2009 Vienna - European Society of Human Genetics

Metabolic disorders
enzymaticaly confirmed diagnosis in the proband.
The diagnostic rate obtained 6.8% shows unabiguosly the efficiency of
the used diagnostic algorithm.
P13.32
mutation analysis of AtP7A, AtP7B and AtOX1 genes in patients
with menkes and Wilson diseases in czech Republic
L. Pospisilova 1 , L. Kralik 2 , R. Bruha 3 , Z. Marecek 4 , E. Flachsova 1 , P. Fruhauf 5 ,
A. Puchmajerova 1 , J. Zeman 1 , P. Martasek 1 ;
1 Department of Pediatrics, 1st School of Medicine, Charles University, Prague,
Czech Republic, 2 Department of Pediatrics, 1st School of Medicine, Charles
University, Prague, Czech Republic, 3 Department of Internal Medicine 4, 1st
School of Medicine, Charles University, Prague, Czech Republic, 4 Department
of Internal Medicine 4,1st School of Medicine, Charles University, Prague,
Czech Republic, 5 Faculty General Hospital Prague, Department of Pediatrics,
Czech Republic.
Copper plays an essential role as a cofactor for many enzymes. There
are two intracellular copper transferring P-ATPases in human: ATP7A
and ATP7B, and a chaperone ATOX1 which delivers copper to them.
Deficiency of ATP7A causes X-linked Menkes disease (MD). A defect in
ATP7B causes autosomally recessive inherited Wilson disease (WD).
Here we report the mutational analysis of the ATP7A and ATP7B genes
of 4 patients with MD and 125 patients with WD from the Czech Republic.
Genomic DNA was used to amplify 23 exons of the ATP7A gene and
21 exons of the ATP7B gene. PCR products were examined by RFLP
and sequenced. We introduced fast mutation screening based on
differences in melting temperature of DNA fragments with sequence
variations. We performed mutation analysis of the ATOX1 gene in patients
whose clinical and biochemical phenotypes suggest impaired
copper transport, but no mutations were found within the ATP7A and
ATP7B genes.
Molecular analysis revealed 4 mutations in the ATP7A gene, two of
which have not been previously published (Q724X and E1249X). 13
mutations were found in the ATP7B gene (including prevalent H1069Q
mutation), and no mutations in ATOX1 gene.
Molecular analysis of the ATP7A gene allows for genetic counselling in
families affected by MD. Screening for the prevalent H1069Q mutation
in the ATP7B gene shows that the frequency- 44% of analysed alleles-
is in accordance with its occurrence in Central Europe.
Supported by Grants IGA MZ NR9406, NR9215, MSMT 1M0520
P13.33
the clinical spectrum of methylmalonic Aciduria secondary to
Cobalamin B Deficiency in Three Saudi Families
N. A. Al-Sanna’a1 , R. Mathew2 ;
1 2 Dhahran Health Center, Dhahran, Saudi Arabia, Vanderbilt University, Vanderbilt,
TN, United States.
We report eight patients with Methylmalinic aciduria secondary to Cobalamin
B deficiency from three Saudi families. Their age ranged between
four to nineteen years. The diagnosis was confirmed by vitamin
B12 complementation study done on cultured skin fibroblasts. Only four
of them had their first symptoms within the first few days of their life.
However, all had become symptomatic by the end of their first year. All
the affected children were subjected to a restricted protein diet, special
formula and L-Carnitine supplement. Multiple hospital admissions per
year were required for acute metabolic decompensation by the majority.
Three patients died at six months, four and fourteen years of age
as a result of their underlying disease. Three had developed a renal
insufficiency, and one had required hemodialysis. Five children were
able to attend regular schools with variable performances. One of the
surviving children had sustained a severe psychomotor retardation. A
detail clinical course and outcome for seven of the affected children
and review of the literature is provided.
P13.34
mitoNEt - German Network for mitochondrial disorders
H. Prokisch 1 , I. Witt 2 , L. Schöls 3 , M. Schülke-Gerstenfeld 4 , P. Freisinger 5 , W.
Kunz 6 , A. Abicht 7 , B. Obermaier-Kusser 8 , T. Meitinger 1 , T. Klopstock 7 ;
1 Technical University of Munich, Institute of Human Genetics, München, Germany,
2 Molecular Bioenergetics, University Clinics Frankfurt, Frankfurt, Germany,
3 University of Tübingen, Department of Neurology and Hertie-Institute
for Clinical Brain Research, Tübingen, Germany, 4 Klinik für Pädiatrie m. S.
Neurologie, Charité Virchow Klinikum, Berlin, Germany, 5 Technical University
of Munich, Stoffwechselzentrum Kinderklinik, München, Germany, 6 University
Bonn, Department of Epileptology and University Jena,, Bonn, Germany,
7 Friedrich-Baur-Institute, Dept. of Neurology Ludwig-Maximilians-University of
Munich, München, Germany, 8 Klinikum der Stadt Ludwigshafen gGmbH, Institute
for Clinical Chemistry and Molecular Diagnostics, Ludwigshafen, Germany.
Aims: The principal goal of mitoNET is to establish a network of clinical
and basic scientists in order to improve health care for patients with
mitochondrial diseases.
Work plan Steps to achieve this are:
i) Buildup of a nationwide network of neurological and paediatric departments
for recruitment and phenotyping of patients, setup of a webbased
register, and conduction of longitudinal studies;
ii) Comprehensive collection and storage of biological materials including
DNA, RNA and myoblasts, providing aliquots to researchers within
and outside the net;
iii) Enhancing the range of diagnostic tools, including new assays to
quantify mitochondrial proteins and dynamics, high-throughput genotyping,
and a systems approach;
iv) in vitro investigations of novel treatments including an approach
to improve respiratory chain deficiency by fibrate-induction of peroxisome
proliferator-activated receptor pathways and an approach to
identify mechanisms behind and strategies against propagation of
mtDNA mutations;
v) Increased collaboration of basic and clinical researchers to boost
synergy effects, interdisciplinary cooperation and training initiatives;
and
vi) Increased public and professional awareness.
Expected results: Progress in the projects of the consortium and the
additional boost for collaboration, synergy and communication will lead
to an improvement in diagnostics, therapy and medical care for patients
with mitochondrial diseases.
P13.35
Respiratory pathology in monozygotic sisters with mPs1
M. O. Mkheidze 1 , D. S. Poliakov 2 ;
1 Medical academy for postgraduate studies, St.Petersburg, Russian Federation,
2 Medical university named after I.P.Pavlov, St.Petersburg, Russian Federation.
Mucopolysaccharidosis 1 (MPS1, Hurler syndrome, MIM252800) is an
autosomal recessive disease characterized by variable systemic manifestations,
increased urinary mucopolysaccharide excretion and the
defective α-L-iduronidase (IDUA, EC 3.2.1.76). The MPS1 gene has
been mapped to chromosome band 4p16.3. Two common nonsense
mutations W402X and Q70X are responsible for between 15 and 65%
of mutant alleles depending on the population. We report on 8-year-old
monozygotic sisters with MPS1 caused by IDUA deficiency (genotype
Q70X/Q70X). The probands have severe variant of MPS1, including
coarse facial features, corneal opacity, skeletal dysplasia, dysostosis
multiplex, mental deficiency and hepatosplenomegaly. They suffer
from frequent attacks of respiratory lung disorders. Both sisters
get rhinitis, acute bronchitis three or four times each year. One of the
monozygotic sisters got bronchopneumonia last year. Both girls had
the sings of emphysema and fibrosis of lung tissue revealed with X-ray
observation. We suppose that pulmonary disorders in our children are
caused by inborn error of mucopolysaccharide degradation because
a deficiency of the lysosomal enzyme IDUA results in accumulation
of the mucopolysaccharides dermatan sulfate and heparin sulfate
throughout tissues and organs of our patients. Pessimistic prognosis,
death from MPS1, is usually caused by upper airway obstruction and
pulmonary complications. We use enzyme replacement therapy with
laronidase. Although the phenotypes were slightly modified there was
still physical handicap and developmental delay.
P13.36
Age-dependent changes of the mitochondrial DNA content in
muscle, liver and fibroblasts
K. Vinsova, M. Pejznochova, E. Trefilova, M. Tesarova, J. Zeman;
Charles University, First Faculty of Medicine, Department of Pediatrics and
Center of Applied Genomics, Prague, Czech Republic.
Tissue-specific depletion of mitochondrial DNA (mtDNA), caused by
mutations in increasing number of genes, often gives rise to serious
mitochondrial disorders. Recently, a real-time PCR (qRT-PCR) has