Download Metabolic medicine: new developments in diagnosis and treatment

Metabolic medicine: new developments in diagnosis and treatment of inborn errors of metabolism
Metabolic medicine: new developments in diagnosis and
treatment of inborn errors of metabolism
Junmin Fang-Hoffmann, Martin Lindner, Noora Shahbek, Ivo Barić, Ghalia Al Thani and
Georg F. Hoffmann
Heidelberg, Germany; Doha, Qatar; and Zagreb, Croatia
Author Affiliations: University Children's Hospital, Heidelberg,
Germany (Fang-Hoffmann J, Lindner M and Hoffmann GF); Department
of Pediatrics, Hamad Medical Corporation, Doha, Qatar (Shahbek N
and Thani GAL); Department of Pediatrics, University Hospital Center,
Zagreb, Croatia (Barić I)
Corresponding Author: Junmin Fang-Hoffmann, MD, Department
of General Pediatrics, University Children's Hospital Heidelberg, Im
Neuenheimer Feld 150, D-69120 Heidelberg, Federal Republic of Germany
(Tel: +49-6221-562338; Fax: +49-6221-564388; Email: [email protected])
©2006, World J Pediatr. All rights reserved.
up to 30 aminoacidopathies, organoacidopathies, and
fatty acid oxidation disorders. Independently, progress
in diagnosis and understanding of the molecular and
pathophysiological bases of inborn errors of metabolism
funnels into the development of successful rational
therapies: new treatment protocols—new therapeutic
agents (drugs and foods)—improved organ, tissue or
cell transplantation and enzyme replacement by other
means.
Novel diagnostic and therapeutic possibilities, like
extended newborn screening or enzyme replacement
therapies, are expensive. Hopefully, the scientific progress
already achieved and to be expected in the future will
be supported by the social, political and economical
advances necessary for transforming the full benefit of
sciences to the people.
Review article
Metabolic medicine has developed from a highly
specialized activity of research-oriented physicians
and scientists, practiced mostly in a very personal
individual interaction from one family to one doctor to a
sophisticated team approach involving different medical
specialties and associated professions such as biochemists,
dietitians, nurses, psychologists, physiotherapists, social
workers, speech therapists, and teachers. The world
health organisation (WHO) as well as the European
Union (EU) have recently announced genetic and orphan
diseases as a major health challenge of the future.
Almost all countries still lack an organized network of
metabolic centers, which are capable of competent and
comprehensive diagnostic and therapeutic services.
Scientific and technological advances transferred
into diagnostic and therapeutic medical progress can
offer enormous benefit to patients suffering from inborn
errors of metabolism, ideally preventing life-long burden
and suffering. To implement this progress, much remains
to be done. For example, it must be assumed that up
to 50% of patients with inherited metabolic diseases,
which are diagnosable today, remain un(mis)diagnosed
in Germany. Early diagnosis and treatment by neonatal
population screening for inborn errors of metabolism
is an important and successful approach. Tandem
mass spectrometry has recently been implemented in
extended general neonatal screening programs in a
few countries including Austria, Australia, Germany,
Qatar, and the USA allowing the early recognition of
World J Pediatr 2006;3:169-176
Key words: metabolic medicine;
inherited metabolic diseases;
newborn screening;
gene therapy;
enzyme replacement therapy
L
ittle more than a century ago Sir Archibald E.
Garrod introduced the term "inborn errors of
metabolism".[1,2] As an extraordinary scientist
and pediatrician Garrod used consanguinity and
distribution of cases in families to introduce the
hypothesis that autosomal recessive inheritance
according to Mendel's rediscovered rules would explain
the occurrence of the alkaptonuria phenotype. Soon
after that, he also recognized albinism, cystinuria
and pentosuria as inborn errors of metabolism. From
that time on, the number of discovered inborn errors
of metabolism has continuously increased, as can be
demonstrated by the steady growth of the book The
Metabolic and Molecular Bases of Inherited Disease,
which traditionally collects the actual knowledge in
this field. The 8th edition, which appeared in 2001,
has some 7000 pages written by over 500 authors and
World J Pediatr, Vol 2 No 3 . August 15, 2006 .
169
World Journal of Pediatrics
Review article
170
contains data on more than 500 hundred inborn errors
of metabolism.[3]
In 1999, the World Health Organisation (WHO)
announced genetic and orphan diseases as a major
challenge to future health followed by similar
initiatives of the European Union (EU). In 2006 the
March of Dimes Birth Defects Foundation issued
the first comprehensive global report on all genetic
birth defects ranging from 82 to 39.7 per 1000 live
births worldwide.[4] Among the orphan diseases, more
than 500 inborn errors of metabolism are especially
important because of their relative frequency, and
because rationale therapy has been or will be available
in the foreseeable future. As a group, they account
for about 1 in 100 births. In terms of medical care,
they have presented a significant challenge to the
public health system, particularly in countries where
the incidences of infectious diseases related to the
inappropriate care in pregnancy and delivery are
greatly reduced.
In addition to the mentioned estimations on the
incidence of "classical" inherited metabolic diseases,
such as aminoacidopathies, organoacidopathies, fatty
acid oxidation disorders, various storage disorders,
disorders of mitochondrial energy production,
neurotransmitters defects, peroxisomal disorders,
and defects of purine and pyrimidine metabolism,
novel powerful techniques are still unravelling "new"
groups of inborn errors of metabolism. Examples are
defects of cholesterol biosynthesis (e.g., Smith-LemliOpitz syndrome) as important monogenetic causes
of malformation syndromes, congenital disorders
of glycosylation (CDG syndromes) causing a broad
spectrum of hemostasiological, endocrinological and
neurological multi-system disorders, bile acid synthesis
defects and defects in leukotriene synthesis.[5]
Newly discovered inborn errors are often the
reflection of novel powerful techniques. In vivo
NMR spectroscopy of the brain has contributed to
the definition of creatine deficiency syndromes, a
group of newly discovered disorders causing mental
retardation and other neurological symptoms.[6]
NMR spectroscopy of body fluids may be even more
promising in diagnosing both known and novel inborn
errors of metabolism, e.g., novel disease in N-acetyl
aspartic acid metabolism identified by in vivo nuclear
magnetic resonance (NMR).[7] "Old" techniques are
still contributable to the discovery of new inborn
errors of metabolism, as can be demonstrated by
two new organoacidopathies from the isoleucine
degradation pathway: 2-methyl-3-hydroxybutyryl-CoAdehydrogenase deficiency and 2-methylbutyryl-CoA
. World J Pediatr, Vol 2 No 3 . August 15, 2006
dehydrogenase deficiency.[8,9] Both of them are revealed
by "classical" gas chromatography/mass spectrometry.
Hence, the field of inborn errors of metabolism is
continuing to increase, both by its size and especially
by our knowledge. Clinical expertise and a good
cooperation between the referring physician and the
metabolic specialist and a broad spectrum of metabolic
investigations in the respective center is or will be the
key to the successful diagnosis and treatment of inborn
errors. But there is not and never will be a single test
or combined approach for the diagnosis of all inborn
errors of metabolism.
Human genome project and progress on
the molecular level
In the past two decades increased knowledge about
inborn errors of metabolism has been obtained
following the development of molecular medicine.
The majority of genes, whose mutations cause
inherited metabolic diseases, have been mapped and
sequenced. This is not only a critical step forward in
understanding the diseases, but has provided possible
way for the management of the patients. Some diseases
can only be diagnosed by molecular genetic analysis.
Until very recently, for instance, Alexander disease, a
neurodegenerative disease affecting the white matter
could only be proven by autopsy or brain biopsy,
indicating the characteristic Rosenthal fibers. The
recent discovery of underlying molecular defect in
the glial fibrillary acidic protein as a gain-of-function
mutation has made a primary molecular diagnosis
possible.[10] For many other diseases, gene analysis
is not the only, but the most convenient way to prove
tentative diagnosis. For example, it is less aggressive
to analyze the gene for common mutations than to
perform liver biopsy in children suspected to suffer
from hereditary fructose intolerance or to screen the
dystrophin gene rather than to perform muscle biopsy
in patients suspected to suffer from Duchenne muscular
dystrophy. Primary molecular diagnosis is especially
convenient in diseases caused primarily by a single
common mutation, e.g., hereditary hemochromatosis
that is mainly caused by the C282Y mutation.[11] Gene
analysis has also significantly improved prenatal
diagnosis and offered the identification of healthy
heterozygotes, thus significantly improving genetic
counseling.
When molecular genetics came to medicine, there
was a widely-held belief that knowing the genotype at
the particular locus would predict the corresponding
Metabolic medicine: new developments in diagnosis and treatment of inborn errors of metabolism
folic acid supplementation, homocysteine metabolism
has become focus of many research groups studying the
development of early vascular diseases.
The study of many genes involved in inborn errors
of metabolism, in particular the more common ones, has
revealed that the spectrum of mutations varies between
different populations. Phenylketonuria (PKU) is a good
example. About 500 mutations of the phenylalanine
hydroxylase (PAH) gene have been described so far
(http://pahdb.mcgill.ca) resulting in total or partial
impairment of the enzyme activity predicting the
metabolic phenotype[15] according to the three subtypes
(Table 1). Less than 10 mutations comprise more than
three quarters of the total number of alleles, and the
others are rare or "private".
The frequency of particular mutations differs
between populations, reflecting the ethnic background
as well as past migration and/or isolation. In the
Mediterranean region, for instance, there can be a
significant difference in the frequency of PKU mutations
despite small distances between countries. The PKU
alleles also document the "out of Africa" evolution of
Homo sapiens with independent appearance of PKU in
oriental and Caucasian populations.[16,17] Obviously, the
mutations tell us much about the diseases, but also about
the history of mankind.
Progress in diagnosis
Since inborn errors of metabolism are relatively
unknown to primary care physicians and nonspecialized pediatricians, and a good outcome relies
on early recognition, timely diagnosis and appropriate
treatment have always been a critical step in the
management of the diseases. This situation led to the
concept of neonatal screening, an important diagnostic
program of preventive pediatrics, which covers the
whole newborn population by searching adequate
Table 1. Enzymatic and metabolic phenotypes, phenylalanine tolerance and therapy of different subtypes of hyperphenylalaninemias
HPA subtype
Residual PAH in vivo activity
estimated by liver biopsy
(enzymatic phenotype)
Blood phenylalanine level
(standardized protein challenge
(metabolic phenotype)
Phenylalanine tolerance
at age 5 years
Therapy
Type I classical PKU
<1%
>1200 µmol/L
<21 mg/kg/d
Dietary treatment for life
Type II Mild PKU
1%-3%
360/600-1200 µmol/L
21-50 mg/kg/d
Type III Non-PKU
HPA/MHP
>3%
<360-600 µmol/L
>115 mg/kg/d
Dietary treatment at least
until adulthood
Treatment only in case of
maternal PKU (MPKU)
HPA: hyperphenylalaninemias; MHP: mild hyperphenylalaninemias; MPKU: maternal PKU; PAH: phenylalanine hydroxylase.
World J Pediatr, Vol 2 No 3 . August 15, 2006 .
Review article
phenotype and assist counseling and treatment. It has
been clear that this was rather naive. Although genotypephenotype correlation is strong in some diseases, there is
still a huge number of examples that the phenotype can
not be explained by the mutations found. More obviously,
besides mutations of the affected gene and environment,
many other factors influence the phenotype. The role of
numerous factors affecting post-transcriptional events,
including transport of RNA, protein synthesis, folding,
degradation, etc, and their mutual relationship is at
best partly understood.[12] It is not surprising that the
topic "genome" is being expanded by "transcriptome",
"proteome", "complexome", "metabolome" or even
"phenome" reflecting acceptance of the complexity of
the biological processes as the reality which has to be
intensively studied in the future.[13] A major benefit of
the Human Genome Project has been the facilitation of
the development of "knock-out mice" and other animal
models which are increasingly utilized for the research
of both pathophysiology and therapeutic options for
many inborn errors of metabolism.
The extensive study of genes involved in inborn
errors of metabolism has not only revealed the diseasecausing mutations, but also many "neutral" ones (without
apparent effect on phenotype). However, significant
numbers of such "benign" mutations and polymorphisms
have been subsequently recognized to carry some risks
for the development of complex multifactorial diseases,
often in association with variations of other genes.
An illustrative example is the C677T polymorphism
of the methylentetrahydrofolate reductase gene
associated with diminished enzyme activity leading
to hyperhomocysteinemia, which has been discovered
as an important risk factor for early-onset vascular
disease. The polymorphism's frequency varies between
populations, but it is found in about 38% of alleles in
some western populations.[14] This can significantly
influence the health of community people. As the
adverse effects of polymorphism can be counteracted by
171
World Journal of Pediatrics
Review article
laboratory tests for inherited metabolic diseases
that fulfill the criteria of relatively high frequency,
irreversible damage following delayed clinical
diagnosis, amenability to treatment, availability
of adequate laboratory test for mass screening at
acceptable costs. These principles of early disease
detection, formulated by Wilson and Jungner in
1968,[18] can be regarded as a guideline whether a
specific disease should be included or excluded from a
panel of diseases of a newborn screening program. The
history of the newborn screening is given in Table 2.
Recent technological advances allow the extension
of neonatal screening to detect more than 30 inborn
errors of metabolism (Table 3).[19] Tandem massspectrometry (MS/MS), a method developed and
introduced few years ago in a few western countries,
is capable to analyze 40-60 different amino acids
and acylcarnitines in a 2-minute run allowing early
detection of the majority of fatty acid oxidation defects,
several organic acidurias and some aminoacidopathies.
The combined frequencies of the disorders detected
in addition to conventional screening amount to about
1:3000 (Table 4). Besides providing complete data on
incidences of various inborn errors of metabolism,
some diseases like 3-methylcrotonyl-CoA carboxylase
deficiency, which was previously thought to be rare but
rather severe, can remain completely asymptomatic and
have a high frequency. Also, some cases of mediumchain acyl-CoA dehydrogenase deficiency are too
mild to diagnose by usual biochemical tests (including
specific loading tests).[20]
Screening amino acid and acylcarnitine profiles by
MS/MS allows detection of several additional diseases
which only fulfill part of the Wilson and Jungner criteria.
Table 2. History of the neonatal screening
172
Year
1953
1961
1961
The early 1970s
1978
1987
1994
1997
1998
Neonatal screening
H. Bickel—first successful treatment of phenylketonuria
H. Bickel—introduction of "Fölling-Windeltest" in Germany
R. Guthrie—development of microbiological inhibition assay ("Guthrie Test") for screening for phenylketonuria
Extension of neonatal screening for galactosemia, maple syrup urine disease, homocystinuria, etc.
Congenital hypothyroidism
Biotinidase deficiency
Switch from "Guthrie Test" to enzymatic micromethods (Heidelberg/Germany)
Congenital adrenal hypoplasia (CAH)
Introduction of ESI-MS/MS = start of Extended Neonatal Screening (Heidelberg/Germany)
Table 3. Inborn errors of metabolism potentially detectable by MS/MS analysis
Amino acidemias
PKU
Tyrosinemia type I
Nonketotic hyperglycinemia (NKH)
Maple syrup urine disease (MSUD)
Citrullinemia (ASS)
Argininosuccinate lyase def. (ASL)
Organic acidurias
Propionic aciduria (PA)
Methylmalonic aciduria (MMA)
Cobalamine disorders A, B, C, D, F (Cbl)
Isovaleric aciduria (IVA)
Glutaric aciduria—type I (GAI)
3-Methylcrotonyl CoA carboxylase
(3-MCC)
Homocystinuria (HCY)
Holocarboxylase synthetase
HHH-syndrome
Biotinidase
Arginase def.
HMG-CoA-lyase
Hyperornithinemia
Methylglutaconic aciduria
Hyperprolinämie
Multiple acyl-CoA dehydrogenase (MAD,
GAII) def.
Hyperhydroxyprolinämie
Isobutyryl-CoA dehydrogenase def.
Glycine N-methyltransferase def.
2-Methylbutyryl-CoA dehydrogenase def.
Hypermethioninemias other than HCY Ethylmalonic encephalopathy
Medium-chain 3-ketoacyl-CoA thiolase
(MCKAT) def.
Succinyl-CoA transferase (SCOT) def.
Beta-ketothiolase (MAT) def.
Malonic aciduria
. World J Pediatr, Vol 2 No 3 . August 15, 2006
Fatty acid oxidation disorders
Short-chain acyl-CoA dehydrogenase (SCAD) def.
Short-chain 3-OH acyl-CoA dehydrogenase (SCHAD) def.
Medium-chain acyl-CoA dehydrogenase (MCAD) def.
Very long-chain acyl-CoA dehydrogenase (VLCAD) def.
Long-chain 3-OH acyl-CoA dehydrogenase (LCHAD) def.
Mitochondrial trifunctional protein (mtTFP) def.
Carnitine-transporter defect (CTD)
Carnitine palmitoyl-transferase I (CPT I) def.
Carnitine palmitoyl-transferase II (CPT II) def.
Carnitine/acylcarnitine translocase (Translocase) def.
Metabolic medicine: new developments in diagnosis and treatment of inborn errors of metabolism
Table 4. Results of the extended newborn screening program by tandem mass spectrometry in the period February 1998 to September 2004 at the
University Children's Hospital Heidelberg (the number of samples analyzed: 534 041)
Thus, it is imperative to assess each condition which
might be found by MS/MS screening for its impact as a
screening disease. Such an assessment has to be open to
change because the reasoning depends on facts, which
may be changing. Increasing knowledge about the natural
course of diseases and their variants, new treatment
options, analytical developments improving sensitivity
and/or specificity of screening tests are some of the
reasons for the necessity of re-assessment referring to the
expansion of screening for additional disorders. Single
case observations or reports of a positive clinical course
in the diseases which are classified as non-treatable
conditions can not justify the decision of adding a disease
to the screening panel. In contrast, timely and aggressive
treatment has changed the outcome in some diseases
which were classified as non-treatable condition before,
thus justifying its embedding as a screening disease, e.g.,
glutaric aciduria type I.[21]
The policy of dealing with these objectives is
different between screening programs and countries
and is still on debate. This discussion is currently on
its way in many countries with very different to-date
results. In the United Kingdom and the Netherlands,
only medium chain acyl-coenzyme A dehydrogenase
(MCAD) deficiency is considered a potential candidate
of expanded MS/MS screening, whereas in the
n
85
27
4
12
Incidence
1 : 4118
1 : 12 963
1 : 133 510
1 : 44 503
46
51
1
4
2
9
1 : 11 610
1 : 10 471
1 : 534 041
1 : 133 510
1 : 267 021
1 : 59 338
39
3
5
1 : 13 693
1 : 178 014
1 : 106 808
2
1
1 : 267 021
1 : 534 041
7
6
5
1 : 76 292
1 : 89 007
1 : 106 808
US, recent recommendations of a task force of the
American College of Medical Genetics commissioned
by the Maternal and Child Health Bureau of the
Health Resources suggest population screening for
29 conditions with an additional 25 disorders which
clearly do not meet the classical screening criteria, but
should also be reported.[22] An "intermediate" approach
is taken in Germany with 14 conditions agreed on and
declared as screening targets.[23] As the genetic basis of
all these countries are to a large extent identical, it is
obvious that the current development is not primarily
based on medical evidence, but on subjective and
political decisions.
Such issues and discussions will have to continue
within medicine and individual societies. Since the
possibility of MS/MS in the study and diagnosis of
inborn errors of metabolism is far from exhausted, it
is possible in the near future to search for even more
diseases. In addition, some other metabolites such as
sterols and bile acids can be analyzed and utilized for
detecting patients with corresponding biosynthesis
defects.[24] In the future, new powerful techniques
are likely to further increase our diagnostic abilities.
Matrix-assisted laser desorption/ionization time-offlight (MALDI-TOF) mass spectrometry, for instance,
has a potential for the rapid and reliable identification
World J Pediatr, Vol 2 No 3 . August 15, 2006 .
Review article
Disorders
Congenital hypothyroidism
Congenital adrenal hyperplasia*
Biotinidase deficiency
Classical galaktosaemia
Aminoacidopathies (Tandem-MS)
Phenylketonuria (PKU)
Hyperphenylalaninaemia (HPA)
Tetrahydrobiopterin (BH4) deficiency
Maple syrup urine disease (MSUD)
Tyrosinaemia type I
Citrullinaemia
Disorders of fatty acid oxidation (Tandem-MS)
Medium-chain-acyl-CoA-dehydrogenase (MCAD) deficiency
Long-chain-3-OH-acyl-CoA-dehydrogenase (LCHAD) deficiency
Very-long-chain-acyl-CoA-dehydrogenase (VLCAD) deficiency
Carnitine cycle defects (Tandem-MS)
Primary carnitine deficiency
Carnitine palmitoyl transferase -II (CPT-2) deficiency
Organic acidurias (Tandem-MS)
Glutaric aciduria type I (GA1)
Isovaleric aciduria (IVA)
Propionic aciduria/Methylmalonic aciduria/Vitamin B12 deficiency
*: since 1999.
173
World Journal of Pediatrics
of altered proteins, while DNA microarrays, or gene
chips, might allow DNA-based screening in a highly
parallel and comprehensive manner.
New therapies
Review article
174
More than diagnostic procedures, advances in therapy
are the most critical aspect for affected patients and
their families. Until the mid-20th century, treatment
did not exist, destiny would take its course, and genetic
counselling about recurrence risks was all that could
be offered. Phenylketonuria was then shown by Horst
Bickel to be a treatable "genetic" disease in which
early diagnosis and dietary treatment prevented mental
retardation. Subsequently, several other inborn errors
became manageable in a similar way, i.e., with substrate
deprivation strategy—maple syrup urine disease, urea
cycle defects, galactosemia, fructosemia, tyrosinemia
type 2, etc. Pharmacological doses of vitamins proved
to be useful in dealing with defects of cobalamine and
biotin metabolism, distinct forms of homocystinuria,
and some others. Avoiding of fasting was recognized
as the cornerstone of successful therapy for defects of
fatty acid oxidation, ketogenesis and glycogenolysis.[25]
The progress in the treatment was initially slow
but is beginning to explode as current progress in
understanding the molecular and pathophysiological
bases of inborn errors of metabolism funnels into the
development of successful rational therapies: new
treatment protocols, new therapeutic agents (drugs and
foods), improved tissue transplantation, and enzyme
replacement by other means.[26]
Many inherited metabolic diseases are still not
amenable to treatment. Lysosomal storage disorders
are particularly hopeless and the outcome is generally
determined by the natural course of the illness. About
20 years ago, transplantation has become an option for
some of them. Bone marrow transplant has partially
corrected the defect and positively changed the disease
course in some patients with mucopolysaccharidoses
type I (particularly IH) and VI, metachromatic leucodystrophy, Niemann-Pick disease type B, Krabbe
disease,[27] and some others. However it failed to prevent
neurological deterioration in mucopolysaccharidoses II,
III and IV as well as in Niemann-Pick disease type A. In
some diseases the number of patients who have received
transplants is too small to make a reasonable assessment,
e.g., in mucopolysaccharidosis type VII. In the future,
umbilical-cord blood from unrelated donors may become
an attractive alternative to bone marrow from matched
donors as it is more readily available.[27]
. World J Pediatr, Vol 2 No 3 . August 15, 2006
Liver transplantation has made considerable
progress during the last two decades. It was first
recognized to be life-saving in patients with late-stage
Wilson disease, α-1-antitrypsin deficiency, Crigler-Najjar
syndrome type 1 as well as some other progressive
liver diseases. Combined liver-kidney transplantation
is needed in patients with hyperoxaluria type 1. With
time the indications for hepatic transplantation have
constantly widened as contra-indications have decreased
simultaneously. It can now be considered a rational
option for definitive therapy in many metabolic diseases,
including diseases where the quality of life may be
impaired by time-consuming procedures such as more
than 12 hours of photo therapy for Crigler-Najar disease,
bad taste in the mouth, and extremely time-consuming
preparation of diets for patients with diseases of amino
acid metabolism including urea cycle defects and
organoacidopathies.[28] Other indications would include
glycogen storage diseases, whereas most patients with
respiratory chain disorders do not benefit or only for a
short time.
The possibility to overcome the shortage of available
donor livers makes hepatocyte transplantation one of the
most fascinating techniques in the field of transplantation
at the present time. Many studies in animal models have
shown that under special circumstances hepatocytes
transplanted into the portal vein, the splenic pulpa or
the peritoneal cavity may engraft and maintain normal
function. Since its first use in man in 1992,[29] hepatocyte
transplantation has been performed in various conditions
such as acute liver failure, liver cirrhosis and some
metabolic diseases.[30] Hepatocyte transplantation is
likely most successful, if only a limited amount of liver
tissue is needed to compensate for hepatic dysfunction.
Being less invasive than whole-liver transplantation, it
may be a promising therapy for poor liver function after
extended liver resection, liver graft dysfunction or many
inborn errors of metabolism.
In most inborn errors of metabolism, only 5%-10% of
hepatic enzyme activity is needed to correct the genetic
defect. Thus, it is of no surprise that such conditions
have been the primary target to consider hepatocyte
transplantation or primary gene therapy. In September
1999, an 18 year old adolescent suffering from urea cycle
disorder or ornithine transcarbamylase (OTC) deficiency
participated in a pilot study of adenovirus-mediated gene
therapy.[31] Unfortunately, he died from a disseminated
adenovirus infection and primary gene therapy studies
for monogenic disorders have not been resumed.
A landmark progress has been achieved by the
development of enzyme replacement therapy, initially
in patients with visceral type of Gaucher disease.
Metabolic medicine: new developments in diagnosis and treatment of inborn errors of metabolism
Metabolic medicine and society
Scientific and technological advances described above
have benefited patients with inborn errors of metabolism.
To utilize them properly, much remains to be done.
Firstly, metabolic physicians and scientists need to
concentrate on international cooperative studies and
development of knowledge based guidelines. Significant
differences still exist in the diagnostic procedure,
treatment and monitoring of many diseases, resulting
in a wide variation in outcome. Even for successful
therapy of phenylketonuria, current international
Table 5. New treatment strategies in inborn errors of metabolism
Substrate deprivation
Supplementation with end products
Enzyme replacement
Chemical chaperon
Blockade of biosynthetic pathways
Blockade of degradation pathways
Blockade of pathophysiological signalling
(Stem) cell therapy
Gene therapy
guidelines recommend different cut-offs for the
indication of treatment ranging from 400 µmol/L in the
United Kingdom, 360-600 µmol/L in the USA to 600
µmol/L in Germany and France. The knowledge of the
academic community must be combined and structured,
transferred to physicians and other medical staff and
implemented in health systems. In the era of computers,
this process has become much easier by means of
numerous recommendations, information and even
projects available on internet, permanent professional
e-mail round tables, internet editions of book and
journals, free-access databases like McKusick's
catalogue OMIM http://www.ncbi.nlm.nih.gov/omim, etc.
In the necessary implementation process, regional
differences like availability of funds, local pathology
(particularly in isolated communities and societies with
high consanguinity rate), religious and geographical
features must be taken into account. Accordingly,
specialized national metabolic centers and appropriate
metabolic networks should be established and properly
maintained. Unfortunately, novel diagnostic and
therapeutic possibilities like extended newborn screening
or enzyme replacement therapy are relatively expensive,
and for many countries, where no screening programs
or even no well organized health care systems exist, still
an unrealistic dream. Hopefully, scientific progresses
will be paralleled by the social, political and economical
ones as necessary prerequisites for transforming the full
benefit of sciences to the people.
Funding: None.
Ethical approval: Not needed.
Competing interest: None declared.
Contributors: FHJ wrote the first draft of this paper. All authors
contributed to the intellectual content and approved the final
version. HGF is the guarantor.
References
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3 Scriver CR, Beaudet AL, Sly WS, Valle D. The metabolic
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4 Christianson A, Howson CP, Modell B. Global report on birth
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6 Schulze A. Creatine deficiency syndromes. Mol Cell Biochem
World J Pediatr, Vol 2 No 3 . August 15, 2006 .
Review article
Worldwide experience with more than 5000 patients
has clearly demonstrated its safety and effectiveness.[32]
Today, enzyme replacement therapy has also become
a reality for Fabry disease, Pompe disease and
mucopolysaccharidosis (MPS) I. In the latter one,
efficacy is limited because recombinant enzymes do not
cross the blood-brain barrier. Efficacy has been shown
only in those more mildly affected MPS I patients
without CNS involvement (i.e., MPS I H/S and MPS I
S). Clinical trials are currently under way for enzyme
replacement therapy in MPS II and VI,[33] with new
approaches being evaluated for targeting directly to the
central nervous system in MPS I, II, and potentially for
MPS III. Strategies for enzyme replacement therapy
are also under development for MPS IV and VII[34] as
well as for Niemann-Pick disease.
Until now, one of the main problems in enzyme
replacement therapy remains crossing the blood-brain
barrier in diseases with brain involvement.
Additional "new" options for future therapy in patients
with lysosomal storage disorders, but also other inborn
errors of metabolism, are inhibition of substrate synthesis
(currently investigated for glycosphingolipidoses),
chaperon-mediated
enzyme
enhancement,
liver
repopulation, transplantation of stem cells of various
specificity and gene therapy (Table 5).[32,35-37] All these are
currently matters of intensive research.
175
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Received March 9, 2006
Accepted after revision June 16, 2006