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neonatal?

Discussion in 'Parents of Children with Monogenic Diabetes' started by uscmedmom, Apr 20, 2011.

  1. uscmedmom

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    My son was diagnosed right after he turned 7 months old. He is now 16 months and has been pumping since we were diagnosed. They did 3 autoantibody studies at diagnosis, and they just did a glutamic acid decarboxylase. He has only tested positive for one autoantibody. Is it possible he could have neonatal diabetes? We have talked with the center at the Univ of Chicago but have not received our test kit in the mail. I called and left a message yesterday. Any thoughts? Thanks!
     
  2. mrcool

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    My son was dx'd at 7 months as well. At dx he was tested for 3 antibodies, I believe, it all came back negative. That was the main reason our endo ordered genetic testing, and we also did it through University of Chicago. He was negative for neonatal diabetes. Our endo thinks he either had small amounts of antibodies that the test didn't detect, or had an antibody that wasn't tested for. Who knows...

    It's good you're getting the test done, it gave me some kind of closure, and I could move on. Otherwise I was just hoping that maybe we can get off insulin. I have heard of babies dx'd at over 6 months old that have neonatal diabetes, so you never know.

    I remember it took many weeks to hear back from University of Chicago once we had sent the test back, so be ready for some waiting. :)
     
  3. C6H12O6

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    The fact that your son's A1C was 8.4 and diagnosis could be indicative of the fact he has monogenic diabetes. I am just speculating though, you may have simply caught the diabetes shortly after he started experiencing hyperglycemia
     
  4. MrsSM

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    Our Endo sent my daughters DNA to the UK for testing...the turnaround was only 2 weeks...I'm not sure where it went but i"ll find out and post for you. I know it was in Exeter.

    :)
     
  5. MrsSM

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  6. redcurls3

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    There is a small possibility that it could be monogenic. You just never know so I say get tested. It is good that you are going ahead with testing. Here is an article about a patient who was dx @ 12 weeks and tested positive for islet cell antibodies. I don't have full access to it, but you may be able to get the full article if you want.

    http://www.ncbi.nlm.nih.gov/pubmed/19692135

    Good luck to you and let us know what you find out.
     
  7. uscmedmom

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    thanks for all your replies! univ of chicago has not called me back yet. i will try again today. i spoke with the researcher a few months ago but never received the kit in the mail. i went to our endo last week and she said to check into it because another family had already received the kit and sent it back.

    do the kids with neonatal diabetes, have more "in range" blood sugar levels? i was just wondering. also i saw some children may have developmental delays. colton will be 17 months old on friday and is not saying any words. we are going to be evaluated by a speech therapist in may. he will only "try" to say "mama" if he is mad or upset.

    thanks for your replies and interest!!!
     
  8. redcurls3

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    I'm not sure about the other kids, but when Andy was on insulin, he was almost never in range. (I think) one of the signs of ND is being extremely sensitive to insulin and needing extremely small amounts of insulin (compared to other T1's of that age). Andy's TDD always stayed around 3U and he hardly ever needed more than that (unless he was sick). We had to put him on the pump at 12months because we were having so many lows on MDI. We were trying to measure out .5U to give him and even that would drop him 300-400 points very quickly. It was a nightmare.

    As for Developmental Delays, it varies for each child. The scientific literature quotes about 20% of those with ND will have some neurological symptoms and developmental delays. It seems like more to me, but maybe it's just that those of us with DD kids tend to talk a lot more to each other than those who don't have problems. They do know that there are certain mutations that are associated with DD so if he does end up positive for the gene, finding out the specific mutation will help you when you research online about it.

    Hopefully you will receive your kit soon. Good luck.
     
  9. Cookie Monster

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    I've had a read of this paper. The antibodies were from the mother. Antibodies that pass through the placenta can persist in the child up to 10 months. In this case they tested at diagnosis and multiple times afterwards. She had less antibodies at 6 months then nothing was picked up at 8 months, 2 years or 6 yrs. The KCNJ11 mutation was only picked up at 6 yrs.
    So the diabetes wasn't caused by the antibodies. Interestingly the mother, positive for the antibody, wasn't diagnosed with diabetes, and still hadn't been by the time the paper was written.

    So for the OP, the answer is that while the antibody presence suggests it's not neonatal diabetes, it can't be ruled out. Probably worth testing. I note in the OP's signature there is Hashimoto's in the family so that might suggest an increased chance of autoimmune disease but probably still worth talking to the experts.

    P.S. I am neither a doctor nor diabetes specialist, just a parent of a CWD. Don't take my thoughts as gospel!
     
  10. C6H12O6

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    here's the full text, I can't paste in one of the figures

    Abstract

    In contrast to the autoimmune type 1 diabetes, patients with monogenic diabetes due to KCNJ11 mutations do not have pancreatic auto-antibodies at onset. Here we describe a patient diagnosed at the age of 12 weeks that showed ICA at diagnosis, yet has been tested with positive result for KCNJ11 mutation.



    Affiliation:

    1 Department of Immunopathology and Genetics, Medical University of Lodz, 36/50 Sporna Street, 91-738 Lodz, Poland

    2 Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, 36/50 Sporna Street, 91-738 Lodz, Poland

    3 Department of Metabolic Diseases, Jagiellonian University, Medical College, Krakow, Poland


    Table of Content:

    1 Introduction

    2 Case report

    3 Measurement of anti-islet auto-antibodies

    4 Discussion

    Conflict of interest



    1 Introduction

    Permanent neonatal diabetes (PNDM) is a rare condition occurring within the first few months of life. About 50% of all PNDM cases are thought to arise from heterozygous activating mutations in the KCNJ11 gene which encodes for potassium channel subunit, Kir6.2 [1?3] .

    Identification of the activating mutation in the KCNJ11 can have a major impact on the choice of therapy. KATP channels are the targets for the sulphonylurea drugs, which stimulate insulin secretion by binding to SUR1 and closing β-cell KATP channels directly, thus bypassing cell metabolism [4?7] . Many patients with activating Kir6.2 mutations have been able to switch from insulin injections to sulphonylurea tablets with an improvement in glycemic control [8?10] .

    In contrast to subjects with the autoimmune type 1 diabetes, patients with KCNJ11 mutations do not have pancreatic auto-antibodies at onset [1,3,11,12] . This observation has been repeatedly confirmed by data coming from all reports published on neonatal diabetes. However, recently we have demonstrated that diabetic patients that are carriers of the KCNJ11 mutation may show seroconversion with long duration of the disease [13] . Here we describe a patient that showed pancreatic auto-antibodies at onset, yet has been tested with positive result for KCNJ11 mutation.

    2 Case report

    This patient (Pol23 according to Polish PNDM registry) was previously described as the first case of objectively confirmed central nervous system improvement following glibenclamide therapy [14] .

    Briefly, the female patient was born at term after an un-eventful pregnancy. At 12 weeks, she presented with insulin-dependent diabetes. The patient received subcutaneous insulin therapy with multiple insulin injections (insulin requirement 1.3U/kg per day). Motor and mental functions were normal at diabetes diagnosis. At 24 months mental retardation and muscle weakness were observed. At the age of 6 years the patient was diagnosed with an intermediate DEND syndrome due to de novo H46L Kir6.2 mutation. Gain-of-function mutations in Kir6.2 that cause permanent neonatal diabetes mellitus can be successfully treated by sulphonylureas instead of insulin injections [9?11] . Thus, after confirmation of diagnosis and obtaining informed consent glibenclamide treatment was initiated. The patient is currently treated with a glibenclamide dose of 0.62mg/kg daily. Glibenclamide treatment led to improvement in both glycemic control and neurological function as described previously [14] .

    3 Measurement of anti-islet auto-antibodies

    Islet cell antibodies (ICAs) were detected by indirect immunofluorescence tests. Glutamic acid decarboxylase 65 antibodies (GADA) and tyrosine phosphatase IA2 antibodies (IA2-Ab) were measured by commercial ELISA kits, Anti-GAD Assay (IgG) and Anti-IA2 Assay (IgG), respectively (EUROIMMUN GmbH, Germany) [13] . Anti-insulin antibodies (IAA) were measured with a standard IAA CT2 radioassay (CIS BioInternational, France).

    At the time of diabetes onset the patient did not have GADA, IA2-Ab nor IAA antibodies. Interestingly, she was positive (20 JDF units) for ICA. Patient's serum was repeatedly tested for ICA. The antibody measurement performed in 2-week time (20 JDF) and at the age of 6 months (10 JDF) was still positive. In successive samples, taken at the age of 8 months, 2 and 6 years ICAs were not detectable (Fig. 1 ).

    Although patient's mother was normoglycemic at pregnancy and delivery, we aim to check her serum for the presence of anti-islet antibodies at the time of diagnosis of diabetes in her daughter. Test results included positive ICA (40 JDF units) and negative GADA, IA2-Ab and IAA. Till the time of writing she did not develop diabetes.

    4 Discussion

    It is well established that diabetes autoimmune markers are absent at the onset of PNDM. Here we describe a patient who tested positively for ICA, but not GADA nor IA2-Ab at the age of 12 weeks, at the time of diagnosis. Antibodies measurements performed in patient's mother serum showed presence of ICA, but no other type 1 diabetes-associated antibodies. Since most of anti-islet antibodies are of the IgG class they are actively transported through the placenta [15] . It has been reported in several publications that anti-islet antibodies are a common finding in newborns of mothers with type 1 diabetes [16?19] . Those antibodies are known to disappear from the circulation of the infant during first months of life. According to Hamalainen et al. the mean elimination time for ICA comes to about 3 months, but in some cases ICA could be detected as late as at the age of 10 months [16] . Consistent antibody profile, decline in antibody level and finally negative test results at the age of 8 months, 2 and 6 years support the concept that ICAs in patient serum were of mother's origin. Moreover, these anti-islet antibodies seem not to be related to autoimmune β-cell destruction since the patient had a good glycemic control on glibenclamide therapy following 6 years of insulin treated diabetes.

    Our observation may raise an important clinical consideration whether to take lack of anti-islet antibodies at onset as one of the inclusion criteria for genetic evaluation. We suggest that patients who are positive with anti-islet antibodies at neonatal diabetes onset should still be considered for genetic assessment.

    Conflict of interest

    The authors declare that they have no conflict of interest.



    Fig. 1

    Dynamics of changes in ICA titer found in PNDM patient with activating H46L mutation of Kir6.2.
     
    Last edited: Apr 26, 2011
  11. C6H12O6

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    this is

    Fig. 1

    Dynamics of changes in ICA titer found in PNDM patient with activating H46L mutation of Kir6.2.
     

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