2008 Barcelona - European Society of Human Genetics

Clinical genetics
pansion . Longer expansions resulted in earlier onset of the symptoms .
Phenotypes varied between congenital onset, classical forms and mild
symptoms even within the same family corresponding to the size of
the expansion .
Additionally, we were able to offer prenatal diagnosis in three families
where all foetuses inherited the pathogenic DMPK gene . In two foetuses
with maternal inheritance the estimated size of the CTG repeat
expansion predicted a congenital form, whereas one foetus with paternal
inheritance inherited a moderate expansion size . This latter baby
has been born recently .
P01.224
Normal variation of (ctG)n repeat in the Dystrophia myotonica
Protein Kinase gene in Slovak non-Romany and Romany
population
J. Radvansky1 , A. Ficek1,2 , M. Baldovic1 , G. Minarik1 , L. Kadasi1,2 ;
1 2 Comenius University, Faculty of Natural Sciences, Bratislava, Slovakia, SAS,
Institute of Molecular Physiology and Genetics, Bratislava, Slovakia.
Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused
by a CTG trinucleotide expansion in the Dystrophia Mytonica Protein
Kinase gene (DMPK) . This repeat is highly polymorphic in healthy
population with alleles in a range of 5 to 37 CTG repeats . The CTG expansion
can vary from 50 to several thousand repeats in affected individuals
. In many populations healthy alleles show trimodal distribution
with 5, 9-17 and 18-35 repeats . A correlation between the frequency
of large-sized normal alleles and the prevalence of DM1 in different
ethnic groups was shown in several studies . We have analyzed the
CTG repeat length in samples of healthy, unrelated individuals from
the Slovak Romany and non-Romany population by PCR with fluorescent
labelled primers using fragment analysis in genetic analyzer .
We have found larger number of different alleles in the sample from
non-Romany population than from Romanies, however the (CTG) al- n
lele size range was broader in the latter group . In both populations
we found trimodal distributions with the majority of chromosomes belonging
to the groups (CTG) and (CTG) . Our results show lower
5 9-17
frequency of (CTG) and (CTG) and higher frequency of (CTG) 5 18-37 9-17
alleles in the Romany than in the non-Romany population . Since many
linguistic and genetic studies place the origin of Romanies to Indian
subcontinent, we decided to compare our results to the available data
about (CTG) allele frequencies in European and Indian populations .
n
Our preliminary comparison showed similar distribution pattern among
Slovak Romany and Indian population, and among Slovak non-Romany
and mixed European population .
P01.225
Application of western blot for analyzing of Dystrophin in iranian
patients with mild Dystrophinopathy
J. Gharesouran, E. Darabi, K. Kahrizi, Y. Shafaghati, M. Banan, H. Najmabadi,
E. Keyhani;
Genetics Research Center, Tehran, Islamic Republic of Iran.
Dystrophinopathies (Duchenne muscular dystrophy and Becker muscular
dystrophy) are X-linked recessive disorders manifesting with muscle
degeneration and weakness . The gene which is defective in Dystrophinopathies
is the largest known gene, consisting of almost 0 .1% of
the human genome (2,500 Kbp) . The product of this gene in normal
muscle, Dystrophin, is a 427 kDa rod-shaped protein . Dystrophin is an
essential part of a large complex that links the actin cytoskeleton with
the cell membrane and the extracellular matrix and stabilizes the myofibers
during contractions . The value of analyzing Dystrophin on western
blots of skeletal muscle for the differential diagnosis of Xp21 muscular
dystrophies is now fairly well established especially for mild forms of
the diseases (BMD) which immunohistochemistry techniques are not
sufficient for the definite diagnosis. Here we describe a sensitive system
based on monoclonal antibodies to Dystrophin . System has been set
up using GAPDH protein as control that extracted from K562 cells . The
specificity of the antibodies was established by dot blot and experiments
were undertaken to identify the source of Dystrophin-related protein
bands which were detected on blots of normal skeletal muscle . In our
study which was the first application of western blot analysis in muscle
disorders in Iran, we examined muscle samples taken from clinically
suspected to BMD and DMD, first by immunohistochemistry methods
and then by western blot analysis . Results show the necessity of blotting
techniques in diagnosis panel of mild forms of Dystrophinopathies .
P01.226
charcot-marie-tooth disease 1B and phenotype-genotyping
correlation
V. P. Fedotov 1 , S. A. Kurbatov 1 , O. A. Schagina 2 ;
1 VOCDC genetic counseling, Voronezh, Russian Federation, 2 Research Centre
for Medical Genetics, Moscow, Russian Federation, Moscow, Russian Federation.
DNA analysis of 96 CMT1-patients revealed 76 cases (79%) of
dup17p11 .2, (PMP22 gene), point mutation CX32 in 15 cases (16%),
and 5 point mutations in the MPZ gene (S63F, R98C, K130R, D134E
and not previously described P133S) .
In three unrelated families (15 affected subjects) mutation K130R in
MPZ was revealed in two families and D134E mutation in one family .
All patients has early manifestation of CMT disease before five years
old . Late onset of independent walking (18-24 month of birth), unsteady
gait, discoordination, distal paresis, muscular atrophies, proprioceptive
and superficial hyperesthesia of feet and hands, generalized tendon
areflexia, ataxia, foot deformity and nervous swelling were present in
all patients with K130R and D134E mutations .
In the patients with R98C and D134E mutations Dejerine-Sottas syndrome
with hearing loss was observed . In contrast, the S63F mutation
leads to a slowly progressive disease . Independent ambulation was
possible until 40-50 years old .
All patients have very low MNCV n . medianus 12,4 +2,4 m/s, n . tibialis
- 8,8 +2,6 m/s, distal motor latency 12,5 +5,1 ms; 21,3 +8,7 ms,
and very low C - 0,27 +0,18 mV during ten years from two years old .
This suggest that abnormalities of nervous fiber myelination may be
congenital in origin .
P01.227
A novel mutation in GDAP1 and a change in mFN2 genes in a
family with a severe form of charcot-marie-tooth
I. Banchs1 , C. Casasnovas2 , L. De Jorge1 , J. Martinez-Matos2 , V. Volpini1 ;
1 2 IDIBELL, L’hospitalet de Llobregat, Spain, Hospital Universitari de Bellvitge-
IDIBELL, L’hospitalet de Llobregat, Spain.
Recessive form of Charcot-Marie-Tooth disease with hoarseness
(CMT2K, MIM#607831) is caused by mutations in ganglioside-induced
differentiation-associated in protein 1 (GDAP1) (MIM606598), located
in chromosome 8 (8q21 .1) . Dominant axonal forms of CMT (CMT2 A2)
(MIM#609260) can be caused by mutations in the mitochondrial fusion
protein mitofusin 2 (MFN2) (MIM608507), in chromosome 1 (1p36 .2) .
We report a patient with a severe form of CMT, with mutations in both
genes and the molecular findings in 9 family members.
PATIENT: A 62-year-old woman with severe distal muscle weakness
since childhood . The patient is wheelchair dependent since she was in
the thirties . Electrophysiological studies revealed a sensory and motor
neuropathy with mild demyelinating features and severe axonal
degeneration . Analysis of GDAP1 revealed the mutation Gln95Stop
in homozygous state . On the other hand, MFN2 analysis revealed
the change Arg468His in heterozygous state . Clinical and Molecular
analysis of eight family members shows two members with the MFN
2 change and no GDAP1 mutation, a 56-years-old male with a mild
axonal form of neuropathy and his 18-year old daughter still without
clinics . Three other members have the mutation in GDAP1 gene but in
heterozygous state and no change in MFN2 gene . They have normal
clinical and electrophysiological examinations . Duplication/deletion
and point mutations in PMP22 and MPZ were ruled out .
P01.228
A case presentation: X-linked pattern of charcot-marie-tooth
Disease
S. Akbaroghli 1,2,3 , M. Houshmand 3 ;
1 Deputy for Cultural Affairs and Prevention of Welafre Organization, Tehran,
Islamic Republic of Iran, 2 Dr. Susan Akbaroghli Genetic Counselling Center,
Tehran, Islamic Republic of Iran, 3 Special Medical Center, Tehran, Islamic Republic
of Iran.
A family with the presence of X-linked pattern of Charcot-Marie-tooth
Disease .The proband is a woman who is coming after a consanguineous
marriage for genetic counseling before pregnancy and her father
has CMT disease and DM type 2 . In the pedigree there are two male
cases of CMT disease that are cousins of the proband case .
The clinical and paraclinic manifestations of the proband’s father are:
-A 50 years old man with muscular weakness and chronic paraparesis