Muscular Dystrophies 265

Muscular Dystrophies

The muscular dystrophies are genetically determined. They typically present with symmetric muscle weakness, which is at first either mainly proximal or mainly distal, and which slowly worsens over the years. The chronically progressive weakness is not accompanied by pain or by any sensory deficit. The muscles usually become atrophic, though this is masked, in some patients, by intramuscular deposition of fatty tissue (pseudohypertrophy). Connective tissue deposition can

lead to muscle shortening and contractures. The reflexes are diminished or lost. Weakness produces characteristic postural abnormalities and deformities, e. g., to lumbar hyperlordosis (a common finding), Duchenne or Trendelenburg gait (p. 15), winging of the scapula, or scoliosis.

Table 14.3 provides an overview of the various types of muscular dystrophy. The major types are described in detail in the following paragraphs.

Table 14.3 The muscular dystrophies

Type	Inheritance	Chromo-	Missing or	Incidence	Age of onset	Clinical features	Prognosis
	pattern	somal or	abnormal	(i. e.,
		genomic	gene	frequency
		defect	product	with respect
				to live births)
Duchenne	X-linked,	Xp21.2	dystrophin	20−30/	2nd−3rd year	onset in pelvic	rapidly progres-
	30 % sporadic		absent	100 000 boys		girdle, pseudo-	sive, most patients
						hypertrophy of	die by age 25
						calves
Becker	X-linked	Xp21.2	dystrophin	3/100 000	1st(−4th) decade	same as in	ambulatory till age
			abnormal	boys		Duchenne muscu-	15 or later, death
						lar dystrophy, but	in 4th or 5th de-
						milder; sometimes	cade or later
						cardiomyopathy
Emery−Dreifuss	X-linked, rarely	Xp28	emerin	1/100 000	childhood,	scapuloperoneal	ambulatory till 3rd
	autosomal				adolescence	dystrophy, con-	decade or for en-
	dominant					tractures, and car-	tire life; cardiac
						diopathy may be	arrhythmia a
						prominent	frequent cause of
							death
Facioscapulo-	autosomal	4q35	homeobox	5/100 000	childhood to	weakness of facial,	practically normal
humeral dystro-	dominant		gene		young adulthood	shoulder girdle,	life expectancy
phy (Duchenne−						and calf muscles
Landouzy−
Dejerine)
Scapulo-	autosomal	unknown	unknown	rare	childhood to	weakness of	usually normal life
peroneal	dominant,				adulthood	shoulder girdle	expectancy
dystrophy	autosomal re-					and dorsiflexors of
	cessive, or					the feet and toes
	sporadic
Limb girdle	autosomal	5q, 13q,	unknown	rare	childhood to	mainly proximal	depending on
dystrophy	recessive,	15q			adulthood	weakness of pelvic	type, premature
	autosomal					or shoulder girdle	death or only
	dominant,						minor disability
	or sporadic						into old age
Distal	autosomal	unknown	unknown	rare	middle age	mainly distal atro-	only minor disabil-
myopathies	dominant					phy and weakness	ity into old age
(Welander type,
Markesbery−
Griggs, Finnish
variant)
Distal	autosomal	Miyoshi:	unknown	rare	adolescence to	mainly distal	progression to
myopathies	recessive	2p12−14			young adulthood	weakness	inability to walk
(Nonaka and		Nonaka:
Miyoshi types)		unknown
							Continued

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Diseases of Muscle

14

266	14 Diseases of Muscle (Myopathies)
		Table 14.3 The muscular dystrophies (Continued)
		Type	Inheritance	Chromo-	Missing or	Incidence	Age of onset	Clinical features	Prognosis
			pattern	somal or	abnormal	(i. e.,
				genomic	gene pro-	frequency
				defect	duct	with respect
						to live births)
		Oculopharyn-	autosomal	unknown	unknown	rare	middle age	oculofaciobulbar	often premature
		geal dystro-	dominant					paresis	death due to dys-
		phies							phagia and aspira-
									tion pneumonia
		Congenital	autosomal	unknown	unknown	rare	at birth	depending on	ranging from mild
		dystrophies	recessive					type: involvement	disability to severe
		(for variants,						of muscles, eyes,	mental retardation
		see text)						and brain; contrac-
								tures, arthrogrypo-
								sis multiplex
		Steinert	autosomal	19q13.3	protein	13.5/100 000,	young adult-	mainly distal	age of significant
		myotonic	dominant		kinase	prevalence	hood, rarely con-	weakness,	disability depends
		dystrophy				5/100 000	genital, earlier	faciobulbar pare-	on age of onset,
							age of onset in	sis, myotonia, cat-	usually middle age;
							each successive	aracts	premature death
							generation
							(“anticipation”)
		Proximal	autosomal	unknown	unknown	0.5/100 000	3rd and 4th de-	mainly proximal	disability in old age
		myotonic	dominant				cades, some-	weakness, myo-
		myopathy					times earlier	tonia, and cata-
		(PROMM)						racts

Fig. 14.3 Duchenne muscular dystrophy in a 10-year-old boy. a Lateral view: note the lumbar lordosis and pseudohypertrophic calves. b When the child walks, the trunk inclines to the side of the stationary leg (Duchenne limp). (From: Mumenthaler M.:

Didaktischer Atlas der klinischen Neurologie. 2nd edn, Springer, Heidelberg 1986.)

a		b

Hereditary Muscular Dystrophies

of X-chromosomal Inheritance−

Dystrophinopathies

The diseases in this group are caused by a genetic defect on chromosome Xp21.2. They are, therefore, almost exclusively seen in boys whose mothers are (healthy) carriers. Dystrophin, a structural protein of the muscle fiber membrane that is also expressed in the brain, is present in reduced amounts or completely absent.

Duchenne Muscular Dystrophy

Clinical manifestations. Boys develop the first signs of the disease in the first decade of life, usually in the preschool years. The conspicuous abnormalities at first are difficulty climbing stairs, hyperlordosis of the lumbar spine, and waddling gait (Fig. 14.3). Over the next few years, weakness becomes progressively severe in the proximal muscles of the lower limbs and then of the upper limbs as well. The affected boys can stand up from a squatting position only by climbing up their own legs with their hands and arms (Gowers sign, Fig. 14.4). Fat

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Muscular Dystrophies 267

deposition leads to pseudohypertrophy of the calves. The waddling gait is due to bilateral hip adductor weakness (Duchenne or Trendelenburg gait, p. 15).

Diagnostic evaluation. The CK is markedly elevated in the initial stages of the disease. The absence of dystrophin can be demonstrated by muscle biopsy with special tissue staining (Fig. 14.5).

Prognosis. The disease progresses relatively rapidly, rendering the affected boys unable to walk in the second decade of life. The scoliosis worsens and causes respiratory difficulty. The cardiac muscle is also affected, though usually not to any clinically evident extent. As dystrophin is expressed in the brain, most of the affected boys are mentally retarded. They usually die of respiratory insufficiency or secondary complications between the ages of 18 and 25.

Becker Muscular Dystrophy

This type of muscular dystrophy is about one-tenth as common as the Duchenne type. Dystrophin is not wholly absent, but is expressed in reduced amounts (Fig. 14.5). The affected boys show the first signs of the disease in the first or second decade; the progression is much slower than in the Duchenne type. Many patients are still able to walk after age 30, but most die in their fourth or fifth decade of life. The EMG and laboratory findings are similar to those of Duchenne muscular dystrophy.

Autosomal Muscular Dystrophies

The genetic localization of the autosomal muscular dystrophies is known in most patients, though the gene products are not. We will only describe the more common forms here.

a

b

Fig. 14.5 Dystrophin stain. a Normal skeletal muscle. Regular, homogeneous distribution of dystrophin on the inner surface of the sarcolemma of each muscle fiber (black contours). b Duchenne dystrophy. Dystrophin is absent. c Becker dystrophy. Dystrophin is ex-

Fig. 14.4 Gowers sign in Duchenne muscular dystrophy. This 7- year-old boy stands up by climbing up his own thighs. (From: Mumenthaler M.: Didaktischer Atlas der klinischen Neurologie. 2nd edn, Springer, Heidelberg 1986.)

Facio-Scapulo-Humeral Type

This is a disease of autosomal dominant inheritance due to a genetic defect in the 4q35 region of chromosome 4, near the telomere. It begins in the second or third decade of life with weakness of the facial and shoulder girdle musculature (eye closure, whistling; raising the arms) (Fig. 14.6). Sensorineural deafness is often present as well. The muscles of the pelvic girdle and the distal muscles of the limbs are not affected until later decades. The life expectancy is normal.

Diseases of Muscle

14

c

pressed to a varying extent on the individual muscle fibers, in diminished quantity and abnormal distribution; in some fibers, it is not expressed at all. The presence of dystrophin—albeit in subnormal amounts—distinguishes Becker from Duchenne dystrophy.

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268 14 Diseases of Muscle (Myopathies)

a

b

Fig. 14.6 Facio−scapulo−humeral muscular dystrophy in a 37- year-old man. A photograph of the face (a),reveals weakness of the orbicularis oris m., because of which the patient cannot whistle. A rear view of the upper body (b), shows the protruding scapulae. The patient cannot raise his arms laterally above a horizontal line. (From Mumenthaler, M., in Hornbostel H., Kaufmann W., Siegenthaler W.: Innere Medizin in Praxis und Klinik, vol. II, 4th edn, Thieme, Stuttgart 1992, cf. Fig. 14.1)

Limb Girdle Types of Muscular Dystrophy

This is a genetically heterogeneous group of diseases: the inheritance pattern is autosomal dominant for some, autosomal recessive for others. Causative genetic defects have been found on chromosomes 5q, 13q, and 15q. The onset of disease can be in childhood or in adulthood. The first sign is always mainly proximal weakness of the muscles of either the shoulder girdle or the pelvic girdle; over time, the other limb girdle is affected as well (ascending vs. descending type). The prognosis is highly

Fig. 14.7 Steinert myotonic dystrophy in a 28-year-old man. Note the flaccid facial features and sunken temples (myopathic facies) and the predominantly distal muscle atrophy in the limbs, particularly the lower limbs. (From: Mumenthaler M.: Didaktischer Atlas der klinischen Neurologie. 2nd edn, Springer, Heidelberg 1986.)

variable: some patients experience rapid progression of the disease within one or two decades, while others live on into old age with hardly any impairment.

Myotonic Dystrophy of Curschmann−Steinert

Type

Epidemiology. This is the most common myopathy of adulthood (see also Table 14.3).

Etiology. This is a disease of autosomal dominant inheritance due to an unstable CTG trinucleotide sequence expansion in a gene on chromosome 19q13.3. Clinical manifestations arise when the sequence contains more than the usual five to 30 trinucleotide repeats. The expansion lengthens from generation to generation when transmitted in the maternal line; this explains the onset of the disease at an earlier age in each successive generation (anticipation).

Clinical manifestations. Muscle involvement is the most prominent sign. Weakness of the facial and distal limb muscles usually becomes apparent in young adulthood. The face develops a typical “tired” appearance with sunken temples, mild ptosis, and loose folds around the often slightly open mouth (myopathic facies, cf. Fig. 14.7). Weakness and atrophy of the dorsiflexors of the feet produce a steppage gait. Myotonia is a striking phenomenon that may appear in a very early stage of the disease: after the patient firmly grips an object, he or she has difficulty letting it go. Delayed muscle relaxation can also be demonstrated after a sharp blow to a muscle (e. g., tongue, ball of the thumb). Other organs, too, are affected: early cataracts, dysphagia, sluggish

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