Organic Acidemias

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Organic Acidemias

A spectrum of disorders characterized by enzymatic defects in biochemical pathways leading to toxic accumulations of molecules normally metabolized and safely excreted from the body.

Numerous types of organic acidemias exist, with methylmalonic aciduria, propionic acidemia and isovaleric acidemia among the most prevalent forms.  In aggregate, these diseases are categorized into five groups:  branched chain organic acidemias, multiple carboxlase deficiencies, glutaric acidurias, fatty acid oxidation defects and disorders of energy metabolism.

Mutations in the DNA sequences of the enzymes in these pathways may lead to either complete absence of a protein or reduced protein activity, hence there is a wide spectrum of severity for any given disorder.  Most organic acidemias are inherited in an autosomal recessive fashion, though some X-linked forms have been described.  Afflicted children experience severe mental retardation, require parental nutrition and significant morbidity and mortality from episodes of metabolic decompensation after diagnosis.

 

Presentation

  Although the organic acidemias are comprised of many distinct entities, most of these disorders present in a non-specific fashion.  Most pregnancies proceed without complication and the newborn period is normal.  In some cases, neonates may experience hypotonia, seizures or sudden death within the first week of life.  More typically, a few weeks or months after birth children start to experience vomiting, lethargy, poor feeding and hypotonia.  An anion gap metabolic acidosis is usually present, however the blood pH can be normal or even alkalotic.  Of note, this typical presentation may be mistaken for sepsis, and the resulting delay in diagnosis can lead to significant negative repercussions.  Treating the present symptoms immediately is imperative and should not be delayed while the precise diagnosis is identified.

As some of these organic acidemias are screened for in newborn testing, it is possible that an afflicted child may be identified while still in the asymptomatic period.  Other indications of an organic acidemia include the presence of persistent acidemia despite normal tissue perfusion, a persistent respiratory alkalosis, suggesting underlying hyperammonemia, as well as other clues such as the characteristic sweet odor in Maple Syrup Urine Disease or the sweaty feet odor in Isovaleric Acidemia.  There may be a family history of children dying shortly after birth for unknown reason.  In some cases, children with milder forms of disease may present later in infancy or within the first years of life with failure to thrive, seizures, abnormal behavior and eye-glazing. 

Children with these disorders are subject to episodes of decompensation and encephalopathy throughout their lives.  These events can be triggered by a concurrent illness, infection, surgery, prolonged fasting or other traumatic event, but this is not a requirement.  Any condition promoting a catabolic state may lead to a decompensation.  Profound neurological sequelae may result, therefore immediate treatment is critical.  Clinical signs as well as laboratory data may indicate impending decompensation, with the former often more helpful than the latter.  Behavior changes are often the first and most important sign, with plasma ammonia levels and the presence of urine ketones being helpful objective measures.  Parents need to be educated about the symptoms of decompensation as they know the habits of their children better than health care providers and can play an invaluable role in detecting decompensation early on in the disease course.   For children with severely diminished levels of activity, parents may wish to perform daily urine tests to pick up on signs of imminent metabolic derangement.

While the organic acidemias are generally thought of as disorders of babies, not all disease states arise as a result of genetic inheritance.  Methylmalonic aciduria may arise later in life as a consequence of vitamin B12 (cobalamin) deficiency.  Dietary deficiency (seen in malnourished patients and vegetarians) as well as impaired absorption of B12 (pernicious anemia) are common causes.

 

Management

As with their presentation, the initial management of the organic acidemias is non-specific.  Intravenous hydration (oral hydration may be impossible due to vomiting) and labs to determine the presence of metabolic abnormalities such as changes in levels of electrolytes, blood pH, ammonia, glucose,  urea, and lactate, with their subsequent correction are the initial steps of therapy.  If levels of toxic metabolites are exceedingly high, dialysis may be used.  If the patient's condition was triggered by another disease process, such as an infection, this will need to be treated as well. 

A low-protein diet should be implemented after therapy has been initiated.  The amount of protein should be progressively further weaned in that first week in order to establish the minimum amount of protein necessary for growth and subsequently kept at this level.  Amino acids involved in the defective metabolic pathways should be excluded from these diets.  Fortifying the diet with other molecules can be helpful.  Certain vitamins used as co-factors in biochemical reactions may be supplemented to enhance the activity of these metabolic pathways.  Carnitine levels are often decreased in organic acidemia, therefore supplementing the diet with this molecule helps promote excretion of toxic substances normally conjugated to acylcarnitine.  Carglumic acid is given to help correct the hyperammonemia often present in methylmalonic aciduria and propionic acidemia, by increasing levels of carbamoyl phosphate synthetase I.

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References

  1. Bodamer, Olaf A. "Organic Acidemias." UpToDate Inc. 28 Jan. 2011. Web. 25 Sept. 2011. <http://www.uptodate.com/contents/organic-acidemias?source=search_result>.
  2. Leonard, Jv, and Aam Morris. "Inborn Errors of Metabolism around Time of Birth." The Lancet 356.9229 (2000): 583-87. Web.
  3. Archives of Disease in Childhood 76.6 (1997): 555-56. Web.

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