Tibial Muscular Dystrophy

Udd, Bjarne; Partanen, Juhani; Halonen, Päivi; Falck, Björn; Hakamies, L; Heikkilä, Heikki; Ingo, Sinikka; Kalimo, Hannu; Kääriäinen, Helena; Laulumaa, Veikko; Paljärvi, Leo; Rapola, Juhani; Reunanen, Mauri; Sonninen, V.; Somer, Hannu

doi:10.1001/archneur.1993.00540060044015

Cited by 133 publications

(20 citation statements)

References 22 publications

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“…Tibial muscular dystrophy (TMD; MIM #600334]) is a mild autosomal dominant distal myopathy involving the anterior compartment muscles of the lower legs but sparing of the short toe extensor digitorum brevis muscles [49]. …”

Section: Titin Variants and Diseasesmentioning

confidence: 99%

Increasing Role of Titin Mutations in Neuromuscular Disorders

Savarese

Sarparanta

Vihola

et al. 2016

JND

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The TTN gene with 363 coding exons encodes titin, a giant muscle protein spanning from the Z-disk to the M-band within the sarcomere. Mutations in the TTN gene have been associated with different genetic disorders, including hypertrophic and dilated cardiomyopathy and several skeletal muscle diseases.Before the introduction of next generation sequencing (NGS) methods, the molecular analysis of TTN has been laborious, expensive and not widely used, resulting in a limited number of mutations identified. Recent studies however, based on the use of NGS strategies, give evidence of an increasing number of rare and unique TTN variants. The interpretation of these rare variants of uncertain significance (VOUS) represents a challenge for clinicians and researchers.The main aim of this review is to describe the wide spectrum of muscle diseases caused by TTN mutations so far determined, summarizing the molecular findings as well as the clinical data, and to highlight the importance of joint efforts to respond to the challenges arising from the use of NGS. An international collaboration through a clinical and research consortium and the development of a single accessible database listing variants in the TTN gene, identified by high throughput approaches, may be the key to a better assessment of titinopathies and to systematic genotype– phenotype correlation studies.

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Section: Titin Variants and Diseasesmentioning

confidence: 99%

Increasing Role of Titin Mutations in Neuromuscular Disorders

Savarese

Sarparanta

Vihola

et al. 2016

JND

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123

121

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“…TMD is clinically characterised by atrophy and weakness in the muscles of the anterior compartment of the lower leg ( tibialis anterior , extensor hallucis longus and extensor digitorum longus ) [3], with typical onset between 35–55 years [12]. Homozygous FINmaj mutations cause the manifestation of the completely different, and much more severe, early onset LGMD2J (OMIM: #608807) [2], [3], [13].…”

Section: Introductionmentioning

confidence: 99%

“…TMD and LGMD2J patients do not have facial muscle weakness, dysphagia or clinically manifest cardiomyopathy. TMD muscle biopsies show myopathic–dystrophic morphology with rare fibre necrosis and frequent rimmed vacuolated fibres in affected muscles [3], [12], [14].…”

Section: Introductionmentioning

confidence: 99%

Gene Expression Profiling in Tibial Muscular Dystrophy Reveals Unfolded Protein Response and Altered Autophagy

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Raheem²,

Holmlund-Hampf

et al. 2014

PLoS ONE

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Tibial muscular dystrophy (TMD) is a late onset, autosomal dominant distal myopathy that results from mutations in the two last domains of titin. The cascade of molecular events leading from the causative Titin mutations to the preterm death of muscle cells in TMD is largely unknown. In this study we examined the mRNA and protein changes associated with the myopathology of TMD. To identify these components we performed gene expression profiling using muscle biopsies from TMD patients and healthy controls. The profiling results were confirmed through quantitative real-time PCR and protein level analysis. One of the pathways identified was activation of endoplasmic reticulum (ER) stress response. ER stress activates the unfolded protein response (UPR) pathway. UPR activation was supported by elevation of the marker genes HSPA5, ERN1 and the UPR specific XBP1 splice form. However, UPR activation appears to be insufficient to correct the protein abnormalities causing its activation because degenerative TMD muscle fibres show an increase in ubiquitinated protein inclusions. Abnormalities of VCP-associated degradation pathways are also suggested by the presence of proteolytic VCP fragments in western blotting, and VCP's accumulation within rimmed vacuoles in TMD muscle fibres together with p62 and LC3B positive autophagosomes. Thus, pathways controlling turnover and degradation, including autophagy, are distorted and lead to degeneration and loss of muscle fibres.

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“…Other large pedigrees and several sporadic cases were reported and renamed tibial distal muscular dystrophy (TMD) to emphasize the dystrophic features (28, 29). Despite phenotypic overlap, recent idenfication of 2 distinct gene mutations led to the definition of 2 subtypes: type 2a related to titin gene defect and type 2b due to ZASP point mutation.…”

Section: Classic Distal Myopathiesmentioning

confidence: 99%

“…In non-scandinavian cases, weakness may over time involve finger and wrist extensor muscles; later, proximal involvement can supervene. Whereas most Finnish patients progressed more slowly and rarely involved the upper extremity or proximal muscles (4), some western Finnish cases exhibited severe limb girdle syndrome (28–30). …”

Section: Classic Distal Myopathiesmentioning

confidence: 99%

Distal Myopathies

Dimachkie

Barohn

2014

Neurologic Clinics

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Over a century ago, Gowers described two young patients in whom distal muscles weakness involved the hand, foot, sternocleidomastoid, and facial muscles in the other case the shoulder and distal leg musculature. Soon after, , similar distal myopathy cases were reported whereby the absence of sensory symptoms and of pathologic changes in the peripheral nerves and spinal cord at postmortem examination allowed differentiation from Charcot-Marie-Tooth disease. In 1951, Welander described autosomal dominant (AD) distal arm myopathy in a large Scandanavian cohort. Since then the number of well-characterized distal myopathies has continued to grow such that the distal myopathies have formed a clinically and genetically heterogeneous group of disorders. Affected kindred commonly manifest weakness that is limited to foot and toe muscles even in advanced stages of the disease, with variable mild proximal leg, distal arm, neck and laryngeal muscle involvement in selected individuals. An interesting consequence of the molecular characterization of the distal myopathies has been the recognition that mutation in a single gene can lead to more than one clinical disorder. For example, Myoshi myopathy (MM) and limb girdle muscular dystrophy (LGMD) type 2B are allelic disorders due to defects in the gene that encodes dysferlin. The six well described distal myopathy syndromes are shown in Table 1. Table 2 lists advances in our understanding of the myofibrillar myopathy group and Table 3 includes more recently delineated and less common distal myopathies. In the same manner, the first section of this review pertains to the more traditional six distal myopathies followed by discussion of the myofibrillar myopathies. In the third section, we review other clinically and genetically distinctive distal myopathy syndromes usually based upon single or smaller family cohorts. The fourth section considers other neuromuscular disorders that are important to recognize as they display prominent distal limb weakness.

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Tibial Muscular Dystrophy

Cited by 133 publications

References 22 publications

Increasing Role of Titin Mutations in Neuromuscular Disorders

Increasing Role of Titin Mutations in Neuromuscular Disorders

Gene Expression Profiling in Tibial Muscular Dystrophy Reveals Unfolded Protein Response and Altered Autophagy

Distal Myopathies

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