Incidental Severe Fatty Degeneration of the Erector Spinae in a Patient with L5-S1 Disc Extrusion Diagnosed with Limb-Girdle Muscular Dystrophy R2 Dysferin-Related.
ABSTRACT: Limb-girdle muscular dystrophy type R2 dysferin-related (LGMD R2 dysferin-related), a phenotype of dysferlinopathy, usually begins with pelvic girdle weakness. A 35-year-old male presented with right leg pain for 2 weeks without a previous history of limb weakness. Magnetic resonance imaging of the lumbar spine showed disc extrusion at L5-S1 and incidental severe fatty degeneration of the lumbar erector spinae. Physical examination demonstrated no definite limb weakness. Serum creatine kinase levels were elevated. Genetic testing using a targeted gene-sequencing panel identified compound heterozygous variants NM_003494.3(DYSF) c.[1284+2T>C]; [5303G>A]. Computed tomography revealed fatty degeneration of lower-limb muscles, which was mild in the adductor muscles and severe in the gluteus minimus. Immunohistochemistry staining of the vastus lateralis showed under-expression of dysferlin. This patient was diagnosed with LGMD R2 dysferin-related. Thus, unusual fatty degeneration of the lumbar paraspinalis can be a manifestation of dysferlinopathy.
Project description:BACKGROUND:Limb-girdle muscular dystrophy (LGMD) is a commonly diagnosed hereditary muscular disorder, characterized by the progressive weakness of the limb-girdle muscles. Although the condition has been well-characterized, clinical and genetic heterogeneity can be observed in patients with LGMD. Here, we aimed to describe the clinical manifestations and genetic variability among a cohort of patients with LGMD in South China. RESULTS:We analyzed the clinical information, muscle magnetic resonance imaging (MRI) findings, and genetic results obtained from 30 patients (24 families) with clinically suspected LGMD. In 24 probands, 38 variants were found in total, of which 18 were shown to be novel. Among the 30 patients, the most common subtypes were dysferlinopathy in eight (26.67%), sarcoglycanopathies in eight [26.67%; LGMD 2C in three (10.00%), LGMD 2D in three (10.00%), and LGMD 2F in two (6.67%)], LGMD 2A in seven (23.33%), followed by LGMD 1B in three (10.00%), LGMD 2I in three (10.00%), and early onset recessive Emery-Dreifuss-like phenotype without cardiomyopathy in one (3.33%). Furthermore, we also observed novel clinical presentations for LGMD 1B, 2F, and 2I patients with hypermobility of the joints in the upper limbs, a LGMD 2F patient with delayed language development, and other manifestations. Moreover, distinct distributions of fatty infiltration in patients with LGMD 2A, dysferlinopathy, and the early onset recessive Emery-Dreifuss-like phenotype without cardiomyopathy were also observed based on muscle MRI results. CONCLUSIONS:In this study, we expanded the clinical spectrum and genetic variability found in patients with LGMD, which provided additional insights into genotype and phenotype correlations in this disease.
Project description:Dysferlin encoded by DYSF deficiency leads to two main phenotypes, limb girdle muscular dystrophy (LGMD) 2B and Miyoshi myopathy. To reveal in detail the mutational and clinical features of LGMD2B in Japan, we observed 40 Japanese patients in 36 families with LGMD2B in whom dysferlin mutations were confirmed.Three mutations (c.1566C>G, c.2997G>T and c.4497delT) were relatively more prevalent. The c.2997G>T mutation was associated with late onset, proximal dominant forms of dysferlinopathy, a high probability that muscle weakness started in an upper limb and lower serum creatine kinase (CK) levels. The clinical features of LGMD2B are as follows: (1) onset in the late teens or early adulthood, except patients homozygous for the c.2997G>T mutation; (2) lower limb weakness at onset; (3) distal change of lower limbs on muscle CT at an early stage; (4) impairment of lumbar erector spinal muscles on muscle CT at an early stage; (5) predominant involvement of proximal upper limbs; (6) preservation of function of the hands at late stage; (7) preservation of strength in neck muscles at late stage; (8) lack of facial weakness or dysphagia; (9) avoidance of scoliosis; (10) hyper-Ckaemia; (11) preservation of cardiac function; and (12) a tendency for respiratory function to decline with disease duration. It is important that the late onset phenotype is found with prevalent mutations.
Project description:Dysferlinopathy is caused by mutations in the DYSF gene. To characterize the clinical spectrum, we investigated the characteristics of 31 Korean dysferlinopathy patients confirmed by immunohistochemistry. The mean age of symptom onset was 22.23 ± 7.34 yr. The serum creatine kinase (CK) was highly increased (4- to 101-fold above normal). The pathological findings of muscle specimens showed nonspecific dystrophic features and frequent inflammatory cell infiltration. Muscle imaging studies showed fatty atrophic changes dominantly in the posterolateral muscles of the lower limb. The patients with dysferlinopathy were classified by initial muscle weakness: fifteen patients with Miyoshi myopathy phenotype (MM), thirteen patients with limb girdle muscular dystrophy 2B phenotype (LGMD2B), two patients with proximodistal phenotype, and one asymptomatic patient. There were no differences between LGMD2B and MM groups in terms of onset age, serum CK levels and pathological findings. Dysferlinopathy patients usually have young adult onset and high serum CK levels. However, heterogeneity of clinical presentations and pathologic findings upon routine staining makes it difficult to diagnose dysferlinopathy. These limitations make immunohistochemistry currently the most important method for the diagnosis of dysferlinopathy.
Project description:Autosomal recessive limb-girdle muscular dystrophies (LGMD type 2) are a group of clinically and genetically heterogeneous diseases with the main characteristics of weakness and wasting of the pelvic and shoulder girdle muscles. Among them are sarcoglycanopathies caused by mutations in at least four genes named SGCA, SGCB, SGCG and SGCD. Here we report a consanguineous Iranian family with two children affected with LGMD type 2E. Mutation analysis revealed a novel homozygous exon 2 deletion of SGCB gene in the patients with the parents being heterozygous for this deletion. This result presents a novel underlying genetic mechanism for LGMD type 2E.
Project description:Objective:GDP-mannose pyrophosphorylase B (GMPPB) related phenotype spectrum ranges widely from congenital myasthenic syndrome (CMS), limb-girdle muscular dystrophy type 2T (LGMD 2T) to severe congenital muscle-eye-brain syndrome. Our study investigates the clinicopathologic features of a patient with novel GMPPB mutations and explores the pathogenetic mechanism. Methods:The patient was a 22-year-old woman with chronic proximal limb weakness for 9 years without cognitive deterioration. Weakness became worse after fatigue. Elevated serum creatine kinase and decrements on repetitive nerve stimulation test were recorded. MRI showed fatty infiltration in muscles of lower limbs and shoulder girdle on T1 sequence. Open muscle biopsy and genetic analysis were performed. Results:Muscle biopsy showed myogenic changes. Two missense mutations in GMPPB gene (c.803T>C and c.1060G>A) were identified in the patient. Western blotting and immunostaining showed GMPPB and α-dystroglycan deficiency in the patient's muscle. In vitro, mutant GMPPB forming cytoplasmic aggregates completely colocalized with microtubule-associated protein 1 light chain 3-II (LC3-II), a classical marker of autophagosome. Degradation of GMPPB was accompanied by an upregulation of LC3-II, which could be restored by lysosomal inhibitor leupeptin. Interpretation:We identified two novel GMPPB mutations causing overlap phenotype between LGMD 2T and CMS. We provided the initial evidence that mutant GMPPB colocalizes with autophagosome at subcellular level. GMPPB mutants degraded by autophagy-lysosome pathway is associated with LGMD 2T. This study shed the light into the enzyme replacement which could become one of the therapeutic targets in the future study.
Project description:We describe a family with a novel TNPO3 mutation of limb-girdle muscular dystrophy D2 (or LGMD 1F), a rare muscle disorder with autosomal dominant inheritance, first identified in an Italo-Spanish family where the causative defect has been found to be due to TNPO3 gene mutation, encoding transportin-3 protein (TNPO3). We present the clinical, histopathological and muscle magnetic resonance imaging (MRI) features in two patients, mother and son Hungarian origin, affected by LGMD D2 and correlate their clinical, MRI and histopathological data found in this condition. The affected son presented early pelvic girdle muscle weakness and thin muscles similar to a congenital myopathy; the mother was less compromised and had an LGMD phenotype. Muscle MRI showed a very pronounced lower limb muscle atrophy in both patients. The most relevant change obtained in the child muscle biopsy was a generalized type 1 fibre atrophy. The two patients presented the same mutation, but a different phenotype has been observed in mother and son.
Project description:Limb-girdle muscular dystrophy type 2 (LGMD2B) is a mild form of dysferlinopathy, characterized by limb weakness and wasting. It is an autosomal recessive disease, with currently 140 mutations in the LGMD2B gene identified. Lack of functional dysferlin inhibits muscle fiber regeneration in voluntary muscles, the main pathological finding in LGMD2B patients. However, the immune system has been suggested to contribute to muscle cell death and tissue regeneration. Serum levels of 27 cytokines were evaluated in a dysferlinopathy patient. Levels of 8 cytokines differed in patient serum compared to controls. Five cytokines (IL-10, IL-17, CCL2, CXCL10, and G-CSF) were higher while 3 were lower in the patient than in controls (IL-2, IL-8, and CCL11). Together, these data on serum cytokine profile of this dysferlinopathy patient suggest immune response activation, which could explain leukocyte infiltration in the muscle tissue.
Project description:<h4>Background</h4>Limb-girdle muscular dystrophy (LGMD) is a genetically heterogeneous, hereditary disease characterized by limb-girdle weakness and histologically dystrophic changes. The prevalence of each subtype of LGMD varies among different ethnic populations. This study for the first time analyzed the phenotypes and genotypes in Taiwanese patients with LGMD in a referral center for neuromuscular diseases (NMDs).<h4>Results</h4>We enrolled 102 patients clinically suspected of having LGMD who underwent muscle biopsy with subsequent genetic analysis in the previous 10?years. On the basis of different pathological categories, we performed sequencing of target genes or panel for NMDs and then identified patients with type 1B, 1E, 2A, 2B, 2D, 2I, 2G, 2?N, and 2Q. The 1B patients with LMNA mutation presented with mild limb-girdle weakness but no conduction defect at the time. All 1E patients with DES mutation exhibited predominantly proximal weakness along with distal weakness. In our cohort, 2B and 2I were the most frequent forms of LGMD; several common or founder mutations were identified, including c.1097_1099delACA (p.Asn366del) in DES, homozygous c.101G?>?T (p.Arg34Leu) in SGCA, homozygous c.26_33dup (p.Glu12Argfs*20) in TCAP, c.545A?>?G (p.Tyr182Cys), and c.948delC (p.Cys317Alafs*111) in FKRP. Clinically, the prevalence of dilated cardiomyopathy in our patients with LGMD2I aged >?18?years was 100%, much higher than that in European cohorts. The only patient with LGMD2Q with PLEC mutation did not exhibit skin lesions or gastrointestinal abnormalities but had mild facial weakness. Muscle imaging of LGMD1E and 2G revealed a more uniform involvement than did other LGMD types.<h4>Conclusion</h4>Our study revealed that detailed clinical manifestation together with muscle pathology and imaging remain critical in guiding further molecular analyses and are crucial for establishing genotype-phenotype correlations. We also determined the common mutations and prevalence for different subtypes of LGMD in our cohort, which could be useful when providing specific care and personalized therapy to patients with LGMD.
Project description:RATIONALE:Limb-girdle muscular dystrophy (LGMD) is a genetic disease, which is characterized by muscle atrophy and weakness mainly involving proximal muscles. Accurate diagnosis of LGMD patient is very important for the appropriate management and long-term prognosis. PATIENT CONCERNS:An 18-year-old woman presented with progressive weakness of limbs, persistent elevated serum creatine kinase, myogenic damages in electromyography, and dysferlin protein deficiency in muscle biopsy. Further next-generation sequencing (NGS) revealed a compound heterozygous variant in dysferlin gene (DYSF), including a novel frameshift variant of c.4010delT. DIAGNOSIS:The patient was diagnosed with LGMD2B clinically and genetically. INTERVENTIONS:Oral levocarnitine and coenzyme Q10 were prescribed to the patient. OUTCOMES:After symptomatic treatments for 1 week, the patient's symptoms were not improved. LESSONS:NGS might be a helpful tool for the diagnosis of LGMD. A novel variant of c.4010delT in DYSF was identified in this case, which broadens the genetic spectrum of LGMD2B.
Project description:Limb-girdle muscular dystrophies (LGMD) are genetically and clinically heterogeneous conditions. We investigated a large family with autosomal dominant transmission pattern, previously classified as LGMD1F and mapped to chromosome 7q32. Affected members are characterized by muscle weakness affecting earlier the pelvic girdle and the ileopsoas muscles. We sequenced the whole exome of four family members and identified a shared heterozygous frame-shift variant in the Transportin 3 (TNPO3) gene, encoding a member of the importin-? super-family. The TNPO3 gene is mapped within the LGMD1F critical interval and its 923-amino acid human gene product is also expressed in skeletal muscle. In addition, we identified an isolated case of LGMD with a new missense mutation in the same gene. We localized the mutant TNPO3 around the nucleus, but not inside. The involvement of gene related to the nuclear transport suggests a novel disease mechanism leading to muscular dystrophy.