PCCA and PCCB genes
Also known as: Propionyl-CoA carboxylase deficiency; PCC deficiency; Glycinemia, ketotic; Hyperglycinemia with ketoacidosis and leukopenia; Ketotic hyperglycinemia
OMIM#606054 https://omim.org/entry/606054
1. The disease
Propionic acidemia (PA) is an organic aciduria caused by the deficient activity of the propionyl Coenzyme A carboxylase and is characterized by life threatening episodes of metabolic decompensation; neurological dysfunction and that may be complicated by cardiomyopathy.
2. The Symptoms
The spectrum of propionic acidemia (PA) ranges from neonatal-onset to late-onset disease. Lack of early signs or symptoms does not exclude the diagnosis.
- Neonatal-onset PA: the most common form, is characterized by a healthy newborn with poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Without prompt diagnosis and management, this is followed by progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death. It is frequently accompanied by metabolic acidosis with increased anion gap, lactic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias.
- Late-onset PA: may remain asymptomatic and suffer a metabolic crisis under catabolic stress (e.g., illness, surgery, fasting) or may experience a more insidious onset with the development of multiorgan complications including vomiting, protein intolerance, failure to thrive, hypotonia, developmental delays or regression, movement disorders, or cardiomyopathy.
- Isolated cardiomyopathy can be observed on rare occasion in the absence of clinical metabolic decompensation or neurocognitive deficits.
Manifestations of neonatal and late-onset PA over time can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, and cardiomyopathy. Other rarely reported complications include optic atrophy, hearing loss, premature ovarian insufficiency, and chronic renal failure.
3. Actions to take in case of early diagnosis
- Babies with a positive genetic test (having 2 pathogenic variants or 2 copies of a single pathogenic variant in one of the gene referred above).
- Babies should continue breastfeeding, avoid fasting or high-protein baby formulas.
- Early treatment is essential in preventing chronic symptoms.
- Biochemical correlation is essential for confirming diagnosis with analysis of organic acids in plasma and/or urine by gas-liquid chromatography and mass spectrometry (elevated 3-hydroxypropionate and the presence of methylcitrate, tiglylglycine, propionylglycine, and lactic acid). Biochemical NBS with tandem mass spectrometry can also help (can show increased propionylcarnitine – C3 and ratios). Plasma acylcarnitine and amino acid profile (high glycine) is also an important tool to diagnosis.
- PA is a lifelong disease that requires lifetime management and regular follow-up with a metabolic physician and dietician, a part from a multidisciplinary approach to care.
- Critically ill individuals must be stabilized by restoring volume status and acid-base balance; reducing or eliminating protein intake; providing increased calories via high glucose-containing fluids and insulin to arrest catabolism; and monitoring serum electrolytes and ammonia, venous or arterial blood gases, and urine output.
- Management includes a high-calorie diet low in propiogenic amino acid precursors; hydroxocobalamin intramuscular injections; carnitine supplementation; antibiotics such as neomycin or metronidazole to reduce propionate production from gut flora; gastrostomy tube placement as needed; and aggressive treatment of infections.
- Other therapies used in a limited number of patients include N-carbamylglutamate for the treatment of acute hyperammonemic episodes; liver, kidney, or combined liver and kidney transplantation.
- Genetic counseling is highly recommended for family planning and evaluation of at-risk family members such as siblings.