Arq. NeuroPsiquiatr. vol.34 número3

Volume 34 - N . ° 3

Setembro de 1976

FAMILIAL MYASTHENIA GRAVIS

R E P O R T O F F O U R C A S E S

JOSÉ LAMARTINE DE ASSIS * MlLBERTO SCAFF * *

Myasthenia gravis ( M G ) is considered a noninherited, sporadic and un-common disease 5

>1 2

. T h e familial occurrence of M G is very rare according to most authors 2

> 3 . 4

> 5 . 6

.13 .14

.11 .

A m o n g 145 patients with M G followed up in the last 20 years in the Neurological Clinic of the University of São P a u l o Medical School, two pairs of siblings from two families without parental involvement w e r e studied. O u r cases are the first in Brazil, considering the best of our knowledge.

R E P O R T O F C A S E S

C A S E 1 — A 11-year-old w h i t e B r a z i l i a n girl h a d b i l a t e r a l a n d symmetric partial ptosis, noted since the first months of a g e by h e r parents. H e r upper lids drooped more a t the end of the day. Difficulty for looking f a r , frequent falls d u r i n g the g a i t and a n inconstant a n d transient d o u b l e vision w e r e referred. T h e patient w a s born after n o r m a l pregnancy, labor, a n d delivery. T h e fetal movements h a v e been normal. Crying a n d sucking w e r e n o r m a l in the nursery. T h e deve-lopmental history is n o r m a l . She h a d measles a n d v a r i c e l l a . T h e parents a r e in good health a n d without consanguinity. H e r brother is affected w i t h the same disease (case 2 ) . Clinical e x a m i n a t i o n w a s n o r m a l . N o m e n t a l a b n o r m a l i t y w a s observed. N e u r o l o g i c a l findings consisted in ptosis of both eyelids, w i t h partial external ophthalmoparesis. T h e pupils w e r e round, r e g u l a r , a n d e q u a l a n d reacted to light b u t not in accommodation. B i f a c i a l w e a k n e s s w a s present, resulting in a n incomplete oclusion of the eyes. T h e h e a d w a s held slightly f o r w a r d . T h e r e was* widespread m u s c u l a r weakness, p a r t i c u l a r l y in the p r o x i m a l l i m b - g i r d l e . T h e muscle w e a k n e s s w a s r a p i d l y increased b y exercise ( F i g . 1, left s i d e ) . Other findings w e r e n o r m a l . L a b o r a t o r y investigations a n d R o e n t g e n studies of the chest w i t h p l a n i -g r a p h y w e r e normal. T h e electromyo-graphic study of the orbicularis oculi muscles showed the characteristic response of M G ( F i g . 2 ) . T h e edrophonium chloride

injected intravenously produced objective improvement of the o c u l a r symptomatology. F o l l o w i n g the injection the patient felt a n intense pain into the eyes. Identical symptom w a s referred d u r i n g the treatment w i t h prostigmine b y oral route. This treatment produced a m a r k e d improvement of the muscle w e a k n e s s of the limbs but not of the o c u l a r muscle. Immunoelectrophoresis of the s e r u m proteins w a s normal. T h y r o i d tests w e r e normal.

C A S E 2 — - A 7-year-old white B r a z i l i a n boy, brother of case 1, h a d b i l a t e r a l a n d symmetric p a r t i a l ptosis, noted since the first months of a g e b y his parents. Generalized muscle w e a k n e s s w a s only noted some time later. T h e disability w a s w o r s e t o w a r d s the evening, w h e n the ptosis w a s also more prominent. A prolonged conversation produced a f a d i n g voice ( n a s a l s p e e c h ) . Sometimes the patient pre-sented a difficulty in c h e w i n g a n d s w a l l o w i n g . B i r t h a n d d e v e l o p m e n t a l history w e r e n o r m a l ( c a s e 1 ) . T h e mother w a s w e l l d u r i n g p r e g n a n c y . T h e fetal m o -vements h a v e been n o r m a l . L a b o r w a s n o r m a l a n d no a b n o r m a l i t y occurred a t birth. H e w a l k e d a t the a g e of one year a n d half. M e a s l e s a t four years of a g e f o l l o w e d by hypoacusis. T h e physical e x a m i n a t i o n showed only a testicular defect (atopic g l a n d s ) . N o m e n t a l r e t a r d a t i o n w a s noted. T h e n e u r o l o g i c a l examination showed a g l o b a l m u s c u l a r hipotonia, a light w e a k n e s s in the four limbs, specially in its p r o x i m a l parts, e x t e r n a l ophthalmoparesis in both sides, a n d a b i l a t e r a l and symmetric w e a k n e s s of the orbicularis oculi muscles. T h e r e w a s no convergence. B i l a t e r a l a n d symmetric ptosis w a s seen ( F i g . 1, r i g h t s i d e ) . O t h e r findings w e r e normal. L a b o r a t o r y investigation a n d R o e n t g e n studies of the chest w e r e n o r m a l . T h e electromyographic study of the o r b i c u l a r i s oculi muscles showed the same myasthenic disorders as observed in case 1. F o l l o w i n g the i n t r a v e n o u s administration of edrophonium cloride there w a s prompt a n d transient relief of symptoms a n d restoration of o c u l a r movements a n d d i s a p p e a r a n c e of ptosis; the treatment w i t h prostigmine b y o r a l route promoted a n i m p r o v e m e n t of the muscle w e a k n e s s b u t not of the ophthalmoparesis. T h e immunoelectrophoresis of s e r u m proteins w a s normal. T h y r o i d tests w e r e n o r m a l .

activity ( F i g . 4, left s i d e ) ) . T h e immunoelectrophoresis of serum proteins w a s n o r m a l . T h e treatment w i t h prostigmine by oral route w a s f o l l o w e d by impro-vement of the m u s c u l a r w e a k n e s s in the limbs b u t not of the ophthalmoparesis.

D I S C U S S I O N

Only 4 among 145 patients with M G have presented familial

characteris-tics. One of them (case 3) has been followed up for 12 years. T h e

rarity of familial M G has been emphasized by many authors

.

>

>

.

.

. In

our group the incidence of familial M G (2.7%) is in agreement with the

incidence in other s e r i e s

. These findings confirm the low frequency in

regard to the incidence of M G in the general population, which is estimated

from 1 in 10,000 to 1 in 40,000 p e r s o n s

,

. T h e familial incidence of M G

really is rare, with 65 cases reported in 29 families in the medical literature

between 1900 and 1 9 6 4

.

. Until 1966 about 80 cases w e r e reported in 36

families. In 1971, N a m b a et a l .

reported 164 patients in 73 families,

this incidence being, greater than in the general population ( P < 0.001).

T h e r e w a s no geographic or racial predilection of familial M G

.

T h e four cases reported in this paper represent two pairs of sibling

of both sexes in two families. T h e parents are healthy and not

consan-guineous. N o other members of the immediate or near family are similarly

affected. Consanguinity is u n c o m m o n

-

.

; except one case

all the other

cases w e r e born of nonmyasthenic m o t h e r

.

. This is in contrast to

tran-sient neonatal myasthenia which invariably occurs in infants born of

myas-thenic mothers.

T h e majority of familial occurrences are in sibships, particularly in

monozygotic twins, or cousins of first g e n e r a t i o n

.

. I t is very rare to

detect the disease in two generations of the same f a m i l y

.

. Until 1969

there w e r e only 7 families involving t w o g e n e r a t i o n s

.

. There are no

reports of three generations being a f f e c t e d

.

, until 1973. There weren't

other cases of M G in near relatives in the families of our patients.

T h e symptomatology w a s noted during the first f e w months after birth

in our cases. T h e prominent symptom w a s a bilateral partial ptosis of

the eyelids. In all cases the pregnancy and labor w e r e normal. T h e fetal

movements w e r e apparently normal at least in two cases (cases 1 and 2 ) .

A l l children had normal crying and sucking at birth.

There w a s a greater proportion of patients with familial myasthenia

starting at younger ages, compared with myasthenic patients in general,

in w h o m the onset of the disease w a s in the first decade in only 3.5%

(2% to 7%) of patients and in the second decade in 14.7% (10% to

2

0 % )

. In spite of the fact that familial myasthenia usually starts at

birth or during infancy

>

, later ages of onset have been r e p o r t e d

.

The symptomatology in the four cases w a s similar: external

opthalmo-paresis with bilateral ptosis; weakness of the orbicularis oculi muscles; light

weakness in the four limbs, specially in its proximal segments; persistance

and stabilization; resistance to drugs, except in one patient (case 3) in w h o m

a significant improvement of the limbs w a s observed with treatment. Mental

deficiency w a s not observed. T h e incidence of mental retardation amongst

familial cases is seven times that of the general population (estimated in

1% or less)

. T h e oculofacial signs w e r e early and prevalent in the four

cases. N o thymoma w a s seen. T h e pneumomediastinography done in two

cases (cases 3 and 4) showed in the case 3 a suggestive image of hypertrophic

thymus ( F i g . 5 ) . T h y m o m a or hypertropric thymus associated to familial

M G is e x c e p t i o n a l

.

.

. T h e lack of careful investigation

(pneumome-diastinography or thymic venography) and the low number of thymectomies

performed may explain this fact.

Thyroid function w a s normal in the four cases. Hyperthyroidism

asso-ciated with familial M G , specially in monozygotic twins, has been

des-c r i b e d

Electromyogram of the orbicularis oculi muscle showed typical

myasthe-nic features in three cases, and the same response w a s obtained of the

levator palpebrae superioris and extraocular muscles in two cases (cases

3 and 4 ) .

The evolution of the four patients has been favorable, seemingly

pro-tracted or stabilized. This fact is frequently observed in familial M G . T h e

mortality rate is low and the prognosis is good. O u r four patients are

being followed for further investigations.

S U M M A R Y

T w o pairs of siblings with myasthenia gravis, belonging to two different

families, are reported. This is the only record of familial myasthenia

du-ring the past twenty years, in a total of 145 patients seen at the Neurological

Clinic of the São P a u l o Medical School. In spite of the fact that myasthenia

gravis does not show hereditary characteristics, the peculiar features of the

four cases justify the present report. T h e two pairs of siblings were born

from non myasthenic nor consanguineous parents. T h e disease started at

birth showing bilateral partial eyelid ptosis in all patients. The course of

the illness has been favorable. There was no thymoma.

R E S U M O

Miastenia grave familial. Registro de quatro casos

Os autores registram dois pares de gêmeos com miastenia grave,

per-tencentes a duas famílias diferentes. Este é o único registro de miastenia

familial durante os últimos 20 anos, num total de 145 pacientes examinados

na Clínica Neurológica da F M U S P . Apesar do fato de a miastenia grave

não ter características hereditárias, os aspectos peculiares dos quatro

pa-cientes justificam o presente registro. Os dois pares de gêmeos nasceram

de pais não miastênicos e sem consanguinidade. A doença iniciou-se no

nas-cimento, evoluindo com ptose bilateral parcial da pálpebra superior precoce¬

mente em todos os pacientes. O curso da moléstia tem sido favorável.

N ã o havia timoma.

R E F E R E N C E S

1. C E L E S I A , G. G. — M y a s t h e n i a g r a v i s in t w o siblings. A r c h s N e u r o l . ( C h i c a g o ) 12:206-210, 1965.

2. F O L D E S , F. F. & M c N A L L , P. G. — U n u s u a l f a m i l i a l occurrence of myasthenia gravis. J. A m . m e d . A s s . 174:418-420, 1960.

3. H E R R M A N N Jr., C. — M y a s t h e n i a g r a v i s o c c u r r i n g in families. N e u r o l o g y ( M i n n e a p . ) 166:75-85, 1966.

5. H E R R M A N N Jr., C. — T h e f a m i l i a l occurrence of myasthenia g r a v i s . A n n . N . Y . A c a d . Sci. 183:334-350, 1971.

6. K O T T , E. & B O R N S T E I N , B. — F a m i l i a l e a r l y infantile myasthenia g r a v i s w i t h a 15-year f o l l o w - u p . J. neurol. Sci. 8:573-578, 1969.

7. L E V I N , P. — C o n g e n i t a l myasthenia in siblings. A r c h s N e u r o l . Psychiat. ( C h i c a g o ) 62:745-758, 1949.

8. M c L E A N Jr., T. W . & M c K O N E , R. C. — Congenital myasthenia g r a v i s in twins. A r c h s N e u r o l ( C h i c a g o ) 29:223-226, 1973.

9. M I L L I C H A P , J. G. & D O D G E , P. R. — D i a g n o s i s and treatment of myasthenia g r a v i s in infancy, childhood, and adolescence: study of 51 patients. N e u r o l o g y ( M i n n e a p . ) 10:1007-1014, 1960.

10. N A M B A , T . ; B R U N N E R , N . G.; B R O W N , S. B . ; M U G U R U M A , M . & G R O B , D . — F a m i l i a l myasthenia g r a v i s : report of 27 patients in 12 families. A r c h s N e u r o l . ( C h i c a g o ) 25:49-60, 1971.

11. N A M B A , T. & G R O B , D . — M y a s t h e n i a g r a v i s and hyperthyroidism o c c u r r i n g in t w o sisters. N e u r o l o g y ( M i n n e a p ) 21:377-382, 1971.

12. O S B O R N E , D . & S I M C O O C K , J. — M y a s t h e n i a g r a v i s in identical twins. B r . med. J. 1:1025-1026, 1966.

13. O S S E R M A N , K . E. — M y a s t h e n i a G r a v i s . G r u n e , N e w Y o r k , 1958.

14. R O T H B A R T , H . B. — M y a s t h e n i a g r a v i s in children: its familial incidence. J. A m . m e d . A s s . 108:715-717, 1937.

15. T E N G , P . & O S S E R M A N , K. E. — Studies in myasthenia g r a v i s : neonatal and j u v e n i l e types. A report of 21 a n d a r e v i e w of 188 cases. J. M t . Sinai H o s p i t a l 23:711-727, 1956.

16. W A L S H , F. B . & H O Y T , W . F. — E x t e r n a l o p h t h a l m o p l e g i a as a p a r t of congenital myasthenia in siblings: myasthenia g r a v i s in children. R e p o r t of a f a m i l y s h o w i n g congenital m y a s t h e n i a . A m . J. O p h t h a l . 47:28-34, 1959. 17. W A R R I E R , C. B . C. & P I L L A I , T. D . G . — F a m i l i a l myasthenia g r a v i s . B r .

m e d . J . 3:839-840, 1967.