Archives of Disease in Childhood, 1975, 50, 505.
Congenital myotonic dystrophy in Britain I. Clinical aspects PETER S. HARPER From the Section of Medical Genetics, Department of Medicine, Welsh National School of Medicine, Cardiff
Harper, P. S. (1975). Archives of Disease in Childhood, 50, 505. Congenital myotonic dystrophy in Britain. I. Clinical aspects. A clinical and genetic study of congenital myotonic dystrophy in Britain has been carried out in 70 patients from 54 sibships. The clinical aspects are analysed here, and the existence of a syndrome clinically distinct from myotonic dystrophy of later onset is confirmed. Characteristic features include neonatal hypotonia, motor and mental retardation, and facial diplegia. A high incidence of talipes occurs at birth together with hydramnios and reduced fetal movements during pregnancy, factors suggesting prenatal onset of the disorder in many cases. Prolonged survival is the rule after infancy, but the occurrence of numerous neonatal deaths in the sibships suggests the existence of unrecognized cases dying in the neonatal period.
Myotonic dystrophy (dystrophia myotonica) is generally considered to be a disease of adult life or adolescence, and in these age groups it shows characteristic diagnostic features including myotonia and progressive muscle degeneration affecting in particular facial, jaw, neck, and distal limb muscles. Vanier (1960) first reported the occurrence of this disorder in early childhood, and recognized that the clinical features might differ considerably from those seen in later life. Subsequent reports (Dodge et al., 1965; Watters and Williams, 1967; Aicardi, Conti, and Goutieres, 1974) have defined the clinical picture of myotonic dystrophy presenting in infancy, and have emphasized that hypotonia, rather than myotonia is the dominant feature, and that it may result in severe, even fatal, respiratory problems in the newborn period. The frequent occurrence of mental retardation and the striking facial diplegia have also been recognized (Parker, 1963; Calderon, 1966; Gordon and Hilson, 1967). In addition to these case reports, studies in the United States (Harper and Dyken, 1972; Dyken and Harper, 1973) have attempted to analyse the clinical features of larger series of patients, and to explain the unexpected finding that in the majority of cases showing congenital onset of the disease the mother is found to be the affected parent. The hypothesis has been proposed that congenital myoReceived 2 January 1975.
505
tonic dystrophy may result from an intrauterine maternal factor acting upon the fetus carrying the gene for myotonic dystrophy (Harper and Dyken, 1972). The present study attempts to investigate the aetiology of congenital myotonic dystrophy, and in particular to test the above hypothesis, by analysis of clinical, genetic, and biochemical data based on as complete and unbiased a series of cases as possible from a defined population. In this paper the clinical data are analysed with special reference to the neonatal and antenatal periods. Subsequent papers (see following article) will discuss the genetic and biochemical data. Method of study An attempt was made to obtain data on all patients in Britain presenting with myotonic dystrophy in childhood in whom there was evidence of onset at or around birth. A letter requesting information was sent to all paediatricians in Britain (excluding Ireland) and to all neurologists and physician superintendents of mental subnormality hospitals. A positive response was followed by a more detailed questionnaire, and by a personal visit to the patient and family in nearly all cases. Cases ascertained purely through family studies were not accepted, nor were those in whom details of infancy were lacking or were completely normal. The study was carried out during the period April 1973-April 1974. In addition to genetic data, information was collected on the pregnancy and neonatal period, and all available
TABLE I Clinical features of patients
with congenital
myotonic
dystrophy
0~~~~~~~~~~~4
co~~~~~~~~~~~~~~~~~~~~~~
0
2
a o
1 2 3 4
5 6 7 8 9 10 11 12
13 14 15
16 17 18 19 20 21 22 23 24 25 26
27
28 29 30 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48
49 50 51 52 53
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
18 19 20 21 22 23 24 25 26 27 28
29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
66 67 68 69
54J170
~~~
4)
0 ~~~~~~~~~~~~~(
39 M M 37 Mj38 M 40 M M 40 40 M 42 M M 42 F 40 F 40 F 40 M 34 M 34 M 43 F 40 17M F 43 F 42 M 40 M 40 M M 42 F 32 M F 43 40 M F 38 F 40 M 40 M F 40 39 F 41 M 40 F 40 M 41 M F 40 40 M 40 F F 40 M 36 M 39 40 F F 36 F 40 43 F F 40 40 F F 40 40 M M 39 F 41 M 40 M 42 F M 41 F 34 F 38 M 36 F M 39 M 40 M 40 M 43 F 38 F 40 M 40 M 37 M 40
3-2 3-25 3-5 2-8 3-3 2-7 3-2 3-9 4-1 2-6 3-2 2-0 2-3 3-7 3-0 39 4-0 4-5 3-4
+ + + + +
N + +
4-1 +
3-3 2-5 3-2 3-4 2-6 3 .5 3-1 2-5 2-2 2-2 3-5 2-8 3-4 3-6 3-8 4-5 3-1 2-8 2-4
+ + + +
N + +
+
N + +
4-1 3 65 3-1 4-3 2-9 2-7 27 4-55 3-0 3-1 3-0 3-4 2-2
N
2-0
N N N N
+ + +
N +
3-1 3-9 3-7 3-7
N
3-2
N N
2-3
3.4.
+
+
+
+
+
41~~~~~~~
0
l
N N
0
R
+ N N N
z0
Z
+ +
+ +
+
IL,
+ +
-
N
N
+ + + + + + + N + N + N + + + + + + + N + + + + + + + N + N + + + + N + ~~ ~~~~~N + + + + + + + + + + + + + N N + + N N + + N N + + + + + + + + + + + N + + + + + + N + + N + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + N + + + + + + + + + + + + + + + + + + + + + + N + + N + + + + + + + + + + + + + + + + + + N + N + + + + + + + + + + + + + + + + + + + + + + N + N N N N N N N + + + N N N + N + + + + + + N N + + N + + + N + N + + + + N + . .. + + +
+ + +
+Present;
to Fig.
-, absent; N,
not
1-3 in subsequent
noted.
pp.
515 and
516.
?G-mother
i+
N N
+ N + + + + +
+
,,3
+1
,
+ + + + +
,,, ,,I ,,,
1 1 1
+
-
+ + + + + + + +
+ + + + + + + +
+ +
+ + + + +
+ + + + + +
3 1 4 4 4
,,2 ,, ,,
G-father
1 2
I,
G,c-mother ,,1 ,,4 ,,4 ,,l
2
3 4
,
,,4 ,,4 ,,
?G-father
2
,,5 ,
+
,,1
N
N N -
+
+ + + +
+1 N +
,
+ +
1 3
,,3 ? G-father
2
G-father ? G-mother ,
2 2
,,1 ,,
+ + + + +
? G-mother
,
,,+ ,,
-
2
,,,
,,1
+
-
G,c-mother
,,, , ,, G-father ,, G-mother
2 2 2
3 3 + 3 + ,,1 1 ,, G-mother + I,, + 1 , ? G-mother + 4 , ? G-father + 2 ,,, + 1 G,c-father + + I, ,,1 + ,, 1 G-mother + 3 , ? G-mother N , 1 ? G-father 1 +,,, 2 ,,G-father + N 1 + + , I. ,,2 + + , ? G-father + N ,,2 + + + G,c-father 1 + N G,c-mother
N
+ + + + + + + + + + + + +
N N
N N
+
i+
+
+
+ +
+ + + N
±
-.
*Family numbers refer
Mother ,, ,
+
N N N
I,,
G,c-father
,,
, ? Mother Father
G-mother
1
Gi-mother
-I
tSee Table V of following article for
3 2
grading,
p.
516.
4
Congenital myotonic dystrophy in Britain. I.
507
family members were examined for the presence of myotonia and other neurological abnormalities. The presence of lens opacities was investigated by ophthalmoscopy and by a portable slit-lamp microscope (Kowa Ltd.).
neonatal life, despite other clear evidence of congenital involvement. Talipes was present at birth in 33 of the 70 patients, varying from a mild degree in which no treatment was required to more severe deformity requiring casts or surgery. The above features provide positive diagnostic Results evidence of myotonic dystrophy in the infant in Data were obtained on 70 patients with congenital whom it is suspected. Equally important is the myotonic dystrophy from 53 kindreds. In all but absence in infancy of some of the cardinal features four instances the families were visited personally. of the adult form of the disease, notably the myoA further 9 patients with myotonic dystrophy were tonia which is such an obvious clinical sign in most excluded because onset was not in the neonatal adult or adolescent patients. period or because of lack of details concerning early childhood, and 2 more patients were considered to TABLE III have myotonia congenita (Thomsen's disease) and Incidence of clinical myotonia were therefore excluded. Details on individual patients and their families are given in Table L.* Main clinical features. The incidence of the major clinical features in the newborn period is given in Table II, and is similar to that reported in previous studies. The majority of patients presented as floppy infants with delayed motor development, and in a number of cases no specific diagnosis was made at this stage, erroneous diagnosis being
% Present
Age group (years)
Present
Absent
Congenital myotonic dystrophy in Britain I. Clinical aspects PETER S. HARPER From the Section of Medical Genetics, Department of Medicine, Welsh National School of Medicine, Cardiff
Harper, P. S. (1975). Archives of Disease in Childhood, 50, 505. Congenital myotonic dystrophy in Britain. I. Clinical aspects. A clinical and genetic study of congenital myotonic dystrophy in Britain has been carried out in 70 patients from 54 sibships. The clinical aspects are analysed here, and the existence of a syndrome clinically distinct from myotonic dystrophy of later onset is confirmed. Characteristic features include neonatal hypotonia, motor and mental retardation, and facial diplegia. A high incidence of talipes occurs at birth together with hydramnios and reduced fetal movements during pregnancy, factors suggesting prenatal onset of the disorder in many cases. Prolonged survival is the rule after infancy, but the occurrence of numerous neonatal deaths in the sibships suggests the existence of unrecognized cases dying in the neonatal period.
Myotonic dystrophy (dystrophia myotonica) is generally considered to be a disease of adult life or adolescence, and in these age groups it shows characteristic diagnostic features including myotonia and progressive muscle degeneration affecting in particular facial, jaw, neck, and distal limb muscles. Vanier (1960) first reported the occurrence of this disorder in early childhood, and recognized that the clinical features might differ considerably from those seen in later life. Subsequent reports (Dodge et al., 1965; Watters and Williams, 1967; Aicardi, Conti, and Goutieres, 1974) have defined the clinical picture of myotonic dystrophy presenting in infancy, and have emphasized that hypotonia, rather than myotonia is the dominant feature, and that it may result in severe, even fatal, respiratory problems in the newborn period. The frequent occurrence of mental retardation and the striking facial diplegia have also been recognized (Parker, 1963; Calderon, 1966; Gordon and Hilson, 1967). In addition to these case reports, studies in the United States (Harper and Dyken, 1972; Dyken and Harper, 1973) have attempted to analyse the clinical features of larger series of patients, and to explain the unexpected finding that in the majority of cases showing congenital onset of the disease the mother is found to be the affected parent. The hypothesis has been proposed that congenital myoReceived 2 January 1975.
505
tonic dystrophy may result from an intrauterine maternal factor acting upon the fetus carrying the gene for myotonic dystrophy (Harper and Dyken, 1972). The present study attempts to investigate the aetiology of congenital myotonic dystrophy, and in particular to test the above hypothesis, by analysis of clinical, genetic, and biochemical data based on as complete and unbiased a series of cases as possible from a defined population. In this paper the clinical data are analysed with special reference to the neonatal and antenatal periods. Subsequent papers (see following article) will discuss the genetic and biochemical data. Method of study An attempt was made to obtain data on all patients in Britain presenting with myotonic dystrophy in childhood in whom there was evidence of onset at or around birth. A letter requesting information was sent to all paediatricians in Britain (excluding Ireland) and to all neurologists and physician superintendents of mental subnormality hospitals. A positive response was followed by a more detailed questionnaire, and by a personal visit to the patient and family in nearly all cases. Cases ascertained purely through family studies were not accepted, nor were those in whom details of infancy were lacking or were completely normal. The study was carried out during the period April 1973-April 1974. In addition to genetic data, information was collected on the pregnancy and neonatal period, and all available
TABLE I Clinical features of patients
with congenital
myotonic
dystrophy
0~~~~~~~~~~~4
co~~~~~~~~~~~~~~~~~~~~~~
0
2
a o
1 2 3 4
5 6 7 8 9 10 11 12
13 14 15
16 17 18 19 20 21 22 23 24 25 26
27
28 29 30 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48
49 50 51 52 53
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
18 19 20 21 22 23 24 25 26 27 28
29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65
66 67 68 69
54J170
~~~
4)
0 ~~~~~~~~~~~~~(
39 M M 37 Mj38 M 40 M M 40 40 M 42 M M 42 F 40 F 40 F 40 M 34 M 34 M 43 F 40 17M F 43 F 42 M 40 M 40 M M 42 F 32 M F 43 40 M F 38 F 40 M 40 M F 40 39 F 41 M 40 F 40 M 41 M F 40 40 M 40 F F 40 M 36 M 39 40 F F 36 F 40 43 F F 40 40 F F 40 40 M M 39 F 41 M 40 M 42 F M 41 F 34 F 38 M 36 F M 39 M 40 M 40 M 43 F 38 F 40 M 40 M 37 M 40
3-2 3-25 3-5 2-8 3-3 2-7 3-2 3-9 4-1 2-6 3-2 2-0 2-3 3-7 3-0 39 4-0 4-5 3-4
+ + + + +
N + +
4-1 +
3-3 2-5 3-2 3-4 2-6 3 .5 3-1 2-5 2-2 2-2 3-5 2-8 3-4 3-6 3-8 4-5 3-1 2-8 2-4
+ + + +
N + +
+
N + +
4-1 3 65 3-1 4-3 2-9 2-7 27 4-55 3-0 3-1 3-0 3-4 2-2
N
2-0
N N N N
+ + +
N +
3-1 3-9 3-7 3-7
N
3-2
N N
2-3
3.4.
+
+
+
+
+
41~~~~~~~
0
l
N N
0
R
+ N N N
z0
Z
+ +
+ +
+
IL,
+ +
-
N
N
+ + + + + + + N + N + N + + + + + + + N + + + + + + + N + N + + + + N + ~~ ~~~~~N + + + + + + + + + + + + + N N + + N N + + N N + + + + + + + + + + + N + + + + + + N + + N + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + + N + + + + + + + + + + + + + + + + + + + + + + N + + N + + + + + + + + + + + + + + + + + + N + N + + + + + + + + + + + + + + + + + + + + + + N + N N N N N N N + + + N N N + N + + + + + + N N + + N + + + N + N + + + + N + . .. + + +
+ + +
+Present;
to Fig.
-, absent; N,
not
1-3 in subsequent
noted.
pp.
515 and
516.
?G-mother
i+
N N
+ N + + + + +
+
,,3
+1
,
+ + + + +
,,, ,,I ,,,
1 1 1
+
-
+ + + + + + + +
+ + + + + + + +
+ +
+ + + + +
+ + + + + +
3 1 4 4 4
,,2 ,, ,,
G-father
1 2
I,
G,c-mother ,,1 ,,4 ,,4 ,,l
2
3 4
,
,,4 ,,4 ,,
?G-father
2
,,5 ,
+
,,1
N
N N -
+
+ + + +
+1 N +
,
+ +
1 3
,,3 ? G-father
2
G-father ? G-mother ,
2 2
,,1 ,,
+ + + + +
? G-mother
,
,,+ ,,
-
2
,,,
,,1
+
-
G,c-mother
,,, , ,, G-father ,, G-mother
2 2 2
3 3 + 3 + ,,1 1 ,, G-mother + I,, + 1 , ? G-mother + 4 , ? G-father + 2 ,,, + 1 G,c-father + + I, ,,1 + ,, 1 G-mother + 3 , ? G-mother N , 1 ? G-father 1 +,,, 2 ,,G-father + N 1 + + , I. ,,2 + + , ? G-father + N ,,2 + + + G,c-father 1 + N G,c-mother
N
+ + + + + + + + + + + + +
N N
N N
+
i+
+
+
+ +
+ + + N
±
-.
*Family numbers refer
Mother ,, ,
+
N N N
I,,
G,c-father
,,
, ? Mother Father
G-mother
1
Gi-mother
-I
tSee Table V of following article for
3 2
grading,
p.
516.
4
Congenital myotonic dystrophy in Britain. I.
507
family members were examined for the presence of myotonia and other neurological abnormalities. The presence of lens opacities was investigated by ophthalmoscopy and by a portable slit-lamp microscope (Kowa Ltd.).
neonatal life, despite other clear evidence of congenital involvement. Talipes was present at birth in 33 of the 70 patients, varying from a mild degree in which no treatment was required to more severe deformity requiring casts or surgery. The above features provide positive diagnostic Results evidence of myotonic dystrophy in the infant in Data were obtained on 70 patients with congenital whom it is suspected. Equally important is the myotonic dystrophy from 53 kindreds. In all but absence in infancy of some of the cardinal features four instances the families were visited personally. of the adult form of the disease, notably the myoA further 9 patients with myotonic dystrophy were tonia which is such an obvious clinical sign in most excluded because onset was not in the neonatal adult or adolescent patients. period or because of lack of details concerning early childhood, and 2 more patients were considered to TABLE III have myotonia congenita (Thomsen's disease) and Incidence of clinical myotonia were therefore excluded. Details on individual patients and their families are given in Table L.* Main clinical features. The incidence of the major clinical features in the newborn period is given in Table II, and is similar to that reported in previous studies. The majority of patients presented as floppy infants with delayed motor development, and in a number of cases no specific diagnosis was made at this stage, erroneous diagnosis being
% Present
Age group (years)
Present
Absent
