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
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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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