neonatal diabetes mellitus ( ndm ) is a rare monogenic form of diabetes starting within the first 6  months of life 13 .
the disease has an incidence of about 1:100,000260,000 live births and can be permanent ( pndm ) , requiring lifelong treatment , or may be transient ( tndm ) , in which case the diabetes may spontaneously remit ( or be so mild as not to require treatment ) , but will often relapse , usually during adolescence 35 .
a genetic diagnosis has been made in up to 90% of these patients 7 . in the majority of them
( around 70% ) , it was found that a genetic or epigenetic alteration in the tndm locus on chromosome 6q24 causing the overexpression of two imprinted genes 7 .
less frequently , activating mutations of the genes kcnj11 and abcc ( accounting for 10% and 13% of the cases , respectively ) may result in tndm 7 .
mutations in these genes lead to a gain - in - function of the pancreatic atp - sensitive potassium ( katp ) channel , which is critical in the regulation of insulin secretion by the beta cell 3,6,8,9 .
the beta cell katp channel is an octameric complex composed of four pore - forming subunits : channel - building inwardly rectifying potassium - channel subunits ( kir6.2 ) encoded by the kcnj11 gene , and four regulatory sulfonylurea - receptor subunits ( sur1 ) and encoded by the abcc8 gene 10,11 .
these subunits regulate the metabolic activity of the channel , which is shut down in response to an increase in intracellular atp , leading to insulin secretion .
gain - in - function mutations of either of these genes keep the channel in open conformation and impair insulin secretion 1012 .
most patients with kcnj11 mutations treated with insulin can be transferred to sulfonylurea ( su ) with a remarkable improvement in metabolic control and patient 's quality of life 13 .
sulfonylureas close katp channels , through an atp- independent route , improving insulin secretion and representing a suitable therapeutic alternative for patients with kcnj11 mutations 10 . for these reasons ,
identification of katp channel mutation can have a major impact on the treatment 's choice .
this is an example about how molecular diagnosis can influence the clinical management of the patients .
herein , we report on a case of ndm in a caucasian boy , who presented severe diabetic ketoacidosis ( dka ) at 17  days of life .
the genetic screening showed a heterozygous missense mutation ( c.679  g > a ) in the kcnj11 gene which leads to the replacement of lysine with glutamic acid at position 227 ( e227k ) of the atp sensitive potassium channel .
an 11-day - old caucasian boy was admitted to the neonatal care unit with complaints of poor weight progression , suppurative conjunctivitis , and mucoral candidiasis .
he was the second child of a 21-year - old woman ( gravida 2 , para 1 ) without history of diabetes , and was born through cesarean section at 38  weeks of pregnancy due to preeclampsia .
apgar score was 5/9/10 ; birth weight was 2890  g ( p15 ) , length 47  cm ( p15 ) and head circumference 34.5  cm ( p50 ) 14 . on physical examination ,
the infant exhibited axial hypotonia and weak suction reflex , demanding a nasogastric tube in order to be feed . at 17 days
the child became irritable , drowsy , dehydrated , tachypneic , tachycardic with poor peripheral perfusion ; rectal temperature was 37.8c .
he was started on intravenous vancomycin after isolation of a methicillin - resistant staphylococcus from the axillary suppurative adenitis .
blood tests revealed a glycemia of 1412  mg / dl with high levels of ketonemia ; serum sodium was 172 
mmol / l ; potassium 3.9  mmol / l , and the ph was 7.0 .
after initial treatment with intravenous 0.9% saline serum , he was started on intravenous insulin perfusion ( 0.01  u / kg / h ) in a 0.45% saline serum supplemented with 15  meq / l of potassium chloride .
three days later , the insulin perfusion was stopped and the child was transferred to a subcutaneous protocol of intensive insulin therapy , consisting in a once daily administration of insulin glargine ( 1  u / day ) , and insulin lyspro every 6  h. further investigations revealed that there was no evidence of pancreatic exocrine failure .
transfontanelar and abdominal ultrasounds ; electroencephalography and brain magnetic resonance imaging showed no relevant findings . an interatrial communication
 ostium secundum  , associated with enlargement of right cavities was found in the echocardiogram .
c - peptide was 0.37  ng / ml ( 0.804.20 ) ; auto antibodies against islet cell ( ica ) , decarboxylase of glutamic acid ( gad ) , and insulin were all negative .
the infant was referred to a tertiary hospital due to instability of his metabolic control , alternating episodes of hypoglycemia with hyperglycemia .
two months later , insulin administration was stopped , given that glycemia was always within normal levels with minimal amounts of insulin . at this stage ,
the c - peptide was already normal . at the age of 9  months , his growth had declined from p10 to p<1 .
the e227k mutation found in our patient is a gain - function mutation that results in both impaired atp sensitivity and higher intrinsic 
the e227k mutation has been reported in several other patients with tndm but also in a few with pndm reflecting the phenotypic variability of kcnj11 mutations ( table1 ) .
the reason why the same mutation causes a relapsing / remitting form of diabetes in some patients whereas in others it produces a permanent diabetes is unclear 15 .
it was not demonstrated a clear relationship between the clinical phenotype and the magnitude of the impairment of the atp - sensitive potassium ( katp ) channels .
tndm may result from a reduction in insulin requirements at the time of remission due to changes in beta cell turnover or to compensatory alterations ( at the level of the beta cell , pancreas , or whole body ) , overcoming the lower effectiveness of the atp sensitive potassium channel .
therefore , the genetic background of the patient as well as other still unrecognized environmental factors may play an important role in the phenotypic expression of the mutation . on the other hand
, the apparent clinical variability may result from confounding factors : patients diagnosed during puberty or early adulthood may have had a period of hyperglycemia that was missed during the neonatal period .
clinical data of patients with heterozygous e227k mutation wks , weeks ; mth , months ; yrs , years ; dka , diabetic ketoacidosis ; mody , maturity - onset diabetes of the young . the e227k may be inherited from affected parents , or occurs as de novo mutation . in our study , the mutation is present in the affected child but also in his asymptomatic mother , suggesting that there was not a complete co - segregation of the mutation with diabetes .
this situation has also been described previously ( table1 ) . in the majority of tndm and
pndm cases caused by kcnj11 mutations 3,13 , including e227k mutations 11 , metabolic control was achieved by replacing insulin therapy with sulfonylureas , which are well - known katp channel inhibitors ( table1 ) .
this finding supports the idea that if our patient has a relapse of diabetes , he may achieve optimal glycemic control with oral sulfonylurea treatment , strengthening the importance of the molecular diagnosis even if neonatal diabetes remits .
the expression of kcnj11 in the central nervous system and skeletal muscle explain the neurological features associated with syndromic forms of pndm , such as developmental delay , muscle weakness , and epilepsy 16,17 .
however , neurological features were also identified in patients with nonsyndromic forms of pndm and tndm who carried kcnj11 mutations as speech delay , autistic spectrum disorder , and learning disability .
until now it is difficult to assure whether these complications are a consequence of the mutation or whether environmental and/or other genetic factors are involved 6 . in the case herein reported , the infant exhibited axial hypotonia and weak suction reflex , that may be caused by the mutation or / and may be due to exposure to hyperglycemia and ketosis during the first days of the child 's life 1,3,18 .
further studies are necessary to clarify the etiology of neurological impairment in tndm patients who carried kcnj11 mutations and to access the effectiveness of su in improving the neurological development . in conclusion
molecular diagnosis should be performed in order to identify those patients who may benefit from su therapy .
further investigation is required to understand clinical heterogeneity and the incomplete co - segregation of the kcnj11 mutation with diabetes , and also the molecular mechanisms underlying the biphasic course of tndm .
 key clinical messageneonatal diabetes is a monogenic form of diabetes . 
 herein , we report on a newborn presenting diabetic ketoacidosis at 17 days of life . 
 a kcnj11 mutation was identified . in such cases , 
 insulin can be replaced by sulfonylurea with a successful metabolic control , as an example of how molecular diagnosis may influence the clinical management of the disorder . 