Overview: What every practitioner needs to know

Are you sure your patient has a disorder of branched-chain amino acid metabolism? What are the typical findings for this disease?

Disorders of branched-chain amino acid metabolism include maple syrup urine disease (MSUD) and the organic acidemias isovaleric acidemia (IVA), methylmalonic acidemia (MMA), propionic acidemia (PA), 3-methylcrotonyl carboxylase deficiency (3-MCC) among others. Each of these disorders can have a variable presentation, including metabolic decompensation in the newborn, an acute intermittent illness of later onset in older childhood or even adulthood, or as a chronic neurodevelopmental childhood illness.

The physician needs to maintain a high index of suspicion for these diseases in any presentation of sudden neurologic decompensation to make a proper, timely, and potentially life-saving intervention. Once a diagnosis is made, these patients require lifelong careful dietary and medical management.

Acute and long-term treatment of these patients requires strict dietary management, and involvement of a biochemical geneticist and a genetic nutritionist is required.

In patients with unrecognized disease, clinical crises will lead to death, since they are refractory to symptomatic therapy. The underlying biochemical abnormality must be addressed for successful management.

Key symptoms and signs of MSUD include the following:

Neonatal presentation

The neonatal presentation is often considered to be the “classic” presentation of organic acidemias, although it is imperative to recognize that these diseases can present throughout life.

Several days after birth, infants with organic acidemias may present to the physician or emergency room with a “sepsis-like” picture including vomiting, lethargy, bulging fontanelle, decreased responsiveness, and/or abnormal respirations. These patients can also have pancytopenia, or depression of a single hematopoetic line, further adding to the sepsis-like picture. They have a metabolic acidosis with an anion gap and ketones in the urine.

To distinguish these disorders from sepsis, a blood ammonia and a blood gas determination should be obtained. Hyperammonemia will be present and point toward the correct clinical diagnosis.

MSUD in the neonate can present with a clinical picture similar to that described above; however, routine laboratory testing will be normal, and there are not typically any blood line dyscrasias.

Newborn Screening

Newborn screening for MSUD, IVA, MMA, PA, and 3-MCC deficiency is now available in many states. However, it is important to note that patients may become symptomatic before the results of a newborn screen are available. In addition, patients born outside the United States may not have had a newborn screen, and older patients may have been born before the screening was available. A negative newborn screening result cannot completely rule out these disorders.

What other disease/condition shares some of these symptoms?

Defects in biotin metabolism, holocarboxylase synthetase (HCS) deficiency, and biotinidase deficiency lead to defective functioning of the biotin-dependent enzymes 3-methylcrotonyl CoA carboxylase, acetyl CoA carboxylase, pyruvate carboxylase, and propionyl CoA carboxylase. In HCS deficiency, binding of biotin to the enzymes is defective, whereas in biotinidase deficiency, biotin recycling is impaired.

HCS deficiency can present similarly to organic acidemias in the newborn period or later in life with developmental delay and hair and skin abnormalities. Diagnostic organic acids found in the urine include 3-methylcrotonylglycine, 3-hydroxyisovaleric acid, methylcitrate, propionylglycine, tiglylglycine, and lactate. Carboxylase activity in lymphocytes will also be deficient.

Biotinidase deficiency typically presents in the newborn period, childhood, or adolescence. Features include neurologic abnormalities (developmental delay, low tone, seizures), respiratory abnormalities, and/or skin and hair findings. Often, classic organic acid findings such as seen in HCS deficiency are not present, and only a mild to moderate elevation in 3-hydroxyisovaleric acid is present. Biotin supplementation is the mainstay of treatment. All patients with biotinidase deficiency respond, and many patients with HCS deficiency also respond.

Urea cycle defects can present with metabolic decompensation in the newborn period and later. Relevant laboratory findings include hyperammonemia, and clinical decompensation can be triggered by stress, illness, or fasting.

Generally, early decompensation in urea cycle defects presents with a respiratory alkalosis (due to medulla stimulation of hyperammonemia), and without metabolic acidosis (as opposed to organic acidemias, which present with a metabolic acidosis). However, this principle can be misleading, since later in decompensation there can be tissue stress and tissue death, leading to a lactic acidosis and respiratory depression; less commonly, hyperammonemia in organic acidemias can cause a respiratory alkalosis.

Diseases of fatty acid oxidation can present with metabolic decompensation in the newborn period and later. Relevant laboratory findings can include hyperammonemia, and clinical crises can be triggered by stress, illness, or fasting. However, these episodes are typically hypoketotic or even nonketotic, as opposed to the organic acidemias.

What caused this disease to develop at this time?

Metabolic decompensation can be triggered by any number of stressors, including fasting, dehydration, intercurrent illness, surgery, trauma, high protein intake, or with no apparent trigger at all.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

MSUD is diagnosed by abnormalities in the plasma amino acid profile. Leucine, isoleucine, and valine will all be elevated, and out of their normal proportion to each other. In addition, the plasma amino acid profile contains a pathognomonic metabolite, alloisoleucine, which is only present in MSUD. It is important to note that in MSUD there may be no other abnormalities on routine laboratory testing. Although not necessary for diagnosis, urinary organic acids will show the abnormal ketoacids. 2-Ketoacids can also be detected in the urine by the 2,4-dinitrophenylhydrazine test.

IVA is diagnosed by abnormalities in the plasma acylcarnitine profile and in the urinary organic acids. The urinary organic acids will show elevated isovalerylglycine and 3-hydroxyisovaleric acid, and the plasma acylcarnitine profile will show an elevation in the C5 species. In states of acute crises, routine laboratory testing can reveal hyperammonemia, metabolic acidosis with an anion gap, possible pancytopenia, or depression of a single hematopoetic line.

MMA is diagnosed by abnormalities in the plasma acylcarnitine profile and in the urinary organic acids. Urinary organic acids will show an elevation in methylmalonate and possibly methylcitrate levels, and the plasma acylcarnitine profile will show an elevation in the C3 species. In states of acute crises, routine laboratory testing can reveal hyperammonemia, metabolic acidosis with an anion gap, ketonuria, possible pancytopenia, or depression of a single hematopoetic line. In MMA caused by a cobalamin C defect, there will also be an elevation of homocysteine and low/normal methionine on the plasma amino acid profile.

PA is diagnosed by abnormalities in the plasma acylcarnitine profile and in the urinary organic acids. Urinary organic acids will show elevation in propionylglycine, 3-hydroxypropionate, and methylcitrate levels, and the plasma acylcarnitine profile will show an elevation in the C3 species. In states of acute crises routine laboratory testing can reveal hyperammonemia, metabolic acidosis with an anion gap, ketonuria, possible pancytopenia, or depression of a single hematopoetic line.

3-MCC deficiency is diagnosed by abnormalities in the plasma acylcarnitine profile and in the urinary organic acids. Urinary organic acids will show elevation in 3-methylcrotonylglycine and 3-hydroxyisovalerate, and the plasma acylcarnitine profile will show an elevation in the C5-OH species. In states of acute crises, routine laboratory testing can reveal hyperammonemia, metabolic acidosis with an anion gap, hypoglycemia, and/or very low plasma carnitine levels.

Would imaging studies be helpful? If so, which ones?

If the patient has an organic acidemia and presents with new-onset neurologic abnormalities, magnetic resonance imaging can be useful in determining the occurrence of a “metabolic stroke,” which can show abnormalities in typical areas such as the basal ganglia. However, these studies are not necessary for treatment or diagnosis in the acute state.

In patients with MSUD, computed tomography will aid in the diagnosis of cerebral edema.

If you are able to confirm that the patient has a disorder of branched-chain amino acid metabolism, what treatment should be initiated?

In MSUD, a biochemical geneticist and biochemical nutritionist should be consulted. The patient may require hemodialysis/hemofiltration for extreme elevations of leucine, together with dietary treatment. Oral intake of branched-chain amino acid (BCAA)-free formula should begin early, and supplementation with valine and isoleucine will often be required early in the initiation of the BCAA-free formula, to allow for protein accretion. Once leucine levels are adequately reduced, allowance of some natural protein will be determined to allow for growth and protein accretion. Dietary adjustments are made based on serial plasma amino acid measurements. Care should be taken in aggressive fluid rehydration, which can lead to severe cerebral edema.

In organic acidemias, a biochemical geneticist and biochemical nutritionist should be consulted. The patient will require hemodialysis for extreme elevations of ammonia. Dextrose-containing intravenous fluids should be administered to provide calories and prevent protein catabolism. Bicarbonate may be required to correct acidosis. Administration of L-carnitine and oral L-glycine may aid in the renal excretion of isovalerate in IVA and of 3-methylcrotonic acid in 3-MCC deficiency. Intravenous L-carnitine can be administered in MMA and PA to aid in the renal excretion of these organic acids and to replete cellular carnitine pools. Long-term dietary therapy includes protein restriction, often with special formulas, and should be monitored by a genetic nutritionist and physician.

A certain percentage of patients with MMA will be responsive to vitamin B₁₂ , with improvement of enzyme function with administration of vitamin B₁₂ and consequently easier long-term control of their disease.

What are the adverse effects associated with each treatment option?

Aggressive intravenous fluid rehydration can lead to or worsen cerebral edema in MSUD.

What are the possible outcomes of disorders of branched-chain amino acid metabolism?

Defects of branched-chain amino acid metabolism are lifelong diseases that require chronic management. Constant vigilance is imperative to avoid situations that might lead to decompensation and to ensure prompt intervention when they occur. Long-term outcomes in various organic acidemias include cardiomyopathy, neurologic deficits, pancreatitis, or renal failure.

What causes this disease and how frequent is it?

These are all genetic diseases with autosomal recessive inheritance. There can be variable expressivity, but generally there is complete penetrance. These diseases are individually rare, with an incidence of 1/50,000-1/500,000 in the general population. In certain inbred populations, such as the Mennonite population in Pennsylvania, the rate of MSUD is as high as 1/176 newborns.

How do these pathogens/genes/exposures cause the disease?

These are all genetic diseases with autosomal recessive inheritance.

MSUD is caused by a defect in one of the branched-chain alpha-keto acid dehydrogenase subunits. A buildup of precursors for that enzyme, leucine and alpha ketoisocaproic acid, likely lead to neurotoxicity.

In MMA, PA, IVA, and 3-MCC deficiency, a defect in enzymatic function leads to a buildup of the precursor for that enzyme and a deficiency of the products of that enzyme, both of which contribute to the disease state.

PA is caused by a defect in one of the genes encoding the propionyl-CoA carboxylase subunits.

MMA is caused by a defect in the gene encoding methylmalonyl-CoA mutase or in specific steps of cobalamin synthesis.

IVA is caused by a defect in the gene encoding isovaleryl CoA dehydrogenase.

3-MCC deficiency is caused by a defect in the gene encoding 3-methylcrotonyl-CoA carboxylase.

Other clinical manifestations that might help with diagnosis and management

Some patients with organic acidemias, particularly in 3-MCC deficiency, can present with a Reye syndrome–like picture, which can include liver dysfunction, encephalopathy, cerebral edema, and elevated ammonia.

Other complications of metabolic decompensation in organic acidemias can include cardiomyopathy, pancreatitis, and renal failure. Although these complications tend to occur at later stages of the disease, they also have been known to be initial presenting features.

What complications might you expect from the disease or treatment of the disease?

Complications from a serious crisis in organic acid disorders can include pancreatitis, stroke, pulmonary hemorrhage, and death. If a crisis episode includes hyperammonemia, in general the longer the patient is hyperammonemic and the higher the ammonia level, the worse the cognitive/functional outcome will be.

Are additional laboratory studies available; even some that are not widely available?

In MMA, molecular and “complementation” studies should eventually be carried out in specialized laboratories to determine the type of MMA. MMA can be caused not only by mutations in the MUT enzyme itself but also by defects in cobalamin synthesis. These tests will help determine the genetic basis for the MMA, as well as explain vitamin B
₁₂ responsiveness in some patients.

Confirmatory molecular testing can be done for MSUD by sequencing the genes encoding the branched-chain alpha-keto acid dehydrogenase subunits.

Confirmatory molecular testing can be done for PA by sequencing the genes encoding the propionyl-CoA carboxylase subunits.

Confirmatory molecular testing can be done for certain types of MMA by sequencing genes encoding methylmalonyl-CoA mutase.

Confirmatory molecular testing can be done for IVA by sequencing the gene encoding isovaleryl CoA dehydrogenase.

Confirmatory molecular testing can be done for 3-MCC deficiency by sequencing the genes encoding 3-methylcrotonyl CoA carboxylase.

How can disorders of branched-chain amino acid metabolism be prevented?

These disorders are genetic in nature and autosomal recessive in their inheritance pattern. Although the diseases themselves cannot be prevented in individuals, proper diagnosis in a patient can help in prenatal diagnosis in future offspring of the parents of the patient.

With proper dietary management and avoidance of certain stressors (dehydration, fasting), it is possible to reduce the episodes of neurologic decompensation in these diseases once a diagnosis has been made. It is important to recognize, however, that even the most compliant patients face episodes of metabolic decompensaton, and these episodes do not necessarily have an obvious trigger.

What is the evidence?

Chuang, D, Shih, V, Scriver, C, Beaudet, A, Sly, W. “Maple syrup urine disease (branch chain ketoaciduria)”. The metabolic and molecular basis of Inherited disease. 2001. pp. 1072-2006.

de Baulny, H, Benoist, J, Rigal, O. “Methylmalonic and propionic acidemias: management and outcome”. J Inherit Metab Dis. vol. 28. 2005. pp. 415-23.

Fenton, W, Gravel, R, Rosenblatt, D, Scriver, C, Beaudet, A, Sly, W. “Disorders of propionate and methylmalonate metabolism”. The metabolic and molecular basis of Inherited disease. 2001. pp. 2165-92.

Knerr, I, Weinhold, N, Vockley, J, Gibson, KM. “Advances and challenges in the treatment of branched chain amino/keto acid metabolic defects”. J Inherit Metab Dis. vol. 35. 2012. pp. 29-40.

Levin, M, Scheimann, A, Lewis, R. “Cerebral edema in maple syrup urine disease”. J Pediatr. vol. 122. 1993. pp. 167-8.

Manoli, I, Venditti, CP. “Methylmalonic Acidemia”. "Gene Reviews.". December 18, 2011.

Morton, D, Strauss, K, Robinson, D. “Diagnosis and treatment of maple syrup urine disease: a study of 36 patients”. Pediatrics. vol. 109. 2002. pp. 999-1008.

“Laboratory medicine practice guidelines: Follow up testing for metabolic diseases identified by expanded newborn screening using tandem mass spectrometry.”. June 2, 2011.

Rinaldo, P, Cowan, T, Matern, D. “Acylcarnitine profile analysis”. Genet Med. vol. 10. 2008. pp. 151-6.

Strauss, K, Puffenberger, E, Morton, D. “Maple syrup urine disease in "Gene Reviews."”. Decemer 18, 2011.

Wendel, U, de Baulny, O, Fernandes, J, Saudubray, J-M, van den Berghe, G. “Branch chain organic acidurias/acidemias”. Inborn Metabolic Diseases. 2006. pp. 245-263.

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Disorders of branched-chain amino acid metabolism