Friday, June 21, 2024

Obesity and Ordinary Weight Gain Linked To Guess What? Not Simply Junk Food But A Gene Called Niemann Pick Type C.

June 2, 2009 by  
Filed under Genetics

The first genetic map of obesity has been constructed using DNA microarray technology and guess what gene obesity is linked to?  The Niemann Pick Type C gene on Chromosome 18 that is mutated in Addi and Cassi and which is causing their deadly cholesterol metabolism disorder.   I have now found out that the NPC gene that is involved in all people’s cholesterol metabolism is liked to the HIV/AIDs viruses ability to assembly itself in the body of infected persons, Cystic Fibrosis, Muscular Dystrophy and now Obesity!

Would the NIH please provide more funding into studying the NPC gene — the NPC cholesterol gene dates back 500 million years to worms, flies and plants and obviously is involved in many critical processes in the human body.

The obesity report was publsihed in Nature Genetics by a research group led by CNRS researcher Philippe Froguel and Inserm researcher David Meyre.  This study led to the discovery of three new genes that increase the risk not only of severe obesity but also ordinary weight gain in the population.  It underlines that there is no difference between being overweight and other forms of obesity (mild, severe or massive).

Even though the increase in the number of obese people over the two last decades is partially due to social causes (inactivity, junk food, etc.), heredity plays an important part in determining body weight (70% hereditary) and the occurrence of obesity, especially when this is severe and appears early in life, according to researchers.

Froguel’s team has been working for 15 years to better understand the molecular basis of type 2 diabetes and the obesity found in 80% of diabetics.  Their work has revealed several genes responsible for monogenic forms of obesity and has demonstrated the essential role these genes play in appetite control.   The scientists first confirmed that the genes FTO and MC4R(4) played a major role in susceptibility to common obesity and weight gain in the population as a whole.  These two genes work by controlling eating behavior.

The researchers also found variations in the DNA close to the genes MAF and PTER(5), and directly in the coding sequence of the NPC1 gene.  Mutations associated with obesity could therefore directly induce an increase in the function of the NPC1 protein, such that it would work too well if the gene had mutated.

As for the MAF gene, it codes for a particular protein involved in the differentiation of adipose tissue (tissue responsible for fat storage) and in the production of a digestive hormone involved in satiety and insulin secretion.  The last gene (PRL) is more particularly associated with obesity and weight gain in adults.  PRL produces prolactin, a hormone well known for its effect in stimulating lactation in women.  Prolactin also plays a role in controlling the amount of food we consume.

Apo E Gene and Diet

April 4, 2009 by  
Filed under Genetics

All afternoon, I have been thinking about the Apo E cholesterol-related gene and what combination of Apo E genes each person in our family inherited.  The Apo E gene provides instructions for making a protein called apolipoprotein E and it is located on Chromosome 19.   This protein combines with fats (lipids) in the body to form molecules called lipoproteins.   Lipoproteins are responsible for packaging cholesterol and other fats and carrying them through the bloodstream.

Some research suggests there is a connection between the Apo E gene and Alzheimer’s and dementia.   I found out that Addi and Cassi have Apo E gene is 3/3, which is considered "neutral" so this doesn’t explain their dementia.  I think their problems have more to do with insulin factors (they have a glucose metabolism problem in frontal lobe of their brains), oxidative stress, and inflammation and the interaction between genes and nutrients/vitamins.

Research suggests that Apo E genes can influence your predisposition to certain illnesses from Alzheimer’s disease, Parkinson’s disease, heart disease and cancer.   I read that persons with the Apo E 4/4 genotype could have up to a 90 percent chance of developing a chronic illness such as Alzheimer’s.   The Apo E gene occurs as three variations in your body: Apo E 2, Apo E 3, and Apo E 4.  Since genes come in matching pairs, we inherit one from each parent.  There are six possible combinations of Apo E gene pairs: 2/2, 2/3, 3/3, 4/2, 4/3, and 4/4.

The Apo E gene could be a factor affecting how your body uses different types of foods and nutrients and different Apo E genotypes likely process foods differently.  There is an interesting book on this topic called The Apo E Diet.

Over the next few weeks, I will be working to have personal genetic testing done on our entire family and we will find out how our Apo E combinations might play a role in our health.

Coriell Institute: The Value of BioBanks To Further Medical Research

June 11, 2008 by  
Filed under Genetic Testing

Coriell tank in use
I had never heard of the term “BioBank” or biorepository until my 4 year old identical twins, Addi and Cassi, were diagnosed with a fatal disease called Niemann Pick Type C, otherwise known as the “Childhood Alzheimer’s.”

Since receiving this nightmare diagnosis, I have become familiar with many organizations I had no idea existed, including an nonprofit research organization called the Coriell Institute based in Camden, New Jersey.  Coriell is a leading biobank that is funded by the NIH and they are dedicated to understanding human genetic diseases.

Coriell collects human biospecimens from people with all types of diseases ranging from Epilepsy to Parkinson’s to Rett Syndrome.   As scientists study the connection points between genes and diseases, they are finding many diseases have complex patterns of inheritance.

I have submitted Addi and Cassi’s “biospecimens” — things like tissue and blood samples — to Coriell which are now being analyzed and stored in tanks.   When researchers are interested in studying Niemann Pick Type C diesase, they order biospecimens from Coriell so they can try and understand the molecular characteristics and clinical progression of the disease.    Once Addi and Cassi’s NPC mutation is fully analyzed, it is given an anonymous number and will be represented by a red dot on Chromosome 18 and can be ordered from Coriell.

Addi and Cassi’s DNA will essentially live on forever in these tanks and my hope is someday their DNA will help solve something researchers have not thought of yet.  Maybe their identical twinship will prove even more important to understanding disease than the genetic disease they were born with?  Who knows, but it’s interesting to think of the possibilities.

Cures for human disease can only happen faster with biobanks providing researchers with critical genetic material.  I am eternally grateful to the NPC families who have already contributed to Coriell’s biobank.   Most of these NPC children have passed away but they live on through current research work and they are now trying to help save Addi and Cassi’s lives.

I hope people who have the opportunity to provide samples to biobanks like Coriell will do so in the future and without fear.  The good news is that the newly enacted genetic discrimination law (GINA) bars health insurers from using genetic information to make coverage decisions.   Many Americans have been reluctant to take advantage of breakthroughs in genetic testing for fear of “genetic discrimination” and that the results could deny them jobs or health insurance.

Understanding Genetic Testing & Sequencing – It’s Greek To Me

January 19, 2008 by  
Filed under Genetics


We have recently learned from the Mayo Clinic that our twins Addi and Cassi have one Niemann Pick Type C gene mutation that has been identified in their bodies — it’s called Exon 12 DNA Change 1920delG.   This DNA sequence change (or deletion) is a “known pathogenic mutation in the sterol-sensing domain.”   The 1920delG mutation leads to a premature stop in the synthesis of the protein after 655 residues, instead of the normal 1278 residues.  We were told that because of the position of Addi and Cassi’s mutation, the lab at Mayo could only get clean DNA sequencing in the forward direction.  We are still trying to figure out what all of this means.

The second mutation in the twins have so far has proved elusive to Mayo Clinic researchers.  At this point, Hugh and I need to have our Niemann Pick Type C genes on Chromosome 18 sequenced in order to try identify our family’s second mutation.  Next week, we will have our blood drawn and sent to Mayo for analysis and hope to find the second mutation.  By finding our genetic mutations, we can learn clues about Niemann Pick Type C disease.  We have also found out that Addi and Cassi do not have a common NPC mutation — that mutation is called I1061C.  It gets more complicated for us and the mystery deepens.

I wonder if I have the Exon 12 DNA Change 1920delG in my body?  Or is Hugh the carrier of this faulty gene?   Which one of us has the gene that is proving elusive and hiding?   How did this even happen to us and our family?  This mystery goes back thousands of years and is so bizarre and so complicated that I simply don’t want to think about it anymore tonight.   God only knows what will happen in my dreams.  Each night, I am afraid to close my eyes for fear as to how my unconscious mind will take over  — my nightmares are beyond comprehension.

Hope, Faith and Love – Our Nations Robotic Heros!

December 7, 2007 by  
Filed under Genetic Testing

National-Chemical-Genomics- We have returned from the National Chemical Genomics Center (NCGC) and are busy working on pushing forward new therapy ideas for Addi and Cassi and Niemann Pick Type C disease using state-of-the-art cheminformatics methods.

The robotic equipment the NCGC has established for testing cells and profiling compounds for large collections of chemicals is incredible.  The whole facility is like something out of a Sci-Fi movie.  It was fascinating to see these three robots in action and we decided to name them, “Hope, Faith and Love.”

It has been an absolute insane six weeks for us since receiving the Niemann Pick Type C diagnosis.  Besides the NCGC trip, we have made trips with the girls to the Mayo Clinic and the National Institutes of Health for a week long study (thankfully with our new portable DVD player and CandyLand CD). I have literally been immersed in trying to get a handle on Niemann Pick Type C, what this means for Addi and Cassi and our family and what we can do to accelerate research into the disease and find therapies.

I have very little science background but I think I may be ready for my Ph.D. in biochemistry!   Try taking a shot at reading the Brown and Goldstein papers after reading my posting and let me know what you think (it takes some time to download).  These new papers are major scientific milestones for understanding Niemann Pick Type C and cholesterol binding at the cellular level but it’s not exactly light reading. I believe we have done a fairly good job on our website by simplifying what is happening to Addi and Cassi — cholesterol is building up in their cells and leading to neurodegeneration in their brains and doctors don’t fully understand why.

At this point, we are doing everything we can to stop this horrible disease and are trying to unearth every stone we can to find near term therapies. I have learned overnight that there is a whole different language in science — it’s a combination of Latin and Greek!  There are words like assays and microarrays (translation: sophisticated tests of cells), IRBs ( institutional review boards are really starting to slow us down in trying to find therapies for Addi and Cassi which I will leave for another post).

BC-Theta, a new kind of cholesterol binding probe (translation: you can see cholesterol in cells better and it’s cool new stuff that could be better than filipin staining (I don’t even want to get into what this is!)  There are words I’m learning like sterols, cyclodextrins, sphingomyelin, cytosolic, pathogenic cascades, hepatomegaly and substrate reduction therapy. I don’t really want to learn any of this but I must in order to try and work towards finding therapies to help Addi and Cassi.

I wish I could go back six weeks to when I was making trips to Baskin-Robbins, the library and Walmart.  I have not been able to spend much time with Addi and Cassi since this all happened and my mother has essentially moved in with us.  Our nanny is working overtime to try and keep things somewhat normal in our household while we try and make headway with doctors and researchers to accelerate research.  We really have no choice.   We can’t simply stand on the sidelines and do nothing so we have decided to take action on multiple levels.

For those of you wanting and update on the drug Zavesca, we still don’t have it and I’ve been working to push this along for weeks now.   After hours of back and forth on the phone and email, we should have the drug by Monday.   I really should not complain.  At least we’re going to get the medication.  I had an email exchange with one Mom and their insurance company won’t cover the drug. It costs $80,000 per year to have a child on Zavesca — $160,000 for Addi and Cassi for the year!   To give you an idea of how expensive this is, in 2006, the median annual household income was $48,201.00!   Obvoiusly, these people don’t make enough money to pay for Zavesca so they have to watch their son slowly die without being able to do anything about it.   If you are feeling sorry for us, can you imagine this hopeless feeling?

This makes me so incredibly ANGRY at our system – a drug that could help slow down this disease should not cost this amount of money.   This is also why I am so motivated to do something to bring awareness to this cholesterol disorder and also what is happening in our medical system (more posts to follow on this for sure!) We are literally in a race against time and unfortunately this is not a marathon.  We are in an outright sprint.  We plan to win this race for all kids with Niemann Pick Type C even though we’ve just come out of the starting blocks.  We appreciate everyone cheering us on!

Finally, we need financial donations to help us accelerete research not only for Addi and Cassi but for a novel medical approach we are pursuing that could impact millions of people.  Please donate today to the Addi and Cassi Fund.

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