When Diabetes is not Type 1 or Type 2 - Monogenic Diabetes

This is an introductory post on Monogenic Diabetes (MD), a form of diabetes that is neither Type 1 nor Type 2.  It is caused by a genetic variation (or error depending on your view) which causes abnormalities in blood sugar regulation.  MD is technically two types of genetic variations, neonatal diabetes and what is called Maturity Onset Diabetes of the Young (MODY).  All the forms of MD are inherent at birth, but MODY typically is first diagnosable in children and young adults, hence the term MODY.  In fact anyone can be diagnosed with MODY at any age and it is thought that at least 1-2% of all diabetes cases are MODY, so there might be more than 500,000 people in the US with MODY.  MODY was first identified in the 1970s and there are now at least 11 forms of MODY that have been identified.  And for many of these forms there are literally dozens of different variations that can lead to the genetic defect.

For years I've wondered whether I might have MODY.  In the following, I'm going to give more background on MODY and in future posts I'll discuss my journey leading up to being tested for MODY.  It may seem strange that I would obsess about this but the most important thing to remember is that being diagnosed with Type 2 isn't a specific diagnosis.  Type 2 is a diagnosis of exclusion and that actually means that you have "Diabetes of Unknown Causes."  And if you don't know your specific diagnosis you can mistreated, potentially severely mistreated.  And unfortunately 95% of patients with MODY are misdiagnosed as either Type 1 or Type 2. In further posts I'll tell you about actually getting the tests and eventually I'll tell you when I hear about the results (which I don't know yet).

MODY is an autosomal dominant condition, thus you only need one copy abnormal gene to express the condition.  This means that if you have MODY then on (or both) of your parents will have the condition.  By the same token, if one parent has the condition there is a 50% chance that a child will have the condition.  And while many genetic variations may or may not result in a disease being expressed, MODY is highly expressed.  Unlike T1 where having the HLA genes may place you at modest risk for T1, if you have the MODY gene you most likely will have the disease.  And because of the heritability of the condition your children are at risk.

There are two major research centers in the world for MODY;  Diabetes Genes at Exeter in the UK run by Professor Andrew Hattersley and colleagues and Monogenic Diabetes at Kovler Diabetes Center at University of Chicago run by Dr. Louis Philipson, Dr. Graeme Bell, Dr. Siri Greeley and colleagues.  Each of these centers have started to make very useful information available to help patients understand the conditions.  While these centers do research and do some clinical work, patients for the most part work with their own local medical team in diagnosing and treating MODY.  And obviously one would expect that a disease that has only been known for a couple of decades and for which treatments have only been partly identified in the last ten years is not well known in the medical community.  And so this is a real challenge for patients which I will discuss in later posts.

Kinds of MODY

So about MODY, there are roughly 11 different forms that have been identified (depending on who you talk with).  Penetrance, which is a measure of how many people display the trait of abnormal blood sugars varies between 40-90% which is pretty high.  The forms are listed below based on what is written in Wiki:

Type	Gene/protein	NickName	Description
MODY 1	hepatocyte nuclear factor 4α	HNF4α	Due to a loss-of-function mutation in the HNF4α gene. 5%–10% cases.
MODY 2	glucokinase	GCK	Due to any of several mutations in the GCK gene. 30%–70% cases. Mild fasting hyperglycaemia throughout life. Small rise on glucose loading.
MODY 3	hepatocyte nuclear factor 1α	HNF1α	Mutations of the HNF1α gene (a homeobox gene). 30%–70% cases. Tend to be responsive to sulfonylureas. Low renal threshold for glucose.
MODY 4	insulin promoter factor-1	IPF1	Mutations of the IPF1 homeobox (Pdx1) gene. < 1% cases. Associated with pancreatic agensis in homozygotes and occasionally in heterozygotes.
MODY 5	hepatocyte nuclear factor 1β	HNF1β	One of the less common forms of MODY, with some distinctive clinical features, including atrophy of the pancreas and several forms of renal disease. Defect in HNF-1 beta gene. 5%–10% cases.
MODY 6	neurogenic differentiation 1		Mutations of the gene for the transcription factor referred to as neurogenic differentiation 1. Very rare: 5 families reported to date.
MODY 7	Kruppel-like factor 11	KLF11	KLF11 has been associated with a form of diabetes that has been characterized as "MODY7" by OMIM
MODY 8	Bile salt dependent lipase	CEL	CEL has been associated with a form of diabetes that has been characterized as "MODY8" by OMIM. It is very rare with five families reported to date. It is associated with exocrine pancreatic dysfunction.
MODY 9	PAX4		Pax4 is a transcription factor. MODY 9 is a very rare medical condition.
MODY 10	INS		Mutations in the insulin gene. Usually associated with neonatal diabetes. Rare < 1% cases.
MODY 11	BLK		Mutated B-lymphocyte tyrosin kinase, which is also present in pancreatic islet cells. Very rare.

The most common forms of MODY are MODY-2 and MODY-3 which are each thought to represent 30-70% of cases. Other common forms include MODY-1 and MODY5.  The other types of MODY appear to be very rare.  Different populations of people may have different rates of MODY which makes sense since you would think that it would be shared across related populations.  My discussion here will be focused on the most common forms of MODY, MODY-2 and MODY-3 which I will now refer to as GCK and HNF1α respectively.   In the remain part of this post, I'll highlight the screening, diagnosis and treatment of MODY and in later posts I'll go into more detail.

Screening for MODY

Screening is the way that our medical system should identify patients who have a good chance of having MODY and properly referring them for genetic testing.  Screening turns out to be very important since testing is expensive.  But screening for MODY is a challenge, the two primary forms GCK and HNF1α present very differently.  Up until recently the screening was almost totally focused on identifying infants and children, but recent revisions screening guidelines by Kovler have more effectively included criteria that apply to adults.  Here are the Kovler screening guidelines:

• a “type 1″ diabetes patient who has negative blood testing for autoantibodies, typically done at the time of diabetes diagnosis (antibodies typically tested include one or more of the following: GAD65, islet cell or ICA,  IA-2, insulin, ZnT8)
• a “type 1″ diabetes patient who generates a significant amount of insulin years beyond diagnosis (detectable blood levels of c-peptide, proinsulin, and/ or insulin)
• a “type 2″ diabetes patient who is normal weight or not significantly overweight and shows no signs of insulin resistance
• a diabetes patient who is part of a family in which three or more consecutive generations have been diagnosed with diabetes
• a diabetes patient with stable, mildly elevated blood sugars, often found incidentally during a check-up. MODY presents with symptoms that often veer from the norm for type 1 or type 2 diabetes.

More practically GCK presents with chronically elevated fasting blood sugars but a response to meals that while delayed actually restores blood sugars to fasting levels (albeit high fastings) in a relative normal manner.  HNF1α patients will generally have normal fastings but have wildly exaggerated responses to meals, they are insulin sensitive and a low renal threshold.

Testing for MODY

Testing for MODY is a challenge, it must be done through an expensive sequencing process.  In general the process looks for variations or defects in a specific gene.  And for a particular form there can be a lot of variations, for instance there are literally several hundred variations known for the GCK gene.  Testing can either be performed at one of the research centers or at a commercial lab.  The two centers at Exeter and Kovler do testing as part of their research and if you qualify and enter one of their trials I suspect they will perform the testing without cost.  But for the majority of patients you must go to a commercial lab, of which I believe there is only one in the US, AthenaDiagnostics.  And make no mistake the cost of MODY testing can be significant.  A study by Kovler on the cost effectiveness of MODY testing pegged the cost of a panel which tested GCK, HNF1α and HNF4α as $2,540.  The cost from a commercial lab is likely much higher.  A full panel from AthenaDiagnostics currently tests for MODY1, 2, 3, 4, 5 and 8.

Your doctor usually requisitions the test from AthenaDiagnostics and the results are sent back to the doctor.  There are only a few insurance plans that currently cover this sort of testing.  It may require a letter of medical necessity in order to get coverage.  I'll be posting more on my experiences getting tested and how the process works.

Treatment of MODY

The whole reason that proper diagnosis of MODY matters is that it can make a difference in treatment.  And make no mistake, mistreatment can not only cost the patient lots of money by mistreatment can expose the patient to harm.  The treatment that seems to work very well for HNF1α (MODY-3) is small doses of sulfonylureas.  In the recent movie "Journey to a Miracle: Freedom from Insulin" this was highlighted as a miracle cure allowing patients to stop insulin treatment and just take a pill.  I'll be posting soon on what I heard at the 2015 75th ADA Scientific Sessions where I saw this movie and heard about other research.  Personally, I'm not convinced it is a cure and I'm not really sure that MODY-3 patients should really expect they can just take a pill and that their condition won't present continued health risks throughout their lives due to abnormal blood sugars.

The GCK form of diabetes on the other hand is touted as not requiring treatment.  There have been various claims made about this and some people apparently believe a low carb diet can be effective.  So depending on who you talk with being diagnosed with GCK may allow a patient to stop all other treatments.  Again, I personally have questions about this and whether elevated blood sugars will continue to present risks to patients.

And finally a lot of the science and evidence supporting current treatment recommendations is weak.  There isn't much data and it isn't long-term.  There have been some limited studies looking at complication rates and treatment effectiveness but certainly not enough to be making definitive statements about optimal treatment regimes.  In future posts I'll touch on some of these topics and what I have heard most recently.


Summary

If you made it this far I'd just like to reinforce what I said at the very beginning.  MODY is a different kind of diabetes than Type 1 or Type 2.  If you are one of the 500,000 people in the US who has been misdiagnosed and you actually have MODY then it can make a huge difference to your treatment and to your health.  Think about it, if you take insulin and suddenly learn you can go off insulin and simply take a little pill or maybe no pill at all.  What a huge difference.  Proper diagnosis can make a huge difference in treatment and avoid years of costly and harmful mistreatment.