2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
P02.062
Leucoencephalopathy with megalencephaly, spongy
degeneration and 17p deletion: A new disease?
A. Verloes, A. C. Tabet, M. Schiff, S. Drunat, S. Passemard, F. Chalard, A.
Aboura;
Robert debré, Bd Sérurrier, France.
This second child from non consanguineous parents was born at term
by cesarean section for unexplained hydramnios. Birth parameters
were at -1 SD. After minor neonatal feeding difficulties, she was investigated
at 3 years of age for moderate and non progressive psychomotor
retardation (with mainly speech delay) and dysmorphic features.
Clinical findings included macrocephaly (head circumference +3 SD),
contrasting with growth delay (weight -1 SD, height -2 SD), wide forehead,
small nose and coarse facial features. There was no hepatosplenomegaly,
no joints contractures and no signs of peripheral neuropathy.
Basic biological findings were normal. Brain MRI disclosed
bilateral and symmetric leucoencephalopathy with triventricular dilation,
micro cysts in periventricular white matter and corpus callosum
and Chiari type 1 malformation. . Activities of hexosaminidases A and
B measured in leukocytes were normal, excluding GM2 gangliosidosis.
CGH-array (Agilent 44K) revealed a large (2 Mb) subtelomeric
deletion of the 17p region between nt 48539 and nt 2104702, thus
from RPH3AL (rabphilin 3A-like, without C2 domains) to SMG6 (nonsense
mediated mRNA decay factor). The deletion encompassed 38
genes, none of which known to be involved in leucoencephalopathy.
The aspartoacylase gene (Canavan) is located centromeric to the deletion.
Although the deletion could be coincidental with the cerebral
phenotype, our patient show («07») ’s presentation suggests that the
17pter region may contain a second locus for leucoencephalopathy
with spongy degeneration. Inheritance could be dominant or recessive
(with haploinsufficency by deletion for one allele, and loss-of-function
point mutation for the second allele).
P02.063
investigations of LHON in iranian Patients
M. Jamali Hendri, M. Houshmand;
Special Medical Center, Tehran, Islamic Republic of Iran.
Leber’s Hereditary Optic Neuropathy is a rare condition which can
cause loss of central vision. It usually affects men. The time when
someone is losing their eyesight is often called the ‘acute’ period. After
a few more weeks, the eyesight stops deteriorating. Although that
course describes the most common pattern for Leber’s, onset can be
sudden or take place over a period of years. Not everyone in a family
affected by Leber’s will lose their eyesight, and we do not yet know
how to tell who will get symptoms. Men cannot pass on Leber’s Hereditary
Optic Neuropathy to their children. Leber’s Hereditary Optic
Neuropathy is linked to a number of genes, all within mitochondrial
DNA (mtDNA). We believe that the particdular gene changes linked to
Leber’s Hereditary Optic Neuropathy lower the amount of energy available
to the cells of the optic nerve and retina. These cells are damaged
and may even die because of this lack of energy. 50 were analysed for
mtDNA mutations by PCR, sequencing and RFLP methods for mitochondrial
genome. 15 cases had a G11788A mutation, 10 cases had
mutation G3460A and 2 patients had mutation T14484C, and no mutations
were detected in the remainder.
P02.064
Leber’s hereditary optic neuropathy and multiple sclerosis:
Harding‘s syndrome
A. La Russa 1 , P. Valentino 2 , V. Andreoli 1 , F. Trecroci 1 , I. C. Cirò Candiano 1 , P.
Spadafora 1 , R. Cittadella 1 ;
1 Institute of Neurological Science, National Research Council, Cosenza, Cosenza,
Italy, 2 Institute of Neurology, University “Magna Graecia,, Catanzaro,
Italy.
The optic neuropathy Leber’s hereditary, usually affects men between
20 and 30 years, although the disease can begin at any age, more
rarely in women. The syndrome of Leber’s due to mitochondrial DNA
alterations (maternal mitochondrial inheritance). However, it is not
possible to predict who may be affected even within the same family
considered “healthy carrier”. Was found that in Caucasian populations
mutations of nucleotides 3460, 11778 and 14484 of the mitochondrial
DNA are present in 95% of cases of Leber’s syndrome. We describe a
33 year old man came to our medical attention complaining of weak-
ness of the lower limbs and pyramidal signs. Oligoclonal bands were
present in the cerebrospinal fluid, and magnetic resonance imaging
(MRI) revealed white matter lesions characteristic of multiple sclerosis
(MS). DNA sample was isolated from peripheral venous blood. The
patient tested for the three pathogenic mtDNA LHON point mutations:
G11778A, G3460A, T14484C and G15257A by means of PCR and
successive analysis of restriction with specific enzymes. Mutations
were confirmed by direct sequencing.The patient was homoplasmic
for the T14484C LHON mutation and heteroplasmic for the G15257A.
The coexistence of multiple sclerosis and Leber’s hereditary optic neuropathy
(Harding’s syndrome) is known to occur more often than would
be expected by chance; therefore, screening for Leber’s mutations in
multiple sclerosis patients should be considered because this has important
prognostic and genetic implications.
P02.065
malignant vascular phenotypes in Loeys-Dietz syndromes
associated with mutations in the tGFBR1 and tGFBR2 genes
M. Grasso 1 , N. Marziliano 1 , E. Disabella 1 , M. Pasotti 1 , A. Serio 1 , V. Favalli 1 , F.
Gambarin 1 , A. Brega 2 , H. C. Dietz 3 , E. Arbustini 1 ;
1 Fondazione IRCCS Policlinico San Matteo, PAVIA, Italy, 2 University of Milan,
Milano, Italy, 3 The Johns Hopkins Medical Institutions, Baltimore, MD, United
States.
Mutations of Transforming Growth Factor beta Receptor 1 (TGFBR1)
and Receptor 2 (TGFBR2) genes cause Loeys-Dietz syndromes
(LDS). Based on the presence or absence of cranio-facial traits the
syndromes are classified as LDS1 and LDS2, respectively.
The probands of 33 families were referred to our attention for suspected
Marfan Syndrome (n=26), EDS-IV (n=1) and Thoracic Aortic
Aneurysm and Dissection (TAAD) (n=6) and found to carry TGFBR1
and TGFBR2 mutations. Probands and relatives underwent genetic
counselling, multidisciplinary clinical and imaging evaluations and molecular
analysis. Of the 33 probands, 24 were diagnosed with LDS1
(18 de novo) and 9 with LDS2 (1 de novo). Of 62 mutated family members,
41 carried TGFBR2 and 21 TGFBR1 mutations; 34 were in LDS1
and 28 in LDS2 families. LDSs shared aortic aneurysm (88% and
86%), dissection (23% and 36%), arterial tortuosity (100%) and, at a
minor rate, aneurysms of other arteries (48% and 26%). The mean age
at first diagnosis was 17±17 vs. 38±16 (pA).
Discussion: This is the first reported patient that carries pathogenic