am i at risk?

Monogenic Diabetes (Permanent Neonatal Diabetes) in Children

Dr. Fran Cogen Health Pro April 27, 2010
  • 1024x768 Normal 0 false false false EN-US X-NONE X-NONE As can be gleaned from many of the previous blogs, the diagnosis of diabetes defines many types that require different treatments. Indeed, it has only been recently that we have eliminated the term "juvenile d...

20 Comments
  • davepoll
    Mar. 22, 2012

    I dont konw the reason why diabetes affect childrens mostly?

     

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    Radiology billing

    • Dr. Fran Cogen
      Health Pro
      Mar. 22, 2012

      Actually 90% of people with diabetes have type 2 and are adults. Please see my previous blogs for more information.
      Dr.Cogen

  • Susie
    Mar. 21, 2012

    My niece has a rare form of the genetic mutation. She was diagnosed after only a few weeks of birth. She has been recently hospitalized. Have you ever seen any case where the child has started to periodically stop breathing? She has had two cardiac arrests, due to her lack of breathing, and the doctors don't seem to know what is wrong. I was doing research...

    RHMLucky777

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    My niece has a rare form of the genetic mutation. She was diagnosed after only a few weeks of birth. She has been recently hospitalized. Have you ever seen any case where the child has started to periodically stop breathing? She has had two cardiac arrests, due to her lack of breathing, and the doctors don't seem to know what is wrong. I was doing research on her condition, and I can't seem to find anyone mentioning this type of symptom associated with her condition. She has gone through every test imaginable, the doctors don't know what to do or test for anymore. Please help if you have any information.

    • Dr. Fran Cogen
      Health Pro
      Mar. 21, 2012

      Hi Susie: I am sorry to hear about your niece. I assume that she has been diagnosed with Permanent Neonatal Diabetes. But, you did not specify which kind. If you can supply me with that information, I could try to find out if that particular mutation is associated with cardiac abnormalities. Offhand, I can't think of any of the mutations within Permanent neonatal...

      RHMLucky777

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      Hi Susie: I am sorry to hear about your niece. I assume that she has been diagnosed with Permanent Neonatal Diabetes. But, you did not specify which kind. If you can supply me with that information, I could try to find out if that particular mutation is associated with cardiac abnormalities. Offhand, I can't think of any of the mutations within Permanent neonatal diabetes that would lead to these issues. But, more and more mutations have been identified. Please send me more information about your niece's diagnosis if you have it and I will see waht I can find out.

      Dr.Cogen

    • Susie
      Mar. 21, 2012

      Thank you so much. My niece has PND, she has the KNCJ11 Kir. 6 V59M mutation, if there is any information you might have I would appreciate it. She is only 20 months old, and it's so hard to see her go through all these tests with no answers as to why she is now not breathing. Thanks again.

    • Dr. Fran Cogen
      Health Pro
      Mar. 21, 2012

      Susie: I did a preliminary literature search for you (including my Pediatric Diabetes paper-no info there re the cardiac arrest). I found an interesting mouse paper. This paper talks about cardiac issues resulting in congestive heart failure due to the problems K-ATP channels in the KCJ11-kir.6 mutation. If she has breathing problems - respiratory arrests leading...

      RHMLucky777

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      Susie: I did a preliminary literature search for you (including my Pediatric Diabetes paper-no info there re the cardiac arrest). I found an interesting mouse paper. This paper talks about cardiac issues resulting in congestive heart failure due to the problems K-ATP channels in the KCJ11-kir.6 mutation. If she has breathing problems - respiratory arrests leading to cardiac problems, that may be different. There is also a syndrome called DEND: Developmental Delay, learning difficulties and epilepsy. I have included the abstract of the paper I discussed below. Keep in mind this does not definatively diagnose your niece's problem; but may provide some clues.

       

      SEARCH

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    • Susie
      Mar. 22, 2012

      The respiratory arrests are what are causing her heart to stop. She randomly just stops breathing, almost in cycles. You have to nudge her to breathe. Thank you for the article and information. She was on the glybride but it didn't seem to improve her condition, so my sister took her off of it. If you know of anyone else that specializes in this field could...

      RHMLucky777

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      The respiratory arrests are what are causing her heart to stop. She randomly just stops breathing, almost in cycles. You have to nudge her to breathe. Thank you for the article and information. She was on the glybride but it didn't seem to improve her condition, so my sister took her off of it. If you know of anyone else that specializes in this field could you pass on their information. Or if anyone reading this has any information, please post.

    • Dr. Fran Cogen
      Health Pro
      Mar. 22, 2012

      Susie: I will ask some of my colleagues to see if they have any additional information. It almost sounds if your niece has apnea which I have not seen associated with PND.

      DrC

  • barb
    May. 15, 2010

    My son was diagnosed with type 1 diabetes at 4 month of age.  He has been on insulin for 14 1/2 years.  We were just hold this week he may have neonatal monogenic diabetes and not type 1.  I am trying to get as much information as to what this is.  Any help you can give would be greatly appreciated

    • Dr. Fran Cogen
      Health Pro
      May. 16, 2010

      Hi Barb! It is very possible that your son my have permanent neonatal diabetes as he was diagnosed with insulin dependent (type 1) diabetes under 6 months of age. As I mentioned, there is now a diagnostic blood test that may be performed on your son checking for the different mutations associated with PND (KCNJ11 being them most common). I am sure your pediatric...

      RHMLucky777

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      Hi Barb! It is very possible that your son my have permanent neonatal diabetes as he was diagnosed with insulin dependent (type 1) diabetes under 6 months of age. As I mentioned, there is now a diagnostic blood test that may be performed on your son checking for the different mutations associated with PND (KCNJ11 being them most common). I am sure your pediatric diabetes team will be able to send the blood work to athena diagnostics to rule out PND. (athena has a website listing these necessary test if your practice does not have access to the forms).  It is definitely worth it to do the lab work as he may be able to be weaned from insulin if he has the mutation.  For more information about PND, check out the Permanent Neonatal Diabetes registry. Where is your geographic location?

      DrC

    • Dr. Fran Cogen
      Health Pro
      May. 16, 2010

      Barb: here is the link to my case report that is very reminiscent of your son's presentation:  clinical.diabetesjournals.org/content/27/1/25.full      

       

      I hope this is helpful. Please feel free to email me with further questions. 

      DrCogen

    • Anonymous
      Anonymous
      Jun. 17, 2010

      We just got the lab work back. he has PNDM, here is the exact terms listed:

       

      INS gene identified a heterozygous missense mutation, R89C

       

      INS Exons 1-3 

      PCR/sequencing   (sequence accession number NM_000207)

       

      He is heterozygous for missense mutation, R89C, in exon 3 of the INS gene. This C>T mutation at nucleotide...

      RHMLucky777

      Read More

      We just got the lab work back. he has PNDM, here is the exact terms listed:

       

      INS gene identified a heterozygous missense mutation, R89C

       

      INS Exons 1-3 

      PCR/sequencing   (sequence accession number NM_000207)

       

      He is heterozygous for missense mutation, R89C, in exon 3 of the INS gene. This C>T mutation at nucleotide 265 (c.265c>T) results in the substitution of cysteine for arginine at codon 89 (p.Arg89Cys)

       

       

    • Dr. Fran Cogen
      Health Pro
      Jun. 18, 2010

      Dear Anonymous: Yes, it appears that your child has PND. See below for an excerpt from the literature for mutations of the INS varients.  The information below supports the diagnosis. I just wanted you to see how it was diagnosed. I know this is for reference only.

       

      INS. PNDM as a result of heterozygous INS mutations presents with diabetic ketoacidosis...

      RHMLucky777

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      Dear Anonymous: Yes, it appears that your child has PND. See below for an excerpt from the literature for mutations of the INS varients.  The information below supports the diagnosis. I just wanted you to see how it was diagnosed. I know this is for reference only.

       

      INS. PNDM as a result of heterozygous INS mutations presents with diabetic ketoacidosis or marked hyperglycemia. Most newborns are small for gestational age [Stoy et al 2007, Polak et al 2008].

       

      The median age at diagnosis is nine weeks, but some children present after age six months.

       

      Is this consistent with your child?

       

       

      The key is how to treat it.

      Children with mutations in KCNJ11 or ABCC8 can be transitioned to therapy with oral sulfonylureas; high doses are usually required (0.4-1.0 mg/kg/day of glibenclamide) [Hattersley & Ashcroft 2005, Pearson et al 2006].

       

      Long-term insulin therapy is required for all other causes of PNDM.

       

      Normal allelic variants. INS is located on chromosome 11p15.5. The gene is made up of three exons and two introns. Exon 2 encodes the signal peptide, the B chain, and part of the C peptide; exon 3 encodes the reminder of the C peptide and the A chain.

      Pathologic allelic variants. At least ten missense mutations have been described in association with PNDM [Stoy et al 2007, Polak et al 2008]. See Table 6.

       

      Table 6. Selected INS Pathologic Allelic Variants

      DNA Nucleotide ChangeProtein Amino Acid ChangeReferenceReference Sequences c.71C>A p.Ala24Asp Stoy et al [2007], Polak et al [2008] NM_000207.2 NP_000198.1 c.94G>A p.Gly32Ser c.94G>C p.Gly32Arg c.127T>G p.Cys43Gly c.140 G>T p.Gly47Val c.143 T>G p.Phe48Cys c.265C>T p.Arg89Cys c.268 G>T p.Gly90Cys c.287G>A p.Cys96Tyr c.323 A>G p.Tyr108Cys

      See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).

      Normal gene product. Insulin is synthesized by the pancreatic beta cells and consists of two dissimilar polypeptide chains, A and B, which are linked by two disulfide bonds. Chains A and B are derived from a 1-chain precursor, proinsulin. Proinsulin is converted to insulin by enzymatic removal of a segment that connects the amino end of the A chain to the carboxyl end of the B chain. This segment is called the C peptide.

      Abnormal gene product. Some reported mutations disrupt normal disulfide bonds (p.Cys43Gly and p.Cys96Tyr) or add an additional upaired cysteine residue (p.Arg89Cys and p.Gly90Cys) at the A-chain C-peptide cleavage site. Mutation p.Tyr108Cys may cause mispairing of cysteines in a critical region close to a disulfide bond [Stoy et al 2007]. All of the mutants are likely to act in a dominant manner to disrupt insulin biosynthesis and induce endoplasmic reticulum (ER) stress. The exact mechanism by which these unpaired cysteines disrupt ER function remains unclear [Izumi et al 2003]. Three other mutations (p.Gly32Ser, p.Gly32Arg, and p.Gly47Val) are located in a residue that is invariant in both insulin and the insulin-like growth factors and must play an important structural role. It is believed that these glycine mutations also act similarly to impair proinsulin folding and thereby induce ER stress via

      Normal allelic variants. INS is located on chromosome 11p15.5. The gene is made up of three exons and two introns. Exon 2 encodes the signal peptide, the B chain, and part of the C peptide; exon 3 encodes the reminder of the C peptide and the A chain.

      Pathologic allelic variants. At least ten missense mutations have been described in association with PNDM [Stoy et al 2007, Polak et al 2008]. See Table 6.

       

      My assumption is that your diabetes physician is aware of all this information. Are you connected with the Permanent Neonatal diabetes experts in your area?

      Let me know if I can be of any further assistance.

       

      Dr.Cogen

       

       

  • Joseph K.
    May. 01, 2010

    Thank you Fran, for not assuming it is cut and dried. I have wondered for several years if my disorder could have anything to do with the loss of a kidney to cancer, or the seizure disorder I grew up with.

  • Anonymous
    Liron
    Apr. 30, 2010

    Dear Dr. Cogen

     

    Thank you so much for bringing to our attention and knowledge such an important information!

    I read there are cases of transient monogenic diabetes, that appear later in life as type 1 or 2, could these cases  actually be misdiagnosed and are monogenic diabetes cases that had a temporary alleviation of symptoms?

     

    And...

    RHMLucky777

    Read More

    Dear Dr. Cogen

     

    Thank you so much for bringing to our attention and knowledge such an important information!

    I read there are cases of transient monogenic diabetes, that appear later in life as type 1 or 2, could these cases  actually be misdiagnosed and are monogenic diabetes cases that had a temporary alleviation of symptoms?

     

    And if this theory is possible, could the first appearance of symptoms be missed and the person is diagnosed for the first time at a later stage in life? maybe there are other cases of monogenic diabetes that are misdiagnosed?

     

    Liron

     

     

     

     

    • Dr. Fran Cogen
      Health Pro
      May. 01, 2010

      Hi Liron: Based on my knowledge (as well as my colleagues at Children's), transient neonatal diabetes that actually resolves and then later recurs is probably not permanent neonatal diabetes. In PND, insulin is unable to be released by the beta cells due to the mutations described in the blog. So, my understanding is that unless treated with an oral hypoglycemic...

      RHMLucky777

      Read More

      Hi Liron: Based on my knowledge (as well as my colleagues at Children's), transient neonatal diabetes that actually resolves and then later recurs is probably not permanent neonatal diabetes. In PND, insulin is unable to be released by the beta cells due to the mutations described in the blog. So, my understanding is that unless treated with an oral hypoglycemic such as glyburide to unlock the ion channels, insulin would always be required and their would be no remission of diabetes. However, I would not rule out the other forms of MODY or even type 2 diabetes or even the remote possibility of autoimmune Type 1 diabetes if the same person developed diabetes. Clearly, Laboratory work would need to be performed to rule out the different forms of diabetes. Hope this helps.

      DrC

  • Judy
    Apr. 29, 2010

    I am still fascinated by your knowledge of different types of diabetes.  Your very thoughtful advise to diabetics and their caretakers is great.  Thank you. I would very much like you to come to my adult type 1 support group meeting in Howard County (MD) Hospital's wellness center on Charter Drive.  I wonder now if we all have the same kind of...

    RHMLucky777

    Read More

    I am still fascinated by your knowledge of different types of diabetes.  Your very thoughtful advise to diabetics and their caretakers is great.  Thank you. I would very much like you to come to my adult type 1 support group meeting in Howard County (MD) Hospital's wellness center on Charter Drive.  I wonder now if we all have the same kind of diabetes! You said that you might be able to come if your schedule allowed it.  We have topics/programs arranged through our June meeting.  We meet the third Monday of each month.  If any other adult T1 reads this and would like to attend we would welcome them.  I tried to answer your other very prompt response but I don't think it worked. 

    • Dr. Fran Cogen
      Health Pro
      May. 01, 2010

      Hi Judy: Thanks for your kind remarks. It might be possible for me to attend depending on my schedule and time. Please email me with specifics.

      DrC

    • Judy
      Jun. 10, 2010

      Thanks for your answers.  I have emailed my adult T1 support group to see if they might be willing to come to a meeting on another night, maybe Wednesday.   So far only 4 people have answered.  Two have said that they couldn't come on a different night and two have been very enthused about the possibility of you coming to a meeting and would...

      RHMLucky777

      Read More

      Thanks for your answers.  I have emailed my adult T1 support group to see if they might be willing to come to a meeting on another night, maybe Wednesday.   So far only 4 people have answered.  Two have said that they couldn't come on a different night and two have been very enthused about the possibility of you coming to a meeting and would be willing to come on almost any other night!  It was also suggested that we invite the parents of T1 children to our meeting if you do come.  (They also meet on the third Monday of the month but in a different location.)  I should be able to find out more at our June 21st meeting.  I was thinking about the third Wednesday in October, if it would work with your schedule. I've had a guest from Oregon with me last week so I haven't spent as much time as I might have on this.

    • Dr. Fran Cogen
      Health Pro
      Jun. 13, 2010

      Judy: I am in Annapolis on October 20. Is that location near you?

      DrC