Home / Resources / Clinical Gems / International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #155: Monogenic Disorders of the Beta Cell Part 5

International Textbook of Diabetes Mellitus, 4th Ed., Excerpt #155: Monogenic Disorders of the Beta Cell Part 5

Dec 11, 2018


Neonatal diabetes (NDM) is defined as monogenic β-cell diabetes which is diagnosed in the first six months of life. It is rare, affecting one in 200,000 live births [48]. The evidence that a diagnosis before 6 months is the cut-off between monogenic neonatal diabetes rather than polygenic T1DM comes from studies of high-risk type 1 HLA, antibodies, birth weight (reduced before 6 months suggests a reduced insulin secretion in utero) and monogenic genetic studies [49–52].


Clinical features

Patients may be detected when glucose is tested in the first few days of life in low-birth weight babies or may present later when the patient is severely unwell with ketoacidosis. Patients are severely insulin deficient and C-peptide is usually not detectable. Approximately 30–40% of cases remit spontaneously and are referred to as transient neonatal diabetes mellitus (TNDM) as opposed to permanent neonatal diabetes mellitus (PNDM) where diabetes persists. TNDM often recurs between the first and third decades of life [53]. Thirteen genes involved in β-cell development, survival, or function have been implicated in the development of neonatal diabetes. Table 28.3 summarizes the known genetic causes of neonatal diabetes.

Permanent neonatal diabetes

Molecular genetics

Over a third of NDM is caused by mutations in the genes KCNJ11 and ABCC8. These encode the Kir6.2 and SUR1 subunits, respectively, of the β cell ATP-sensitive potassium channel (KATP channel) [54–57]. Normally, the KATP channel closes in response to raised intracellular ATP levels that occur as blood glucose rises. Channel closure causes depolarization of the β-cell membrane which results in insulin secretion. Activating mutations in KCNJ11 and ABCC8 prevent the KATP channel closing, in response to increased ATP, preventing insulin release [58]. The KATP channel is also present in the brain, nerves, and muscles. In those with more functionally severe KCNJ11 mutations (∼20% patients), and occasional patients with ABCC8 mutations, there is associated neurodevelopmental delay [52,54,55,58].

The majority (80%) of PNDM resulting from KATP channel mutations arise spontaneously from de novo heterozygous mutations, with the remainder inherited mainly in an autosomal dominant pattern. About 25–40% of neonatal diabetes resulting from ABCC8 mutations is inherited in an autosomal recessive fashion [57].

Heterozygous mutations in the insulin gene (INS) have been identified in 10% of cases of neonatal diabetes [59]. EIF2AK3 recessive mutations cause Wolcott–Rallison syndrome and are the commonest cause of neonatal diabetes when the parents are consanguineous and account for 24% of these cases [60]. A number of other genetic causes have been found which all are relatively rare as outlined in Table 28.3 [61].

Clinical features of the common subtypes of permanent neonatal diabetes

Neonatal diabetes, caused by KCNJ11, ABCC8, and INS mutations, typically present within the first six months of life (median 6–10 weeks). Infants are unwell, failing to thrive, with marked hyperglycemia often accompanied by ketosis. C-peptide is usually undetectable and pancreatic autoantibodies negative [54]. Birth weight is low (∼2.5 kg) as a result of reduced insulin secretion in utero with consequent decreased insulin-mediated growth.

About 20% of patients with PNDM and KCNJ11 mutations have neurologic features, the commonest being developmental delay, sometimes with muscle weakness and/or epilepsy. The most severe form where neonatal diabetes is accompanied by developmental delay and epilepsy has been named “DEND” (developmental delay, epilepsy, and neonatal diabetes). “Intermediate DEND” (iDEND) refers to neonatal diabetes with less severe developmental delay. The severity of the clinical condition relates closely to the underlying mutation and its effect on KATP channel ATP sensitivity [58,62].

Neonatal diabetes caused by ABCC8 mutations leads to TNDM almost as often as PNDM and rarely has associated neurodevelopmental features [55–57]. Neonatal diabetes due to INS mutations causes PNDM but patients do not have extrapancreatic features [63].

Patients with Wolcott–Rallison syndrome typically develop diabetes before six months, and skeletal dysplasia occurs within the first two years of life. Other manifestations vary between patients in their nature and severity and include frequent episodes of acute liver failure, renal dysfunction, exocrine pancreas insufficiency, intellectual deficit, hypothyroidism, neutropenia, and recurrent infections [60,64].

Treatment of permanent neonatal diabetes

At diagnosis of neonatal diabetes, all patients should be commenced on insulin treatment to stabilize blood sugars. All patients with neonatal diabetes should be referred for urgent molecular genetic testing, results of which should be available within a week. This is because over a third of patients will have a KATP-channel mutation (KCNJ11 or ABCC8) the majority of whom can successfully transfer from insulin to sulfonylurea therapy; 90% of those with KCNJ11  mutations are able to discontinue insulin. There are usually significant improvements in glycemic control without an increase in hypoglycemia [56,65]. Sulfonylureas work by closing the β cell KATP channel by an ATP-independent route thus allowing β-cell depolarization and insulin release [65].

Glibenclamide has been used in the majority of NDM cases. It was initially used as it is nonselective and widely available; however there is evidence that it may be more effective than other sulfonylurea agents [66]. The doses needed are higher than those needed for the treatment of T2DM: a median dose of 0.45mg kg−1 per day is required with doses up to 1.5mg kg−1 d−1 needed in some cases [65,67]. Sulfonylurea therapy may result in some improvement in neurologic features even when they are commenced in adulthood [66,68,69].

All other causes of neonatal diabetes need treatment with insulin. A molecular genetic diagnosis is still important as it will inform on extrapancreatic clinical features and allow genetic counseling [70].

Transient neonatal diabetes

Molecular genetics

The genetic etiology of more than 80% of transient neonatal diabetes has been established. The commonest cause is abnormalities in the q24 region of chromosome 6 (6q24) affecting imprinted genes [61,71]. Genetic imprinting occurs when only The maternal or paternally inherited allele of a gene is expressed. In TNDM, paternal uniparental disomy, paternal duplication of 6q24 or abnormal methylation of the maternal copy of the chromosome causes overexpression of the paternal copies of the genes PLAGL1 (also known as ZAC) and HYMAI [71,72]. Paternal duplication of 6q24 can be inherited; therefore this abnormality causes the majority of inherited TNDM cases. Uniparental disomy causes sporadic TNDM; cases resulting from abnormal methylation of the maternal copy of chromosome 6 may be sporadic or inherited [71,72]. The majority of TNDM not associated with 6q24 abnormalities are caused by mutations in KCNJ11 and ABCC8 [52,53,56,73–76].

Clinical features of transient neonatal diabetes

6q24 diabetes usually presents in the first week of life. Neonates often have severe hyperglycemia and dehydration but are usually not ketotic [71]. Islet cell antibodies are usually negative and C-peptide is low or negligible [71]. Low birth weight is common (mean birth weight 2 kg), and there may be associated macroglossia and/or umbilical hernia. Insulin treatment is required for a median of 12 weeks before the patient goes into remission. Diabetes recurs later in life in 50–60% of patients as a result of pancreatic β-cell dysfunction. The average age of recurrence is 14 years. In some cases hyperglycemia may be intermittent and seen only at times of stress [71,77].

Where TNDM is caused by KCNJ11 and ABCC8 mutations, diabetes tends to present later (median 4 weeks), takes longer to remit, and is associated with less intrauterine growth restriction (median birth weight 2.6 kg). Remission occurs in about 50% of patients and tends to occur in the first decade (median 4.7 years  (3–15)) [53].

Management of transient neonatal diabetes

Insulin is required at diagnosis in the neonatal period; however, on relapse in later life, treatment requirements vary: diet; oral hypoglycemic agents or insulin [77]. In TNDM cases that result from KCNJ11 or ABCC8 mutations, infants may be switched from insulin to sulfonylurea treatment [53,56]. The sulfonylurea doses required are lower than for infants with KATP-channel mutations causing PNDM and care should be given to monitor for hypoglycemia.

Genetic counseling depends on the underlying genetic etiology. Cases caused by uniparental disomy are sporadic and therefore have low risk of occurrence in either siblings or offspring of the affected child. Methylation defects often result from homozygous mutations in the transcription factor gene ZFP57 and therefore may be inherited in an autosomal recessive manner [72]. Offspring of males with 6q24 duplication have a 50% chance of developing TNDM whereas if the abnormality is inherited from the mother they will not be affected but the TNDM may occur in the following generation [77].

Genetic testing in neonatal diabetes

At the time of diagnosis of neonatal diabetes it is not known whether diabetes will be transient or permanent. We advise testing for 6q24 abnormalities, KCNJ11, ABCC8, and INS mutations at diagnosis in all diabetes diagnosed before 6 months. Identifying mutations in these genes is important as it will influence treatment. An early diagnosis and very low birth weight make 6q24 most likely. A genetic cause (KCNJ11 or INS) can be established in approximately 7% of diabetes diagnosed between 6 months and 1 year of age so consideration should be given to testing this age group, especially where autoantibody tests are negative [51].

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