2008 Barcelona - European Society of Human Genetics

Clinical genetics
-Paresthesia in lower extrimities ,tingling and burning sensations of
the feet
-Sensitivity of the lower extrimities to the cold weather
-Gait problems
-Foot drop
-Pes cavus
-Hair loss of the lower limbs
-Tenar and hypotenar atrophy
-Loss of deep tendon reflexes
-Finger movement disorder in feet and hands
-High levels of LDH
-Chronic sensory-motor polyneuropathy in EMG and NCV .
P01.229
mFN2 point mutations occur in 2% of charcot-marie-tooth
families - An investigation of 400 Norwegian cmt families
G. J. Braathen 1,2,3 , J. C. Sand 2 , A. Lobato 2 , H. Høyer 3 , M. B. Russell 1,2,4 ;
1 Faculty Division Akershus University Hospital, University of Oslo, Oslo, Norway,
2 Department of Neurology, Akershus University Hospital, Oslo, Norway,
3 Department of Laboratory Medicine, Section of Medical Genetics, Telemark
Hospital, Skien, Norway, 4 Center of Research, Akershus University Hospital,
Oslo, Norway.
Background . Mutations in mitofusin 2 (MFN2) is the most common
cause of Charcot-Marie-Tooth type 2 (CMT2) .
Methods . Four-hundred Norwegian CMT families were screened for
point mutations in the MFN2 gene .
Results . Of the 400 families eight had mutations in the MFN2 gene .
We identified four novel point mutations located in exon 14, 15 and
18 (2 families) . Clinically the known point mutations caused CMT2 .
The novel point mutations caused CMT2, distal Hereditary Motor Neuronopathy
(dHMN), intermediate CMT and CMT1 in each of the other
families .
Conclusions . Our mutations broaden the clinical picture that can be
seen with mutations in the MFN2 gene .
P01.230
De novo point mutations in Cx32, EGR2, MFN2, MPZ, PMP22
and simPLE. A population based survey of charcot-marie-tooth
disorder
G. J. Braathen 1,2,3 , J. C. Sand 2 , A. Lobato 2 , H. Høyer 3 , M. B. Russell 1,2,4 ;
1 Faculty Division Akershus University Hospital, University of Oslo, Oslo, Norway,
2 Department of Neurology, Akershus University Hospital, Oslo, Norway,
3 Department of Laboratory Medicine, Section of Medical Genetics, Telemark
Hospital, Skien, Norway, 4 Center of Research, Akershus University Hospital,
Oslo, Norway.
Background. An analysis of de novo mutations in persons residing in
eastern Akershus County with Charcot-Marie-Tooth (CMT) disease .
Methods. The CMT patients were recruited from the Institute of Medical
Genetics, University of Oslo and Departments of Neurology, Neurophysiology
and Paediatric in eastern part of Akershus County, Norway
. The CMT patients were examined by geneticist and neurologist
GJB . The Cx32, EGR2, MFN2, MPZ, PMP22 and SIMPLE genes were
analyzed . Paternity tests were performed .
Results. We identified one de novo mutation in the MPZ gene and two
de novo mutations in MFN2 .
Conclusion. De novo point mutations are rare but less rare than previously
anticipated .
P01.231
Hereditary motor and sensory neuropathy type i in Russia
T. B. Tiburkova1 , O. A. Schagina1 , E. L. Dadaly1 , V. P. Fedotov2 , A. V.
Polyakov1 ;
1 2 Research centre for medical genetics, Moscow, Russian Federation, VOCDC
genetic counseling, Voronezh, Russian Federation.
Hereditary motor and sensory neuropathy, also known as Charcot-Marie-Tooth
(CMT) disease, is a large group of genetically heterogeneous
hereditary disorders of distal nervous system . A group of 298 families
with clinical and electrophysiological CMTI phenotype was investigated
by us .
Mutations analysis was performed for three genes: PMP22, GJB1 and
P0 . First, the duplication in chromosome 17 (17p11 .2-p12) was investigated
by PCR-AFLP analysis of STR . Mutations analysis for PMP22,
GJB1 and P0 genes was performed by direct automatic sequence on
Genetic Analyzer 3130 (Applied Biosystems) .
Duplication of chromosome 17 was found in 189 families . This is 63,4%
of all cases CMTI in Russian patients . GJB1 gene mutations caused
of CMTI in 60 families, or 20,1% . Mutations in the P0 gene were found
in 19 families, equaling 6,4% . Point mutation in the PMP22 gene were
found in 2 families, that is 0,7% . In 28 families mutations were not
found in any of these genes . Other genes, mutations of witch lead to
this disorder, will be analyzed in our next investigations .
P01.232
the ARG94GLN mutation in mFN2 gene can be the cause of
axonal charcot-marie-tooth desease with optic atrophy
L. De Jorge1 , I. Banchs1 , C. Casasnovas2 , J. Martinez-Matos2 , V. Volpini1 ;
1 2 IDIBELL, L’hospitalet de Llobregat, Spain, Hospital Universitari de Bellvitge-
IDIBELL, L’hospitalet de Llobregat, Spain.
Some mutations in the mitochondrial GTPase mitofusin 2 (MFN 2)
(MIM608507) have been related to the axonal form of Charcot-Marie-Tooth
(CMT) disease with optic atrophy . We report a family with
severe CMT disease and dominant inheritance . Electrophysiological
studies revealed a severe sensory and motor neuropathy with conserved
nerve conduction velocities (NCV) . One of the family members
presented a sub acute visual impairment . The ophtamological studies
revealed optic atrophy (OpA) . Cranial Magnetic Resonance studies
were normal . Molecular studies revealed the Arg94Gln mutation in
exon 4 of MFN2 gene . This mutation had been previously reported,
but only associated with “pure” axonal CMT and CMT with tremor . This
is the first family with this mutation related to CMT with OpA reported,
showing the importance of ophtalmological examinations in patients
with axonal CMT caused by mutations in MFN2 gene .
P01.233
molecular study of mFN2 gene in spanish population
C. Casasnovas1 , I. Banchs2 , L. De Jorge2 , J. Martinez-Matos1 , V. Volpini2 ;
1Hospital Universitari de Bellvitge-IDIBELL, L’Hospitalet de Llobregat, Spain,
2IDIBELL, L’Hospitalet de Llobregat, Spain.
The axonal dominant form Charcot-Marie-Tooh type 2A (CMT2 A2)
(MIM#609260) is caused by mutations in mitochondrial fusion protein
mitofusin 2 (MFN2) (MIM608507) . We report the molecular analysis of
101 families with suspected CMT 2 . The 19 exons of the MFN2 have
been amplified by polymerase chain reaction with the previously decribed
primers by Zuchner et al. (2004) Amplified DNA samples were
directly sequenced by applying the BigDye V3 .1 (Applied Byoystems)
and subjected to an capillary sequencer genetic analyzer . Duplication/
deletion and point mutations of PMP22, connexin 32 and MPZ were
previously ruled out .
The 83% of the families have been already studied . We have found 7
point mutations in 9 different families . The mutations were located in
exons 4, 8, 9, 11 and 14 . The study of the promotor region reveals one
change of one nucleotide and two families with a deletion of 15 nucleotides
. On the other hand, we have found 18 different polymorphisms .
One of the found point mutations was not previously described . The
frequencies of changes in MFN2 found in our population are similar
to previously described studies; these findings confirm the importance
of this gene in the physiopathology of the axonal type of CMT 2 A2 in
our population too .
P01.234
Dating the mutation Leu239Phe of the GDAP gene in cmt
Russian families
A. V. Polyakov1 , O. A. Schagina1 , E. L. Dadali1 , V. P. Fedotov2 ;
1 2 Research Centre for Medical Genetics, Moscow, Russian Federation, VOCDC
genetic counseling, Voronezh, Russian Federation.
Mutations in the ganglioside - induced differentiation-associated protein
1 (GDAP1) gene are common a cause of the Charcot-Marie-Tooth
(CMT4A) disease with autosomal recessive mode of inheritance . To
date more than twenty mutations in the GDAP1 gene have been reported
in patients suffering from the demyelinating, axonal or mixed
form of Charcot-Marie-Tooth disease .
In our study 110 patients from 72 unrelated families with CMT were
screened for mutations by SSCP analysis with following direct sequencing
of abnormal conformers .
A c .715C>T at substitution codon 239 (Leu239Phe) was detected in
nine affected subjects from six apparently unrelated families . Allelic