Clinical Genetics 1989: 36. 92-99

Linkage studies of Myotonia congenita and Paramyotonia congenita

K. BENDER'. H. SJWF', A. STEIERT', H. LAGODNY', T. F. WIENKER' AND M. KOCH' Institut fur Humangcnetik und Anthropologie der Universitiit Freiburg. and

'Institut f i r Humangenetik und Genetiscbe Poliklinik der Universitiit Marburg, FRG

Six German families segregating for Myotonia congenita (MC) and eight families from Ger- many and Great Britain with Paramyotonia congcnita (PC) were tested for linkage relationships using 35 serological and biochemical markers. No linkage of MC to any of the markers was evident, but a positive sum of lod scores for PC vs. the HP locus (2= 1.16, #=O.l6) was found. The results encourage firther investigations involving chromosome I6 markers.

Received 24 February, accepted for publication 18 March 1989

Key wordc dominant non-progressive myotonic disorders; exclusion mapping; serological and biochemical markers.

To date, four different forms of genetic dominant myotonic disorders have been re- ported in man: one systemic progressive type, Myotonic dystrophy (DM, Steinert 1909), and three non-progressive types, My- otonia congenita (MC, Thomsen 1876), Pa- ramyotonia congenita (PC, Eulenburg 1886), and Hyperkalemic Periodic Paralysis (Gamstorp 1956). The DM gene has been mapped to chromosome 19 within the re- gion 19cen-ql3.2 (Eiberg et al. 1983, Shaw & Eiberg 1983, whereas the chromo- somal localizations of the genes for the non- progressive myotonias are stil l unknown. In two authoritative monographs, Becker

(1970, 1977) presented diagnostic, genetic and epidemiologic features of the non-pro- gressive myotonic disorders in the German population; the extensive and well-defined pedigrees involved were the basis for the present btudy. Here, analysis of linkage was camed out to enable construction of an

exclusion map as an initial step towards mapping the MC and PC genes within the human genome.

Familles

The data analyscd came from: (a) Six Ger- man families with Myotonia congenita found in BecKer (1977). including the Ger- man branch of the original Thomsen family, and (b) eight families with Paramyotonia congenita, including seven German families (four published earlier by Bkker 1970,1977 and three referred to us through a neuro- physiological research group in the Federal Republic of Germany) and one British fam- ily (described earlier by Trush et al. 1972). Family members who agreed to participate in the study were visited by one of us (M.K.). The diagnosis was confiied by neurological examination and review of clinical records. Blood samples for serologi-

MC A N D P C L I N K A G E S T U D I E S 93

cal and biochemical analyses and DNA ex- traction were taken from 49 individuals (28 affected) of the MC families and from 120 individuals (64 affected) of the PC families.

Methoak Thirty-five serological and biochemical markers were tested by standard methods and commercial reagents (Tables 1 and 2). Lod scores were computed using the LIPED 3 computer program (Ott 1974).

Results

1. Linkage Studies in MC Families The sums of lod scores from 30 informative marker loci are given in Table 1; PGD, AK 1, GOTl, PEPD, ADA, and AHCY did not segregate in an informative way in any of the families investigated. Slightly positive lod scores were obtained with IGK and ESD. Strongly negative lod scores allowed exclusion of the MC gene from most chro- mosomal regioss examined. In some cases the exclusion encompassed fairly extended segments, in particular on chromosomes 1 and 19. On chromosome 1 the region from p36 to about q32, which spans the collinear linkage group RH (lp36) ubi PGMl (lp22.1) AMY2 (lp21) um FY (lq22-q23) (Povey et al. 1985), was ex- cluded. In fact, the total segment excluded may be larger if F13B (lq31) and FY are linked, as suggested by published data (Ben- der et al. 1987). On chromosome 19 we ex- cluded the region p13 to q12-13 within which are located the genes LE C3 (19~13) APOC2 (19q12-ql3) (Eiberg et al. 1983, Shaw & Eiberg 1987).

2. Linkage Studies with PC The sums of pair-wise lod scores between the PC locus and each of 31 informative marker loci are listed in Table 2; AMY2, GOTl, PEPD, and AHCY were not in- formative in any of the families studied. The

PC gene was excluded from the majority of chromosomal regions examined, including the segments lp36 (RH) to lq22-23 (FY) and 6p23.1 (BF) to 6q12 (PGM3). The ex- clusion may extend down to 6q2-27 where the PLG locus resides (Murray et al. 1987), if indeed linkage between PGM3 and PLG is confinned (c.f. Bissbort et al. 1983). In addition, a segment on the distal long arm of chromosome 14 was also excluded, viz., PI.(14q32.1) to IGHG (14q32.3).

Two positive lod scores are of interest, i.e. that of PC vs. PGD (i= 1.38, 8=0.00) and PC vs. HP (2= 1.19,8=0.16). Theposi- tive lod scores concerning PGD are derived from one family with informative segre- gation in female meioses only, and are not supported by the values for the adjacent RH locus; the data therefore must be re- garded with reservation. Location of PC on the short arm' of chromosome 1 seems unlikely. On the other hand, the possibility of a chromosome 16 focus for the PC gene as indicated by the HP values may find support from the slightly positive lod scores concerning PGP. Slightly positive lod scores were also observed with F13B, ACP1, IGK, TF, GC, LE and P1.

Discussion

After the myotonic disorders were identified (Thomsen 1876, Eulenburg 1886, Steinert 1909), clinicans experienced difliculty in dis- tinguishing PC and MC from DM, and the genetic homogeneity of the diseases was de- bated (c.f. Maas & Patterson 1953). Longi- tudinal studies showed that MC and PC involve the voluntary musculature exclus- ively and pursue a benign course (Becker 1977). In contrast, DM involves several or- gan systems, in addition to the musculature, and is progressive in nature (Becker 1977). These observations indicated that the my- otonic disorders are a genetically hetero- geneous group of diseases. This conclusion

94 B E N D E R E T A L .

lablo 1

Linkage relations of MC vs. 30 marker lolcl

Locus (chromosomal

Lod 8coraa at recombination fractlon (8)

assignment) Sex' 0.05 0.1 0.2 0.3 0.4 t 8

M F J M F J M F J M F J M F J M F J M F J M F J M F J M F J M F J M F J M F J M F J M F J M F J M F J M F J

- 0.64 - 0.80 - 1.45 - 1.36 - 2.40 - 4.03 - 1.02 +0.14 - 1.42 - 0.31 - 0.62 - 0.77 - 0.81 - 0.37 -1.18 - 0.65 + 0.43 - 0.67 +0.10 + 0.25 + 0.35 - 0.28

0.00 -0.27 +0.21 - 1.28 -1.04 - 0.76 -1.07 - 2.61 - 0.96 - 0.68 -1.58 -0.05 - 0.55 -0.17 - 0.41 + 0.20 - 0.23 + 0.04 -0.19 - 0.30 - 1.33 - 1.74 -3.07 - 0.28 - 0.41 - 0.54 - 2.81 - 0.28 - 3.07 + 0.24 + 0.02 + 0.25

- 0.34 - 0.49 -0.83 -0.68 -1.58 - 2.37 - 0.69 +0.12 - 0.66 -0.12 -0.43 - 0.43 -0.55 -0.13 - 0.67 -0.34 + 0.43 -0.14 + 0.08 + 0.21 +0.29 - 0.21 + 0.01 -0.19 +O.l6 -0.68 -0.55 - 0.45 - 0.69 -1.57 - 0.42 - 0.42 - 0.78 - 0.03 - 0.40 -0.13 -0.30 +0.17 -0.14 + 0.03 -0.15 -0.21 - 0.95 -1.16 -2.11 -0.15 - 0.26 - 0.30 -1.71 - 0.20 -1.80 +0.14 + 0.02 +0.16

- 0.08 -0.19 - 0.27 -0.15 - 0.75 - 0.93 - 0.34 +0.10 - 0.36 - 0.02 - 0.20 -0.16 -0.32 - 0.03 - 0.28 - 0.06 + 0.31 +0.18 f O . 0 6 +0.13 +O. lQ - 0.1 1 + 0.03 - 0.08 + 0.07 - 0.20 -0.16 -0.11 - 0.30 - 0.57 +0.03 -0.16 -0.10

0.00 -0.18 - 0.06 -0.14 +0.11 -0.03 + 0.03 - 0.09 - 0.09 - 0.55 - 0.54 - 1.10 - 0.02 - 0.10 - 0.08 - 0.73 -0.10 - 0.83 - 0.03 + 0.01 - 0.02

+ 0.02 - 0.06 - 0.04 + 0.03 - 0.32 - 0.30 -0.16 + 0.07 -0.13 +0.01 - 0.08 - 0.04 -0.19 + 0.05 -0.13 + 0.04 +0.15 +0.18 + 0.04 + 0.06 +0.10 - 0.65 + 0.03 - 0.02 + 0.01 - 0.05 - 0.04 + 0.03 -0.12 -0.13 +0.15 - 0.06 - 0.1 1 + 0.01 - 0.05 - 0.01 - 0.04 + 0.05 +0.01 + 0.03 - 0.05 - 0.02 - 0.31 - 0.22 - 0.53 + 0.03 - 0.04 - 0.01 - 0.29 - 0.04 - 0.03 -0.14

0.00 -0.14

+ 0.04 - 0.01 + 0.02 + 0.07 - 0.09 -0.03 - 0.06 + 0.03 -0.04 + 0.02 - 0.01 - 0.00 70.10 + 0.03 - 0.06 + 0.08 + 0.03 + 0.09 + 0.02 + 0.02 +O.M 0.40 0.0 - 0.02 + 0.02 + 0.02 - 0.01 - 0.01 - 0.02 + 0.05 - 0.03 + 0.02 +0.12 - 0.01 +0.11 + 0.01 + 0.01 + 0.02

0.00 +0.01 +0.02 + 0.02 - 0.01 + 0.01 -0.13 -0.05 -0.18 + 0.03 - 0.01 + 0.03 - 0.09 - 0.01 -0.10 -0.12

0.00 -0.12 0.38 0.0

M C A N D P C L I N K A G E S T U D I E S 95

Locus (chromosomal

Lod scores at recombination fraction (8)

assignment) Sex' 0.05 0.1 0.2 0.3 0.4 2 6 PI (1 4q32.1)

JGHG (14q32.3)

PGP (16P13)

HP (16q22)

(1 8q 1 l-q 12)

(19)

c3 (19~13.3-p13.2)

APOC1 IC2" (19q12413.2) LU (19)

JK A

LE

P1 (22ql1.2-qter)

co (?I

KEL (?)

M F J M F J M F J M F J M F J M F J M F J J

M F J M F J M F J M F J

-0.48 -0.32 +0.04 +0.03 -0.44 -0.29 -0.49 -0.25 -0.10 -0.08 -1.02 -0.51 -0.75 -0.49 +0.39 +0.32 - 1.89 -1.25 -1.68 -1.10 -0.33 -0.19 -2.20 - 1.37 -0.78 -0.44 -0.63 -0.31 - 1.41 -0.75 -1.93 -1.22 -0.04 -0.03 -1.98 -1.23 -1.09 -0.71 -0.87 -0.56 -1.99 -1.29 -3.63 -1.91

-0.21 -0.15 +0.01 +0.02 -0.09 -0.06 -0.05 -0.02 -0.94 -0.64 -0.98 -0.66 -1.23 -0.65 0.00 0.00

- 1.23 -0.65 -0.91 -0.53 -0.24 -0.20 -0.90 -0.61

-0.14 + 0.02 -0.12 - 0.02 - 0.05 - 0.1 1 - 0.27 + 0.20 - 0.64 - 0.55 - 0.06 - 0.64 - 0.26 - 0.05 - 0.31 -0.55 - 0.01 - 0.55 - 0.31 - 0.26 - 0.57 + 0.48 - 0.06 + 0.03 - 0.02 0.00

- 0.30 - 0.30 -0.15 0.00

- 0.15 -0.19 -0.14 - 0.30

- 0.05 + 0.01 - 0.04 + 0.05 - 0.03 0.00

-0.16 + 0.09 -0.31 - 0.28 - 0.02 - 0.30 - 0.25 + 0.01 - 0.24 - 0.23 0.00

- 0.23 -0.11 -0.10 - 0.21 + 0.01 - 0.01 + 0.03 + 0.01 0.00

-0.12 -0.12 + 0.05 0.00

+ 0.05 - 0.05 - 0.09 -0.13

- 0.01 0.00 0.00

+ 0.04 - 0.02 + 0.01 - 0.08 + 0.02 -0.12 -0.11 0.00

- 0.1 1 -0.17 + 0.01 -0.16 - 0.07 0.00

- 0.07 -0.01 - 0.02 - 0.04 +0.09

+ 0.01 + 0.02 + 0.02 0.00

- 0.03 - 0.03 + 0.08 0.00

+ 0.08 - 0.01 - 0.04 - 0.05

The data are given in three lines: Line M is attributed to recombination in the male only (assuming absence of linkage in the female: z, (Om.,.: 8~.m.l.=0.5): line F is the reverse situation: Z2 (OI.,& Om.l.=0.5); line J (joint) gives the lod scores for recombination fractions assumed to be equal in both sexes: z3 (Bm.,.=Ol.m,k). Pedigrees with double intercrosses and untested ancestors contribute to the z-scores to a varying degree. ** From Koch et al. (1989a).

was confirmed when linkage studies ex- cluded both MC and PC from linkage to the APOCZ locus, which is closely linked to the DM gene on chromosome 19 (Koch et al. 1989a, 1989b).

In this study, linkage analyses using sero-

logical and biochemical markers from suit- able families were undertaken as an initial step toward localizing the genes for MC and PC. This seemed to us to be a reasonable approach, as the classical markers are even- ly distributed over the human genome with

96 B E N D E R ET A L .

Tablo 2

Linkage relations of PC vs. 31 marker loci

Lod score8 at recomblnatlon fraction (0 Locus (chromosomal assignment) Sex' 0.05 0.1 0.2 0.3 0.4 2 9

M F J M F J M F J M F J M F J M F JJ M F J M F J M F J M F J M F J M F J M F J M F J M F J M F J M F J M F J

+ 0.03 +1.34 + 1.38 - 2.47 - 1.20 -4.80 - 3.83 - 9.38 - 12.81 - 1.86 - 1.12 - 8.40 + 0.21 -1.85 -1.33 - 1.18 + 0.01 - 0.97 + 0.04 + 0.02 + 0.07 +0.11 + 0.02 +0.14 + 0.09 - 0.83 - 1.00 - 0.47 - 1.12 - 5.85 -0.19 - 1.82 - 3.50 -1.82 - 1.58 - 7.63 -2.16 - 1.14 - 3.87 -2.15 - 1.08 - 3.54 - 2.48 - 0.00 - 4.42 -0.52 + 0.02 - 0.49 -1.85 - 0.61 - 2.49 -1.53 -3.14 - 3.83

+ 0.02 + 1.23 + 1.28 - 1.61 - 0.43 - 2.49 - 2.22 - 6.35 - 8.22 - 1.09 - 0.53 - 3.88 + 0.32 - 1.08 - 0.48 - 0.24 + 0.34 +0.12 + 0.03 + 0.01 + 0.05 + 0.09 + 0.02 +0.11 + 0.38 - 0.37 -0.11 + 0.24 - 0.58 -3.17 - 0.01 - 0.68 -1.82 - 0.75 - 0.97 - 4.44 - 1.58 - 0.45 -2.10 - 1.44 - 0.88 - 2.25 -1.39 - 0.42 - 2.43 - 0.33 + 0.01 - 0.31 -1.50 - 0.43 - 1.07 - 0.89 - 1.60 - 2.08

+0.01 + 0.08 + 0.w - 0.88 +0.16 - 0.82 - 0.78 - 3.31. - 3.89 - 0.45 -0.10 - 1.58 + 0.27 - 0.43 + 0.03 + 0.33 + 0.52 + 0.73 + 0.02 + 0.01 + 0.03 + 0.05 + 0.01 + 0.08 + 0.37 + 0.01 + 0.37 + 0.55 -0.16 - 1.11 + 0.04 - 0.24 - 0.52 -0.40 - 0.40 - 1.76 - 0.81 + 0.04 - 0.88 - 0.72 - 0.30 - 1.08 - 0.49 - 0.08 - 0.78 -0.15 + 0.01 -0.13 - 1.12 - 0.21 - 1.35 - 0.30 - 0.62 - 0.57

+ 0.01 + 0.89 + 0.70 - 0.49 + 0.30 - 0.21 -0.17 -1.88 - 1.78 - 0.19 - 0.01 - 0.60 +0.14 -0.18 + 0.07 + 0.35 + 0.44 + 0.88 + 0.01

0.00 + 0.02 + 0.02 + 0.01 + 0.03 + 0.24 +0.11 + 0.34 + 0.41 - 0.02 - 0.31 -0.01 + 0.01 -0.10 + 0.07 -0.14 - 0.87 - 0.36 +0.14 -0.17 - 0.34 -0.12 - 0.47 -0.15 - 0.05 -0.17 -0.08

0.00 - 0.05 - 0.70 -0.08 - 0.79 - 0.08 -0.17 -0.10

0.00 + 0.37 +0.37 1.45 0.0 -0.22 + 0.23

0.00 + 0.05 - 0.86 - 0.60 - 0.08 - 0.02 -0.18 +0.04 - 0.04 +0.01 0.07 0.27 + 0.20 + 0.25 +0.41 0.74 0.23

0.00 0.00

+0.01 0.06 0.00 + 0.01

0.00 +0.01 0.17 0.0 +0.12 + 0.08 +0.18 0.39 0.24 +0.18

0.00 - 0.03 - 0.04 + 0.08

0.00 + 0.02 - 0.04 -0.18 -0.11 + 0.09 - 0.01 -0.12 - 0.03 -0.15 - 0.03 + 0.05

0.00 -0.01

0.00 -0.01 -0.30 -0.02 - 0.32

0.00 - 0.03 +0.01

M C A N D PC L I N K A G E S T U D I E S 97

Locus (chromosomal

Lod scores at recombination fraction (0)

assignment) Sex' 0.05 0.1 0.2 0.3 0.4 2 e

PI (74q32.f)

IGHG (14q32.3)

PGP (16P13)

( 1 6q22) HP

JK (1 8q 1 l - q 1 2)

LE (19)

c3 (19p13.Sp13.2)

APOC2" (1 9q 12-9 13.2) LU (19)

ADA (20q13.2-qter)

P1 (22ql1.2-qter)

co (?I KEL (7)

M F J M F J M F J M F J M F J M F J M F J M F J J

M F J M F J M F J M F J M F J

-1.88 -1.23 -6.47 -4.47 -8.66 -5.77 -3.21 -1.94 -1.96 -1.37 -6.12 -3.95 -0.74 -0.09 -7.09 -4.80 -8.20 -5.18 -1.20 -0.75 -1.27 -0.54 - 1.59 -0.59 -0.45 +0.11 +0.97 +0.96 +0.49 +1.05 -0.16 +0.12 -1.88 -1.02 -4.97 -2.67 -0.88 -0.56 -1.94 -1.08 -2.17 -1.08 -0.64 -0.24 -3.64 -2.41 -4.39 -2.57 -8.87 -4.66

+0.10 +0.08 -0.11 -0.08 -0.02 -0.02 -0.62 -0.42 -0.61 -0.39 -1.29 -0.81 -1.55 -0.91 +1.05 +0.92 -0.29 +0.16 -0.14 -0.08 -0.49 -0.25 -0.92 -0.45 +0.03 +0.02 +0.02 +0.02 +0.05 +0.04

- 0.55 - 2.44 - 2.97 - 0.83 - 0.78 - 1.94 + 0.28 - 2.50 - 2.37 - 0.34 - 0.02 + 0.03 + 0.35 + 0.80 +1.14 + 0.20 - 0.28 - 0.81 - 0.20 - 0.31 - 0.24 + 0.03 -1.22 - 1.02 - 1.29

+ 0.05 - 0.05 - 0.01 -0.19 -0.18

0.36 - 0.35 + 0.65 + 0.37 - 0.02 - 0.08 -0.12 + 0.01 + 0.01 + 0.02

- 0.21 - 1.29 - 1.47 - 0.36 - 0.44 -0.94 + 0.27 -1.25 - 1.04 -0.14 + 0.08 +0.10 + 0.27 + 0.55 + 0.81 + 0.07 - 0.02 - 0.19 - 0.05 + 0.01 + 0.03 -I- 0.06 - 0.60 - 0.41 -0.12

+ 0.02 - 0.02

0.00 - 0.08 - 0.07 -0.15 -0.12 + 0.38 + 0.29

0.00 - 0.02 - 0.02 i- 0.01 + 0.01 i. 0.01

- 0.04 - 0.52 - 0.56 -0.13 -0.19 - 0.35 +0.15 - 0.47 - 0.34 - 0.04 + 0.01

+0.12 + 0.27 +0.38 1.19 0.16 - 0.02 + 0.02 - 0.04

0.00 +0.10 +0.10 0.10 0.39 + 0.03 - 0.23 -0.15 + 0.10

0.00 0.11 0.27

+ 0.01 - 0.01

0.00 - 0.02 - 0.02 - 0.04 - 0.02 +0.15 +0.13 0.37 0.20

0.00 0.00 0.00 0.00 0.00 0.00

For explanation see Table 1. ** From Koch et al. (1989b).

well-defined chromosomal locations, and are typed rapidly and economically. This strategy has been employed successfully in earlier studies, e.g. by Morton (1956) in es- tablishing linkage between the genes for el-

liptocytosis and the RH blood type on chro- mosome 1, by Eiberg et aI. (1983) in assig- ning DM to the linkage group C3, LU, LE, SE, PEPD on chromosome 19, and most recently by Eiberg et al. (1985) in localizing

98 B E N D E R E T A L .

the cystic fibrosis (CF) gene on chromo- some 7 by synteny to the paraoxonase (PON) gene.

Our data did not demonstrate linkage between MC and any of the markers stud- ied, although slightly positive lod scores were obtained with IGK on chromosome 2 and ESD on chromosome 13. The PC gene was excluded from the majority of the examined regions. Encouraging posi- tive lod scores were found for PC vs the locus for HP (k=1.16, 8=0.16) on the long arm of chromosome 16, which also find support from the slightly positive lod scores (if data from both sexes are com- bined) associated with PGP on the short arm of the same chromosome.

These preliminary findings are being ex- tended by analyses of DNA markers on chromosomes I and 16. Further efforts will be directed towards constructing a more de- tailed exclusion map with highly polymor- phic DNA markers in order to localize the gene for PC.

Acknowledgements

We greatly appreciate the cooperation of the families who participated in the study. We express our thanks to Professor Laura Newell-Morris for her editorial help.

The work was supported by the Deutsche Forschungsgemeinschaft.

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Address: Dr. Klaus Bender Institut f2r Hwnangenetik tlnd An fhropologie der Univ. Freiburg Albertstrmse 11 0-7800 Freiburg FRG