American Journal of Medical Genetics 41:lO-14 (1991)
MASA Syndrome: Clinical Variability and Linkage Analysis M.Rietsche1, W. Friedl, S. Uhlhaas, M. Neugebauer, D. Heimann, and K. Zerres Institut fur Humangenetik der Universitat Bonn, Bonn (M.R., W.F., S.U., K . ZJ, Institut fur Medizinische Statistik, Dokumentation und Datenverarbeitung der Universitat Bonn (M.N.), and Pflege- und Bildungsheim Kloster Ebernach, Cochem (D.H.) We report on a family with three males with MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs).One patient demonstrated spastic paraplegia and psychomotor retardation but no adducted thumbs. The described family underlines the clinical variability in MASA syndrome. DNA studies confirm linkage to DNA markers of the Xq28 region. Analysis of published cases with hereditary spastic paraplegia (HSP), where linkage studies have been carried out, emphasizes the clinical variability in MASA syndrome and other types of HSP, thus making a definite diagnosis in single cases often impossible.
KEY WORDS: hereditary spastic paraplegia, adducted thumb, molecular linkage INTRODUCTION The MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs) is an X-linked type of hereditary spastic paraplegia (HSP) first described by Bianchine and Lewis [19741. Similar cases have been reported by Gareis and Mason [1984], Yeatman et al. [1984], Kenwrick et al. 119861, Winter et al. [19891,and Schrander-Stumpel et al. [19901. Kenwrick et al. [1986], Winter et al. [19891, and SchranderStumpel et al. [1990] found close linkage t o DXS15 and DXS52. We report on a family with MASA syndrome. The comparison of clinical findings and linkage data gives evidence that our family presents the same disorder as that described by Winter et al. 119891 and Kenwrick et al. [1986].
Received for publication October 17,1990; revision received January 7, 1991. Address reprint requests to Dr. med. Klaus Zerres, Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, D-5300 Bonn 1, Germany.
0 1991 Wiley-Liss, Inc.
METHODS Two affected males and three female carriers (Fig. 1) were examined by the authors (D.H., M.R., K.Z.) and by different neurologists. Chromosome analysis was carried out in one patient (11-4). Information about one deceased affected male was obtained by reports from relatives. Linkage studies were performed with DNA markers from the proximal and distal Xq: DXYSl (pDP34), DXS3 (p19-2), DXS17 (S9), DXSll (p22-33), DXS42 (43-15),DXS98 (4D8B),DXS304 (U6.2),DXS15 (DX13), DXS52 (St14), and DXS305 (St35.691). CLINICAL REPORTS Patient 1 (11-2) He was born in 1928 after a normal pregnancy and delivery with cleft palate and bilateral adduction of thumbs. His psychomotor development was severely retarded. He was able to sit at 11/2 years and to walk unaided at 2% years. He always walked unsteadily and his knees kept knocking together. He showed severe mental retardation and no development of speech (which could also have been influenced by the cleft palate).Bowel and bladder control were never achieved. He was killed in 1943. Patient 2 (11-4)(Fig. 2a-c) He was born in 1940 after a normal pregnancy and delivery with club feet predominantly on the right side. On examination he showed hammer toes, bilateral adduction of thumbs, radial abduction of the right index finger, and deep set eyes. He underwent operations for knee contractures at age 9 years and elongation of achilles tendons at age 12. Chromosome analysis was normal. His psychomotor developmentwas significantly delayed with an IQ of 52. He was able to sit and made his first attempts to walk at age 2 years. He could never walk without support and then always tired quickly. He became wheel chair dependent at age 9 years. His bladder and sphincter control insufficiency slightly improved by toilet training. He suffered recurrent urinary infections. At age 46 years operation of meatal stenosis, phimosis, and inguinal hernia was performed. Neurological examination showed spastic paraparesis with hy-
MASA Syndrome 1
11
2
I
I
0. d
d,d
d 1 8
2.3 B.b 1
1
d 3 b
2
III
N U
U
d
d 3 b
1
B
Fig. 1. Pedigree and results of linkage analysis in a family with MASA syndrome. pDP34, alleles P,p: S9, alleles S,s; p22-33, alleles T,t; U6.2, alleles U,u; DX13, alleles D , d St 14, alleles 1,2 and 3; St 35.691, alleles B,b.
Fig. 2. a: Patient 11-4 with MASA syndrome with characteristic deep-set eyes. b/c: Abnormalities of thumbs and index fingers in patient 11-4.
perreflexia. Since age 13years he has lived in a n institution for the mentally handicapped.
predominantly on right) was noticed. There was no loss of sensibility. Unaided sitting was possible at 1% years. At age 3% years the boy was unable to walk. He was able to produce two- to three-word sentences, comparable to the mental capabilities of a 2-year-old child. By that time neither bowel nor bladder control was possible. The neurological examination of female carriers did not show any abnormality.
Patient 3 (IV-2) He was born in 1986 a t term by normal delivery (weight 3.470 g, length 54 cm, and head circumference 34 cm). He is said to have been a “very quiet baby.” At age 6 months a bilateral foot deformity was noticed. Clinical examination at 2% years showed strabismus predominantly of the right eye. There was no adduction of the thumbs, although during the first months of life i t was observed that they were mostly held in folded form. His eyes were deep-set, and he had a prominent forehead with a depressed nasal bridge. His father also has deepset eyes. The psychomotor development was delayed. The mother noticed from the very beginning that the baby did not react adequately. Spastic paraparesis only appeared when moving, otherwise he was hypotonic. Disturbance of coordination and hyperreflexia of the lower limbs (ankle clonus) became more visible when he started to stand up. At the same time, a slight improvement of the symptoms of the upper limbs (hyperreflexia
LINKAGE ANALYSIS Six out of ten DNA markers tested were informative. The results are shown in Figure 1.The lod scores were calculated by two-point analysis, using the family analysis program by Neugebauer and Baur [19841 (Table I). All informative markers from the proximal Xq (pDP34 and S9) were recombinant with the disease locus, whereas the markers from Xq28 (U6.2, St14, and St35.691) cosegregate with the disease locus, with lod scores of 0.90-1.20 a t no recombination. DX13 is only partially informative in the investigated family; thus, the peak ofthe lod score with this probe is only 0.30, with no recombination. The results of DNA analysis indicate that female
12
Rietschel et al,
TABLE I. Lod Scores for the Disease Locus and Markers on Xa Recombination fraction Chromosomal location 0.0 0.01 0.1 0.2 0.3 ~~
Marker
pDP34 (DXYS1) S9 (DXS17) p22-33 (DXS11) U6.2 (DXS304) St14 (DXS52) St35.691 (DXS305)
~
Xq21.31 xq22 Xq24-q25 Xq27 Xq28 Xq28
M M
0.60 1.11 1.20
0.90
-4.80 -1.11 0.59 1.09 1.18 0.89
-1.84 -0.19 0.51 0.89 0.98 0.77
-0.99 0.01 0.41 0.67 0.74 0.61
-0.52 0.07 0.29 0.44 0.50 0.44
0.4 -0.21 0.06 0.16 0.22 0.25 0.24
11111, who presented for genetic counselling, has a very low risk of being a carrier for the MASA syndrome.
the authors discuss the possible relationship between MASA syndrome and X-linked hydrocephalus. In the pure form [Keppen et al., 19871 the gene was DISCUSSION mapped to the middle of the long arm of the X-chromoX-linked spastic paraplegia is a rare disorder some, showing close linkage to the markers DXS287 (McKusick 31200). Clinical descriptions of pure forms of (pYNH3)and DXS17 (S21). In a family with a complihereditary spastic paraplegia (HSP) [Thurmon et al., cated form, Goldblatt et al. [19891found close linkage to 1971; Zatz et al., 1976; Raggio et al., 19731 and those of the chromosomal region considered responsible for the complicated HSP including mental retardation, optic pure form, described by Keppen et al. [19871. However, nerve defects, and upper extremity involvement since Goldblatt et al. [19891did not use any probes distal [Blumel et al., 1957;Johnston and McKusick 1962;Baar to Xq13-q21.1, a possible linkage to the Xq28 region and Gabriel, 19661 suggest causal heterogeneity. cannot be ruled out. Fischbeck et al. [1987] could not find any linkage to To date linkage analyses have been carried out in seven families [Kenwrick et al., 1986; Keppen et al., DXS52 or other markers on the distal long arm of the 1987; Fischbeck et al., 1987; Goldblatt et al., 1989; Win- X-chromosome in two families with complicated HSP ter et al., 1989; Schrander-Stumpel et al., 19901 (Table and therefore suggest genetic heterogeneity of X-linked 11).In five families linkage could be demonstrated: One spastic paraplegia. family was described as pure HSP [Keppen et al., 19871 Mental retardation is the only constant symptom and four families as complicated. Three of these families found in the complicated forms (in all affected persons with complicated forms have been considered to have showing linkage to the Xq28 region and in all but one the MASA syndrome [Kenwrick et al., 1986; Winter et affected person showing linkage to the X- q13-q21 real., 1989; Schrander-Stumpel et al., 19901, the putative gion) (Table 11). Mental retardation and additional gene being localized to the Xq28 region, with close link- symptoms like optic atrophy and nystagmus are not age to loci DXS15 (DX13) and DXS52 (St14). found in the pure form described by Keppen et al. 119871. As the two affected males in the family described by Urinary tract symptoms, lordosis, and kyphosis as well Schrander-Stumpel et al. [19901 showed gross enlarge- as additional anomalies (e.g., foot deformities, hammer ment of the lateral ventricles of the brain and a third toes, and cleft lip) are described in both forms. The adducted thumb was only noticed in complicated male in this family died from congenital hydrocephalus,
Family
TABLE 11. X-Linked HSP: Families Where Linkage Analyses Have Been Carried Out SchranderKeppen Goldblatt et al. Kenwrick et al. Winter et al. Stumpel et al. et al.
Number of cases
Form
Linkage to
Early onset Mental retardation
Optic nerve defect Nystagmus Speech problems Urinary tract problems
Contractures
[1987] 12 Pure xq21-22 3112 0112 0112 0112 0112 4112 616
Adducted thumb Skeletal abnormalities (hammer toes, kyphosis, scoliosis) Normal sensibilitv a
Macrocephaly in both patients.
-
414 111
[1989] 5 Compl. Xq13-21 515 3I4 414 414 213 015
111 -
015 515
[1986] 119891 6 3 Compl. (MASA) Compl. (MASA) Xq28 Xq28 616 313 616 313 213 016 111 111 112 212 212 416 213 111 111
212 -
[1990] Own cases 2 3 Compl. (MASA) Compl. (MASA) Xq28 Xq28 212 313 212 313 012 012 012 012 212 313 112 112 213 212 a
313
212
212
2,700
n
2,600
n
55
IQ
80.8.
=
+
+
-
0.a.
+
+
40
+
3
+
3Y
30
M
+
5Y
+
+
+
75
+
3
+
3Y
+
+
M
+
+
40
+
+
M
+
str
+
+
-
+ +
+
-
10 m
i
3,400 98
+
+
-
7.5
+
5Y
1 Y
1
3,900 >97
+
36
2.6
+
M
+
+
i
3.5
+
1 Y 3.5 y
4
t
+ + + +
+
str.
98
L
I
>97
45
M
35
M
Winter et al. (1989)
M
SchranderStumpel et al. (1990)
+
-
+
+
+
+
+
t
t -
+
t
+
+ +
+
+ +
+
+
+
t
+
n
+
str.
-
+
+ +
+
+
+
-
1.5 y
I
+
3,600 n
+
49
+
M 3.5
M
Own cases
1 . 5 ~2 y 2.5 y -
+
+
+
M
ventricular widening i n CT (third male in this family died from congenital
0.8.
+
V.W. =
+
-
+
+
+
4Y
5Y
5Y
+
+
t
+
+
+
+
40
4
+
+
4
+
61
+ +
3
+
i
I
6
+
+ +
+ +
+
18 m
t
+
4.5
+
6~
+
+
i
+
+
33
8 3,200
M
M
Kenwrick et al. (1986)
t
4.5
+
10 m 2Y
+
+
t
3,000
13
M
+ + + +
+
24
M
+ +
2
+
3.5 y
2Y
+
+
+
+
t
2,950 n
t
20
M
75
+ +
2Y
+
3,345 n
26
M
Yeatman (1984)
617 m
1
s.b.
+ +
(+I
n
+
25
M
optic atrophy; str. = strabism; s.b. = spina hifida occulta; cV. = camptodactyly of fifth fingers; hydrocephalus); m. = myopia; a. = astigmatism.
Chromosomal aberrations Ftagile X Pos. linkage to Xq28
Walking problems Spasticity Hyperreflexia Ankle clonus Pos. Babinski Bowelhladder control achieved Urinary tract problems Ocular abnormalities
+
36
+ + +
23 m
-
12 m 27 m
12 m 18 m
+ + 4
13 m
+
3,436 n
3,398 n
4
+
11
+
M
16
+
M
Gareis and Mason (1984)
i
i
+
Foot deformities Adducted thumbs Index finger abnormalities Deep set eyes Spine deformities Contractures Delay in psychomotor development Anaided sitting Anaided walking Speech: delayed Possible at (years) Problems in talking Mentally retarded
+
5
8.5
Age examined (years) Normal pregnancy Birthweight (grammsJ Headcircumference (perc.)
+
M
F
Sex
Bianchine et al. (1974)
TABLE 111. MASA Syndrome: Comparison of Literature and Present Cases
14
Rietschel et al.
forms and then led to the diagnosis of MASA syndrome. In our family and in the families of Kenwrick et al. [19861and Winter et al. [19891not all the affected persons showed the sign to the same extent and some did not show it at all (Table 111). Therefore, considering the clinical symptoms of the family described by Goldblatt et al. 119891(Table 111,it would be difficult, if not impossible, to make the diagnosis of MASA syndrome in an affected person not showing an adducted thumb without knowledge of a positive family history. Further clinical and molecular investigation must show whether the “adducted thumb” can be regarded as a valuable discriminating sign in the complicated forms. In two other families described by Gareis and Mason [1984] and Yeatman et al. [1984] the “adducted thumb” and other features compatible with MASA syndrome were found. However Yeatman et al. [19841did not mention whether there was any impairment of gait, and Gareis and Mason [19841did not find any (Table 111).An adducted thumb is by itself a nonspecific symptom and is reported in many other conditions [Zerres et al., 19831. Up to now there seems to be a t least two different genes responsible for X-linked HSP. It remains a subject of further investigation whether allelic mutation may cause the various phenotypes of HSP. Considering the fact that even in the complicated form there exists marked clinical diversity and overlap with different features of X-linked spastic ataxia [Apak et al. 1989; Harding, 19841 further linkage analyses are necessary to define MASA syndrome as a distinct entity.
ACKNOWLEDGMENTS We thank Susanna Winters for her careful typing of the manuscript as well as Peter Heldsdorfer for his help. We thank N. Dahl, K.E. Davies, L. Kunkel, J.-L. Mandel, and D.C. Page for the probes. We thank PD Dr. A. Goe for his kind support. REFERENCES Apak S. Yiiksel M, Ozmen M, Saka N, Darendeliler F, Neuhauser G (1989):Heterogeneity ofX-linked recessive (spino)cerebellarataxia with or without spastic diplegia. Am J Med Genet 34:155-158.
Baar HS, Gabriel AM (1966):Sex linked spastic paraplegia. Am J ment Defic 71:13-18. Bianchine JW, Lewis RC (1974):The MASA syndrome: A new hereditable mental retardation syndrome. Clin Genet 5298-306. Blumel J , Evans EB, Eggers GWN (1957):Hereditary cerebral palsy: A preliminary report. J Pediatr 50:454-458. Fischbeck KH, Shi Y, Ritter A, Bird T, Jankovic J, Puckett C (1987): Linkage studies of X-linked spastic paraplegia. Am J Hum Genet 41:165A. Gareis FJ, Mason J D (1984): X-linked mental retardation associated with bilateral clasp thumb anomaly. Am J Med Genet 17333-338. Goldblatt J, Ballo R, Sachs B, Moosa A (1989):X-linked spastic paraplegia: evidence for homogeneity with a variable phenotype. Clin Genet 35:116-120. Harding AE (1984):The Hereditary Ataxias and Related Disorders. Edinburgh: Churchill Livingstone, pp 174-204. Johnston AW, McKusick VA (1962): A sex-linked recessive form of spastic paraplegia, Am J Hum Genet 14:83-94. Kenwrick S, Ionasescu V, Ionasescu G, Searby C, King A, Dubowitz M, Davies KE (1986): Linkage studies of X-linked recessive spastic paraplegia using DNA probes. Hum Genet 73:264-266. Keppen LD, Leppert MF, OConnell P, Nakamura Y, Stauffer D, Lathrop M, Lalouel JM, White R (1987): Etiological heterogeneity in X-linked spastic paraplegia, Am J Hum Genet 41:933-943. Neugebauer M, Willems J , Baur MP (1984): Analysis of multilocus pedigree data by computer. In Albert ED et al. (eds): “Histocompatibility Testing.” Berlin, Heidelberg, Springer: pp 52-58. Raggio JF, Thurmon TF, Anderson EE (1973):X-linked hereditary spastic paraplegia, J Louisiana State Med SOC125:4-6. Schrander-Stumpel C, Legius E, Fryns JP, Cassiman JJ (1990):MASA syndrome: New clinical features and linkage analysis using DNA probes. J Med Genet 27:688-692. Thurmon TF, Walker BA, Scott CI, Abbott MH (1971):Two kindreds with a sex-linked recessive form of spastic paraplegia. Birth Defects 7:219-221. Winter RM, Davies KE, Bell MV, Huson SM, Patterson MN (1989): MASA syndrome: Further clinical delineation and chromosomal localisation. Hum Genet 82:367-370. Yeatman GW (1984):Mental retardation-clasped thumb syndrome. Am J Med Genet 17:339-344. Zatz M, Penha-Serrano C, Otto PA (1976):X-linked recessive type of pure spastic paraplegia in a large pedigree: Absence of detectable linkage with Xq. J Med Genet 13:217-222. Zerres K, Majoor-Krakauer D, Schwanitz G, Kowalewski S, Toussaint W (1983):The adducted thumb syndrome (ATS).Acta Med Auxol 15:151-163.
MASA Syndrome: Clinical Variability and Linkage Analysis M.Rietsche1, W. Friedl, S. Uhlhaas, M. Neugebauer, D. Heimann, and K. Zerres Institut fur Humangenetik der Universitat Bonn, Bonn (M.R., W.F., S.U., K . ZJ, Institut fur Medizinische Statistik, Dokumentation und Datenverarbeitung der Universitat Bonn (M.N.), and Pflege- und Bildungsheim Kloster Ebernach, Cochem (D.H.) We report on a family with three males with MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs).One patient demonstrated spastic paraplegia and psychomotor retardation but no adducted thumbs. The described family underlines the clinical variability in MASA syndrome. DNA studies confirm linkage to DNA markers of the Xq28 region. Analysis of published cases with hereditary spastic paraplegia (HSP), where linkage studies have been carried out, emphasizes the clinical variability in MASA syndrome and other types of HSP, thus making a definite diagnosis in single cases often impossible.
KEY WORDS: hereditary spastic paraplegia, adducted thumb, molecular linkage INTRODUCTION The MASA syndrome (mental retardation, aphasia, shuffling gait, and adducted thumbs) is an X-linked type of hereditary spastic paraplegia (HSP) first described by Bianchine and Lewis [19741. Similar cases have been reported by Gareis and Mason [1984], Yeatman et al. [1984], Kenwrick et al. 119861, Winter et al. [19891,and Schrander-Stumpel et al. [19901. Kenwrick et al. [1986], Winter et al. [19891, and SchranderStumpel et al. [1990] found close linkage t o DXS15 and DXS52. We report on a family with MASA syndrome. The comparison of clinical findings and linkage data gives evidence that our family presents the same disorder as that described by Winter et al. 119891 and Kenwrick et al. [1986].
Received for publication October 17,1990; revision received January 7, 1991. Address reprint requests to Dr. med. Klaus Zerres, Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, D-5300 Bonn 1, Germany.
0 1991 Wiley-Liss, Inc.
METHODS Two affected males and three female carriers (Fig. 1) were examined by the authors (D.H., M.R., K.Z.) and by different neurologists. Chromosome analysis was carried out in one patient (11-4). Information about one deceased affected male was obtained by reports from relatives. Linkage studies were performed with DNA markers from the proximal and distal Xq: DXYSl (pDP34), DXS3 (p19-2), DXS17 (S9), DXSll (p22-33), DXS42 (43-15),DXS98 (4D8B),DXS304 (U6.2),DXS15 (DX13), DXS52 (St14), and DXS305 (St35.691). CLINICAL REPORTS Patient 1 (11-2) He was born in 1928 after a normal pregnancy and delivery with cleft palate and bilateral adduction of thumbs. His psychomotor development was severely retarded. He was able to sit at 11/2 years and to walk unaided at 2% years. He always walked unsteadily and his knees kept knocking together. He showed severe mental retardation and no development of speech (which could also have been influenced by the cleft palate).Bowel and bladder control were never achieved. He was killed in 1943. Patient 2 (11-4)(Fig. 2a-c) He was born in 1940 after a normal pregnancy and delivery with club feet predominantly on the right side. On examination he showed hammer toes, bilateral adduction of thumbs, radial abduction of the right index finger, and deep set eyes. He underwent operations for knee contractures at age 9 years and elongation of achilles tendons at age 12. Chromosome analysis was normal. His psychomotor developmentwas significantly delayed with an IQ of 52. He was able to sit and made his first attempts to walk at age 2 years. He could never walk without support and then always tired quickly. He became wheel chair dependent at age 9 years. His bladder and sphincter control insufficiency slightly improved by toilet training. He suffered recurrent urinary infections. At age 46 years operation of meatal stenosis, phimosis, and inguinal hernia was performed. Neurological examination showed spastic paraparesis with hy-
MASA Syndrome 1
11
2
I
I
0. d
d,d
d 1 8
2.3 B.b 1
1
d 3 b
2
III
N U
U
d
d 3 b
1
B
Fig. 1. Pedigree and results of linkage analysis in a family with MASA syndrome. pDP34, alleles P,p: S9, alleles S,s; p22-33, alleles T,t; U6.2, alleles U,u; DX13, alleles D , d St 14, alleles 1,2 and 3; St 35.691, alleles B,b.
Fig. 2. a: Patient 11-4 with MASA syndrome with characteristic deep-set eyes. b/c: Abnormalities of thumbs and index fingers in patient 11-4.
perreflexia. Since age 13years he has lived in a n institution for the mentally handicapped.
predominantly on right) was noticed. There was no loss of sensibility. Unaided sitting was possible at 1% years. At age 3% years the boy was unable to walk. He was able to produce two- to three-word sentences, comparable to the mental capabilities of a 2-year-old child. By that time neither bowel nor bladder control was possible. The neurological examination of female carriers did not show any abnormality.
Patient 3 (IV-2) He was born in 1986 a t term by normal delivery (weight 3.470 g, length 54 cm, and head circumference 34 cm). He is said to have been a “very quiet baby.” At age 6 months a bilateral foot deformity was noticed. Clinical examination at 2% years showed strabismus predominantly of the right eye. There was no adduction of the thumbs, although during the first months of life i t was observed that they were mostly held in folded form. His eyes were deep-set, and he had a prominent forehead with a depressed nasal bridge. His father also has deepset eyes. The psychomotor development was delayed. The mother noticed from the very beginning that the baby did not react adequately. Spastic paraparesis only appeared when moving, otherwise he was hypotonic. Disturbance of coordination and hyperreflexia of the lower limbs (ankle clonus) became more visible when he started to stand up. At the same time, a slight improvement of the symptoms of the upper limbs (hyperreflexia
LINKAGE ANALYSIS Six out of ten DNA markers tested were informative. The results are shown in Figure 1.The lod scores were calculated by two-point analysis, using the family analysis program by Neugebauer and Baur [19841 (Table I). All informative markers from the proximal Xq (pDP34 and S9) were recombinant with the disease locus, whereas the markers from Xq28 (U6.2, St14, and St35.691) cosegregate with the disease locus, with lod scores of 0.90-1.20 a t no recombination. DX13 is only partially informative in the investigated family; thus, the peak ofthe lod score with this probe is only 0.30, with no recombination. The results of DNA analysis indicate that female
12
Rietschel et al,
TABLE I. Lod Scores for the Disease Locus and Markers on Xa Recombination fraction Chromosomal location 0.0 0.01 0.1 0.2 0.3 ~~
Marker
pDP34 (DXYS1) S9 (DXS17) p22-33 (DXS11) U6.2 (DXS304) St14 (DXS52) St35.691 (DXS305)
~
Xq21.31 xq22 Xq24-q25 Xq27 Xq28 Xq28
M M
0.60 1.11 1.20
0.90
-4.80 -1.11 0.59 1.09 1.18 0.89
-1.84 -0.19 0.51 0.89 0.98 0.77
-0.99 0.01 0.41 0.67 0.74 0.61
-0.52 0.07 0.29 0.44 0.50 0.44
0.4 -0.21 0.06 0.16 0.22 0.25 0.24
11111, who presented for genetic counselling, has a very low risk of being a carrier for the MASA syndrome.
the authors discuss the possible relationship between MASA syndrome and X-linked hydrocephalus. In the pure form [Keppen et al., 19871 the gene was DISCUSSION mapped to the middle of the long arm of the X-chromoX-linked spastic paraplegia is a rare disorder some, showing close linkage to the markers DXS287 (McKusick 31200). Clinical descriptions of pure forms of (pYNH3)and DXS17 (S21). In a family with a complihereditary spastic paraplegia (HSP) [Thurmon et al., cated form, Goldblatt et al. [19891found close linkage to 1971; Zatz et al., 1976; Raggio et al., 19731 and those of the chromosomal region considered responsible for the complicated HSP including mental retardation, optic pure form, described by Keppen et al. [19871. However, nerve defects, and upper extremity involvement since Goldblatt et al. [19891did not use any probes distal [Blumel et al., 1957;Johnston and McKusick 1962;Baar to Xq13-q21.1, a possible linkage to the Xq28 region and Gabriel, 19661 suggest causal heterogeneity. cannot be ruled out. Fischbeck et al. [1987] could not find any linkage to To date linkage analyses have been carried out in seven families [Kenwrick et al., 1986; Keppen et al., DXS52 or other markers on the distal long arm of the 1987; Fischbeck et al., 1987; Goldblatt et al., 1989; Win- X-chromosome in two families with complicated HSP ter et al., 1989; Schrander-Stumpel et al., 19901 (Table and therefore suggest genetic heterogeneity of X-linked 11).In five families linkage could be demonstrated: One spastic paraplegia. family was described as pure HSP [Keppen et al., 19871 Mental retardation is the only constant symptom and four families as complicated. Three of these families found in the complicated forms (in all affected persons with complicated forms have been considered to have showing linkage to the Xq28 region and in all but one the MASA syndrome [Kenwrick et al., 1986; Winter et affected person showing linkage to the X- q13-q21 real., 1989; Schrander-Stumpel et al., 19901, the putative gion) (Table 11). Mental retardation and additional gene being localized to the Xq28 region, with close link- symptoms like optic atrophy and nystagmus are not age to loci DXS15 (DX13) and DXS52 (St14). found in the pure form described by Keppen et al. 119871. As the two affected males in the family described by Urinary tract symptoms, lordosis, and kyphosis as well Schrander-Stumpel et al. [19901 showed gross enlarge- as additional anomalies (e.g., foot deformities, hammer ment of the lateral ventricles of the brain and a third toes, and cleft lip) are described in both forms. The adducted thumb was only noticed in complicated male in this family died from congenital hydrocephalus,
Family
TABLE 11. X-Linked HSP: Families Where Linkage Analyses Have Been Carried Out SchranderKeppen Goldblatt et al. Kenwrick et al. Winter et al. Stumpel et al. et al.
Number of cases
Form
Linkage to
Early onset Mental retardation
Optic nerve defect Nystagmus Speech problems Urinary tract problems
Contractures
[1987] 12 Pure xq21-22 3112 0112 0112 0112 0112 4112 616
Adducted thumb Skeletal abnormalities (hammer toes, kyphosis, scoliosis) Normal sensibilitv a
Macrocephaly in both patients.
-
414 111
[1989] 5 Compl. Xq13-21 515 3I4 414 414 213 015
111 -
015 515
[1986] 119891 6 3 Compl. (MASA) Compl. (MASA) Xq28 Xq28 616 313 616 313 213 016 111 111 112 212 212 416 213 111 111
212 -
[1990] Own cases 2 3 Compl. (MASA) Compl. (MASA) Xq28 Xq28 212 313 212 313 012 012 012 012 212 313 112 112 213 212 a
313
212
212
2,700
n
2,600
n
55
IQ
80.8.
=
+
+
-
0.a.
+
+
40
+
3
+
3Y
30
M
+
5Y
+
+
+
75
+
3
+
3Y
+
+
M
+
+
40
+
+
M
+
str
+
+
-
+ +
+
-
10 m
i
3,400 98
+
+
-
7.5
+
5Y
1 Y
1
3,900 >97
+
36
2.6
+
M
+
+
i
3.5
+
1 Y 3.5 y
4
t
+ + + +
+
str.
98
L
I
>97
45
M
35
M
Winter et al. (1989)
M
SchranderStumpel et al. (1990)
+
-
+
+
+
+
+
t
t -
+
t
+
+ +
+
+ +
+
+
+
t
+
n
+
str.
-
+
+ +
+
+
+
-
1.5 y
I
+
3,600 n
+
49
+
M 3.5
M
Own cases
1 . 5 ~2 y 2.5 y -
+
+
+
M
ventricular widening i n CT (third male in this family died from congenital
0.8.
+
V.W. =
+
-
+
+
+
4Y
5Y
5Y
+
+
t
+
+
+
+
40
4
+
+
4
+
61
+ +
3
+
i
I
6
+
+ +
+ +
+
18 m
t
+
4.5
+
6~
+
+
i
+
+
33
8 3,200
M
M
Kenwrick et al. (1986)
t
4.5
+
10 m 2Y
+
+
t
3,000
13
M
+ + + +
+
24
M
+ +
2
+
3.5 y
2Y
+
+
+
+
t
2,950 n
t
20
M
75
+ +
2Y
+
3,345 n
26
M
Yeatman (1984)
617 m
1
s.b.
+ +
(+I
n
+
25
M
optic atrophy; str. = strabism; s.b. = spina hifida occulta; cV. = camptodactyly of fifth fingers; hydrocephalus); m. = myopia; a. = astigmatism.
Chromosomal aberrations Ftagile X Pos. linkage to Xq28
Walking problems Spasticity Hyperreflexia Ankle clonus Pos. Babinski Bowelhladder control achieved Urinary tract problems Ocular abnormalities
+
36
+ + +
23 m
-
12 m 27 m
12 m 18 m
+ + 4
13 m
+
3,436 n
3,398 n
4
+
11
+
M
16
+
M
Gareis and Mason (1984)
i
i
+
Foot deformities Adducted thumbs Index finger abnormalities Deep set eyes Spine deformities Contractures Delay in psychomotor development Anaided sitting Anaided walking Speech: delayed Possible at (years) Problems in talking Mentally retarded
+
5
8.5
Age examined (years) Normal pregnancy Birthweight (grammsJ Headcircumference (perc.)
+
M
F
Sex
Bianchine et al. (1974)
TABLE 111. MASA Syndrome: Comparison of Literature and Present Cases
14
Rietschel et al.
forms and then led to the diagnosis of MASA syndrome. In our family and in the families of Kenwrick et al. [19861and Winter et al. [19891not all the affected persons showed the sign to the same extent and some did not show it at all (Table 111). Therefore, considering the clinical symptoms of the family described by Goldblatt et al. 119891(Table 111,it would be difficult, if not impossible, to make the diagnosis of MASA syndrome in an affected person not showing an adducted thumb without knowledge of a positive family history. Further clinical and molecular investigation must show whether the “adducted thumb” can be regarded as a valuable discriminating sign in the complicated forms. In two other families described by Gareis and Mason [1984] and Yeatman et al. [1984] the “adducted thumb” and other features compatible with MASA syndrome were found. However Yeatman et al. [19841did not mention whether there was any impairment of gait, and Gareis and Mason [19841did not find any (Table 111).An adducted thumb is by itself a nonspecific symptom and is reported in many other conditions [Zerres et al., 19831. Up to now there seems to be a t least two different genes responsible for X-linked HSP. It remains a subject of further investigation whether allelic mutation may cause the various phenotypes of HSP. Considering the fact that even in the complicated form there exists marked clinical diversity and overlap with different features of X-linked spastic ataxia [Apak et al. 1989; Harding, 19841 further linkage analyses are necessary to define MASA syndrome as a distinct entity.
ACKNOWLEDGMENTS We thank Susanna Winters for her careful typing of the manuscript as well as Peter Heldsdorfer for his help. We thank N. Dahl, K.E. Davies, L. Kunkel, J.-L. Mandel, and D.C. Page for the probes. We thank PD Dr. A. Goe for his kind support. REFERENCES Apak S. Yiiksel M, Ozmen M, Saka N, Darendeliler F, Neuhauser G (1989):Heterogeneity ofX-linked recessive (spino)cerebellarataxia with or without spastic diplegia. Am J Med Genet 34:155-158.
Baar HS, Gabriel AM (1966):Sex linked spastic paraplegia. Am J ment Defic 71:13-18. Bianchine JW, Lewis RC (1974):The MASA syndrome: A new hereditable mental retardation syndrome. Clin Genet 5298-306. Blumel J , Evans EB, Eggers GWN (1957):Hereditary cerebral palsy: A preliminary report. J Pediatr 50:454-458. Fischbeck KH, Shi Y, Ritter A, Bird T, Jankovic J, Puckett C (1987): Linkage studies of X-linked spastic paraplegia. Am J Hum Genet 41:165A. Gareis FJ, Mason J D (1984): X-linked mental retardation associated with bilateral clasp thumb anomaly. Am J Med Genet 17333-338. Goldblatt J, Ballo R, Sachs B, Moosa A (1989):X-linked spastic paraplegia: evidence for homogeneity with a variable phenotype. Clin Genet 35:116-120. Harding AE (1984):The Hereditary Ataxias and Related Disorders. Edinburgh: Churchill Livingstone, pp 174-204. Johnston AW, McKusick VA (1962): A sex-linked recessive form of spastic paraplegia, Am J Hum Genet 14:83-94. Kenwrick S, Ionasescu V, Ionasescu G, Searby C, King A, Dubowitz M, Davies KE (1986): Linkage studies of X-linked recessive spastic paraplegia using DNA probes. Hum Genet 73:264-266. Keppen LD, Leppert MF, OConnell P, Nakamura Y, Stauffer D, Lathrop M, Lalouel JM, White R (1987): Etiological heterogeneity in X-linked spastic paraplegia, Am J Hum Genet 41:933-943. Neugebauer M, Willems J , Baur MP (1984): Analysis of multilocus pedigree data by computer. In Albert ED et al. (eds): “Histocompatibility Testing.” Berlin, Heidelberg, Springer: pp 52-58. Raggio JF, Thurmon TF, Anderson EE (1973):X-linked hereditary spastic paraplegia, J Louisiana State Med SOC125:4-6. Schrander-Stumpel C, Legius E, Fryns JP, Cassiman JJ (1990):MASA syndrome: New clinical features and linkage analysis using DNA probes. J Med Genet 27:688-692. Thurmon TF, Walker BA, Scott CI, Abbott MH (1971):Two kindreds with a sex-linked recessive form of spastic paraplegia. Birth Defects 7:219-221. Winter RM, Davies KE, Bell MV, Huson SM, Patterson MN (1989): MASA syndrome: Further clinical delineation and chromosomal localisation. Hum Genet 82:367-370. Yeatman GW (1984):Mental retardation-clasped thumb syndrome. Am J Med Genet 17:339-344. Zatz M, Penha-Serrano C, Otto PA (1976):X-linked recessive type of pure spastic paraplegia in a large pedigree: Absence of detectable linkage with Xq. J Med Genet 13:217-222. Zerres K, Majoor-Krakauer D, Schwanitz G, Kowalewski S, Toussaint W (1983):The adducted thumb syndrome (ATS).Acta Med Auxol 15:151-163.
