Natural History of Disease: Propionic Acidemia, Research Paper Example

Introduction of Topic/Disease

Propionic acidemia is an autosomal recessive disease that is characterized by poor feeding, seizures, lethargy, dehydration, hypotonia, vomiting, and dehydration among newborns. These symptoms become evident shortly after birth of a newborn and are life-threatening if they are not treated immediately. Since this illness is caused due to an autosomal recessive genetic inheritance, the prevalence of the disease is 1 in 35,000 live births in the United States. The incidence of the disease is expected to be between 1 in 50,000 live births and 1 in 100,000 live births worldwide. It is therefore evident that certain areas of the world have a higher risk for this disease base on their gene pool. This incidence is even higher among the Inuit in Greenland, as the disease impacts 1 out of 1,000 live births, and in Saudi Arabia where the disease impacts 1 out of 2,000 live births.

Propionic acidemia impacts the ability for individuals to properly convert amino acids and fats into energy sources. Specifically, in affected individuals, CoA carboxylase cannot convert propionyl CoA to methylmalonyl CoA. Therefore, several amino acids and odd-chain fatty acids are converted to propionyl CoA, which builds upon in the blood stream due to the body’s ability to convert this molecule to the expected final product. This buildup is acid and toxic and is therefore able to damage the organs it comes in contact with, contributing to the symptoms of this disease.

While propionic acidemia is considered to be a rare disease in some populations, it is necessary to consider that it is difficult to treat and failure to do so adequately can contribute to a high rate of death among infants with the inability to metabolize propionyl CoA. Therefore, it is important to gain a more thorough knowledge of this order so that researchers and physicians can develop more efficient ways to treat the disease before it causes significant bodily harm. Furthermore, if a child with the disease lives, it is necessary to note that the bodily damage caused when these individuals were newborns can be permanent. Ultimately, this molecule buildup impacts the ability of afflicted individuals to walk and talk. Throughout their lives, these individuals must regularly visit the hospital to ensure that propionic acid does not contribute to further organ damage. Each individual needs to be closely monitored and participate in a strict diet plan to ensure that propionic acid buildup will not be higher than normal. As a consequence, individuals who live with propionic acidemia have lower qualities of life than those who are disease free. More attention needs to be drawn to this illness so that ways can be found to make the day to day lives of these individuals easier.

The purpose of this paper is to provide a comprehensive understanding of propionic acidemia in a manner that calls for a need for further research regarding the disease’s mechanism of action and related treatment. The natural history of the disease will be discussed in order to reveal how the disease develops in addition to the populations that are disproportionately affected due to genetic predisposition. Prepathogenesis will be discussed to indicated disease development and occurrence. Last, health policy implications related to the disease will be summarized.

Stages in the Natural History of the Disease 

Propionic acidemia is a genetically inherited disease. Since the illness is autosomal recessive, individuals that have one parent that is afflicted with the disease may carry the disease allele. Specifically, mutations in the PCCA and PCCBgenes cause propionic acidemia. These two genes code for proteins that are the subunits of propionyl-CoA carboxylase (Campeau et al., 2001). Two parents who are heterozygous carriers for the allele have a 25% chance of having a child with propionic acidemia. If two parents with propionic acidemia are able to have children, there is a 100% chance that their children will have the disorder. Therefore, individuals with family history of the disease should get genetic testing to determine how their genetics will influence the development of disease symptoms in their children. This is ideal for individuals who are not certain whether they are carriers of the disease, as there is a 50% chance for a child to be born with the illness of two disease carriers.

There are disparities according to race in terms of the individuals who are most likely to be afflicted by the disease. This phenomenon is due to the gene pool available in certain areas of the world. Ultimately, gene pools that are less diverse are likely to contain a higher disease allele frequency due to the recessive nature of this trait. In particular, this recessive allele is highly prevalent in Greenland and Saudi Arabia, which are generally considered to have self-contained populations. The Inuit population in Greenland has a disease frequency of 1 in 1,000 at birth, which is the highest propionic disease rate currently known in a single population. Similarly, the Saudi Arabian people have a disease frequency of 1 in 1,000 at birth, which is also problematic. There is no disease disparity with regards to gender or socioeconomic status. Genetically counseling is especially recommended for the Inuit and Saudi Arabian population in addition to individuals of Inuit and Saudi Arabian descent, as this disease disproportionately impacts these groups.

 At the cellular level, individuals with propionic acidemia have a mutation in either the PCCA or PCCB genes. As a consequence, the blood and urine of newborns and adults with the disease demonstrate elevated levels of propionylcarnitine. Other aberrant detections include the presence of compounds including 3-hydroxypropionate, methylcitrate, tiglylglycine, and propionylglycine (Ah Mew et al., 2010). These metabolic byproducts become prevalent when the body is unable to properly metabolize propionyl CoA. Individuals with propionic acidemia symptoms therefore have difficulty achieving normal propionyl CoA metabolism due to improper propionyl-CoA carboxylase folding at either the protein or gene level. It is possible for individuals without the recessive disease alleles to suffer from this illness as a consequence of abnormal improper propionyl-CoA carboxylase protein folding due to an alteration of environmental conditions, such as pH, in the body. In addition, there are many specific mutations that contribute to the inability of propionyl-CoA carboxylase to function properly. There are five mutations that can occur in PCCA that will result in a defective protein. These include p.Ala138Thr, p.Ile164Thr, p.Arg288Gly, p.Arg313Ter, p.Ser562Ter. At the DNA level, this is caused by a single nucleotide replacement in each situation.

There are many physiological consequences that result due to propionyl-CoA carboxylase dysfunction. These symptoms are categorized broadly into neonatal onset symptoms and late onset symptoms (Haberlandt et al., 2009). Neonatal onset symptoms include dietary problems, vomiting, irritability, lethargy, progressive encephalopathy, seizures, coma, and respiratory failure. Acute, intermittent late onset symptoms include encephalopathy, coma, and seizures precipitated by catabolic stressors. Chronic progressive late onset symptoms include vomiting, an inability to tolerate protein, failure to grow and metabolic deficiency, hypotonia, and difficulty moving. A final late onset symptom is isolated cardiomyopathy. Researchers have determined that the neonatal onset symptoms are caused by high anion-gap metabolic acidosis, ketonuria, hyperammonemia, hypoglycemia, teevated 3-OH propionic acid and methylcitric acid, hyperglycinemia, elevated propionylcarnitine, neutropenia, and thrombocytopenia. The late onset symptoms are caused by

+/- Metabolic acidosis or hyperammonemia, elevated 3-OH propionic acid and methylcitric acid, hyperglycinemia, and MRI abnormalities, including basal ganglia lesions 2 (Davison et al., 2011).

A definitive diagnosis is made by testing for propionyl-CoA carboxylase (PCC) deficiency. Newborns that are suspected to be at risk for the disorder are tested for C3 propionylcarnitine as a part of their newborn screening. In addition, a urine test is given to detect elevated levels of 3-hydroxypropionate, methylcitrate, tiglylglycine, and propionylglycine in the urine, which are also indicative of the disease. An additional test that is performed is an amino acid profile in the blood. Individuals with propionic acidemia are likely to have elevated glycine levels. Additional testing is conducted to detect deficient PCC activity or double mutations in PCCA or PCCB for confirmation.

While it is challenging to prevent disease symptoms, individuals with propionic acidemia are monitored closely to ensure that their lifestyle choices prevent the problems related to the disease. A primary medical intervention related to the prevention of illness progression is dietary management that focuses on the reduction of propionic substrates. Tube feeding is occasionally necessary to ensure these individuals have adequate calorie intake to prevent against catabolism. Affected individuals are provided with L-carnitine, N-carbamoylglutamate, and oral metronidazole supplements to reduce the amount of propionate production caused by bacteria living in the gut (Ah Mew et al., 2010). Occasionally, an orthotopic liver transplantation (OLT) may be necessary patients with restricted growth. There is no cure for this disorder and treatment focuses on preventing cationic activity. It is expected that an individual with these symptoms will need to be monitored regularly throughout his or her life.

This disease is unique because it is a relatively rare autosomal recessive genetically inherited trait. As a consequence, public health policies could consider the benefit of screening parents for this disorder before they have children, as this could reasonably determine the potential risk of their child receiving this order. This is especially important for the Inuit population in Greenland and the people of Saudi Arabia because the disease prevalence is extremely high in these two locations. Genetic knowledge would significantly decrease disease incidence. However, in many nations around the world, genetic testing is considered to be unethical. It would therefore be reasonable to bring education programs to these locations to demonstrate the benefit of genetic screening for populations with a high prevalence of propionic acidemia.

Prepathogenesis

Genetic factors favor the development and occurrence of the disease. The disease host can be any individual that carries a homozygous recessive PCCA or PCCB genetic mutation. The agent of the disease is propionyl-CoA carboxylase (PCC). The environment is any geographical region that has a gene pool containing disease alleles. The Inuit people living in Greenland and individuals living in Saudi Arabia are disproportionately impacted by this disorder due to the prevalence of disease alleles in their gene pool. Primary and secondary prevention activities can therefore be directed towards members of these populations.

Primary prevention focuses on the prevention of catabolic activities and propionic acid buildup. Dietary management is utilized to prevent the ingestion of propionic compounds. Nasogastric or gastrostomy feeding is occasionally required to ensure that patients are able to maintain the proper caloric intake. These individuals also need to regularly visit their physicians for unrelated maintenance care, as infections can be more detrimental to these individuals. Afflicted individuals take supplements consisting of L-carnitine, N-carbamoylglutamate, and oral metronidazole to prevent the buildup of propionic acid in the stomach. Orthotopic liver transplantation is occasionally used to prevent this buildup if the patient is predisposed to more severe symptoms. In addition, patients with propionic acidemia must be well-educated about the disease so that they are able to maintain this primary prevention regimen. Secondary prevention consists of an evaluation of the protein intake of an individual because deficiency can result in impaired growth and metabolic decompensation. Secondary prevention also involves regular visits to physicians so they can determine whether the patient is following the prescribed primary intervention methods. There are no recommended tertiary prevention procedures because the organ damage caused as a consequence of the propionic acid buildup is generally considered to be irreversible. A potential improvement to this is the implementation of support groups for individuals with propionic acidemia in order to increase their quality of life with regards to mental health. Unfortunately, physicians and their patients must focus on the recommended primary prevention methods, as there are not many known ways to rectify the symptoms related to propionic acidemia once they begin.

Pathogenesis

 Propionic acidemia is caused by a propionyl-CoA carboxylase deficiency that prevents the conversion of propionyl-CoA to methylmalonyl-CoA. Methylmalonyl-CoA is a component of the citric acid cycle and gluconeogenesis and is therefore needed to create energy for the body and create glucose, respectively. The first step of these cycles involves converting odd-chain fatty acids, such as cholesterol, and the amino acids methionine, threonine, isoleucine, and valine to a 3-carbon containing propionyl CoA. The next step of the cycle involves a catalysis of this molecule to form a 4-carbon methylmalonyl CoA, which is further catalyzed to form the succinyl CoA that is needed for the citric acid cycle and gluconeogenesis. The conversion of the 3-carbon containing propionyl CoA to the 4-carbon methylmalonyl CoA is catalyzed by propionyl-CoA carboxylase, meaning that individuals with propionic acidemia cannot catalyze this reaction. ATP combines with CO₂ to produce ADP to power this process. Therefore, the bodies of patients with this disorder are unable to undergo normal energy metabolism, and a buildup of propionyl CoA occurs.

The propionyl CoA buildup occurs in the propionyl-CoA blood, causing the related symptoms. A majority of these symptoms are related to the fact that individuals with propionic acidemia cannot utilize glucose properly. However, normal levels of glucose are seen in the blood because the metabolic defect in afflicted patients is related to the parts of the citric acid cycle and gluconeogenesis that follow the initial use of glucose. It is the anticipated final products of these cycles that cannot be made. As a consequence, the propionyl acid buildup creates toxic effects in the body. Infants with the disease suffer from neutropenia thrombocytopenia, and hypoglycemia or hyperglycemia due to the toxicity of propionyl acid in the blood. These blood cells require a normal pH environment to thrive, but the presence of propionyl acid alters their ability to do so. If the level of this chemical is too high, it will put the body into shock, leading to seizures, coma, and respiratory failure. In adults, MRI abnormalities that indicate lesions of the basal ganglia are indicative of a long-term neurotoxic effect of the propionyl acid. Furthermore, growth deficiencies are common among these individuals because their bodies are not properly able to utilize and generate the ATP needed for growth processes.

Treatment of this disorder focuses primarily on prevention, as the buildup of propionyl acid causes irreversible organ damage. Therefore, nurses can become involved with the treatment of patients with this disorder by providing them with medical information that they require to remain on track with necessary lifestyle changes. When individuals with propionic acidemia are hospitalized, nurses can ensure that they are taking relevant supplements and determining what the proper dose of the supplements should be for each individual and determining whether symptoms are severe to the extent that an OLT operation is necessary (Barshes et al., 2006). Nurses can ensure secondary prevention in their patients by conducting tests to evaluate protein and caloric intake. Nurses could recommend the use of a feeding tube if they believe that the diets of their patients are inadequate.

Medical professionals conduct a series of tests to determine whether an infant has propionic acidemia. If this disease is not diagnosed at birth, it is highly unlikely that the infant will live until adulthood because primary prevention must be implemented immediately to ensure the health of the growing child. Basic biochemical profiles that are used to test for propionic acidemia include an examination of urine organic acids, a plasma amino acid profile, and an acylcarnitine profile. The profile of the urine organic acids that need to be detected include: elevated 3-hydroxypropionate (over 3-10 mmol/mol Cr), methylcitrate (any presence), tiglylglycine (any presence), propionylglycine (any presence), and lactate (presence). The plasma amino acids profile is used solely to detect for elevated glycine. The acylcarnitine profile us utilized to determine whether there are elevated levels of propionylcarnitine. Molecular and genetic testing is also available for the detection of mutated PCCA and PCCB genes. The most notable symptoms that medical professionals look for in newborns is poor feeding, as this is typically the first symptom to occur. The medical professional’s knowledge of propionic acidemia disease status and their family’s health history is also utilized to determine whether a newborn should be formally tested for the disorder.

Secondary prevention involves a screening of symptoms. This must occur regularly for infants so that their parents are aware of their child’s needs. Furthermore, adults with propionic acidemia must continue to attend these monitoring sessions to determine whether dietary changes or supplement changes are needed. Nurse could intervene at this stage by asking their patients to record the food items they are eating and determining whether they are aware of which foods contain high levels of propionic acid. Recommendations can then be made to adjust this dietary intake. Tertiary prevention is not relevant for this patient population, although support groups could be formed in order to support the mental health of individuals with this disorder. The end of life care for this patient population is similar to the end of life care implemented for the elderly. Ultimately, the prognosis for individuals living with propionic acidemia is not good, and a choice to not follow the prescribed lifestyle changes can lead to a decrease in the average lifespan of individuals with this diagnosis. Therefore, patients should be made as comfortable as possible and be provided with pain medication as needed to ease the symptoms. During end of life care, a feeding tube will be needed.

Health Policy

Healthy People 2020 has found that there has been a 10% improvement in care of patients with propionic acidemia since the initiative was launched. However, it was found that many laboratories do not test for the disease. In fact, laboratories around the country earned a score of 0.034 out of 1 for their ability to service individuals with this disease. However, laboratories are well-prepared to assist individuals with secondary infections in a timely manner, which is important to the well-being of people with this disorder as well. A goal associated with Healthy People 2020 is to improve the amount of labs that currently test for this order. Unfortunately, the Healthy People 2020 site contained little information regarding propionic acidemia, indicating that is a commonly ignored illness despite its large prevalence in some populations. In addition, while many state, local, federal, and institutional policies strive for quality improvement across the board, there is no specific mentioning of how propionic acid treatment will be improved.

There are two charity organizations in the world that work to fund propionic acidemia research and to provide treatment to patients who are unable to afford care. These organizations are the Propionic Acidemia Foundation and the Organic Acidemia Association. However the Propionic Acidemia Foundation is the only organization that is dedicated solely to the research and treatment of propionic acidemia, indicating the lack of consideration in health policies that this disorder has. Therefore, the primary disparity related to this problem is that fact that it is not well-known and consequently not well-funded. It is therefore necessary to educate the public about this disease with the hope that better tertiary prevention could be provided to the affected individuals. Ultimately, propionic acidemia needs to receive more attention so that better treatment could be provided.

Conclusion/Summary

 Propionic acidemia is a genetically inherited disorder that is expressed only by individuals who are homozygous recessive for the disease allele. This illness disproportionately affects the Inuit people in Greenland in addition to the population of Saudi Arabia. Despite the high prevalence in these two geographic regions, people around the world have this disorder, although the likelihood of getting it increases with the number of diseases alleles that are present in the population. While propionic acidemia is a relatively rare disorder on a world level, it is severely detrimental to those who have it, as there are currently no suitable tertiary preventions. Individuals who are born with the disorder must stick to stringent diet plans and take supplements in order to reduce the amount of propionic acid in their system. Furthermore, to achieve secondary prevention, they must regularly visit medical professionals for monitoring to ensure that they do not have a detrimental protein buildup and that they are receiving the correct caloric intake. Unfortunately, individuals with the illness must rely on primary prevention programs in order to remain healthy. High levels of propionic acid creates irreversible organ damage and their treatment regimen therefore revolves around this process. Tertiary prevention must therefore focus on counseling to promote mental health and end of life care for these individuals. People living with propionic acidemia are aware that if their symptoms become out of control, their lives are in danger.

Unfortunately, the lack of knowledge that the general population has regarding this disease means that there is not a significant amount of funding available for research or to support the individuals with disease treatment and management. In order to rectify this problem, it would be valuable for nurses to create education programs that would educate the general public about this disorder. Doing so has the potential to generate an interest in the creation of a greater number of charitable organization to help the individuals that have this illness. Furthermore, basic science researchers will be able to gain a greater understanding of the disease’s mechanism, which could lead to the development of drugs that would mimic normal propionyl-CoA carboxylase activity in the body, preventing against the buildup of dangerous levels of propionic acid. While a lot of information is currently known about the disease, there is a continuous need to learn more. The current treatment methods available for these individuals is unsatisfactory, as most have a poor prognosis. It is therefore necessary to educate the public about propionic acidemia so that we may begin working towards a cure.

References

Ah Mew N, McCarter R, Daikhin Y, Nissim I, Yudkoff M, Tuchman M. (2010). N-carbamylglutamate augments ureagenesis and reduces ammonia and glutamine in propionic acidemia. Pediatrics, 126: e208–14.

Barshes NR, Vanatta JM, Patel AJ, Carter BA, O’Mahony CA, Karpen SJ, Goss JA. (2006). Evaluation and management of patients with propionic acidemia undergoing liver transplantation: a comprehensive review. Pediatr Transplant, 10: 773–81.

Campeau E, Desviat LR, Leclerc D, Wu X, Pérez B, Ugarte M, Gravel RA. (2001). Structure of the PCCA gene and distribution of mutations causing propionic acidemia. Mol Genet   Metab., 74: 238–47.

Davison JE, Davies NP, Wilson M, Sun Y, Chakrapani A, McKiernan PJ, Walter JH, Gissen P, Peet AC. (2011). MR spectroscopy-based brain metabolite profiling in propionic         acidaemia: metabolic changes in the basal ganglia during acute decompensation and effect of liver transplantation. Orphanet J Rare Dis., 6:19

Haberlandt E, Canestrini C, Brunner-Krainz M, Möslinger D, Mussner K, Plecko B, Scholl-Bürgi S, Sperl W, Rostásy K, Karall D (2009). Epilepsy in patients with propionic a cidemia. Neuropediatrics, 40: 120–5.