2009 Vienna - European Society of Human Genetics

Metabolic disorders 0
position -62) and is predicted to result in a larger protein with an inframe
insertion of twenty amino acids. In silico analysis of the putative
impact of the insertion shows serious clashes in protein conformation:
this insertion disrupts the α5 helix of the dGK kinase domain, rendering
the protein unable to bind purine deoxyribonucleosides. In addition, a
common haplotype that segregated with the disease in both families
was detected by haplotype reconstruction with ten markers (microsatellites
and SNPs), which span 4.6 kb of DNA covering the DGUOK
locus. In conclusion, we report a new DGUOK splice site mutation that
provide insight into a critical protein domain (dGK kinase domain) and
the first founder mutation in a North-African population
P13.11
High incidence of Fabry Disease - causing mutations in Galicia,
North-west spain
P. Rana-Diez 1 , C. Colon 2 , J. Alonso-Fernandez 2 , J. Fraga 2 , R. Gonzalez-Bouzon
1 , A. Carracedo 1 , F. Barros 1 ;
1 Fundacion Publica Galega de Medicina Xenomica, Santiago de Compostela,
Spain, 2 Complejo Hospitalario Universitario de Santiago, Santiago de Compostela,
Spain.
Fabry disease (FD) is an X-linked lysosomal storage disorder that results
from mutations in the α-galactosidase A (α-Gal A) gene which
lead to a deficient activity of the enzyme and a progressive lysosomal
deposition of globotriaosylceramide and other glycosphingolipids in
different cells of the body.
In its classic form, with a typical onset in childhood or adolescence, the
major disease manifestations include angiokeratoma, acroparesthesias
and vascular disease of the heart, kidneys and brain.
The bibliography shows an estimated incidence of 1/117000 newborns,
representing the second most prevalent lysosomal lipid storage
disease. However, recent studies suggest that FD is underdiagnosed
demonstrating that neonatal incidence may fluctuate between 1/3100
and 1/4600.
Material and methods.
We designed primers for the direct bidirectional sequencing of the coding
region of the α-Gal A gene and carried out an study of the mutations
of the gene in 112 newborns with low α-galactosidase A activity
(less than 2 µmol/L/h) measured by fluorimetry.
Results.
In the sample of 112 newborns, we found 10 unrelated cases with
pathological missense mutations (R118C: 5 hemizigous males; A143T:
4 hemizigous male and 1 heterozigous female). In adittion, 4 previously
undescribed intronic variants surrounding intron-exon boundaries
were identified in six cases.
Since the disease follow an X-linked dominat mode of inheritance (heterozygous
females typically have milder symptoms at a later age of
onset than males) these results demonstrate an inusual neonatal incidence
of 1/1400 in the North-West Spanish population of Galicia, the
highest Fabry disease rate known to us in the literature.
P13.12
two different related Fabry mutations in the same family: “Who
isn´t saying the truth?”
L. Monserrat1 , M. I. Rodríguez-García2 , L. Núñez1 , M. Ortiz1 , R. Barriales-Villa1 ,
E. Maneiro1 , L. Cazón1 , X. Fernández1 , E. Veira1 , A. Castro-Beiras1 , M. Hermida-Prieto1
;
1Instituto Universitario de Ciencias de la Salud- CHUAC, A Coruña, Spain,
2Complejo Hospitalario Universitario A Coruña- SERGAS. Instituto de Ciencias
de la Salud, A Coruña, Spain.
Introduction Fabry disease (FD) is an X-linked lysosomal α-galactosidase
A deficiency that causes multisystemic problems, including renal,
neurological, ocular, skin, and cardiac manifestations.
Methods. A 43 year old female, with arterial hypertension, was remitted
to our clinic because of a suspected diagnosis of hypertrophic cardiomyopathy.
Clinical, electrocardiographic, echocardiographic, plasma
alfa-galactosidase A activity and genetic study was made of all available
relatives.
Results. The index case echocardiogram shown left ventricular hypertrophy
mainly of posterior-lateral wall (16mm). Her adolescent son had
been diagnosed of erythromelalgia, with cutaneous lesions consistent
with angiokeratomas and suffering for intense pains in his feet and
hands (the mother had suffered the same pains in her youth). The son
also presented mild left ventricular hypertrophy (13mm, postero-basal
wall). A probably FD with the classical form of the disease was suspected
in both, due to a low plasma alfa-galactosidase enzymatic activity.
Moreover, her aunt and her cousin, diagnosed of a mild FD form,
presented the A143T mutation in alpha-galactosidase A gen (GLA).
We suspected that the mutation A143T in the GLA was responsible for
the disease in the new cases. However, the genetic analysis showed
that they were not carriers of the A143T mutation but they presented
the mutation IVS5+2T>C previously associated with the classic form
of FD. This intronic mutation was no present in the patient with the
A143T mutation.
Conclusion. In this family we described two mutations previously associated
with FD, but with available data we think that the pathogenicity
of the A143T mutation must be revaluated.
P13.13
Five novel mutation in Fabry disease in a series of Russian
patients.
L. Golivets, E. Zakharova, T. Boukina, P. Tsygankova;
Research Center for Medical Genetics, Moscow, Russia, Moscow, Russian
Federation.
Fabry disease is an X-linked recessive abnormality related to lysosomal
storage disorders. It is caused by deficiency of α-D-Galactosidase
A (α-GAL). Main symptoms include renal failure , cardiovascular
disease, angiokeratoma, acroparaesthesia. In this issue we include 10
male patients with classical clinical picture of Fabry disease. α-GAL
activity in leukocyte ranges from 0,01-7 nmol/mg/h. Using the adopted
method we measured the α-GAL activity in dried blood spots (DBS) in
5 patients. Enzyme activity in DBS range from 0-0,04 nmol/spot*45h.
The enzyme deficiency was detected in all samples. We made sequences
of GLA gene; mutations were revealed in all cases and were
privet for each family. Five mutations have been already described
(R112C, Cys142R,R227X, Thr282P, c.238delAA). And the rest five are
novel (R301L, c.782delG,Cys63R, R220X, c.541del18). Biochemical
assay combined with DNA-testing gives the most effective diagnostic
approach. DNA analysis is preferable in Fabry carries as the α-GAL
activity could be at the cut-off range in this group.
P13.14
Acute Abdomen Reasoned surgery Frequency and mEFV
mutations in the Patients with FmF
H. Samli1 , F. Mutlu Icduygu2 , A. Ozgoz2 , G. Akbulut3 , K. Hekimler2 , N. Imirzalioglu2
;
1 2 Uludag University, Department of Moleculer Biology, Bursa, Turkey, Afyon
Kocatepe University, Department of Medical Genetics, Afyonkarahisar, Turkey,
3Afyon Kocatepe University, Department of General Surgery, Afyonkarahisar,
Turkey.
Familial Mediterranean Fever (FMF), is an autosomal recessive disease
characterized by recurrent fever, peritonitis, arthritis, pleuritis and
neuropathic amyloidosis. The disease is common in North African and
Iraqi Jews, Turks, Armenians, Middle East Arabs and in ethnic groups
living in this region. More than 95% of FMF patients have peritoneal
involvement mimicking acute abdomen, and sometimes this involvement
causes unnecessary surgical intervention. In the current study
we objected to determine the frequency of acute surgical abdomen
intervention and MEFV gene mutations in FMF patients
In the interview of 159 patients referred to our department by prediagnosis
of FMF, totally 26 (16.4%) were detected to be operated. Of
these 17 (10,7%) were operated by the reason of appendicitis and 9
(5,7%) were operated by other acute abdomen reasons. When the
mutations of these patients evaluated, M694V(40.5%) and E148Q
(21.4%) mutations were the most frequent ones.
The mutation frequency in FMF patients with acute surgical abdomen
intervention (80.8%) was significantlty high than the ones without
(56.4%). The increase of mutation scanning in FMF patients will
significantly decrease unnecessary surgical intervention in this patient
group.
P13.15
the bone mineral density in patients with Familial mediterranean
Fever
S. Yuksel 1 , H. Samli 2 , M. Colbay 3 , U. Dundar 4 , G. Acarturk 5 , S. Demir 5 , T. Koken
6 , O. Aktepe 7 , V. Kavuncu 8 , M. Solak 9 ;
1 Suleyman Demirel University, Department of Internal Medicine, Turkey, 2 Ko-