The cornerstone of nutrition therapy for Phenylketonuria has been limiting the consumption of Phenylalanine to avoid accumulation in the blood.
This concept of limiting phenylalanine in the diet was first demonstrated in early 1950’s, as it had a positive impact on the behaviour in a young patient with PKU. Specialized amino acid based formula with low phenylalanine made dietary treatment for these patients possible. Although earlier it was believed that formula should be given only for 6 years, later data indicated that “diet for life” is the optimal mode of treatment.
Despite these significant results in behaviour, cognitive deficits were found in poorly managed individuals going to adulthood. Compliance for strict regimen among PKU individuals was found to be difficult which led to undesirable clinical outcomes.
Different approaches in nutrition management were explored such as glycomacropeptide protein-based medical foods and large neutral amino acids. Here we elaborate on Large Neutral Amino Acids.
What are Large Neutral Amino Acids?
LAT-1 transporter helps these amino acids pass the blood brain barrier.
In an individual with PKU due to the absence of enzyme Phenylalanine hydroxylase (PAH) & tetra hydrobiopterin (BH4), phenylalanine does not get metabolised to tyrosine, which thus gets accumulated in the liver and results in increased levels in the blood. Phenylalanine passes the blood-brain barrier with the help of LAT 1 transporter which leads to cognitive deficits, neurophysiological & neuropsychological dysfunction.
Supplementation of LNAA increases the levels in the brain and reduces the concentration of Phenylalanine as they compete with LAT1 transporter for crossing the blood-brain barrier. This was suggested 40 years ago while experimenting on artificially induced hyperphenylalaninemic rats. The successful lowering of phenylalanine levels in the brain led to further research in this area. Data suggests that various combinations of LNAA were tried depending upon the treatment goal.
LNAA treatment goal – to decrease cerebral Phenylalanine concentration
- LNAA supplementation:
- Increases the levels in the plasma thus competing with Phe for uptake at the blood-brain barrier. The concentration of Phe in the brain was decreased by 20 % when studied in humans. (Moats, 2003)
- Increases branched amino acids like isoleucine, valine and leucine concentration in the brain showing improvement in verbal ability, cognitive functions and protein synthesis in the brain (Moats, 2003)
- Improves neurotransmitter synthesis serotonin and dopamine known as feel good chemicals depending upon the concentration of tyrosine and tryptophan in the brain. Although, reports find deficiency of tyrosine in the brain, thus indicating higher concentration of the tyrosine in LNAA supplementation (van Spronsen FJ, 2010)
LNAA supplementation to decrease blood phenylalanine concentration
- LNAA supplementation in PKU mice had shown reduction of Phe by 47-63.5 % (Matalon, 2006).
- It is hypothesized that due to supplementation of LNAA there is competition of Phe for uptake from GI tract into the blood (van Spronsen FJ, 2010)
- Reports suggest that, the availability of high concentration of essential amino acid in the blood results in Phe utilization for protein synthesis. This leads to decrease in Phe in the blood (Danique van Vilet, 2015)
LNAA is seen as an alternative to conventional dietary therapy in PKU treatment especially for individuals, like adolescents and adults, who have uncontrolled phenylalanine levels. The concentration of LNAA supplementation depends upon different treatment strategies.
Methylmalonic acidemia (MMA) is a rare genetic disorder with an incidence of one in 50,000 live births, affecting males and females from all demographics. MMA was first identified in 1967. In MMA, the body is unable to break down certain amino acids namely methionine, threonine, isoleucine and valine which leads to the inability in properly digesting specific fats and proteins, leading to build up of a toxic level of methylmalonic acid in blood and disrupts the normal amino acid metabolism. Symptoms of MMA include poor feeding, vomiting, trouble in breathing, and lethargy. [1,2]
MMA AND GENETICS
Methylmalonic acidemia is inherited in an autosomal recessive pattern. In MMA, one copy of the altered gene is inherited from the mother and the other copy of the altered gene is inherited from the father. Therefore, each parent of an affected child has one copy of the gene that is altered and one that is unaltered. Parents are called “carriers”. Carriers are asymptomatic. MMA is a major concern in countries such as Palestine where immediate family members often marry and have children that inherit MMA at a much higher prevalence than neonates in western countries.
TYPES OF MMA
There are different types of MMA. The types of MMA which can be treated with vitamin B12 injections are called ‘vitamin B12 responsive.’ The other type, called ‘MMA with homocystinuria’ occurs when special enzymes which change vitamin B12 into a form that the body can use is either missing or not working properly. As a result homocystine, methylmalonic acid, and other harmful substances build up in the blood.
HOW IS MMA DIAGNOSED?
MMA is diagnosed at birth through newborn screening – a simple heel stick blood sample at birth used to check for numerous diseases. MMA is typically confirmed when proteins are introduced in the infant’s diet. The presence of MMA can also be suspected through the use of a CT or MRI scan or ammonia test. Elevated levels of ammonia, glycine, and ketone bodies may also be present in the blood and urine. However, these tests are by no means specific and require clinical and metabolic/correlation.
Additional tests for MMA diagnosis include:
- Biochemical testing for abnormal levels of specific chemicals
- Testing for responsiveness to vitamin B12
- Genetic testing for mutations in one of the genes associated with methylmalonic acidemia.
One such case is of a child from Children’s Hospital of Philadelphia. In less than 24 hours of being brought home, the baby had trouble eating and breathing. The baby was unable to open his eyes and the arms would flop. The temperature was critically low and neonatologists found dangerously high levels of ammonia in his system. MMA was diagnosed through newborn screening. His condition was treated through medications and a special diet low in protein.
MMA- NUTRITIONAL INTERVENTIONS & OTHER TREATMENTS
Currently, one of the main treatment is a diet low in the amino acids leucine, valine, methionine, and threonine with limited amounts of protein. There are also specially formulated foods such as special low-protein flours, pastas, rice and snacks such as biscuits that are made especially for children with organic acid disorders.
A liver transplant or a combination kidney-liver transplant is another alternative treatment used to treat MMA when repeated metabolic decompensation cannot be relieved by medication or nutrition therapy. Transplantation helps to prevent metabolic crises, lowers plasma and MMA levels in the urine, and also enhances overall quality of life. Even though the surgery is known to be lifesaving, it does not totally cure the disorder. Majority of the patients still maintain a low protein diet even after the surgery.
MMA- GENETIC THERAPY
On May 29, 2021, a 9-year-old patient, Eddie Axelson, of Monroe Carell Jr. Children’s Hospital at Vanderbilt was the first in the world to receive an investigational gene editing therapy for MMA. Axelson received the dose of hLB-001, administered via IV infusion. In gene editing therapy, a harmless virus is used to transport the missing gene into liver cells, so that the liver cells will start producing the deficient enzyme to correct the defect in body chemistry.
- Methylmalonic acidemia. (2021, August 15). Wikipedia. https://en.wikipedia.org/wiki/Methylmalonic_acidemia
- Methylmalonic acidemia: MedlinePlus Genetics. (n.d.). Medlineplus.gov. https://medlineplus.gov/genetics/condition/methylmalonic-acidemia/
- Methylmalonic acidemia | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. (2016). Nih.gov. https://rarediseases.info.nih.gov/diseases/7033/methylmalonic-acidemia
- Clark, P. A., & Myers, A. T. (2017, August 11). To Treat or Not To Treat: The Case of Methylmalonic Acidemia. Www.heraldopenaccess.us. https://www.heraldopenaccess.us/openaccess/to-treat-or-not-to-treat-the-case-of-methylmalonic-acidemia
- MMA (methylmalonic acidemia) – newbornscreening.info. (n.d.). Retrieved September 6, 2021, from https://www.newbornscreening.info/mma-methylmalonic-acidemia/
- Philadelphia, T. C. H. of. (2014, March 30). Methylmalonic Acidemia: Gavin’s Story. Www.chop.edu. https://www.chop.edu/stories/methylmalonic-acidemia-gavin-s-story
- About Methylmalonic Acidemia. (n.d.). Genome.gov. https://www.genome.gov/Genetic-Disorders/MMA-Study-General-Information
- Jiang, Y.-Z., & Sun, L.-Y. (2019). The Value of Liver Transplantation for Methylmalonic Acidemia. Frontiers in Pediatrics, https://doi.org/10.3389/fped.2019.00087
- Echegaray, C. (2021, June 3). Patient of Monroe Carell Jr. Children’s Hospital at Vanderbilt first in world to receive new investigational gene editing therapy. Vanderbilt University. https://news.vumc.org/2021/06/03/patient-of-monroe-carell-jr-childrens-hospital-at-vanderbilt-first-in-world-to-receive-new-investigational-gene-editing-therapy/