BRCA1 mutation and neuronal migration defect: implications for chemoprevention
D Eccles, D Bunyan, S Barker and B Castle
J. Med. Genet. doi:10.1136/jmg.2004.028084
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J Med Genet 2005;42:e42 (http://www.jmedgenet.com/cgi/content/full/42/7/e42). doi: 10.1136/jmg.2004.028084
39 years, breast magnetic resonance imaging
as well as conventional breast mammography
(MIM 251200), in which biallelic mutations
led to primary microcephaly, contains three
Multiplex ligation dependent probe ampli-
fication eventually revealed that exons 9–12
possible prenatal insults that could give rise
of the BRCA1 gene in twin 1 were deleted.
Predictive testing confirmed that this multi-
include infection and an early vascular event
exonic deletion was also present in twin 2.
leading to hypoperfusion, however the loca-
Previously we described a BRCA1 carrier with
Closer attention to the neurological pro-
lised nature of the abnormality in this case
a neuronal migration defect and postulated
blems and history of twin 2 revealed that the
makes these explanations less likely than the
twins were born at home to non-consangui-
second hit hypothesis postulated here.
neous parents after an uneventful pregnancy,
describe another family in which a similar
trant with a lifetime cumulative breast cancer
prenatally. Both twins were healthy at birth
risk of 70–80% and a median age at onset of
occurred in one of female identical twins
and had an uneventful neonatal period. At 11
around 43 years. Penetrance is likely to be
with a BRCA1 gene mutation (MIM 113705).
months of age twin 2 developed focal right
affected by modifying genes and by environ-
sided seizures usually progressing to grand mal
mental factors. In identical twins the effect of
multiple primary breast cancers while the
seizures for which she required anti-convul-
Environmental factors presumably therefore
school with her sister. Twin 1 was right handed
standing epilepsy and focal subcortical het-
whereas twin 2 was left handed. Anti-con-
free 10 years after her sister developed the
erotopia. We hypothesise that the neuronal
vulsant treatment initially was with sodium
first of three unusually early onset primary
migration defect is due to focal nullisomy of
valproate, and phenobarbitone was added at
age 5 years and phenytoin at age 21 years,
cancer risk is due to the anti-oestrogenic
Sodium valproate was stopped 3 years later.
effects of long term anticonvulsant therapy.
9 years compared to 4 years for twin 2.
Thirty three year old identical twins were
but mild right sided motor weakness in upper
There is some evidence suggesting that oral
referred for genetic counselling. Twin 1 had
contraceptive pill use increases breast cancer
developed breast cancer aged 29 years and a
extensor plantar reflex on the right hand
risk in BRCA1 gene carriers.7 Twin 1 took
second primary breast cancer aged 33 years.
side with no gross sensory abnormality. The
6 months of clomiphene for primary inferti-
MRI brain scan (fig 2) demonstrates focal
lity just prior to the diagnosis of her first
subcortical heterotopia and reduced volume
breast cancer, but this is less likely to be
family history (fig 1) suggested an inherited
implicated as it is a synthetic anti-oestrogen
and was taken probably after the first cancer
lial developmental anomalies incompatible
had started to develop. Her only full term
from twin 1 using the protein truncation test
pregnancy occurred after her second breast
and denaturing high performance liquid chro-
life. They exhibit structural disorganisation
cancer was diagnosed and is unlikely to have
matography failed to reveal any abnormality in
and in particular the neuroepithelium shows
influenced either of the first two cancers. A
signs of rapid proliferation and excessive cell
more compelling modifying factor, however,
markers spread across chromosomes 6, 11, and
death.2 A second somatic hit affecting the
X were used to compare DNA from twin 1 with
wild type BRCA1 allele in an early neuronal
taken by twin 2 since infancy. Many anti-
stem cell would result in focal nullisomy for
convulsant drugs, including phenytoin and
concordant making it highly unlikely that they
BRCA1 and would mimic focally the situation
phenobarbitone, act as potent liver inducing
were not identical. Annual ovarian and breast
in a BRCA1 null developing brain. Although
enzymes that reduce the bioavailability of
screening was established for both twins.
both exogenous oestrogen and progesterone.
have been described, there are no reported
In addition, most categories of anti-convul-
breast carcinoma 10 years after the initial
cases of viable homozygous BRCA1 mutation
sant cause an increase in serum sex hormone
diagnosis. At her most recent screen, age
carriers in any species. Given that the carrier
binding globulin (SHBG).8 This increase in
Ashkenazi Jewish population is around 1% in
oestrogens including tamoxifen and clomi-
zygote mutation carriers would be expected
bioavailability of endogenous sex steroid
were compatible with life.3–5 BRCA1 has few
oestrogen receptor positive breast cancer over
homologies, but interestingly another gene
a 5 year treatment period in older women but
Breast cancer at 29Breast cancer at 33Breast cancer at 38
Figure 1 Family history. The early onset, high
grade, oestrogen receptor negative breast
cancer with multiple new primaries in the index
case are typical for BRCA1. The young onset
breast and ovarian cancer cases in immediate
Figure 2 Coronal inversion recovery (A) and axial T2 (B) MRI images show a small left cerebral
relatives in the previous generation are also
hemisphere with a nodular mass of grey matter in the left parieto-occipital region extending down
to and around the lateral ventricle.
current trials start recruitment only after
5 Struewing JP, Abeliovich D, Peretz T, Avishai N,
Wessex Neurological Centre, Southampton General
Kaback MM, Collins FS, Brody LC. The carrier
frequency of the BRCA1 185delAG mutation isapproximately 1 percent in Ashkenazi Jewish
gene carriers clearly reduces breast cancer
individuals. Nat Genet 1995;11:198–200.
risk so there does appear to be a role for long
6 Jackson AP, Eastwood H, Bell SM, Adu J,
term reduction in endogenous oestrogen in
Wessex Clinical Genetics Service, Princess Anne
Toomes C, Carr IM, Roberts E, Hampshire DJ,
modifying risk.10 The earlier the age at which
Crow YJ, Mighell AJ, Karbani G, Jafri H, Rashid Y,
Identification of microcephalin, a protein
Professor Diana M Eccles, MD, FRCP, Wessex Clinical
implicated in determining the size of the human
Genetics Service, Princess Anne Hospital, Coxford
brain. Am J Hum Genet 2002;71:136–42.
options for individuals with a genetic predis-
Road, Southampton SO16 5YA, UK; de1@soton.ac.
7 Narod SA, Dube MP, Klijn J, Lubinski J, Lynch HT,
position to cancer and a better understanding
Ghadirian P, Provencher D, Heimdal K, Moller P,
Robson M, Offit K, Isaacs C, Weber B, Friedman E,
Gershoni-Baruch R, Rennert G, Pasini B, Wagner T,
Furthermore, since long standing epilepsy
Daly M, Garber JE, Neuhausen SL, Ainsworth P,
without any change in clinical status may not
prompt investigation in adults, any localised
Foulkes WD, Warner E, Kim-Sing C, Olopade O,Tung N, Saal HM, Weitzel J, Merajver S, Gauthier-
neurological signs or symptoms in a BRCA1
Villars M, Jernstrom H, Sun P, Brunet JS. Oral
gene carrier may warrant more detailed inves-
1 Eccles DM, Barker S, Pilz DT, Kennedy C.
contraceptives and the risk of breast cancer in
tigation including an MRI brain scan although
Neuronal migration defect in a BRCA1 gene
BRCA1 and BRCA2 mutation carriers. J Natl
this is likely to be a rare phenomenon.
carrier: possible focal nullisomy? J Med Genet
8 Murialdo G, Galimberti CA, Gianelli MV,
2 Gowen LC, Johnson BL, Latour AM, Sulik KK,
Rollero A, Polleri A, Copello F, Magri F, Ferrari E,
Koller BH. Brca1 deficiency results in early
Sampaolo P, Manni R, Tartara A. Effects of
Hilary Bullman, Margaret Connarty, and Julie
valproate, phenobarbital, and carbamazepine on
Sillibourne in the Wessex Regional Genetics NHS
sex steroid setup in women with epilepsy. Clin
Laboratory contributed to the molecular genetic
3 Gal I, Sadetzki S, Gershoni-Baruch R, Oberman B,
9 Cuzick J, Powles T, Veronesi U, Forbes J,
analyses described. We are grateful to the family
Edwards R, Ashley S, Boyle P. Overview of the
members for permission to report this case.
Eisenberg-Barzilai S, Friedman E. Offspring
main outcomes in breast-cancer prevention trials.
spontaneous miscarriages in Jewish women at
10 Rebbeck TR, Friebel T, Lynch HT, Neuhausen SL,
Wessex Clinical Genetics Service, Princess Anne
high risk for breast/ovarian cancer. Am J Hum
van’t Veer L, Garber JE, Evans GR, Narod SA,
Hospital, Coxford Road, Southampton SO16 5YA, UK
Isaacs C, Matloff E, Daly MB, Olopade OI,
4 Roa BB, Boyd AA, Volcik K, Richards CS.
Weber BL. Bilateral prophylactic mastectomy
Ashkenazi Jewish population frequencies for
reduces breast cancer risk in BRCA1 and BRCA2
Wessex Regional Genetics Laboratory, Salisbury
mutation carriers: the PROSE Study Group. J Clin
District Hospital, Odstock, Salisbury, UK
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