pathological features are peculiar to LGMD1F and support the hypothesis that the genetic defect leads to a myopathy phenotype associated with disarrangement of the cytoskeletal network.

Spinal muscular atrophy, John Griffin, and mentorship

Hereditary canine spinal muscular atrophy is an inherited motor neuron disease that occurs in Brittany Spaniels and has remarkable similarities with human spinal muscular atrophy. Both disorders are characterized by proximal limb and truncal muscle weakness of variable severity. Detailed pathological studies indicate that there is early dysfunction of motor neuron synapses, particularly the neuromuscular junction synapse, prior to motor neuron death. This period of synaptic dysfunction may define a critical window of opportunity for disease reversibility in motor neuron disease.

Limb‐girdle myasthenia with tubular aggregates associated with novel GFPT1 mutations

Limb-girdle myasthenia with tubular aggregates (LGM with TAs) is a subtype of congenital myasthenic syndrome caused by recessive mutations of glutamine-fructose-6-phosphate transaminase 1 (GFPT1). Clinical and neurophysiological assessment was made in a Korean boy who had proximal limb muscle weakness. Findings suggested a diagnosis of congenital myasthenic syndrome. Muscle biopsy disclosed numerous TAs in muscle fibers, and DNA sequence analysis disclosed 2 novel missense mutations (p.E256Q and p.M499T) in GFPT1. Treatment with oral cholinesterase inhibitors produced a dramatic improvement in muscle strength. GFPT1 is the key enzyme in the hexosamine biosynthesis pathway, and mutations in GFPT1 cause defective glycosylation in the proteins of the neuromuscular junction. Identification of LGM with TAs among patients with congenital myasthenic syndrome is important because treatment with cholinesterase inhibitors can produce symptomatic improvement.

G.P.58 Muscle MRI in a filaminopathy family: Involvement of paraspinals is earlier and more severe than of thigh muscles

Mild to severe weakness of proximal and distal limb muscles is common in all types of myofibrillar myopathies (MFM). In clinical practice, it is important to know the specific distribution patterns of muscle involvement in order to differentiate the various subtypes. Muscle MRI is a useful tool to show the distribution and severity of muscle involvement in different muscle diseases. Here we report two patients with p.W2710X in FLNC gene mutation from a Macedonian family with 18 affected members. The patients were a male at 55 and a female at 51 years of age with 14 and 8years of disease duration, respectively. The onset symptom in both patients was difficulty in holding the waist up upon rising from a chair or climbing stairs. Muscle strength evaluation revealed that the most severely affected muscles were the lower extremity proximal and the trunk muscles in each patient without a significant difference in weakness distribution pattern. Muscle MRI scans for thigh, pelvic and lower paraspinal muscles were performed. Regardless of the duration of the disease the most severely affected muscles were the paraspinals, practically almost totally replaced by fat in both patients. Although to a slightly lesser degree, another relatively severely affected group was the posterior thigh muscles. Involvement in this latter group and in even the less affected gluteus maximus showed correlation with the disease duration. Anterior thigh compartment muscles seemed to remain relatively spared. Filaminopathy has not been listed among the myopathies that predominantly involve the trunk muscles. Although more reports are needed, our experience in two patients suggests that the inclusion of the lower paraspinal region in muscle MRIs in the work-up of MFMs may be a useful tool to differentiate filaminopathies from the other MFM subgroups.

Clinical and genetic analysis of a pedigree of Kennedy disease

To review the clinical and genetic features of a pedigree of Kennedy disease in China. The clinical data of patients from a Kennedy disease family were collected. The numbers of trinucleotide CAG repeats in exon 1 of the androgen receptor gene were determined by DNA sequencing and repeat fragment analysis. In the pedigree, 4 patients were identified as Kennedy disease. Clinical manifested with adult-onset, progressive proximal limb muscle weakness and atrophy, gynecomastia, oligospermia were also presented. The number of trinucleotide CAG repeats in exon 1 of the androgen receptor gene was 51 in the proband. The electrophysiological study showed sensory and motor involvement and their serum triglycerides values were elevated significantly. Androgen receptors gene testing is the most reliable diagnosing method, the patients suspected as Kennedy disease should have a gene testing of androgen receptors.

Anti-Signal Recognition Particle Myopathy in the First Decade of Life

Autoantibodies to signal recognition particle have been associated with juvenile and adult-onset necrotizing myopathy. However, only a few teenage patients with anti-signal recognition particle myopathy have been reported, and to date, to our knowledge, no patient younger than 10 years has been documented. We describe 2 Japanese girls with anti-signal recognition particle myopathy who developed symptoms from the ages of 5 and 9 years, respectively. Both patients had progressive muscle weakness and atrophy without myalgia. Facioscapulohumeral muscular dystrophy was initially suspected because of asymmetric shoulder girdle muscle involvement in one patient, and limb girdle muscular dystrophy due to proximal limb muscle weakness in the other. There were no extramuscular manifestations, including fever or arthritis. Serum creatine kinase levels were elevated to 2,467-4,629 IU/L. Results of muscle biopsy revealed necrotizing myopathy with minimal to mild endomysial fibrosis but without inflammatory infiltrates. Immunosuppressive agents were not effective for muscle weakness, resulting in marked disability. Anti-signal recognition particle myopathy can occur in the first decade of life and should be included in the differential diagnosis for children with progressive limb girdle muscle weakness and high creatine kinase levels.

Limb-Girdle Myasthenia Gravis in a 10-Year-Old Girl

A 10-year-old girl presented with progressive proximal limb muscle weakness without facial, ocular, or bulbar muscle involvement. There was no fatigability or diurnal fluctuation in symptoms. Her weakness worsened with febrile illnesses and recovered with accruing disabilities over a few weeks. Serum creatine kinase levels and muscle biopsy were normal. A significant decrement on repetitive nerve stimulation test and positive response to therapeutic neostigmine challenge test confirmed the diagnosis of limb-girdle myasthenia. She responded well to corticosteroids and thymectomy, demonstrating a likely autoimmune etiology. This case highlights the long-term fluctuations in a case of myasthenia gravis and the need for a high index of suspicion for myasthenia in children presenting with unexplained muscle weakness, even in the absence of typical features such as fatigability, diurnal fluctuation, and oculobulbar weakness.

Diagnosis by Electron Microscopy of Late Onset Pompe Disease with Previous Normal or Non Specific Muscle Biopsies by Light Microscopy

ntroduction: The diagnosis of late onset Pompe disease may be delayed for many years following onset of muscle eakness. Muscle biopsy may be normal or non specific by light microscopy. ase Reports: Two men are described with late onset acid maltase deficiency and delay from clinical onset to iagnosis of 38 and 30 years, respectively, based on reduced alpha-glucosidase activity on a dried blood spot. The rst man experienced the onset of proximal lower limb muscle weakness at age 27 years. He underwent muscle iopsy at age 43 years which was reported as showing fibre type variability but no diagnostic abnormality. He was iagnosed at age 65 years following a review of his biopsy by electron microscopy which demonstrated multiple mall membrane bound vacuoles containing glycogen particles. The second patient experienced lower limb weakess at 40 years of age and underwent biopsies at 52 and 61 years of age, the first reported as normal and the second s non specific with increased fibre size variability. He was finally diagnosed by electron microscopy at age 70. Both atients developed dyspnea and orthopnea early in the clinical course requiring nocturnal ventilatory support. onclusion: These patients emphasize the importance of considering the diagnosis of late onset Pompe disease even n patients with normal or non specific changes on muscle biopsy. The clinical features strongly suggesting this isorder are respiratory involvement with orthopnea early in the course of disease, and predominantly lower limb roximal weakness. Electron microscopy may be diagnostic when histochemistry has not shown the characteristic ndings of acid phosphatase staining and increased glycogen. Diagnosis based on dried blood spot should be onsidered when there is a clinical suspicion of PD and is simple and inexpensive.

Paraneoplastic dermatomyositis accompanying nasopharyngeal carcinoma: Diagnosis, treatment and prognosis

Dermatomyositis (DM) is a multisystem inflammatory disorder primarily affecting the skin and muscles. Its pathophysiology is still very poorly understood, but humoral and cellular immune dysregulation is apparent. Diagnosis of DM is based on five criteria: proximal limb muscle weakness, serum muscle enzyme elevation, histopathologic muscle abnormalities on muscle biopsy, electromyographic abnormalities, and clinical inflammatory dermatological manifestations (heliotrope rash, poikiloderma, and inflammatory lesions on the hands and facing joints). DM is frequently associated with certain cancers, and may appear before, concurrent with, or after diagnosis of cancer. DM has been reported to be associated with approximately one per 1000 cases of nasopharyngeal carcinoma. Treatment is based on long-course nonselective immunosuppression, particularly corticosteroids, by general route, even when malignancy is present, but new-targeted therapies may modify the treatment strategy in the near future. Despite iatrogenic immunosuppression, the prognosis of nasopharyngeal cancer is not worse in patients with paraneoplastic DM. We report one case as an illustration of this paraneoplastic course (evolving in parallel with the cancer), and to make an update on the state of knowledge on paraneoplastic DM in such cancers.

Polymyositis associated with autoimmune hepatitis, primary biliary cirrhosis, and autoimmune thrombocytopenic purpura

We describe a 40-year-old woman with polymyositis (PM) who developed autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and autoimmune thrombocytopenic purpura (AITP) concurrently. About 4 years earlier, she suffered from muscle weakness probably due to PM. When she visited our hospital, she had polyarthritis, myalgia, symmetrical proximal limb-muscle weakness, elevated muscle enzymes, and myogenic abnormalities on electromyogram. Pathological findings obtained by muscle biopsy showed histological findings consistent with PM. Her serum liver enzymes were also elevated. The histology obtained by liver biopsy revealed the mixture findings of chronic active hepatitis and biliary cirrhosis. As antibodies to mitochondria M2 and liver/kidney microsome type 1 (LKM-1) were present, we concluded her liver disease was due to an overlap of AIH and PBC. Furthermore, purpura on the legs with thrombocytopenia appeared in parallel with liver dysfunction. She was diagnosed as having AITP by clinical and laboratory findings. Her serum showed a speckled pattern in immunofluorescence antinuclear antibody testing, but the antigen specificities were distinct from those of the known myositis-related autoantigens. This is a first case report of PM accompanied by AIH, PBC, and AITP. It was notable that there was an overlap of disease-associated immunological findings and immunogenetic backgrounds. This case provides a possible insight into the mechanisms and interplay of autoimmune diseases.

Cognitive impairment and reduced life span of oculopharyngeal muscular dystrophy homozygotes

To assess the evolution and life expectancy in patients with oculopharyngeal muscular dystrophy (OPMD) who are homozygotes for two (GCN)13 expansions in the PABPN1 encoding gene. OPMD is particularly frequent among French Canadians (FCs) and Uzbek Jews (UJs), who carry a same size, (GCN)13, PABPN1 mutation. The high rate of consanguinity among UJs together with late disease onset and normal fertility results in homozygous cases. For 15 to 20 years, we followed 4 FC and 6 UJ homozygotes with OPMD and compared them with their heterozygous parents and siblings. In addition to clinical evaluation, electrodiagnostic tests, psychological tests, and brain imaging studies were performed. In all (GCN)13-(GCN)13 patients, OPMD started before age 35 years, with bilateral ptosis and dysphagia; external ophthalmoparesis and dysphonia followed within a few years, as well as weakness in proximal limb muscles. All patients had recurrent aspirations and lost weight; 4 patients required surgical interventions to alleviate dysphagia, and 5 required feeding gastrostomies. Most patients were followed by psychiatrists due to cognitive decline, recurrent depression, or psychotic episodes. Six patients died at ages 50, 51, 53, 56, 56, and 57 years. The eldest patient is now 51 years old; she is cachectic and requires special diet and psychiatric care for paranoid psychosis and uninhibited behavior. Oculopharyngeal muscular dystrophy progresses faster in homozygote compared with heterozygote patients. It is not restricted to the muscles, but also involves the CNS with cognitive decline and psychotic manifestations and leads to a reduced life expectancy.

ABNORMAL EYE MOVEMENTS IN KENNEDY DISEASE

Kennedy disease, also known as spinal and bulbar muscular atrophy, is a neurodegenerative disease affecting lower motor neurons.1 The underlying genetic abnormality, a triplet (CAG) repeat expansion in the androgen receptor gene on the X chromosome, produces a toxic polyglutamine expansion in the androgen receptor protein.2 The disease is characterized by slowly progressive proximal muscle atrophy, weakness, and fasciculations, with prominent bulbar involvement, tremor, and, reportedly, sparing of eye movements.1,3,4 Stigmata of androgen insufficiency, such as gynecomastia, may be present.3 We report a patient with genetically confirmed Kennedy disease who had abnormal eye movements. ### Case report. A 58-year-old Caucasian man with a history of dyslipidemia and bilateral retinal detachments presented with progressive onset of proximal muscle atrophy, weakness, fasciculations, and tremor over 20 years. He also reported a progressive decline in mobility and fine motor control, as well as dysarthria and dysphagia. He denied sensory symptoms, sphincter disturbance, or visual symptoms, such as diplopia. On examination, there was atrophy of facial, bulbar, and limb muscles. Perioral, tongue, and limb muscle fasciculations were noted. There was moderate weakness of facial, palatal, tongue, and proximal limb muscles, with milder weakness of distal limb muscles. The reflexes were depressed and the plantar responses flexor. There were no cerebellar signs. Mild distal sensory loss was noted in the lower limbs. Visual acuity and color vision were within normal limits. Visual fields were full to confrontation. There was no optic atrophy, and his pupillary responses were normal. Ocular motor examination revealed a small exophoria, no …

Lambert–Eaton myasthenic syndrome

A 64-year-old man presented with proximal lower limb muscle weakness that had ascended over 3 months to involve the upper limb, bulbar and periocular muscles. In addition, he had muscle aches, dry eyes and mouth, with 10 kg of weight loss. He was an ex-smoker of 50 pack-years. On examination, he had mild dysarthria, bilateral ptosis and proximal muscle weakness (MRC power 4/5) in all limbs that improved transiently after muscle use. All limb tendon reflexes were absent at rest but returned after sustained muscle contraction for 10 seconds. The serum voltage-gated calcium-channel antibody titre was 237 pmol/litre (normal <45 pmol/litre). High frequency repetitive nerve stimulation (Figure 1) produced a successive increase in compound muscle action potential amplitude, confirming the diagnosis of Lambert–Eaton myasthenic syndrome. On spiral computed tomography there was a pretracheal mass extending into the right paratracheal region (Figure 2). Tissue biopsy confirmed small cell lung carcinoma.

Myofibrillar myopathies

The aim of this communication is to provide an up-to-date overview of myofibrillar myopathies. The most important recent advance in the myofibrillar myopathies has been the discovery that mutations in Z band alternatively spliced PDZ-containing protein and filamin C, as well as in desmin, alphaB-crystallin and myotilin, result in similar pathologic alterations in skeletal muscle that are typical of myofibrillar myopathy. Despite the increasing genetic heterogeneity, the clinical and morphologic phenotypes are remarkably homogeneous. The typical clinical manifestation is slowly progressive proximal, distal or both proximal and distal limb muscle weakness. Cardiomyopathy can be associated and is sometimes the presenting finding. Peripheral neuropathy also occurs in some patients. In every myofibrillar myopathy, there is abnormal accumulation of an array of proteins at ectopic sites as well as accumulation of degraded myofibrillar proteins forming large aggregates. The key issue now is to analyze the molecular mechanisms underlying the cascade of events that destroy the myofibrillar architecture and trigger the aberrant expression of multiple proteins. Several disease genes have recently been recognized in myofibrillar myopathies. So far, the disease proteins identified are components of or chaperone for the Z-disk. In each case, the molecular defect leads to a stereotyped cascade of structural events in the muscle fiber.