Propionic Acidemia

Propionic Acidemia

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Propionic acidemia is an autosomal recessive, inherited, metabolic disorder that is caused by a defective form of the enzyme propionyl-coenzyme A (CoA) carboxylase, which results in the accumulation of propionic acid. Propionyl-CoA carboxyalse converts propionyl-CoA to methylmalonyl-CoA. 

Patients may present with vomiting, dehydration, lethargy, and encephalopathy. 

Patients who are diagnosed before birth (from the family history or sibling history) or soon after birth have the best prognosis. [1] Surtees et al divided patients with propionic acidemia into two subgroups: those with early onset disease presenting in the first week of life and those with late-onset disease presenting after age 6 weeks. The early onset group was characterized by mental retardation and early death, with the median survival period being 3 years. The late-onset group was characterized by severe movement disorders and dystonias. [2] Patients with late-onset disease usually have permanent neurologic damage.

Newborn screening for propionic acidemia is available in many states and countries. 

To improve patient outcome, educate the patient’s family to recognize early signs of dehydration, poor feeding, seizures, and respiratory distress. This education is important because metabolic decompensation plays a major role in the neurologic problems and sequelae observed in patients with propionic acidemia. [3] For patient education information, see the Brain and Nervous System Center, as well as Stroke.

Propionic acidemia is classified as an inherited, autosomal recessive, organic acid disorder. The metabolism of isoleucine, valine, threonine, and methionine produces propionyl-CoA. To a lesser degree, cholesterol and odd-chain fatty acids also contribute to propionyl-CoA levels. The enzyme propionyl-CoA carboxylase, which requires biotin as a cofactor, catalyzes conversion of propionyl-CoA to methylmalonyl-CoA. Several genetic mutations, broadly categorized as defects in 2 subunits of the propionyl-CoA carboxylase gene (PCCA and PCCB), may give rise to varying levels of functioning propionyl-CoA carboxylase. [4]  

Defects in the metabolic pathway produce several potentially toxic metabolites. Toxic buildup of propionic acid can be found in the brain and other parts of the nervous system. Although most children have neurologic damage during a metabolic crisis, rare cases without an identifiable precipitating factor have been reported. The metabolic crisis may result from changes in feeding, or they may be secondary to an infection. [5, 6, 7, 8, 9, 10, 11, 12]  

Clinical and imaging evidence suggests that propionic acidemia predisposes patients to bilateral infarcts of the basal ganglia involving the caudate, putamen, and globus pallidus. Milder forms may be characterized by the absence of some of these clinical characteristics. Numerous theories regarding basal ganglia infarction resulting from the effects of these metabolites have been suggested. [13] Hamilton et al. suggested that metabolites of the dysfunctional propionic acid and methylmalonic acid pathways may be selectively toxic to the endothelial cells in the basal ganglia. [14] Endothelial damage is the presumed basis for strokes. The authors confirmed that basal ganglia lesions were not due to hypoxemia, because the hippocampus, which is relatively more sensitive to hypoxemia, was spared.

An alternative hypothesis implicates direct basal ganglia damage due to dysfunction of cytochrome-c oxidase. Accumulation of propionic acid apparently results in an abnormal cytochrome-c oxidase. Another competing hypothesis states that hyperammonemia, which is often associated with propionic acidemia, leads to an accumulation of glutamine and/or glutamate in astrocytes. This excess glutamate may be excitotoxic to neuronal cells in the basal ganglia.

A mouse model lacking the PCCA gene has been developed. Experiments with this model may improve our understanding of the pathophysiology of this disease. [15]

Antisense morpholino oligonucleotides directed at intronic pseudoexons have been shown to increase propionyl-CoA carboxylase activity to normal levels in fibroblast cell lines derived from patients suffering from propionic acidemia. [16]

The estimated incidence of propionic acidemia in the United States is 1:105,000–130,000 people, highest amongst the Amish populations. [17, 18, 19] The incidence is highest in the Inuit of Greenland—1:1,000 [17, 20] and next highest is in some Saudi Arabian populations—1:2,000- 28,000. [17, 21, 22]  The true prevalence may be higher, because many neonatal deaths may be caused by undocumented acidopathies.

Mild forms of the disease may exist due to differences in the mutations of PCCA or PCCB in different parts of the world. The true incidence of propionic acidemia may be as high as 1 case in 18,000 people. [23]

Patients with propionic acidemia often present in the neonatal period or during early infancy. Patients with mild forms of the disease may present later in life. [24, 25, 26] In a study of 65 patients, a slight female predominance was found, with a female-to-male ratio of 1.4:1.

Patients with propionic acidemia may present with vomiting, seizures, lethargy, hypotonia, and encephalopathy. These symptoms may be recurrent, with episodes triggered by the onset of feeding, a change in feeding, or an infection.

The patient may have a family history of the disease, especially a history of unexplained neonatal death or a sibling with an acidopathy.

Neonates may present in the first few days of life with decreased feeding, vomiting, lethargy, and seizures. Hepatomegaly may be present. Patients with infantile or late-onset forms may have failure-to-thrive, developmental delay, seizures, and spasticity.

In patients in whom propionic acidemia was previously diagnosed, the acute onset of abnormal movements may be a presenting sign of an infarction of the basal ganglia. Such abnomal movements can include dystonia, rigidity, and choreoathetosis. Case reports suggest that propionic acidemia should be considered in patients with new choreoathetoid movements, even if the traditional symptoms of metabolic decompensation are absent.

Rarely, optic atrophy, hearling loss, premature ovarian failure, and chronic renal failure has been reported. [17]  Isolated cases of cardiomyopathy has been reported as the sole clinical presentation of propionic acidemia. [17, 27, 28]  There are some incomplete reports of co-morbidities such as attention-deficit disorder, autism, anxiety, and acute psychosis seen in patients with propionic acidemia. [17, 29, 30, 31, 32]

The low incidence of propionic acidemia, coupled with the condition’s nonspecific presenting symptoms [33] , make the diagnosis difficult. The patient’s family history and sibling history must be obtained and carefully investigated when one deals with any inherited disease. Prenatal and neonatal diagnosis must be pursued aggressively. The differential diagnosis of propionic acidemia includes the following disorders:

Brainstem syndromes

Cyanotic heart disease

Ehlers-Danlos syndrome

Marfan syndrome

Mitochondrial cytopathies

Organic acidurias

Patent foramen ovale

Sickle cell disease


Anterior circulation stroke

Aseptic meningitis

Basilar artery thrombosis

Cardioembolic stroke

Disorders of carbohydrate metabolism

Fabry Disease

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome

Posterior cerebral artery stroke

Initial laboratory studies may reveal metabolic acidosis with anion gap, hypoglycemia, hyperammonia, and ketonuria. One should eliminate the common causes of ketoacidosis and lactic acidosis first. Seizures, diabetes, alcoholic ketoacidosis, liver disease, shock, and anoxic and/or ischemic injury of tissues are often present with acidosis.

If the clinical picture suggests a metabolic disorder, a presumptive diagnosis may be made on the basis of blood analysis for ammonia levels, amino acids, and organic acids. Serum levels of ammonia, glycine, B-hydroxybutyrate, and acetoacetate should be elevated. A complete blood count (CBC) may reveal neutropenia and thrombocytopenia. [34]  C3 propionylcarnitine will be elevated as well. 

Perform a urinalysis for amino acids and organic acids. Methyl citrate, 3-hydroxy propionate, propionyl glycine, tiglate, and tiglyl glycine should be increased in the urine.

Diagnosis is confirmed when molecular genetic testing reveals a pathogenic variant in PCCA or PCCB or when there is deficient propionyl-CoA carboxylase enzyme activity. If molecular testing is equivocal, a combination of enzymatic and molecular testing may be necessary. [35]

During the workup of a young patient with suspected stroke, exclude other causes of stroke by obtaining blood, brain, vascular, and cardiac studies. [36]

Acute changes in neurologic status (eg, stroke, seizure, encephalopathy) warrant a neuroimaging study. Several reports confirm that patients with propionic acidemia and movement disorders most likely have lesions in the bilateral lenticular and caudate nuclei. By convention, computed tomography (CT) scanning and magnetic resonance imaging (MRI) were used in these reports to identify these lesions. However, positron emission tomography (PET) scanning has subsequently been used in patient evaluation, to show decreased glucose uptake in the basal ganglia. [37, 38, 39, 40]  MR spectroscopy can reveal increased myoinositol, N-acetylaspartate and elevated glutamine, glutamate, and gamma-aminobutyric acid peaks in the basal ganglia. [38]

Consider EEG if patient is lethargic/comatose if suspicious for subclinical seizures/non-convulsive status epilepticus.

A protein-restricted diet is the cornerstone of treatment. A low-protein diet (1.5-2mg/kg/day), L-carnitine supplementation (100mg/kg/day), and biotin supplementation (10mg/day) are required. [41] Carnitine, an enzyme involved in the metabolism of long-chain fatty acids, buffers the acyl-CoA metabolites that accumulate with protein-restricted diets. The acyl-carnitine that is produced by the buffering action is excreted in the urine.

Biotin is a cofactor for propionyl-CoA carboxylase (and for 3 other carboxylases). Therefore, propionic acidemia may be present in a patient suffering from the broader metabolic problem of multiple carboxylase deficiency. Biotin responsiveness may depend on the genetic heterogeneity of isolated propionic acidemia versus propionic acidemia existing as a subset of multiple carboxylase deficiency. In patients with biotin-unresponsive disease, restricting their intake of isoleucine, valine, threonine, and methionine is the only solution.

Prompt dietary modification and supplementation may reverse clinical symptoms and normalize laboratory findings. The success of therapy can be measured as changes in propionic acid level in the serum. In-home testing of urine for ketones, especially during suspected infections, has been advocated.

In the acute phase, identify and treat intercurrent infections that have triggered an acidotic episode. Dietary modifications must be made in a hospital setting.

In the acute setting, all protein intake should be held. Treatment should be aimed at treating metabolic acidosis, hypoglycemia, and hyperammonemia.  

The incidence of propionic acidemia is low, and the expertise to deal with this disease may be available only in tertiary medical centers. Life-threatening issues (eg, acidosis, dehydration, seizures) can possibly be addressed locally. However, when acidemia is suspected, the patient may need to be transferred to a facility with a high level of expertise in this area.

Consultation with a pediatric neurologist and/or biochemical geneticist is necessary when a patient presents with stroke, seizure, or encephalopathy. Dietary and/or nutritional specialists may help in modifying the patient’s diet, and a physical therapist and/or an occupational therapist should also be consulted, for functional assessment and therapeutic recommendations. 

Because gastrointestinal bacteria produce propionic acid, neomycin and metronidazole have been proposed as treatments. Clinical data about this treatment regimen are limited. [42]

Hemodialysis may be required for life-threatening acute phases of illnesses that are triggered by infections or other stresses.

Organ transplantation of the liver or of the liver and kidney has been attempted. However, perioperative and postoperative complications are apparently high, and the long-term benefits are unclear. [43, 44, 45, 46, 47]

If a patient with propionic acidemia requires surgery, it is important to provide adequate hydration and caloric supplementation before surgery and post-operatively. One should try to limit fasting/NPO status as much as possible. 

NG tube or G-Tube placement should be considered if the patient is not alert enough to feed by mouth during a crisis or if the patient remains encephalopathic.

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Felicia J Gliksman, DO, MPH Assistant Professor, Department of Pediatrics and Department of Neurology, Hackensack Meridian School of Medicine at Seton Hall University; Attending Physician, Division of Pediatric Neurology, Hackensack University Medical Center

Felicia J Gliksman, DO, MPH is a member of the following medical societies: American Academy of Neurology, American Epilepsy Society, Child Neurology Society

Disclosure: Nothing to disclose.

Helmi L Lutsep, MD Professor and Vice Chair, Department of Neurology, Oregon Health and Science University School of Medicine; Associate Director, OHSU Stroke Center

Helmi L Lutsep, MD is a member of the following medical societies: American Academy of Neurology, American Stroke Association

Disclosure: Medscape Neurology Editorial Advisory Board for: Stroke Adjudication Committee, CREST2; Executive Committee for the NINDS-funded DEFUSE3 Trial; Physician Advisory Board for Coherex Medical.

Pitchaiah Mandava, MD, PhD Assistant Professor, Department of Neurology, Baylor College of Medicine; Consulting Staff, Department of Neurology, Michael E DeBakey Veterans Affairs Medical Center

Pitchaiah Mandava, MD, PhD is a member of the following medical societies: American Academy of Neurology, Stroke Council of the American Heart Association

Disclosure: Nothing to disclose.

Thomas A Kent, MD Professor and Director of Stroke Research and Education, Department of Neurology, Baylor College of Medicine; Chief of Neurology, Michael E DeBakey Veterans Affairs Medical Center

Thomas A Kent, MD is a member of the following medical societies: American Academy of Neurology, Royal Society of Medicine, Stroke Council of the American Heart Association, American Neurological Association, New York Academy of Sciences, Sigma Xi

Disclosure: Nothing to disclose.

Howard S Kirshner, MD Professor of Neurology, Psychiatry and Hearing and Speech Sciences, Vice Chairman, Department of Neurology, Vanderbilt University School of Medicine; Director, Vanderbilt Stroke Center; Program Director, Stroke Service, Vanderbilt Stallworth Rehabilitation Hospital; Consulting Staff, Department of Neurology, Nashville Veterans Affairs Medical Center

Howard S Kirshner, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, American Heart Association, American Medical Association, American Neurological Association, American Society of Neurorehabilitation, National Stroke Association, Phi Beta Kappa, and Tennessee Medical Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

Richard M Zweifler, MD Chief of Neurology, Sentara Healthcare, Norfolk, VA; Professor of Neurology, Eastern Virginia Medical School, Norfolk, VA

Richard M Zweifler, MD is a member of the following medical societies: American Academy of Neurology, American Heart Association, American Medical Association, American Stroke Association, Royal Society of Medicine, and Stroke Council of the American Heart Association

Disclosure: Nothing to disclose.

Propionic Acidemia

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