Propionic Acidemia

Summary

Disease characteristics (I)The spectrum of propionic acidemia (PA) ranges from neonatal-onset to late-onset disease.

• Neonatal-onset propionic acidemia (PA), the most common form, is characterized by poor feeding, vomiting, and somnolence in the first days of life in a previously healthy infant, followed by lethargy, seizures, coma, and death. It is frequently accompanied by metabolic acidosis with anion gap, ketonuria, hypoglycemia, hyperammonemia, and cytopenias.

• Late-onset propionic acidemia (PA) includes developmental regression, chronic vomiting, protein intolerance, failure to thrive, hypotonia, and occasionally basal ganglia infarction (resulting in dystonia and choreoathetosis) and cardiomyopathy. Affected children can have an acute decompensation that resembles the neonatal presentation and is precipitated by a catabolic stress such as infection, injury, or surgery.

• Isolated cardiomyopathy and arrhythmia can be observed on rare occasion in the absence of clinical metabolic decompensation or neurocognitive deficits.

Disease characteristics (II)

• Manifestations of neonatal and late-onset propionic acidemia (PA) over time include:

– growth impairment,

– intellectual disability,

– seizures,

– basal ganglia lesions,

– pancreatitis,

– cardiomyopathy.

• Other rarely reported complications include optic atrophy, hearing loss, premature ovarian insufficiency (POI), and chronic renal failure.

Diagnosis/testing

• propionic acidemia (PA) is caused by deficiency of propionyl-CoA carboxylase (PCC), the enzyme that catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA.

• Newborns with propionic acidemia (PA) tested by expanded newborn screening have elevated C3 (propionylcarnitine).

• Testing of urine organic acids in persons who are symptomatic or those detected by newborn screening reveals elevated 3-hydroxypropionate and the presence of methylcitrate, tiglylglycine, and propionylglycine, which are normally not observed in the urine.

• Testing of plasma amino acids reveals elevated glycine.

• Confirmation of the diagnosis relies on detection of either deficient PCC enzymatic activity or biallelic mutations in PCCA or PCCB.

Management

Treatment of manifestations

• The treatment of persons with acutely decompensated PA is a medical emergency:

• treat precipitating factors such as infection;

• arrest catabolism by providing high calorie and fluid intake;

• minimize protein intake to reduce propiogenic precursors;

• give intravenous carnitine;

• correct hypoglycemia and metabolic acidosis;

• care for the patient in a center with biochemical genetics expertise and the ability to support urgent hemodialysis, especially if hyperammonemia is present.

Prevention of primary manifestations• Individualized dietary management to restrict propiogenic substrates;

nasogastric or gastrostomy feeding as needed; increased caloric intake during illness to prevent catabolism; and continued multidisciplinary care with metabolic specialists.

• Medications may include:

– L-carnitine supplementation;

– oral metronidazole to reduce propionate production by gut bacteria; and/or N-carbamoylglutamate.

• Orthotopic liver transplantation (OLT) may be indicated in those with frequent metabolic decompensations, uncontrollable hyperammonemia, and/or restricted growth.

Prevention of secondary complications

• Consistent evaluation of the protein intake, depending on age, gender, severity of disease and presence of other factors such as growth spurts, can avoid insufficient or excessive protein restriction.

• The latter can result in deficiency of essential amino acids and impaired growth, as well as catabolism-induced metabolic decompensation.

Surveillance• Monitor closely patients with a catabolic stressor (fasting, fever, illness,

injury, and surgery) to prevent and/or detect and manage metabolic decompensations early.

• Regularly assess:

(1)growth, nutritional status, feeding ability, psychomotor development;

(2)metabolic status by monitoring urine organic acids and plasma amino acids;

(3)renal function;

(4)complete blood count.

• At intervals not yet determined, screen for: cardiomyopathy and arrhythmias; optic atrophy; and premature ovarian insufficiency in females.

Diagnosis

Clinical Diagnosis

• Neonatal-onset propionic acidemia (PA), the most frequently recognized form of PA, manifests in the neonatal period as EITHER:– An abnormal newborn screening (NBS): elevated propionylcarnitine (C3)

– OR

– Acute clinical deterioration of unexplained origin, in which an infant who appeared healthy at birth develops nonspecific symptoms including vomiting, refusal to feed, and hypotonia in the first few days of life. If untreated, encephalopathy, coma, seizures, and cardiorespiratory failure can ensue.

• Late-onset propionic acidemia PA includes developmental regression, chronic vomiting, protein intolerance, failure to thrive, hypotonia, and movement disorders (i.e. dystonia, choreoathetosis). These children can have an acute decompensation that resembles the neonatal presentation and is precipitated by a catabolic stress such as infection, injury, or surgery.

• Isolated cardiomyopathy is a recently recognized presentation.

Testing (I)

• PA is caused by deficiency of propionyl-CoA carboxylase (PCC), the mitochondrial enzyme that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. PCC enzymatic activity deficiency results in accumulation of propionic acid and other metabolites in plasma and urine.

• Abnormalities frequently (but not universally) seen during acute decompensation common to other organic acidemias:

◦ Mild to severe high-anion gap metabolic acidosis

◦ Elevated ketones in blood or urine (normally absent in healthy newborns)

◦ Low to normal blood glucose concentration

◦ Hyperammonemia (frequent)

◦ Neutropenia and occasionally thrombocytopenia

Testing (II)

Specialized biochemical evaluations for the diagnosis of propionic acidemia:

• Urine organic acids:

– Elevated 3-hydroxypropionate (normal value: 3-10 mmol/mol Cr)

– Methylcitrate (normally absent)

– Tiglylglycine (normally absent)

– Propionylglycine (normally absent)

• Occasionally lactate

• Plasma amino acids:

– Elevated glycine

– Acylcarnitine profile: Elevated C3 (propionylcarnitine)

Metabolic pathway

Propionyl-CoA carboxylase (PCC) catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA, which enters the Krebs cycle via succinyl-CoA. Sources of propionate include: valine, isoleucine, threonine, methionine, odd-chain fatty acids, and cholesterol. Deficiency of PCC results in propionic acidemia (PA) and accumulation of 3-OH propionate, methylcitrate and glycine, among other metabolites. PCC is located inside the mitochondrion. PCC, a heterododecamer (α6β6), comprises 6 α-subunits (orange) and six β-subunits (purple). Biotin (blue), bicarbonate, and ATP have binding sites in the α-subunit. The β-subunits form a central core.

Clinical Description

Natural History (I)

• Neonatal onset. The typical presentation involves a healthy newborn who develops poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Unless diagnosed correctly and managed promptly, neonates develop progressive encephalopathy, seizures, and coma that result in death.

• Late onset. The onset of symptoms in propionic acidemia (PA) varies depending on several factors including residual enzymatic activity, the intake of propiogenic precursors, and the occurrence of catabolic stressors.

• Isolated cardiomyopathy in the absence of clinical metabolic decompensation or neurocognitive deficits has been reported on rare occasion [Lee et al 2009].

Clinical Phenotypes

Onset Clinical features Findings

Neonatal onset

Poor feedingVomitingIrritabilityLethargyProgressive encephalopathySeizuresComaRespiratory failure

High anion-gap metabolic acidosisKetonuriaHyperammonemia (~80%)HypoglycemiaElevated 3-OH propionic acid and methylcitric acidHyperglycinemiaElevated propionylcarnitineNeutropeniaThrombocytopenia

Late onset

Acute, intermittent: Encephalopathy, coma, and/or seizures precipitated by catabolic stressors (e.g., intercurrent illness, surgery)

Chronic progressive:Vomiting, protein intolerance, failure to thrive, hypotonia, developmental regression, movement disorders

Isolated cardiomyopathy 1

+/- Metabolic acidosis or hyperammonemiaElevated 3-OH propionic acid and methylcitric acidHyperglycinemiaMRI abnormalities including basal ganglia lesions 2

1. Lee et al [2009]2. Broomfield et al [2010]

Natural History (II)

Early detection by newborn screening (NBS) and optimized management strategies offer the potential to improve the survival and long-term outcome of individuals with propionic acidemia (PA):

• A study of 49 patients with PA treated at European centers showed a lower mortality rate (~30%) in the first year of life than previously reported [Sass et al 2004].

• A more recent study showed that although mortality was decreased in patients with PA diagnosed through NBS, their neurologic outcome did not improve [Grünert et al 2012]. In this study, 63% of those detected through NBS were symptomatic at the time of diagnosis.

Natural History (III) Metabolic decompensations

• Children with propionic acidemia (PA) can develop episodic metabolic decompensations, especially in the first years of life.

• Acidosis, hyperammonemia, pancreatitis, metabolic stroke, cardiomyopathy, bone marrow suppression, seizures, and encephalopathy can accompany acutely deranged metabolism.

• These episodes, which typically require hospitalization and can be life threatening, are usually precipitated by illnesses, infections, surgery, or any stress augmenting catabolism.

• The long-term cognitive outcome of individuals with propionic acidemia (PA) is negatively correlated to the number of metabolic decompensations. Therefore, metabolic decompensations should be recognized and treated promptly.

• Of note, normal cognitive development has been described in several individuals with late-onset (mild) forms of propionic acidemia (PA).

Natural History (III) Growth impairment

• Growth impairment may become evident with age.

• Failure to thrive may be exacerbated by malnutrition secondary to poor feeding and excessive protein restriction

Natural History (IV) Neurologic Manifestations

• Neurologic manifestations include hypotonia, developmental regression, neurocognitive deficits, stroke-like episodes, seizures, and movement disorders.

• Seizures are frequent in early-onset PA and include tonic-clonic, myoclonic, focal, or absence seizures. EEG abnormalities may precede the onset of seizures.

• Individuals with PA are predisposed to basal ganglia lesions, especially during episodes of acute encephalopathy or metabolic instability.

• Basal ganglia infarction may be preceded by an acute “stroke-like” episode and manifest as altered mental status, dystonia, choreoathetosis, and/or hemiplegia.

• Brain MRI shows delayed myelination, symmetric basal ganglia disease, and cerebral atrophy.

Natural History (V) Cardiomyopathy

• Cardiomyopathy has recently been recognized as a common complication of propionic acidemia (PA). Romano et al [2010] reported cardiomyopathy in six of 26 children from a retrospective study; mean age of detection was age seven years. The age of diagnosis of PA, amount of metabolic control, or amount of residual enzymatic activity do not seem to modify the risk for cardiomyopathy.

• Most individuals with cardiomyopathy have mild to moderate forms of PA that are well controlled. Cardiomyopathy may resolve or progress to cardiac failure and has been associated with sudden death in a child with PA

• Cardiac rhythm abnormalities include prolonged QTc interval associated with syncope and cardiac arrest .

Pancreatitis, a well-known complication of PA and other organic acidemias, may be recurrent and should be suspected in those with anorexia, nausea, and/or abdominal pain.

Hematologic abnormalities. Neutropenia, thrombocytopenia, and rarely pancytopenia are seen during acute decompensations. Affected persons are predisposed to infections. Myelodysplasia has also been reported [Sipahi et al 2004].

Dermatologic manifestations resembling acrodermatitis enteropathica are frequently associated with deficiency of essential amino acids, particularly isoleucine, which is excessively restricted in the diet of persons with PA [Domínguez-Cruz et al 2011].

Other rare complications:

• Optic atrophy with acute visual loss [Williams et al 2009]

• Hearing loss

• Premature ovarian insufficiency (POI), described in some long-term survivors

• Chronic renal failure

Natural History (VI) Other complications

Genotype-Phenotype Correlations

• In general: – Null alleles (PCCA: p.Arg313X, p.Ser562X; PCCB: p.Gly94X and several small

deletions/insertions and splicing mutations) are associated with a more severe form of PA;

– Missense mutations, in which partial enzymatic activity is retained (PCCA: p.Ala138Thr, p.Ile164Thr, p.Arg288Gly; PCCB: p.Asn536Asp), are associated with a milder phenotype.

Exceptions include, for example, the three PCCB missense mutations p.Gly112Asp, p.Arg512Cys, and p.Leu519Pro, which affect heterododecamer formation and are associated with undetectable PCC enzyme activity and the severe phenotype.

• Other PCCB mutations such as p.Glu168Lys result in a wide variety of clinical manifestations among affected individuals.

• The PCCB mutation p.Tyr435Cys has been identified in asymptomatic children through newborn screening in Japan.

Incidence/Prevalence

• The worldwide incidence of PA is estimated at 1:50,000 to 1:100,000.

• The incidence is much higher in certain populations:

– Among the Inuit in Greenland the frequency at birth is 1:1000.

– In Saudi Arabia an incidence of 1:2000 to 1:5000 births has been reported.

One Hundred Eighty-two Cases with Organic Acidurias Detected from 9566

High-risk PatientsDiseases No. %

Methylmalonic aciduria 116 63.7

Propionic aciduria 16 8.8

Multiple carboxylase deficiency 15 8.2

Glutaric aciduria type 2 11 6.0

Glutaric aciduria type 1 7 3.8

Maple syrup urine disease 5 2.7

Oxoprolinemia 3 1.6

Ketothiolase deficiency 3 1.6

Isovaleric aciduria 3 1.6

Methylcrotonyl CoA carboxylase deficiency

2 1.1

Alcaptonuria 1 0.5

Yang, Ann Acad Med Singapore 2008;37(Suppl 3):120-2

Differential Diagnosis

Elevated C3 on newborn screening (NBS) can be caused by methylmalonic acidemias (resulting from methylmalonyl-CoA mutase deficiency, intracellular cobalamin metabolism) and severe maternal B12 deficiency.

The differential diagnosis of propionic acidemia (PA) as suspected by the elevation of 3-hydroxypropionate and methylcitrate on urine organic acids includes the following:

• Biotin disorders, which also show elevation of 3-hydroxyvalerate and 3-methyl-crotonylglycine. Biotinidase and holocarboxylase synthetase activities differentiate between biotinidase deficiency and multiple carboxylase deficiency.

• Methylmalonic acidemias, which have elevations of 2-methylcitric acid and 3-hydroxypropionate, and additionally show massive elevations of methylmalonic acid

• 3-hydroxyisobutyric aciduria, which also has elevation of 3-hydroxyisobutyric acid

• Bacterial contamination (including Propionibacterium)

Differential Diagnosis

Propionic acidemia should also be included in the differential diagnosis of many common pediatric conditions:

• Increased anion-gap metabolic acidosis. Possible causes are numerous and may include the following:

• Those conditions included in the commonly used mnemonic MUDPILES: methanol, uremia (chronic renal failure), diabetic ketoacidosis, propylene glycol, infection, iron, isoniazid, lactic acidosis, ethylene glycol, salicylates

• Organic acidemias

Differential Diagnosis

• Neonatal “sepsis” of unclear etiology in the newborn period should always prompt a metabolic evaluation.

• Pyloric stenosis. Infants with PA or other organic acidemias presenting with vomiting and refusal to feed may be given the diagnosis of pyloric stenosis which may lead to unnecessary surgery that provokes acute metabolic decompensation. Blood gas analysis of infants with pyloric stenosis usually shows hypochloremic alkalosis.

• Failure to thrive or recurrent vomiting of unclear etiology may be the only manifestation of PA and other inborn errors of metabolism.

Differential Diagnosis

• Child abuse or intoxication. PA should always be considered in the differential diagnosis of intoxications. In at least one individual with an organic acidemia the laboratory misidentified propionic acid as ethylene glycol.

• Diabetic ketoacidosis. Persons with propionic acidemia (PA) usually have ketoacidosis associated with hypoglycemia; however, hyperglycemia has also been reported and confused initially with diabetic ketoacidosis.

• Cardiomyopathy. An evaluation for propionic acidemia (PA) and other inborn errors of metabolism is warranted in the evaluation of children with cardiomyopathy of unknown origin.

Management

• The management of patients with propionic acidemia (PA) is ideally performed at a center with expertise in inborn errors of metabolism. The metabolic team comprises a metabolic physician, nutritionist, and genetic counselor.

Evaluations Following Initial Diagnosis (I)

To establish the extent of disease and needs of an individual diagnosed with PA the following evaluations are recommended :

• Serial metabolic evaluations of blood gases, electrolytes, glucose, serum ammonia concentration; plasma amino acids, carnitine and acylcarnitines; urine ketones and urine organic acids to guide acute management until the patient stabilizes

• Complete blood count to evaluate for cytopenias

• Molecular genetic testing of PCCA and PCCB if not previously performed to aid in genetic counseling and prediction of disease severity

Evaluations Following Initial Diagnosis (II)

Once the patient becomes stable, evaluations may include:

• Clinical assessment of growth parameters, ability to feed, developmental status, and neurologic status

• Laboratory assessment of nutritional status (electrolytes, albumin, prealbumin, plasma amino acids, vitamin levels [including thiamine and 25-hydroxyvitamin D], and trace minerals) and renal function; complete blood count to monitor for cytopenias.

• ECG and echocardiogram

• EEG and brain MRI in symptomatic individuals

• Age-appropriate developmental evaluation

• Eye examination

• Hearing evaluation

Treatment of Manifestations

Neonatal/Acute Decompensation

• Injuries, illness, infections, birth, surgery, other forms of stress and hormonal changes can produce a catabolic response that leads, among other things, to protein breakdown with massive release of amino acids which may include propiogenic precursors that cannot be metabolized in PA. The stress response may be perpetuated by release of hormones. The goal of the acute management of persons with decompensated PA is to reverse this process and to remove accumulated toxins.

• The treatment of persons with acutely decompensated PA is a medical emergency and requires care in a center with biochemical genetics expertise and the ability to support urgent hemodialysis, especially if hyperammonemia is present.

Inpatient Management (I)

• Manage ventilation and circulation as necessary.

• Treat precipitating factors (fever, infection, dehydration, pain, vomiting, and other sources of stress).

• Aggressively stop catabolism by giving fluids and calories approximately 1.5 times above the estimated baseline requirement in a glucose infusion rate of 10 mg/kg/min, and more than 40% of calories with a parenteral lipid suspension. The use of anabolic hormones (i.e., intravenous insulin drip) that may be needed to stop catabolism is preferably undertaken in an intensive care setting.

• Restrict intake of propiogenic precursors by avoidance of protein transiently (< 24-36 hours), or ideally, by the use of propiogenic-free parenteral amino acids, if available. Transition to enteral feedings as soon as they are tolerated.

Inpatient Management (II)

Detoxify to reduce hyperammonemia.

• Carnitine supplementation (100 mg/kg/day IV) may increase the detoxification of propionic acid by conjugating into propionylcarnitine, which is excreted by the kidneys. Alternatively, it may relieve intracellular coenzyme A accretion and provide a benefit through this mechanism.

Inpatient Management (III)

Detoxify to reduce hyperammonemia.

• Pharmacologic detoxification: – Scavenger medications, such as those used in urea cycle disorders to help

control ammonia levels during acute decompensations, should be used with caution in the treatment of hyperammonemia associated with PA as they lower glutamine levels, which may in turn contribute to hyperammonemia. Scavenger medications include intravenous sodium benzoate (250 mg/kg) and sodium phenylacetate (250 mg/kg) alone or in combination (Ammunol®), L-Carnitine (Carnitene®),

– Oral N-carbamoylglutamate (carglumic acid; 100-250 mg/kg) has also been reported to aid in the detoxification of ammonia during neonatal and acute decompensations [Filippi et al 2010, Schwahn et al 2010], L-Carnitine (Carnitene®).

• Extracorporeal detoxification (hemodialysis or extracorporeal membrane oxygenation [ECMO]) is frequently required in the acute infantile presentation of PA to control severe metabolic acidosis and/or hyperammonemia. Peritoneal dialysis is not recommended in this setting.

Home Management of Metabolic Status

The detection and management of metabolic decompensations at home are a critical part of the chronic management of PA. Strategies to achieve home management should be tailored for the conditions of each patient and family and may include the following:

• At-home detection and monitoring of ketones

• Use of anti-emetics such as ondansetron

• Close monitoring of clinical status

• Control of fluid-balance status

• Modification of the diet under the direction of the metabolic team

Other

• Any injury, illness, hospitalization, or surgical procedure should involve consultation with the metabolic team.

• The diagnosis and management of pancreatitis is the same as for pancreatitis of other causes.

• Neutropenia and other cytopenias usually improve with metabolic control of PA.

• The management of cardiomyopathy and arrhythmias is similar to that from other causes.

• Dermatologic manifestations are usually secondary to nutritional deficiencies of essential amino acids; these should be corrected.

• The management of chronic renal failure does not differ from that for other causes of renal failure; renal transplantation may be required.

Prevention of Primary Manifestations

• The long-term management of propionic acidemia PA includes the following:

• Individualized dietary management in order to restrict propiogenic substrates (valine, methionine, isoleucine, threonine, and odd chain fatty acids), while ensuring normal protein synthesis and preventing protein catabolism, amino acid deficiencies, and growth restriction

• Avoiding fasting and increasing calorie intake during illness to prevent catabolism

• Metabolic monitoring (see Surveillance)

• Supportive feeding (nasogastric or gastrostomy) as needed

• Ongoing multidisciplinary care, including caregiver teaching and emergency bracelet

Prevention of Primary Manifestations

• Medications including:

– L-carnitine supplementation at a dose of 50-100 mg/kg/day

– Intermittent oral metronidazole at a dose of 10-20 mg/kg/day to reduce propionate production by gut bacteria

– N-carbamoylglutamate. However, its chronic use in PA needs to be further studied.

– Antiepileptic drugs, as needed

– Therapy of arrhythmias, as needed

Prevention of Primary Manifestations

• Management before, during, and after any surgery by a metabolic team to ensure adequate hydration and caloric intake in order to minimize the risk of decompensations

• Orthotopic liver transplantation (OLT). May be indicated in those with frequent metabolic decompensations, uncontrollable hyperammonemia, and restricted growth. Reported benefits of OLT include decrease in the frequency of metabolic decompensations, improved quality of life, and reversal of dilated cardiomyopathy. Liver transplantation has been performed successfully from unrelated donors and from heterozygous related donors.

• Continuous hemofiltration, extracorporeal membrane oxygenation (ECMO), and left ventricular assist devices have been used while waiting for OLT

Prevention of Secondary Complications

• It is suggested that protein intake be regularly monitored by a biochemical geneticist and a nutritionist to avoid insufficient or excessive protein restriction.

• Many factors should be taken into account to guide protein restriction: age, gender, severity of PA, nutritional status, and presence of other factors such as intercurrent illness, surgery, or growth spurts.

• The effects of excessive protein restriction can include impaired growth, essential amino acid deficiencies, and catabolism-induced metabolic decompensation.

Surveillance (I)• Monitor closely patients with a catabolic stressor (fasting, fever, illness,

injury, and surgery) to prevent and/or detect and manage metabolic decompensations early.

• The following evaluations are performed at different intervals depending on factors including age, disease severity, and presence of catabolic stressors.

• Clinical evaluation should include assessment of the following:

– Growth

– Nutritional status

– Feeding ability

– Developmental and neurocognitive progress, as age-appropriate

Surveillance (II)

Laboratory evaluation should include:

• Metabolic studies: urine organic acids (if available, quantitative plasma methylcitric and propionate are preferable), plasma amino acids, serum ammonia concentration, and quantitative acylcarnitine profile;

• Nutritional studies: electrolytes, albumin, prealbumin, plasma amino acids, vitamin levels (including thiamine and 25-hydroxyvitamin D), and trace minerals;

• Complete blood count to monitor for cytopenias;

• Renal function tests;

• Amylase and lipase as needed to evaluate for pancreatitis.

Surveillance (III)

Evaluations:

• Screening for cardiomyopathy and arrhythmias by echocardiogram, ECG, and Holter monitor. The ideal screening frequency has not been defined.

• Brain MRI and/or EEG as clinically indicated

• Ophthalmologic evaluations to assess optic nerve changes. Frequency has not been determined.

• Screening for premature ovarian insufficiency (POI) in females. Frequency and recommended age to begin screening has not been determined.