Diabetes Mellitus, Permanent Neonatal
A number sign (#) is used with this entry because of evidence that permanent neonatal diabetes mellitus can be caused by homozygous mutation in the glucokinase gene (GCK; 138079), by heterozygous mutation in the KCNJ11 (600937) gene, or by heterozygous or homozygous mutation in the ABCC8 (600509) and INS (176730) genes.
Pancreatic agenesis, which results in exocrine pancreatic deficiency as well as permanent neonatal-onset diabetes mellitus, can be caused by mutation in the PDX1 gene (600733). Pancreatic agenesis associated with cerebellar agenesis (609069) can be caused by mutation in the PTF1A gene (607194). Pancreatic agenesis associated with congenital cardiac defects (600001) can be caused by mutation in the GATA6 gene (601656).
DescriptionNeonatal diabetes mellitus (NDM), defined as insulin-requiring hyperglycemia within the first 3 months of life, is a rare entity, with an estimated incidence of 1 in 400,000 neonates (Shield, 2000). In about half of the neonates, diabetes is transient (see 601410) and resolves at a median age of 3 months, whereas the rest have a permanent insulin-dependent form of diabetes (PNDM). In a significant number of patients with transient neonatal diabetes mellitus, type II diabetes (see 125853) appears later in life (Arthur et al., 1997). PNDM is distinct from childhood-onset autoimmune diabetes mellitus type I (IDDM; 222100).
Massa et al. (2005) noted that the diagnostic time limit for PNDM has changed over the years, ranging from onset within 30 days of birth to 3 months of age. However, as patients with the clinical phenotype caused by mutation in the KCNJ11 gene have been identified with onset up to 6 months of age, Massa et al. (2005) suggested that the term 'permanent diabetes mellitus of infancy' (PDMI) replace PNDM as a more accurate description, and include those who present up to 6 months of age. The authors suggested that the new acronym be linked to the gene product (e.g., GCK-PDMI, KCNJ11-PDMI) to avoid confusion with patients with early-onset, autoimmune type I diabetes.
Colombo et al. (2008) proposed that, because individuals with INS gene mutations may present with diabetes well beyond 6 months of age and cannot be distinguished from patients with type 1 diabetes except for the absence of type 1 diabetes autoantibodies, the term PNDM should be replaced with 'monogenic diabetes of infancy (MDI),' a broad definition including any form of diabetes, permanent or transient, with onset during the first years of life and caused by a single gene defect.
Clinical FeaturesPermanent diabetes of infancy is primarily characterized by onset of hyperglycemia within the first 6 months of life. Among 12 patients with PNDI, Gloyn et al. (2004) reported a mean age of 7 weeks at diagnosis (range birth to 26 weeks). All affected patients had hyperglycemia (270 to 972 mg/dl), and 3 had ketoacidosis. None of the patients had pancreatic autoantibodies associated with IDDM. Patients did not secrete insulin in response to glucose or glucagon but did secrete insulin in response to tolbutamide. All patients had low birth weight. Three of 12 patients had similar neurologic abnormalities, including developmental delay, muscle weakness, and epilepsy. All 3 patients with neurologic abnormalities had dysmorphic features, including prominent metopic suture, a downturned mouth, bilateral ptosis, and limb contractures.
Gloyn et al. (2006) reported 4 unrelated patients with developmental delay, epilepsy, and neonatal diabetes (DEND) associated with mutations in the KCNJ11 gene. All had infantile-onset of diabetes without pancreatic autoantibodies (diagnosed from day 1 of life to 3 months) with hyperglycemia, polydipsia, polyuria, and ketoacidosis in some. The most severely affected child had seizures with hypsarrhythmia, neurologic deterioration with social withdrawal, and mild dysmorphic features, including prominent metopic suture, downturned mouth, and bilateral ptosis. She died from aspiration pneumonia at age 6 months; genetic analysis revealed a novel mutation in the KCNJ11 gene (C166F; 600937.0015). Two other patients had developmental delay and axial hypotonia, but only 1 of these also had dysmorphic features and seizures. The fourth child, who had no dysmorphic or neurologic features, had a diabetic mother who also had no neurologic involvement. Gloyn et al. (2006) noted the phenotypic variability between patients, even between those with the same mutation.
Clinical ManagementZung et al. (2004) reported an infant with PNDM due to a mutation in the KCNJ11 gene (R201H; 600937.0002) who showed a better response to oral sulfonylurea (glibenclamide) treatment than to insulin pump therapy.
Pearson et al. (2006) assessed glycemic control in 49 diabetic patients with known heterozygous mutations in the KCNJ11 gene; 44 (90%) successfully discontinued insulin after receiving appropriate doses of sulfonylureas. The extent of tolbutamide blockade of K(ATP) channels in vitro reflected the response seen in patients. Glycosylated hemoglobin levels improved significantly in patients who switched to sulfonylurea therapy, and improved glycemic control was sustained at 1 year.
Stanik et al. (2007) also reported patients with PNMD due to mutation in the KCNJ11 or ABCC8 gene who were successfully transferred from insulin to sulfonylurea therapy with dramatic improvement in diabetes control and quality of life.
Shimomura et al. (2007) reported an Italian boy with severe neonatal diabetes with neurologic features caused by a de novo mutation in the KCNJ11 gene (I167L; 600937.0016). He had persistent hyperglycemia from birth and developed refractory neonatal seizures with hypsarrhythmia. By age 3.5 years, psychomotor retardation was severe, with hypotonia, athetotic movements, inability to roll over or sit without support, decreased eye contact, and inability to speak. The patient showed a good response to sulfonylurea treatment, with both improved glycemic control without insulin and neurologic improvement. Shimomura et al. (2007) noted that this was the first report of a child with severe DEND who had clinical improvement of both diabetes as well as neurologic features after sulfonylurea therapy.
MappingStoy et al. (2007) studied a family in which neonatal diabetes segregated as an autosomal dominant trait and affected family members were negative for mutation in the KCNJ11 and ABCC8 genes. Linkage analysis led to the identification of INS on chromosome 11p15 as a candidate gene.
Molecular GeneticsMutation in GCK
Njolstad et al. (2001) described 2 patients in whom complete deficiency of glucokinase caused permanent neonatal-onset diabetes mellitus. Both patients showed total absence of basal insulin release, and both had homozygous missense mutations in the GCK gene (138079.0010 and 138079.0011).
Gloyn et al. (2002) concluded that complete glucokinase deficiency is not a common cause of permanent neonatal diabetes.
Mutation in KCNJ11
In 10 of 29 patients with permanent neonatal diabetes, Gloyn et al. (2004) identified 6 novel, heterozygous missense mutations in the KCNJ11 gene (see, e.g., 600937.0002-600937.0003). In 2 patients the diabetes was familial, and in 8 it arose from a spontaneous mutation. In 4 of the 10 families, the mutation was an arg201-to-his substitution (R201H; 600937.0002). When the most common mutation, R201H, was coexpressed with SUR in Xenopus oocytes, the ability of ATP to block mutant ATP-sensitive potassium channels was greatly reduced.
Edghill et al. (2007) noted that the majority of KCNJ11 mutations resulting in neonatal diabetes mellitus occur de novo. They found that germline mosaicism was indicated by pedigree analysis in 2 of 18 families in which neither parent was affected and in 1 of 12 additional parents tested for somatic mosaicism. Edghill et al. (2007) concluded that de novo KCNJ11 mutations can arise during gametogenesis or embryogenesis, thus increasing the risk of neonatal diabetes for subsequent sibs.
Mannikko et al. (2010) reported 2 novel mutations on the same haplotype (cis), F60Y (600937.0023) and V64L, in the slide helix of Kir6.2 (KCNJ11) in a patient with neonatal diabetes, developmental delay, and epilepsy. Functional analysis revealed that the F60Y mutation increased the intrinsic channel open probability, thereby indirectly producing a marked decrease in channel inhibition by ATP and an increase in whole-cell potassium-ATP currents. When expressed alone, the V64L mutation caused a small reduction in apparent ATP inhibition, by enhancing the ability of MgATP to stimulate channel activity. The V64L mutation also ameliorated the deleterious effects on the F60Y mutation when it was expressed on the same, but not a different, subunit. The authors concluded that F60Y is the pathogenic mutation and that interactions between slide helix residues may influence KATP channel gating.
Mutation in ABCC8
In a 27-year-old man who had permanent neonatal diabetes, severe developmental delay, and generalized epileptiform activity on EEG, Proks et al. (2006) identified heterozygosity for a de novo missense mutation (F132L; 600509.0016) in the ABCC8 gene. Functional studies showed that F132L markedly reduced the sensitivity of the K(ATP) channel to inhibition by MgATP, thereby increasing the whole-cell K(ATP) current; the authors noted that the functional consequence of the F132L mutation mirrors that of KCNJ11 mutations causing neonatal diabetes.
From a group of 73 patients with neonatal diabetes, Babenko et al. (2006) screened the ABCC8 gene in 34 who did not have alterations in chromosome 6q or mutations in the KCNJ11 or GCK genes. In 2 PNDM patients, they identified heterozygosity for a mutation (600509.0017 and 600509.0018, respectively). They also identified heterozygosity for 5 different mutations (see, e.g., 600509.0019 and 600509.0020) in 7 patients with transient neonatal diabetes (TNDM2; 610374). Mutant channels in intact cells and in physiologic concentrations of magnesium ATP had markedly higher activity than did wildtype channels. These overactive channels remained sensitive to sulfonylurea, and treatment with sulfonylureas resulted in euglycemia. The mutation-positive fathers of 5 of the probands with transient neonatal diabetes developed type II diabetes mellitus (125853) in adulthood; Babenko et al. (2006) proposed that mutations of the ABCC8 gene may give rise to a monogenic form of type II diabetes with variable expression and age at onset. The authors noted that dominant mutations in ABCC8 accounted for 12% of cases of neonatal diabetes in the study group.
Mutation in INS
In affected members of a 3-generation family with autosomal dominant neonatal diabetes, who did not have mutations in the KCNJ11 and ABCC8 genes, Stoy et al. (2007) identified heterozygosity for a missense mutation in the INS gene (176730.0008). The authors then sequenced the INS gene in 83 probands with PNDM without a known genetic cause and identified 9 additional heterozygous missense mutations in the INS gene in 15 families (see, e.g., 176730.0009-176730.0011). PNDM patients with mutations in the INS gene presented at a median age of 9 weeks, usually with diabetic ketoacidosis or marked hyperglycemia, did not have beta-cell autoantibodies, and were treated from diagnosis with insulin. C-peptide values where measured were very low or undetectable, with all values less than 200 pmol/liter.
Edghill et al. (2008) screened the INS gene in a series of 1,044 patients with permanent diabetes diagnosed during infancy, childhood, and adulthood and identified 16 different heterozygous INS mutations in 35 PNDM probands (see, e.g., 176730.0010-176730.0013), 12 of whom had been previously reported by Stoy et al. (2007). The median age at diagnosis for the INS mutation carriers was 11 weeks, and they presented with either symptomatic hyperglycemia (41%) or diabetic ketoacidosis (59%). All patients were treated with insulin replacement therapy. Autoantibodies, when measured, were not detected. Birth weights were reduced (median, 2.7 kg, corresponding to the sixth percentile), consistent with in utero growth retardation due to reduced insulin secretion.
Polak et al. (2008) analyzed the INS gene in 38 patients with PNDM and 1 with nonautoimmune early-infancy diabetes who were negative for mutations in the GCK, KCNJ11, and ABCC8 genes, and identified heterozygosity for 3 different missense mutations in critical regions of the preproinsulin molecule (see 176730.0010-176730.0012) in 4 probands with marked variability in age of diagnosis and disease progression. The authors stated that in their cohort, INS mutations represented approximately 10% of all PNDM cases, and patients with INS mutations had a later presentation of diabetes and no associated symptoms, compared to patients with K(ATP) channel mutations.
In 9 probands with PNDM who were known to be negative for mutations in the KCNJ11 gene (600937), Colombo et al. (2008) identified heterozygosity for 7 different mutations in the INS gene (see, e.g., 176730.0010). Expression of the mutant proinsulins in HEK93 cells demonstrated defects in insulin protein folding and secretion. The authors noted that 9 of 11 patients studied showed near-normal weight at birth, a finding clearly different from the low birth weight in patients with KCNJ11 mutations; they suggested that the beta-cell insufficiency in patients with INS mutations may occur primarily after birth, and noted that the observed postpartum decline in C-peptide was consistent with the hypothesis that a postnatal failure to maintain beta-cell mass due to proteotoxic proinsulin misfolding is a primary cause of PNDM in these patients.
Carmody et al. (2015) studied a male infant, born to first-cousin Southeast Asian parents, who had severe hyperglycemia at birth and required subcutaneous insulin thereafter, who also displayed a structurally normal pancreas on ultrasound but had undetectable C-peptide. The proband was negative for mutation in 36 known monogenic diabetes-associated genes, including INS; however, examination of low-coverage intronic regions revealed homozygosity for a deep intronic INS variant (176730.0017). The mutation was present in heterozygosity in his parents and 1 brother, none of whom had diabetes, although his mother had required insulin to treat gestational diabetes in all 3 of her pregnancies. In addition, the proband's maternal grandmother, who was heterozygous for the mutation, developed insulin-requiring diabetes mellitus at age 45, and a maternal aunt and uncle, for whom DNA was not available, were diagnosed with insulin-requiring diabetes mellitus at 28 and 36 years of age, respectively. The nondiabetic paternal grandmother also carried the mutation. Noting that 20 to 30% of neonatal monogenic diabetes cases have no known etiology, the authors suggested that mutations within deep noncoding regions might be the cause.
Heterogeneity
Of 31 Japanese patients with NDM, including 15 with PNDM and 16 with transient NDM (TNDM), Suzuki et al. (2007) identified a 6q24 abnormality (see 601410) in 11, a KCNJ11 mutation in 9, and an ABCC8 mutation in 2. Seven patients with a KCNJ11 mutation, including 2 with DEND and the 2 with an ABCC8 mutation, had PNDM. All of the patients with the 6q24 abnormality and 2 patients with a KCNJ11 mutation had TNDM. Suzuki et al. (2007) concluded that the 6q abnormality and KCNJ11 mutations are major causes of NDM in Japanese.