A CASE OF MODY 2 - ASSOCIATED HYPERGLYCEMIA DIAGNOSED AS GESTATIONAL DIABETES
Chakarova N.1, Balabanski L.2,3, Dimova R.1, Tsarkova P.1, Tankova T.1
*Corresponding Author: Nevena Chakarova, MD, PhD, Department of Endocrinology Medical University Sofia, 1431 Sofia, 2 Zdrave Str., e-mail: veni_chakarova@abv.bg, ORCID ID 0000-0001-7606-5060
page: 4

DISCUSSION

The presented case has the typical characteristics of MODY: early onset, generally before the age of 25 years, no signs of autoimmunity or insulin resistance, as well as the related traits of the metabolic syndrome, preserved endogenous insulin secretion and family history consistent with autosomal dominant pattern of inheritance [1-3]. The presentation of MODY as gestational diabetes is also rather typical [3, 4]. Although dysglycemia during pregnancy is usually considered a main risk factor for future development of type 2 diabetes, the phenotype of a patient with MODY, who generally does not have the characteristics of the metabolic syndrome, should be considered for further diagnostic assessment. Our patient had BMI in the low-normal range, no concomitant hypertension or dyslipidemia, no history of PCOS or other traits of the insulin resistance state. Still, a specific form of diabetes had not been suspected, and the patient had received the standard pharmacologic approach to subjects with prediabetes or newly diagnosed type 2 diabetes with metformin. Generally, the mild hyperglycemia of MODY 2 does not require pharmacologic treatment and the administration of different agents does not usually affect the HbA1c level [3]. Metformin therapy, in our case, supports this observation, as fasting glycemia was not influenced by this therapy throughout the years. However, a treatment approach to MODY 2 during pregnancy, when glycemic targets are at their lowest levels, is a rather complicated situation. It may negatively affect the development of the fetus depending on whether it carries the GSK pathogenic variant or not. In the case that the fetus has inherited the mutation, achievement of glycemic targets by insulin treatment would lead to decreased insulin secretion in the fetus, as the normal maternal glucose levels cannot stimulate the defective beta-cells. As a result, fetal weight could be severely affected. If the baby does not carry the mutation, maternal hyperglycemia would stimulate fetal insulin secretion that will result in approximately 500 g additional weight and fetal macrosomia. That is why it is recommended to use insulin treatment during pregnancy in women with MODY 2, based on the presence of ultrasound signs of fetal macrosomia not on maternal glucose concentrations [5]. In our case, insulin was not administered during both pregnancies, but this decision was not based on the presence of MODY 2, as the diagnosis was not established at that time. We do not have data on the genotype of the two children, as the parents decided not to perform genetic testing at this point. Based, however, on their birth weight and a difference of 650 g between the babies, preterm in the case of the larger baby, we can speculate that a possible scenario could be that the first child does not carry the mutation, as the untreated maternal hyperglycemia during pregnancy resulted in a relatively large gestational aged baby - approaching the 90th percentile according to both the original and revised Fenton charts [8]. Yet the second child probably carries the mutation, as the untreated maternal hyperglycemia has resulted in a normal weight for the baby. In case both the mother and the fetus carry the mutation, fetal growth is not affected because the insulin secretion of the fetus is triggered at the same glycemic threshold as that of the mother [5]. Regarding the genetic background, the detected pathogenic variant in the GCK gene in our patient is a substitution of cytosine with thymine at position 44192924 on chromosome 7 (GRCh37/hg19). It is denoted as c.184G>A at transcript level (NM_000162.5) and results in the substitution of valine with methionine at codon 62 (V62M) of the amino acid sequence of the protein (NP_000153.1). This variant (rs1064793998) is extremely rare and is not reported in large population databases, such as gnomAD, ExAC and GenomeAsia 100K. V62M in GCK has been found, however, in multiple individuals with MODY 2 around the world [9-11] and is classified as pathogenic in the ClinVar database (Variation ID: 419624). There is a clinical correlation between our patient and other carriers of the V62M variant, as they also had elevated fasting plasma glucose levels [9, 11]. Heterozygous inactivating mutations in GCK cause MODY 2, while heterozygous activating mutations result in hyperinsulinemic hypoglycemia [12]. Functional studies about the consequences of the V62M variant detected in our patient demonstrated that the mutation leads to lowered catalytic activity, mild thermal instability, weaker glucose binding and diminished interaction with the glucokinase regulatory protein [9, 13, 14]. Therefore, the expected inactivating effect of the mutation is consistent with the MODY 2-related hyperglycemia phenotype observed in our patient. The presented case clearly illustrates that the mild fasting hyperglycemia of MODY 2 may not necessarily fulfill the criteria for diabetes. Thus, not only some patients with diabetes, but also a certain proportion of the subjects with prediabetes with atypical phenotype, are candidates for further diagnostic evaluation and genetic testing. Fasting hyperglycemia in our patient was almost constantly in the range of impaired fasting glucose. The normal 2-hour value during OGTT is also typical for MODY 2 and the underlying glucokinase defect and the shifted to the right dose-response curve of glucose concentrations and insulin secretion [1]. Apart from the typical characteristics, the presented case is interesting for two additional issues also of genetic character that elaborate the diagnosis and management of the patient: the concomitant autoimmune disease and betathalassemia. The presence of autoimmune thyroid disease in the patient together with the constellation of autoimmune polyglandular syndrome type 3c in her mother suggested the possibility of autoimmune diabetes. Although the long evolution of dysglycemia was not supportive of this hypothesis, the absolute differentiation between the entities of MODY and type 1 diabetes were the negative immunologic markers and mainly the preserved endogenous insulin secretion during IVGTT. The presence of the other monogenic disease - beta thalassemia, compromised the usage of HbA1c as a criterion for the assessment of glucose tolerance and glycemic control of the patient [15]. The limitations of HbA1c were overcome with the new metrics of glycemic control derived from CGM. In conclusion, MODY could be diagnosed at any stage of glucose dysregulation, including the early stages of glucose intolerance. Each patient with any degree of dysglycemia and clinical and laboratory findings that do not match the standard profile of type 1 and type 2 diabetes should undergo genetic testing for a specific form of diabetes. The recognition of MODY 2 during pregnancy has important clinical implications, as the treatment approach may differ from those established in gestational diabetes. In many countries like Bulgaria, where routine screening is not performed, national healthcare systems should be involved in the reimbursement of the genetic testing of the suspected patients and the family members of the detected individuals. CGM could be useful in patients with mild hyperglycemia like the one observed in MODY 2 when deciding whether to initiate pharmacologic therapy.



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