2008 Barcelona - European Society of Human Genetics

Clinical genetics
roborate the existence of a clinically recognizable group of AOS patients
with psychomotor delay, mental retardation, central nervous system
(CNS) manifestations and seizures . Furthermore, subependymal
heterotopia, never reported before in AOS, broadens the phenotypic
spectrum of CNS abnormalities to include neuronal migration defects .
This severe variant of AOS, whose phenotype has been recently delineated,
is likely inherited in autosomal recessive fashion . Hence, the
importance of a timely diagnosis not only to manage CNS manifestations
but also to properly counsel the families .
P01.240
Aplasia cutis congenita type iii, congenital scalp defects with
distal limb reduction anomalies - Adams-Olivier syndrome.
J. Paprocka 1 , E. Jamroz 1 , A. Pyrkosz 2 , A. Jezela-Stanek 3 , S. Hacia 4 , J. Baron 4 ,
E. Marszał 1 ;
1 Child Neurology Department, Silesian Medical University, Katowice 40-752,
Poland, 2 Department of Molecular Biology and Genetics, Silesian Medical University,
Katowice 40-752, Poland, 3 Department of Clinical Genetics, Memorial
Children’s Health Institute, Warsaw, Poland, 4 Student’s Association at the Child
Neurology Department, Silesian Medical University, Katowice 40-752, Poland.
Aplasia cutis congenita (ACC) are the heterogeneous group of disorders
with various clinical manifestations . Adams-Oliver syndrome
(AOS, MIM 100300), a rare congenital disorder, belongs to the type III
by Sybert classification of ACC, and is characterized by aplasia cutis
congenita of the scalp and variable degrees of terminal transverse limb
defects . Other associated anomalies include vascular defects: cutis
marmorata, dilated scalp veins, small eyes, hypoplastic optic nerve,
submucous cleft palate, cardiovascular and brain malformations (cortical
malformations- polymicrogyria, encephalocoele, hypoplasia of the
left arteria cerebri media) .
Adams-Oliver syndrome is a genetic defect that causes a vasculopathy
and leads to a variety of phenotypes . Inheritance of Adams-Olivier
syndrome is autosomal dominant but there are also reports of possible
autosomal recessive mode of inheritance .
The authors present a 27-month-old-boy with phenotype of Adams-Olivier
syndrome and Peter’s anomaly (central leukomata with variable
iridocorneal and keratolenticular adhesions and cataract), refractory
epilepsy and psychomotor retardation . The molecular investigation is
ongoing in order to identify the genetic cause of AOS .
P01.241
manifestation of X-linked Adrenoleukodystrophy in
heterozygous carriers
S. V. Mikhaylova 1 , G. E. Rudenskaya 2 , N. Y. Kalinchenko 3 , O. V. Shekhter 2 ;
1 Russian Children’s Hospital, Moscow, Russian Federation, 2 Research Centre
for Medical Genetics, Moscow, Russian Federation, 3 Endocrinological Research
Center, Moscow, Russian Federation.
X-linked adrenoleukodystrophy (ALD, MIM 300100) has several phenotypes,
clinical manifestation in women-heterozygous carriers among
them . About 15_20% of carriers develop neurological signs, typically
lower spastic paraparesis resembling adrenomyeloneuropathy (AMN)
without adrenal insufficiency. After 40 yrs this proportion amounts
50% . Though, ALD manifestation is women is often misdiagnosed . In
our sample of 50 unrelated families with verified ALD there were two
families with evident manifestation in women . Low proportion of these
cases may be partly due to the young age of most mothers in the
sample . In one family, 7-year-old proband had childhood cerebral ALD,
in his younger brother presymptomatic stage of disease was found
out . Their 26-year-old maternal uncle showed typical presentations of
AMN, 52-year-old grandmother had progressive spastic paraparesis
since 35_40 yrs . Prior to ALD discovering in the proband they had diagnosis
of Strumpell’s disease despite evident adrenal insufficiency in
the uncle . In 3-year-old proband from another family ALD manifested
by adrenal insufficiency as early as in 2.5 yrs, brain MRI proved childhood
cerebral form . His 32-year-old mother and her monozygotic twin
since 27 yrs suffered spastic paraparesis with bladder disturbances
and normal MRI, their previous diagnosis was multiple sclerosis . Such
cases along with reported earlier [Krenn et al, 2001; O’Neill et al, 2001;
Shaw-Smith et al, 2004] point that women suspicious for Strumpell’s
disease or familial multiple sclerosis should be tested for ALD if pedigree
permits X-linked inheritance. Both families, particularly the first
one, also support the known fact of diffferent ALD phenotypes intrafamilial
co-existence .
P01.242
New mutations and sequence variations in galician patients with
familiar Alzheimer´s Desease
M. Garcia-Murias 1 , A. Robles 2 , G. Martínez-Nieto 1 , M. Arias 2 , A. Koukoulis 3 , B.
Quintáns 4,5 , P. Blanco-Arias 6,5 , A. Sesar 2 , A. Carracedo 1,6,5 , M. Sobrido 1,5 ;
1 Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela,
Spain, 2 Department of Neurology, Hospital Clínico, Santiago de Compostela,
Spain, 3 Department of Neurology, Hospital Xeral-Cíes, Vigo, Spain, 4 Hospital
Clínico-SERGAS, Santiago de Compostela, Spain, 5 Centro Para Investigación
en Red de Enfermedades Raras CIBERER, ISCIII, Santiago de Compostela,
Spain, 6 Grupo de Medicina Xenómica-USC, Santiago de Compostela, Spain.
Mutations in presenilin 1 (PSEN1) are detected in 30-70% of familiar
Alzheimer disease (FAD) while presenilin 2 (PSEN2) and amyloid precursor
protein (APP) mutations are much less frequent . We studied 61
clinical-based cases with a diagnosis of probable FAD . We sequenced
all coding exons of PSEN1 and PSEN2, as well as exons 16 and 17
of APP on an ABI3730 sequencer . Sequence analysis was performed
with the Staden package. A novel L424V mutation was identified in
exon 12 of PSEN1 in a patient with very young onset dementia . Another
new mutation, I408T, was identified in exon 11 of PSEN1 in a
family . In two other cases of FAD missense mutations were detected in
PSEN2: A415T and R435Q, both in exon 12 . Five patients showed intronic
changes of unknown significance not reported in the searchable
databases if human polymorphisms. We identified the single nucleotide
substitution c .338+39G>A in intron 4 of PSEN1, a 6 bp deletion in
intron 17 of APP and three intronic variants in PSEN2: c .119-31G>A
(intron 4), c .887-19A>C (intron 8), c .1191+57T>A (intron 11) . A synonymous
change (S236S) in PSEN2 was present in two individuals . All
new mutations and sequence variations were screened in a panel of
186 Galician control individuals without neurological disorders . Globally
mutations were detected in 6 .6% of the cases (18% if we consider
both missense mutations and sequence variations of unknown significance)
. This low frequency of mutations may be due to not very restrictive
referring criteria . Alternatively, other genes may explain most FAD
in our region .
P01.243
Left Ventricular Outflow Tract Obstructions (LVOTO): family data
and NOTCH mutations
W. S. Kerstjens-Frederikse, R. M. F. Berger, Y. J. Vos, R. M. W. Hofstra;
University Medical Center, Groningen, The Netherlands.
Left ventricular outflow tract obstructions (LVOTO) are often familial.
Early detection of (latent) LVOTO or increased familial risk can prevent
unexpected cardiac death . To analyse the percentage of familial cases
all new and known patients with left sided anomalies seen after april 1 st
2006 by the department of pediatric cardiology (170) were offered genetic
counselling . Thirty-one patients refused genetic counseling, the
others were seen by the same clinical geneticist . In 44 an aortic valve
stenosis was diagnosed, in 21 a bicuspid aortic valve without stenosis,
in 28 a hypoplastic left heart, in 67 an aortic coarctation and in 10 other
left sided anomalies . In 17 patients the family history combined with
ultrasound of first degree relatives revealed a LVOTO and in another
19 probands a relative with yet another congenital heart defect was
found .
The first mutations in NOTCH1 were published in 2005 by Garg et
al . in two families with bicuspid aortic valve and other heart defects,
and so far two small series showed mutations in approximately 4% of
the patients. In our patient group, sequencing has been finished in 40
patients, and 3 mutations have been found .
We conclude that LVOTO is often familial and most pedigrees are
compatible with autosomal dominant inheritance with incomplete penetrance
. NOTCH1 mutations are found in a small percentage of familial
and non-familial cases .
P01.244
Asymptomatic neurocutaneous melanosis: A case report and
review of literature
N. O. Dávalos 1,2 , V. M. Anguiano-Alvarez 3 , G. H. Galicia-Hernandez 3 , R.
E´Vega 3,4 , D. A. Guzmán-Sánchez 5 , M. Gonzalez-Cruz 6 , M. E. Sánchez-Castellanos
7 , J. C. Salas-Alanis 3 ;
1 Instituto de Genética Humana, CUCS, Universidad de Guadalajara, Gudalajara,
Mexico, 2 Hospital Valentin Gomez Farias, Servicio de Genética, ISSSTE.
Guadalajara, Jalisco, México., Guadalajara, Mexico, 3 Instituto de Genética Hu-