Treatments

1) Avoid fasting and prolonged exercise

2) Feed at regular intervals during the day and limit overnight fasting

3) In take of medium chain triglyceride (MCT) oils which can provide (10-20)% energy


Reference:

Unknown. (n.d.) Exercise. [image online] Available at: http://us.123rf.com/400wm/400/400/goodshotalan/goodshotalan1108/goodshotalan110800044/10257978-vector-cartoon-of-man-exercising.jpg [Accessed: 17th January 2013].

Fun Fact #2

Patients suffering from VLCADD should not go without food intake longer than 

:4 hours for the first 4 months of life
:6 hours for ages 4-8 months
:no longer than 8 hours thereafter

Reference:

Unknown. (2013) State of CT Genetics Newborn Screening Program Health Care Provider Fact Sheet. [online] Available at: http://www.ct.gov/dph/lib/dph/family_health/newborn_screening/pdf/hpvlcadd.pdf [Accessed: 16th January 2013].

Fun Fact #1

Apparently......

"VLCAD deficiency is estimated to affect 1 in 40,000 to 120,000 people".

Reference:

Genetics Home Reference (2013) Very long-chain acyl-CoA dehydrogenase deficiency. [online] Available at: http://ghr.nlm.nih.gov/condition/very-long-chain-acyl-coa-dehydrogenase-deficiency [Accessed: 10th January 2013].

Different Stages of VLCADD And It's Symptoms

VLCADD is variable and can cause mild effects in some people and more serious health problems in others. Symptoms may start in infancy or not until adulthood. There are three forms of VLCADD:  “Early”, “Childhood” and “Adult”.  

Early VLCADD

About half of babies diagnosed with VLCADD have the “early” type. They usually start to show effects between birth and 4 months. In addition to metabolic crises, babies can also have:

• enlarged heart, irregular heartbeat and other heart problems
• enlarged liver and other liver problems
• muscle problems

If not treated, babies with early VLCADD usually die young. 

Childhood VLCADD

 
About one third of people with VLCADD have the childhood type. They usually show symptoms in late infancy or early childhood. Episodes of hypoglycemia or full metabolic crisis happen during illness or after long periods of not eating. Other effects can include:

• enlarged liver
• other liver problems
• muscle weakness, especially after exercise

Heart problems are usually not seen in childhood VLCADD.
Some children with VLCADD have never had symptoms and are only found to be affected after a brother or sister has been diagnosed.

Adult VLCADD

 
About one fifth of people with VLCADD have the adult type. They usually show symptoms starting in the teen years or in adulthood. Periods of muscle weakness are common. Breakdown of muscle fibers can occur. This usually happens during heavy exercise or after going without food for a long period of time.
Signs of muscle breakdown are: 

• muscle aches
• weakness
• cramps
• reddish-brown color to the urine.

Reference:

Adults with muscle symptoms who do not get treatment can develop kidney failure.
STAR-G (n.d.) Expanded Newborn Screening Using Tandem Mass Spectrometry Finanacial, Ethical, Legal and Social Issues. [online] Available at: http://www.newbornscreening.info/Parents/fattyaciddisorders/VLCADD.html#2 [Accessed: 10th January 2013].

Early detection (before birth) – Aminocentesis

In the previous post, we discussed how Tandem mass spectrometer can detect VLCAD in a newborn.
 

How about early detection of very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency?

We were thinking if it would be possible to use aminocentesis to detect VLCAD in an unborn. Since VLCAD is caused by ACADVL gene mutations in bands found on the chromosome 17, we were wondering if carrying out a karyotype and sequencing chromosome 17 on the baby’s amniotic sample will allow for the detection of VLCAD.

Procedure:

1. Doctor injects a long, thin hollow needle into mother’s tummy and into baby’s amniotic sac. 
2. A small amount of amniotic fluid will be drawn.
3. Sample will be sent to laboratory to karyotype and isolate chromosome 17. 
4. Chromosome 17 will be examined further to see if there’s mutation on the p11.2 and p11.13105 bands. 

References:

babycenter (2012) Aminocentesis. [online] Available at: http://www.babycenter.com.sg/a327/amniocentesis#ixzz2Gzvjcnbr [Accessed: 9th January 2013]. 

Unknown. (n.d.) Untitled. [image online] Available at: http://www.modernmedicalguide.com/amniocentesis/ [Accessed: 9th January 2013]. 

Detection in Newborn using Tandem Mass Spectrometry

The application of tandem mass spectrophotometry has been used in the research and development of newborn screening. It started in the early 1990’s and is still very much in use today. A tandem mass spectrophotometry- Tandem MS or MS/MS- is a type of mass spectrophotometry which is used to analyze the components of any type of substance especially biological substances.

 

In the case of screening for VLCAD in a newborn, the Tandem MS is used. The Tandem MS is made of two mass spectrometers that are joined by a chamber. The chamber will break the molecule to many different components that made the substance.

Schematic of Tandem Mass Spectroscopy

 

When a sample of the newborn’s blood is inserted, it is “sorted” and “weighed” by the mass spectrometer to get amino acids and acylcarnitines*. The acylcarnitines are identified by the size of the fatty acid that’s attached to the carnitine. After identifying and weighing the acylcarnitines, the mass spectrometer will produce results showing us how much of fatty acid is present. Depending on the amount of fatty acid present (eg; small, medium or long chain), the individual will then be diagnosed with the type of fatty acid oxidation disorder.

*acylcarnitine- a fatty acid attached to a carnitine (transportation system for fats) Acylcarnitine profile is a diagnostic test for inherited disorders of fatty acid and branched-chain amino acid catabolism. Patients with this type of metabolic disorder accumulate disease-specific acylcarnitines that correlate with the acyl co-enzyme.

Reference:

Unknown. (2011) Acylcarnitines: analysis in plasma and whole blood using tandem mass spectrometry.. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21207283 [Accessed: 8th January 2013].

Unknown. (n.d.) A Layperson's guide to Tandem Mass Spectrometry and Newborn Screening. [e-book] Bridgeville, PA, USA: NeoGen Labs. p.1-3. http://masspec.scripps.edu/metabo_science/Tandem%20Mass%20Spectrometry%20Chace.pdf [Accessed: 8th January 2013].

Unknown. (2009) Lovely Baby. [image online] Available at: http://www.webmastergrade.com/top-15-cute-babies-wallpaper/ [Accessed: 10th January 2013]. 

Unknown. (n.d.) Schematic of Tandem Mass Spectroscopy. [image online] Available at: http://en.wikipedia.org/wiki/File:MS_MS.png [Accessed: 10th January 2013]. 

VLCAD Deficiency

Our project will focus on a disorder of β-fatty acid oxidation. This disorder is known as Very Long-Chain Acyl-CoA Dehydrogenase (VLCAD) deficiency. 

Introduction to VLCADD

VLCAD deficiency is an autosomal recessive disorder. This happens when the enzyme, very long-chain acyl-CoA dehydrogenase, essential to oxidize fatty acids are absent or simply mutated. These results in the inability of the body to oxidize fats from the food we eat or the fatty acids stored in our liver and muscles. In short, the VLCAD deficiency inhibits the oxidation of fats to produce energy. 

 
VLCAD is an enzyme that is encoded by the acyl-CoA dehydrogenase very long chain gene (ACADVL). The ACADVL gene is 5.4 kb long containing 20 exons and is found on chromosome 17 between bands p11.2 and p11.13105. However, the ACADVL is infamously known to have “more than 100 mutations” that causes VLCAD deficiency. Mutations in the ACADVL gene will lead to a truncated VLCAD enzyme. An example is a deletion mutation that causes the VLCAD to be a truncated protein. Since the VLCAD is shorter than it should be, it won’t be able to carry out its normal function. Therefore, fatty acid oxidation cannot be carried out properly. 
 
When a person is said to be suffering from VLCAD deficiency, they will feel lethargy and incur low blood sugar-hypoglycemia- as our body relies on a limited amount of glucose for energy. Furthermore, death may consume a patient because all the unconverted fats will accumulate in tissues and damage the liver, heart and muscles.





Biochemistry behind VLCADD

Normal fatty acid oxidation can go from carbon-16 or carbon-18 down to carbon-4 and carbon-4 will produce “ketone bodies” in the liver that can be exported to other organs as a source of acetyl-CoA for energy production from their citric acid cycle. 

In VLCAD deficiency the ability to produce and export these “ketone bodies” is severely diminished thus causing energy deficits in other organs that depend on them for energy production. This is especially true for skeletal muscle and the heart and results in muscle cell breakdown  and cardiomyopathy with heart failure during illness in the severe form of VLCADD.

References:

Unknown. (n.d.) ACADVL Gene in genomic location. [image online] Available at: http://www.genecards.org/cgi-bin/carddisp.pl?gene=ACADVL [Accessed: 16th January 2013].  
 
R.Roe, C. (2011) My experiences and understanding of VLCAD deficiency and its treatment. [e-book] p.1. http://www.fodsupport.org/documents/DrRoeandVLCADexperiencesEdited2011.pdf [Accessed: 5th January 2013].

Unknown. (2010) rip-tombstone. [image online] Available at: http://www.forevergeek.com/2010/03/death_and_the_web_inevitable_tech_decisions/rip-tombstone/ [Accessed: 10th January 2013]. 

Unknown. (2005) Very Long Chain Acyl-CoA Dehydrogenase Deficiency (VLCADD). [image online] Available at: http://www.ct.gov/dph/lib/dph/family_health/newborn_screening/pdf/hpvlcadd.pdf [Accessed: 1st January 2013].