Contents
Methylmalonic acidemia (MMA) and propionic acidemia (PA) are rare, autosomal recessive, multisystemic inborn errors of branched chain amino acid metabolism which cause significant morbidity and mortality in infancy and childhood, and, for survivors, significant debilitating end-organ damage into adulthood.
Etiopathogenesis
Inborn errors of metabolism (IEM) affecting enzymes and/or transport proteins required for catabolism of amino acids (AAs), lipids, or carbohydrates lead to pathologic buildup of upstream substrates/metabolites resulting in the clinical manifestations of organic acid disorders (OADs), also known as organic acidemias or acidurias.
MMA and PA, as organic acidopathies (OAs), result in defective mitochondrial metabolism of coenzyme A (coA)-activated carboxylic acids, which are largely derived from the metabolism of branched-chain amino acids, odd-chain fatty acids, and cholesterol. Clinical features of OAs may occur due to accumulation of toxic metabolites, altered mitochondrial energy metabolism, carnitine depletion, and coenzyme A sequestration.
Presentation
PA and MMA classically present in a term neonate within the first 3 days of life, who feeds poorly, is pancytopenic, becomes progressively encephalopathic, and ultimately progresses to coma and death without prompt identification and management
Acute illness:
- Metabolic acidosis
- Acute alterations of consciousness or encephalopathy
- Aanorexia
- Nausea and vomiting
Chronic complications:
Because normal mitochondrial function requires sufficient energy production through the citric acid cycle and oxidative phosphorylation, MMA and PA result in multi-systemic chronic disease, particularly in the highly energetic organs such as brain, heart, kidney, and eye. End-organ injury occurs due to both primary toxicity of both the accumulating primary and secondary metabolites and deficiency of succinyl-CoA resulting in Kreb cycle and oxidative phosphorylation dysfunction. Periods of acute illness frequently chronically worsen the patient’s basal condition due to increased energetic dysfunction.
- Poor growth
- Movement disorders, progressive spastic quadraparesis, epilepsy
- Cardiac dysfunction (PA>MMA)
- Progressive renal disease (MMA)
- Osteopenia/osteoporosis
- Vision loss (MMA>PA)
- Functional immunodeficiency
Case study:
Diagnosis
Diagnosis typically occurs during an initial decompensation event in the neonatal period, which may resemble neonatal sepsis and present with poor feeding, vomiting, lethargy, and progression to coma and death without prompt and effective therapy.
Expanded newborn metabolic screening (NMS)
Workup for intoxication-type inborn errors of metabolism (IEM) should occur immediately upon clinical indication and include the following:
- Blood gas (non-capillary)
- Comprehensive metabolic panel
- Complete blood count (CBC)
- Blood culture
- Urinalysis (specifically for urine ketones, which should be negative in a healthy newborn without and IEM)
- Lactate, ammonia
- Urine organic acids
- Plasma amino acids
- Acylcarnitine profile
Diagnosis is based on clinical presentation and laboratory analysis, metabolic acidosis, ketoacidosis, lactic acidosis, hyperammonemia, hypoglycemia, pancytopenia, and elevated C3 acylcarnitines and organic acids in the urine.
Differential diagnosis:
- Sepsis
- Hypoxic-ischemic encephalopathy (HIE)
- Drug intoxication (from maternal exposure before and/or during delivery)
- Other inborn errors of metabolism
Management
Optimal metabolic control and regular monitoring is key to long-term management and prevention of morbidity, disability and mortality.
Dietary Management:
The primary dietary goal in OA patients should remain prevention of catabolism and allow normal growth, without causing obesity. Thus, providing sufficient protein, preferably from natural protein sources with as little amino acid-deficient protein from medical foods as possible, is preferred. Coordination with a metabolic dietician is strongly recommended to ensure that nutritional and amino acid deficiencies are prevented, and future prospective studies on the safety and efficacy of medical foods for OAs should occur to ensure that iatrogenic secondary effects are prevented in this already vulnerable population.
- Dietary protein restriction
- Medical supplementation:
- Carnitine supplementation: Prevent secondary carnitine deficiency (L-carnitine, enterally administered at 50–100mg/kg/day)
- Hydroxocobalamin daily injections: Indicated in B12 responsive MMA (cblA disease)
Acute Metabolic Decompensation
Patients with OAs may become very ill from otherwise mild viral illnesses, and other events that cause physical or emotional stress may trigger catabolism, including surgical procedures, labor and childbirth, and abrupt changes in nutritional status. Reversal of catabolism, promotion of anabolism and identification and treatment of the underlying precipitating etiology are paramount to management of the acute decompensation.
- Removing all source of protein
- Dextrose containing fluids (reversal of catabolism): Glucose infusion (rate of 6–8 mg/kg/min)
- Intralipids (2–3 grams/kg/day)
Acute Metabolic Decompensation:
Patients with OAs may become very ill from otherwise mild viral illnesses, and other events that cause physical or emotional stress may trigger catabolism, including surgical procedures, labor and childbirth, and abrupt changes in nutritional status. Aggressive acute management of intercurrent illness and mitigation of other stressors must be undertaken to limit the degree of decompensation and sequelae from these events. Reversal of catabolism, promotion of anabolism and identification and treatment of the underlying precipitating etiology are paramount to management of the acute decompensation.
With intercurrent illness, PA and MMA patients typically present with nausea and vomiting, worsening anorexia, and encephalopathy, with laboratory studies demonstrating metabolic acidosis, ketonuria, hyperammonemia, pancytopenia, and electrolyte disturbances. These decompensation events typically present with decreased oral intake or enteral feeding intolerance, vomiting, and altered mental status or lethargy.
- Aggressive reversal of catabolism:
- IV dextrose-containing fluids
- Intralipid: Additional caloric support
- Ammonia scavenging therapy:
- Sodium phenylacetate-sodium benzoate (Ammonul): Allow conjugation of amino acids to the scavenger compounds to bypass the urea cycle and permit excretion
- N-carbamylglutamate (Carbaglu): Disinhibiton of urea cycle function
Once catabolism has been reversed and acidosis corrected, complete nutrition should be reinitiated as soon as possible, preferably via the enteral route. Once the precipitating source is identified and treated or managed, the patient may be transitioned back to standard diet.
Chronic Management and Screening Recommendations:
Optimal management of individuals with MMA and PA includes careful dietary management and regular screening for known complications of the OAs
Organ transplant:
Some individuals have received liver transplants to treat PA and liver, kidney, or combined liver-kidney to metabolically stabilize MMA and/or address the chronic renal failure associated with MMA disease