BIOTECH
PROGRAM CEEX
MI
CONTRACT No. 150/2006
COMPLEX CLINICAL, BIOCHEMICAL AND CYTOGENETIC APPROACH OF
PEDIATRIC NEUROGENETIC DISEASES IN ORDER TO INITIATE A REGIONAL
REGISTER FOR PEDIATRIC NEUROLOGIC DISEASES
Director of the project,
Prof. Dr. Sanda Magureanu
Participants:
1. Clinical Hospital of Psychiatry “Prof. Dr. Alex. Obregia” – Coordonator
2. National Institute of Research-Development “Victor Babes” – Partner
3. Institute of Mother and Child Health “Alfred Russescu” – Partner
4. National Center for Organisation and Assurance of Informatic and
Informational System in Health Bucharest
Centrul National Pentru Organizarea si Asigurarea Sistemului Informatic si
Informational in Domeniul Sanatatii Bucuresti
Neurogenetic diseases represent an important group of conditions in pediatric neurology
practice. Due to their complexity, this project intent to make a integrate evaluation of the
metabolic and chromosomal diseases in order to initiate a Regional Register of Neurogenetic
Diseases.
Metabolic diseases result from a single mutant gene that codes for an enzymatic protein that
in most instances is involved in a catabolic pathway. The consequent homeostatic
disturbances produce a neurologic or developmental abnormality.
Since 1975, almost all of the nearly 500 neurologic and neuromuscular diseases caused by
known enzymatic or protein defects have been mapped to a specific chromosome region, and
a large proportion of them have been cloned.
Inborn errors of metabolism affect only approximately 1 in 5,000 live births, and are therefore
relatively uncommon in the practice of pediatric neurology. Their importance rests in part on
the insight they offer into the relationship between a genetic mutation, the resultant
disturbance in homeostasis, and a disorder of the nervous system.
The mechanisms by which inborn errors of metabolism produce brain dysfunction remain
largely uncertain, although, for some conditions, a plausible theory of pathogenesis has been
proposed. Not all enzyme defects lead to disease; a large number of harmless metabolic
variants exist.
The spectacular advances of molecular biology have facilitated the diagnosis and prevention
of genetic diseases and have brought humanity to the threshold of gene therapy. The clinician
must, therefore, strive for an early diagnosis of inborn errors of metabolism to offer treatment
whenever possible, provide appropriate genetic counselling, and, in many instances, give
parents an opportunity for an antenatal diagnosis on the occasion of a subsequent pregnancy.
The clinical syndromes with an underlying metabolic cause include: neurologic disorder,
including mental retardation replicated in sibling or close relative; recurrent episodes of
altered consciousness or unexplained vomiting in an infant; recurrent unexplained ataxia or
spasticity; progressive central nervous system degeneration; mental retardation without
obvious cause.
A great number of hereditary syndromes are generated by numeric (trisomies, monosomies)
or structural (deletions, translocations, inversions), balanced or unbalanced chromosomal
abnormalityes.
All of these syndromes are associated with mental retardation, diverse dismorphic features
and visceral malformations.
Recently, using high resolution techniques (in situ hybridisation, molecular biology), a new
syndrome has been described – the contiguous gene syndrome. This syndrome was described
by Schmickel (1986) in patients with phenotypic abnormalities due to the involvement of
closely spaced genes. These are, generally, microdeletions and they cause different
phenotypic expression according to the sex of the transmitting parent. The classical example
is Prader-Willi and Angelman syndromes, the anomaly being a microdeletion 15q11-q12, of
paternal origin in first case and of maternal origin in the second one. The modern techniques
of molecular genetics allowed description of a new mechanisms of chromosomal anomaly,
monoparental disomy (a pair of chromosome inherited from a single parent).
Among rare chromosomal syndromes are included and malformative syndromes.
Visceral malformations are frequently associated with CNS maldevelopment, either as part of
malformation syndromes or associations, or in isolation, so their presence in patients with
neurological disorders is an argument for a malformative origin. Even in nonsyndromal
associations, some peripheral malformations tend to be electively associated with CNS
abnormalities, e.g. choanal atresia and certain cardiac malformations such as truncus
arteriosus and hypoplastic left heart. Glauser et al (1990) found that 29 per cent of children
with left heart hypoplasia had brain maldevelopment such as holoprosencephaly or callosal
agenesis and 27 per cent had microcephaly, while only 17 per cent had a recognized
malformation syndrome. The recognition of such anomalies should therefore prompt a search
for neurological abnormalities.
Sex chromosome abnormalities are associated with a slightly increased risk of mental
retardation, especially for XXY, XXX or XYY syndromes. The mean IQ of XO (Turner) girls
in normal, but many XO females do exhibit right-left disorientation and defects in perceptual
organization, and their verbal IQ tends to be higher than the performance IQ but with
considerable interindividual variation (Temple and Carney, 1993). Fragile X syndrome is the
most frequent cause of mental retardation; the disorder is due to the presence in the FMR-1
gene of an expansion of a repeat trinucleotide (CGG).
The objectives of the project are:
General objectives: 1. The building, development, integration and consolidation of research
networks, which level of activity will have the excellence level, in conformity with the
international criteria; 2. The improving of the diagnostic in the pediatric neurogenetic
disorders through application of new clinical investigations, such as the genetic counseling
and through new modern genetical techniques; setting up a group of patients with neurogentic
disorders who are to be followed in time and extensively investigated, as in European Union
and abroad; 3. Complex evaluation of the rare cromosomial disorders, (clinical, biochemical,
cytogenetical, molecular) and follow up of the patients, in order to create a regional database.
4. Genetic counselling of the at risk families, in order to prevent the appearance of new cases
and to a precocious treatment; 5. Introduction of new minimal invasive methods, for an
accurate diagnosis of the pediatric neurogentic disorders; 6. The transpher of the research
results in clinical practice and the development of new, patient oriented strategies, from
prevention through diagnosis and treatment. 7. Development of knowledge in the field of
medical sciences and definition of application in the child and adolescent pathology; 8.
Elimination of the present differences with the European level regarding medical services,
objective in conformity with that of the program of the European Union integration process
acceleration.
Measurable objectives. Creation of a database which will include the patients with pediatric
neurogenetic disorders taken into study; 2. Creation of a standard protocol for examination of
the patients with pediatric neurogenetic disorders, of international level, which would include
the genetic examination; 3. initiation of a Regional Registry of Rare Chromosomal Disorders,
as a first step of a national database, in order to be able to take part to european programme
ORPHANET. 4. Initiation of a web site of the pediatric neurogenetic disorders from Romania;
5. Decreasing the number of the patients with pediatric neurogenetic disorders through
counselling of the at risk families; 6. Dissemination of the data obtained to the pediatric and
pediatric neurology clinics from Romania, through communications and round tables; 7.
Education of the pediatric, pediatric neurology and genetic medical residents in the field of
the pediatric neurogenetic disorders; 8. Communication of original works at national and
international scientific meetings; 9. Publishing of original papers in national and international
journals; 10. Accomplishing of doctorate papers and disertation themes, through interes of the
young graduates in research.
For the selection of the supposed carriers of chromosomal abnormalities, the following steps
have been performed 1. Complete clinical and paraclinical examination which means:

Accurate genealogical pedigree

History of child ‘s psychomotor development;

Stature-pondered and cranial circumference growing;

Dysmorphic features examination;

Imagistic studies (EEG, CT, MRI)

Behaviour and mental development of the child by psychiatric examination
2. Biochemical examination for metabolic diseases.
3. Cytogenetical investigations
4. Integration of clinical and cytogenetical data for diagnosis establishment.
5. Transfer of information to clinician specialists and involved families.
6. Elaboration of registration formulary for clinical data in order to set up an unitary
clinical and cytogenetic database.
7. Facilitate dissemination of these data by a WWW-accessible database.
8. Establish of patient management: family information about the nature of the disease;
discussion the possibilities of the child institutionalisation or growing in the family
frame; early establish of therapeutic interventions.