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Response to oral gliclazide in a pre-pubertal child with hepatic nuclear factor-1 alpha maturity onset diabetes of the young.

Habeb AM, George ET, Mathew V, Hattersley AL - Ann Saudi Med (2011 Mar-Apr)

Bottom Line: Patients with HNF-1α mutations typically present after puberty, and oral sulfonylureas (SU) have been shown to be effective in adults with this condition.Initial management with diet alone was not sufficient, but he responded well to 20 mg oral gliclazide once a day with an improvement of HbA 1C from 7.2% to 6.5% within 3 months of treatment.The case is an illustration of the clinical utility of molecular genetic tests in the management of childhood diabetes.

View Article: PubMed Central - PubMed

Affiliation: Paediatric Endocrine Unit, Maternity and Children Hospital, Medina, Saudi Arabia. amhabeb@hotmail.com

ABSTRACT
The term "maturity onset diabetes of the young" (MODY) describes a heterogeneous group of monogenic diabetes of which hepatic nuclear factor-1 alpha (HNF-1α) MODY is the most common. Patients with HNF-1α mutations typically present after puberty, and oral sulfonylureas (SU) have been shown to be effective in adults with this condition. A 7-year-old boy presented with asymptomatic hyperglycemia ranging between 6.2 and 10.1 mmol/L and glycosuria for nearly a year. The child's initial HbA 1c was 6.9% and the pancreatic Islet cell autoantibodies were negative. His response to the oral glucose tolerance test (OGTT) showed a large increment of glucose from basal level of 7.7 to 21.1 mmol/L in 120 min. The mild presentation, family history, and negative autoantibodies were suggestive of HNF-1α MODY, which was confirmed by mutation analysis. Initial management with diet alone was not sufficient, but he responded well to 20 mg oral gliclazide once a day with an improvement of HbA 1C from 7.2% to 6.5% within 3 months of treatment. The case is an illustration of the clinical utility of molecular genetic tests in the management of childhood diabetes.

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Chromatogram of the c.526+1G>A mutation taken from the Mutation Surveyor sequencing analysis software provided by Soft Genetics. The upper sequence is the normal control and the lower sequence is the patient. The mutation is indicated by the peak in the comparison trace at the bottom (arrowed). The top frame contains the reference nucleotide and amino acid sequences.
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Figure 1: Chromatogram of the c.526+1G>A mutation taken from the Mutation Surveyor sequencing analysis software provided by Soft Genetics. The upper sequence is the normal control and the lower sequence is the patient. The mutation is indicated by the peak in the comparison trace at the bottom (arrowed). The top frame contains the reference nucleotide and amino acid sequences.

Mentions: The patient was given dietary advice with a follow-up appointment in the diabetes clinic. Two months later he was admitted to the hospital with a viral illness and his blood glucose rose to >20 mmol/L with no ketonuria. His blood glucose improved without insulin, but his HbA1c rose to 7.8%. An oral glucose tolerance test (GTT) using 1.75 g/kg glucose showed a blood glucose of 7.7, 15.7, 18.7, 20.6, and 21.7 mmol/L at 0, 30, 60, 90, and 120 minutes, respectively. Direct DNA sequencing of all exons and intron-exon bounders of the HNF-1a gene was done at Peninsula University, Exeter. The analysis showed that the child was heterozygous for a known GT-AT mutation (c.526+1G>A) of the splice donor site in intron 2 of the HNF-1a gene. A chromatogram of this mutation is shown in Figure 1. This confirmed the diagnosis of HNF1A-MODY, also known as MODY 3. The father was not keen to be tested as he was depressed at the time and the rest of the family were not screened as they were asymptomatic and the mutation had already been described in patients with MODY 3. After discussion with the family, he was placed on oral gliclazide 20 mg once daily. He was followed up at the clinic on an every 3 month basis. His home blood glucose profile showed no significant hyperglycemia and he reported no symptoms of hypoglycemia. His HbA1C was reduced from 7.2% to 6.5% within 3 months of starting gliclazide and this improvement in HbA1C was maintained for the following 18 months (Figure 2).


Response to oral gliclazide in a pre-pubertal child with hepatic nuclear factor-1 alpha maturity onset diabetes of the young.

Habeb AM, George ET, Mathew V, Hattersley AL - Ann Saudi Med (2011 Mar-Apr)

Chromatogram of the c.526+1G>A mutation taken from the Mutation Surveyor sequencing analysis software provided by Soft Genetics. The upper sequence is the normal control and the lower sequence is the patient. The mutation is indicated by the peak in the comparison trace at the bottom (arrowed). The top frame contains the reference nucleotide and amino acid sequences.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3102482&req=5

Figure 1: Chromatogram of the c.526+1G>A mutation taken from the Mutation Surveyor sequencing analysis software provided by Soft Genetics. The upper sequence is the normal control and the lower sequence is the patient. The mutation is indicated by the peak in the comparison trace at the bottom (arrowed). The top frame contains the reference nucleotide and amino acid sequences.
Mentions: The patient was given dietary advice with a follow-up appointment in the diabetes clinic. Two months later he was admitted to the hospital with a viral illness and his blood glucose rose to >20 mmol/L with no ketonuria. His blood glucose improved without insulin, but his HbA1c rose to 7.8%. An oral glucose tolerance test (GTT) using 1.75 g/kg glucose showed a blood glucose of 7.7, 15.7, 18.7, 20.6, and 21.7 mmol/L at 0, 30, 60, 90, and 120 minutes, respectively. Direct DNA sequencing of all exons and intron-exon bounders of the HNF-1a gene was done at Peninsula University, Exeter. The analysis showed that the child was heterozygous for a known GT-AT mutation (c.526+1G>A) of the splice donor site in intron 2 of the HNF-1a gene. A chromatogram of this mutation is shown in Figure 1. This confirmed the diagnosis of HNF1A-MODY, also known as MODY 3. The father was not keen to be tested as he was depressed at the time and the rest of the family were not screened as they were asymptomatic and the mutation had already been described in patients with MODY 3. After discussion with the family, he was placed on oral gliclazide 20 mg once daily. He was followed up at the clinic on an every 3 month basis. His home blood glucose profile showed no significant hyperglycemia and he reported no symptoms of hypoglycemia. His HbA1C was reduced from 7.2% to 6.5% within 3 months of starting gliclazide and this improvement in HbA1C was maintained for the following 18 months (Figure 2).

Bottom Line: Patients with HNF-1α mutations typically present after puberty, and oral sulfonylureas (SU) have been shown to be effective in adults with this condition.Initial management with diet alone was not sufficient, but he responded well to 20 mg oral gliclazide once a day with an improvement of HbA 1C from 7.2% to 6.5% within 3 months of treatment.The case is an illustration of the clinical utility of molecular genetic tests in the management of childhood diabetes.

View Article: PubMed Central - PubMed

Affiliation: Paediatric Endocrine Unit, Maternity and Children Hospital, Medina, Saudi Arabia. amhabeb@hotmail.com

ABSTRACT
The term "maturity onset diabetes of the young" (MODY) describes a heterogeneous group of monogenic diabetes of which hepatic nuclear factor-1 alpha (HNF-1α) MODY is the most common. Patients with HNF-1α mutations typically present after puberty, and oral sulfonylureas (SU) have been shown to be effective in adults with this condition. A 7-year-old boy presented with asymptomatic hyperglycemia ranging between 6.2 and 10.1 mmol/L and glycosuria for nearly a year. The child's initial HbA 1c was 6.9% and the pancreatic Islet cell autoantibodies were negative. His response to the oral glucose tolerance test (OGTT) showed a large increment of glucose from basal level of 7.7 to 21.1 mmol/L in 120 min. The mild presentation, family history, and negative autoantibodies were suggestive of HNF-1α MODY, which was confirmed by mutation analysis. Initial management with diet alone was not sufficient, but he responded well to 20 mg oral gliclazide once a day with an improvement of HbA 1C from 7.2% to 6.5% within 3 months of treatment. The case is an illustration of the clinical utility of molecular genetic tests in the management of childhood diabetes.

Show MeSH
Related in: MedlinePlus