2008 Barcelona - European Society of Human Genetics

Clinical genetics
Results and discussion
In this population 65/68 pathologic alleles were identified, including 21
new mutations . Our molecular study on French GSDIII patients of various
ethnic ancestries confirms both the allelic heterogeneity of AGL
gene mutations and the strong influence of individual genetic background
on genotype-phenotype relationships . Nevertheless in some
ethnical groups, some specific mutations were prevalent, probably
because of founder effects . As previously reported, we were not able
to show genotype-phenotype correlations . Even so we raise the hypothesis
of the role of the c .3199C>T and c .3343G>A polymorphisms
on the severity of the clinical symptoms . We postulate that these mutations
do not confer by themselves GSDIII phenotype, but their association
with other disease-causing mutations could accentuate muscular
manifestations .
P01.042
Clinical and molecular findings of metachromatic
leukodystrophy; A case report of an iranian family
S. Seyedhassani 1,2 , T. Majidzadeh 2,3 , M. Rostami 3 , M. Dehghan Manshadi 3 , M.
Houshmand 2,3 ;
1 Research and clinical center for infertility, Yazd, Islamic Republic of Iran, 2 National
institute of genetic engineering and biotechnology, Tehran, Islamic Republic
of Iran, 3 Special medical center, Tehran, Islamic Republic of Iran.
Metachromatic leukodystrophy (MLD) is a rare autosomal recessive
disorder of impaired breakdown of sulfatides that occur throughout the
body, but are found in greatest abundance in nervous tissue, kidneys,
and testes . The three clinical subtypes of MLD include late-infantile
MLD, comprising 50-60% of cases; juvenile MLD, comprising about
20-30%; and adult MLD, comprising about 15-20% . Age of onset within
a family is usually similar . All individuals eventually lose motor and intellectual
functions . The disease course may be from three to ten or
more years in the late infantile-onset form and up to 20 years or more
in the juvenile- and adult-onset forms .
ARSA is the only gene associated with arylsulfatase A deficiency. This
is located on chromosome 22q13, consists of eight exons encoding
the 507 amino acid enzyme . Over 90 largely missense mutations and
polymorphisms have been identified in the ARSA gene. The majority of
mutations identified in patients with MLD are unique within individual
families .
The patient was 5 years old boy and was referred with delayed development,
mental retardation, loss of speech, urinary incontinence, seizure,
spastic quadriplegia and hyporeflexia. EEG was abnormal and
brain advanced dysmyelogenesis was reported in MRI . His parents
had consanguineous marriage and three similar cases were seen in
familial pedigree. The identity of the mutation was confirmed by amplifying
all eight exons by PCR which was followed by direct DNA sequencing
. The individual described in our study showed a homozygous
known missense mutation at c .1173C>G (p .T391S) in exon 7 .
P01.043
two cases of morquio iVB type in Bulgaria
E. Paschke1 , M. Stancheva2 , B. Radeva2 ;
1University of Graz,Laboratory of Metabolic diseases, Department of Pediatrics,
Graz, Austria, 2University Children`s Hospital, Sofia, Bulgaria.
The authors report two cases with Morquio IVB type .The first child
present with typical clinical presentation -normal intelligence, dysostosis
multiplex .The DMB test showed increased level of MPS .Electrophoresis
showed chondroitin sulfate.The diagnosis was confirmed by
low beta-galactosidase in leukocytes . The DNA analysis showed the
most common in Europe mutation W273L/W273L .The second child
present with skeletal anomalies, coarse facial features, astigmatism,
myopia, joint hyperflexibility, dyslalia, cortical atrophy with enlarged
subarachnoidal spaces on the convex , ventricules and basal cisterns,
slightly expressed hypotonia. The electrophoresis showed unidentified
oligosaccharides .The enzyme assays -low beta galactosidase in leukocytes
and fibroblasts.The DNA -analysis showed two nonpathogenic
polymophysms c .29C>T/heterozygote/, c .34T>C/homozygote/ and a
heterozygous state for a common mutation R201H in exon 6 of GLB1
gene and a novel mutation P597S in exon 16 of GLB1 gene .A genetic
counseling, carier testing was proceded to the parents and the brother
of the child .
P01.044
monozygotic sisters with mPs i: a year later
M. O. Mkheidze1 , D. S. Poliakov2 , M. M. Schavlovsky1 ;
1Medical Academy for postgraduate study, St.Petersburg, Russian Federation,
2Paediatric Medical Academy, St.Petersburg, Russian Federation.
Mucopolysaccharidose type 1 (MPS1, Hurler syndrome) is an hereditary
disease caused by a deficiency of the lysosomal enzyme alpha-Liduronidase
(IDUA; EC 3 .2 .1 .76) . Non degraded glycosaminoglycans
(GAGs) are stored in the lysosomes and excreted with urine . Last
year we reported on a family with monozygotic sisters suffered from
MPS1 (EJHG 2007,15(S1):77) . The probands are homozygous for
Q70X/Q70X . Last year they were under observation by a geneticist,
a lung diseases specialist, a neurologist, an orthopedist, an otorhinolaryngologist,
a pediatrician and a surgeon . Every specialist found a
lot of the pathologic features . The disease was taking a severe progressive
course . Clinical symptoms of MPS I become progressively
worse . Children’s general state is serious . It was possible to launch an
enzyme treatment (Aldurazyme® (laronidase) . Each child was treated
with enzyme infusion five times. After this treatment, both the liver and
the spleen enlarged were found to abate their size, however some
allergic symptoms appeared . The immunological study has revealed
antibodies to Aldurazyme . Probands need a complex follow-up .
P01.045
Niemann-Pick disease, clinical course and molecular Findings;
A case Report of an iranian Patient
T. Majidizadeh 1,2 , M. Dehghan Manshadi 2 , M. Rostami 2 , M. Banoei 1 , K. Banihashemi
2 , M. Sanati 1 , M. Houshmand 1,2 ;
1 National Institute of Genetic Engineering & Biotechnology, Tehran, Islamic
Republic of Iran, 2 Special Medical Center, Tehran, Islamic Republic of Iran.
Niemann-Pick disease (NPD) is an autosomal recessive inherited
lipid storage disorder that results from deficiency of the enzyme-acid
sphingomyelinase . In people with this condition, this enzymatic defect
causes harmful amounts of lipids to accumulate in the spleen, liver,
lungs, bone marrow, and brain . Thus patients present with progressive
lung disease, hepatosplenomegaly, short stature and pancytopenia .
NPD is divided into four main types based on the genetic cause and
the signs and symptoms (Niemann-Pick disease type A ., B, C & D) .
Mutations in the SMPD1 gene cause NPD types A (neurodegenerative
form) and B (visceral form) . This gene provides instructions for producing
an enzyme called acid sphingomyelinase . Mutations in either the
NPC1 or NPC2 gene cause NPD type C . The NPC1 gene provides
instructions for producing a protein that is involved in the movement of
cholesterol and lipids within cells .
The SMPD1 gene consists of six exons located on chromosome 11q
and the NPC1 gene contains of 20 exons located on 18q11-q12 are
found responsible for the most NPD cases .
A 16 year old girl second of two children born of third degree consanguineous
marriage was referred to our clinic . The long term of jaundice,
delayed motor milestones, abnormal function of liver and Bone
marrow aspiration were showing Niemann Pick’s Disease . Using direct-sequencing
of the entire coding region and splice junctions of the
SMPD1 and NPC1 genes is obtained and analyzed . A G/C mutation at
exon 5 was found in SMPD1 gene .
P01.046
Growth and nutritional status of some micronutrients and trace
elements in patients with phenylketonuria
E. R. Raouf, N. A. Mohamed;
National Research Center, Cairo - Giza, Egypt.
certain micronutrient deficiencies occur either due to rigid therapeutic
dietary restriction, aversion to certain food stuffs or due to recurrent
episodes of vomiting and diarrhea . Semi-synthetic formula containing
low phenylalanine (Phe) content provides the majority of protein and
energy in the diet while the rest of phenylalanine are met by low protein
natural foods . Restricted intake of high biological value protein, let children
with phenylketonuria (PKU) vulnerable to have lower than normal
plasma concentrations of certain micronutrients . Aim of the study is to
assess the effects of phenylalanine restricted diet on the growth of our
PKU patients after one year of dietary management . We also aimed
to investigate the nutritional status of the following trace elements and
micronutrients; zinc, copper, vitamins C, E, A, and B-carotene among