European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Clinical genetics
apparently sporadic case. We also screened the available members of
one of the FALS cases. In this family we identified an affected and an
unaffected individual carrying the D90A mutation in homozygous and
heterozygous state respectively. According to previous data that reported
for all D90A homozygous ALS patients a phenotype characterized
by slow progression of the disease, also our patients show a mild
phenotype with a prolonged survival. In conclusion, our study provides
further evidence that D90A is an autosomal recessively inherited mutation
in ALS patients in Southern Italy.
P0015. High level of hypermetabolism in patients with familial
amyotrophic lateral sclerosis
B. Funalot 1,2 , J. C. Desport 3 , M. Lacoste 1 , F. Sturtz 2,4 , P. Couratier 1 ;
1 Dept of neurology, Limoges, France, 2 EA4021 Faculté de médecine, Limoges,
France, 3 Nutrition unit, Limoges, France, 4 Dept of biochemistry and molecular
genetics, Limoges, France.
An abnormally elevated level of resting energy expenditure (REE,
measured by indirect calorimetry) has been reported in a subset of
patients with amyotrophic lateral sclerosis (ALS). Hypermetabolism
(measured REE/calculated REE ≥ 1.1 or 110%) was found in 42/62
ALS patients in a previous study. Interestingly, hypermetabolism has
also been observed in transgenic mice harbouring ALS-causing mutations
in the SOD1 gene. We tested whether patients with familial
ALS (FALS) had a REE level differing from patients with sporadic ALS
(SALS). Eleven patients with FALS (from ten different families, all negative
for the screening of SOD1 mutations by direct sequencing) who
had performed an indirect calorimetry in our centre during the last seven
years were compared with 33 SALS patients matched for age and
sex. 11/11 (100%) patients with FALS were hypermetabolic, compared
with 17/33 (52%) patients with SALS (p=0.009). The mean level of
hypermetabolism was significantly higher in FALS patients (124±8%)
than in SALS patients (113±12%, p=0.01). Subjects with FALS are
supposed to carry mutations or strong genetic risk factors predisposing
to the disease, which may also be responsible for the higher REE
observed in these patients. In the absence of infection, inflammation or
hyperthyroidism, the observed hypermetabolism is likely to result from
mitochondrial uncoupling. Several other lines of evidence support the
occurrence of a mitochondrial dysfunction in the course of ALS. Our
results suggest that this mitochondrial dysfunction may be genetically
driven in patients with FALS and could therefore be directly involved in
the pathogenesis of FALS.
P0016. Phenotypic diversity in androgen insensitivity syndrome:
About two families
F. Kallebi 1 , M. Fourati 2 , D. Sallemi 2 , R. Frikha 1 , T. Rebai 1 , N. B. Abdelmoula 1 ;
1 Faculty of Medicine, Sfax, Tunisia, 2 Private sector, Sfax, Tunisia.
The androgen insensitivity syndrome (AIS), a rare X-linked disorder
caused by defects in Androgen Receptor (AR). Variable phenotypic expression
has allowed the classification of AIS into complete and partial
forms. Mutational screening of the AR gene have revealed over 300
mutations.
Here, we describe pedigrees of two families with three affected subjects.
Pedigrees patterns were consistent with X-linked recessive inheritance.
Index cases were referred to our consultation at adult age
for genetic counselling.
At the first family, a 28 year old female consults because primary
amenorrhea and hirsutism. She had a blind vaginal pouch without
uterus. Abdominal surgery with bilateral gonadectomy was done at
age 18 years but histology report was not available. Two nieces have
an inguinal hernia with an apparently female phenotype. Karyotype
of 3 patients reveal a 46,XY formula and diagnosis of Complete AIS
was done.
At the second family, a 31 and 32 year old cousins had under masculinised
external genitalia, pseudofemale hairless and breast development.
Gonads were absent even after chirurgical exploration. The
nephew of the first patient has ambiguous genitalia. A male karyotype
was revealed for the three cases and diagnosis of incomplete AIS was
done.
AR molecular investigation are conducted. Correlation between the
phenotypic features and the abnormalities identified on mutational
analysis of the AR gene will be discussed.
We emphasize through this report the need for accurate and early diagnosis
of AIS which govern bearing on the sex of rearing, genetic
counselling, and subsequent management.
P0017. Androgen receptor gene mutations in 46, XY females
M. D. Omrani, S. Saleh-Gargari;
Uromieh Medical Science University, Uromieh, Islamic Republic of Iran.
The androgen insensitivity syndrome is a heterogeneous disorder with
a wide spectrum of phenotypic abnormalities, ranging from complete
female to ambiguous forms that more closely resemble males. The
primary abnormality is a defective androgen receptor protein due to a
mutation of the androgen receptor gene. This prevents normal androgen
action and thus leads to impaired virilization. A point mutation of
the androgen receptor gene affecting two siblings with complete androgen
insensitivity syndrome is described. On examination they both
had normal external female genitalia.
Genomic DNA was extracted from EDTA-preserved blood samples
and isolated according to standard procedures. The androgen receptor
gene was screened for mutations using an automated sequence
analyzer (ABI Prism 310). Both girls possess one substitutions (G>A
at position 2086 in exon 4), leading to D695N mutation. Mother was
found to be a heterozygous carrier for this mutation. GTG banded
karyotype of the girls showed they both have male karyotype (46, XY).
In addition, the SRY gene screening showed they both have intact
SRY gene. The labioscrotal folds contained palpable gonads measuring
1.5 cm in largest diameter. Ultrasound examination of the pelvis
revealed absence of the uterus.
Serum follicle stimulating hormone (FSH), luteinizing hormone (LH),
and testosterone values were higher than normal range.
To our knowledge this is the first confirmed instance of AIS due to an
AR mutation occurring in familial cases in this country. Furthermore,
the phenotype has complete association with this mutation.
P0018. Aniridia in a three-generation family
C. C. Albu, E. Severin, D. Albu;
Carol Davila Univ Med Pharm, Bucharest, Romania.
Background: Aniridia is a rare development eye anomaly.As an isolated
ocular abnormality, aniridia is an autosomal dominant disorder. Clinical
phenotypes of aniridia are associated with PAX6 mutations. We report
a case of aniridia in a three-generation family in which the proband
has a severe ocular phenotype similar to her maternal grandmother.
Objectives: to describe and compare clinical manifestations of aniridia
in younger and older generations; to study the intrafamilial variability of
aniridia and management implications. Patients and Methods: A threegeneration
Caucasian family with aniridia was investigated. Four of
the family members (a one-year-old girl, her mother, her maternal aunt
and her maternal grandmother) were affected and expressed variable
ocular phenotypes. Evaluation included physical examination and a
detailed medical history and family history. Genomic DNA was isolated
from affected individuals (clinically diagnosed aniridia) and analyzed
by PCR. Results: The clinical expression of aniridia was variable in this
family: bilateral complete or partial aniridia, unilateral complete aniridia
and iris coloboma. Aniridia was associated with other ocular defects:
cataract, glaucoma, nystagmus, amblyopia and strabismus. The family
pedigree showed an autosomal dominant mode of inheritance with
complete penetrance and variable expressivity. The patient and her
grandmother shared similar phenotype (more severe than their relatives).
All cases were defined by clinical signs. All cases had the same
PAX6 mutations.Conclusions: aniridia appears as a hereditary condition
with clinical variation; molecular-genetic data should be integrated
with the corresponding clinical findings; all patients with aniridia should
be evaluated by an ophthalmologist and a geneticist.
P0019. SOX2 anophthalmia syndrome: point mutations, large
deletions and a broader phenotype.
N. K. Ragge 1 , P. Bakrania 1 , D. J. Bunyan 2 , A. Salt 3 , A. Martin 1 , J. A. Crolla 2 , A.
Wyatt 1 , A. Fielder 4 , J. Ainsworth 5 , A. Moore 3 , D. Laws 6 , D. Pascuel-Salcedo 7 , C.
Ayuso 8 , L. Allen 9 , J. Collin 3 , D. O. Robinson 2 ;
1 University of Oxford,Dept of Physiology, Anatomy and Genetics, Oxford,
United Kingdom, 2 Wessex Regional Genetics Laboratory, Salisbury District
Hospital, Salisbury, United Kingdom, 3 Moorfields Eye Hospital, London, United
Kingdom, 4 Western Eye Hospital, London, United Kingdom, 5 Dept. of Ophthalmology,
Birmingham Children’s Hospital, Birmingham, United Kingdom, 6 Singleton
Hospital, Swansea, United Kingdom, 7 Hospital La Paz, Madrid, Spain,
8 Fudacion Jiminez Diaz, Madrid, Spain, 9 Addenbrookes Hospital, Cambridge,