2009 Vienna - European Society of Human Genetics

Clinical genetics and Dysmorphology
P02.183
Five novel CDKL mutations in girls with severe mental
retardation, early onset epilepsy, movement disorder and lack of
expressive speech
I. Stefanova 1 , V. Kalscheuer 2 , M. Kautza 3 , W. Lieb 1 , P. Muschke 4 , T. Polster 5 , S.
Purmann 1 , J. Sperner 6 , R. Voigt 7 , C. Zühlke 1 , G. Gillessen-Kaesbach 1 ;
1 Institut für Humangenetik, Lübeck, Germany, 2 Max Planck Institute for Molecular
Genetics, Berlin, Germany, 3 Praxis für Humangenetik, Kiel, Germany,
4 Institut für Humangenetik, Magdeburg, Germany, 5 Krankenhaus Mara, Epilepsie-Zentrum
Bethel, Bielefeld, Germany, 6 Klinik für Kinder- und Jugendmedizin,
Lübeck, Germany, 7 Pränatalzentrum Hamburg und Humangenetik im Gynaekologicum,
Hamburg, Germany.
Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene
have been reported in the last years in nearly 50 patients as a cause
for a neurodevelopmental disorder, characterized by drug resistant
early-onset seizures, movement disorder, microcephaly and severe
psychomotor impairment.
We screened the CDKL5 gene for mutations in a cohort of 20 female
and six male patients. Clinical information was available for 24 of them.
All these patients showed epilepsy and moderate to severe mental
retardation. 12 patients showed microcephaly, 13 hypotonia and two
had dysmorphic features. Movement disorder (ataxia, athetotic movements)
was present in ten patients. We detected five novel and one
reported heterozygous mutations in the CDKL5 gene in six female
patients aged two to 16 years. The mutational spectrum consisted of
three frame-shift mutations, leading to a premature stop codon, two
missense and one nonsense mutation. One patient with a missense
mutation has been already published (PMID 15499549).
Our patients with CDKL5 mutations show a consistent phenotype including
treatment resistant seizures starting in the first months of life
after a normal newborn period. Additional features are hypotonia, severe
psychomotor retardation, microcephaly, stereotype hand movements
as well as ataxia and restlessness. Feeding difficulties, gastrooesophageal
reflux and scoliosis were present in some patients. All
our patients with CDKL5 mutations lack expressive speech.
The clinical findings in our patients with CDKL5 mutations confirm that
CDKL5 deficiency represents a consistent phenotype. We discuss the
clinical features with respect to the main differential diagnoses like Rett
and Angelman syndromes.
P02.184
MECP de novo duplication in a girl with mild mental retardation
and no obvious dysmorphic features
P. Makrythanasis1,2 , I. Moix1 , S. Gimelli1 , S. E. Antonarakis1,2 , F. Bena1 , M. A.
Morris1 , A. Bottani1 ;
1 2 University Hospitals of Geneva, Geneva, Switzerland, University of Geneva,
Geneva, Switzerland.
Mutations of MECP2 are responsible for Rett Syndrome (RS), an Xlinked
neurodevelopmental disorder affecting mainly girls. The availability
of MECP2 testing has led to the identification of mutations in
girls with atypical RS features and the recognition of milder forms. Furthermore,
duplication of the entire gene has recently been described
in boys presenting a different clinical picture, featuring severe mental
retardation and recurrent infections.
We describe a girl with a heterozygous MECP2 duplication. The patient,
aged 19 years, has mild mental retardation, a kind, friendly but
anxious character. She has neither dysmorphic features nor malformations.
As a child she presented no particular health problems. Her motor
development was slightly delayed with walking at 20 months, hypotonia
and minor balance difficulties but otherwise within normal limits.
Speech is fluid with good pronunciation but is simple and repetitive.
Diagnosis was made after sequencing and MLPA analysis of MECP2.
Parental analysis demonstrated that the duplication was de novo.
CGH analysis defined a duplication of 0.129Mb (from position 152.930
Mb to 153.059Mb) long, including MECP2 and part of IRAK1 genes.
X-inactivation is not skewed (in leukocyte DNA).
We conclude that it is highly likely that this duplication has phenotypic
consequences.
These findings raise considerable issues concerning the diagnosis of
girls with mild mental retardation and no dysmorphic signs and the
genetic counselling for the parents.
P02.185
congenital variant of Rett syndrome due to the FOXG gene.
F. Mari 1 , M. Mencarelli 1 , A. Spanhol-Rosseto 1 , R. Artuso 1 , D. Rondinella 1 ,
N. Bahi-Buisson 2 , J. Nectoux 2 , R. Rubinsztajn 2 , T. Bienvenu 2 , A. Moncla 3 , B.
Chabrol 3 , L. Villard 4 , Z. Krumina 5 , J. Armstrong 6 , A. Roche 7 , M. Pineda 6 , B. Ben-
Zeev 8 , E. Gak 9 , F. Ariani 1 , A. Renieri 1 ;
1 Medical Genetics, University of Siena, Siena, Italy, 2 Université Paris Descartes,
Institut Cochin, Paris, France, 3 Université de la Méditerranée, Assistance Publique
Hopitaux de Marseille, Hopital de la Timone, Marseille, France, 4 Université
de la Méditerranée, Faculté de Médecine de la Timone, Marseille, France,
5 Medical Genetics Clinic of Latvian State, Children’s University Hospital, Latvia,
Latvia, 6 Hospital Sant Joan de Deu, Esplugues, Barcelona, Spain, 7 Hospital
Sant Joan de Deu, Esplugues, Barcelona, Italy, 8 Pediatric Neurology Unit, Dana
Children’s Hospital, Tel Aviv Medical Center, Tel Aviv, Israel, 9 Sagol Neuroscience
Center, Sheba Medical Center, Tel Hashomer, Tel Aviv University, Tel Aviv,
Israel.
Rett syndrome is a severe neurodevelopmental disorder representing
one of the most common genetic causes of mental retardation in girls.
The classic form is caused by MECP2 mutations. By candidate gene
approach, we recently identified FOXG1 as responsible for the congenital
variant of Rett. FOXG1 encodes a brain-specific transcriptional
repressor, essential for early development of the telencephalon, that
exhibits an expression pattern in the postnatal cortex partially overlapping
with that of MeCP2. Sixty MECP2/CDKL5 mutation-negative European
Rett patients (classical and variants), 43 patients with encephalopathy
with early-onset seizures and 4 atypical Rett patients were
analyzed for mutations in FOXG1. Mutations of FOXG1 were identified
in 4 patients, independently classified as congenital Rett variant
from France, from Spain and from Latvia. Clinical data were compared
with the two previously reported FOXG1 mutated patients. In all cases
there is an early onset of symptoms. In the perinatal period the girls
are floppy, passive and easy to cry. Deceleration of head growth starts
before the fourth month and leads to severe microcephaly. Motor development
is severely impaired and the voluntary hand use absent.
In contrast with classic Rett, patients have poor eye contact. Typical
stereotypic hand movements with hand-washing and hand-mouthing
activities were constant and present all time. Some patients present
tongue movements. Jerky movements of upper limb were also present.
Brain MRI shows corpus callosum hypoplasia in most cases, while
epilepsy is a variable sign. Scoliosis is usually severe. Neurovegetative
symptoms typical of Rett are frequently present.
P02.186
A 2, 8 mb 14q12 deletion in a boy with severe encephalopathy
and Rett-like features
O. Boute1 , J. Andrieux2 , A. Lepine3 , L. Vallee3 , S. Manouvrier1 ;
1 2 Service de génétique clinique, Lille, France, Laboratoire de génétique, Lille,
France, 3Service de neurologie infantile, Lille, France.
We report on a six-years- old boy with a de novo 2,8 Mb interstitial
deletion of chromosome 14q12 identified by array-CGH. He presents
a severe mental retardation, post-natal microcephaly, epilepsy, jerky
movements of the upper limbs and minor dysmorphic features: large
ears and a tented upper lip. FOXG1 gene, which encodes a brain-specific
transcriptional repressor essential for early development of the
telencephalon, is the only gene entirely included in the deleted region.
Alteration of FOXG1 has been previously described in four girls with
severe mental retardation, seizures and Rett-like features: jerky movements
of the upper limbs, stereotypic activities, abnormal breathing
patterns. Two girls presented a de novo 14q 12 deletion detected by
array-CGH ( Bisgaard, 2005; Papa, 2O08), the others had truncating
mutation of FOXG 1 gene ( Ariani, 2008). These patients and our case
report suggest that haploinsufficiency of FOXG1 gene may cause a
severe encephalopathy mimicking the congenital variant of Rett syndrome.
Array -CGH should be performed in boys presenting with such
clinical features and in girls without MECP2 mutation. FOXG1 gene
analysis should also be discussed if array -CGH is normal.