Complement C5 Inhibitor Ameliorates a Case of Dysferlinopathy

Elevated serum creatine kinase levels are one of the major criteria for the diagnosis of myocardial injury. Noncardiac causes such as muscular and brain damage may also be associated with...

Popeye domain containing 3 (POPDC3) gene encodes a protein involved in membrane trafficking and is highly expressed in skeletal muscles. POPDC3 pathogenic variants are associated with LGMDR26. Only a few reports of POPDC3 LGMD exist worldwide and none from India. Herein, we describe the first case of POPDC3 LGMD26. This is a case report from a neurology referral center in India. All the clinical, laboratory and electrophysiological data were collected from the medical records. A 34-year-old man born to non-consanguineous parents presented with progressive proximal weakness of lower limbs from 22 years of age. He developed calf muscle pain and recurrent falls on walking for 7 years. He had atrophy of calves (medial gastrocnemius more than lateral) along with weakness of hip extensor, adductors and knee flexors and normal upper limb power, resembling Miyoshi myopathy. Serum creatine kinase ranged from 3524 to 6531 U/L. Muscle MRI showed selective atrophy of gluteus maximus, quadriceps femoris, semimembranosus and gastrocnemius with sparing of rectus femoris, gracilis and sartorius. Muscle biopsy done elsewhere and reported to show dystrophic features and immunohistochemistry showed positive staining for dystrophins and sarcoglycans. Clinically the possibility of LGMDR2/Dysferlinopathy, was considered and whole exome sequencing was done which revealed a novel homozygous pathogenic nonsense premature termination codon (PTC) variant (NM_022361.5) c.316C > T (NP_079130.2:) p.Arg106Ter) in exon 2 of POPDC3 gene. This is the first report of POPDC3- LGMDR26 from India detected among a large cohort (461 genetically confirmed cases). POPDC3 gene variations should be considered in distal onset LGMDs with markedly elevated serum creatine kinase levels.

Treatment with statins requires close monitoring of serum creatine kinase (CK) levels to prevent myopathy, a common and potentially serious dose-dependent adverse effect of these drugs. We have investigated the correlation between elevated CK levels and polymorphisms in the genes encoding transporters involved in statin disposition. Patients with and without statin-induced elevated serum CK levels were genotyped for polymorphisms in SLCO1B1 (SLCO1B1 A388G and SLCO1B1 T521C), ABCB1 (ABCB1 C1236T and ABCB1 C3435T) and ABCG2 (ABCG2 C421A). Patients carrying SLCO1B1 T521C or ABCB1 C1236T single nucleotide polymorphisms (SNPs) had an odds ratio (OR) for statin-induced elevated serum CK levels of 8.86 (p<0.01) and 4.67 (p<0.05), respectively, while patients carrying the SLCO1B1 A388G SNP had an OR of 0.24 (p<0.05). An arbitrary score based on genotype combination discriminated patients with and without CK elevation at a specificity of 97 % and a sensitivity of 39 %. Genotyping of the SLCO1B1, ABCB1 and ABCG2 genes deserves consideration as a clinical approach to improve statin safety while concomitantly reducing the burden of blood tests for CK measurements.

Variants in the TTN gene have been associated with distal myopathies and other distinctive phenotypes involving skeletal and cardiac muscle. Through whole-exome sequencing we identified a novel stop-gain variant (c.107635C>T, p.(Gln35879Ter)) in the TTN gene, coding a part of the M-line of titin, in 14 patients with autosomal recessive distal myopathy and Serbian ancestry. All patients share a common 1 Mb core haplotype associated with c.107635C>T, suggesting a founder variant. In compound heterozygotes, nine other TTN variants were identified: four stop-gain, three frameshift, one missense and one splice donor variant. Patients homozygous for the common variant did not show significant clinical differences to the compound heterozygous patients. The clinical presentation of all patients was an adult onset distal myopathy with predominant lower limb involvement. In addition, most patients had normal to mildly elevated serum creatine kinase levels, myopathic electromyograms, normal cardiologic and respiratory tests and muscle pathology consistent with a dystrophic process. In this study, we describe a distinct phenotype for patients with distal myopathy associated with novel recessive TTN variants including a Serbian founder variant. Our results expand the phenotypic and genetic spectrum of titinopathies and will facilitate the diagnosis of this condition in patients of Serbian origin.

IntroductionChronic myelogenous leukemia is often treated using tyrosine kinase inhibitors such as dasatinib. Here we describe a rare case of inflammatory myopathy in a patient with chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib.Case presentationA 69-year-old Caucasian man with imatinib-resistant chronic myelogenous leukemia achieved complete molecular remission in response to dasatinib therapy. However, from a normal initial serum creatine kinase level, he developed elevated serum creatine kinase levels and gradual-onset progressive muscle weakness after dasatinib therapy was initiated. Our patient was eventually diagnosed with inclusion body myositis. However, we were unable to determine the mechanism underlying the dasatinib-associated muscle weakness. Given the efficacy of dasatinib in the treatment of chronic myelogenous leukemia and our patient’s mild symptoms of inclusion body myositis, he continued to receive dasatinib under close clinical and laboratory observation.ConclusionDespite the wide use of dasatinib and its documented safety, we report a case of severe muscle injury of unknown etiology. Therefore, patients with chronic myelogenous leukemia receiving dasatinib and perhaps all tyrosine kinase inhibitors should be carefully monitored for signs of muscle injury, especially if this is associated with significant elevations in serum creatine kinase levels.

Heterogeneous nuclear ribonucleoprotein A1 is involved in nucleic acid homeostatic functions. The encoding gene HNRNPA1 has been associated with several neuromuscular disorders including an amyotrophic lateral sclerosis-like phenotype, distal hereditary motor neuropathy, multisystem proteinopathy, and various myopathies. We report two unrelated individuals with monoallelic stop loss variants affecting the same codon of HNRNPA1. Two individuals with unsolved juvenile-onset myopathy were enrolled under approved institutional protocols. Phenotype data were collected and genetic analyses were performed, including whole-exome sequencing (WES). The two probands (MNOT002-01 and K1440-01) showed a similar onset of slowly progressive extremity and facial weakness in early adolescence. K1440-01 presented with facial weakness, winged scapula, elevated serum creatine kinase (CK) levels, and mild neck weakness. MNOT002-01 also exhibited elevated CK levels along with facial weakness, cardiomyopathy, respiratory dysfunction, pectus excavatum, a mildly rigid spine, and loss of ambulation. On quadriceps muscle biopsy, K1440-01 displayed rounded myofibers, mild variation in fiber diameter, and type 2 fiber hypertrophy, while MNOT002-01 displayed rimmed vacuoles. Monoallelic stop-loss variants in HNRNPA1 were identified for both probands: c.1119A>C p.*373Tyrext*6 (K1440-01) and c.1118A>C p.*373Serext*6 (MNOT002-01) affect the same codon and are both predicted to lead to the addition of six amino acids before termination at an alternative stop codon. Both stop-loss variants in our probands are likely pathogenic. Our findings contribute to the disease characterization of pathogenic variants in HNRNPA1. This gene should be screened in clinical diagnostic testing of unsolved cases of sporadic or dominant juvenile-onset myopathy.

Research Article| January 01 2010 Delayed Diagnosis of Duchenne Muscular Dystrophy AAP Grand Rounds (2010) 23 (1): 3. https://doi.org/10.1542/gr.23-1-3 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Twitter LinkedIn Tools Icon Tools Get Permissions Cite Icon Cite Search Site Citation Delayed Diagnosis of Duchenne Muscular Dystrophy. AAP Grand Rounds January 2010; 23 (1): 3. https://doi.org/10.1542/gr.23-1-3 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search nav search search input Search input auto suggest search filter All PublicationsAll JournalsAAP Grand RoundsPediatricsHospital PediatricsPediatrics In ReviewNeoReviewsAAP NewsAll AAP Sites Search Advanced Search Topics: delayed diagnosis, duchenne's muscular dystrophy Source: Ciafaloni E, Fox DJ, Mathews KD, et al. Delayed diagnosis in Duchenne muscular dystrophy: data from the Muscular Dystrophy Surveillance, Tracking, and Research Network (MD STARnet). J Pediatr. 2009; 155(3): 380– 385; doi: https://doi.org/10.1016/j.jpeds.2009.02.007Google Scholar Investigators from New York, Iowa, Arizona, and Colorado collaborated in a study to assess delay in diagnosis of Duchenne muscular dystrophy (DMD) in patients without a known family history. Study patients were identified using a four-state registry system established by the Muscular Dystrophy Surveillance, Tracking and Research Network. Initially, records of 453 children diagnosed with either Duchenne or Becker muscular dystrophy, born since 1982, were reviewed. Patients classified as having definite or probable DMD, without a known family history prior to birth, were included in the analysis. Abstracted information from patient records included place of birth; residential history; growth data; symptoms; diagnostic tests; disease effects on pulmonary, cardiac and musculoskeletal systems; clinical treatment; and changes in mobility and function over time. The final data set included a cohort of 156 boys with definite or probable DMD. The initial signs and symptoms (SS) of possible DMD in study patients were noted by parents or caregivers at a mean age of 2.5 years. In 28% of these boys the first SS were noted before 1.5 years of age; 58% had SS prior to the age of 3 years. The most frequent SS were motor delay and muscle weakness. There was an average delay of over one year before boys with SS were taken to a health care professional for evaluation. The mean age at which concerns about the initial SS led to a clinical evaluation of the child was 3.6 years. The initial evaluation of the SS by a health care provider included a serum creatine kinase (CK) test in only 35% of cases. For the entire cohort of nonfamilial patients with DMD, the mean age for obtaining the first serum CK was 4.7 years. Between 1982 and 2000, the age at which care providers obtained the first CK in boys with nonfamilial DMD remained unchanged. Overall, there was a delay of about 2.5 years between the onset of DMD symptoms and the time of diagnosis. The authors conclude that there is a significant time lag between onset of SS and diagnosis of DMD and recommend that a CK test be a standard tool in the assessment of developmental delay in boys. DMD, the most common muscular dystrophy in children, is an X-linked recessive disorder occurring in 1 of every 3,500 male newborns,1 resulting from an absence of an essential transmembrane muscle protein. Thirty percent of cases arise from spontaneous mutation in the dystrophin gene. The diagnosis should be suspected in boys with motor difficulties. Global developmental delay does not exclude the diagnosis of DMD as cognitive, behavioral, and language abnormalities are found in one third of cases.2 An elevated serum CK level is a sensitive marker for early detection of DMD.... You do not currently have access to this content.

Creatine Kinase Elevation, Lactacidemia, and Metabolic Myopathy in Adult Patients with Diabetes Mellitus

Background:Idiopathic Inflammatory Myositis(IIM) is a rare autoimmune disease distinguished by progressive proximal muscle weakness, elevated serum creatine kinase (CK) levels, and histopathological evidence of inflammation in muscles. Anti-signal recognition particle...

Autosomal dominant Emery‐Dreifuss muscular dystrophy is caused by mutations in the LMNA gene that code for the nuclear membrane protein lamin A/C. We investigated skeletal muscle fibers from several muscles for cytoplasmic degenerative changes in three patients with genetically confirmed Emery‐Dreifuss muscular dystrophy. Methods included quantitative light and electron microscopy and PCR‐based mutational analysis. The degenerative pathway was characterized by the gradual replacement of individual myofibers by connective tissue. Early stages of degeneration typically involved only a segment of the cross‐sectional area of a myofiber. Intermediate stages consisted of myofiber shrinkage due to “shedding” of peripheral cytoplasmic portions into the endomysial space, and fragmentation of the myofibers by interposed collagen fibrils. Empty basement membrane sheaths surrounded by abundant deposits of extracellular matrix marked the end stage of the degenerative process. The pattern of degeneration described herein differs from muscular dystrophies with plasma membrane defects (dystrophinopathy, dysferlinopathy) and explains the frequently found absence of highly elevated serum creatine kinase levels in autosomal dominant Emery‐Dreifuss muscular dystrophy.

We report a family in which two male siblings with Becker muscular dystrophy (BMD) developed severe dilated cardiomyopathy (DCM) and progressive heart failure (HF) at age 11; one died at age 14 years while awaiting heart transplant and the other underwent left ventricular assist device (LVAD) implantation at the same age. Genetic analysis of one sibling showed a novel frameshift mutation in exon 27 of Duchenne muscular dystrophy (DMD) gene (c.3779_3785delCTTTGGAins GG), in which 7 base pairs are deleted and two are inserted. While this predicts an amino acid substitution and premature termination (p.Thr1260Argfs*8), muscle biopsy dystrophin immunostaining instead indicates that the mutation is more likely to alter splicing. Despite relatively preserved skeletal muscular performance, both siblings developed progressive heart failure secondary to early onset DCM. In addition, their 7 year old nephew with delayed gross motor development, mild proximal muscle weakness, and markedly elevated serum creatine kinase (CK) level (> 13,000 IU/L) at 16 months was recently demonstrated to have the familial DMD mutation. Here we report a novel genotype of BMD with early onset DCM and progressive lethal heart failure during early adolescence.

Objectives: Myocardial infarction is a leading cause of death worldwide. The effect of opioid dependence on myocardial infarction outcomes remains uncertain, with conflicting results in the literature. This study aimed to assess the in-hospital and six-month outcomes of opioid-dependent compared to non-dependent patients with ST-elevation myocardial infarction (STEMI) at Afshar Heart Center, Yazd. Methods: This cross-sectional analytical study included 200 STEMI patients admitted to Afshar Heart Center in Yazd, Iran, between 2020 and 2021. Patients were divided into opioid-dependent and non-opioid-dependent groups based on the DSM-IV criteria for opioid use. The inclusion criteria were chest pain lasting at least 30 minutes, specific ST-segment elevation on ECG, and elevated serum creatine kinase levels. Patients with a history of myocardial infarction or other cardiac or pulmonary diseases were excluded. Demographic and clinical data were collected from hospital records and analyzed using SPSS v.22. Results: Multivariate analysis showed that opioid dependence was significantly linked to in-hospital outcomes. Although in-hospital mortality was higher for opioid-dependent patients compared to non-dependent patients (8.3% vs. 1.7%, p = 0.34), this difference was not statistically significant. Interestingly, six-month mortality occurred only in the non-dependent group (3.4% vs. 0%, p = 0.095). The duration from symptom onset to hospital arrival was considerably shorter in opioid users (154.01 ± 190.38 minutes) than in non-users (271.62 ± 287.58 minutes, p &lt; 0.01), which may have contributed to earlier reperfusion. Despite these differences, there were no significant differences between the groups regarding revascularization strategies or left ventricular ejection fraction (EF: 38.15% vs. 38.52%, p = 0.974). Conclusions: Opioid dependency greatly affects the prognosis of STEMI patients, highlighting the importance of targeted interventions and additional research

The present article describes the clinical and pathological findings in 5 human immunodeficiency virus (HIV)-infected patients with muscle toxoplasmosis. The patients had marked lymphopenia (5/5), with less than five CD4+ cells/mm3 (3/3), when they developed fever (5/5), and multiorgan failure (5/5), including diffuse encephalitis, pneumonia, pancytopenia, and myopathy. Muscle involvement included weakness and wasting (4/5), myalgias (3/5), and high serum creatine kinase levels (3/3). Serology for toxoplasmosis showed high IgG titers in 3 patients (3/4). Anti-Toxoplasma therapy resulted in complete recovery in 2 patients. Muscle toxoplasmosis was detected by biopsy (3/5) or postmortem evaluation (2/5), and was identified using immunocytochemistry and electron microscopy. Toxoplasma cysts were detected in 0.5 to 4% of muscle fibers close to or remote from necrotic fibers and inflammatory infiltrates. Muscle fibers strongly expressed the major histocompatibility complex class I antigen (2/2) as in polymyositis. We suggest that Toxoplasma gondii should be sought by muscle biopsy in patients who have acquired immunodeficiency syndrome with fever, encephalitis, multiorgan dysfunction, and elevated serum creatine kinase levels of obscure origin.

Duchenne muscular dystrophy (DMD) is a progressive disease characterized by the wasting of the muscles that eventually lead to difficulty moving and, ultimately, premature death from heart and respiratory complications. DMD deficiency is caused by mutations in the gene encoding dystrophin, which prevents skeletal muscle, cardiac muscle, and other cells from producing the functional protein. Located on the cytoplasmic face of the plasma membrane of muscle fibers, dystrophin serves as a component of the dystrophin glycoprotein complex (DGC), mechanically reinforces the sarcolemma, and stabilizes the DGC, preventing it from contraction-mediated muscle degradation. In DMD muscle, dystrophin deficiency leads to progressive fibrosis, myofiber damage, chronic inflammation, and dysfunction of the mitochondria and muscle stem cells. Currently, DMD is incurable, and treatment involves the administration of glucocorticoids in order to delay disease progression. In the presence of developmental delay, proximal weakness, and elevated serum creatine kinase levels, a definitive diagnosis can usually be made after an extensive review of the patient’s history and physical examination, as well as confirmation through muscle biopsy or genetic testing. Current standards of care include the use of corticosteroids to prolong ambulation and delay the onset of secondary complications, including respiratory muscle and cardiac functions. However, different studies have been carried out to show the relationship between vascular density and impaired angiogenesis in the pathogenesis of DMD. Several recent studies on DMD management are vascular targeted and focused on ischemia as a culprit for the pathogenesis of DMD. This review critically discusses approaches—such as modulation of nitric oxide (NO) or vascular endothelial growth factor (VEGF)-related pathways—to attenuate the dystrophic phenotype and enhance angiogenesis.

Creatine kinase release from isolated EDL muscles in chronic ethanol-treated rats