Type Inheritance Locus Gene Clinicopathologic Features

1A Autosomal-dominant 5q31 Myotilin Onset in adult life with slow progression of limb weakness, but sparing of facial

muscles; dysarthric speech

1B Autosomal-dominant 1q21 Lamin A/C Onset before the age of 20 years in lower limbs, progression during many years with

cardiac involvement

1C Autosomal-dominant 3p25 Caveolin-3 (M-caveolin) Onset before the age of 20, clinically similar to type 1B

1D Autosomal-dominant 7p Unknown Limb girdle muscle weakness, adult onset

2A Autosomal-recessive 15q15.1-21.1 Calpain 3 Onset in late childhood to middle age; slow progression during 20–30 years

2B Autosomal-recessive 2p13.3-q13.1 Dysferlin Mild clinical course with onset in early adulthood

2C Autosomal-recessive 13q12 g-Sarcoglycan Severe weakness during childhood, rapid progression; dystrophic myopathy on muscle

biopsy

2D Autosomal-recessive 17q21 a-Sarcoglycan (adhalin) Severe weakness during childhood, rapid progression; dystrophic myopathy on muscle

biopsy

2E Autosomal-recessive 4q12 b-Sarcoglycan Onset in early childhood, with Duchenne-like clinical course

2F Autosomal-recessive 5q33 d-Sarcoglycan Early onset and severe myopathy; dystrophic myopathy on muscle biopsy

2G Autosomal-recessive 17q11-q12 Telethonin Distal weakness with limb-girdle weakness in late childhood to adulthood; rimmed

vacuoles in muscle cells

2H Autosomal-recessive 9q31-q34.1 Tripartite motifcontaining

protein 32

(TRIM32)

Limb-girdle and facial weakness with onset in childhood, mild, slowly progressive

course

feature of anticipation. Expansion of the trinucleotide repeat influences the eventual level of protein product.

The pathologic features of the disease relate only in part to altered DMPK function. RNA that contains trinucleotide repeat expansions can directly affect splicing of other RNAs,

including those for the ClC-1 chloride channel.[55] A second form of myotonic dystrophy is associated with untranslated CCTG expansion in a gene called ZNF9 on chromosome 3.[56]

Morphology.

Skeletal muscle may show variation in fiber size. In addition, there is a striking increase in the number of internal nuclei, which on longitudinal section may form conspicuous chains.

Another well-recognized abnormality is the ring fiber, with a subsarcolemmal band of cytoplasm that appears distinct from the center of the fiber. The rim contains myofibrils that are

oriented circumferentially around the longitudinally oriented fibrils in the rest of the fiber. The ring fiber may be associated with an irregular mass of sarcoplasm (sarcoplasmic mass)

extending outward from the ring. These sarcoplasmic masses stain blue with hematoxylin and eosin, red with Gomori trichrome, and intensely blue with the nicotinamide adenine

dinucleotide-tetrazolium reductase (NADHTR) histochemical reaction. Histochemical techniques have demonstrated a relative atrophy of type 1 fibers early in the course of the disease

in some cases. Of all the dystrophies, only myotonic dystrophy shows pathologic changes in the intrafusal fibers of muscle spindles, with fiber splitting, necrosis, and regeneration.

Clinical Course.

The disease often presents in late childhood with abnormalities in gait secondary to weakness of foot dorsiflexors and subsequently progresses to weakness of the hand intrinsic muscles

and wrist extensors. Atrophy of muscles of the face and ptosis ensue, leading to the typical facial appearance. Cataracts, which are present in virtually every patient, may be detected

early in the course of the disease with slit-lamp examination. Other associated abnormalities include frontal balding, gonadal atrophy, cardiomyopathy, smooth muscle involvement,

decreased plasma immunoglobulin G, and an abnormal glucose tolerance test response. Dementia has been reported in some cases.

ION CHANNEL MYOPATHIES (CHANNELOPATHIES)

The ion channel myopathies, or channelopathies, are a group of familial diseases characterized clinically by myotonia, relapsing episodes of hypotonic paralysis (induced by vigorous

exercise, cold, or a high-carbohydrate meal), or both. Hypotonia variants associated with elevated, depressed, or normal serum potassium levels at the time of the attack are called

hyperkalemic, hypokalemic, and normokalemic periodic paralysis, respectively.

Pathogenesis.

As their name indicates, at the molecular level these diseases are caused by mutations in genes that encode ion channels.[57] [58] Hyperkalemic periodic paralysis results from mutations

in the gene that encodes a skeletal muscle sodium channel protein (SCN4A), which regulates the entry of sodium into muscle during contraction. The gene for hypokalemic periodic

paralysis encodes a voltage-gated calcium channel.

TABLE 27-6-- Congenital Myopathies

Date: 2016-04-22; view: 595