Acta Neurnl Scand 1998. 98 369-371 Printed in UK - all rights resewed

Copyright 8 Munksgaard 1998 ACTA NEUROLOGICA

SCANDINAVICA ISSN 0001-6314

Editorial

Familial cavernous angioma: an unknown, known disease

I A.M.Siege’ Siegel AM. Familial cavernous angioma: an unknown, known disease. Acta Neurol Scand 1998: 98: 369-371. 0 Munksgaard 1998.

Adrian M Siegel. Section of Neurology. Epilepsy Program, Dartmouth-Hitchcock Medical Center, Lebanon. New Hampshire, 03756 USA

Accepted for publication September 17, 1998

Familial aggregation of cavernous angiomas (CA) of the central nervous system (CNS) has been well described in the literature. In 1928, Hugo Friedrich Kufs (1) first assumed a common pathological basis in two members of the same family. He reported on an 81-year-old male patient whose autopsy showed multiple cerebral and hepatic CA. At the age of 17, his daughter presented with an “apoplexia pontis”, consisting of a right-sided hemiparesis and hemi- hypesthesia. Although no pathological confirma- tion was available in the daughter, Kufs has to be given the credit for the first description of this entity. Subsequently, only 2 additional families with this syndrome were described until the era of computer tomography and magnetic resonance imaging. Since then, however, the number of reported families has enormously increased. A literature review (see Table 1) yielded a total of 109 families with at least two members harboring either pathologically or radiologically confirmed CA. In these families, with up to four affected generations, a total of 431 affected individuals have been reported. Among the 379 individuals in whom data were available, 91 (24%) were asymptomatic at the time of presentation. In symptomatic individuals, the most common symptoms encoun- tered were epileptic seizures (in 162 individuals or 43%0), followed by gross hemorrhages (108 or 28%), chronic headache (88 or 23%0), or focal neurological deficits (56 or 15%). Although the majority of individuals (69%) harbored multiple CA, a single lesion does not exclude the inherited form of this vascular malformation. In 30 families at least one member harbored only one CA. In 6 additional families, the reported individuals had exclusively single lesions. Coexistence of CA of the CNS and other organs (e.g. skin or retina) has been

described in several families. The question is still open whether each type among the various location patterns represents an own entity or whether there is only one entity with ubiquitous CA. Analysis of large kindreds with familial CA of the CNS showed an autosomal dominant inheritance with a high penetrance.

At present, the identification of the candidate genes responsible for the inherited form of CA is the focus of considerable research. In 1995, Dubovsky et al. (2) mapped a gene for familial CA in a 33 cM (33 million base pairs) interval on the long arm of chromosome 7q (7q11-22) bracketed by markers D7S502 and D7S821 or D7S479. Subsequently, this finding was confirmed by several groups studying familial CA (e.g. the Yale study group and the study group at the Duke University). However, the candidate gene on chromosome 7q has yet been identified. Moreover, Giinel et al. (3) excluded linkage to chromosome 7q in 2 families indicating genetic heterogeneity. Recently, a French national multi-center study found linkage to chromosome 7q only in 50% of the studied 35 families (4).

In this issue of Acta Neurologica Scandinavica the “Znternational Familial Cavernous Angioma Study” (IFCAS) group presents an interesting observation which could facilitate the search for the candidate genes. The authors report on anticipation in 55 families with inherited CA. Anticipation describes the progressively earlier age of onset andlor increase in severity of an inherited disease in successive generations. This phenomenon has already been described by the French Benedict Auguste Morel in the last century (‘‘Trait6 des DCgCnCrescences”, 1857) but the term “anticipation” was coined b y the English Mott (5)

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Siege1

Table 1. Synopsis of the literature on familial cavernous angiomas of the central nervous system (only families with either radiologically or pathologically confirmed cavernous angiomas are listed)

Symptoms Mult

Year Author Fam Gen Aff Ca EPI Ha Hem FOC

1936 1970 1978 1978 1982 1983 1984 1985 1985 1986 1986 1987 1988 1988 1988 1989 1989 1989 1989 1989 1989 1989 1989 1989 1990 1990 1990 1990 1991 1992 1992 1992 1992 1992 1992 1992 1992 1992 1993 1993 1993 1994 1994 1994 1995 1995 1995 1995 1995 1995 1995 1995 1996 1996 1996 1996 1996 1996 1996 1996 1997 1997

Michael & Levin Clark Bicknell et al Giombini & Morello Hayrnan et al Combelles et al Takarniya et al Andermann et al Pancurak Nakahara et al lagle et al Dobyns et al Mason et al Rigamonti et al Rutka et al Allard et al Bicknell Buckingham et al Corboy & Galena Fuji et al Kim et al Lejeune et al Okada et al Shiroyama et al Eononi et al Gangemi Lee et al Nakagawa et al Traverso Berg & Erba Bergeson et al Bertalanffy et al Filling-Katr et al Malik et al Ohkuma et al Scon et al Steichen-Gersdorf et al van Schayck et al Acciarri et al Oellemijn & Vanneste Facchineni et al Drigo et al Muiior MBlaga et al Zabramski et al Day et al Deya et al Dubovsky et al Gbnel et al HorowiQ & Kondziolka Johnson et al Kattapong et al Yamamura et al Gil Nagel et al ** Gbnel et al Gunel et al Jato & Marques Kimura et al Mori et al Mouly et al Passarin et al Notelet et al*** Polymeropoulos et al

1 1 2 1 1 2 1 2 1 1 1 1 1 6 1 1 1 1 1 1 1 2 1 2 1 3 1 1 1 2 1 1 1 1 1 2 1 1 4 1 1 1 1 6 1 1 1 2 1 3 6 1 1

14 2 1 1 1 1 1 1 4

1 2 2 2 4 2 1 2 2 2 1 3 2 2 -4 2 2 2 2 3 1 1 2 1 1 3 2-3 1 2 3 2-3 unk 1 2 4 2 2 4 2 unk 2 2 4 2 1-3 2 2 4 2-3 3 3 unk 1 3 unk 2-3 3 1 3 2 1 3 3

2 2 6 2

15 5 2 8 2 2 2 3

10 28

3 7 2 3 3 2 3 4 2 4 3 9 2 3 3 5 3 2 4 4 3 9 6 3

unk 6 2

10 3

31 7 2

14 16

5 12 unk

2 12 47 14 4 2 3 2 3

11 42

2 1 2 0 7 1 2 4 1 0 1 3 5

15/21 2 4 1 012 2 0 2 1 2 0 2 3 2 1 2 414 011

unk 1 4 3 316 4 3

unk 5 1

10 3

26 7 2

11/13 7 5

unk unk

1 313

unk unk

111 2 2 2 3 8

unk

2 1 2 0 5 2 0 7 1 1 0 2 5 911 6 1 0 0 212 1 2 1

unk 2 2 2 4 0 0 2 414 111

unk 1 1 0 116 1 1

unk 2 1 8 1

12 2 0 5

unk 1

unk unk

1 11 22

2/10 2 0 1 2 1 4

18

1 1 0 0 2 1 0 2 0 1 0 1 0 1/16 1 3 0 012 0 0 0

unk 0 0 0 0 0 0 1 014 011

unk 3 0 1 016 0 0

unk 1 0 1 0

16 0 0 2

unk 0

unk unk

0 0

28 1/10 1 0 0 0 1 1

17

1 2 2 1 5 4 2 2 0 0 1 0 0 1/16 0 0 2 012 2 0 2

unk 0 2 0 2 1 3 0 014 111

unk 1 1 0 416 2 1

unk 4 1 0 0 0 0 1 1 215 2

unk unk

1 3

24 411 0 1 1 2 1 1 2

12

0 0 4 1 3 0 0 1 0 0 1 0 0 5/16 1 1 2 012 0 0 0 unk 0 0 1 0 0 0 1 014 011 unk 1 2 2 216 1 1 unk 0 0 5 0 5 0 1 1 unk 0 unk unk 0 6 0 0/10 0 2 0 0 1 4 1

Onset None

8 25-27

0-38 6 3 4 7-22 5-39

23-28 2-27

21 28-48 4 3 4 5

711 12-25 unk 24-52

4-76 23-25

8-1 612 12-3012 2-5

34-37 unk 15-19 2-32 8-54 0-15

30 6011

%2/2 911 011

unk unk

unk 4 5-79

0 .74 812 15-65

unk unk

3611

24 unk unk 1411 unk 1111

unk unk

2-53

2 5-39

5-40R

3-1 6 4-61

unk 7-35

unk 53-64

4-63 7-9

28-56 5-47 1-71

0 0 0 0 5 0 0 0 1 0 0 1 5 3/16 0 3 0 012 0 0 1 0 0 1 0 3 1 0 0

unk unk unk

0 0 0

116 2 1

unk 0 0 2 2

12 5 0 6 315 2

unk unk

0 1

10 411 0 0 0 0 0 1 2

t3

Abbreviations: number of reported families (Faml. affected generations per family (Gen), and affected individuals (Aff). Mult Ca, number of individuals with confirmed multiple cavernous angiomas; number of individuals with epileptic seizures (Epi), chronic headache (Ha), gross hemorrhages (Hem). focal neurological onset (Foc). or no symptoms (None). Onset, age at symptom onset (range in years). If data not available in all reported patients then fractional result is given (e.g 15/21). Unknown (unk)=data not reported 'See also Marchuk 1995; ** see also Gil-Nagel 1995; "'see also Bison 1990.

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Editorial

in 1911 who observed an earlier age at onset and increased severity in inherited psychiatric diseases in successive generations. In 1918, anticipation was first reported in a neurological disease by the German Fleischer who found congenital myotonic dystrophy in successive generations of some of his patients with cataracts and suspected a genetic connection (6). The concept of anticipation subse- quently fell into oblivion for many decades, after the influential geneticist Lionel Penrose claimed anticipation was a pure result of several ascertain- ment biases (statistical anticipation) (7). However, it is now clear that statistical anticipation can be avoided by careful control for biases (8). Recently, there has been a revival of interest in anticipation because molecular studies have shown expansion of unstable trinucleotide repeat as the cause for anticipation in many neurological diseases. Dis- orders that have been associated with trinucleotide repeats include Huntington’s disease, myotonic dystrophy, spinocerebellar atrophy, dentatorubral pallidoluysian atrophy, Rolandic epilepsy with speech dyspraxia, etc. Whether or not trinucleotide repeats are the cause for the observed anticipation in familial CA is not known. In the paper by the ZFCAS group, common ascertainment biases were carefully addressed by using different methods in order to test for anticipation. Since all employed test methods resulted in highly significant anticipa- tion, it is suggestive that trinucleotide repeats are involved in the genetic mechanisms of inheritance in this entity. However, whether such trinucleotide repeats directly influence the CA causing genes, or whether they are associated with a “modifying

gene” (as the authors suggest) requires further molecular studies.

While the current research in this entity is focussed on the underlying genetic mechanism there are other important questions such as the prevalence of the inherited form of CA. This question is addressed by one of the ongoing studies of the IFCAS group that follows 101 families with inherited CA (for further information see web page: http://nerd.dartmouth.edu/ifcas/). These stu- dies should provide valuable information for more complete understanding of this disease and enable us to give more accurate and appropriate genetic counseling for families with inherited CA.

References I

1. KUFS H. ijber die heredofamike Angiomatose des Gehirns und der Retina, ihre Beziehungen zueinander und zur Angiomatose der Haut. Z Neurol Psychiatrie 1928;113:651-86.

2. DUBOVSKY J, ZABRAMSKI JM, KURTH et al. A gene responsible for cavernous malformations of the brain maps to chromo- some 7q. Hum Mol Genet 1995;4(3):453-8.

3. GUNEL M, AWAD IA, FINBERC K et al. Genetic heterogeneity of inherited cerebral cavernous malformation. Neurosurgery

4. LABAUGE P, LABERGE S, BRUNEREAU L et al. Clinical and genetic study of 57 French familial cavernomas pedigrees. Neurology 1998;SO (Supp1.4):441 (abstract).

5. MOT FW. A lecture on heredity and insanity. Lancet

6. FLEISCHER B. Uber myotonische Dystrophie mit Katarakt: eine hereditare familiare Degeneration. Arch Ophthalmol

7. PENROSE LS. The problem of anticipation in pedigrees of dystrophia myotonica. Ann Eugenics 1948;14125-32.

8. MCINN~S MG, MCMAHON FJ, CHASE G A et al. Anticipation in bipolar affective disorder. Am J Hum Genet 1993;53:385-90.

1996;38:1265-71.

1911;1:1251-9.

1918;%:91-133.

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