Nicola Minuto

Maturity-onset diabetes of the young in children with incidental hyperglycemia: a multicenter Italian study of 172 families

OBJECTIVE To investigate the prevalence of maturity-onset diabetes of the young (MODY) in Italian children with incidental hyperglycemia. RESEARCH DESIGN AND METHODS Among 748 subjects age 1–18 years with incidental hyperglycemia, minimal diagnostic criteria for MODY were met by 172 families. Mutational analyses of the glucokinase (GCK) and hepatocyte nuclear factor 1α (HNF1Α) genes were performed. RESULTS We identified 85 GCK gene mutations in 109 probands and 10 HNF1Α mutations in 12 probands. In GCK patients, the median neonatal weight and age at the first evaluation were lower than those found in patients with HNF1A mutations. Median fasting plasma glucose and impaired fasting glucose/impaired glucose tolerance frequency after oral glucose tolerance testing were higher in GCK patients, who also showed a lower frequency of diabetes than HNF1A patients. CONCLUSIONS GCK mutations are the prevailing cause of MODY (63.4%) when the index case is recruited in Italian children with incidental hyperglycemia.

Wolfram Syndrome (Diabetes Insipidus, Diabetes, Optic Atrophy, and Deafness): Clinical and genetic study

OBJECTIVE—Wolfram syndrome is an autosomal recessive neurodegenerative disorder characterized by diabetes insipidus, diabetes (nonautoimmune), optic atrophy, and deafness (a set of conditions referred to as DIDMOAD). The WFS1 gene is located on the short arm of chromosome 4. Wolfram syndrome prevalence is 1 in 770,000 live births, with a 1 in 354 carrier frequency. RESEARCH DESIGN AND METHODS—We evaluated six Italian children from five unrelated families. Genetic analysis for Wolfram syndrome was performed by PCR amplification and direct sequencing. RESULTS—Mutation screening revealed five distinct variants, one novel mutation (c.1346C>T; p.T449I) and four previously described, all located in exon 8. CONCLUSIONS—Phenotype-genotype correlation is difficult, and the same mutation gives very different phenotypes. Severely inactivating mutations result in a more severe phenotype than mildly inactivating ones. Clinical follow-up showed the progressive syndromes seriousness.

Association of alleles at polymorphic sites in the osteopontin encoding gene in young type 1 diabetic patients

The Osteopontin (OPN) encoding gene, SPP1, can be considered as a candidate for genetic susceptibility to type 1 diabetes (T1D) because of its known function in immune response and inflammation. This work aimed to evaluate the role of SPP1 gene in susceptibility to T1D. Patients (238: 130 male, 108 female) and unaffected adult control individuals (137: 68 males and 69 females) have been genotyped for three variants in the SPP1 gene: -156 (G/GG) and -66 (T/G) in the promoter and a biallelic ins/del variant (TG/TGTG) at +245 in the first intron. The G allele at the -66 SNP had significantly higher frequency in controls than T1D patients. Interestingly, case-control comparison in males showed no significant association, whereas the association was confirmed in females. These results suggest that SPP1 can play a role as susceptibility gene, possibly by a sex-specific mechanism acting in the autoimmune process.

WOLFRAM SYNDROME (DIABETES INSIPIDUS, DIABETES MELLITUS, OPTIC ATROPHY AND DEAFNESS [DIDMOAD]: SIMILAR PHENOTYPES BY DIFFERENT GENETIC MECHANISMS

OBJECTIVE—Wolfram syndrome is an autosomal recessive neurodegenerative disorder characterized by diabetes insipidus, diabetes (nonautoimmune), optic atrophy, and deafness (a set of conditions referred to as DIDMOAD). The WFS1 gene is located on the short arm of chromosome 4. Wolfram syndrome prevalence is 1 in 770,000 live births, with a 1 in 354 carrier frequency. RESEARCH DESIGN AND METHODS—We evaluated six Italian children from five unrelated families. Genetic analysis for Wolfram syndrome was performed by PCR amplification and direct sequencing. RESULTS—Mutation screening revealed five distinct variants, one novel mutation (c.1346C>T; p.T449I) and four previously described, all located in exon 8. CONCLUSIONS—Phenotype-genotype correlation is difficult, and the same mutation gives very different phenotypes. Severely inactivating mutations result in a more severe phenotype than mildly inactivating ones. Clinical follow-up showed the progressive syndromes seriousness.

Beta-cell autoantibodies and diabetes mellitus family history in cystic fibrosis

OBJECTIVE To verify whether autoimmunity against beta-cells and family history of type 1 and/or type 2 diabetes mellitus (DM) play a role in the pathogenesis of cystic fibrosis (CF)-related diabetes mellitus (CFRD). PATIENTS AND METHODS The prevalence of beta-cell autoantibodies (GADA and IA-2A) was investigated in a group of patients with CF compared with patients with type 1 DM (DM1) and controls. Family history of DM1 and/or DM2 was investigated among patients with CF. RESULTS Frequency of beta-cell autoantibodies was significantly lower (p = 0.0001) in patients with CF with CFRD (IA-2A: 0%; GADA 12.5%) than in patients with DM1 (64.1% vs 52.8%, respectively) and it did not differ from the frequency in patients with CF without CFRD. Prevalence of family history for DM1 or DM2 was not significantly higher in CF patients with CFRD than in CF patients without CFRD. CONCLUSIONS The investigated factors did not show correlation with the pathogenesis of CFRD.

Type 1 diabetes and epilepsy: more than a casual association?

To the Editors: In 2006, McCorry et al. reported a strong epidemiologic association between type 1 diabetes mellitus (T1DM) and idiopathic generalized epilepsy (IGE) and claimed that this link would support an autoimmune pathogenesis for IGE (McCorry et al., 2006). However, O’Connel and coworkers did not confirm an increased risk of epilepsy among a series of patients with T1DM (O’Connell et al., 2008). We reviewed 249 T1DM patients (145 male; mean age 16.3 € 7.02 years, range 1.7–34.5 years; mean age at disease onset 7.7 € 6.9 years; range 0.8–18 years) attending the Diabetes Clinic at G. Gaslini Institute, Genoa, where a collaborative network provides epidemiologic data by an active surveillance model (Cotellessa et al., 2003). Extensive research was undertaken through the electronic database and subjects not followed up during the previous year were excluded. Epilepsy was diagnosed when ‡2 unprovoked euglycemic seizures (blood glucose >3.9 and <11.1 mmol/L) and syndromic classification (Commission on Classification and Terminology of the ILAE, 1989) was confirmed by reviewing clinical (family history, seizures type onset and frequency, response to treatment) and instrumental [electroencephalography (EEG), neuroimaging] data. Among 249 T1DM patients, 6 showed the electroclinical features of idiopathic epilepsy (4 IGE, 2 focal idiopathic epilepsy) (Table 1). In this group, mean age of T1DM onset was 4.6 € 2.7 years; mean age at first seizure was 6.7 € 4.4 years. None of these patients had a family history of epilepsy in firstand second-degree relatives. In all patients but one (case 4), T1DM preceded epilepsy onset, with a mean of 2.8 years (range 0.7–6.9 years). Patient 1 had concomitant celiac disease. Dosage of glutamic-acid decarboxylase antibodies (GADA) was available in two patients at T1DM diagnosis and in all cases at the last follow-up (Table 1). The high proportion of IGE observed in our series (4 of 249, 1.6%) (Hauser & Banerjee, 2008) confirms the data reported by McCorry et al. (McCorry et al., 2006). In all patients but one, T1DM manifested years before epilepsy. This may simply reflect different age of onset of the two conditions. Alternatively, it could support an autoimmune mechanism starting with T1DM and then affecting the central nervous system (McCorry et al., 2006). We did not perform GADA evaluation methodically at epilepsy onset in our patients, so that no definitive conclusion can be drawn about the existence of a pathogenetic link between GADA and epilepsy in T1DM patients (Striano et al., 2008). Interestingly, the patient with partial response to antiepileptic therapy (case 4) is the only one with recent GADA positivity. Because of the retrospective analysis, epilepsy could be underrecognized or overestimated in our T1DM population, but this is unlikely to explain the higher than expected degree of the association. Because both epilepsy and T1DM are serious worldwide problems with high medical and social management costs, this possible association deserves further investigation by prospective studies involving multiple centers.

Epilepsia partialis continua in type 1 diabetes: evolution into epileptic encephalopathy with continuous spike-waves during slow sleep.

Hyperglycemic status may be rarely complicated by Epilepsia partialis continua (EPC) that usually responds to metabolic normalization. Anti-glutamic acid decarboxylase antibodies (GAD-Ab) play a pivotal role in the autoimmune process that leads to clinical onset of type 1 diabetes mellitus (T1DM). GAD-Ab have been recently reported in association with rare forms of refractory epilepsy, with or without association to T1DM. Here we describe a young patient who developed EPC five months after T1DM onset; GAD-Ab were detected in his cerebrospinal fluid with evidence of oligoclonal bands. His epileptic disorder evolved over time into drug-resistant epilepsy with continuous spike-waves during slow sleep and severe behavioral impairment. The role of both metabolic imbalance and GAD autoimmunity is discussed.

A Multicenter Retrospective Survey regarding Diabetic Ketoacidosis Management in Italian Children with Type 1 Diabetes

We conducted a retrospective survey in pediatric centers belonging to the Italian Society for Pediatric Diabetology and Endocrinology. The following data were collected for all new-onset diabetes patients aged 0–18 years: DKA (pH < 7.30), severe DKA (pH < 7.1), DKA in preschool children, DKA treatment according to ISPAD protocol, type of rehydrating solution used, bicarbonates use, and amount of insulin infused. Records (n = 2453) of children with newly diagnosed diabetes were collected from 68/77 centers (87%), 39 of which are tertiary referral centers, the majority of whom (n = 1536, 89.4%) were diagnosed in the tertiary referral centers. DKA was observed in 38.5% and severe DKA in 10.3%. Considering preschool children, DKA was observed in 72%, and severe DKA in 16.7%. Cerebral edema following DKA treatment was observed in 5 (0.5%). DKA treatment according to ISPAD guidelines was adopted in 68% of the centers. In the first 2 hours, rehydration was started with normal saline in all centers, but with different amount. Bicarbonate was quite never been used. Insulin was infused starting from third hour at the rate of 0.05–0.1 U/kg/h in 72% of centers. Despite prevention campaign, DKA is still observed in Italian children at onset, with significant variability in DKA treatment, underlying the need to share guidelines among centers.

Insulin pump failures in Italian children with Type 1 diabetes: retrospective 1‐year cohort study

Insulin pump failure and/or malfunction requiring replacement have not been thoroughly investigated. This study evaluated pump replacement in children and adolescents with Type 1 diabetes using insulin pump therapy.

Strong Association Between Time Watching Television and Blood Glucose Control in Children and Adolescents With Type 1 Diabetes Response to Margeirsdottir et al.

We reply to Margeirsdottir et al. (1), reporting our experience in 237 type 1 diabetic Italian patients (139 male), aged (mean ± SD) 16.8 ± 7.1 years (range 1.8–36.3) with mean disease duration 9.0 ± 6.3 years (1.0–27.6), mean A1C 7.7 ± 1.1% (5.2–13.5), and mean insulin requirement 0.82 ± 0.24 units · kg−1 · day−1 (0.24–1.58). Between January and March 2007, in all patients we evaluated by direct or telephone interviews the influence of leisure time in TV watching …