2009 Vienna - European Society of Human Genetics

Therapy for genetic disorders
of mental deficiency, hypogonadism, scoliosis, osteoporosis and frequent
pathological fractures.
The aim of this study is to provide recommendation and clinical pathways
for the diagnostic and management of surgical problems of PWS
patient.
We encountered a case of a 20 year’s old PWS female with typical
obesity, short stature and mental retardation. She had a history of congenital
hip dislocation, severe muscular hypotonia in infancy and a left
femur fracture and delayed healing in childhood. The patient had an inactive
lifestyle with low level of physical activity. Clinical exam showed
unbalanced thoraco-lumbar scoliosis, lower limb length discrepancy,
severe walking and equilibrium maintenance difficulties. Polysomnogram
revealed sleep disordered breathing, nocturne sinusal tachycardia
of 88/ min, apnea-hypopnea index 54.8/ h, mean nocturnal arterial
saturation was 96% and total reduction of sleep efficiency to 28%.
Surgical issues are a major concern for PWS patients and regular
systematic examination is mandatory. In respect for the good clinical
practice procedures we propose an orthopedic treatment, dietary intervention,
psychological and educational counseling. We opened a
regional data base for patients with PWS for better medical assistance
efficient cost management.
P14.17
the prevalence of protrombin G20210A mutation by PcR-RFLP
in iranian patients with thromboembolic evidence
L. Mohammadi Ziazi, Z. Mohammadtaheri, A. Rakhshan, M. Poorabdola, F.
Mohammadi;
National Research Institute of Tuberculosis, Tehran, Islamic Republic of Iran.
Deep vein thrombosis is one of the leading causes of mortality with
an annual incidence of 1 per 1000 .Interaction between multiple genetic
and environmental risk factor is responsible for thromboembolic
tendency. A single nucleotide exchange at position 20210 in the 3’ untranslated
region of prothrombin gene which results in guanine to adenine
transition. This mutation was found as the second most common
genetic risk factor for venous thrombosis.
The aim of this study was to determine the prevalence of this mutation
in Iranian patients with a history of thromboembolism in national
research institute of tuberculosis and lung disease (NRITLD) by PCR
RFLP. All thromboemboli patients were from the Iranian population
(n=43). The result was compared with matched control group (n=50)
that were kidney donor without any known thromebophilic defects .
Genomic DNA was used as a template for PCR amplification of exon
14 and PCR product was digested by HindIII enzyme.
The mean age of patient was 52.7±16.1 (range 19-84). They consist
of 25 (55.6%) male and 20 (44.4%) female. The mean age of control
group was 42 (range 29-60). They consist of 34 male and 16 female.
All the patients and controls had homozygote G/G genotype. We had
no heterozygous G/A or homozygous mutation (A/A).
In our study none of control subjects and none of patients were carrier
for prothrombin A gene mutation which is correlate to finding of two
studies in China and Thailand and support the previous report that this
mutation is rare in Asia country.
P14.18
combined L-Dopa and selegiline therapy greatly improves
the clinical picture in segawa syndrome: A follow-up study
on three siblings with a novel c1475G mutation on thyrosine
Hydroxylase (tH) gene
E. Yosunkaya, E. Karaca, B. Okcesiz, S. Basaran Yilmaz, G. S. Guven, M.
Seven, A. Yuksel;
Istanbul University, Cerrahpasa Medical School, Department of Medical Genetics,
Istanbul, Turkey.
Three siblings, of whom the elder are monozygotic twins, born to first
cousin parents were referred for neurodevelopmental delay and diffuse
dystonia. Initial physical examination of the sibs, twins at age 4 6/12
and the youngest boy 1 9/12 years, revealed body measurements below
third centile. They had minor dysmorphic features, such as bifrontal
narrowing, downslanting palpebral fissures, low-set ears, up-turned
nostrils and retrognathia. Cognitive functions were severely retarded.
Increased deep tendon reflexes, diffuse muscle atrophy and spasticity
were evident. Absent of eye contact and head control, diffuse dystonia,
hypokinesia, choreatetosis and tremor also noted in neurological
examination. Molecular testing of tyrosine hydroxylase (TH) gene
revealed a novel mutation, P492R (1475 C>G), which confirmed the
diagnosis of Segawa syndrome. After the onset of L-Dopa/Carbidoba
(2 mg/kg/day), no response with regard to relieve of symptoms appeared
after one month of therapy. Selegiline, an agent selectively inhibits
MAO-B, added to the therapy regimen, which in turn, markedly
improved the clinical picture. Here, we report the follow-up period of
three siblings with Segawa syndrome resulting from a novel mutation
in TH gene.
P14.19
Deferasirox reduced iron-load in patient with Ferroportin disease
refractory to phlebotomy: a case report.
T. Sura, S. Pingsuthiwong, J. Eu-ahsunthornwattana, A. Tunteeratum, K.
Srichan;
Ramathibodi Hospital, Bangkok, Thailand.
We report a patient with a mutation in the SLC40A1 gene, which encodes
the protein Ferroportin 1 (FPN1) resulting in hemochromatosis
type 4 (HFE4), who has been treated with Deferasirox. He was 32
year-old when first seen, asymptomatic but with dusky complexion,
and has strong family history suggestive of autosomal dominant hemochromatosis.
DNA sequencing from the proband had shown a Cys326Tyr
(TGC>TAC) mutation in exon 7 of the SLC40A1 gene, which
is also found in the other affected family members. Although a few family
members including himself had previously been treated with regular
phlebotomy, his serum ferritin remained unsatisfactorily high (3,624
ng/mL), along with high transferrin saturation (137%; serum iron = 171
μg/dL; TIBC = 125 μg/dL). He was commenced on a therapeutic trial
of the oral chelating agent Deferasirox (ICL670). After a period of dosage
titration, his serum ferritin declined steadily, as did his transferrin
saturation. At the most recent visit, one year after treatment initiation,
his serum ferritin decreased to 619 ng/mL, the transferrin saturation
to 75% (serum iron = 218 μg/dL; TIBC = 292 μg/dL), and no adversed
reaction was noticed. Among the four defined types of primary hemochromatosis,
HFE4 is the only type with autosomal dominant inheritance.
It also differs from the other HFE’s in that most of the iron is
deposited in the tissue making phlebotomy ineffective and potentially
complicated by anemia. Iron chelating agents therefore seems to be a
better option, particularly the orally administered agents as was demonstrated
in this patient.
P14.20
Pharmacogenetic approach to the treatment of smA patients
with valproic acid and carnithin preparations
V. Vakharlovsky 1 , G. Zheleznyakova 2 , A. Kiselev 1 , M. Danilova 2 , A. Glotov 1 , V.
Komantsev 3 , A. Baranov 1 , V. Baranov 1 ;
1 Ott’s Institute of Obstetrics and Gynecology RAMS, Saint-Petersburg, Russian
Federation, 2 Saint-Petersburg State University, Saint-Petersburg, Russian Federation,
3 Institute of Human Brain RAS, Saint-Petersburg, Russian Federation.
Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular
disorder, with an incidence in European populations of 1 in
10000 newborns. The telomeric survival motor neuron gene (SMN1)
is the SMA disease gene, and the centromeric gene (SMN2) is the
main modifier of the disease severity. Recent research suggests that
valproic acid (VPA), a commonly used epilepsy drug, may be able
to upregulate expression of SMN2 gene and to slow progression of
the disease. Since 2003 we were involved in combined clinical trial
of VPA + carnithine treatment in SMA patients. Over 60 SMA patients
were collected and studied so far with at least half of them being enrolled
in the trial. Liver functional activity is monitored and SMN2 gene
copy number is determined by means of real-time PCR. Nerve activity
testing was performed by means of electroneuromyography. Also
the patients were tested on presence of (c.681 G>A) polymorphism in
CYP2C19 gene contributing to VPA metabolism and thus to efficacy
of treatment. Highly positive curative effects including general health
improvements and progress in motion abilities were registered in SMA
patients especially of the II type. The results of the study are relevant
to elaboration of efficient strategy in SMA patients’ treatment.