Hereditary myopathies with early respiratory insufficiency in adults

Naddaf, Elie; Milone, Margherita

doi:10.1002/mus.25602

Cited by 26 publications

(14 citation statements)

References 32 publications

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“…In ATPase reacted sections, there was grouping of type 1 fiber in several fascicles suggesting reinnervation (data not shown). Proband 2 was patient #9 in a case series of myopathy with respiratory insufficiency ( 17 ). No bone abnormalities were evident by leg CT or hip radiograph.…”

Section: Resultsmentioning

confidence: 99%

Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features

et al. 2018

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ObjectiveThe aim of this study is to identify the molecular defect of three unrelated individuals with late-onset predominant distal myopathy; to describe the spectrum of phenotype resulting from the contributing role of two variants in genes located on two different chromosomes; and to highlight the underappreciated complex forms of genetic myopathies.Patients and methodsClinical and laboratory data of three unrelated probands with predominantly distal weakness manifesting in the sixth-seventh decade of life, and available affected and unaffected family members were reviewed. Next-generation sequencing panel, whole exome sequencing, and targeted analyses of family members were performed to elucidate the genetic etiology of the myopathy.ResultsGenetic analyses detected two contributing variants located on different chromosomes in three unrelated probands: a heterozygous pathogenic mutation in SQSTM1 (c.1175C>T, p.Pro392Leu) and a heterozygous variant in TIA1 (c.1070A>G, p.Asn357Ser). The affected fraternal twin of one proband also carries both variants, while the unaffected family members harbor one or none. Two unrelated probands (family 1, II.3, and family 3, II.1) have a distal myopathy with rimmed vacuoles that manifested with index extensor weakness; the other proband (family 2, I.1) has myofibrillar myopathy manifesting with hypercapnic respiratory insufficiency and distal weakness.ConclusionThe findings indicate that all the affected individuals have a myopathy associated with both variants in SQSTM1 and TIA1, respectively, suggesting that the two variants determine the phenotype and likely functionally interact. We speculate that the TIA1 variant is a modifier of the SQSTM1 mutation. We identify the combination of SQSTM1 and TIA1 variants as a novel genetic defect associated with myofibrillar myopathy and suggest to consider sequencing both genes in the molecular investigation of myopathy with rimmed vacuoles and myofibrillar myopathy although additional studies are needed to investigate the digenic nature of the disease.

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Section: Resultsmentioning

confidence: 99%

Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features

et al. 2018

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“…Respiratory failure is a common and life-threatening condition in metabolic myopathy that demands prompt diagnosis, assessment and appropriate management (20). A report referring to 22 hereditary myopathies with early respiratory insufficiency in adults pointed out that a MELAS patient with m.3243A>G mutation suffered from orthopnea and dyspnea on exertion at 39 years old (21). Another report studied adults with apnea, and implied that 8.5% patients were finally diagnosed as mitochondrial myopathy (17).…”

Section: Discussionmentioning

confidence: 99%

Clinical Profile and Outcome of Pediatric Mitochondrial Myopathy in China

Zhao

et al. 2020

Front. Neurol.

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Introduction: Mitochondrial myopathy in children has notable clinical and genetic heterogeneity, but detailed data is lacking. Patients and Methods: In this study, we retrospectively reviewed the clinical presentation, laboratory investigation, genetic and histopathological characteristics, and follow-ups of 21 pediatric mitochondrial myopathy cases from China. Results: Twenty-four patients suspected with mitochondrial myopathy were enrolled initially and 21 were genetically identified. Fourteen patients were found to harbor mitochondrial DNA point mutations (14/21, 66.7%), including m.3243A>G (9/15, 60%), m.3303C>T (2/15, 13.3%), m.3302A>G (1/15, 6.7%), m.3250T>C (1/15, 6.7%), m.3251A>G (1/15, 6.7%), of whom 12 patients presented with progressive proximal mitochondrial myopathy (12/14, 85.7%). Three patients revealed large-scale deletion in blood or muscle tissue (3/21, 14.3%), presenting with Kearns-Sayer syndrome (1/3, 33.3%) or chronic progressive external ophthalmoplegia (2/3, 66.7%). Four patients were found to harbor pathogenic nuclear gene variants (4/21, 19.0%), including five variants in TK2 gene and two variants in SURF1 gene. During the follow-ups up to 7 years, 10 patients developed cardiomyopathy (10/21, 47.6%), 13 patients occurred at least once hypercapnic respiratory failure (13/21, 61.9%), six experienced recurrent respiratory failure and intubation (6/21, 28.6%), eight patients failed to survive (8/21, 38.1%). With nocturnal non-invasive ventilation of BiPAP, three patients recovered from respiratory failure, and led a relative stable and functional life (3/21, 14.3%). Conclusion: Mitochondrial myopathy in children has great clinical, pathological, and genetical heterogeneity. Progressive proximal myopathy is most prevalent. Mitochondrial DNA point mutations are most common. And respiratory failure is a critical risk factor of poor prognosis.

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“…2 Fourteen percent of patients with myasthenia gravis and 3% of those with amyotrophic lateral sclerosis may present in this manner. 3 The table shows a list of neuromuscular diseases associated with early respiratory failure.…”

Section: Sectionmentioning

confidence: 99%

“…The most common hereditary myopathies presenting like the aforementioned include adult Pompe disease, myotonic dystrophy, and congenital and mitochondrial myopathies. 3,4 Pompe disease, also named glycogen storage disease type II, is an autosomal recessive condition due to mutations in the gene encoding the lysosomal enzyme acid α-glucosidase (GAA). Primary symptoms in one-third of the adult patients are those of respiratory insufficiency while still ambulatory.…”

Section: Sectionmentioning

confidence: 99%

Clinical Reasoning: A 54-year-old man with dyspnea and muscle weakness

et al. 2019

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A 54-year-old man was referred due to a 15-year history of unexplained dyspnea and progressive muscle weakness. The patient had an unremarkable birth and development history. His mother also had dyspnea of unidentified cause and died suddenly at age 70 years. At age 40, a reduced vital capacity (VC) was identified in pulmonary tests during a smoking cessation treatment. He was asymptomatic. At age 45, he developed dyspnea while playing tennis without "second wind" phenomenon or worsening with fasting. At that time, a creatine kinase (CK) level of 490 U/L (normal <200 U/L) was identified during treatment with statins. These were stopped but no resolution was observed. At age 46, he was hospitalized for pneumonia. Chest X-ray only revealed elevation of right diaphragm. Despite resolution of the infection, he developed orthopnea and started sleeping in the sitting position. Due to the acknowledgment of diaphragmatic weakness and the persistence of elevated CK, chest specialists referred him to the neurology department. Examination revealed unremarkable cognitive abilities, normal cranial nerves, appropriate neck strength with mild weakness (4/5) bilaterally on deltoids, iliopsoas, and quadriceps. Calf muscles were hypertrophic. The patient was unable to sit from a recumbent position without using his arms. He did not present paradoxical breathing. Muscle tone was normal. He had no atrophy, fasciculations, or scoliosis. His deep tendon reflexes were absent. Sensory and cerebellar examinations were normal. He lacked ptosis, diplopia, jaw claudication, or dysphagia. Weakness did not fluctuate throughout the day. He was on losartan 50 mg/d and clonazepam 1 mg/d. Pulmonary tests revealed a restrictive pattern with a predictive forced vital capacity of 48% with only mild deterioration during a decade of follow-up. A severe drop in the VC (>50%) was observed in the supine position, indicating diaphragmatic weakness. An oral pyridostigmine trial did not improve VC. Polysomnography revealed reduced sleep efficiency, nocturnal hypoventilation, elevated central apneas (10/h), and a saturation below 90% during 71% of total sleep time. The patient did not present sleep-related symptoms. Questions for consideration: 1. What is the clinical scenario? 2. What diagnoses should we consider? GO TO SECTION 2

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Hereditary myopathies with early respiratory insufficiency in adults

Abstract: We highlighted the most common hereditary myopathies associated with early respiratory insufficiency as the predominant clinical feature, and underscored the importance of a timely diagnosis for patient care. Muscle Nerve 56: 881-886, 2017.

Cited by 26 publications

References 32 publications

Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features

Myopathy With SQSTM1 and TIA1 Variants: Clinical and Pathological Features

Clinical Profile and Outcome of Pediatric Mitochondrial Myopathy in China

Clinical Reasoning: A 54-year-old man with dyspnea and muscle weakness

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