Report on the results of the program
for selective screening of hereditary neurometabolic disorders in
2001-2004
This program has been under way since 2001
at the Department of Psychoneurology-2
of the Russian Children's Clinical Hospital, which works on it together with
the Medical Genetic Research Center of the Russian Academy
of Medical Sciences. It is also supported by the Regional Public
Charity Foundation for Seriously ill and Abandoned Children.
The Department of Psychoneurology No. 2 was opened on August 19, 1991,
for examination and treatment of early-age children with various pathologies
of the nervous system. Each year, over 400 children receive
treatment at this department. Presently its patients are
children with perinatal nervous system disorders, inflammatory cerebral
diseases, epilepsy, and hereditary neurometabolic disorders.
Presently, owing to success of genetic research, a breakthrough in
diagnosis and treatment of neurometabolic disorders has taken place
in Russia and in the whole world.
Hereditary metabolic disorders play an important role in
pediatric neurology along with other pathologies of the nervous
system. They form a large group of diseases where clinical manifestations
are due to metabolic disorders in the organism. As a result, some
metabolic reactions proceed abnormally, thus causing serious
lesions of the nervous system and marked, sometimes fatal disabilities
in patients.
Over a hundred years have passed since the discovery of the first forms of
hereditary neurometabolic disorders. Presently over 500 forms of hereditary
disorders are known, and this number continuously increases.
The problems in diagnosing these disorders are due not only to
their very low occurrence in the population and large number of
different clinical entities but also to marked clinical polymorphism
of hereditary diseases from this group.
In the overwhelming majority of cases, hereditary metabolic disorders
have no distinctive clinical features, only nonspecific symptoms
in the early neonatal period: delayed physical development,
nursing problems, drowsiness, etc. Or sometimes they are taken
for other disorders, such as epilepsy, neural infections, or
perinatal pathologies. As a result, the first diagnosis may be
wrong.
At the same time, early diagnosis of such conditions often enables
the physician to apply efficient treatment techniques, which
are notably less successful or totally inefficient at
later stages of the pathological process. In addition, the correct
final diagnosis is necessary for providing adequate genetic
consultations to the affected family. There is no universal test
that would exclude all hereditary metabolic disorders, and so
a pediatrician encounters a challenging problem: to suspect
such disorders as early as possible and to direct the
patient to a laboratory providing specific examinations.
Over the last two hundred years, up to the 1930s, detection
of a hereditary disorder was more like a death sentence for
a patient and his or her family. Empirical attempts to treat
patients with these severe disorders failed. In the
beginning of the 1930s, S.N. Davidenkov, a Russian neurologist
and geneticist, was the first to state that hereditary metabolic
diseases can be cured in principle. His opinion was based on
his own clinical experience and achievements of experimental genetics.
However, the lack of information on the pathogenetic mechanisms
causing the development of these diseases limited the elaboration of
treatment techniques at that time, and all such attempts, in spite
of correct theoretical principles, remained solely empirical
for a long time. And note that early detection, treatment, and
prevention are not only of medical but also of social and
economic importance in this case.
Presently, owing to significant progress in theoretical and practical
medicine, including studies of pathogenetic mechanisms leading
to many hereditary metabolic disorders, it became possible not
only to invent pathogenetic treatment of some conditions
but also to use it successfully. The applications of treatment based on
pathogenetic principles must soon become much wider, following
the progress in molecular and biochemical genetics. So far
its contribution to the creation of treatment tactics for
hereditary disorders is minor, but progress during the last
years is doubtless.
Presently the treatment is based on corrections of certain
disrupted metabolic pathways, although it would be more efficient
to interfere in the pathological process at the level of systemic
reactions.
We can list some diseases for which efficient pathogenetic
therapeutic methods have already been developed. They include
phenylketonuria, maple syrup urine disease, homocystinuria,
glycogenoses, lysosomal storage diseases (Gaucher disease,
Fabry disease, mucopolysaccharidoses types 1, 2, and 6), biotinidase
deficiency, glutaric aciduria type 1, and others. Since 2001,
thanks to enormous support from the Regional Public Charity
Foundation for Seriously ill and Abandoned Children
and close cooperation with the Laboratory of Hereditary Metabolic
Disorders (Moscow City Scientific Center, Russian Academy of Medical
Sciences), headed by Dr. E.Yu. Zakharova, we have been performing
selective screening for hereditary metabolic disorders on the
basis of our Department of Psychoneurology and Epilepsy. The results
of this screening may be regarded as quite successful.
Within this cooperation, we have managed to confirm a number of rare
diagnoses via not only clinical but also laboratory findings:
GM1 and GM2 gangliosidoses, neuronal ceroid lipofuscinosis,
metachromatic leukodystrophy, gluratic aciduria, biotinidase
deficiency, some forms of mitochondrial diseases,
X-linked adrenoleukodystrophy.
Each year, several patients with rare hereditary disorders receive
treatment abroad, thanks to financial help provided by the Regional
Public Charity Foundation.
Presently diagnostic programs for earlier detection of these rare
disorders are developing further. In 2007, with support from the
Regional Public Charity Foundation for Seriously ill
and Abandoned Children together with the International Italian
Association of Geneticists (MAGI), our two countries will share
their experience in treatment and diagnosis of neurometabolic
disorders. This program will make it possible to improve the
detection, treatment, and prevention of these diseases in
our country.
Report on the results of the program
for selective screening of hereditary neurometabolic disorders in
2001-2004
Hereditary metabolic disorders form a wide class of
human hereditary disorders, which includes more than 600
different forms. Some of them are rare or
even extremely rare. However, their summarized incidence is
fairly high, 1:3000 to 1:5000 live births. Hereditary metabolic
disorders have grave and often fatal manifestations, but, at
the same time, methods of effective pathogenetic treatment
have been developed for such diseases more successfully
than for any other hereditary pathologies.
Unfortunately, patients with hereditary metabolic disorders often
(if not predominantly) receive no diagnosis and due treatment in our
country. The only exception is phenylketonuria: screening of
all newborn babies for this disorder has been organized for
the last 20+ years, and it also includes a set of therapeutic
measures that enables us to achieve almost complete correction of
this disease and thus raise virtually healthy people
instead of severely disabled ones.
At the clinical level, diagnosis of hereditary metabolic disorders
is very difficult and often simply impossible. These hereditary
disorders are revealed using a wide set of biochemical and
molecular genetic methods. One of the novel methodical approaches
to the diagnosis of hereditary metabolic disorders is tandem mass
spectrometry (MS/MS).
This is one of contemporary chromatographic analytical methods,
used worldwide for quantitative and qualitative detection
of many compounds. In the diagnosis of hereditary metabolic disorders,
spectrometric techniqes are used to reveal disorders related
to metabolism of organic acids and amino acids, as well
as mitochondrial b-oxidation defects. MS/MS is especially
important for mass and selective screening, because it
enables one to analyze over 100 different metabolites in
microamounts of the biological sample within a short time.
Many forms of hereditary metabolic disorders have not
been included in mass screening programs, either because
there are no methods of their efficient therapy or because
their incidence in the population is very low. The main
approach in diagnosis of this group of disorders is selective
screening. It includes two stages: (1) the use of simple tests to reveal
patients with assumed metabolic disorders and (2) special
methods for confirming the diagnosis.
Estimating the occurrence rate and providing routine diagnosis of
hereditary metabolic diseases among patients of child
psychoneurology departments is especially important. Selective
screening among just these patients is natural, because the
overwhelming majority of such disorders affect the nervous
system.
Our approach consisted of two stages. At the first stage, we
determined the content of amino acids and acylcarnitines using
MS/MS, measured the activity of certain lysosomal enzymes,
and determined the blood lactate level. At the second stage,
after analyzing these results and the clinical findings,
we performed additional tests to verify the diagnosis (DNA diagnostic
routines, enzyme activity determination, chromato-mass-spectrometric
measurement of organic acid levels).
From 2001 to 2004, 217 patients aged from 1 month to 7 years were
examined.
The patients for selective screening were chosen according to
the following criteria:
Progressive development of disease
Neurological symptoms:
Psychomotor retardation
Loss of acquired skills
Convulsions resistant to basic anticonvulsant therapy
Muscular hypotonia/hypertonia
Visual impairment
Hearing impairment
Mental retardation
Comatose conditions
Extraneural symptoms:
Physical retardation
Vomiting
Strange smell of urine
Jaundice of unknown origin
Ascites
Hepatomegaly
Metabolic alkalosis/acidosis
Breathing disorders
Alopecia
Hypoglycemias of unknown origin
The concentrations of the aforementioned compounds were
measured on a Wallac Sciex API 2000 tandem mass spectrometer (Perkin-Elmer
Sciex, Toronto, Ontario, Canada). The activity of lysosomal enzymes
(tripeptidyl peptidase, palmitoyl thioesterase, chitotriosidase,
and galactosidase) was determined by standard techniques.
As a result of this work, the exact diagnosis was found
for 23 patients. In 8 of them, we revealed organic
acidurias and/or aminoacidopathies; 12 patients had various
forms of lysosomal storage diseases (neuronal ceroid lipofuscinosis,
GM1 gangliosidosis, Krabbe disease, mucopolysaccharidosis, metachromatic
leukodystrophy), and three patients had mytochondrial disorders
(Leigh's disease). For the first time in Russian medicine,
we diagnosed three patients with biotinidase deficiency,
one patient with glutaric aciduria of type I, and two
patients with Leigh's disease due to mutations in the nuclear
gene SURF1.
These results are comparable to international standards, because
the proportion of hereditary metabolic disorders revealed
in developed countries by selective screening programs ranges
from 4 to 12%.
Selective screening enabled us to diagnose biotinidase deficiency
for the first time in Russian medicine. This disease can be
efficiently corrected by taking large doses of biotin, and only
its low incidence (1 : 40 000 in European countries) prevents
its inclusion in mass screening programs. Within two years,
we found three children with this pathology. This fact means
that children with this disorder become patients of psychoneurological
clinics, and this face induces us to recommend selective screening for
biotinidase deficiency in the case of early-onset epilepsy.
Since the number of patients thus examined is not yet large,
we cannot draw conclusions concerning the incidence
of separate forms of hereditary metabolic disorders
among patients of psychoneurology departments in child
clinics. However, it is evident that these disorders
should be considered in differential diagnostic
search concerning any progressive disease that affects
the central nervous system.
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