Myotonic Syndromes and Periodic Paralysis Syndromes 269
	bowel function, cardiomyopathy, pulmonary involve-	Rarer Types of Muscular Dystrophy
	ment, diabetes, testicular atrophy, and infertility are all
	possible manifestations of the disease.	Congenital muscular dystrophies are a heterogeneous
	Diagnosis. The diagnosis can be made tentatively based	group of diseases characterized by dystrophic changes
		in muscle fibers that are present at birth and then either
	on the typical clinical features and the demonstration of	remain constant or slowly progress. Muscular dystrophy
	myotonic discharges in the EMG. It is confirmed by	that has already exerted its effects in prenatal life pre-
	genetic testing.	sents in the newborn with arthrogryposis multiplex, i. e.,
	Prognosis. The life expectancy is markedly lowered;	fixed, abnormal positions of the joints.
	most patients die around age 50.	Oculopharyngeal dystrophy is a disease of autosomal
		dominant inheritance that first becomes evident in
	Congenital Myotonic Dystrophy	middle age. The initial signs are progressively severe
		ptosis and restriction of eye movements, without di-
	This disease is due to a genetic defect involving a very
		plopia. Later, dysphagia develops, which may be life
	large trinucleotide expansion (more than 2000 copies).	threatening. Other muscle groups are sometimes paretic
	It is usually passed on from mothers to their children,	as well. This condition requires diagnostic differentia-
	particularly when the mother already possesses a long	tion from myasthenia gravis (p. 275) and Kearns−Sayre
	expansion. The affected individuals suffer from birth	syndrome (p. 273).
	onward from dysphagia and weakness of drinking, flac-
	cid facial muscles, a high palate, mental retardation, and
	other signs like those of Curschmann−Steinert myotonic
	dystrophy.

Myotonic Syndromes and Periodic Paralysis Syndromes

These inherited muscle diseases belong to the group of so-called channelopathies: they involve abnormalities of the chloride, sodium, or calcium channels in the muscle fiber membrane. They are caused by a variety of different genetic defects and manifest themselves clinically either with myotonia (delayed relaxation of muscle after active contraction) or with episodic paralysis.

Table 14.4 provides an overview of the major types of channelopathy. A selection of these will be discussed in the following paragraphs.

Table 14.4 Myotonias and periodic paralyses (“channelopathies,” channel diseases)

Type	Inheritance	Chromo-	Missing or	Incidence	Age of	Clinical features	Prognosis
	pattern	somal or	abnormal	(i. e.,	onset
		genomic	gene pro-	frequency
		defect	duct	with respect
				to live
				births)
Myotonia	autosomal	7q35	abnormal	1/23 000	early in 1st	generalized myotonia	stable,
congenita,	dominant		chloride		decade		nonprogressive
Thomsen type			channels
Myotonia	autosomal	7q35	abnormal	1/23 000−	end of 1st	generalized myotonia	stable,
congenita,	recessive		chloride	1/50 000	decade		nonprogressive
Becker type			channels
Myotonia fluctu-	autosomal	17q23−25	abnormal	very rare	1st decade;	generalized, myo-	nonprogressive
ans, myotonia	dominant		sodium		myotonia	tonia fluctuans only
permanens,			channels		fluctuans in	episodic, other types
acetazolamide-					adolescence	severe, potassium
sensitive myo-						loading worsens
tonia						myotonia, aceta-
						zolamide-sensitive
						myotonia is painful
							Continued

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270	14 Diseases of Muscle (Myopathies)
		Tabelle 14.4 Myotonias and periodic paralyses (“channelopathies,” channel diseases) (Continued)
		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)
		Paramyotonia	autosomal	17q23−25	abnormal	very rare	1st decade	generalized myotonia	persistent, tendency
		congenita of	dominant		sodium			induced by cold and	to improve over
		Eulenburg			channels			worsened by exer-	time
								tion, occasionally
								combined with para-
								myotonic and hyper-
								kalemic paralyses
		Hyperkalemic	autosomal	17q23−25	abnormal	very rare	1st decade	paralysis occurring	persistent, often im-
		periodic paralysis	dominant		sodium			on fasting, or rest	proves over time.
					channels			after physical activity	Permanent myo-
									pathy and weakness
									are less severe than
									in hypokalemic para-
									lysis
		Hypokalemic	autosomal	1q31−32	abnormal	very rare	age 5−30,	paralysis occurring	persistent, often
		periodic paralysis	dominant		calcium		usually in	after carbohydrate	slowly developing
					channels		2nd decade	consumption or	permanent myo-
								physical activity	pathy and weakness

Fig. 14.8 Thomsen congenital myotonia in a 20-year-old man. The patient is of athletic build and has normal muscle strength, but active muscle contraction during the physical examination is followed by marked myotonia. (From: Mumenthaler M.: Didaktischer Atlas der klinischen Neurologie. 2nd edn, Springer, Heidelberg 1986.)

Diseases Mainly Causing Myotonia

Congenital Myotonia

Congenital myotonia has both dominant (Thomsen) and recessive (Becker) forms. Both are due to a genetic defect on chromosome 7q35 that impairs the transporting ability of chloride channels.

Clinical manifestations. The most prominent manifestation is myotonia, i. e., markedly slowed muscle relaxation after active contraction. A tightly grasped object can be let go again only after a delay. The patient cannot make any sudden movements, but the movements do become more fluid after a few attempts (the warming-up phenomenon). Raw muscle strength may be transiently diminished after a powerful contraction (= myotonic paralysis) but is otherwise normal. There is no atrophy; on the contrary, patients often have a markedly athletic habitus (Fig. 14.8). In the Becker form, the myotonic manifestations are more severe and mild distal atrophy may be present in the late stage of the disease.

Diagnostic evaluation. Tonic muscle relaxation and transient indentations of muscle, the key features of myotonia, can be seen after a contraction induced by a tap or electrical stimulation of the muscle (Fig. 14.9). The diagnosis is confirmed by the typical electromyographic findings (Fig. 14.10).

Treatment. Antiarrhythmic drugs such as procainamide and mexitil, antiepileptic drugs such as phenytoin, or acetazolamide can be used.

Prognosis. The prognosis is favorable, in that the severity of disease manifestations tends to lessen over the years and the life expectancy is normal.

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Myotonic Syndromes and Periodic Paralysis Syndromes

Other Diseases with Myotonic Manifestations

Other diseases with myotonic manifestations are listed in Table 14.4. Curschmann−Steinert myotonic dystrophy is described above on p. 268; a few more rare diseases are described in the following paragraphs.

Proximal myotonic myopathy (PROMM). In this disease, mainly proximal muscle atrophy (particularly of the thigh muscles) is accompanied by mild myotonia. Cardiac arrhythmias and cataracts may also be present. The progression of the disease, and the impairment that it causes, are mild. The responsible gene is located on chromosome 3q.

Neuromyotonia is also known as the syndrome of continuous muscle fiber activity and as Isaacs syndrome. Its characteristic feature is continuous stiffness of the musculature, with myokymia. The patient’s movements are correspondingly viscous. The EMG reveals continuous spontaneous muscle activity. This disease can arise at any age and is thought to be due to an autoimmune process. Antiepileptic drugs are an effective form of treatment, as is plasmapheresis in some patients.

“Stiff man” syndrome is also characterized by continuous muscle fiber activity, as revealed by EMG. The muscles are stiff and subject to painful spasms, which worsen in response to external stimuli and emotional stress. The disease manifestations progress slowly over months or years. Here, too, the pathogenesis is thought to be autoimmune. Effective treatments include diazepam, antiepileptic drugs, baclofen, and immunoglobulins.

Diseases Causing Periodic

Paralysis

The genetically determined periodic paralyses are characterized by suddenly arising abnormalities of the serum potassium concentration leading to transient inexcitability of the muscle fiber membrane and therefore to muscle dysfunction. They share the following clinical features:

episodes of paralysis of sudden onset, of varying severity and duration, which may last for hours to days;

usually, sparing of the facial and respiratory muscles;

in some patients, permanent muscle weakness later on in the course of the disease.

There are normokalemic, hyperkalemic, and hypokalemic types (Fig. 14.4). We will describe only the lastnamed type here as a paradigmatic example.

Hypokalemic Periodic Paralysis

Pathogenesis. This is a disease of autosomal dominant inheritance caused by dysfunction of the dihydropy- ridine-sensitive calcium channels in the transverse tubular system of muscle fibers. These channels are encoded by a gene on chromosome 1q31−32. The disease has higher penetrance in men.

Fig. 14.9 Myotonic reaction of the tongue musculature in Steinert myotonic dystrophy. Repeated tapping of the edge of the tongue (here, the left edge) produces a lasting indentation. (From: Mumenthaler M.: Didaktischer Atlas der klinischen Neurologie. 2nd edn, Springer, Heidelberg 1986.)

0.1mV

0.5s

muscle percussion

Fig. 14.10 Electromyogram in a 29-year-old woman with Steinert myotonic dystrophy. Tapping on the thenar muscles evokes long-lasting high-frequency electrical activity, whose amplitude dies down slowly.

Clinical manifestations. The initial paralytic attacks occur between the ages of five and 30, usually in the second decade of life. Their frequency is highly variable, ranging from daily attacks in some patients to a few attacks per year in others. Each attack lasts from a few hours to an entire day.

Diagnostic evaluation. The CK is usually normal. The EMG during an attack reveals only a few low-voltage potentials, or none at all. There are flat T and U waves in the ECG. Rare symptomatic (nonfamiliar) cases have been described in persons with hypothyroidism.

Treatment. The prognosis of each individual attack is good. The frequency of attacks can be reduced by a lowsalt and low-carbohydrate diet, as well as by potassium supplementation. Intravenous administration of potassium shortens the duration of an attack.

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