What is the role of FHL1 mutations in the etiology of congenital myopathies?

Updated: Mar 11, 2019
  • Author: Matthew Harmelink, MD; Chief Editor: Amy Kao, MD  more...
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This is an X-linked dominant disease due to a mutation in Four and a half LIM domain 1 (FHL1). [67]

The LIM domain is a cysteine-rich double zinc-finger structure that bind zinc ions for protein stabilization. FHL proteins scaffold cytoskeletal and cell signaling complexes and help regulate gene transcription. FHL proteins are thought to be involved in myoblast migration and elongation as well as sarcomere formation through binding of myosin-binding protein C. In adult myofibers, FHL1 through the calcineurin signaling pathway helps to regulate myoblast fusion, skeletal muscle hypertrophy, and oxidative fiber-type shifting.

Cardiomyopathy is common in patients with FHL1 mutations and FHL1 plays multiple roles in the heart including modulation of conduction through interaction with the potassium channel KCNA5, regulation of cardiac hypertrophy through binding components of the MAPK signaling pathway and detection of mechanical stretch through interaction with the elastic N2B region of titin.

In most patients FHL1 levels are reduced suggesting that loss of normal protein function via reduced FHL1 protein expression of impairment of protein-partner binding may also be important in disease pathogenesis.

EM reveals numerous subsarcolemmal, non–membrane-bound aggregates composed of granulofilamentous and tubular structures, which stain pink with H&E and purple with the modified GT stain. The name "reducing body" was coined when the inclusions were found to have reducing activity when salts are applied to the muscle fiber.

Immunohistochemical analysis has shown features similar to that of aggresomes including perinuclear location and the presence of desmin, ubiquitin, and luminal endoplasmic reticulum chaperone GRP78. Wild-type and mutated FHL1 is also present in the inclusions and the aggregation of these (and other as yet unidentified) proteins may play a role in the pathogenesis of the disease through a toxic gain of function.

The clinical syndrome demonstrates overlapping features include progressive weakness, a rigid spine, scapular winging, and contractures. Cardiomyopathy and respiratory involvement are seen in most subtypes. However, there are also differences in age of onset, distribution, and severity of weakness and rate of progression. [67]

The most severe of the FHL1 myopathies is reducing body myopathy, named because of staining characteristics of intracytoplasmic aggregates. Age of onset varies from infancy to childhood and a few adult cases. In severe cases early-onset motor delay leads to progressive weakness with spine rigidity, early loss of ambulation, and death in infancy or childhood due to respiratory failure. Adult-onset cases present in the third or fourth decade of life with asymmetric proximal and scapuloperoneal weakness, which is slowly progressive. Cardiomyopathy is uncommon. [68]

Other subtypes, include:

  • X-linked dominant scapuloperoneal myopathy presents in the third or fourth decade of life with footdrop, proximal weakness, scapular winging, and cardiomyopathy. Rigid spine and contractures are late features. Men are affected earlier and more severely usually becoming wheelchair bound. [69]

  • X-linked myopathy with postural muscle atrophy presents in the third decade with scapulo-axial-peroneal weakness, atrophy of postural muscles, and bent/rigid spine. Hypertrophy of proximal upper limb muscles gives patients a pseudoathletic appearance. [70]

  • Emery-Dreifuss Muscular Dystrophy presentation is more fully described elsewhere. Typical features include cardiomyopathy and arrhythmia, progressive scapuloperoneal weakness, and contractures of the elbow, ankle, and spine. [71]

  • Rigid spine syndrome has been described in only one patient, a 13-year-old presenting with rigid spine, contractures, proximal weakness, scapular winging, and respiratory involvement. Cardiomyopathy was present. [72]

Why different mutations in FHL1 cause different syndromes is unknown, but mutations causing the more severe reducing body myopathy are often in exons 4/5, whereas mutations in the less severe Emery-Dreifuss muscular dystrophy are in exons 5–8.

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