2009 Vienna - European Society of Human Genetics

Metabolic disorders
respectively. GSD-III is characterized by excessive accumulation of
abnormal glycogen with short outer chains, in the liver and/or skeletal
and cardiac muscles. GSD-IV is characterized by the accumulation
of amylopectin-like polysaccharides. The typical presentation is liver
disease of childhood and progressing to lethal cirrhosis. GSD-III and
GSD-IV are clinically heterogeneous disorders.
Using a gene-driven ENU-mutagenesis approach, the mice carrying
the missense mutation T531M in AGL gene, or the stop coden mutation
E609X in GBE1 gene have been generated respectively. The
homozygous GSD-III T531M mice appeared normal at birth. Glycogen
highly accumulated in the liver of the 20-week-old homozygous
GSD-III T531M mice was observed. The mice carrying the homozygous
E609X stop codon mutation in the GBE1 gene showed perinatal
death. The heartbeats in some homozygous GSD-IV E609X mutation
fetus stopped at around 10.5 days of gestation, and the histopathology
studies from the fetus revealed no glycogen accumulated in the wall
of heart chamber and liver primodium, however glycogen is significant
accumulated in these regions at the same stage of wild type fetus. In
the new born GSD-IV E609X mice the diastase-resistant PAS positive
material was observed in the liver and cardiomyocytes.
These mice represent important animal models for the study of abnormal
glycogen metabolism and its related toxicity and to investigate
pathophysiology and treatment strategies for human GSD-III and
GSD-IV.
P13.24
Hereditary folate malabsorption: case report and response to
treatment with folinic acid
L. Russell, A. Karalis, S. ABISH;
McGill University Health Centre, Montreal, QC, Canada.
Draft #6
Hereditary folate malabsorption (HFM) is a rare autosomal recessive
disorder in which folic acid cannot be absorbed from the gastrointestinal
tract or transported from the blood stream into the brain. As a result,
patients present with failure to thrive, megaloblastic anemia, and,
without treatment, progressive neurologic deterioration. A defective
folate transport protein (Proton-coupled folate transporter, PCFT) was
recently identified as the cause of the disorder. Less than 20 cases of
HFM have been reported in the literature, most of them female. We
report another case in whom treatment with folinic acid resulted in improved
growth and stabilization of neurologic status.
A 12 month old girl, product of consanguineous parents, was referred
for evaluation of seizures and occipital calcifications. Despite these
findings, her development was normal. The past medical history
was significant for failure to thrive and for megaloblastic anemia at 3
months of age that responded only partially to treatment with folic acid.
CSF 5-methyltetrahydrofolate, a folate metabolite, determination was
T mutation in intron 6 of the EXT2 gene which affects
most likely proper splicing of exon 6 , resulting in the formation of an
unstable mRNA or a truncated non-functional EXT1 protein.The DNA
analysis was performed for a first time in Bulgarian patients and confirmed
the clinical diagnosis. Genetic consultation and prenatal diagnosis
were offered to both families.
P13.27
Expression profiling of androgen and insulin pathway regulating
genes unveils sOs 1 as candidate gene for idiopathic hirsutism
D. Minella1 , F. D’amico1 , M. Biancolella1 , F. Amati1 , B. Testa1 , I. M. Pedrazzi1 , S.
Bueno2 , F. Raducci1 , F. Gullotta1 , D. Lauro3 , G. Novelli1,4 , C. Moretti3 ;
1Medical Genetic Dept. of Biopathology, Tor Vergata University, Rome, Italy,
2 3 Caspur, Rome, Italy, Dept. of Internal Medicine, Tor Vergata University, Rome,
Italy, 4Fatebenefratelli Hospital “S. Pietro”, Rome, Italy.
Hirsutism (IH) is defined as the presence of terminal hairs in females
in a male-like pattern affecting about 5% -15% of women. Hirsutism
results from the interaction between the androgen level and the sensitivity
of the hair follicle to the androgen. The pathophysiology of IH is
presumed to be associated to SRD5A activity and generally related to
an alteration of androgen receptor function. IH can lead to the metabolic
syndrome, visceral obesity, dyslipidemia, insulin resistance, and
hypertension.
With the aim to identify genes involved in the pathogenesis of this disorder,
we investigated the expression profile of 190 genes involved
both in the androgen biosynthesis and metabolism, and other genes
coding for products active in the insulin pathway. The analysis was
done in skin genital fibroblasts of 5 idiopathic hirsute women and 2
related controls. The array gene signature in the hirsute patients identified
4 differentially expressed genes, 2 up-regulated and 2 downregulated
(FC≥± 1.5). Differentially expressed genes included products
involved in the insulin signalling while no alteration of expression
level was found altered for androgens related genes. Specifically one
of the over expressed transcript, coding for the SOS1 gene product,
was overproducted in patients compared to controls. After sequencing
the complete SOS1 gene, its promoter region and the 3’UTR region,
we identified 18 SNPs potentially affecting the binding of transcription
factors and the correct splicing of the gene. These findings propose