ON T H E AGE O F ONSET A N D AGE AT DEATH I N H E R E D I T A R Y MUSCULAR DYSTROPHY WITH

SOME OBSERVATIONS BEARING ON T H E QUESTION OF ANTEDATING

BY JULIA BELL

THE types of muscular dystrophy included for the purposes of this investigation are those commonly known as pseudohypertrophic, scapulo-humeral and facio-scapulo-humeral muscular dystrophy. I have obtained records of some 1250 cases, from the literature of the subject and from the case records a t the National Hospital, Queen Square. It is often very difficult to decide to what clinical category a particular case belongs, but I have divided my material into three groups as follows:

Group A, a pseudohypertrophic group in which definite localized enlargement of muscles, and their hardness, has been noted a t some stage of the disease in association with their progressive weakness; other affected muscles waste from the outset; the face muscles remain free from signs of disease until a late stage, and the patient retains the power to carry out all his facial movements.

Group C includes cases in which the affection of the face muscles is commonly noted as the first sign of disease ; the patient has a characteristic facies myopathica, and is sometimes noted in infancy to sleep with half-closed eyes, though progressive signs of disease may not occur until some years later, when weakness in the arms and difficulty in raising the arms may call attention to the presence of the disease; these cases may or may not have a history of localized muscular pseudohypertrophy a t some stage of the disease, but such condition is not found in the face muscles whose affection provides the characteristic criterion of the group; the muscles of mastication and the mechanism of swallowing are not affected in these cases.

Group B includes all other cases of the disease in which muscular wasting and weakness progress together ; no enlargement of muscles has been noted a t any stage of the disease, and the mobility of the face remains relatively unimpaired ; these cases are indistinguishable from those of groap A at a late stage of the disease.

Of these clinical types A and C are commonly well defined, those of group B are more mixed. Certain of the cases showing severe atrophy at the time of observation may have been unaware of the enlargement of muscles at an earlier stage of the disease; for the most part cases of group B show an earlier and predominant affection of the upper extremities and shoulder muscles, and may describe a difficulty in raising their arms as the earliest sign of disease. Cases of group A generally report difficulty in walking up stairs or in rising from the floor as the first sign of affection.

JULIA BELL 273

When I am able to publish the series of pedigrees of muscular dystrophy which I have collected, it will be seen that all these clinical varietiw may 'he found in the same family; it may thus be deduced that the same gene may manifest itself in any one of these clinical types, though the correlation between clinical type in members of the same stock is undoubtedly very high. It will further be seen that three genetic types are prevalent in the muscular dystrophies, and that, though representatives of each of the clinical types occur in each genetic group, their association is not a random one ; in particular, a marked excess of the cases of pseudohypertrophic muscular dystrophy fall into the sex-linked genetic category, and a large majority of cases of facio-scapulo-humeral dystrophy arise from a dominant genetic source.

Table 1 shows the relative distributions of clinical and genetic types. Cases which I have designated R' refer to affected brothers in single sibships, with normal parents; it is evident that some of these cases belong to the sex-linked genetic group and that others may arise

Sex-linked 8 sex-incidence Recessive 8 sex-incidence Dominant 8 sex-incidence R' all males Single cases 8 sex-incidence

Totals

Table 1. Frequencies of clinical and genetic types

A

165 98. I 8

91 36.78 22 -

I 28

183

589

83.63 --

C

9

16

I35

-

-

47-66 1 1

19 -

190

B 3 Type Totals

I 2 230

4 221

3 333

97'39

43'44

52'45

-

-

-

2 178

I3 283 81-55 -

34 1245

44 97'73

50.91 I73 54'34 37 68 77'94

I I 0

432

from a recessive gene, and should contribute to raise the male sex-incidence of 36.78 in the corresponding recessive- cases, reduced through the rejection from this category of all pedigrees in which only affected males occurred in a single sibship. With regard to single cases, I noted references to these when particulars of age of onset and death were given, with a view to increasing my numbers and in the assurance that single cases of this disease can only arise from a genetic determination; the history of the case and the characteristic localization of symptoms are such as to prohibit any source in an acquired pathological process or environmental reaction. These cases, like those included under R', must belong to the sex-linked genetic group or fall into the recessive category; it is extremely unlikely that the case would have been reported without a reference to affection in the parent, if such had occurred, and examples of suppressed dominance in pedigrees of the condition are rare. I have thus apportioned the R' and single cases in accordance with Table 2 below, taking into consideration such factors as sex, clinical type, and family history when available, also various other factors which I was able to study for the sex-linked and

274

A

Sex-linked 387 6 sex-incidence 99'22 Recessive 171 6 sex-incidence 49'70 Dominant 22 3 sex-incidence -

Totals 580 __

H E R E D I T A R Y MUSCULAR D Y S T R O P H Y

- _ ~ _ _ _ _ _ _ _ _ _ _ _ _ _ _ B C ? Type Totals

_______ ~ _ _ _ ~

107 20 '5 5 29 98437

52.10

52'45

- - 99'07 152 34 6 363

'73 I35 3 333

- - 54.61

54'34 47.66 -

- _ _ ~ ~ _ ~ ~ __ 432 189 24 I225

weakness, or enlargement of certain muscles with weakness, first called attention to the presence of disease. Evidently the more observant parent, or the parent who has previously watched the development of the disease, will recognize its onset a t an earlier stage than the less anxious parent who may fail to notice the progressive signs until some relatively severe degree of disability has been reached. I think we may be assured that the true age of onset is usually a little earlier than that given in the records ; the rate of progress of the disease, moreover, differs markedly from case to case, so that when the advance of symptoms is slow the disease may have been in operation for some years before it is recognized.

The recorded ages of onset, subject to these errors in determination, are given in Tables 3 and 4. In my subsequent analysis of these tables I have combined the clinical types and considered the material under the heading of the three genetic types only. When the pedigrees and histories of cases are published it will, I think, become evident that such grouping is legitimate, in view of the considerable number of families which include cases of more than one clinical type. If the figures as they stand do not appear to justify entirely this procedure, I would note that a high frequency in one particular entry may well be due to a single large family exhibiting a particular age of onset highly eorrelated in all its

. . . ~

I I I

N - l 1 - 1 * - I I I I I I I I I l m l \ o l I I I I I I

k I I 4 (CIN n

I I I I I I I I I I I I I I I d - 1 - N

d - n N

N * I N l I

m l N l l n I I I I I

m m m t b N I I

m m m m - - - - I I I I l l 1 I

I n ( I z\D m -

000 -J-n b N I I

276 HEREDITARY MUSCULAR DYSTROPHY

Clinical type ... A i B C P -

- 0-4 3 I 0 I 0

5- 9 3 3 I7 22 24 10-14

15-19 3 23 15 9 9 20-24

- - - - - - + 8 25-29 - I 2 I -

Q rcl 30-34 2 3 I I

35-39 I 2 I 40-44 3 I 2 - 45-49 I 7 50-54

3 55-59 60-64

Totals 16 98 I 79, 2

- 0

- - I - - -

- - - - - -

-

affected members. To give one example-ten of the thirteen sex-linked cases of clinical type B with an age of onset later than 9 years, entered in Table 3, come from two families; all the patients had had the disease for a considerable term of years, and, though no pseudohypertrophy was described at the date of observation, we cannot be sure that this sign had not been present to some extent at the date of onset, maybe 20 years or so pre- viously; if such cases were transferred to the clinical group A, to which I suspect certain of them belong, differences between the distributions would be smoothed out. Certainly Fig. 1 gives support to the view that the distribution of genetic types, neglecting clinical grouping, do not provide any conspicuous evidence of heterogeneity.

The curve representing the age of onset in dominant cases suggests the possibility of some error in the determination of age of onset early in life; examination of the histories

Totals

s o 16 7 I 1 I 2

I9 27 22 19 1 1 7 9 4 5 2

5 1 4 4

2 2

I - 2 1 I 1

108 87

supports the view that cases with facio-scapulo-humeral dystrophy were sometimes noted by their mother to sleep with their eyes incompletely closed in infancy, and the onset of the disease was dated in accordance with this observation; other and progressive signs of disease were not noted until a later age; perhaps the age of onset should have been dated from the time that signs of progressive disease were recognized.

Table 5 gives the means and standard deviations calculated from the figures of Tables 3 and 4 ; it will be seen that the three genetic types apparently account for three types of disease with an average age of onset at 5-7, 11.4 and 18.7 years respectively; the variation about these means differs markedly in the three groups. The statistical constants provided by cases classified from pedigrees only are not significantly modified by the distributions of the R' group of affected brothers and the single cases amongst my records. The collection of pedigrees from which the figures in Table 5 are mostly taken will be published later in

JULIA BELL

Age of onset

0-0 Sex-linked (399 cases). 0- - - -0 Recessive (326 cases). @---a Dominant (196 cases).

Fig. 1.

277

Age st death

0-0 Sex-linked (160 cases). 0- - - -0 Recessive (82 casea). @-@ Dominant (84 cases).

Fig. 2.

278 HE R E D I TA R Y MUS CU LAR DY STR 0 P H Y

the Treasury of Nirrnnn Inheritance: it is unique within my experience in the inclusion of so large a number of examples of each genetic type. Colour-blindness of the red-green variety and hereditary optic atrophy in Europe are almost exclusively sex-linked ; con- genital stationary night blindness may arise from a sex-linked or a dominant source; other conditions, such as peroneal atrophy or hereditary ataxia, may arise from recessive or dominant genes, but are only very rarely produced by a sex-linked gens; I know of no condition for which any of three main types of gene are seen to be so commonly responsible as this group of muscular dystrophies.

Standard deviation

3.905 f 0.164 4.586 f 0.115

._

Table 5

___

N O .

-_ 90 150

Pedigrees Pedigrees + R' +singles

9'494 f 0.483 9.067 f 0.708 9.824 f 0.665

10.239 f 0'557 10.579 f 0.597

13.182 f 0.667 13.870 f 0.944

10.397 f 0.406

12.197 f0.925

5.964 f 0.349

9.548 f 0.416 8.636 f 0.428

11.863 f 1.198

Pedigrees 9 , 3 1 , ?

9 9 3 9 9 ?

Pedigrees + R' +singles

65 32 3 I 82 44 34

84 42

__

42

27

60 45 -

Pedigrees 9 9 d 9 , ?

R' 6

Single cases 9 9 3 ,f 0

I Age of onset Age at death

Mean

5'514 * 0'329 5'746 f 0.230

10.220 f 0.683 9'939 k 1'001

11.418 k0.574 I I '701 f 0.788 I 1.226 f 0.844

10.574 f 0.941

I 8.705 f 0.946 19'537 * 1'335 17.673 f 1.308

7'055 f 0.494

9'053 f0.588

12'704 f 1.695 8.236 f 0.605

I--

Mean

25.731 f 2.294 27.657 f 3.605 25'242 f 2.836 26.769 f 2.007 29'091 f 2.989 24'559 f 2.620

I 8.834 f 1.440 19.167 f 1'772

-

Standard deviation

8.133 f0.606 6.993 * 0'404

18.496 f 1.622 20'393 f 2'549 15.789 f 2.005 18.175 f 1.419 19.827 f 2-1 14 15.277 f 1.853

23.690 f 1.828 24.188 f 2.639 22.958 f 2.505

6.967 f 0.948

It would appear that the course of cases of muscular dystrophy of sex-linked recessive origin are the most rigidly determined, with an onset early in life and subject to small variation; indeed, it is clear that this series of cases, predominantly of the pseudohyper- trophic clinical variety, could not have arisen from a dominant gene, for the disease is very disabling, and a t the child-bearing age few survivors would retain the power to transmit the disease; this remains true, though we have no evidence that the uterine muscle, or indeed other vitally important muscles, such as the heart or the muscles of respiration, have any direct share in the localization of the disease i,n any of the clinical or genetic types under qonsideration.

The question of variability in age of onset, as measured by the standard deviation, is inevitably limited to some extent by such practical controls as an early mean age of onset. ;

J U L I A BELL 279

thus to compare the inherent variability of our three groups the coefficient of variation

is perhaps a more potent guide. On the basis of this measure, variation is at ( mean ) a maximum in cases arising from a recessive source, whether the age of onset or the age a t death be considered ; variation is of similar scope in the sex-linked and dominant groups of cases; variation in age a t death is always less than that of age at onset, a fact markedly reversed if the phenomena be measured by the standard deviation. It may be of interest to record here that I can find no evidence that the younger of pairs of afiected siblings are noted to show signs of disease a t an earlier age than their elders, through an earlier recogni- tion of symptoms on the part of parents who have previously noted the sequence of events. The mean age at death, and its variability, for sufferers from muscular dystrophy in the

100 X S.D.

141 399 193 328 I95

- r

70.8

92'9 91.1

70'5

7943

Genetic source

Sex-linked (pedigrees) Sex-linked with R' and single cases Recessive (pedigrees) Recessive with R' and single cases Dominant

Table 6

Age of onset

Coefficient No. i of variation

Age a t death ~

Coefficient of Variation No. 1

Tab19 7. Mean age of onset in pairs of siblings

No.of pairs

Sex-linked I37 5.20 5'35 Recessive 202 8.52 8'79 Dominant 1 116 I 20'35 I 20.65 1

various genetic kypes are given in Tables 5 and 6. Some of the figures contributing to those values are given in Table 8. It is evident that the sex-linked group of cases represents the most malignant type of the disease, the onRet is commonly very early in life, and death may be expected after an interval of about 12 years; moreover, Table 8 reveals that, whereas only 8 yo of the sex-linked cases survive the age of 24 years, 44 o/o of the recessive cases live to a greater age than 24, and within the dominant group it is rare to die earlier than 24. Such facts have a bearing on the question of the propagation of the disease by affected members, but do not measure the deadliness of the disease to individuals, without further knowledge of the duration of the disease when death occurs.

It will be realized that in published family histories, such as provide the basis of this investigation, sometimes the age of onset is known and the patient may be still living; in other cases we are told only the age a t death; the figures of Table 9, giving the mean

2 80

*Recessive *Sex- linked

HEREDITARY MUSCULAR DYSTROPHY

Dominant

6 0

u3 .9

0 - 4 5- 9

10-14 15-1 9 20-24 25-29 30-34 35-39 40-44 45-49 50-54 55-59 60-64

7 - 7 4 7 5 7 9 80-84

65-69

85-89

Standard deviation

Pedigrees 60 14'300 f 0.993 7-695 f 0.702

No.

Pedigrees + R' + singles 123 6.431 f 0.410

- I0

43 65 20

8 I

I I -

4' *17*963 f 1.829 *18*500 f 2.396

I7 *17.206 f 2.822

4 2 2

3 - 5 5 - 4 5 - 4 7 - 5 3 - 4 2 I I

2 - I

5 I 4 I - 2 - - - I - 2

3 - - I - -

2 - -

11.711 t 1.293 11.737 t 1.694 I 1.634 f 1.995

4 3 I - - -

I 3

4 - 2 3

6 2

2 3 3 I

3 5 4 4 3 7 3 5 2 I I -

I I

2 -

2 2

24 I 11~500f 1.331

13.391 toe851 55 14.525 k 0.853 41

* With cases allotted from the R' and single-cme groups.

Table 9. Total duration of the disease

- 6.519 f 0.941

6.310 f 0.602 5.460 f 0.603

Pedigrees 9 9 s 9, Q

I , s $ 9 Q

Pedigrees + R' +singles

55 26 27 71 37 30

15.245 f 1.617 15.461 f 2.590 16.056 f 2-022 15.782 f 1.371 16.824 f I .987 15.200 f 1-915

Pedigrees

* Underestimation due to selection of cases for which full information was available.

J U L I A BELL 281

duration of the disease, depend upon cases for which both these ages were reported; the means given there should approximate closely to the difference between the mean age at onset and mean age at death given in Table 5. Now, such an agreement, between the values of Tables 5 and 9, is reasonably close so far as the sex-linked and recessive groups of cases are concerned; the dominant group, however, gives widely divergent results for the mean duration of disease as deduced from Table 5, or calculated for Table 9. On seeking the source of this divergence it would appear that there tends to be a selection in the cases for which full information, giving both age of onset and age at death, is available. Those cases with a short history are more completely recorded, whilst for many who tended to die at a late age, with perhaps a long duration of disease, only the age at death is recorded, the age of onset being presumably unknown. Thus for no fewer than forty-three of the eighty-four individuals whose age at death contributes to the mean in Table 5, the age of onset was unknown; the mean age at death of these forty-three patients was 60.8 years; the mean age at death for the remaining forty-one patients, who contribute to the values of Table 9, was 39-5 years. Evidently the observed mean duration of disease given in Table 9 is much too low to be accepted as the characteristic value for the dominant group of cases. Another point in support of this view is that the average duration of disease at the date of the record, prior to death, based on 127 observations of the dominant genetic group, is 18-06 years, which must of necessity be below the total duration of disease when death has intervened. It is of importance to reveal such sources of error and to be fully aware of their liability, which mu& be inherent in records dependent on memory of former generations; in view of them I think all we can safely state is that the sex-linked group of cases tend to arise very early in life and to run a rapid course terminating in death at a relatively early age; the cases from a dominant source tend to arise much later in life, to run a slowly progressive course, and to survive to old age in a considerable proportion of cases. The cases represented in our recessive genetic group are intermediate with regard to all the factors under consideration. It is clear that the statistical constants throughout have remained substantially unchanged by my apportioning of the cases from the R' and single-case categories between the sex-linked and recessive groups.

To consider now the correlation of age of onset and age at death in members of affected families. With all due caution in the interpretation of the coefficients obtained, their relative values are of some considerable interest.

I would suggest : (a) If the correlation is raised from the fact that members of families who are doomed to become affected late in life have not reached their age of onset, this effect would reach a maximum in the dominant group and be at a minimum in the wx- linked group where variability in age of onset is low. ( b ) The age at death is more exactly determinable than the age of onset, but the smallness of the available numbers detracts from the value of the correlation coefficients. I think, however, they support the view that the age at death is largely determined by genetic control, and is not demonstrably subject to environmental eff ects-a conclusion which would certainly be endorsed by observations

19 V O l . 11

282 H E R E D I T A R Y MUSCULAR D Y S T R O P H Y

j, 2 4

on the result of treatment and the care of patients. The correlation coefficients for age at death may also be raised from the fact that patients who die young tend to have the fact recorded at a time when their longer-lived relatives have not yet succumbed; again such pseudo-correlation should be a t a minimum in the sex-linked group. Such coefficients as I have been able to obtain from Tables 17-27 below, together with comparative values relating to Huntington’s chorea, peroneal atrophy, and hereditary optic atrophy, are given in Table 10. The source of the comparative material has been The Treasury of Human Inheritance in each case; only pedigrees of hereditary optic atrophy which are definitely sex-linked have been utilized, and of these, sibships containing affected females and those which are the offspring of affected females have not been used; there is evidence of a modifying factor operating in sibships including affected women.

Pairs of siblings Pairs with R’ cases Pairs of first cousins Uncle and nephew

Table 10. Correlation coeficients

Pairs of siblings Pairs of first cousins Parent and offspring Avuncular pairs

Pairs of siblings Pairs with R‘ cases

Muscular dystrophy

Age of onset

Hereditary optic

atrophy

:584) 0.477

:248) 0.021 :287) 0.241

-

Muscular dystrophy

(80) 0.815 -

Muscular dystrophy

Age at death I Hun-

tington’s chorea

(278) 0.521 (1 14) 0.044 (152) 0’472 (118)0*190

I

Peroneel atrophy

(112)0’45‘ - - -

- +

7 / 2 These correlation coefficients present a number of points of interest requiring an ex-

planation ; I would, for example, note the high value of first cousin and avuncular correlation in muscular dystrophy of dominant source and in peroneal atrophy as compared with those obtained from pedigrees of Huntington’s chorea, hereditary optic atrophy and muscular dystrophy of sex-linked source. It is of undoubted interest to have these measures of the relative stability or instability af age of onset and age at death in hereditary atlictions put on record, but I would prefer to regard them as indicators for further avenues of exploration rather than as a basis from which to reason, owing to the small number of cases which contribute to some tables and the inexact character of material so largely subject to per- sonal error.

JULIA BELL 283

In working out correlation coefficients, for age of onset in hereditary disease, between parent and offspring, I have become accustomed to the fact that the age of onset in the parent tends on the average to be considerably older than that of their offspring; the ex- planation of this fact has repeatedly been sought in the selection of parents who, if the disease be sufficiently disabling, are rendered unfit for parentage if their disease starts early in life. The present series of tables, however, has revealed an extension of this position which cannot be so directly explained. Thus, not only is the average age of onset of the parents later than that of their offspring by a considerable term, but the average age of aunts or uncles is later than that of their corresponding nephews and nieces by a similar interval. The same phenomenon will be noted if the age of death be under consideration

Off- spring

- -

21'32 19.36 31-98

Table 11. Mean age of onset

Differ- ence

_ _ _ ~ - -

~~

+6*6 +4'9 +8-8

Parent Aunt or

uncle

7'57 26.19

28.54 27.73 38-60

55'93

Muscular dystrophy Hereditary optic atrophy

Nephew or niece

5'53 23.81

22'54 22-92 32-41

47.46

Muscular dystrophy Peroneal atrophy Huntington's chorea

Chorea (mean age at death) 1 58.75

Muscular dystrophy Huntington's chorea Peroneal atrophy

Differ- ence

+ 2'0 + 2.4

+ 6.0 + 4-8 + 6.2

+ 8.5

Table 12. Mean age of onset in 'Parents' and in single individuals over the age of 25 years

instead of the age at onset, the parents tending to die at a later age than their affected offspring, and the aunts and uncles tending to live longer than their affected nieces or nephews. The actual figures demonstrating this are given in Table 11. Clearly this brings up the whole question of 'antedating' in human genetic populations, and I propose to examine tbe situation with regard to this from the material as a whole.

The fact that the avuncular examination reveals differences in age of onset between two generations similar to that indicated by the parental investigation, does not eliminate the question of the inevitable selection of parents from amongst those who retain the power to produce children at the child-bearing age; and, indeed, such selection is demonstrated by the figures of Table 12, from which it is evident that the mean age of onset of the disease in affected parents of either sex is considerably later than that of single members of

2 84 HEREDITARY MUSCULAR DYSTROPHY

pedigrees over the age of 25. The face value of selection measured in this way varies from one disease to another, and is, of course, related to the characteristic age of onset of the disease and to its disabling potentialities.

Having now presented some figures relating to the selection of parentage in three examples of dominant disease, and some figures suggesting the reality of antedating in the later age of onset in aunts and uncles as compared with that of their nephews and nieces, I propose to seek further evidence on the question of antedating by comparing the age of onset in successive generations as a whole, excluding, so far as one can judge, the more recent generations for which information is incomplete, in that those members with a possibly late age of onset have not yet reached the age to show whether they are or are not free from the disease. It will be seen that the personal equation must very seriously influence such a procedure, but if antedating is conspicuous it should be revealed in this way. Table 13 gives the mean age of onset for successive generations for two sex-linked and two dominant sources of disease. I have further calculated the value of x2 for the series corresponding to the two generations to see whether they can reasonably be taken to provide random sam- ples from the same populations.

Table 13. Mean age of onset

First generation Second generation

I I I Sex-linked source I Dominant source I Muscular Huntington's Hereditary Muscular

dystrophy chorea optic atrophy dystrophy

(86) 25-12 (1x0) 39'55 ( 1 1 1 ) 26-69 (36) 483 (106) 21.89 (160) 35'72 (138) 25.00 (51) 6.15

With regard to material available from sex-linked genetic sources, that arising from pedigrees of muscular dystrophy is sparse and largely dependent upon cases with a very early age of onset in both generations. For what it is worth, I find xa = 7.1607, with n = 6 giving P = 0.31. Hereditary optic atrophy provides much more adequate figures on which to base an estimation; from these I find x2 = 14.8216, n = 10, giving P = 0.15. I think we may conclude from these facts that they do not provide evidence of antedating in our two examples of sex-linked disease; in particular, I would note that the contributions to x2 for both series under consideration receive only small additions from the older age groups, indicating that little error has been introduced through the omission in the second generation of potential cases of late onset which had not yet reached the age of mani- festation.

The case for or against antedating in diseases of dominant source as studied by this method is less clear, as is perhaps to be expected from an examination of Tables 11 and 13, and I propose to give my figures in more detail. With regard to muscular dystrophy, I first formed a table including 199 individuals, of whom eighty-seven belonged to the first generation; this gave x 3 = 11.346, n = 6, P = 0.1. Most of the contribution to xa arose from

J U L I A BELL 285

the first age group containing a large excess of cases in the second generation, cont,ributed to largely by children who were noted to sleep with their eyes incompletely closed in infancy; when these cases were transferred to the age groups at which progressive signs of disease were first noticed, I obtained the figures shown in Table 14, giving x2 = 4.792, P = 0.6, with n = 6.

A similar examination into the ages of onset in successive generations in patients with Huntington's chorea provides Table 15, giving x 2 = 9.328, P = 0.15, with n = 6.

Table 14. Age of onset in muscular dystrophy

. 40-49

.

I 2

9.85 0.469 -~

I 0

12-15 0.380 -

22

1 !! 1 1 5.338

x"m 1.053

m.2 Observed 9

8 Expected 6.62

cn $ x2/m 0.856

Totals I 2

--__

.-

41

0.192

57 54-10 0.155

98

43'90

____~

___

- 1.63 1.630

8 8.56 0.037

4

1.121

4

2'37

______

I3

0.025 12'44

___ 21

20-29 30-39 50-59

8 7'17 0.096

4 2.69 0.638

I7 15.68 0'1 I I

I 8 19'32 0.090

8 8.83 0.078

2

3'31 0.518

35 I 16 6

Table 15. Age of onset in Huntington's chorea ____._

~-~

Observed Expected xa/m

-

Observed Expected xa/m

Totals

65-74 5-14 I 15-24 35-44 j 45-54 55-64 ____ ___

32 29 5 33.00 22-41 3.26 0.030 1.938 0.929

25-34 Totals

I I 0

110'01

5'525

I 60 159'99

3.803

- 0.41 0.410

I

0.59 0.285

64 59.26 0.379

I00 I 270

I do not for a moment claim that such results disprove the phenomenon of antedating in human genetic material; they, on the other hand, do fail to demonstrate its presence, and they leave us with Table 11 unexplained.

It will be remembered that Table 11 suggested the possibility of antedating of the age at death in successive generations in Huntington's chorea, as well as in the age of onset- a result to be expected to follow, from the constancy of the duration of disease in this condition, and thus bringing some measure of confidence to the figures relating to the age of onset, rather than a new problem to solve. If we proceed to calculate the probability that the ages of death in successive generations provide random samples of the same population, we obtain Table 16, giving x2 = 4.341, P = 0.7, with n = 7.

286 HEREDITARY MUSCULAR DYSTROPHY

75-84 85-94 , Totals

5 2 79 4‘37 “59 79-01 0.091 0.106 2.616

6 2 120 6.63 2.41 119.99 0.060 0.070 1.725

11 4 I99

--

--

-~

Table 16. Age at death in Huntington’s chorea -

Mean

56-61 - -

53.96 - -

-

15-24

- 0.40 0.400

I 0.60 0.267

I

25-34 35-44 45-54

2 16 21

2.38 15.48 25.01 0.607 0.017 0.643

4 23 42 3.62 23’52 37.99

- ~ ~ _ _ _

-~~~

0.399 0’011 -0’423 ~ - _ _ _ _ _ _

6 39 63

3’ _________

I4 33

55-64 65-74

I9 18-66 0.006

I4 11‘12

0.746

0 bserved Expected x”m

28

0.004

47

28.34 I4

16.88 0.491

28

I think we may conclude that the methods employed have not revealed evidence of antedating. It seems probable that the appearance of antedating suggested by Table 11 is brought about by the incomplete knowledge of the age factors in earlier generations being selective in character-the facts concerning those members who became affected early in life tending to be forgotten and to remain unrecorded. That such selection does occur was shown earlier in this paper on consideration of the divergence between two methods of discovering the mean duration of disease, and I have little doubt that the same selection is in operation to produce the appearance of antedating in Table 11.

The correlation Tables 17-27 appended refer to muscular dystrophy and are those which provided the source of correlation coefficients given in Table 10.

Table 17. Age of onset in pairs of siblings-sex-linked cases

0-2 I 3-5 I 6-8 1 9-11 I 12-14 I 15-17 I 8-20 Totals

2 2

272

I - 88 I4 4 I4 38 9 3 3

3 4 18 I 4 9 32 4 5 -

12-14 15-17 I 8-20

Totals 2

Table 18. Age of onset in pairs of Jirst cousins-sex-linked cases

0-2 1 3-5 1 6-8 g-11 I 12-14 15-17 18-20 Tot&

29

0- 2

3- 5 6- 8 9-1 I 12-14 15-17 I 8-20

I4 4 6 4 2 - I

6 2

I1

3 7 2 2

I 3 I 2 1 15 29

4 4 2 I 2 I -

Totals 7 6

JULIA BELL 287

k f 8 2 8

d ." 4

Table 19. Age of onset in uncle and neplbetc-sex-linked cases ___

0-2

0- 2 9 3- 5 3 6- 8 -

9-1 I 3 12-14 - 15-17 18-20 -

-

Totals I 5

3

4 6 3

I I - 6 16 2

3-5 6-8

4 I 1 2

8 4 20 I 2 - I

7 2

I7 36

Table 20. Age of onset-airs of siblings-recessive cases

0-4 5-9 I10-14 3-34 35-39 ___ ~- 40-44 145-49

I-- Totals

181 93 70 27 I4 5

3

~-

I 0

I 2

15-19 25-29 20-24

- 0- 4 5- 9 10-14 15-19 20-24 25-29 30-34 35-39 40-44 45-49

'7 6 52 18 18 32 5 4

5

4

- - I -

I -

- - I - - I -

5 4

4 I 2

I

- I

4 - I

2 - 2 - 2 -

- - I - - I - -/: -

- I - I I I - - I -

- I I - I - - I

Totals 181 27 406 5 '4

Table 21. Age of onset-pairs of siblings-dominant cases

I 0-9 10-19 20-29 30-39 40-49 ___-___

- I - 50-59 Totals

40

23 18 25 6

I20

2

234

0- 9 10-19 20-29 30-39 40- 49 50-59 60-69

34 5 I

5

8 3

I02

I I

I 8 I 2 I

- I

Totals 40 6

288

50-59

- - - 2

5 - -

HEREDITARY MUSCULAR DYSTROPHY

Table 22. Age of onset-pairs of first cousins-dominant cases

Totals

9 47 14 7 6

_______.

2 2

1 0-9

2-29 30-39 40-49 _______ - - - I 2 4 3 2 4 6

1-19

50-59 - 3 4

20-29

60-69

- 2 - - - I -

3

30- 39

Totals

11

71 17 I 2 I1

5 3

130

~~

Q .a $ B 2

0-9 10-19 20-29 30-39 40-49 50-59 6-69

Totals

I34

0-9 10-19 20-29 3-39 40-49 50-59 60-69

-

9

3 3

I 2

I -

- -

3 4 3 I 2

Totals 10 68 28 7 1 4 1 4

Table 23. Age of onset-p:snt and offspring

Parent

0-9 10-19 20-29 30-39 40-49

I I I I - - I

bD 10-19 20-29 30-39 0-9 40-49 50-59 60-69

0-9 1-19

1 0

45 I - 2 -

1 Totals 3 58

JULIA BELL

Table 25. Age at death in pairs of siblings-sex-linked cases

30-39 40-49 50-59 60-69

_ _ _ ~ Totals

289

- - - -

-_-__ 22

___ 3-5 6- 8 9-1 I 12-14

3- 5 6- 8 9-1 I 12-14 15-17 I 8-20 21-23 24-26 27-29

I 0

26

4 I 7

3

3 I 1 0

- I 40 -

I I 2 -

__ _____

I I

40 j 4

- 6 -

I 0 I I

-

~~

7 12 Totals 4 I 0 4 __

Table 26. Age at death in pairs of siblings-recessive cases

40-49 60-69 Totals 10-19

4 6 4 I I - -

16

20-29

2 4 8 3 3 - - 20

22 16

5 20

1 0

2

5

I

3

4 I

I

I 0 5 80

Table 27. Age at death in pairs of siblings-dominant cases

15-24 35-44 45-54 _____

15-24 25-34 35-44 45-54 55-64 6574 75-84

I I -

3 3 -

--

8 9

I am much indebted to Prof. J. B. S. Haldane for his interest and a number of suggestions during the preparation of this paper.