Organic Acidemia Metabolic Disorders

(MHBD) 2-Methyl-3-Hydroxybutyrl CoA Dehydrogenase deficiency

(2MBCD) 2-Methylbutyryl-CoA Dehydrogenase Deficiency

(HMG) 3-hydroxy-3 -methylglutaryl-CoA lyase deficiency

(3-MCC) 3-methylcrotonyl- CoA carboxylase deficiency

(MGA) 3-Methylglutaconic acidemia or 3-Methylglutaconyl-CoA Hydratase Deficiency

5-oxoprolinemia

(D2-HGA) D-2 Hydroxyglutaric Aciduria

(GA-I) Glutaryl CoA Dehydrogenase Deficiency Type I aka Glutaric Acidemia Type I

(ICBD) Isobutyryl-CoA Dehydrogenase Deficiency 3-Hydroxyisobutyric aciduria

(IVA) Isovaleryl CoA Dehydrogenase Deficiency aka Isovaleric Acidemia

(L2HGA) L-2-Hydroxy- glutaricaciduria

(MA) Malonyl-CoA Decarboxylase Deficiency aka Malonic Acidemia

(MMA) Methlymalonic Acidemia

(BKT) Mitochondrial Acetoacetyl CoA Thiolase- (3-Ketothiolase)

(MCD, holocarboxylase synthetase) Multiple carboxylase deficiency

(PA) Propionyl CoA Carboxylase Deficiency aka Propionic Acidemia

(HIBCH) 3-Hydroxyisobutyryl-CoA Hydrolase Deficiency

What Are Organic Acidemias?

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.

  1. 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

  2. Evaluation

    Once you suspect the possibility of an IEM, how should it be evaluated? There are 5 parts to the evaluation of an IEM.

    1. 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.

    2. 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
  3. 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.
    1. 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.

    2. 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.

  4. Stabilization

    The basic principles for treatment of the acute inborn errors are:

    1. 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.
    2. Limit the intake of the offending substance - if possible, through manipulation of the diet.
    3. 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.
    4. 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.
    5. 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.

  5. 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.

  6. 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).