Recognition and Treatment of Organic Acidemias...

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Recognition and Treatment of Organic Acidemias CME/CE Supported by an independent educational grant from Recordati Rare Diseases

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Recognition and Treatment of Organic Acidemias CME/CE

Target AudienceThis activity is intended for gastroenterologists, primary care physicians, emergency medicine physicians, nurses, NPs, and others involved in the diagnosis and treatment of organic acidemias.

Goal StatementThe goal of this activity is to provide clinicians with the knowledge to suspect an organic acidemia as the cause of a patient’s acute illness.

Learning ObjectivesUpon completion of this activity, participants will be able to:

1. Recognize clinical presentations of organic acidemias, including methylmalonic acidemia (MMA) and propionic acidemia (PA)

2. Outline strategies for early, accurate diagnosis of MMA and PA

3. Summarize current and emerging management options for MMA and PA

Credits AvailablePhysicians - maximum of 0.50 AMA PRA Category 1 Credit(s)™

Nurses - 0.50 ANCC Contact Hour(s) (0.25 contact hours are in the area of pharmacology)

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CME/CE Released: 4/25/2016; valid for credit through 4/25/2017

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FacultyGregory M. Enns, MDProfessor of PediatricsDirector, Biochemical Genetics Program Stanford University Stanford, California

Andrea L. Gropman, MDProfessor of Pediatrics and Neurology The George Washington University School of Medicine and Health Sciences Chief, Neurodevelopmental Disabilities and Neurogenetics Children’s National Health SystemWashington, D.C.


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Gregory M. Enns, MD: Hello, I am Gregory Enns, professor of pediatrics and director of the Biochemical Genetics Program at Stanford University. Welcome to this program on the Recognition and Treatment of Organic Acidemias. Joining me today is Dr Andrea Gropman, chief of neurogenetics at Children’s National Health System, in Washington DC.

Andrea L. Gropman, MD: Thank you. Pleasure to be here today.

Dr Enns: Our discussion today will center on what emergency medicine and pediatric providers need to know about acute acidotic crises. Note that we will not discuss cobalamin C disease (cbl-C), an organic acidemia, and will concentrate on conditions that cause acute acidotic crises. Andrea, can you get us started by providing an overview of organic acidemias?

Dr Gropman: Sure, Greg. Although the organic acidemias are rare disorders individually, altogether they account for an incidence of 1:800 to 1:5000. Organic acidemias are broadly defined as an inherent deficiency in key metabolic pathways resulting in cellular intoxication, energy deprivation, or sometimes a combination of both. Organic acidemias are caused by enzyme deficiencies that impair the metabolism of amino acid carbon skeletons. The symptoms are caused by accumulation of organic acids upstream of the enzyme blockage leading to metabolic acidosis, with an anion gap and hyperammonemia secondary to impaired urea cycle function.

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Although organic acidemias are rare causes of disease, they should always be considered because many are potentially treatable, and recurrent attacks are potentially avoidable. In addition, although clinical presentations are usually seen early in life, often with an abrupt onset, these disorders can present subacutely during later childhood or even in the adult years. Additional features of these conditions include episodic relapses as well as nonspecific clinical or physical features. Although many metabolic disorders are identified through newborn screening programs, screening for specific inherited metabolic disorders remains important, especially for patients who did not undergo newborn screening or who have an atypical presentation.

Organic acidemias biochemically result from deficiencies of mitochondrial enzymes that metabolize Coenzyme A- (CoA) activated carboxylic acids derived from amino acid breakdown. Symptoms include acute onset of episodic metabolic acidosis caused by buildup of toxic metabolites and disturbance of mitochondrial energy production. Neurologically, patients may present with acute or chronic encephalopathy -- acutely with changes in the level of consciousness -- and some patients may present with seizures.


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Dr Enns: Organic acidemias are inborn errors of metabolism (IEMs). They are inherited and typically appear after an interval of good health. The interval could be minutes, hours, or days, but in the neonatal presentation, we are typically talking about hours and days. Stressors unmask the organic acidemia, which can lead to catabolism. Important triggers of an organic acidemia crisis include infection -- especially a viral illness -- fasting, dehydration, excessive protein intake, and, in neonatal presentations, the birth process itself. In neonates, presentations are nonspecific, because these infants have a limited response ability to different forms of stress. Examples of organic acidemias with a typical presentation include methylmalonic acidemia (MMA), propionic acidemia (PA), isovaleric acidemia (IVA), multiple carboxylase deficiency (MCD), and ketone utilization disorder (KUD).

Common signs and symptoms of these disorders usually start with lethargy, progressing to coma in otherwise well-appearing infants and children. Left untreated, children can become comatose and develop more severe neurologic problems. Common signs of a subacute presentation include vomiting or poor feeding. Many patients have recurrent pancreatitis, so when evaluating a patient with abdominal pain, think pancreatitis and obtain serum amylase and lipase levels. Because they can have poor feeding, dehydration is relatively common. Patients who have severe poor feeding may require supplementation via a nasogastric or gastrostomy tube. They can have chronic failure to thrive or respiratory distress because of acidosis, and some patients will develop a pancytopenia. The pancytopenias typically occur after a metabolic crisis. You might not have that as the main presentation, but an acidotic child who is having a metabolic crisis and has high acid in the blood will eventually develop a neutropenia, thrombocytopenia, and anemia can also be present. Some patients have distinctive abnormal odor, such as the “sweaty feet” odor associated with IVA.

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The classic, or typical, presentation is an acute overwhelming illness. Depending on the severity of the patient’s disorder and environmental stressors, the patient can experience recurrent metabolic crises. Another presentation may be developmental delay with or without seizures, progressive dystonia, or even a choreoathetosis in early childhood. Andrea will fill us in on the details of the neurology in a bit.

Overall, it is important to know that the age of onset and the severity in these conditions is highly variable, from the neonatal period through childhood. In the neonate, the presentation might be confused with a number of the more common pediatric disorders, such as sepsis. Congenital heart disease and gastrointestinal disorders are also mistakenly diagnosed in a patient who has an organic acidemia. In the older infant and child, it might be misdiagnosed of an ingestion, or gastroenteritis, or a central nervous system disorder.


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Patients with MMA eventually develop renal failure in early childhood, or later in adolescence or adulthood, especially in the classic MMA, mut- form. In PA, cardiomyopathy is a common complication and can be fatal. Consider the cardiac component in a child who has PA and an acute episode; an echocardiogram would be very important. PA may also present with long QT syndrome or other arrhythmias. Optic atrophy might be a complication in MMA. Immunodeficiency also may be present in patients with an organic acidemia.

Andrea, I have just described the nonneurologic presentations associated with organic acidemias. Can you please tell the audience about the neurologic features and complications?

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Dr Gropman: There are several categories of neurologic affectation in these disorders, and the overlapping neurologic features of MMA and PA make clinical differentiation difficult. Tone abnormalities -- hypotonia, hypertonia, or a combination -- are seen in the majority of patients. Seizures are another symptom complex that we observe. Seizures can be a part of the initial manifestation of the organic acidemia and the acute presentation, and can be a chronic problem for patients who have these conditions. You already mentioned the fact that many of these patients may be at risk for a development delay or intellectual disability (mental retardation). Movement disorders also are associated with these metabolic disorders.

Hypotonia, low muscle tone, can delay a child’s gross motor, fine motor, and speech milestones, and it may also affect feeding. Hypotonia usually involves trunk muscles more than muscles of the extremities. Hypertonia, on the other hand, is a high resting muscle tone, producing stiff and contracted muscles that, obviously, prevent movement, particularly in limbs. Therapies are directed toward stretching, and medical treatments for hypertonia are available, as well as surgeries such as tendon releases and transfers. When possible, we try to work with therapies and medications before recommending surgery.

Dr Enns: Do you see hypertonia as a presentation in a child coming into the emergency department (ED)?

Dr Gropman: Generally, we see hypotonia first, so it evolves over time. We would see the so-called “floppy baby“ who presents with acute metabolic crisis, and then as time goes on, the muscles of the extremities become contracted and stiff, although the core muscles remain hypotonic over time.

The last category I want to discuss is movement disorders. One type of movement disorder is a fixed posture, or a dystonia, in which the limb is in an abnormal position, even at rest. Movement disorders in general can interfere with purposeful movement, and also, movement may activate them. A patient may have no movement at rest, and then, reaching for something or making some other purposeful movement may bring on the movement disorder. Other types that are more dynamic include a writhing or rapid movement, such as the choreoathetosis you mentioned. Any type of rapid, uncoordinated movement may be present.


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Seizures are an important consideration in these disorders. They can be a single event at presentation, and may be provoked by the metabolic disruption. Hypoglycemia, for example, which can be seen in these conditions, can be sufficient to produce a seizure, which we would consider a provoked seizure. It may or may not require chronic treatment. Likewise, hyperammonemia can be associated with seizures. However, many patients have repeated generalized or focal seizures. Antiepileptics may be required, and the choice of antiepileptic must be made very carefully and on an individual basis. It is also possible that the patient’s seizures will not coincide with metabolic decompensation. A patient may have seizures with an injection, for example, but clinicians must remain mindful that an increase in seizures can portend a metabolic decompensation.

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Developmental delay and cognitive disability also can occur in these disorders to varying degrees. Significant hypoglycemia can cause structural and functional changes in the brain. Seizures usually indicate abnormal brain function and conductivity, and a prolonged seizure could cause additional damage. These disorders may have repeated metabolic decompensation or repeated injury, so the total developmental aspects of the patient may be the result of how many metabolic episodes they have had, the severity of the initial episode, and other factors that accumulate over time.

Dr Enns: I have seen children who have been absolutely normal for several years, and then experience a metabolic crisis that resulted in the sequelae that you have mentioned, such as a movement disorder.

Dr Gropman: Exactly. We also have seen patients with a new neurologic symptom without a clear-cut metabolic episode. Performing serial neurologic evaluations on patients to look for new symptoms can be informative -- to go back and consider whether there has been a metabolic stroke, for example, which may not have been heralded by a typical crisis.


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Dr Enns: A common laboratory test result in organic acidemias is metabolic acidosis, usually associated with a ketoacidotic crisis, and sometimes accompanied by hyperammonemia. In fact, the ammonia level may be sufficiently high to suspect a urea cycle defect, for example, but in my experience, a low blood urea nitrogen (BUN) level can help rule out a urea cycle defect. In organic acidemia, you have ketosis and a high BUN level, as well as the classic metabolic acidosis. A hyperammonemic crisis in a child who has a urea cycle defect may include a respiratory alkalosis, because the ammonia is a central stimulant. In an organic acidemia, these children are acidotic, sometimes with a pH level below 7 -- quite severe. In a milder case, that pH level might not be quite that acidotic, but still it is quite clearly acidotic.

An elevated glycine level may be seen, but because an amino acid result can take a while to obtain in the ED, it is important to look at the ketone bodies production, and simple laboratory test results -- electrolytes, anion gap, etc. Lactic acidemia may also be present because some organic acidemias seem to affect mitochondrial metabolism that will result in a lactic acidemia.

Pancytopenia is less often associated with the initial presentation, but after a crisis you might see bone marrow suppression and thrombocytopenia, anemia, or even leukopenia. Newborn screening has been very beneficial. A characteristic C3-acylcarnitine can be detected on a newborn blood spot screening, so many times PA, MMA, and other organic acidemias can be detected presymptomatically just on a simple blood spot test.

Andrea, let us now focus on some specifics about MMA and PA.

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Dr Gropman: The defect in MMA is in the enzyme methymalonyl-CoA mutase (MCM). Adenosylcobalamin, the active form of vitamin B12, is a cofactor for the mutase enzyme, but there are genetically distinct vitamin B12-responsive and non-responsive forms of MMA. Defects in cobalamin synthesis and transport also result in MMA. It is important to determine vitamin B12 responsiveness clinically.

Renal disease is a common complication of MMA. Pancreatitis is also a very common complication. The metabolic stroke, mentioned earlier, producing the movement disorder choreoathetosis, may occur. In addition, optic atrophy may be a late complication of this disorder and merits periodic patient screening.

The enzyme responsible in PA is propionyl-CoA carboxylase, and biotin is the coenzyme for this disorder. Although biotin is a cofactor for the enzyme, there is no biotin-responsive form of PA. As in MMA, recurrent pancreatitis is a common complication. Cardiomyopathy is a common complication in PA and a common cause of death as you stated -- the etiology is unclear.

In addition to arrhythmias and long QT syndrome, optic atrophy also has been reported. There is also some evidence for immunodeficiency, which can put these patients at risk for infections that can be a trigger for metabolic decompensation, so that should be evaluated as well. Then, the metabolic stroke involving the basal ganglia may occur acutely or progressively, with an extrapyramidal syndrome developing.

Greg, now that we have described the basics on recognizing organic acidemias and what they are, do you want to talk about the goals of management and the treatments for these patients?


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Dr Enns: Most simply, I want to protect the brain, and all our management and therapies focus on doing just that. We want to decrease the number of metabolic crises. We want to keep these children at home with their families, thriving and doing well, so preventive care is critical, including vaccinations.

A child known to have an organic acidemia can come into the ED or a pediatrician’s office, where intravenous (IV) placement with appropriate IV fluids with dextrose can be lifesaving. Dehydration in these patients is relatively common, which we have to correct.

Vitamin supplementation is effective for disorders such as the B12-responsive forms of MMA cobalamin A (cbl-A) or cobalamin B (cbl-B) defects. A dose of hydroxocobalamin or hydroxycobalamin can alter the clinical course in some patients.

We typically withhold protein over a period of 12 to 24 hours while the acidotic crisis is being managed. Severely ill patients may require hemodialysis, hemofiltration, or other such measures. In addition, we commonly provide IV carnitine, because these children are carnitine deficient, and acylcarnitine production is increased during an acute crisis. Some centers have used nitrogen-scavenging agents, such as a combination of IV phenylacetate and benzoate, but we try to avoid that if at all possible. These nitrogen-scavenging IV agents may not be the best solution in a child who is highly acidotic, and they should be used on a case-by-case basis and in consultation with an expert center.

Dr Gropman: We provide patients and their parents with letters for emergency situations in the ED. This would be for patients who have a known diagnosis. Can you comment on the utility of such a letter for ED physicians, one that provides direction?

Dr Enns: We provide every patient who has a diagnosis or who is undergoing evaluation with an emergency letter. I try to keep it pretty simple: IV access, IV fluids, and in boldface type we provide our center’s contact information. Operators are standing by, we want to help. Such letters are particularly important for families who are traveling.

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Long-term management of organic acidemias including MMA and PA commonly involves protein restriction. Patients with mild disease may require only a protein-restricted diet, but others require special medical foods that limit certain amino acids that these children cannot metabolize. In PA and MMA, these amino acids are valine, methionine, isoleucine, and threonine. Patients also have difficulties with odd-chain fatty acids. The mnemonic is easy to remember -- VOMIT: Valine, Odd-chain fatty acids, Methionine, Isoleucine, and Threonine.

Using a metabolic specialist center with a dietitian who is skilled in the management of these patients is important to avoid protein malnutrition, which can lead to catabolism, which can lead to further metabolic crises. It’s quite clear that these patients should be cared for by a metabolic center.

Carnitine supplementation long-term is used to maintain adequate carnitine stores, prevent a crisis, and keep these children as healthy as we can. We instruct our families to bring the child into the pediatrician’s office sooner rather than later. Sometimes a fever and feeling unwell may not be a metabolic crisis, it might be a simple upper respiratory infection or otitis that can be addressed with the child observed carefully, but at home. Not everything develops as a metabolic crisis.

Some patients require periodic gut sterilization using metronidazole or neomycin. Microbes in the gut can produce propionate and propionic acid metabolism, and can be an important source of propionate in the system.

In patients whose disease is B12-responsive, supplementation with hydroxycobalamin or hydroxocobalamin is life-changing. These patients tend to do better than patients whose disease does not respond to vitamin B12.


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Novel therapies are in development and are currently being considered for use in treating these organic acidemias, including carglumic acid. We have been using it in our patients only in a clinical trial. Case reports suggest that carglumic acid can lower ammonia levels in patients who have organic acidemias such as MMA or PA, as well as certain urea cycle defects. Carglumic acid is a structural analog of N-acetylglutamate, a critical factor in activating the urea cycle. Patients with MMA or PA have a tendency to accumulate propionyl-CoA which decreases the synthesis of this N-acetylglutamate.

Other agents are used by some centers on a case-by-case basis, including nitrogen-scavenging medicines. I talked briefly about the IV form, but even using oral nitrogen scavengers in some cases can help control hyperammonemia. Sodium benzoate has been used, but we lack evidence other than case reports at this time to understand whether or not these agents work in these conditions.

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In our center, especially for MMA, we have been performing liver transplantation or a combined liver/kidney transplantation. Other institutions have used kidney transplantation for the treatment of MMA. These patients can have chronic kidney disease. They develop an interstitial nephritis, and, as I have said earlier, this can develop in patients as early as a couple of years of age and can go on for many years. We have been using hemodialysis for adolescents and adults, but a possible long-term therapeutic approach is a liver or liver/kidney transplantation. Newborn screening has allowed us to detect these children quite early, so we have also been performing liver transplantation before there is any evidence of kidney involvement -- 6 to 9 months of age. Time will tell whether liver transplantation will protect against the development of kidney disease.

It does seem apparent that after transplantation these children tend to have fewer metabolic crises and seem a bit more stable. Of course, transplantation cannot reverse significant neurologic damage, but it may stabilize the situation sufficiently so that improvement can occur. Transplantation is, however, not curative. Providers need to know that even if a child has undergone transplantation, they remain at risk for neurologic complications. A child with an organic acidemia who has undergone transplantation and who is having a metabolic crisis must be treated in the same manner as a patient who has not undergone transplantation -- very aggressively, and please call the metabolic center.

Thank you so much, Andrea, for participating in this conversation about organic acidemias.


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BIBLIOGRAPHY

1. Seashore MR. The organic acidemias: an overview. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews. Seattle, WA: University of Washington; 2009.

2. Matsui SM, Mahoney MJ, Rosenberg LE. The natural history of the inherited methylmalonic acidemias. N Engl J Med. 1983;308:857-861.

3. Splinter K, Niemi AK, Cox R, et al. Impaired health-related quality of life in children and families affected by methylmalonic acidemia. J Genet Couns. 2015. [Epub ahead of print].

4. Nuria Carrillo-Carrasco N. Propionic acidemia. In: Pagon RA, Adam MP, Ardinger HH, et al, eds. GeneReviews. Seattle, WA: University of Washington; 2016.

5. Carbaglu® [package insert]. Paris, France: Orphan Europe SARL; 2016.

6. Daniotti M, la Marca G, Fiorini P, Filippi L. New developments in the treatment of hyperammonemia: emerging use of carglumic acid. Int J Gen Med. 2011;4:21-28.

7. Niemi A-K, Kim IK, Krueger T, et al. Treatment of methylmalonic acidemia by liver or combined liver-kidney transplantation. J Pediatr. 2015;166:1455-1461.

Recognition and Treatment of Organic Acidemias...

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