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

Therapy for genetic disease
P1409. The Hunter Outcome Survey (HOS): clinical
characteristics of patients with mucopolysaccharidosis type II
J. E. Wraith 1 , M. Beck 2 , R. Giugliani 3 , B. K. Burton 4 , L. DeMeirleir 5 , J. Zeman 6 ,
on behalf of the HOS investigators;
1 Royal Manchester Children’s Hospital, Manchester, United Kingdom, 2 Children’s
Hospital University of Mainz, Mainz, Germany, 3 Hospital de Clinicas de
Porto Alegre, Porto Alegre, Brazil, 4 Children’s Memorial Hospital, Chicago, IL,
United States, 5 University Hospital of the Vrije Unversiteit Brussel, Brussels,
Belgium, 6 Charles University, Prague, Czech Republic.
Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is a rare,
progressive, X-linked disorder of glycosaminoglycan (GAG) metabolism
caused by a deficiency of the enzyme iduronate-2-sulfatase. This
results in progressive GAG accumulation within multiple tissues and
organs. In 2006, a global survey of MPS II patients - the Hunter Outcome
Survey (HOS) - was established to enhance our understanding
of the natural history of MPS II, monitor the safety and efficacy of enzyme
replacement therapy, and provide the basis for the development
of clinical management guidelines. As of October 2006, 100 patients
had enrolled in HOS at centres in 11 countries. The median ages at enrolment,
onset of symptoms and diagnosis of MPS II were 11.3 years,
1.5 years and 3.5 years, respectively. The prevalence of clinical features
at the time of enrolment into HOS was variable; nasal obstruction
was reported in 28% of patients, enlarged tonsils or adenoids in
68%, enlarged liver or spleen in 88%, joint stiffness in 87% and facial
dysmorphia by 98%. Cardiovascular manifestations of MPS II were
found in approximately 75% of patients. These included murmur in
77%, valve disease in 69%, and cardiomyopathy in 12% of patients.
Life-table analyses indicated that by age 7 years, approximately 50%
of patients with Hunter syndrome display some cardiovascular abnormalities,
increasing to 95% by age 15 years. As enrolment increases,
HOS will improve our understanding of MPS II, advance the assessment
of the long-term impact of ERT, and allow the development of
evidence-based clinical management guidelines.
P1410. Oxidative stress in Peroxisomal disorders
H. T. El-Bassyouni;
National Research Center, Guiza, Egypt.
Peroxisomal disorders are subdivided into peroxisome biogenesis
disorders (PBDs) and single peroxisomal enzyme deficiencies. Many
peroxisomal diseases exhibit excessive oxidative stress leading to
neurological alterations and dysfunction. This study aimed to investigate
whether oxidative stress is involved in the pathogenesis of peroxisomal
disorders by estimating various oxidative stress parameters
in cases suffering from peroxisomal disorders.
A total of twenty patients with peroxisomal disorders, their ages ranged
from 6 months to 13 years (mean 5.9 ±3.2) were compared to fourteen
healthy controls. All individuals were subjected to full history taking
including three-generation pedigree analysis concerning parental
consanguinity and similarly affected members in the family with meticulous
clinical examination to detect any malformation or anomaly.
VLCFAs and phytanic acid estimation was done to verify the diagnosis.
Other investigations including brain magnetic resonant image (MRI),
electric encephalogram (EEG), visual evoked potential (VEP), auditory
potential and plain X- rays were done to asses the pathological condition
of the patients. Oxidative stress parameters including nitric oxide
(NO), malondialdehyde (MDA) and superoxide dismutase (SOD) were
estimated in both patients and controls.
This study showed significant increase of both MDA and NO in PBDs.
It was also demonstrated that SOD was significantly low in PDB more
than controls.
Conclusion: Lacking functional peroxisomes leads to generalized increase
in oxidative stress confirming the important role of peroxisomes
in homeostasis of reactive oxygen species (ROS) and the implications
of its disturbances in cell pathology. The study recommends supplementation
with antioxidants besides other lines of treatments.
P1411. Activation of PPAR pathway stimulates mitochondrial
oxidative phosphorylation and is a potential therapy in
respiratory chain defects.
J. Bastin 1 , F. Aubey 1 , A. Munnich 2 , F. Djouadi 1 ;
1 CNRS UPR 9078, Paris, France, 2 INSERM U781, Paris, France.
The mitochondrial Respiratory Chain (RC) disorders are the largest
group of inborn errors of metabolism and still remain without treat-
ment in most cases. Here, we tested whether bezafibrate, a drug acting
as a Peroxisome Proliferator Activated Receptor (PPAR) agonist,
could induce a stimulation of RC residual capacities in four patient cell
lines carrying mutations in the Fp (flavoprotein, complex II, CII), or
BCS1 (complex III, CIII), or SURF1 (complex IV, CIV), or COX10 (CIV)
genes. Exposure to bezafibrate (400µM, 72h) was found to increase
(+38 to +50%) the CII, CIII and CIV activities in control fibroblasts,
and immunoblots showed parallel increases (+82 to +150%) in Fp,
Core 2, SURF1, COX2 and COX4 protein levels. A similar treatment
by bezafibrate improved RC capacities in BCS1- and COX10-deficient
fibroblasts, as indicated by the stimulation of CIII (+133%) and CIV
(+71%) enzyme activity, and by the higher expression of representative
proteins. This was related to a drug-induced augmentation in
the mRNA abundance of the mutated BCS1 or COX 10 gene. Fp and
SURF1 mRNA were also induced by bezafibrate, but without changes
in RC residual capacities due to the mutated protein instability. The
molecular mechanisms underlying these effects likely involved PPARδ
and the co-activator PGC1α that could induce the expression of genes
encoding structural subunits or ancillary proteins of the OXPHOS apparatus,
leading to stimulate the activity and protein levels of RC complex.
These effects could find applications for the correction of some
moderate RC disorders due to mutations in nuclear genes.
P1412. Growth Hormone is Effective in Treatment of Short
Stature Associated with SHOX Deficiency: Two-year Results of a
Randomized, Controlled, Multi-Center Trial
W. F. Blum 1 , B. J. Crowe 1 , C. A. Quigley 2 , H. Jung 3 , D. Cao 2 , J. L. Ross 4 , L.
Braun 2 , G. Rappold 3 ;
1 Lilly Research Laboratories, Eli Lilly and Company, Bad Homburg, Germany,
2 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, United
States, 3 Department of Molecular Human Genetics, Institute of Human Genetics,
University of Heidelberg, Heidelberg, Germany, 4 Department of Pediatrics,
Thomas Jefferson University, Philadelphia, PA, United States.
SHOX encodes a homeodomain transcription factor responsible for a
significant proportion of long-bone growth. Patients with mutations or
deletions of SHOX, including those with Turner syndrome [TS] who are
haploinsufficient for SHOX, have variable degrees of growth impairment,
with or without a spectrum of skeletal anomalies consistent with
dyschondrosteosis.
Fifty-two prepubertal subjects (24 male, 28 female; age 3.0-12.3
years) with a molecularly-proven SHOX gene defect and height below
the 3rd percentile for age and gender were randomized to either a
growth hormone (GH)-treatment group (n=27) or an untreated control
group (n=25) for 2 years. To compare the GH treatment effect between
subjects with SHOX-deficiency (SHOX-D) and those with TS, a third
study group, comprised 26 pts with TS aged 4.5-11.8 years, who also
received GH. Between-group comparisons of height velocity, height
standard deviation score (SDS) and height gain (cm) were performed
using analysis of covariance accounting for diagnosis, sex and baseline
age.
The GH-treated SHOX-D group had a significantly greater first-year
height velocity than the untreated control group (p