Propionic Acidemia

Alternative Names

  • Propionyl-CoA Carboxylase Deficiency
  • PCC Deficiency
  • Glycinemia, Ketotic
  • Hyperglycinemia with Ketoacidosis and Leukopenia
  • Ketotic Hyperglycinemia
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WHO-ICD-10 version:2010

Endocrine, nutritional and metabolic diseases

Metabolic disorders

OMIM Number

606054

Mode of Inheritance

Autosomal recessive

Gene Map Locus

3q21-q22,13q32

Description

Propionic Acidemia is an autosomal recessive branched-chain organic acidemia, characterized by a deficiency of the propionyl-CoA carboxylase enzyme, which helps in the normal breakdown of several essential amino acids.

Patients may initially present some minor symptoms including poor feeding, vomiting, loss of appetite, hypotonia, and lethargy. Later, most children will show different degrees of motor, social and language delay. They also show more serious medical problems, including neutropenia, cardiac abnormalities, periodic thrombocytopenia, hypogammaglobulinemia, developmental retardation, seizures, and coma. Death is likely, if the condition is not intervened with. In most cases, the condition presents itself in the infantile stage. However, it may also rarely manifest itself in a childhood form, which is less severe, and is triggered by stress conditions, such as fasting, or infections. In the US, recorded incidence of the disease is about 1 in every 35,000 live births. However, in some other populations, the incidence is much higher. These include the Inuit population of Greenland, some Amish communities, and the Saudi population.

A neonate with symptoms that resemble organic acidemia requires biochemical investigations. The most comprehensive method to assess is by using the technique of Gas Chromatography with Mass Spectrometry (GC/MS). This enables the identification of the toxic compounds accumulated in the body. Therapy involves a three pronged strategy. As the first line strategy, protein intake is completely halted and other calorie sources are provided to the patient. For the ketoacidosis, correction involves providing increased carbohydrate calories, bicarbonate replacement, and increased fluid intake. After the condition has somewhat normalized, the patient is restarted on a low protein diet (<1.5g/kg body weight a day). In addition, intermittent administration of antibiotics needs to be provided to partially destroy the gut flora and reduce the propionate production by them. A special low-protein diet needs to be maintained for the rest of the patients' life.

Molecular Genetics

Propionic acidemia results from mutations in both the PCCA and PCCB genes. These genes code for the two subunits of the propionyl-CoA carboxylase enzyme (PCC), which is involved in the metabolism of valine, isoleucine, threonine, and methionine, in addition to certain odd-chained fatty acids. Defects in this enzyme lead to a harmful accumulation of these amino acids and fatty acids, as well as ketones and other toxic compounds in the blood. This accumulation is what results in the signs and symptoms of propionic acidemia.

The condition is transmitted in an autosomal recessive manner, and mutations in both the genes are required for the disease to develop.

Epidemiology in the Arab World

View Map
Subject IDCountrySexFamily HistoryParental ConsanguinityHPO TermsVariantZygosityMode of InheritanceReferenceRemarks
606054.1LebanonFemaleYesYes Muscular hypotonia; Motor delay; Encep... NM_000282.3c.1209+3A>GHomozygousAutosomal, RecessiveNair et al. 2018 Has affected sibling...
606054.2Oman NM_000532.5:c.990dupHeterozygousAutosomal, RecessiveAl-Shamsi et al. 2014 Emirati tribe of Oma...
606054.3Oman NM_000532.5:c.990dupHeterozygousAutosomal, RecessiveAl-Shamsi et al. 2014 Emirati tribe of Oma...
606054.4United Arab EmiratesUnknown NM_000532.5:c.1142G>AHomozygousAutosomal, RecessiveAl-Shamsi et al. 2014
606054.Gr.1United Arab EmiratesUnknown NM_000282.4:c.1594_1597delTTGTHomozygousAutosomal, RecessiveAl-Shamsi et al. 2014 Two patients with pr...

Other Reports

Bahrain

Al-Arrayed (Personal communication, Dubai, 2006) indicated that propionic acidemia occurs in Bahrain at an approximate incidence of 1/10,000 births.

Lebanon

In a retrospective analysis of IEMs diagnosed over a 12-year period (1998-2010) in a hospital in Lebanon, Karam et al. (2013) found 11 patients diagnosed with propionic acidemia. Two of these were through newborn screening. The median age of diagnosis was 4-months. 

Oman

Joshi et al. (2002) carried out a retrospective analysis of all patients born with inborn errors of metabolism in Oman between June 1998 and December 2000. Among the 82 patients, four were diagnosed with propionic academia [CTGA Database Editor's note: Computed annual incidence rate is 3.1/100,000]. Few years later, Joshi and Venugopalan (2007) conducted a study over a seven year period (1998-2005) to evaluate the clinical profiles of 166 neonates at high risk of having inborn errors of metabolism using Tandem Mass Spectrometry (TMS). Out of a total of 38 neonates with positive TMS results, six babies, all with consanguineous parents, were diagnosed with propionic acidemia. Their ages ranged from one to four days, six were males, and two were females. Two of these patients underwent TMS analysis due to suspicion because of the presence of family history of the condition.

Al-Riyami et al. (2012) reported on the types and patterns of IEMs encountered in a sample of 1100 high-risk neonates referred to SQU Hospital in Oman over a 10-year period (1998-2002). MS/MS was used to analyze blood samples from heel pricks. A total of 119 of these neonates were found to test positive for an IEM. Propionic Acidemia was detected in 14 neonates (nine males, five females), belonging to 11 families. Nine of the patients had a family history of the condition, while 11 had consanguineous parents.

The Centre for Arab Genomic Studies Work Group (2006) conducted a retrospective study for organic acid disorders described at AlWasl Hospital in Dubai between 1997 and 2006. Three cases with propionic acidemia were observed, at least two of the patients were males, including a 3-month-old child from Oman. No further details could be obtained.

Qatar

Al-Rikabi and Al-Homsi (2004) described a 7-year old Qatari child, who presented with erythematous and scalded skin lesion on her limbs and trunk. Her lower limbs showed several flaccid bulla, while perioral, periorbital and genital areas showed erythematous scaly patches. The patient had previously been diagnosed with propionic acidemia, resulting from a complete deficiency of propionyl carboxylase. 

Saudi Arabia

Al Essa et al. (1998) pointed out that not only do acute intercurrent infections precipitate acidosis in propionic acidemia, but such infections are unusually frequent in propionic acidemia in Saudi Arabia. Propionic acidemia is unusually frequent in Saudi Arabia, with a frequency of 1 in 2,000 to 1 in 5,000, depending on the region. The disorder has a severe phenotype in Saudi Arabia. Al Essa et al. (1998) had information on approximately 90 patients; certain tribes accounted for almost 80% of these cases, suggesting a founder effect. The number of other cases of organic acidemias observed during the same period was 656. Longitudinal data, in some instances up to 8 years, were available for 38 patients with propionic acidemia. A high frequency of infections was observed in 80% of the patients. Most microorganisms implicated were unusual, suggesting an underlying immune deficiency. The infections occurred despite aggressive treatment with appropriate diets, carnitine, and, during acute episodes of the disease, with metronidazole, which suggested a global effect of the disease on T and B lymphocytes as well as on the bone marrow cells.

Kaya et al. (2010) screened two siblings affected with propionic acidemia for putative mutations in the PCCA and PCCB genes. Both patients had a mild-severe form of propionic acidemia.

Moammar et al. (2010) reviewed all patients diagnosed with inborn errors of metabolism (IEM) from 1983 to 2008 at Saudi Aramco medical facilities in the Eastern province of Saudi Arabia. During the study period, 165530 Saudi infants were born, of whom a total of 248 newborns were diagnosed with 55 IEM. Affected patients were evaluated based on clinical manifestations or family history of similar illness and/or unexplained neonatal deaths. Almost all patients were born to consanguineous parents. Organic acidopathies (OA) were diagnosed in 48 out of 248 cases (19%), which constituted the second largest group of IEM found in this cohort after lysosomal storage disease. Among OA patients, six cases from three families were found to have Propionic academia (PPA). The estimated incidence of PPA cases in this cohort is 4 in 100,000 live births.   The authors concluded that data obtained from this study underestimate the true figures of various IEM in the region. Therefore, there is an urgent need for centralized newborn screening program that utilizes tandem mass spectrometry, and offers genetic counseling for these families.

United Arab Emirates

Al-Shamsi et al. (2014) undertook a study to calculate the birth prevalence of IEMs among Emiratis in the UAE by taking into consideration all neonates born with an inherited metabolic condition at Tawam Hospital between 1995 and 2012. Propionic Aciduria was found to be one of the most prevalent IEMs identified in this study, with birth prevalence of between 2.2 and 4.9 per 100,000 live births. 

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