RESUMEN
BACKGROUND: Children with neonatal diabetes often present with diabetic ketoacidosis and hence are at risk of cerebral oedema and subsequent long-term neurological deficits. These complications are difficult to identify because neurological features can also occur as a result of the specific genetic aetiology causing neonatal diabetes. CASE REPORTS: We report two cases of neonatal diabetes where ketoacidosis-related cerebral oedema was the major cause of their permanent neurological disability. Case 1 (male, 18 years, compound heterozygous ABCC8 mutation) and case 2 (female, 29 years, heterozygous KCNJ11 mutation) presented with severe diabetic ketoacidosis at 6 and 16 weeks of age. Both had reduced consciousness, seizures and required intensive care for cerebral oedema. They subsequently developed spastic tetraplegia. Neurological examination in adulthood confirmed spastic tetraplegia and severe disability. Case 1 is wheelchair-bound and needs assistance for transfers, washing and dressing, whereas case 2 requires institutional care for all activities of daily living. Both cases have first-degree relatives with the same mutation with diabetes, who did not have ketoacidosis at diagnosis and do not have neurological disability. DISCUSSION: Ketoacidosis-related cerebral oedema at diagnosis in neonatal diabetes can cause long-term severe neurological disability. This will give additional neurological features to those directly caused by the genetic aetiology of the neonatal diabetes. Our cases highlight the need for increased awareness of neonatal diabetes and earlier and better initial treatment of the severe hyperglycaemia and ketoacidosis often seen at diagnosis of these children.
Asunto(s)
Edema Encefálico/etiología , Discapacidades del Desarrollo/etiología , Diabetes Mellitus/fisiopatología , Cetoacidosis Diabética/etiología , Neuropatías Diabéticas/etiología , Hiperglucemia/etiología , Cuadriplejía/etiología , Adolescente , Adulto , Edema Encefálico/fisiopatología , Discapacidades del Desarrollo/fisiopatología , Diabetes Mellitus/sangre , Diabetes Mellitus/genética , Cetoacidosis Diabética/fisiopatología , Neuropatías Diabéticas/fisiopatología , Personas con Discapacidad , Salud de la Familia , Femenino , Humanos , Hiperglucemia/fisiopatología , Masculino , Mutación , Canales de Potasio de Rectificación Interna/genética , Cuadriplejía/fisiopatología , Calidad de Vida , Índice de Severidad de la Enfermedad , Receptores de Sulfonilureas/genéticaRESUMEN
AIMS: Mutations in the KCNJ11 gene, which encodes the Kir6.2 subunit of the pancreatic KATP channel, cause neonatal diabetes. KCNJ11 is also expressed in the brain, and ~ 20% of those affected have neurological features, which may include features suggestive of psychiatric disorder. No previous studies have systematically characterized the psychiatric morbidity in people with KCNJ11 neonatal diabetes. We aimed to characterize the types of psychiatric disorders present in children with KCNJ11 mutations, and explore their impact on families. METHODS: The parents and teachers of 10 children with neonatal diabetes due to KCNJ11 mutations completed the Strengths and Difficulties Questionnaire and the Development and Wellbeing Assessment. Strengths and Difficulties Questionnaire scores were compared with normative data. Diagnoses from the Development and Wellbeing Assessment were compared with known clinical diagnoses. RESULTS: Strengths and Difficulties Questionnaire scores indicated high levels of psychopathology and impact. Psychiatric disorder(s) were present in all six children with the V59M or R201C mutation, and the presence of more than one psychiatric disorder was common. Only two children had received a formal clinical diagnosis, with a further one awaiting assessment, and the coexistence of more than one psychiatric disorder had been missed. Neurodevelopmental (attention deficit hyperactivity disorder and autism) and anxiety disorders predominated. CONCLUSIONS: Systematic assessment using standardized validated questionnaires reveals a range of psychiatric morbidity in children with KCNJ11 neonatal diabetes. This is under-recognized clinically and has a significant impact on affected children and their families. An integrated collaborative approach to clinical care is needed to manage the complex needs of people with KCNJ11 neonatal diabetes.
Asunto(s)
Diabetes Mellitus/genética , Diabetes Mellitus/psicología , Trastornos del Neurodesarrollo/genética , Canales de Potasio de Rectificación Interna/genética , Adolescente , Sustitución de Aminoácidos , Niño , Trastornos de la Conducta Infantil/complicaciones , Trastornos de la Conducta Infantil/epidemiología , Trastornos de la Conducta Infantil/genética , Comorbilidad , Diabetes Mellitus/epidemiología , Femenino , Humanos , Recién Nacido , Enfermedades del Recién Nacido/genética , Masculino , Mutación Missense , Trastornos del Neurodesarrollo/complicaciones , Trastornos del Neurodesarrollo/epidemiología , Manifestaciones NeurológicasAsunto(s)
Diabetes Mellitus Tipo 1/tratamiento farmacológico , Gliburida/uso terapéutico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , Mutación Missense/genética , Canales de Potasio de Rectificación Interna/genética , Compuestos de Sulfonilurea/uso terapéutico , Humanos , MasculinoRESUMEN
AIMS: Hepatocyte nuclear factor 1ß (HNF1B) mutations cause a syndrome of renal cysts and diabetes, with whole gene deletions accounting for approximately 50% of cases. The severity of the renal phenotype is variable, from enlarged cystic kidneys incompatible with life to normal renal development and function. We investigated the prevalence of HNF1B deletions in patients with diabetes but no known renal disease. METHODS: We tested 461 patients with familial diabetes diagnosed before 45 years, including 258 probands who met clinical criteria for maturity-onset diabetes of the young (two generations affected and at least one family member diagnosed under 25 years). A fluorescent polymerase chain reaction assay was used to analyse two intragenic polymorphic HNF1B markers and identify heterozygous patients who therefore did not have whole gene deletions. Those patients homozygous for both markers were then tested for an HNF1B deletion using multiplex ligation-dependent probe amplification. RESULTS: Heterozygous HNF1B intragenic polymorphisms were identified in 337/461 subjects. Multiplex ligation-dependent probe amplification analysis showed an HNF1B gene deletion in three of the remaining 124 probands, all of whom met the criteria for maturity-onset diabetes of the young. Testing of their relatives identified three additional deletion carriers and ultrasound scanning showed renal developmental abnormalities in three of these six patients. CONCLUSIONS: We estimate that HNF1B mutations account for < 1% of cases of maturity-onset diabetes of the young. Although HNF1B mutations are a rare cause of diabetes in the absence of known renal disease, a genetic diagnosis of renal cysts and diabetes syndrome is important as it raises the possibility of subclinical renal disease and the 50% risk of renal cysts and diabetes syndrome in the patient's offspring.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Nefropatías Diabéticas/genética , Eliminación de Gen , Factor Nuclear 1-beta del Hepatocito/genética , Polimorfismo Genético/genética , Adolescente , Adulto , Niño , Preescolar , Femenino , Pruebas Genéticas , Homocigoto , Humanos , Lactante , Enfermedades Renales Quísticas/genética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
AIMS/HYPOTHESIS: The ABCC8 gene encodes the sulfonylurea receptor 1 (SUR1) subunit of the pancreatic beta cell ATP-sensitive potassium (K(ATP)) channel. Inactivating mutations cause congenital hyperinsulinism (CHI) and activating mutations cause transient neonatal diabetes (TNDM) or permanent neonatal diabetes (PNDM) that can usually be treated with sulfonylureas. Sulfonylurea sensitivity is also a feature of HNF1A and HNF4A MODY, but patients referred for genetic testing with clinical features of these types of diabetes do not always have mutations in the HNF1A/4A genes. Our aim was to establish whether mutations in the ABCC8 gene cause MODY that is responsive to sulfonylurea therapy. METHODS: We sequenced the ABCC8 gene in 85 patients with a BMI <30 kg/m², no family history of neonatal diabetes and who were deemed sensitive to sulfonylureas by the referring clinician or were sulfonylurea-treated. All had tested negative for mutations in the HNF1A and HNF4A genes. RESULTS: ABCC8 mutations were found in seven of the 85 (8%) probands. Four patients were heterozygous for previously reported mutations and four novel mutations, E100K, G214R, Q485R and N1245D, were identified. Only four probands fulfilled MODY criteria, with two diagnosed after 25 years and one patient, who had no family history of diabetes, as a result of a proven de novo mutation. CONCLUSIONS/INTERPRETATION: ABCC8 mutations can cause MODY in patients whose clinical features are similar to those with HNF1A/4A MODY. Therefore, sequencing of ABCC8 in addition to the known MODY genes should be considered if such features are present, to facilitate optimal clinical management of these patients.
Asunto(s)
Transportadoras de Casetes de Unión a ATP/genética , Diabetes Mellitus Tipo 2/genética , Heterocigoto , Mutación , Canales de Potasio de Rectificación Interna/genética , Receptores de Droga/genética , Transportadoras de Casetes de Unión a ATP/química , Adulto , Sustitución de Aminoácidos , Estudios de Cohortes , Análisis Mutacional de ADN , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Femenino , Estudios de Asociación Genética , Humanos , Hipoglucemiantes/uso terapéutico , Leucocitos/metabolismo , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Linaje , Canales de Potasio de Rectificación Interna/química , Subunidades de Proteína/química , Subunidades de Proteína/genética , Receptores de Droga/química , Compuestos de Sulfonilurea/uso terapéutico , Receptores de Sulfonilureas , Reino Unido , Adulto JovenRESUMEN
AIMS/HYPOTHESIS: Maturity-onset diabetes of the young is frequently misdiagnosed as type 1 or type 2 diabetes. A correct diagnosis of MODY is important for determining treatment, but can only be confirmed by molecular genetic testing. We aimed to compare the regional distribution of confirmed MODY cases in the UK and to estimate the minimum prevalence. METHODS: UK referrals for genetic testing in 2,072 probands and 1,280 relatives between 1996 and 2009 were examined by region, country and test result. Referral rate and prevalence were calculated using UK Census 2001 figures. RESULTS: MODY was confirmed in 1,177 (35%) patients, with HNF1A (52%) and GCK mutations (32%) being most frequent in probands confirmed with MODY. There was considerable regional variation in proband referral rates (from <20 per million in Wales and Northern Ireland to >50 per million for South West England and Scotland) and patients diagnosed with MODY (5.3 per million in Northern Ireland, 48.9 per million in South West England). Referral rates and confirmed cases were highly correlated (r = 0.96, p < 0.0001). The minimum prevalence of MODY was estimated to be 108 cases per million. CONCLUSIONS/INTERPRETATION: Assuming this minimal prevalence throughout the UK then >80% of MODY is not diagnosed by molecular testing. The marked regional variation in the prevalence of confirmed MODY directly results from differences in referral rates. This could reflect variation in awareness of MODY or unequal access to genetic testing. Increased referral for diagnostic testing is required if the majority of MODY patients are to have the genetic diagnosis necessary for optimal treatment.
Asunto(s)
Diabetes Mellitus Tipo 2/diagnóstico , Tamizaje Masivo/normas , Adolescente , Adulto , Edad de Inicio , Niño , Preescolar , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/genética , Inglaterra/epidemiología , Familia , Pruebas Genéticas/estadística & datos numéricos , Accesibilidad a los Servicios de Salud/normas , Accesibilidad a los Servicios de Salud/estadística & datos numéricos , Humanos , Lactante , Tamizaje Masivo/estadística & datos numéricos , Irlanda del Norte/epidemiología , Prevalencia , Derivación y Consulta/estadística & datos numéricos , Escocia/epidemiología , Gales/epidemiología , Adulto JovenRESUMEN
AIMS/HYPOTHESIS: Heterozygous mutations of glucokinase (GCK) and hepatocyte nuclear factor-1 alpha (HNF1A; also known as hepatic transcription factor 1 [TCF1]) genes are the most common cause of MODY. Genomic deletions of the HNF1B (also known as TCF2) gene have recently been shown to account for one third of mutations causing renal cysts and diabetes syndrome. We investigated the prevalence of partial and whole gene deletions in UK patients meeting clinical criteria for GCK or HNF-1alpha/-4alpha MODY and in whom no mutation had been identified by sequence analysis. METHODS: A multiplex ligation-dependent probe amplification (MLPA) assay was developed using synthetic oligonucleotide probes for 30 exons of the GCK, HNF1A and HNF4A genes. RESULTS: Partial or whole gene deletions were identified in 1/29 (3.5%) probands using the GCK MLPA assay and 4/60 (6.7%) of probands using the HNF1A/-4A MLPA assay. Four different deletions were detected: GCK exon 2, HNF1A exon 1, HNF1A exons 2 to 10 and HNF1A exons 1 to 10. An additional Danish pedigree with evidence of linkage to HNF1A had a deletion of exons 2 to 10. Testing other family members confirmed co-segregation of the deletion mutations with diabetes in the pedigrees. CONCLUSIONS/INTERPRETATION: Large deletions encompassing whole exons can cause GCK or HNF-1alpha MODY and will not be detected by sequencing. Gene dosage assays, such as MLPA, are a useful adjunct to sequence analysis when a diagnosis of MODY is strongly suspected.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Eliminación de Gen , Glucoquinasa/genética , Factor Nuclear 1-alfa del Hepatocito/genética , Adolescente , Adulto , Edad de Inicio , Preescolar , Femenino , Glucoquinasa/deficiencia , Factor Nuclear 1-alfa del Hepatocito/deficiencia , Humanos , Masculino , Linaje , FenotipoRESUMEN
Mitochondrial DNA (mtDNA) from petite strain K45 of Saccharomyces cerevisiae contains about 7% circular DNA molecules which comprise a simple oligomeric series based on a monomeric size of 1.7 kilobase pairs. Electrophoresis of K45 mtDNA on a polyacrylamide-agarose slab gel fractionates the mtDNA into a major band (containing linear DNA) and several faster running minor bands each containing particular size class of circular DNA molecules. From study of mtDNA from K45 and two other simple petites it was found that the mobility of circles is inversely proportional to the logarithm of the circle size. Polyacrylamide gel electrophoresis thus permits the separation of circular mtDNA from the linear mtDNA of simple petites, and physically resolves circles of different size from one another.