Methylmalonic Acidemia
Overview
Plain-Language Overview
Methylmalonic acidemia is a rare genetic disorder that affects the body's ability to break down certain proteins and fats. This condition causes a buildup of methylmalonic acid in the blood, which can be harmful. Symptoms often appear in early infancy and may include poor feeding, vomiting, lethargy, and developmental delays. Without proper management, it can lead to serious complications such as metabolic crises and damage to the brain and other organs. Treatment focuses on managing symptoms and preventing the accumulation of toxic substances.
Clinical Definition
Methylmalonic acidemia is an autosomal recessive inborn error of metabolism characterized by a deficiency in the enzyme methylmalonyl-CoA mutase or defects in adenosylcobalamin synthesis, leading to impaired conversion of methylmalonyl-CoA to succinyl-CoA. This results in the accumulation of methylmalonic acid and other toxic metabolites in the blood and urine. Clinically, it presents with metabolic acidosis, ketosis, hyperammonemia, and neurological manifestations such as developmental delay, hypotonia, and seizures. The disorder can manifest in neonatal or late-onset forms, with the former being more severe. Laboratory findings include elevated methylmalonic acid levels, metabolic acidosis with an increased anion gap, and secondary hyperglycinemia. Genetic mutations in the MUT gene or genes involved in cobalamin metabolism (e.g., MMAA, MMAB) are responsible. Management requires early diagnosis and intervention to prevent metabolic decompensation and long-term complications such as chronic kidney disease and neurological impairment.
Inciting Event
- Metabolic stress such as infection, fasting, or high protein intake can precipitate acute metabolic decompensation.
- Administration of cobalamin in responsive forms may temporarily improve symptoms.
- None in cases of severe enzyme deficiency where symptoms are present from birth.
Latency Period
- Symptoms typically manifest within the first few days to weeks of life after birth.
Diagnostic Delay
- Nonspecific early symptoms such as poor feeding and vomiting can mimic common neonatal illnesses, delaying diagnosis.
- Lack of routine newborn screening in some regions contributes to delayed recognition.
- Variable biochemical presentation and overlap with other organic acidemias complicate early diagnosis.
Clinical Presentation
Signs & Symptoms
- Poor feeding and vomiting in neonates.
- Lethargy and hypotonia are common early signs.
- Development of metabolic acidosis with rapid breathing.
- Delayed developmental milestones and failure to thrive.
- Episodes of encephalopathy during metabolic crises.
History of Present Illness
- Neonate or infant presents with poor feeding, vomiting, and lethargy.
- Episodes of metabolic acidosis with hyperammonemia and hypoglycemia may occur.
- Development of hypotonia, seizures, and failure to thrive are common in untreated cases.
Past Medical History
- Previous episodes of unexplained metabolic acidosis or neurologic symptoms may be present.
- History of poor growth or developmental delay in older infants or children.
- No significant past medical history in newborns presenting acutely.
Family History
- Positive family history of methylmalonic acidemia or other organic acidemias.
- Consanguinity or affected siblings increases suspicion for inherited metabolic disorder.
- Carrier status may be identified in parents through genetic testing.
Physical Exam Findings
- Patients may exhibit hypotonia and poor muscle tone.
- There can be signs of dehydration such as dry mucous membranes and decreased skin turgor.
- Some patients show hepatomegaly due to metabolic stress.
- Neurologic exam may reveal lethargy or altered mental status.
Diagnostic Workup
Diagnostic Criteria
Diagnosis of methylmalonic acidemia is confirmed by detecting elevated levels of methylmalonic acid in plasma and urine using mass spectrometry. Additional laboratory findings include metabolic acidosis with an increased anion gap, ketosis, and hyperammonemia. Enzymatic assays demonstrating deficient methylmalonyl-CoA mutase activity or genetic testing identifying pathogenic mutations in the MUT gene or related cobalamin metabolism genes support the diagnosis. Newborn screening programs often detect elevated propionylcarnitine, prompting further confirmatory testing.
Pathophysiology
Key Mechanisms
- Methylmalonic acidemia results from a deficiency of the enzyme methylmalonyl-CoA mutase or defects in its cofactor, adenosylcobalamin, leading to accumulation of methylmalonic acid.
- The buildup of toxic organic acids causes metabolic acidosis and disrupts normal cellular metabolism.
- Impaired conversion of methylmalonyl-CoA to succinyl-CoA interferes with the Krebs cycle, reducing energy production.
| Involvement | Details |
|---|---|
| Organs | Kidneys are involved in excreting excess organic acids and can suffer damage from their accumulation. |
| Central nervous system is affected by neurotoxicity from elevated methylmalonic acid causing developmental delay and encephalopathy. | |
| Tissues | Liver tissue is critical for metabolism of amino acids and organic acids affected in methylmalonic acidemia. |
| Brain tissue is vulnerable to damage from toxic metabolite accumulation leading to neurological symptoms. | |
| Cells | Hepatocytes are primary cells involved in metabolism of methylmalonic acid and are affected in this disorder. |
| Renal tubular cells participate in excretion of organic acids and can be damaged by their accumulation. | |
| Chemical Mediators | Methylmalonic acid accumulates due to enzyme deficiency and causes metabolic acidosis and toxicity. |
| Propionic acid is a related organic acid that also accumulates and contributes to metabolic disturbances. |
Treatment
Pharmacological Treatments
Vitamin B12 (cobalamin)
- Mechanism: Serves as a cofactor for methylmalonyl-CoA mutase, reducing methylmalonic acid accumulation
- Side effects: Injection site pain, allergic reactions
Carnitine supplementation
- Mechanism: Enhances excretion of toxic organic acids by forming acylcarnitines
- Side effects: Gastrointestinal upset, fishy body odor
Non-pharmacological Treatments
- A protein-restricted diet limits intake of propiogenic amino acids to reduce toxic metabolite production.
- Emergency management includes intravenous glucose to prevent catabolism during metabolic crises.
- In severe cases, dialysis may be used to remove accumulated organic acids rapidly.
Prevention
Pharmacological Prevention
- Administration of hydroxocobalamin to improve enzyme function in responsive cases.
- Use of carnitine supplements to enhance excretion of toxic metabolites.
- Oral antibiotics like metronidazole to reduce propionate-producing gut flora.
Non-pharmacological Prevention
- Dietary restriction of protein intake to limit precursor amino acids.
- Avoidance of fasting to prevent catabolic states.
- Early newborn screening for prompt diagnosis and management.
Outcome & Complications
Complications
- Metabolic stroke causing permanent neurologic damage.
- Severe metabolic acidosis leading to multi-organ failure.
- Pancreatitis due to metabolic derangements.
- Progressive renal failure.
| Short-term Sequelae | Long-term Sequelae |
|---|---|
|
|
Differential Diagnoses
Methylmalonic Acidemia versus Isovaleric Acidemia
| Methylmalonic Acidemia | Isovaleric Acidemia |
|---|---|
| Elevated methylmalonic acid without characteristic odor. | Elevated isovaleric acid in blood and urine. |
| No deficiency of isovaleryl-CoA dehydrogenase enzyme. | Characteristic sweaty feet odor due to isovaleric acid accumulation. |
| Absence of sweaty feet odor in clinical presentation. | Deficiency of isovaleryl-CoA dehydrogenase enzyme. |
Methylmalonic Acidemia versus Multiple Carboxylase Deficiency
| Methylmalonic Acidemia | Multiple Carboxylase Deficiency |
|---|---|
| Normal biotin-dependent carboxylase activity with isolated methylmalonic acid elevation. | Deficiency of biotin-dependent carboxylases including pyruvate carboxylase. |
| Absence of skin rash and alopecia. | Presence of skin rash and alopecia due to biotin deficiency. |
| Elevated methylmalonic acid without elevation of 3-hydroxyisovaleric acid. | Elevated 3-hydroxyisovaleric acid and other organic acids in urine. |
Methylmalonic Acidemia versus Propionic Acidemia
| Methylmalonic Acidemia | Propionic Acidemia |
|---|---|
| Elevated methylmalonic acid in blood and urine. | Elevated propionic acid levels in blood and urine. |
| Deficiency of methylmalonyl-CoA mutase or vitamin B12 metabolism defect. | Deficiency of propionyl-CoA carboxylase enzyme activity. |
| Normal or mildly elevated propionic acid levels compared to methylmalonic acid. | Presence of ketonuria with metabolic acidosis and hyperammonemia. |