NOTES AND NEW DEVELOPMENTS

AUTOSOMAL RECESSIVE GENERALIZED MYOTONIA

H. Zellweger, MD, L. Pavone, MD, A. Biondi, MD, V. Cimino, MD, F. Gullotta, MD, M. Hart, MD, V. lonasescu, MD, F. Mollica, MD, and R. Schieken, MD

Abstract: Four cases of autosornal recessive general- ized myotonia are reported. Attention is drawn to the fact that this condition represents a disease entity distinct from the myotonia congenita of Thornsen, which is transmitted as an autosomal dominant trait. The clinical features of the two conditions are similar, apart from minor quantita- tive differences. The family history is the major tool for the differential diagnosis. The possibility of the detection of heterozygotes by electrornyography is discussed.

MUSCLE & NERVE 3~176-180 1980

The exist.ence of an autosomal recessive variety of myotonia congenita has been suspected for half a century.' An extensive survey in West Germany by Becker has yielded conclusive evidence that such a disease entity indeed exists.' Becker separated this variety from autosomal dominant myotonia con- genita (Thomsen disease) and coined the term ro- cessiue generalized mytuniu (RGMy). In contrast to

From the Department of Pediatrics, University of Iowa, Iowa City, IA (Drs. Zellweger. lonasescu, and Schieken), the Clinica Pediatrica, University di Catania. Catania, Sicily, Italy (Drs Pavone and Mollica), the Ospedale Santa Venera, Acireale Sicily, Italy (Drs Biondi and Cimino). the lnstitut f j r Neuropathologie, University of Bonn, Germany (Dr. Gullotta): and the Department of Pathology, University of Iowa. Iowa City, iA (or. Hart).

Address reprint requests to Dr. Zellweger at the Division of Medical Ge- netics. Department of Pediatrics, University Hospitals, Iowa City, IA 52242.

Received for publication April 4, 1979; revised manuscript accepted for publication June 22. 1979

0148-639)(/0302/0176 $00 OOiO 1980 Houghton Mifflin Protessionai Publishers

Thonisen disease, which may occur in several gen- erations, RGMy is generally found in one sibship of one generation only.

Parental consanguinity in the German study was at least 10 times more frequent than in the control population, and such a finding is compati- ble with the existence of an autosomal recessive in- heritance pattern for RGMy. The incidence of RGMy in Germany is about the same as that of Thornsen disease: approximately 1 in 25,000. Lit- tle is known about RGMy in other countries and only a very few cases have been reported from England ,8 France, , 3~12 India, l4 and the United States.".' l 'his paper reports four cases of RGMy, two studied in Sicily and two studied in the United States (Iowa), and emphasizes means to identify persons who are heterozygous for this condition.

CASEREPORTS

Case 1 . W.B., a 15-year-old Caucasian male, pre- sented to the Genetic Clinic of University Hospitals in Iowa City because of hypertrophied skeletal musculature and muscle stiffness.

His parents had noticed an athletic body build when he was about three or four years old. There- after, some muscle stiffness was noted. He had some diffic:ulties in running, but nevertheless par- ticipated in sports. Cold did riot increase his stiff- ness. Cold drinks and ice cream did not affect his swallowing. Muscular weakness was never noted.

At the time of examination at the age of 15 years, height and weight were 165 cm (25th per- centile) and 70 kg (86th percentile), respectively. He had pronounced muscular hypertrophy, par- ticularly of his thighs and calves. There was de- layed relaxation of harid and forearm muscles; percussion myotonia could be elicited in thenar, tongue, arid forearm muscles. N o weakness was noted. The rest of the clinical examination, in- cluding a thorough ophthalmological study, was normal.

176 Generalized Myotonia MUSCLE & NERVE MariApr 1980

Case 2. T.B., the six-year-old sister of case 1, was seen in the same clinic. Her parents had noted stiffness and muscular hypertrophy since the child was four years old.

Physical examination at the age of six years re- vealed height and weight of 119 cm (95th percen- t.ile) and 28 kg (80th percentile), respectively. She showed considerable muscularity, although com- paratively less than her brother. Delayed relaxa- tion of grip and percussion myotonia of thenar, mngue, and forearm niuscles were present. The rest of the clinical examination, including a thorough ophlhalniological study, was normal.

Normal laboratory findings for cases 1 and 2 included serum potassium, plasma protein im- niunoelectrophoresis, electrocardiogram, motor and sensory nerve conduction velocities, and serum creatine kinase (CK). CK isoenzymes showed only MM. In both cases, electromyograms revealed myotonic bursts and prolonged insertion potentials without other abnormalities. Echocar- diogram revealed increased thickness of t.he in- traventricular septum in case 1, but was normal in case 2. Muscle biopsy (vastus lateralis) showed hypertrophy of type 2A fibers arid absence of type 2B fibers in case 1 (fig. lA), but was normal in case 2 , in whom all three fiber types were present (fig. IB).

l h e family history of cases 1 and 2 revealed no evidence of clinical rnyotonia in either parent. Thorough ophthalniological examinations of both parents provided no evidence of dystrophia myotonica, and the plasma protein inimunoelec- trophoresis, serum CK levels, and motor nerve conduction velocities of both were normal. The father’s electrocardiogram and echocardiogram were normal; the mother’s electrocardiogram showed changes compatible with an old myocardial infarction. Her echocardiogram showed a slightly increased thickness of the intravcntricular septum. The electrornyograms of both revealed increased insertional activity, and a run of positive waves suggest.ive of early myotonia (fig. 2).

Case 3. C.T., a five-year-old Sicilian boy, was seen in the Ospedale Santa Venera iri Acireale and re- ferred to the liniversity Hospital in Catariia be- cause of stiff gait. The parents had noted that he had difficulty walking and clinibing stairs when he was two years old. Examination at age five-and- one-half years revealed a pleasant, cooperative boy of normal intelligence and Herculean body build (fig. 3). Height and weight. were 1 18 cm (95th per- centile) and 28 kg (95th percentile), respectively.

Delayed relaxation of fist and percussion myotonia of thenar, tongue, and forearm muscles were rioted. Cold did r i o t affect the myotonia, and intake of ice cream had no effect on swallowing. No mus- cle weakness was rioted. The rest of the physical examination, including ophthalmological exam- iriation, was normal.

Case 4. T.C., the three-year-old sister of case 3, was also examined. When she was one-and-one-half years old, her parents noted the same difficulties they had seen in her brother. Clinical examination at age three years revealed a well-built girl of nor- mal intelligence. Height and weight were 95 cm (90th percentile) and 17.4 kg (95th percentile), re- spectively. There was generalized muscular hyper- trophy and the same myotonic phenonieria as in her brother. The remainder of the physical exam- ination, including ophthalmological examination, was normal.

Normal laboratory studies of cases 3 and 4 in- cluded blood glucose, blood urea nitrogen, serum potassium, calcium, inorganic phosphorus, al- kaline phosphatase, total seru111 protein, protein immunoelectrophoresis, growth hortnone levels after insulin and after arginine, serum CK, and an electrocardiograni. Electromyogram showed typi- cal myotonic changes. Muscle biopsy did not show any light-microscopic, histochemical, or electron- niicroscopic abnormalities in either case.

The parents of cases 3 and 4 were first cousins (fig. 4), and neither showed any evidence of clinical myotonia. Ophthalmological examinations showed no evidence of dystrophia myotonica. Elcc- trornyograrns of both parents showed triyotoriic bursts and increased insertional activity. Several brothers and sisters of both parents were exam- ined, but no abnormal neurological or ophthal- mologid findings appeared.

DISCUSSION

In each of the two families reported here, two siblings showed generalized myotonia without weakness. Absence of myotoriia in other family rnernbers as well as parental consanguinity in one family support the diagnosis of RGMy. The clinical findings of the four patients are compatible with, although riot pathognornoriic: of, that diagnosis. The clinical features of Thomsen disease and RGMy canriot be different,iated, although certain differences can be recognized if large series are studied.‘ These differences are more quantitative than qualitative, and they are of no help in indi- vidual cases. The importance of the family history

Generalized Myotonia MUSCLE & NERVE MarIApr 1980 177

Figure I (A) Muscle biopsy of case 1 Note the complete absence of type 2 8 muscle fibers Forrnol-glycine-ATPase, bar = 50 prn (8) Bfopsy of case 2 Note the presence of type 7 (light staining), 2A (intermediate sta!ning), and 26 (dark staining) fibers Formoi-glycine-ATPase, bar = 50 prn

178 Generalized Myotonia MUSCLE & NERVE Mar/Apr 1980

Figure 2. Run of positive sharp waves foilowing the insertion of the needle (right anterior tibial muscle of the father of cases 7 and 2). Vertical bar = 700 mV; horizontal bar = 1 msec. (Courtesy of Dr. J. Kimura.)

I

I t

I l l

I V

cases 3 4

f igure 4. Abbreviated pedigree of cases 3 and 4 . The parents of the probands are first cousins.

for the differential diagnosis between Thomsen disease and RGMy should be emphasized.

Dyst.rophia myotonica or myotonia atrophica did not enter seriously into diagnostic considera- tions for these patients. The absence of cataracts and other ocular manifestations such as low in- traocular tension, a shift of retinal pigment, ab- normal electrorelinogram, arid pupillary myo- tonia-and the absence of abnormal conduction in the electrocardiogram, rncntal retardation, frontal balding, and low levels of immuno- globulins-were evidence against that diagnosis.

I t is well known that some patients with myo- tonia show initial weakness when a muscle be- gins to be e~erc ised .~ This weakness is transient and subsides after a few contractions. It occurs in both Thomsen disease arid KGMy, yet it is more

Figure 3. Case 3 : herculean body bui/d with excessive muscular hypertrophy.

frequent in the latter. In earlier years, this phe- nomenon has confused the strict distinction be- tween the myotonias on one hand and paramyo- tonia and dystrophia myotonica on the other.4 None of our four patients had ever shown any weakness.

The electromyograms of the four patients were typical for myotonia and did not show “myopathic” features. The muscle biopsies were normal in cases 2,3, and 4; but in case 1, the oldest of the four pa- tients, type 2B fibers were completely abserit.’” Re- duction of type 2B fibers can be seen in various myopathies, including limb-girdle dystrophy and dystrophia myotonica.6 Absence of these fibers has been found only in Thornsen disease arid in RGMy;’ although i t is not found in all cases.”

The echocardiographic finding of increased veritricular septa1 thickness in case 1 and in his mother is interesting. The interventricular thick- ness of the left ventricular posterior wall did not exceed the normal thickness by more than 30%; nor was there evidence of left-ventricular out- flow-tract obstruction or hypercontractility as

Generalized Myotonia MUSCLE & NERVE Mar:Apr 1980 179

might be expected in an obstructive cardiomy- opathy.Y Although there may be myocardial tis- sue abnormalities which result in septal hyper- trophy, the usual findings of cardiomyopathy were absent. Additional echocardiographic investiga- tions to evaluate the diagnost,ic significance of in terventricular-septurn thickness for RCMy and het.erozygous gene carriers may indeed be worth- while.

An interesting Finding was the discovery of electrornyographic activity suggestive of rnyotonia in the four parents. Similar observations were re- ported by Becker.' Some het.erozygotes show inyotonic bursts, others show only increased inser- tional activities, and some have no electromyo- graphic change.2.R 71hus, the absence of the above electromyographic changes does not rule out heterozygosity, while their presence in the EMG of parents of RGMy paticnts represents laboratory evidence of the carrier state. Whether or not EMG changes without clinical myotonia occur in the par- ent of a patient with 'Thornsen disease who carries the dominant mutant gene is not known. If no myotonic changes are found in the EMGs of either parent of a patient. with sporadic myotonia, it could be either a spont.aneous mutation of Thomsen dis- ease or an RGMy, since clinical and electrophys- iologic differentiation of the two conditions is of- ten impossible.

It should be mentioned that chcniical distinc- tion may be possible. Kuhn and SeilerLo found that

the fatty acid pattern in the phosphatides of RGMy is normal and differs from that of Thornsen dis- ease. Differences hetwecri RGMy and Thornsen disease also seem to exist with respect to the trans- port of calcium by sarcoplasmic reticulum."

If more than one offspring of normal parents with normal EMGs are affected, RGMy is the more plausible diagnosis, since the occurrence of the same dominant mutalion in rriore than one sibling is most unlikely in Thomsen disease.

We advocate EMG examination in both parents of a patient with sporadic myotonia. 'The presence of increased insertion activity, myotonic bursts. or both in the parents would help t o ascertain the diagnosis of RGMy in the proband. This could help in arriving at a prognosis and in genetic c-oun- seling of the proband. ?'he myotonia congenita of Thorrisen, present at hirth or early childhood, has a tendency to remain stationary, while the myotonia in RGMy has a tendency to worsen dur- ing adolescence, remaining stationary thereafter. With regard to genetic counseling, RGMy in the offspring would occur only if the mating partner were homozygous (affected) or heterozygous (gene carrier) for the same mutant gene. In the former situation, all offspring would be homo~ygous and affected. In the latter situation, the risk of an af- fected offspring would be 50%. However, the gene frequency ( 1 : 80) is not of sufficient magnitude that such mating is likely to occur, if consanguine- ous mating is precluded.

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