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

Clinical genetics
Ras-MAPK signaling cascade, leading to constitutive activation of the
pathway, with specific mutations in HRAS being detected in the majority
of individuals with CS.
We screened four unrelated patients (2 male , 2 female) previously
reported with myopathy, muscle spindle excess in striated muscle,
HOCM, variable features of NS and early death for mutations in
PTPN11, KRAS, NRAS and HRAS. Heterozygous de novo HRAS
mutations were found in three of the four patients examined. In the
first case the 2 bp substitution c.35-36GC->TT predicting the amino
acid exchange G12V was present, and in the second case another
missense mutation at the same codon, G12S (c.34G->A). In the third
patiënt a novel HRAS mutation c.187G->A (E63K)was detected in
DNA derived from blood cells.
We present the clinical details and results of the molecular studies in
the four patients with HOCM, myopathy with muscle spindle excess
and NS features and conclude that these patients represent the severe
end of CS.
P0138. HTRA1 Polymorphism in Dry and Wet Age-Related
Macular Degeneration
J. Lin, F. Tsai, Y. Tsai;
China Medical University Hospital, Taichung, Taiwan.
Objective: To investigate HTRA1 polymorphisms in unrelated Taiwan
Chinese patients with age-related macular degeneration (AMD) and
control subjects without AMD.
Methods: 95 unrelated Taiwan Chinese patients with AMD and 90 age-
and sex-matched control subjects were enrolled in our study. Genomic
DNA was prepared from peripheral blood obtained from all AMD patients
and control subjects. Polymerase chain reactions were used to
analyze two HTRA1 single-nucleotide polymorphisms [rs11200638 (G/
A) and rs10490924 (G/T)].
Results: Of the 95 participants with AMD, dry AMD was diagnosed
in 52 patients and wet AMD in 43 patients. Both rs11200638 (G/A)
and rs10490924 (G/T) were significantly associated with all AMD
[rs11200638: P = 6.7 × 10 -7 for an additive allele-dosage model, OR het
= 1.97 (0.81, 4.81), OR hom = 8.59 (3.28, 22.49), A allele: 73% in all AMD
versus 47% in controls; rs10490924: P = 9.2 × 10 -6 , OR het = 1.86 (0.79,
4.35), OR hom = 5.08 (2.21, 11.70), T allele: 73% in all AMD versus 50%
in controls]. In terms of significance of association, rs11200638 was
the most significantly associated variant. Subtype analysis including
dry and wet AMD also revealed the similar results. Haplotype analysis
demonstrated that AT was significantly associated with wet and all
AMD (P = 0.011 and 0.004, respectively), whereas GG was significantly
associated with the control group when compared with all AMD
(P = 0.035).
Conclusions: Our study demonstrated that both SNPs were significantly
associated with dry and wet AMD and the rs11200638 was the most
significantly associated variant in a Taiwan Chinese population.
P0139. Early energy deficit in Huntington disease: identification
of a plasma biomarker traceable during disease progression.
F. Mochel 1 , P. Charles 2 , F. Seguin 3 , J. Barritault 3 , C. Coussieu 4 , L. Perin 5 , Y.
Le Bouc 5 , C. Gervais 6 , G. Carcelain 7 , A. Vassault 8 , J. Feingold 2 , D. Rabier 8 , A.
Durr 1,2 ;
1 INSERM U679, Hôpital La Salpetrière, Paris, France, 2 Département de génétique
et cytogénétique, Hôpital La Salpetrière, Paris, France, 3 Faculté de médecine
et de pharmacie and Hôpital La Milétrie, Poitiers, France, 4 Laboratoire
d´endocrinologie, Hôpital La Salpetrière, Paris, France, 5 Explorations fonctionnelles
endocriniennes, Hôpital d´enfants Armand Trousseau, Paris, France,
6 Service de diététique, Hôpital La Salpetrière, Paris, France, 7 Laboratoire
d´immunologie, Hôpital La Salpetrière, Paris, France, 8 Laboratoire de biochimie
métabolique, Hôpital Necker-Enfants malades, Paris, France.
Huntington disease (HD) is a fatal neurodegenerative disorder, without
effective treatment. In the absence of clear underlying mechanisms
in HD, weight loss is an appealing phenotype associated with chorea
and cognitive decline. We performed a multiparametric study exploring
body weight and the mechanisms of its loss in 32 presymptomatic
carriers and HD patients in the early stages of the disease, compared
to 21 controls. We combined it to a multivariate statistical analysis,
based on proton nuclear magnetic resonance (1H NMR) spectroscopy
of plasma. We demonstrated an early hypermetabolic state in HD.
Weight loss was observed in the HD group even in presymptomatic
carriers, although their caloric intake was higher than controls. Inflam-
matory processes and primary hormonal dysfunction were excluded.
1H NMR spectroscopy on plasma did, however, distinguish HD patients
at different stages of the disease and presymptomatic carriers
from controls. This distinction was attributable to low levels of the
branched chain amino acids (BCAA), valine, leucine and isoleucine.
BCAA levels were correlated with weight loss and, importantly, with
disease progression and abnormal triplet repeat expansion size in the
HD1 gene. Levels of IGF1, which is regulated by BCAA, were also
significantly lower in the HD group. Therefore, early weight loss in HD
is associated with a systemic metabolic defect. BCAA levels may be
used as a biomarker, indicative of disease onset and early progression.
The decreased plasma BCAA levels in HD likely represent a critical
need for Krebs cycle energetic substrates provided by peripheral
organ metabolism for the brain.
P0140. Vitamin D dependent Rickets Type II; Report of Two
Affected Siblings in a Consanguineous Iranian family with a
Novel Mutation in VDR Gene
N. Momenin 1 , Y. Shafeghati 1 , S. Esfahani 2 , E. Reyniers 3 , W. Wuyts 4 ;
1 Genetics Research Center, Tehran, Islamic Republic of Iran, 2 Children`s Hospital
Medical Center,Tehran Medical Science University, Tehran, Islamic Republic
of Iran, 3 Medical Genetics Center, University and University Hospital, Antwerp
(UA/UZA), Belgium, 4 Medical Genetics Center, University and University Hospital
of Antwerp (UA/UZA)., Antwerp, Belgium.
Hereditary vitamin D resistant rickets type II(HVDDRII) is a rare autosomal
recessive disorder, most often caused by mutations in the VitD
receptor gene. It is usually presented with rickets not responsive to
VitD treatment. Circulating levels of 1,25(OH)2 VitD3 are elevated.
Alopecia of the scalp or totalis is seen in some families with HVDDRII.
This is usually associated with a more severe phenotype.
In this report, we present clinical findings on a family with the typical
clinical features and molecular findings in two affected siblings..
The cardinal findings in the index patient were: alopecia totalis, renal
tubular acidosis, mild generalized aminoaciduria, refractory rickets,
high alkaline phosphatase, and hyperparathyroidism. Other routine
biochemical tests were WNL. Skin biopsy was performed and was
compatible with alopecia areata. Proband has had an older brother just
with the same disease he deceased at the age of 32 months. Mutation
analysis of the VDR gene by direct sequencing analysis of all coding
exons showed a homozygous c.122G>A(p.Cys41Tyr) variant in exon
2 with several arguments pointing to a pathogenic effect. It was a novel
mutation in VDR gene has not been reported before.
Two children of a consanguineous Iranian family showed the classical
clinical features of HVDRR II and a novel mutation in VDR gene. We
should be aware of this very rare disease, whenever we see a patient
who is suffering from refractory rickets with alopecia.
P0141. Early neurological phenotype in 4 children with biallelic
PRODH mutations
A. Afenjar 1 , M. Moutard 1 , D. Doummar 1 , L. Burglen 2 , D. Heron 3 , D. Campion 4 ,
T. Billette de Villemeur 1 , D. Rodriguez 1 ;
1 AP-HP, Service de neuropédiatrie, Hôpital Armand Trousseau, 75012 Paris,
France, 2 AP-HP, Service de génétique, Hôpital Armand Trousseau, 75012
Paris, France, 3 AP-HP, Service de génétique, Hôpital Pitié-Salpétrière, 75012
Paris, France, 4 INSERM U614 Faculté de Médecine, Rouen, France.
Hyperprolinemia type I (HPI) results from a deficiency of proline oxidase
(POX), involved in the first step in the conversion of proline to
glutamate. Diverse phenotypes were described in patients with HPI,
prior to the identification of the POX gene (PRODH): whereas various
patients were asymptomatic, others had neurological and extraneurological
defects. PRODH gene is located in the region deleted in velocardiofacial
syndrome (VCFS). Heterozygous and homozygous mutations
have been identified in patients with variable hyperprolinemia
and various features (patients with schizophrenia, chromosome 22q11
microdeletions and/or neurological defects). A functional study has divided
the PRODH missense mutations into three groups: those leading
to mild, moderate, or severe reduction of POX activity. In this study,
we report four unrelated children with HPI and a homogeneous severe
neurological phenotype. We identified biallelic abnormalities in
PRODH in these patients that led to severe reduction of POX activity.
These included missense and nonsense mutations, deletions of
PRODH and a 22q11 microdeletion. Four other children have been reported
with severe biallelic PRODH mutations. The phenotype of these