Muscle weakness in myotonic dystrophy associated with misregulated splicing and altered gating of CaV1.1 calcium channel

Neuromuscular junction disorders affect the pre- or postsynaptic nerve to muscle transmission due to autoimmune antibodies. Members of the group like myasthenia gravis and Lambert-Eaton syndrome have pathophysiologically distinct characteristics. However, in practice, distinction may be difficult. We present a series of three patients with a myasthenic syndrome, dropped-head syndrome, bulbar and respiratory muscle weakness and positive testing for anti-N-type voltage-gated calcium channel antibodies. In two cases anti-acetylcholin receptor antibodies were elevated, anti-P/Q-type voltage-gated calcium channel antibodies were negative. All patients initially responded to pyridostigmine with a non-response in the course of the disease. While one patient recovered well after treatment with intravenous immunoglobulins, 3,4-diaminopyridine, steroids and later on immunosuppression with mycophenolate mofetil, a second died after restriction of treatment due to unfavorable cancer diagnosis, the third patient declined treatment. Although new antibodies causing neuromuscular disorders were discovered, clinical distinction has not yet been made. Our patients showed features of pre- and postsynaptic myasthenic syndrome as well as severe dropped-head syndrome and bulbar and axial muscle weakness, but only anti-N-type voltage-gated calcium channel antibodies were positive. When administered, one patient benefited from 3,4-diaminopyridine. We suggest that this overlap-syndrome should be considered especially in patients with assumed seronegative myasthenia gravis and lack of improvement under standard therapy.

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A male with oligozoospermia and muscle weakness subsequently diagnosed with myotonic dystrophy

Case Studies in Assisted Reproduction ◽

10.1017/cbo9781139794671.007 ◽

2015 ◽

pp. 24-26

Author(s):

Inge Liebaers ◽

Willem Verpoest ◽

Nick S. Macklon ◽

Human M. Fatemi ◽

Robert J. Norman ◽

...

Keyword(s):

Myotonic Dystrophy ◽

Muscle Weakness

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Myotonic dystrophy-2: Unusual phenotype due to a small CCTG-expansion

Balkan Journal of Medical Genetics ◽

10.2478/bjmg-2018-0024 ◽

2018 ◽

Vol 21 (2) ◽

pp. 39-43

Author(s):

J Finsterer ◽

C Stöllberger ◽

A Reining-Festa ◽

M Loewe-Grgurin ◽

M Gencik

Keyword(s):

Myotonic Dystrophy ◽

Muscle Weakness ◽

Factor V Leiden ◽

Myotonic Dystrophy Type ◽

Multisystem Disease ◽

Myotonic Dystrophy Type 2 ◽

Factor V Leiden Mutation ◽

Endocrine Organs ◽

Vesico Ureteral Reflux

Abstract Myotonic dystrophy type 2 (MD2) is a multisystem disease, predominantly affecting the proximal limb muscles, eyes, endocrine organs, heart and intestines. Longterm asymptomatic creatine kinase (hyper-CKemia) of more than 20 years duration, in association with hyperlipidemia and diabetes, as a manifestation of MD2 has not been reported. A 52-year-old female with a history of hyper-CKemia since the age of 32 years associated with diabetes, hyperlipidemia and hyperuricemia, developed anginal chest pain and proximal muscle weakness together with clinical myotonia when opening the fists at age 51 years. Examination revealed a left anterior hemiblock, sensorimotor neuropathy, extensive myotonic discharges on needle electromyography (EMG) and a CCTG-expansion of 134 bp on the ZNF9 gene. The family history was positive for hyper-CKemia and muscle weakness. In addition, over the previous years, she had developed vesico-ureteral reflux, cutaneous melanoma, renal cysts, cervix dysplasias, thrombocytosis, cataracts, arterial hypertension, heterozygous Factor V Leiden mutation, cholecystolithiasis, multiple ovarial cysts and vitamin D deficiency. Asymptomatic, long-term hyper-CKemia in association with multisystem disease should raise the suspicion of a MD2. Rare manifestations of MD2 may be thrombocytosis, hyperuricemia, vesico-ureteral reflux, gallstones, hypertension and cyst formation. In patients with asymptomatic hyper-CKemia, needle EMG should be considered. Myotonic dystrophy type 2 may take a mild course over many years if the CCTG-expansion is short.

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Relationship Between Chronic Hypercapnia and Inspiratory-Muscle Weakness in Myotonic Dystrophy

American Journal of Respiratory and Critical Care Medicine ◽

10.1164/ajrccm.156.1.9509041 ◽

1997 ◽

Vol 156 (1) ◽

pp. 133-139 ◽

Cited By ~ 89

Author(s):

PAUL BÉGIN ◽

JEAN MATHIEU ◽

JOSÉ ALMIRALL ◽

ALEJANDRO GRASSINO

Keyword(s):

Myotonic Dystrophy ◽

Muscle Weakness ◽

Inspiratory Muscle

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Paving the way for a better understanding of the pathophysiology of gait impairment in myotonic dystrophy: a pilot study focusing on muscle networks

Journal of NeuroEngineering and Rehabilitation ◽

10.1186/s12984-019-0590-0 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 2

Author(s):

Antonino Naro ◽

Simona Portaro ◽

Demetrio Milardi ◽

Luana Billeri ◽

Antonino Leo ◽

...

Keyword(s):

Myotonic Dystrophy ◽

Muscle Weakness ◽

Rehabilitation Program ◽

Muscle Coordination ◽

Gait Impairment ◽

Time Frequency ◽

Lower Limb Muscles ◽

Muscle Impairment ◽

System Disorder ◽

Muscle Connectivity

Abstract Background A proper rehabilitation program targeting gait is mandatory to maintain the quality of life of patients with Myotonic dystrophy type 1 (DM1). Assuming that gait and balance impairment simply depend on the degree of muscle weakness is potentially misleading. In fact, the involvement of the Central Nervous System (CNS) in DM1 pathophysiology calls into account the deterioration of muscle coordination in gait impairment. Our study aimed at demonstrating the presence and role of muscle connectivity deterioration in patients with DM1 by a CNS perspective by investigating signal synergies using a time-frequency spectral coherence and multivariate analyses on lower limb muscles while walking upright. Further, we sought at determining whether muscle networks were abnormal secondarily to the muscle impairment or primarily to CNS damage (as DM1 is a multi–system disorder also involving the CNS). In other words, muscle network deterioration may depend on a weakening in signal synergies (that express the neural drive to muscles deduced from surface electromyography data). Methods Such an innovative approach to estimate muscle networks and signal synergies was carried out in seven patients with DM1 and ten healthy controls (HC). Results Patients with DM1 showed a commingling of low and high frequencies among muscle at both within– and between–limbs level, a weak direct neural coupling concerning inter–limb coordination, a modest network segregation, high integrative network properties, and an impoverishment in the available signal synergies, as compared to HCs. These network abnormalities were independent from muscle weakness and myotonia. Conclusions Our results suggest that gait impairment in patients with DM1 depends also on a muscle network deterioration that is secondary to signal synergy deterioration (related to CNS impairment). This suggests that muscle network deterioration may be a primary trait of DM1 rather than a maladaptive mechanism to muscle degeneration. This information may be useful concerning the implementation of proper rehabilitative strategies in patients with DM1. It will be indeed necessary not only addressing muscle weakness but also gait-related muscle connectivity to improve functional ambulation in such patients.

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Premature senescence in primary muscle cultures of myotonic dystrophy type 2 is not associated with p16 induction

European Journal of Histochemistry ◽

10.4081/ejh.2014.2444 ◽

2014 ◽

Cited By ~ 11

Author(s):

L.V. Renna ◽

R. Cardani ◽

A. Botta ◽

G. Rossi ◽

B. Fossati ◽

...

Keyword(s):

Skeletal Muscle ◽

Myotonic Dystrophy ◽

Muscle Weakness ◽

Premature Senescence ◽

Myotonic Dystrophy Type ◽

Myotonic Dystrophy Type 2 ◽

Histopathological Features ◽

Progressive Muscle Weakness

Myotonic dystrophy type 1 (DM1) and type 2 (DM2) are multisystemic disorders linked to two different genetic loci and characterized by several features including myotonia, muscle weakness and atrophy, cardiac dysfunctions, cataracts and insulin-resistance. In both forms, expanded nucleotide sequences cause the accumulation of mutant transcripts in the nucleus deregulating the activity of some RNAbinding proteins and providing an explanation for the multisystemic phenotype of DM patients. However this pathogenetic mechanism does not explain some histopathological features of DM skeletal muscle like muscle atrophy. It has been observed that DM muscle shares similarities with the ageing muscle, where the progressive muscle weakness and atrophy is accompanied by a lower regenerative capacity possibly due to the failure in satellite cells activation. The aim of our study is to investigate if DM2 satellite cell derived myoblasts exhibit a premature senescence as reported for DM1 and if alterations in their proliferation potential and differentiation capabilities might contribute to some of the histopathological features observed in DM2 muscles. Our results indicate that DM myoblasts have lower proliferative capability than control myoblasts and reach in vitro senescence earlier than controls. Differentely from DM1, the p16 pathway is not responsible for the premature growth arrest observed in DM2 myoblasts which stop dividing with telomeres shorter than controls. During in vitro senescence, a progressive decrease in fusion index is observable in both DM and control myotubes with no significant differences between groups. Moreover, myotubes obtained from senescent myoblasts appear to be smaller than those from young myoblasts. Taken together, our data indicate a possible role of DM2 premature myoblast senescence in skeletal muscle histopathological alterations i.e., dystrophic changes and type 2 fibre atrophy.

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SAT-510 Association of Myotonic Dystrophy with Autoimmune Endocrinopathies and Thyroid Carcinoma

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1550 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Nikoletta Proudan ◽

Murray B Gordon

Keyword(s):

Insulin Resistance ◽

Thyroid Carcinoma ◽

Myotonic Dystrophy ◽

Cognitive Dysfunction ◽

Muscle Weakness ◽

Hashimoto’S Thyroiditis ◽

Hashimoto's Thyroiditis ◽

Type I ◽

Follicular Variant ◽

History Of

Abstract Myotonic dystrophy (MD) is a multisystemic, autosomal dominant disorder associated with progressive muscle weakness, premature cataracts, frontal baldness, and cardiac disturbances. MD has been associated with several endocrinopathies including primary testicular failure, autoimmune endocrinopathies (hypothyroidism, hyperthyroidism, multinodular goiter, and Addison’s disease), thyroid carcinoma (primarily papillary), insulin resistance, and type 2 DM. Development of diabetes is thought to be related to formation of an insulin-resistant receptor because of aberrant regulation of mRNA. We describe the first reported case of a patient with MD associated with type I diabetes mellitus, Hashimoto’s thyroiditis with hypothyroidism, and follicular variant of papillary thyroid cancer. A 49-year-old female presented with acute congestive heart failure. The patient had history of type I DM diagnosed at the age of 26, complicated by mild background retinopathy, peripheral neuropathy, and nephropathy with microalbuminuria. The patient first noticed proximal muscle weakness 1 year ago that gradually progressed resulting in multiple falls. She had history of bilateral cataracts status post cataract extraction at age 26. She also had progressive dysphagia requiring PEG placement, and cognitive dysfunction with mood disorder and depression. Family history was significant for myotonic dystrophy in both maternal aunt and uncle as well as 2 cousins. EMG confirmed myotonia however genetic testing was not obtained due to cost. Due to her cognitive dysfunction and depression, she had difficult to control diabetes with HbA1c of 9.9%, and multiple previous admissions for DKA. She was status post total thyroidectomy in 2008 for follicular variant of papillary carcinoma and Hashimoto’s thyroiditis followed by I-131 therapy in 2009 and maintained on levothyroxine suppression therapy. Most recent Tg and Tg Ab were undetectable. On physical exam, the patient had a narrow, sallow face with temporal muscle atrophy, percussion myoclonus involving the thenar eminence of the hands, but no frontal balding. Work up showed LVEF of 20-24% with regional hypokinesis that led to catherization and PCI to LAD. The patient had recurrent NSTEMI which eventually resulted in CABG 1 year after presentation. The association of autoimmune endocrinopathies, thyroid carcinoma and MD suggests a possible cause and effect relationship between these disorders. In patients with diabetes and MD, previously described insulin resistance as well as cognitive dysfunction can hinder good glycemic control increasing risk for complications. Although patients with MD are typically treated by neurologists, evaluation and therapy of endocrine dysfunctions are also necessary.

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