Organic
Acidaemias are a group of inheritable genetic metabolic disorders
in which there is a defect in protein metabolism where an essential
enzyme is absent or malfunctioning. This defect results in
a build up of chemicals, in this case usually acids, on one
side of the metabolic blockage and a deficiency of vital chemicals
on the other. This causes an overdosage of one chemical (often
toxic) and the shortage of another which is essential to normal
body functioning.
The effect of the disorder will depend upon the age at which
symptoms occur. Children with less severe forms of the conditions
develop symptoms later.
Characteristics of the conditions include general malaise,
reluctance to feed, breathing problems, vomiting, hypotonia
(floppiness) and/or spasticity (stiffness).
Early detection and treatment can greatly mitigate the effects
of the disorder.
Inheritance patterns
Autosomal recessive
Pre-natal diagnosis
Chorionic villus sampling at 8-10 weeks is now the usual method of testing.Maple
Syrup Urine Disease can also be identified where DNA testing, prior to pregnancy,
was informative. Amniocentesis at 16-20 weeks is also sometimes used.
Due to the increasing number of conditions identified
as coming under the umbrella of Organic Acidaemias, it is
not possible to include them all in this entry. They can
now be found listed individually in the index and are updated
regularly. Where there is an alternative parent support network
for individual conditions this is indicated.
METABOLISM is the means by which the body derives energy and
synthesizes the other molecules it needs from the fats, carbohydrates
and proteins we eat as food, by enzymatic reactions helped
by minerals and vitamins. This global statement masks the complicated
network of enzyme- catalyzed reactions that occurs in cells.
Although this page is devoted to diseases caused by errors
in metabolic processes, there is actually a significant level
of tolerance of errors in the system: often, a mutation in
one enzyme does not mean that the individual will suffer from
a disease. A number of different enzymes may compete to modify
the same molecule, and there may be more than one way to achieve
the same end result for a variety of metabolic intermediates.
Disease will only occur if a critical enzyme is disabled, or
if a control mechanism for a metabolic pathway is affected.
Here, we highlight the diseases of metabolism for which a gene
has been identified, cloned and mapped. Many of these are inborn
errors of metabolism: inherited traits that are due to a mutation
in a metabolic enzyme; others involve mutations in regulatory
proteins and in transport mechanisms.
Infants presenting acutely with an inborn error of metabolism
(IEM) frequently remain undiagnosed until late in the course
of their illness. Delay in the recognition and treatment of
an IEM may have tragic consequences. Unfortunately, the acute
presentation of an IEM often resembles more common disorders
such as sepsis.
Incidence of IEM
The cumulative incidence of IEM is about 1/5000 live births.
This is equivalent to the incidence of juvenile diabetes mellitus.
It has been estimated that 20% of infants presenting with a "sepsis" picture
in the absence of risk factors (such as prematurity, chorioamnionitis,
etc.) have an IEM.
General Concepts
In spite of the variety of disorders and the different phenotypes
described, some generalizations can be made. A generic metabolic
pathway might take substrate A and convert it to a product,
C:
A -----> B -----> C
If there is a block in the conversion of B to C, then an alternative
pathway may be activated:
A -----> B --//--> C | | D -----> E
The specific metabolic effect of a given enzymatic block may
be through the effect of increased precursors (A and B), the
lack of the product (C), or the presence of increased amounts
of alternate products (D and E). Because the amount of enzymatic
block, activity of alternate pathways, and endogenous production
of precursors can differ between patients, the phenotype for
a given disorder can be quite variable. Anything that causes
an increased metabolic flux through the defective pathway can
result is clinical deterioration (i.e. a metabolic crisis).
The largest source of many metabolites is from endogenous catabolism
rather than from exogenous sources. Factors that increase catabolism
such as illness, fever, and starvation make many IEM much worse.
Classification of IEM
There are many classification schemes for IEM, all with their
own limitations. One popular scheme divides IEM into three
categories: cellular intoxication, energy deficiency, and mixed
types. Disorders with cellular intoxication exert their effect
by poisoning cells with excess precursors or alternate products.
The cellular intoxication category is usually divided into
small molecule disorders (eg. amino and organic acidurias)
and large molecule disorders (eg. storage diseases). The small
molecule disorders may be further subdivided by two types of
clinical presentation: an insidious effect with few to no acute
crises; and a chronic effect punctuated by acute metabolic
decompensations, often brought on by illness and increased
catabolism. The energy deficient disorders exert their effects
by depriving cells of the energy they need to function properly
(eg. mitochondrial and fatty acid oxidation disorders). While
many people would place disorders such as peroxisomal diseases
in the energy deficiency category, there is also a component
of cellular intoxication, so they may best be placed in a mixed
category.
- Suspicion
An important key to diagnosing an IEM is thinking about
the possibility in the first place. The symptoms and
signs that should make you think about an IEM are common
and nonspecific:
- Acute illness following a period of normalcy
- Lethargy and coma
- Hypotonia, seizures (especially if hard to control),
intractable hiccups
- Apnea or respiratory distress
- Sepsis, particularly with E. coli
- Unusual odor
- Jaundice
- Dysmorphic features
- Organomegaly
- Positive family history or parental consanguinity
- Evaluation
Once you suspect the possibility of an IEM, how should
it be evaluated? There are 5 parts to the evaluation
of an IEM.
- History, Family History
The history largely focuses around the features
that made you suspicious for an IEM. The neonate
will often be well for 24 hours or more then decompensate.
The slightly older infant may have had episodic
problems associated with minor illnesses or may
just have failure to thrive and developmental delay.
The family history is very important but often
not taken. Most IEM are autosomal recessive, so
there may have been siblings with similar illnesses
or deaths from "sepsis" or "SIDS". The parents
may be consanguineous or come from a genetic isolate
such as a small village in Mexico. There are also
X-linked, and mitochondrial inherited IEM, so a
family history must include information about the
mother's siblings, their children, etc. A pedigree
only containing nuclear family members is inadequate.
- Physical Examination
The physical exam of patients with IEM is usually
normal except for nonspecific findings such as
lethargy, coma, apnea or hyperpnea, seizures, hypotonia,
etc. Physical findings that are important and will
help to narrow the differential diagnosis include:
- facial dysmorphism
- cataracts, retinopathy
- structural brain anomalies
- hypertrophic or dilated cardiomyopathy
- hepatomegaly
- multicystic dysplastic kidneys
- myopathy
An unusual odor can be particularly helpful in
several disorders:
Odor Disorder
musty |
phenylketonuria |
cabbage |
tyrosinemia |
maple syrup |
maple syrup urine disease |
sweaty feet |
isovaleric acidemia, glutaric acidemia type
II |
cat urine |
3-methylcrotonyl CoA carboxylase and multiple
carboxylase deficiencies
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- Initial Screening Tests
The initial evaluation of an acutely ill infant
for an IEM should include:
- CBC - neutropenia is frequent in some organic
acidemias.
- Electrolytes, ABG - to evaluate for acidosis
and anion gap.
- Glucose - hypoglycemia is a feature of many
IEM.
- Ammonia - hyperammonemia is present in urea
cycle abnormalities and some organic acidemias.
Rapidly flowing blood should be obtained and
the sample placed on ice and hand carried to
the lab. The test should be done within 1 hour,
so the lab may need prior notification.
- Uric acid - if neurologic abnormalities are
present, low uric acid is suggestive for molybdenum
cofactor deficiency.
- Urinalysis - the presence of ketones is unusual
even in sick neonates and suggests an organic
acidemia. Clinitest for reducing substances should
be performed*, but should be interpreted carefully
because of a high false positive rate.
* Older tests that may be useful include
ferric chloride for ketoacids (positive
in phenylketonuria, tyrosinemia, maple
syrup urine disease, histidinemia, alkaptonuria,
and in the presence of other substances
such as acetoacetic acid, salicylates,
phenothiazines, antipyrin, isoniazid, and
acetaminophen), and a cyanide nitroprusside
test for disulfides (positive in cystinuria
and homocystinuria).
- Lactate, pyruvate - elevation of lactate is
a frequent secondary finding in many IEM, but
there are primary lactic acidoses due to defects
in energy metabolism. The lactate/pyruvate ratio
(normal < 25) will help to evaluate the possibilities.
It often takes a week to get pyruvate results,
but lactate results should be back quickly. These
tests are notoriously subject to artifactual
changes because of sample collection or handling
errors. Freely flowing blood (usually arterial
or from a line) should be drawn with a minimum
of tourniquet time and muscular action of the
infant. For a lactate and pyruvate measurement,
exactly 1 cc of blood should be injected into
a tube containing 2 ml of cold perchloric acid
(trichloroacetic acid is used at Cedars), shaken
vigorously, and placed on ice. The deproteinized
blood sample should then be hand carried to the
lab. If the blood is placed in a fluoride tube
(as at Cedars for a lactate only) instead of
being deproteinized with perchloric acid, the
lactate will be artifactually elevated 8-23%
depending on the hematocrit. Pyruvate, on the
other hand, is rapidly metabolized (half life
about 10 minutes) if the sample is not deproteinized
at the bedside -- making the results worthless.
- Plasma amino acids - 1-2 cc of blood in a heparin
or EDTA tube, on ice. It is important to draw
this while the patient is ill, not after treatment.
Many abnormalities will disappear when the child
improves and may make the diagnosis difficult.
It may take several days for results.
- Urine organic acids - 10-20 cc of urine, frozen.
The urine may be frozen in aliquots. If the sample
is allowed to sit at room temperature or even
in the refrigerator volatile organic acids may
disappear. It is important to obtain this sample
when the patient is ill. It generally takes several
days for results.
- In addition, freeze 1-2 cc of plasma, 10-20
cc of urine - additional tests may be needed
later, and specimens obtained at the time of
illness are the most valuable.
- Advanced Screening Tests
Numerous other specialized tests are performed
depending on the clinical context. Examples include
carnitine, acylcarnitines, very long chain fatty
acids, lysosomal enzymes, etc. Many of these tests
are done at only one place in the country and it
can take weeks to months to get results. These
tests should generally be ordered after consultation
with Genetics.
- Definitive Diagnostic Tests
A definitive diagnosis may sometimes be made from
screening tests but often specific enzymatic analysis
or DNA testing is required. It may be necessary
to biopsy tissues such as liver or muscle. These
tests, if done at all, are usually done in research
laboratories and it may take months for results.
After you have sent the initial screening tests,
you need to sort out the type of IEM you may be
dealing with. The categories of IEM that may present
in the neonatal period include:
- organic acidemias
- amino acidurias
- urea cycle
- glycogen storage
- lysosomal storage
- peroxisomal
- fatty acid oxidation
- mitochondrial- defects in energy generation
- galactosemia
- nonketotic hyperglycinemia
- molybdenum cofactor deficiency
- Menke's disease
- Lowe's syndrome
This daunting list can be simplified to disorders
presenting with:
- hypoglycemia
- increased anion gap metabolic acidosis
- hyperammonemia without acidosis
- prominent neurologic features
- dysmorphic features
and two important exceptions:
- galactosemia
- phenylketonuria
Before examining algorithms for sorting out these
disorders it is important to realize that all medical
algorithms are imperfect and vary somewhat depending
on who devises them. An important concept is the
pleiotropic effects that some disorders have. A
good example is the organic acid disorder propionic
acidemia. While elevation in propionic acid causes
an anion gap acidosis, there are many other effects
including a functional pyloric stenosis. Some patients
have even gone to surgery for pyloromyotomy in
the past. Propionic acid accumulates in cells in
the form of CoA esters, depleting the pool of CoA.
This results in a deficiency of acetyl CoA, the
substrate for oxidative phosphorylation and an
important regulator of the urea cycle. Secondary
lactic acidosis and hyperammonemia result. Patients
often have hypoglycemia. Propionic acid is also
conjugated to carnitine and excreted in the urine
depleting the body of carnitine. Carnitine depletion
causes a block in the metabolism of fatty acids,
further interrupting energy generation.
- Stabilization
The basic principles for treatment of the acute inborn
errors are:
- Prevent catabolism - the dietary intake of offending
substances is usually a small fraction of the amount
contained within the body. Since cellular proteins
turn over about every 24 hours, an increase in catabolism
due to stress from infection, surgery, birth, etc.
can rapidly overwhelm the compensatory mechanisms and
result in clinical decompensation. Administration of
calories is used in the treatment of acute episodes
to try to slow down catabolism. A poor intake of calories
can contribute to poor metabolic control just as much
as an excessive intake of the offending substance.
- Limit the intake of the offending substance - if
possible, through manipulation of the diet.
- Increase excretion of toxic metabolites - by using
alternative pathways. For example, carnitine is useful
in the elimination of organic acids in the form of
carnitine esters. Sodium benzoate and phenylacetate
are useful in treating hyperammonemia.
- Increase the residual enzyme activity (if possible)
- this is usually accomplished by administration of
pharmacologic doses of the vitamin cofactor for the
defective enzyme. If the binding constant for the vitamin
has been altered and the enzyme is otherwise reasonably
functional, increasing the vitamin concentration will
increase enzyme activity via a mass action effect.
- Transplantation, gene therapy - potentially these
treatments can cure many IEM, but irreversible brain
damage may have occurred before there is an opportunity
to use these therapies.
- Specific Treatment
The specific treatment provided depends a lot on the
particular disorder, but follows the general principles
listed in the section on treatment protocols. Treatment
should be supervised by a IEM specialty team including
a physician, dietician, and social worker. In many respects
these patients are similar to diabetics in terms of the
psychosocial aspects of chronic disease, recurrent hospitalizations,
etc. Dealing with psychosocial issues can be at least
as important as any prescription.
- Genetic Counseling
Since IEM are hereditary in nature, the family should
have formal genetic counseling including prognosis for
the patient, recurrence risk, possibility of prenatal
diagnosis, and screening of other family members (if
appropriate). Female carriers of X-linked recessive disorders
may be at risk for milder forms of the same disease afflicting
their sons (for example, ornithine transcarbamylase deficiency
and X-linked adrenoleukodystrophy).
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