In this review we want to report a rare case of a 50 years-old man diagnosed with MODY6. An informed consent was obtained by the patient for the publication of his laboratoristic and clinical data.
The patient came for the first time to our clinic in 2017. His prior medical history included diabetes diagnosed in 1994 and classified as diabetes type II associated to a dilated cardiomyopathy treated with a pacemaker in 2011.
He had a family history of diabetes because his mother had been diagnosed with the disease, while his father was dead for natural causes. At the contrary his brother and sister were reported to be healthy, with no sign of hyperglycemia. He also had two children, in apparently very good health.
At the moment of our first medical control the patient had no signs of diabetic complications (nephropathy, neuropathy or retinopathy) and he was following a treatment with basal-bolus insulin associated to metformin. Patient’s clinical features, blood parameters and therapy are summarized in Table 1 and Table 2, respectively.
Table 1
Patient’s clinical features and blood parameters over time
|
Visit 1
|
Visit 2
|
Visit 3
|
Arterial blood pressure systolic/diastolic (mmgHg)
|
134/78
|
110/70
|
120/80
|
Body weight (kg)
|
68
|
66
|
67
|
BMI (kg/m2)
|
21,7
|
21,1
|
21,4
|
Glycated hemoglobin (%)
|
8,6
|
10,7
|
7,5
|
Fructosamine (micromol/L)
|
341
|
missing data
|
264
|
Fasting blood glucose (mg/dL)
|
111
|
288
|
83
|
C-peptide (ng/mL)
|
0.4
|
0.8
|
0.6
|
Creatinine (mg/dL)
|
0,73
|
0,64
|
0,74
|
VFG (ml/min)
|
108
|
114
|
107
|
GOT (UI)
|
13
|
17
|
21
|
GPT (UI)
|
19
|
31
|
30
|
Total cholesterol (mg/dL)
|
140
|
115
|
105
|
Triglycerides (mg/dL)
|
72
|
71
|
79
|
LDL cholesterol (mg/dL)
|
74,2
|
47
|
38
|
HDL cholesterol (mg/dL)
|
52
|
54
|
51
|
Microalbuminuria (mg/L)
|
15
|
< 5
|
10
|
Urinary ketones
|
not detected
|
not detected
|
not detected
|
Fructosamine normal range (118–282 micromol/L); C-peptide normal range (0.9–7.1 ng/mL) |
Table 2
Patient’s therapy over time
|
Visit 1
|
Visit 2
|
Visit 3
|
Insulin glargine 100 U/ml
|
18–22 UI at 10.00 pm
|
.
|
16–18 UI at 10.00 pm
|
Insulin lispro 100 U/ml
|
5 UI before breakfast, 6 UI before lunch and 6 UI before dinner
|
.
|
.
|
Metformin
|
500 mg tid
|
=
|
=
|
Gliclazide 60 mg RM
|
.
|
1 tablet od
|
1 tablet od
|
Bisoprolol
|
5 mg od + 10 mg od
|
=
|
=
|
Ramipril
|
10 mg od
|
=
|
=
|
Simvastatin/ezetimibe
|
10/10 od (poor compliance)
|
10/10 od (good compliance)
|
=
|
Lansoprazole
|
15 mg od
|
=
|
=
|
=: continued without modification |
Due to the poor glycemic control we scheduled a medical examination after a month asking the patient to monitor capillary blood glucose at home in the morning and before every meal, writing the values on a diary. We also required the detection of beta-cells antibodies in order to investigate the possibility of an autoimmune etiology of diabetes.
When the patient came back in October 2017, blood test results were not significant for autoimmune diabetes (beta cells antibodies were negative) and the values of capillary blood glucose at home showed a good trend of diabetes (most of them were between 90 and 130 mg/dL in the morning and before meals). According to the good glycemic control, we modified the patient’s treatment by removing Lispro insulin before meals and introducing an oral hypoglycemic agent of the SGLT2 inhibitors group (dapagliflozin) associated to metformin (dapagliflozin/metformin 5/1000 mg 2 tablets per day).
The patient had to interrupt the treatment with dapagliflozin/metformin about ten days later, due to the appearance of severe abdominal pain that spontaneously resolved at the suspension of the therapy. The symptoms were not attributed at the metformin component of the drug, that the patient was already taking since many months. On the contrary, we suspected an euglycemic ketoacidosis caused by the effect of dapagliflozin but unfortunately, we didn’t have the chance to confirm it because the patient informed us by phone several days after.
We therefore chose to set up a therapy with only metformin (500 mg 3 tablets per day) and insulin glargine scheduling a new control after ten days. When the patient came back after monitoring capillary blood glucose at home for ten days, the values were still very good (90–130 mg/dL) despite the reduction of the pharmacological therapy.
Six months later the medical condition of the patient was still very confounding because glycated hemoglobin had remained high at updated blood test, while glucose values at home before meals continued to be normal.
In consideration of the young age of the patient and of his clinical picture, we decided to plan a genetic test in order to investigate the possibility of a mutation of MODY genes.
Targeted NGS of the 14 MODY genes, as well as WFS1 and INSR was performed by using amplicon-based libraries and Ion Gene Studio System S5, according to the manufacturer’s instructions (Thermo Fisher Scientific Inc.). Variant classification was performed according to the American College of Medical Genetics and Genomics (ACMG) standards by using the VarSomeClinical platform (https://varsome.com) [20]. Possible pathogenic variants were confirmed by Sanger sequencing. Large rearrangements in MODY1, 2, 3 and 5 genes were excluded by MLPA (MRC-Holland, Amsterdam, NL).
The genetic test showed heterozygosity for the missense variant p.Met114Leu c.340A > C in NEUROD1 (NM_002500.4), linked to MODY6. The variant was not found in GnomAD exomes and genomes, and resulted with pathogenic prediction from 10 computational analyses (DEOGEN2, EIGEN, M-CAP, MVP, MutationAssessor, MutationTaster, PrimateAI, REVEL, PolyPhen-2 and SIFT) versus two benign predictions (DANN and FATHMM-MKL).
At the time of the molecular diagnosis, this variant was previously undescribed and we classified it as variant of uncertain significant (VUS).
Since MODY is characterized by an autosomal dominant inheritance, family counseling was provided for the patient. His brother and sister didn’t show hyperglycemia and no evidence of this NEUROD1 variant was found at genetic testing on them. We therefore report that the patient’s mother had been diagnosed with diabetes type 2 since many years but, because of her old age and immobility, genetic testing has never been performed on her.
More recently, Bouillet et al. described the same NEUROD1 variant associated to MODY6 in a French family and classified it as mutation [21].
International guidelines report sulfonylureas as the first-line treatment for monogenic diabetes, so the patient started a treatment with gliclazide RM (60 mg) and no basal insulin.
Unfortunately glycemic values didn’t benefit from the treatment with sulfonylureas and at the following medical examination the patient showed a very bad glycemic control (glycated hemoglobin 93 mmol/mol, fasting glucose 288 mg/dL). We therefore decided to restore the therapy with basal insulin, also in consideration of a very low c-peptide value in addition to gliclazide and metformin. With this kind of therapy the patient obtained a very good glycemic control, practising only one injection, and without the necessity to measure sugar after every meal. He referred us that his quality of life has improved, although this data was not measured with specific questionnaires.