The genetic aetiology of more than 90% of TNDM has been established. The majority (70%) of cases result from abnormalities in the q24 region of chromosome 6 (6q24) affecting imprinted genes. Genetic imprinting occurs when only the maternally or paternally inherited allele of a gene is expressed and this is usually controlled by methylation. 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. 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. The majority (90%) of TNDM not associated with 6q24 abnormalities are caused by variants in KCNJ11 and ABCC8.
Clinical features
6q24 diabetes usually presents in the first week of life, often with severe hyperglycaemia and dehydration but usually without keto sis. Pancreatic auto- antibodies are usually negative and C- peptide is low or negligible. Low birth weight is common (mean birth weight approximately 2.0 kg), and there may be associated macroglossia and/or umbilical hernia. Insulin treatment is required for a median of 12 weeks before the child goes into remission. Diabetes recurs later in life, with an average age of recurrence of 14 years in approximately 50% as a result of β- cell dysfunction. In some cases, hyperglycaemia may be intermittent and seen only at times of stress. Where TNDM is caused by KCNJ11 and ABCC8 variants, diabetes tends to pre sent later (median 4 weeks), takes longer to remit, and is associated with less intrauterine growth restriction (median birth weight 2.6 kg). Importantly, in KCNJ11- and ABCC8- related TNDM individuals may not present in the neonatal period and may only present in the relapse phase in adolescence or young adult hood, usually with a dominant family history, and they are sulfonylurea sensitive.
Management
Insulin is required in the neonatal period for all cases initially, whereas treatment following relapse varies from diet to oral anti- diabetes agents or insulin. In TNDM cases resulting from KCNJ11 and ABCC8 variants, diabetes may be successfully managed with sulfonylureas. The best treatment options for 6q24- related TNDM following relapse remain unclear; however, recent data indicate that non- insulin- based therapies, including sulfonylureas, may be effective.
Genetic counselling depends on the underlying genetic aetiology. 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 variants in the transcription factor gene ZFP57 and therefore may be inherited in an autosomal recessive manner. Offspring of men with 6q24 duplication have a 50% chance of developing TNDM, whereas if the abnormality is inherited from the mother they will not be affected because both maternal copies would be inactive due to methylation; however, the TNDM may occur in the following generation.
