Predominant Muscle Weakness Research Articles

Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.

ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series. We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant. We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing. This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease.

Post‐COVID‐19 vaccination Guillain–Barré syndrome with sensory ataxia, gaze‐evoked nystagmus, mental‐status change and positive pathological reflex

AbstractBackgroundVarious neurological disorders have been reported after vaccination against coronavirus disease 2019, one of which is Guillain–Barré Syndrome (GBS).Case PresentationWe report a case of a 73‐year‐old woman who developed GBS and extra‐GBS manifestations 19 days after the second dose of BNT162b2 mRNA vaccine. She presented lower limb predominant muscle weakness and loss of tendon reflexes. Nerve conduction study showed acute motor and sensory axonal neuropathy. In addition, she developed notable deep sensory ataxia, and showed positive pathological reflex, gaze‐evoked nystagmus and altered consciousness, which suggested brainstem involvement.ConclusionsThis is the first coronavirus disease 2019 vaccine‐related GBS complicated with such central nervous system manifestations.

Findings of limb-girdle muscular dystrophy R7 telethonin-related patients from a Chinese neuromuscular center.

Limb-girdle muscular dystrophy (LGMD) is a group of clinically and genetically heterogeneous neuromuscular disorders. LGMD-R7, which is caused by telethonin gene (TCAP) mutations, is one of the rarest forms of LGMD, and only a small number of LGMD-R7 cases have been described and mostly include patients from Brazil. A total of two LGMD-R7 patients were enrolled at a Chinese neuromuscular center. Demographic and clinical data were collected. Laboratory investigations and electromyography were performed. Routine and immunohistochemistry staining of muscle specimens was performed, and a next-generation sequencing panel array for genes associated with hereditary neuromuscular disorders was used for analysis. The patients exhibited predominant muscle weakness. Electromyography revealed myopathic changes. The muscle biopsy showed myopathic features, such as increased fiber size variation, muscle fiber atrophy and regeneration, slight hyperplasia of the connective tissue, and disarray of the myofibrillar network. Two patients were confirmed to have mutations in the open reading frame of TCAP by next-generation sequencing. One patient had compound heterozygous mutations, and the other patient harbored a novel homozygous mutation. Western blotting analysis of the skeletal muscle lysate confirmed the absence of telethonin in the patients. We described two LGMD-R7 patients presenting a classical LGMD phenotype and a novel homozygous TCAP mutation. Our research expands the spectrum of LGMD-R7 due to TCAP mutations based on patients from a Chinese neuromuscular center.

Intramedullary Cavernoma: Case Report and Literature Review

Introduction: Cavernomas are benign vascular anomalies consisting of cavities where the blood circulates at low flow and at low pressure. Intramedullary localization is unusual, represents approximately 5 to 12% of spinal vascular malformations and 3% of intra-dural vascular malformations (5% of medullary vascular lesions). Observation: A patient, aged 59, consulted for the abrupt installation of moderate back pain followed by predominant muscle weakness in the two lower limb of progressive worsening, responsible for gait disorders. The patient reported thermal hypoesthesia and heaviness of the two lower limbs that had been evolving for two years. The examination found a dorsal spinal cord compression syndrome. On the MRI, there were abnormalities of intramedullary signal of the dorsal (D11) spinal cord with bleeding stigmas suggestive of intramedullary cavernomas. Conclusion: The management of the medullary cavernoma is essentially neurosurgical with complete microsurgical resection of the malformation. In the absence of surgical treatment, evolution can be to chronic myelopathy or neurological aggravation.

Genetic distal myopathies

Distal myopathies are a group of rare muscle disorders that are characterized by selective weakness of the distal muscles of the lower and/or upper limbs at disease onset. Predominant muscle weakness can affect distal lower legs, including calf muscles and/or foot dorsiflexors, and/or distal upper limb muscles. In a later stage of the disease sometimes proximal muscles are also involved. Age of onset varies from early-childhood to late-adulthood. Creatine kinase in serum can range from normal to highly elevated. Electromyography usually reveals a myogenic pattern often associated with spontaneous activity. Histopathological changes on muscle biopsy can vary from nonspecific myopathic changes to the presence of rimmed vacuoles or central nuclei to myofibrillar pathology. Muscle MRI can be a useful tool in the differential diagnosis of distal myopathies. The majority of distal myopathies have a genetic etiology. The underlying molecular defect in distal myopathies is heterogeneous and the number of causative genes and novel mutations in known genes are constantly increasing due to the application of recent next-generation sequencing techniques such as (whole) exome sequencing. In addition, there is a considerable overlap with neurogenic disorders, since it has been demonstrated that distal myopathies can result from defective proteins encoded by genes causative of neurogenic disorders. Moreover, also acquired neuromuscular disorders and myopathies can present with distal weakness. In this presentation, I will provide an overview on the clinical, histopathological, muscle imaging and molecular aspects of distal myopathies, as well as their differential diagnoses, focusing on the most recent developments in the field.

Intramedullary Cavernoma: Case Report and Literature Review

Introduction: Cavernomas are benign vascular anomalies consisting of cavities where the blood circulates at low flow and at low pressure. Intramedullary localization is unusual, represents approximately 5 to 12% of spinal vascular malformations and 3% of intra-dural vascular malformations (5% of medullary vascular lesions). Observation: A patient, aged 59, consulted for the abrupt installation of moderate back pain followed by predominant muscle weakness in the two lower limb of progressive worsening, responsible for gait disorders. The patient reported thermal hypoesthesia and heaviness of the two lower limbs that had been evolving for two years. The examination found a dorsal spinal cord compression syndrome. On the MRI, there were abnormalities of intramedullary signal of the dorsal (D11) spinal cord with bleeding stigmas suggestive of intramedullary cavernomas. Conclusion: The management of the medullary cavernoma is essentially neurosurgical with complete microsurgical resection of the malformation. In the absence of surgical treatment, evolution can be to chronic myelopathy or neurological aggravation.

The unfolding spectrum of inherited distal myopathies.

Distal myopathies are a group of rare muscle diseases characterized by distal weakness at onset. Although acquired myopathies can occasionally present with distal weakness, the majority of distal myopathies have a genetic etiology. Their age of onset varies from early-childhood to late-adulthood while the predominant muscle weakness can affect calf, ankle dorsiflexor, or distal upper limb muscles. A spectrum of muscle pathological changes, varying from nonspecific myopathic changes to rimmed vacuoles to myofibrillar pathology to nuclei centralization, have been noted. Likewise, the underlying molecular defect is heterogeneous. In addition, there is emerging evidence that distal myopathies can result from defective proteins encoded by genes causative of neurogenic disorders, be manifestation of multisystem proteinopathies or the result of the altered interplay between different genes. In this review, we provide an overview on the clinical, electrophysiological, pathological, and molecular aspects of distal myopathies, focusing on the most recent developments in the field. Muscle Nerve 59:283-294, 2019.

Prevalence of muscular dystrophy in patients with muscular disorders in Tehran, Iran.

Muscular dystrophy is a group of diseases that is characterized by progressive muscle wasting and the weakness of variable distribution and severity. On the basis of the distribution of predominant muscle weakness, there are many different kinds of muscular dystrophy. Some dystrophies are especially frequent in certain populations. There are no studies on the prevalence of muscular dystrophy in Iran. This study was aimed to survey the prevalence of muscular dystrophy among Iranian patients with muscular disorders. This analytical cross-sectional study was conducted on 1000 patients with musculoskeletal disorders who visited the dystrophy association of Bou-Ali Hospital (Tehran) from June 2014 to June 2016. Patients’ data were extracted using a checklist that included age, gender, age of onset, family history, findings from clinical diagnostic tests and types of muscular dystrophy. The clinical findings were the results of genetic tests; EMG-NCV; para-clinical findings, including LDH and CPK; and pathological findings. All data were analyzed by SPSS V.22 (IBM Inc., NY) with Chi Square and One way ANOVA tests. All analyses were performed with P = 0.05 considered as the threshold of statistical significant. Out of the 337 patients studied, 262 (77.7%) were male and 75 (22.3%) were female. Subjects had a mean (± SD) age of 26.08 (± 11.86) years with an age range of 3 to 59 years. The most common types of muscular dystrophy were found to be Duchenne dystrophy (131 cases, 38.9%), limb-girdle dystrophy (91 cases, 27%), Becker dystrophy (58 cases, 17.2%), FSHD dystrophy (31 cases, 9.2%), and SMA (26 cases, 7.7%), respectively. The results showed that a statistically significant relationship between dystrophy types and gender, age, family history, age of diagnosis, CPK and LDH levels (P < 0.001). There were no statistical relationship between dystrophy types and pathological findings (P = 0.57), EMG-NCV test results (P = 0.062), and genetic findings (P = 0.06). Since muscular dystrophies often appear during the first decade of life, any information in regard to their prevalence can contribute to better planning and provisioning of required services, as well as better treatment or control of the condition. The results also showed that genetic tests, para-clinical tests, pathology analysis, and EMG-NCV tests can serve as good diagnostic tools for different varieties of dystrophy. Thus, facilitation of these diagnostic tests, particularly the genetic tests, can lead to a faster and more accurate diagnosis of dystrophy, especially in people with a family history of the disease.

IgM MGUS anti‐MAG neuropathy with predominant muscle weakness and extensive muscle atrophy

We report a patient with anti-myelin-associated glycoprotein (MAG) neuropathy, predominantly exhibiting severe motor symptoms, accompanied by extensive muscle atrophy mimicking Charcot-Marie-Tooth disease. Nerve conduction studies revealed mild retardation of motor conduction velocities and significant prolongation of distal latency. Sural nerve biopsy revealed widely spaced myelin and positive staining of myelinated fibers with an IgM antibody. Predominant motor symptoms with muscle atrophy can be one of the clinical manifestations of anti-MAG neuropathy.

Muscular dystrophy: from pathogenesis to strategy.

Muscular dystrophies are a genetically heterogeneous group of degenerative muscle disorders. It characterized by progressive muscle wasting and weakness of variable distribution and severity. There are several subgroups including Duchenne/Becker, fascioscapulohumeral, limb-girdle, oculopharngeal, and congenital muscular dystrophy. Diagnosis is dependent to the characteristic clinical features in distribution of predominant muscle weakness, disease course and age onset as well as variable serum concentration creatine kinase, muscle histology, and genetic inheritance. Nearly 30 genes and encoded proteins are known to give rise to various forms of muscular dystrophy. Development of new prospects therapy for the muscular dystrophies is a big challenge. The target of strategies is aimed at inducing of a functional protein and improving the function of muscle weakness. These strategies include gene, cell and pharmacological therapies. However, efficiency of systemic delivery vectors to targets, immune reaction to vector and gene products, and toxicity to vector that must be solved before an effective treatment is available.

Emery-Dreifuss muscular dystrophy and other related disorders.

There are some 30 or so different forms of muscular dystrophy which are conveniently classified according to the mode of inheritance. Emery-Dreifuss X-linked muscular dystrophy is characterized by the triad of: (1) early contractures of the elbows, Achilles tendons and postcervical muscles; (2) slowly progressive muscle wasting and weakness with a humero-peroneal distribution in the early stages; and (3) a cardiomyopathy usually presenting as heart-block. The insertion of a cardiac pace-maker can be life saving and therefore the recognition of the condition is essential. The responsible gene has been localized to Xq28. The autosomal recessive dystrophies are classified into congenital forms (the Fukuyama type is particularly common in Japan); a childhood form (similar to Duchenne) which occurs frequently in certain inbred communities; and adult onset limb girdle dystrophy. The autosomal dominant dystrophies are classified on the distribution of predominant muscle weakness into facioscapulohumeral, scapuloperoneal (with or without early contractures and cardiomyopathy), proximal, distal and ocular forms. The basic biochemical defects and the localizations of the responsible genes are as yet unknown in any of the autosomal recessive or autosomal dominant dystrophies.