OOA (Old Order Amish)

MEN (General Swiss-German Mennonites)

Inheritance: autosomal recessive
Genes: PCCA

PCCB

Hyperglycinemia with ketoacidosis and leukopenia
Ketotic glycinemia
Ketotic hyperglycinemia
PCC deficiency
PROP
Propionyl-CoA carboxylase deficiency

Dilated cardiomyopathy
Ketotic hyperglycemia
Lethargy
PCC deficiency
Weight loss
Weak muscle tone
Poor feeding
Acidosis
Ketosis
Ketonuria

Propionic Acidemia

Clinical Characteristics

General description (for patients):

This is a metabolic disorder resulting from a defect in an enzyme needed to process amino acids as well as some fatty acids from the diet. The symptoms result from an accumulation of organic acids in the blood, urine, and tissues which at toxic levels cause serious health problems. It commonly becomes apparent within a few days after birth with symptoms of poor feeding, vomiting, loss of appetite, weak muscle tone, and general listlessness. Seizures, coma, and possibly death can follow if not diagnosed and treated promptly. Susceptibility to infection is common. These symptoms can also present much later.  Heart disease in young adults is a risk that requires monitoring. Some affected children may have mental retardation or delayed development.  In children with this later-onset form of the condition, events of more serious health problems can be triggered by prolonged periods without food (fasting), fever, or infections. Outcome is enhanced by diagnosis in the first ten days of life.

Medical description: 

A defect in propionyl-CoA carboxylase results in this amino acid disorder and the ketoacidosis which may be life-threatening within days following birth. It should not be confused with glycinuria which can present with similar symptoms. Prompt diagnosis and treatment with vigorous alkali therapy and protein restriction is essential. The diagnosis should be suspected when the metabolic profile shows glycinemic ketosis, ketotic hyperglycinemia, and high ammonia levels. High levels of propionic acid can have a cascading effect by reacting with oxaloacetate to form methylcitrate which impairs the citric cycle as well. Methylcitrate can also be useful in prenatal diagnosis when found in the amniotic fluid. The diagnosis can be aided by serum electrolyte measurements, and by assaying urinary organic acid levels. Neutropenia, periodic thrombocytopenia, hypogammaglobulinemia, intolerance to protein, hyperglycinuria and susceptibility to recurrent infections are often seen. Leukocyte propionyl-CoA carboxylase activity can also be measured and biotin enhances this activity, at least in vitro. Periodic EKG and echocardiography are recommended in all patients because of the frequency of prolonged Q-T intervals and decreased left ventricular contractility.
A significant number of individuals are asymptomatic throughout life in spite of having documented metabolic abnormalities characteristic of the disease.  Dilated cardiomyopathy is an uncommon feature in young adults who were previously healthy without childhood symptoms.

Genetics:

This autosomal recessive disorder is caused by mutations in the PCCA and PCCB genes found on the long arm of chromosomes 3 and 13 (13q32, 3q21-q22).The PCCA and PCCB genes are responsible for synthesising two parts (subunits) of an enzyme called propionyl-CoA carboxylase. Mutations in PCCB (1606A>G) have been identified in the Lancaster County, Pennsylvania, Amish. According to unpublished information, this diagnosis has been made in at least one child in an Indiana Amish community in which family members recall similarly affected children as long as 70 years ago. Propionic acidemia also occus with high frequency in Saudi Arabia where it is clinically more severe.

Treatment:

Treatment strategies usually include dietary restriction of precursor amino acids and by the use of adjunctive compounds to either dispose of toxic metabolites or increase the activity of the deficient enzymes. Metabolic acidosis must be vigorously managed. In this condition intermittent administration of non-absorbed antibiotics is employed to reduce the production of propionate by gut bacteria. Regular monitoring of growth, development, and biochemical parameters is essential. Commercially available protein supplement formulas are available to restrict the four amino acids (isoleucine, valine, threonine, and methionine) whose breakdown leads to proprionate production. As these are essential amino acids, they must be carefully added and closely monitored.  

Prognosis:

This condition can be lethal in the untreated condition. Developmental and growth retardation, sepsis, bleeding, and optic nerve atrophy are risks. Prompt diagnosis, vigorous treatment, and careful, long-term monitoring are essential.

Ancillary treatments and support:

Careful monitoring of diet and developmental milestones.

Specialists and specialty centers:

Nutritionist, Pediatrician, Cardiologist, Neurologist.

References: 

Kidd, J.R ., Wolf, B., Hsia, E., and Kidd, K.K.:  Genetics of propionic acidemia in a Mennonite-Amish kindred.  Am. J. Hum. Genet. 32: 236-245, 1980. PubMed ID: 7386459

Dionisi-Vici, C., et al.:  'Classical' organic acidurias, propionic aciduria, methylmalonic aciduria and isovaleric aciduria: long-term outcome and effects of expanded newborn screening using tandem mass spectrometry.  J. Inherit. Metab. Dis. 29: 383-389, 2006.  PubMed ID: 16763906

Deodato, F., et al.:  Methylmalonic and propionic aciduria.  Am. J. Med. Genet. Semin. Med. Genet. 15: 104-12, 2006. PubMed ID: 16602092

Ando, T., Rasmussen, K., Wright, J.M., and Nyhan, W.L.:  Isolation and identification of methylcitrate, a major metabolic product of propionate in patients with propionic acidemia.  J. Biol. Chem. 247: 2200-2204. PubMed ID: 5016650

Sweetman, L., Weyler, W., Shatai, T., Young, P.E., and Nyhan, W.L.: Prenatal diagnosis of propionic acidemia.  J.A.M.A. 242: 1048-1052, 1979. PubMed ID: 470045

Resources:

Organic Acidemia Association

Associated Graphics