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    Neonatal Diabetes Mellitus: Anietie Daniel Jeremiah BMS1701994

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    Anietie
    Neonatal diabetes mellitus is a rare form of diabetes that occurs in the first few months of life and results from either abnormal pancreatic development or beta cell dysfunction. It can be transient or permanent. The most common genetic causes are abnormalities in the 6q24 locus or mutations in the ABCC8 and KCNJ11 genes which code for the potassium channel in beta cells. These genetic defects lead to insufficient insulin production. Treatment involves blood glucose management through insulin or sulfonylureas depending on the underlying cause. Understanding the genetics of neonatal diabetes provides insights into pancreatic development and function as well as more common forms of diabetes.

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    Neonatal Diabetes Mellitus: Anietie Daniel Jeremiah BMS1701994

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    Anietie
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    Neonatal diabetes mellitus is a rare form of diabetes that occurs in the first few months of life and results from either abnormal pancreatic development or beta cell dysfunction. It can be transient or permanent. The most common genetic causes are abnormalities in the 6q24 locus or mutations in the ABCC8 and KCNJ11 genes which code for the potassium channel in beta cells. These genetic defects lead to insufficient insulin production. Treatment involves blood glucose management through insulin or sulfonylureas depending on the underlying cause. Understanding the genetics of neonatal diabetes provides insights into pancreatic development and function as well as more common forms of diabetes.

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    NDM-1

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    Neonatal diabetes mellitus is a rare form of diabetes that occurs in the first few months of life and results from either abnormal pancreatic development or beta cell dysfunction. It can be transient or permanent. The most common genetic causes are abnormalities in the 6q24 locus or mutations in the ABCC8 and KCNJ11 genes which code for the potassium channel in beta cells. These genetic defects lead to insufficient insulin production. Treatment involves blood glucose management through insulin or sulfonylureas depending on the underlying cause. Understanding the genetics of neonatal diabetes provides insights into pancreatic development and function as well as more common forms of diabetes.

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    © All Rights Reserved
    Download as PPTX, PDF, TXT or read online from Scribd
    Download as pptx, pdf, or txt
    28 views12 pages

    Neonatal Diabetes Mellitus: Anietie Daniel Jeremiah BMS1701994

    Uploaded by

    Anietie
    Neonatal diabetes mellitus is a rare form of diabetes that occurs in the first few months of life and results from either abnormal pancreatic development or beta cell dysfunction. It can be transient or permanent. The most common genetic causes are abnormalities in the 6q24 locus or mutations in the ABCC8 and KCNJ11 genes which code for the potassium channel in beta cells. These genetic defects lead to insufficient insulin production. Treatment involves blood glucose management through insulin or sulfonylureas depending on the underlying cause. Understanding the genetics of neonatal diabetes provides insights into pancreatic development and function as well as more common forms of diabetes.

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    NEONATAL DIABETES MELLITUS

    Anietie Daniel Jeremiah


    BMS1701994
     INTRODUCTION
    Diabetes mellitus most commonly occurs after the neonatal period and results from complex interactions
    between both environmental and incompletely-penetrant genetic factors.
    Neonatal (or congenital) diabetes mellitus (NDM) is now known to occur in approximately 1 in 90,000-
    160,000 live births (Iafusco D, 2012).
    NDM may be categorized by phenotypic characteristics into transient, permanent and syndromic forms.
    The most frequent genetic causes of neonatal diabetes mellitus with abnormal β cell function are
    abnormalities of the 6q24 locus and mutations of the ABCC8 or KCNJ11 genes coding for the potassium
    channel in the pancreatic β cell.
     NEONATAL DIABETES
    MELLITUS
    It is defined by the presence of severe hyperglycaemia requiring treatment and occurs between the
    neonatal period and infancy.
    This hyperglycaemia is associated with insufficient or no circulating insulin.
    Two clinical forms have been distinguished, based on the duration of the treatment: a so called “transient
    form” and a permanent form.
    The disease is explained by two major groups of mechanism: malformation of the pancreas or abnormal
    function of the pancreatic β cell that secretes insulin (by poor insulin cell mass development or malfunction
    of a cell component or by destruction of the β cell)
    The most frequent genetic causes of neonatal diabetes with normal pancreas morphology are
    abnormalities of the 6q24 locus and mutations of the genes coding for the ATP-dependent potassium
    channel.
     6q24 (MIM#601410 and 603044)
    The first genetic causes identified were abnormalities of the 6q24 locus, which include paternal uniparental
    disomy of 6q24 (pUPD6) etc.
    All these abnormalities lead to over-expression of imprinted genes located in 6q24, such as PLAGL1/ZAC
    (pleiomorphic adenoma gene-like 1) and HYMAI (Hydatidiform mole-associated and imprinted transcript),
    which are the most “likely” candidate genes.
    The 6q24 abnormalities are associated with “transient” neonatal diabetes (Cave H, 2000).
     Mutations of the ABCC8 and KCNJ11 Genes Coding
    for the KATP Channel: (MIM ∗600509 and ∗600937)
    The ATP-dependent potassium channel (KATP channel) plays a central role in stimulating insulin secretion
    by the pancreatic β cell in response to glucose.
    At low blood sugar levels (e.g., fasting), the KATP channels are open (activated) and their activity maintains
    a hyperpolarized resting membrane potential (around −70 mV).
    They are coded by the KCNJ11 and ABCC8 genes, respectively. Activating mutations in one of these two
    genes are responsible for neonatal diabetes with normal pancreas morphology.
     Mutations of the Insulin Gene (INS)
    (MIM ∗176730)
    The third cause of neonatal diabetes, by frequency, is mutations of the insulin gene (INS).
    The majority are heterozygous mutations affecting the structure of proinsulin; these are transmitted in an
    autosomal dominant manner.
    The abnormal proinsulin undergoes degradation in the endoplasmic reticulum, leading to severe
    endoplasmic reticulum (ER) stress and β cell death.
     ABNORMAL PANCREAS
    MORPHOLOGY
    Several genes are linked to neonatal diabetes with abnormal pancreas morphology.
    These genes are involved in development of the pancreas at various stages in early morphogenesis.
    These neonatal diabetes cases may be associated with a deficiency of the exocrine pancreas, based on the
    severity of pancreatic damage or to other congenital malformations.
    The RFX-6 transcription factor is involved in the differentiation of beta-cells in the pancreas during
    embryonic development of the pancreas. It is also expressed in mature cells where it has a role in
    regulating insulin transcription and secretion.
    It actually controls the expression and activation of calcium channels and its inactivation alters insulin
    secretion in response to glucose.
     CLINICAL DESCRIPTION
    There are two clinical forms of neonatal diabetes based on the duration of insulin-dependency.
    In the transient form, treatment may be stopped at any time from the first weeks of life to 5 years of age.
    In the permanent forms, life-long treatment is necessary.
    The clinical difference between transient and permanent neonatal diabetes is not always underpinned by
    distinct molecular mechanisms.
    Abnormalities of the 6q24 locus are exclusively linked to transient neonatal diabetes. However, mutations
    of the ABCC8, KCNJ11, and INS genes are linked to both permanent and transient forms (Bonnefond A,
    2011).
    In neonatal diabetes with normal pancreas morphology, there are associated neurological disorders and
    developmental defects.
    Patients with a 6q24 locus abnormality may have developmental defects (macroglossia, umbilical hernia,
    cardiac malformations, renal and urinary malformations, non-autoimmune anemia (Docherty LE, 2013).
     TREATMENT
     The initial treatment aims to rebalance carbohydrate metabolism. It should be started
    immediately following diagnosis.
    Patients ABCC8 or KCNJ11 mutatons are treated succesfully using hypoglycemic sulfonylureas.
     CONCLUSION
    Neonatal diabetes is a model of rare human genetic disease, important in the understanding of the
    development and function of the pancreatic β cell, and in helping to resolve the pathophysiology of more
    frequent adult diabetes, such as type 2 diabetes.
    Neonatal diabetes is often associated with specific neuropsychological or developmental disorders of
    underlying genetic causes.
    Knowing the natural history and complete phenotype of this disease makes it possible, firstly, to offer
    patients better treatment and, secondly, to broaden the scope of genetic analyses to genes involved in the
    development and function of other organs.
    THANK YOU

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