Clinical Genetics 1975: 7 : 209-218
The significance of “unspecific neuropathy“ in hereditary ataxias and related disorders HIVARDSKRE Institute of Medical Genetics, University of Oslo, and Department of Neurology, School of Medicine, University of Bergen, Norway Neurological findings such as polyneuropathy, hyporeflexia, deformities, ataxic signs, and inverted plantar responses were found more frequently in unaffected sibs and other close relatives of people with hereditary ataxias or allied disorders (HA) than in a normal population sample. Introduction of a scoring system for neurological signs allowed the degree of neurological impairment to be estimated. The number of people with scores exceeding the limit of normality (sum score higher than 3.4) was counted among the members of HA families. This number was found to be greater in families where HA segregated as a recessive trait than in those where it segregated as an autosomal dominant trait. The frequency of cases with high scores (“unspecific neuropathy” (Un)) observed in 1st and 2nd degree relatives of patients with dominant HA, suggested a hereditary basis for Un. The ratios were not compatible with simple Mendelism, but the observations fitted well with a hypothesis of polygenic inheritance. U n clustering in families with autosomal dominant HA could be due to a selection phenomenon through a negative assortative mating. Un cases observed in families with recessive HA may, in several instances, reflect disease manifestations in heterozygotes. Received 19 August, accepted for publication 17 October I974
Attention has previously been directed (Skre 1974a, b, c, d) t o the high prevalence, compared with that in a normal population, of minor neurological findings in the relatives of persons with hereditary ataxias and related disorders (HA, Table 1). Similar observations have been reported by other workers (Curtius et al. 1935, Klein 1937, Spillaine 1940, AndrC van Leeuwen 1948, Schut & Book 1953, McNutt et al. 1960, Tyrer & Sutherland 1961). Unspecific neuropathy (Un) was proposed as a common
designation for such minor neurological findings, and was defined according t o a scoring system (Skre 1972, 1974a). The scores, which were corrected for age and sex effects, comprised findings in a routine neurological examination, thus representing a wide range of signs. Ninety-five per cent of a presumably normal population had a sum score lower than 3.5. Accordingly, a total score of 3.5 was selected as a n operational limit for “normality”. I n H A , longevity and reproductive capabi-
This work was supported by grants to the author and the Institute of Medical Genetics from the Norwegian Research Council for Science and the Humanities.
SKRE
210 Table 1
Index Cases and Their Famllies
C1assificat;on of hereditary ataxia and related disorders (HA)
Index cases (primary probands), the starting points for the family investigations, were patients with one or other of the diagnoses listed in Table 1, and who had been admitted t o the Department of Neurology, School of Medicine, University of Bergen, between 1952 and 31 December 1967. The family investigations comprised first degree relatives of primary probands, and a random selection of more distant relatives. For the purpose of the present analysis, sporadic cases, except X-linked CMT (Table l), were assumed to represent autosoma1 recessive disease. Five cases of sporadic SCA, with deviating clinical patterns were added to diagnostic category 5.
gory 1 2
3 4
5 6
Diagnosis Charcot-Marie-Tooth's disease Roussy-Levy's syndrome and myatrophic ataxia Friedreich's ataxia Hereditary spastic paraplegia Spino-cerebellar and cerebellar ataxias Clinical syndromes not agreeing with any of the above-mentioned diagnoses, constituting a heterogeneous group'
Abbreviations CMT RL FA HSP SCAlCA
* The index case diagnoses were: In pedigree 6: Ataxia and Huntington's chorea In pedigree 25: Refsum's disease In pedigree 45: Refsum's syndrome (R) In pedigree 57: Spino-cerebellar ataxia, rigidity and
dystonia In pedigree 68: Cerebellar ataxia and choreo-athetosis In pedigrees 72 and 80: Kugelberg-Welander's syndrome (K-W)
lity are generally only moderately affected. However, since the disease is often manifest in early adult life, mating may be assortative (negative assortative mating), and carry a risk for the introduction of other traits into the family. If this hypothesis holds true, for every generation in dominant H A in particular, there would exist the possibility of new, genetically influenced, disorders entering the kindred (Skre 1974b, c,d). Such a hypothesis might explain the high prevalence of U n in families with autosomal dominant HA. When Un occurs in kindreds with recessively inherited HA, the condition may reflect minor disease manifestations in the heterozygotes (Skre 1974a, b). The aim of the present work was to test the hypotheses outlined above, by analysis of the Un ratios observed in the pedigrees and of the clinical patterns expressed by the scores.
Clinlcal Examlnatlon
A standard neurological examination (Monrad-Krohn 1962) was performed on each person entering this study, except in three cases, where reports from local physicians formed the basis for the clinical evaluation. All but 30 of the total entering the HA study were seen by the author, nevertheless, all except the three persons mentioned were examined by neurologists, according to the standard criteria. One hundred and thirtythree persons were admitted to a department of neurology, 234 were seen in outpatient wards, and the remainder were examined in their homes. Scoring of Observations
The diagnosis of monomeric disease (HA) followed traditional criteria (Becker 1966, Pratt 1967). The clinical observations made on those who did not have classical neurological disease were scored according to a system described previously (Skre 1972); corrections for age and sex differences were employed, based on findings in a normal population (Skre 1974a).
S I G N I F I C A N C E 0 F ’‘ U N S P E C I F I C N E U R 0 P A T H Y
211
”
Table 2 Examined subjects: numbers, relationships, and reasons for non-excrnination -
~
~~
Reason no examination Relationship to index case (I)
Sibs Half sibs
No. Qlo No.
Parents
No.
Offspring
No. %
Q/n
010
Total No. of 1st degree relatives and half sibs
Total No.
No. examined
Living far away
Too young, < 5 years
Exam. refused
Deceased
Other
427 100 30 100 176 100 114 100
295 69.1 13 43.3 71 40.3 63 54.4
26 6.1 7 23.3 1 0.6 8 7.9
2 0.5 2 6.7 0 0 2 1.8
7 1.6
90 21.1 1 3.3 92 52.3 3 2.6
7
747
442
42
6
9
Index cases
87
Nephews, nieces
86
Uncles 8 aunts, paternal
11
Uncles & aunts, maternal
31
1st cousins, paternal
28
1st cousins, maternal
12
Grandparents
0 0 1 0.6 1 0.9
186
1.6 7 23.3 11 6.3 37 32.5 62
4
More distant relatives Total No. examined
56 757
Persons whose total corrected score was 3.5 or higher were classified as having unspecific neuropathy (Un), if other neurological diagnoses could be excluded. Results and Analyses
U n distribution in HA families The totaI examined was 757; 383 males and 374 females, belonging to 87 kindreds. Table 2 shows the number of examined relatives of index cases and the reasons for failure to examine all 1st degree relatives. Fig. 1 shows the age distribution of all examined persons at the ladonly examination. Table 3 shows the neurological disorders observed segregating in the families, other than the classical HA; these comprise 5 % of the total sample. For the purpose of
Table 3 Neurological diagnoses” (score higher than 3.4 in the quantitative test system) other than HA recorded in the HA pedigrees Diagnosis Poliomyelitis sequelae Epilepsy, secondary Cerebral palsy Essential tremor Arteriosclerotic neuropathies Parkinsonism Posterior fossa tumors Chronic encephalitis Guiilain-BarrB’s syndrome Subacute combined sclerosis Dorsal tabes (syphilitic) Multiplo sclerosis Senile dementia Ocular myopathy Brachial plexus lesion Ulnar nerve neuritis Congenital dysraphia & paraplegia Down’s syndrome Total
No. 8 5 4 3
2 2 2 1 1 1 1 1 1 1 1 1 1 1
37
* Cerebro-vascular accidents and sciatica were dis-
regarded in the scoring procedure.
SKRE
212
Age distribution at (last)
examination
H-A families
% 2(
19
0
6-33
No.
161
9a
1-53
iia
140
I+
119
64-13
82
n ‘
~
3
Age
39
Flg. 1. Age distribution at (last) examination H-A families.
family analyses, these persons were scored as normals. Table 4 presents the total series distributed in main diagnostic groups and types of manifestation. Table 5A shows the distribution of Un in 1st and 2nd degree relatives who were not affected by HA, in kindreds of probands with autosomal dominant and recessive disorders. Significantly higher Un incidence was found in 1st degree than in 2nd degree relatives of dominant cases, but not in those of recessives. In addition, significantly higher Un incidences were observed in kindreds with recessive HA than in kindreds with dominant disease. Tests for observed U n incidence in the HA families versus
expected Un incidence calculated from the frequency in the general population (5 %) yielded ~2~ values of 23.21, 2.37, 87.62, and 39.33 for categories (i)-(iv) in Table 5A, with corresponding probabilities of less than 0.001 for all categories except (ii). These results indicate that a true Un aggregation exists in the HA families investigated, and that there is a major difference between families with autosomal dominant and recessive HA with regard t o Un distribution.
Un distribuiion in families with autosornal dominant H A traits If Un in HA families were caused by polygenic inheritance, the genes involved being
S I G N I F I C A N C E 0 F '' U N S P E C I F I C N E U R 0 P A T H Y
213
"
Table 4 Distribution of manifestation types within diagnostic groups Manifestation type: HA Un
Category
Diagnosis
1
CMT,
autosomal dominant X-linked recessive autosomal recessive
83 15 8
(21) (11)
2
RL,
autosomal dominant sporadic
38
4
FA, HSP.
5
SCA,
3
6
Classical
Normal
Sum
23 24 10
73 30 9
179 69 27
(6) (2)
8
5
24 1
70 8
(5)
2
autosomal recessive
10
(7)
29
29
68
autosornal dominant autosomal recessive
23 11
(3)
4 19
11
31
38 61
autosornal dominant autosomal recessive sporadiclatypic CAI, autosomal recessive CA2, Marinesco-Sjogren's disease Ataxia and basal ganglia syndromes: autosomal dominant autosomal recessive U-W, autosornal recessive R, autosomal recessive
11 11 5 16 5
(4) (6) (5) (10) (2)
10 14 13 19 2
11 28 10 29 7
32 53 28 64 14
9 2 3 3
(2) (11
4 1 4 2
5 3
4 6
18 6 11 11
191
311'
757
(5)
(2) (2) ~
Total
225
~~
(87)
Number of index cases in brackets ( ). * 37 cases with other neurological diagnoses included.
Table 5 A: Distribution of persons with Un and healthy people (N) among 1st and 2nd degree relatives of HA index cases ~~
1st degree
2nd degree
N
Un
N
x=
74 (69.8 %)
(ii) 6 (13.3 %)
39 (86.7 %)
4.77
Un
(i) Autosomal dominant conditions
32 (30.2 %)
~
P
< 0.05 ~
X-linked or autosomal recessive conditions
(iii) 96 (42.5 010)
130 (57.5 " 0 )
(iv) 40 (47.6 010)
4.60
x2
0 66
< 0.5
15.01
< 0.05
P
44 (52.4 010)
< 0.001
B: Distribution of people with Un and healthy persons (N) among 1st and 2nd degree relatives of Un probands in the non-HA portion of families with dominant HA 2nd degree
1st degree
Autosoma1 dominant conditions
Obs. Exp.
Un
N
Un
N
10 (21.7 O h ) 10.3 (22.4 %)
36 (78.3 01.3) 35.7 (77.6 010)
5 (11.6 %) 4.9 (11.3 010)
(88.4 0%) 38.1 (88.7 %)
x2
P
1.62
0.2
38
-
-
~~
214
SKRE
independent of the genes for HA, certain ratios would be expected between the Un incidence in 1st and in 2nd degree relatives, as well as between these incidences and the incidence in the general population. The validity of such a hypothesis was tested in families where classical disease segregated as a dominant trait, since the “dominant” families displayed differences in Un incidence between 1st and 2nd degree relatives of HA patients (Table 5A). The Un ratios in the examined non-HA relatives were the basis for the calculations. Un probands were defined as the first examined Un case in each family. Table 5B shows the Un distribution between 1st and 2nd degree relatives of Un probands, after exclusion of all family members with manifest HA and of all families in which no Un case was found. Tests for goodness of fit between the ratios of Un to healthy persons amongst the 1st and 2nd degree relatives among the non-HA portion of families with dominant HA and ratios of Un to healthy persons in a general population sample resulted in ~2 values of 5.56 (0.01 < P < 0.02) and 0.84 (0.3 < P < 0.5) for 1st and 2nd degree relatives, respectively. Again, an important difference appeared to exist beTable 6 A: Distribution by sex of non-HA sibs of HA probands in families w:th X-linked recessive HA Males
Females
Total
Normal
1 12
12 9
21
Total
13
21
34
Un
xz = 6.35; 0.01
13
< P < 0.02
B: Distribution of healthy parents in tho same families as above
Un Normal
Fathers
Mothers
0 4
5 1
tween Un incidence in non-affected relatives of cases with autosomal dominant H A and that in the normal population. However, the difference in Un incidence between 1st and 2nd degree Un relatives was not significant, although there was a clear tendency for more Un cases to occur among 1st degree relatives (Table 5B). For polygenic traits, the incidence of affection amongst 1st degree relatives of probands equals the square root of the incidence in the population (Edwards 1960). Un incidence in the population was 5 %, giving an expected Un incidence in 1st degree relatives of 22.4 %, equalling 10.3 cases. This compares with the observed 80 %, 21.7 % (10 cases) (heritability Falconer 1965) (Table 5B). The expected ratio between the Un incidence in 1st and 2nd degree relatives of the Un probands (assuming polygenic inheritance) is given by the equations (Falconer 1965): bl = (xg - xl)/(A - G ) = 1/2 hz hz bz = (xg - x&‘(A - G ) = hence, x ( x f i - xi) = xg - xg x is the interval, in standard deviations, between the threshold for Un manifestation and Un liability mean: (xg) in the population; (xi) in 1st degree relatives; and (x2) in 2nd degree relatives. From the observed incidence of Un in 1st degree relatives (ql) and Un in the general population (qfi), values for xi and xB were extracted from the tables of Falconer (1965), and q2 estimated to be 11.3 %, corresponding to an expected number of 4.9 Un cases, as against the observed 5 cases in kindreds with autosomal dominant disease (Table 5B).
>
U n ratios in families with recessive H A traits Table 6A gives the distribution by sex of Un in non-HA relatives of persons whose HA is assumed to be X-linked recessive. Un was far more frequent in females than in
S IG N I F I CA N C E 0F
’I
U NS PEC I F I C NE U R 0PAT HY
”
215
Table 7
Distribution of individuals in proband sibships with autosomal recessive HA. Expected n u r n h r s for U n were cclrulated on the assumption that U n represents manifestation in HA heterozygotes Non-affected Diagnosis
Un
Manifest HA*
% of total,
Normal
index
Total“
cases exc Iuded CMT Fa
HSP SCA CA Other
Total
Difference
Obs. Exp. Obs. Exp. Obs. Exp. Obs. Exp. Obs. Exp. Obs. Exp. Obs. Exp.
23
(10)
7
9.75 (2) 3.5
5 6.5 12 15.5 9 10.5 9 8.5 8 19.5 5 7
33.75 (26)
48 67.5
-7.75
-19.5
8 10 10 11
(3) 3.25 (3) 7.75 (5) 5.25 (3) 4.25
69
(38.5) (38.7) (42.9) (52.9) (20.5) (35.7)
(36.2)
5 3.25 16 7.75 7 5.25 5 4.25 21 9.75 7 3.5
61 33.75
18 38
26 25 52 19
177
(13) 13 (31) 31 (21) 21 (17) 17 (39) 39 (14) 14 (135) 135
+27.25
* Total No. of HA cases; in parentheses: No. of HA cases, index cases excluded. ’* Total No. of sibs; in parentheses: No. of sibs, index cases excluded.
males, and the difference was statistically significant (xz = 6.35; 0.01 P 0.02). The distribution is compatible with a hypothesis that the Un state in heterozygotes for X-linked recessive H A may frequently represent gene manifestation. Similar findings in parents support such a hypothesis. The Un ratios in sibships with autosomal recessive HA would, t o a certain extent, be compatible with the view that Un may represent manifestations in H A heterozygotes in many families (Table 7). In spino-cerebellar ataxia (SCA), close to the expected 50 % of sibs of index cases had Un, as opposed to about 40 % in Charcot-MarieTooth’s disease (CMT), Friedreich’s ataxia (FA), and hereditary spastic paraplegia (HSP). Too few Un cases were observed in cerebellar ataxia, both in the type 5 of Zulch and in Marinesco-Sjogren’s disease,
<
The significance of “unspecific neuropathy“ in hereditary ataxias and related disorders HIVARDSKRE Institute of Medical Genetics, University of Oslo, and Department of Neurology, School of Medicine, University of Bergen, Norway Neurological findings such as polyneuropathy, hyporeflexia, deformities, ataxic signs, and inverted plantar responses were found more frequently in unaffected sibs and other close relatives of people with hereditary ataxias or allied disorders (HA) than in a normal population sample. Introduction of a scoring system for neurological signs allowed the degree of neurological impairment to be estimated. The number of people with scores exceeding the limit of normality (sum score higher than 3.4) was counted among the members of HA families. This number was found to be greater in families where HA segregated as a recessive trait than in those where it segregated as an autosomal dominant trait. The frequency of cases with high scores (“unspecific neuropathy” (Un)) observed in 1st and 2nd degree relatives of patients with dominant HA, suggested a hereditary basis for Un. The ratios were not compatible with simple Mendelism, but the observations fitted well with a hypothesis of polygenic inheritance. U n clustering in families with autosomal dominant HA could be due to a selection phenomenon through a negative assortative mating. Un cases observed in families with recessive HA may, in several instances, reflect disease manifestations in heterozygotes. Received 19 August, accepted for publication 17 October I974
Attention has previously been directed (Skre 1974a, b, c, d) t o the high prevalence, compared with that in a normal population, of minor neurological findings in the relatives of persons with hereditary ataxias and related disorders (HA, Table 1). Similar observations have been reported by other workers (Curtius et al. 1935, Klein 1937, Spillaine 1940, AndrC van Leeuwen 1948, Schut & Book 1953, McNutt et al. 1960, Tyrer & Sutherland 1961). Unspecific neuropathy (Un) was proposed as a common
designation for such minor neurological findings, and was defined according t o a scoring system (Skre 1972, 1974a). The scores, which were corrected for age and sex effects, comprised findings in a routine neurological examination, thus representing a wide range of signs. Ninety-five per cent of a presumably normal population had a sum score lower than 3.5. Accordingly, a total score of 3.5 was selected as a n operational limit for “normality”. I n H A , longevity and reproductive capabi-
This work was supported by grants to the author and the Institute of Medical Genetics from the Norwegian Research Council for Science and the Humanities.
SKRE
210 Table 1
Index Cases and Their Famllies
C1assificat;on of hereditary ataxia and related disorders (HA)
Index cases (primary probands), the starting points for the family investigations, were patients with one or other of the diagnoses listed in Table 1, and who had been admitted t o the Department of Neurology, School of Medicine, University of Bergen, between 1952 and 31 December 1967. The family investigations comprised first degree relatives of primary probands, and a random selection of more distant relatives. For the purpose of the present analysis, sporadic cases, except X-linked CMT (Table l), were assumed to represent autosoma1 recessive disease. Five cases of sporadic SCA, with deviating clinical patterns were added to diagnostic category 5.
gory 1 2
3 4
5 6
Diagnosis Charcot-Marie-Tooth's disease Roussy-Levy's syndrome and myatrophic ataxia Friedreich's ataxia Hereditary spastic paraplegia Spino-cerebellar and cerebellar ataxias Clinical syndromes not agreeing with any of the above-mentioned diagnoses, constituting a heterogeneous group'
Abbreviations CMT RL FA HSP SCAlCA
* The index case diagnoses were: In pedigree 6: Ataxia and Huntington's chorea In pedigree 25: Refsum's disease In pedigree 45: Refsum's syndrome (R) In pedigree 57: Spino-cerebellar ataxia, rigidity and
dystonia In pedigree 68: Cerebellar ataxia and choreo-athetosis In pedigrees 72 and 80: Kugelberg-Welander's syndrome (K-W)
lity are generally only moderately affected. However, since the disease is often manifest in early adult life, mating may be assortative (negative assortative mating), and carry a risk for the introduction of other traits into the family. If this hypothesis holds true, for every generation in dominant H A in particular, there would exist the possibility of new, genetically influenced, disorders entering the kindred (Skre 1974b, c,d). Such a hypothesis might explain the high prevalence of U n in families with autosomal dominant HA. When Un occurs in kindreds with recessively inherited HA, the condition may reflect minor disease manifestations in the heterozygotes (Skre 1974a, b). The aim of the present work was to test the hypotheses outlined above, by analysis of the Un ratios observed in the pedigrees and of the clinical patterns expressed by the scores.
Clinlcal Examlnatlon
A standard neurological examination (Monrad-Krohn 1962) was performed on each person entering this study, except in three cases, where reports from local physicians formed the basis for the clinical evaluation. All but 30 of the total entering the HA study were seen by the author, nevertheless, all except the three persons mentioned were examined by neurologists, according to the standard criteria. One hundred and thirtythree persons were admitted to a department of neurology, 234 were seen in outpatient wards, and the remainder were examined in their homes. Scoring of Observations
The diagnosis of monomeric disease (HA) followed traditional criteria (Becker 1966, Pratt 1967). The clinical observations made on those who did not have classical neurological disease were scored according to a system described previously (Skre 1972); corrections for age and sex differences were employed, based on findings in a normal population (Skre 1974a).
S I G N I F I C A N C E 0 F ’‘ U N S P E C I F I C N E U R 0 P A T H Y
211
”
Table 2 Examined subjects: numbers, relationships, and reasons for non-excrnination -
~
~~
Reason no examination Relationship to index case (I)
Sibs Half sibs
No. Qlo No.
Parents
No.
Offspring
No. %
Q/n
010
Total No. of 1st degree relatives and half sibs
Total No.
No. examined
Living far away
Too young, < 5 years
Exam. refused
Deceased
Other
427 100 30 100 176 100 114 100
295 69.1 13 43.3 71 40.3 63 54.4
26 6.1 7 23.3 1 0.6 8 7.9
2 0.5 2 6.7 0 0 2 1.8
7 1.6
90 21.1 1 3.3 92 52.3 3 2.6
7
747
442
42
6
9
Index cases
87
Nephews, nieces
86
Uncles 8 aunts, paternal
11
Uncles & aunts, maternal
31
1st cousins, paternal
28
1st cousins, maternal
12
Grandparents
0 0 1 0.6 1 0.9
186
1.6 7 23.3 11 6.3 37 32.5 62
4
More distant relatives Total No. examined
56 757
Persons whose total corrected score was 3.5 or higher were classified as having unspecific neuropathy (Un), if other neurological diagnoses could be excluded. Results and Analyses
U n distribution in HA families The totaI examined was 757; 383 males and 374 females, belonging to 87 kindreds. Table 2 shows the number of examined relatives of index cases and the reasons for failure to examine all 1st degree relatives. Fig. 1 shows the age distribution of all examined persons at the ladonly examination. Table 3 shows the neurological disorders observed segregating in the families, other than the classical HA; these comprise 5 % of the total sample. For the purpose of
Table 3 Neurological diagnoses” (score higher than 3.4 in the quantitative test system) other than HA recorded in the HA pedigrees Diagnosis Poliomyelitis sequelae Epilepsy, secondary Cerebral palsy Essential tremor Arteriosclerotic neuropathies Parkinsonism Posterior fossa tumors Chronic encephalitis Guiilain-BarrB’s syndrome Subacute combined sclerosis Dorsal tabes (syphilitic) Multiplo sclerosis Senile dementia Ocular myopathy Brachial plexus lesion Ulnar nerve neuritis Congenital dysraphia & paraplegia Down’s syndrome Total
No. 8 5 4 3
2 2 2 1 1 1 1 1 1 1 1 1 1 1
37
* Cerebro-vascular accidents and sciatica were dis-
regarded in the scoring procedure.
SKRE
212
Age distribution at (last)
examination
H-A families
% 2(
19
0
6-33
No.
161
9a
1-53
iia
140
I+
119
64-13
82
n ‘
~
3
Age
39
Flg. 1. Age distribution at (last) examination H-A families.
family analyses, these persons were scored as normals. Table 4 presents the total series distributed in main diagnostic groups and types of manifestation. Table 5A shows the distribution of Un in 1st and 2nd degree relatives who were not affected by HA, in kindreds of probands with autosomal dominant and recessive disorders. Significantly higher Un incidence was found in 1st degree than in 2nd degree relatives of dominant cases, but not in those of recessives. In addition, significantly higher Un incidences were observed in kindreds with recessive HA than in kindreds with dominant disease. Tests for observed U n incidence in the HA families versus
expected Un incidence calculated from the frequency in the general population (5 %) yielded ~2~ values of 23.21, 2.37, 87.62, and 39.33 for categories (i)-(iv) in Table 5A, with corresponding probabilities of less than 0.001 for all categories except (ii). These results indicate that a true Un aggregation exists in the HA families investigated, and that there is a major difference between families with autosomal dominant and recessive HA with regard t o Un distribution.
Un distribuiion in families with autosornal dominant H A traits If Un in HA families were caused by polygenic inheritance, the genes involved being
S I G N I F I C A N C E 0 F '' U N S P E C I F I C N E U R 0 P A T H Y
213
"
Table 4 Distribution of manifestation types within diagnostic groups Manifestation type: HA Un
Category
Diagnosis
1
CMT,
autosomal dominant X-linked recessive autosomal recessive
83 15 8
(21) (11)
2
RL,
autosomal dominant sporadic
38
4
FA, HSP.
5
SCA,
3
6
Classical
Normal
Sum
23 24 10
73 30 9
179 69 27
(6) (2)
8
5
24 1
70 8
(5)
2
autosomal recessive
10
(7)
29
29
68
autosornal dominant autosomal recessive
23 11
(3)
4 19
11
31
38 61
autosornal dominant autosomal recessive sporadiclatypic CAI, autosomal recessive CA2, Marinesco-Sjogren's disease Ataxia and basal ganglia syndromes: autosomal dominant autosomal recessive U-W, autosornal recessive R, autosomal recessive
11 11 5 16 5
(4) (6) (5) (10) (2)
10 14 13 19 2
11 28 10 29 7
32 53 28 64 14
9 2 3 3
(2) (11
4 1 4 2
5 3
4 6
18 6 11 11
191
311'
757
(5)
(2) (2) ~
Total
225
~~
(87)
Number of index cases in brackets ( ). * 37 cases with other neurological diagnoses included.
Table 5 A: Distribution of persons with Un and healthy people (N) among 1st and 2nd degree relatives of HA index cases ~~
1st degree
2nd degree
N
Un
N
x=
74 (69.8 %)
(ii) 6 (13.3 %)
39 (86.7 %)
4.77
Un
(i) Autosomal dominant conditions
32 (30.2 %)
~
P
< 0.05 ~
X-linked or autosomal recessive conditions
(iii) 96 (42.5 010)
130 (57.5 " 0 )
(iv) 40 (47.6 010)
4.60
x2
0 66
< 0.5
15.01
< 0.05
P
44 (52.4 010)
< 0.001
B: Distribution of people with Un and healthy persons (N) among 1st and 2nd degree relatives of Un probands in the non-HA portion of families with dominant HA 2nd degree
1st degree
Autosoma1 dominant conditions
Obs. Exp.
Un
N
Un
N
10 (21.7 O h ) 10.3 (22.4 %)
36 (78.3 01.3) 35.7 (77.6 010)
5 (11.6 %) 4.9 (11.3 010)
(88.4 0%) 38.1 (88.7 %)
x2
P
1.62
0.2
38
-
-
~~
214
SKRE
independent of the genes for HA, certain ratios would be expected between the Un incidence in 1st and in 2nd degree relatives, as well as between these incidences and the incidence in the general population. The validity of such a hypothesis was tested in families where classical disease segregated as a dominant trait, since the “dominant” families displayed differences in Un incidence between 1st and 2nd degree relatives of HA patients (Table 5A). The Un ratios in the examined non-HA relatives were the basis for the calculations. Un probands were defined as the first examined Un case in each family. Table 5B shows the Un distribution between 1st and 2nd degree relatives of Un probands, after exclusion of all family members with manifest HA and of all families in which no Un case was found. Tests for goodness of fit between the ratios of Un to healthy persons amongst the 1st and 2nd degree relatives among the non-HA portion of families with dominant HA and ratios of Un to healthy persons in a general population sample resulted in ~2 values of 5.56 (0.01 < P < 0.02) and 0.84 (0.3 < P < 0.5) for 1st and 2nd degree relatives, respectively. Again, an important difference appeared to exist beTable 6 A: Distribution by sex of non-HA sibs of HA probands in families w:th X-linked recessive HA Males
Females
Total
Normal
1 12
12 9
21
Total
13
21
34
Un
xz = 6.35; 0.01
13
< P < 0.02
B: Distribution of healthy parents in tho same families as above
Un Normal
Fathers
Mothers
0 4
5 1
tween Un incidence in non-affected relatives of cases with autosomal dominant H A and that in the normal population. However, the difference in Un incidence between 1st and 2nd degree Un relatives was not significant, although there was a clear tendency for more Un cases to occur among 1st degree relatives (Table 5B). For polygenic traits, the incidence of affection amongst 1st degree relatives of probands equals the square root of the incidence in the population (Edwards 1960). Un incidence in the population was 5 %, giving an expected Un incidence in 1st degree relatives of 22.4 %, equalling 10.3 cases. This compares with the observed 80 %, 21.7 % (10 cases) (heritability Falconer 1965) (Table 5B). The expected ratio between the Un incidence in 1st and 2nd degree relatives of the Un probands (assuming polygenic inheritance) is given by the equations (Falconer 1965): bl = (xg - xl)/(A - G ) = 1/2 hz hz bz = (xg - x&‘(A - G ) = hence, x ( x f i - xi) = xg - xg x is the interval, in standard deviations, between the threshold for Un manifestation and Un liability mean: (xg) in the population; (xi) in 1st degree relatives; and (x2) in 2nd degree relatives. From the observed incidence of Un in 1st degree relatives (ql) and Un in the general population (qfi), values for xi and xB were extracted from the tables of Falconer (1965), and q2 estimated to be 11.3 %, corresponding to an expected number of 4.9 Un cases, as against the observed 5 cases in kindreds with autosomal dominant disease (Table 5B).
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U n ratios in families with recessive H A traits Table 6A gives the distribution by sex of Un in non-HA relatives of persons whose HA is assumed to be X-linked recessive. Un was far more frequent in females than in
S IG N I F I CA N C E 0F
’I
U NS PEC I F I C NE U R 0PAT HY
”
215
Table 7
Distribution of individuals in proband sibships with autosomal recessive HA. Expected n u r n h r s for U n were cclrulated on the assumption that U n represents manifestation in HA heterozygotes Non-affected Diagnosis
Un
Manifest HA*
% of total,
Normal
index
Total“
cases exc Iuded CMT Fa
HSP SCA CA Other
Total
Difference
Obs. Exp. Obs. Exp. Obs. Exp. Obs. Exp. Obs. Exp. Obs. Exp. Obs. Exp.
23
(10)
7
9.75 (2) 3.5
5 6.5 12 15.5 9 10.5 9 8.5 8 19.5 5 7
33.75 (26)
48 67.5
-7.75
-19.5
8 10 10 11
(3) 3.25 (3) 7.75 (5) 5.25 (3) 4.25
69
(38.5) (38.7) (42.9) (52.9) (20.5) (35.7)
(36.2)
5 3.25 16 7.75 7 5.25 5 4.25 21 9.75 7 3.5
61 33.75
18 38
26 25 52 19
177
(13) 13 (31) 31 (21) 21 (17) 17 (39) 39 (14) 14 (135) 135
+27.25
* Total No. of HA cases; in parentheses: No. of HA cases, index cases excluded. ’* Total No. of sibs; in parentheses: No. of sibs, index cases excluded.
males, and the difference was statistically significant (xz = 6.35; 0.01 P 0.02). The distribution is compatible with a hypothesis that the Un state in heterozygotes for X-linked recessive H A may frequently represent gene manifestation. Similar findings in parents support such a hypothesis. The Un ratios in sibships with autosomal recessive HA would, t o a certain extent, be compatible with the view that Un may represent manifestations in H A heterozygotes in many families (Table 7). In spino-cerebellar ataxia (SCA), close to the expected 50 % of sibs of index cases had Un, as opposed to about 40 % in Charcot-MarieTooth’s disease (CMT), Friedreich’s ataxia (FA), and hereditary spastic paraplegia (HSP). Too few Un cases were observed in cerebellar ataxia, both in the type 5 of Zulch and in Marinesco-Sjogren’s disease,
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