Case report
Monogenic diabetes and type 1 diabetes mellitus: a challenging combination Dr Suma Uday1
Abstract
Registrar, Department of Paediatric Diabetes and Endocrinology
The co-existence of maturity onset diabetes of the young (MODY) due to a glucokinase gene (GCK) mutation and type 1 diabetes mellitus (T1DM) is rarely diagnosed. We present a family with GCK mutation, where one member also has T1DM. We highlight the challenges faced in the management of a child with dual diagnosis, due to the higher threshold for activation of counter-regulatory hormones in GCK mutations. Fluctuations in blood glucose (BG) levels and significant hypoglycaemia on attempts at normalising BG levels complicate management in these patients. Resetting the threshold for hypoglycaemia and target BG, combined with insulin pump therapy, enabled us to significantly reduce hypoglycaemia and improve quality of life. The population prevalence of GCK-MODY is 1.1 in 1000. T1DM neither predisposes to nor protects from GCK-MODY; one would therefore expect the prevalence of GCK-MODY to be the same in T1DM patients. In conclusion, it is important to recognise the co-existence of T1DM and GCK-MODY as symptoms of hypoglycaemia at BG levels usually considered ‘within target’ pose management challenges. A combined diagnosis warrants careful consideration of BG target. Copyright © 2014 John Wiley & Sons. Practical Diabetes 2014; 31(8): 327–330
Dr Fiona M Campbell2 Consultant Paediatrician, Children and Young People’s Diabetes Service
Julie Cropper2 Paediatric Diabetes Specialist Nurse, Children and Young People’s Diabetes Service
Dr Maggie Shepherd3 Honorary Reader 1
Leeds Children’s Hospital, Leeds, UK Leeds Children’s Hospital, St James’s Multi-specialty Day Hospital, Leeds, UK 3 University of Exeter Medical School and Royal Devon and Exeter NHS Foundation Trust, Exeter, Devon, UK 2
Correspondence to: Dr Suma Uday, Department of Paediatric Diabetes and Endocrinology, Leeds Children’s Hospital, Great George Street, Leeds LS9 7TF, UK; email:
[email protected] Received: 29 July 2014 Accepted in revised form: 20 August 2014
Key words type 1 diabetes mellitus; maturity onset diabetes of the young; GCK-MODY; monogenic diabetes; glucokinase gene mutation
Introduction Maturity onset diabetes of the young (MODY) is a form of monogenic diabetes that is inherited in an autosomal dominant fashion. Mutations within the glucokinase (GCK) gene account for around 20% of UK MODY and are characterised by mild, stable hyperglycaemia. Type 1 diabetes mellitus (T1DM), in contrast, is an autoimmune condition caused by auto-antibodies against pancreatic islet cells, leading to betacell destruction. A combination of the two conditions is very rarely diagnosed despite the population prevalence of 1.1 in 1000 for GCK-MODY. We share the challenges faced in the management of a child with a dual diagnosis of T1DM and GCKMODY and discuss some key considerations in the management of these children.
Case description A 14-month-old Caucasian boy presented with polyuria and polydipsia to his local hospital. His blood glucose (BG) was 23mmol/L, he was ketotic and his HbA1c was 13% (119mmol/mol). He was suspected to have T1DM and was commenced on insulin therapy. Islet cell and
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glutamic acid decarboxylase (GAD) antibodies were positive. Three months later, his older sibling aged three years presented with similar symptoms and T1DM was suspected. His hyperglycaemia (BG 8.6mmol/L) and ketonuria resolved promptly with insulin therapy. Islet cell and GAD antibodies were negative. His HbA1c was 6.6% (49mmol/mol). Negative antibodies and minimal insulin requirements prompted consideration of monogenic diabetes. On oral glucose tolerance test, fasting BG was 6.5mmol/L and 2-hour post glucose load BG was 6.6mmol/L. His insulin was stopped. Concomitantly, his younger sibling aged two months was also found to have fasting hyperglycaemia (8mmol/L) during investigation for failure to thrive. Further family history revealed an accidental discovery of raised BG level in the paternal grandfather at 41 years of age; he was thought to have type 2 diabetes and was diet controlled. This prompted a BG check on the father, who had fasting hyperglycaemia (8.6mmol/L). Hyperglycaemia in three generations of the family prompted genetic
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Case report Monogenic diabetes and type 1 diabetes
investigation for monogenic diabetes. All family members with hyperglycaemia tested positive for a heterozygous deletion on exons 5 and 6 of the glucokinase gene on chromosome 7, confirming the coexistence of T1DM and GCK-MODY in the index case (Figure 1).
Challenges The index case was initially managed on multiple daily injections (MDI) at his local hospital. However, this proved to be very challenging, as attempts to normalise BG levels resulted in recurrent episodes of disabling hypoglycaemia with going pale, limp and having seizures. He was referred to our centre for tertiary care and consideration of continuous subcutaneous insulin infusion (CSII), with a view to improving glycaemic control and reducing the frequency of hypoglycaemic episodes.
Male: GCK gene mutation positive
Male: GCK gene mutation positive + type 1 diabetes
Unaffected male
Unaffected female
Figure 1. Family tree demonstrates members with positive glucokinase gene mutation in three generations and our patient with GCK-MODY and type 1 diabetes
Management and progress Following referral to our centre, he was commenced on CSII. The family received intense education and CSII was optimised by adjusting hourly basal rates based on BG readings and use of dual wave (square wave) bolus to prevent late post-prandial BG rise. His glycaemic control improved following this, as expected. However, he continued to have episodes of hypoglycaemia, although with slightly reduced frequency. We undertook diagnostic continuous glucose monitoring (CGM) on the father (Figure 2) and our patient (Figure 3) to determine BG targets. The father’s lowest BG was 5.5mmol/L. Our patient was less than five years of age at the time; we therefore set the lower limit of his BG at 6.5mmol/L, which was 1mmol/L higher than the father’s lower limit. Any BG
