5.1 Monogenic defects causing pancreatic -cell dysfunction

1.

MODY: Maturity-onset diabetes of young (MODY) is the most common type of monogenic diabetes and is inherited in an autosomal dominant fashion. The various genes involved are HNF4A (MODY 1), GCK (MODY 2), HNF1A (MODY 3), IPF1 (MODY 4), HNF1B (MODY 5), NEUROD1 (MODY 6), KLF11 (MODY 7), CEL (MODY 8), PAX4 (MODY 9), INS (MODY 10), BLK (MODY 11), ABCC8 (MODY 12) and KCNJ11 (MODY 13). Identification of these genes is crucial not only for genetic counseling but also for planning the treatment and for screening other organs. For example, MODY is easily misdiagnosed as type 1 DM. It is important to differentiate it from type 1 DM as those caused by defects in HNF1A and KCNJ11 gene respond to low or high dose sulfonylureas respectively instead of insulin. HNF1B mutations often cause renal cysts, and hyperechoic kidneys in the fetus is a presentation of HNF1B sequence variations or whole gene deletion (Vasileiou et al., 2019). In addition to heterozygous sequence variation in HNF1B gene, an approximate 1.3 Mb deletion at chromosome 17q12, which includes the entire HNF1B gene is a cause of DM with renal cysts and variable degree of neurodevelopmental abnormalities.

2.

Neonatal DM (NDM): It is the second most common monogenic type of DM which usually manifests in infants under 6 months of age. Rare occurrence in infants up to 12 months of age has also been reported (Rubio-Cabezas & Ellard, 2013). Infants with insulin-dependent hyperglycemia, with blood glucose persistently greater than 250 mg/dL, lasting for more than 7-10 days without an alternative etiology should undergo genetic testing for neonatal DM.

NDM can be classified into transient (TNDM) and permanent forms. Approximately 50% of cases are transient in nature and the diabetes resolves on its own. The most common cause for TNDM is overexpression of the chromosome region 6q24. Although hyperglycaemia remits in TNDM patients by the age of 18 months, a relapse of diabetes occurs in 50% of the patients, usually during adolescence or early adulthood (Mackay & Temple, 2010). On the other hand, permanent NDM most often results from gain of function mutations in KCNJ11 or ABCC8 gene. These can be successfully treated with high doses of sulfonylureas unlike other NDM which require treatment with insulin. The most common genes and associated features involved in NDM are described in Table 2.

5.2 Monogenic causes of insulin resistance

They are less common than monogenic β-cell defects. They typically present with features of insulin resistance in the absence of obesity, including hyperinsulinemia, acanthosis nigricans or virilization. Diabetes only develops when the β-cells fail to compensate for the insulin resistance. The common genes and syndromes associated with insulin resistance are listed in Table 3.

6 Gestational Diabetes Mellitus (GDM)

Type 2 DM can remain undiagnosed and can be recognised initially during pregnancy. It is essential to distinguish between GDM and type 2 DM in pregnancy as the latter is associated with a higher incidence of fetal malformations like caudal regression syndrome, congenital heart defects, renal anomalies etc. Family history of GDM and type 2 DM can act as a guide to predict risk of GDM. Women diagnosed with GDM are also at a significant risk for developing type 2 DM later in life.

Identification of monogenic diabetes has very significant relevance in pregnancy. Hyperglycemia in pregnancy is invariably always labelled as GDM but some of these patients may harbour mutation in the GCK (glucokinase) gene and identification of these women is important as the management differs substantially. Glucose-lowering agents are generally not required in GCK-associated MODY in normal individuals as the hyperglycemia is usually subclinical. Pregnancy is an exception where the requirement of treatment for GCK-associated MODY in pregnant woman depends on fetal inheritance of the GCK mutation. If the fetus inherits a maternal GCK mutation, then treatment of maternal hyperglycemia is not indicated as these fetuses have a similarly elevated glucose set-point as their mother and can have normal birth weight. On the other hand, treatment of maternal hyperglycemia is required in those fetuses who do not inherit GCK mutation, as they have a higher risk of developing macrosomia. When the fetal genotype is unknown, it can be indirectly inferred from monitoring serial fetal growth and an accelerated fetal growth would indicate that the fetus is probably not carrying the GCK mutation, warranting strict control of maternal hyperglycemia (Rudland, 2019).

7 Approach to a patient with DM

The common situation for counselling in genetic clinics pertaining to DM arises when a pregnant diabetic mother consults to know the impact of diabetes on her fetus. Apart from that situation, very rarely counseling is sought for family or personal history of DM. An exception to this situation arises when the diagnosis of DM is made in a young individual where family members are anxious about recurrence in the offspring and in the siblings of the affected child. Due to increasing incidence of the disease, increasing list of genes and susceptible loci and studies showing monogenic diabetes being misdiagnosed as type 1 or 2 DM (Pihoker et al., 2013), it is important to make an accurate and timely diagnosis for appropriate genetic counselling regarding the optimal therapy. Though the risk of recurrence is negligible in majority of cases, counselling in the rare types of autosomal recessive, X-linked and syndromic DM is vital as parents can opt for prenatal testing after establishing molecular diagnosis in the index patient.

7.1 History taking

The following points are pertinent:

• The age of onset; Table 4 enumerates the age-wise distribution of different types of DM and a few key points to differentiate one type from the other.

• Type of intervention required and response to those medications

• Associated visual or hearing impairment

• Birth history including birth weight and birth defects

• Detailed development history

• Three-generation family history

While examining the patient, special attention should be given to look for presence of dysmorphic features, obesity, distribution of fat, signs of hyperinsulinemia and multisystem involvement like anemia, deafness, renal cyst and neurocognitive abnormalities. For example, Thiamine-responsive megaloblastic anemia (TRMA) is a rare disorder which may present with severe anemia responding to thiamine. Presence of macrocytosis and deafness may be a clue for this disorder. Diabetes may sometimes manifest later and may need evaluation.

After obtaining necessary information and baseline investigations like autoantibodies profile if available, one can ascertain the type of DM and can decide whether to proceed with genetic testing. Molecular testing is indicated in monogenic forms of diabetes. This should be followed by discussion regarding the risk of recurrence in subsequent pregnancies and options for prenatal testing.

7.2 Genetic counseling regarding recurrence risk

For monogenic disorders, counseling regarding recurrence risk in autosomal recessive and X-linked disorders is quite straight forward once the molecular diagnosis is established. However, rare autosomal dominant disorders pose significant challenge in counselling as the genetic evidence on penetrance of these genes is weak (Misra & Owen, 2018). Counselling for the recurrence risks of Type 1 and type 2 DM on the other hand is complex. Empiric risks can be used based on the family history and the community prevalence of the disease but these have their own limitations.

Type 1 DM: Previous studies have reported that younger age at diagnosis, young-onset diabetes of parents, male gender, and an older parental age at delivery increased the risk of type 1 DM in siblings. Younger age at diagnosis in the index patient is the strongest predictor of the risk of type 1 diabetes in siblings (Gillespie, 2002). Information on autoantibody status and levels, HLA-conferred disease susceptibility, and insulin secretion and sensitivity are also useful in predicting the occurrence of disease in siblings. The cumulative risk of type 1 diabetes up to ages 10, 20, 30, 40 and 50 years in brothers and sisters of patients with childhood-onset diabetes is 1.5 per cent, 4.1 per cent, 5.5 per cent, 6.4 per cent, and 6.9 per cent, respectively (Harjutsalo et al., 2005).

Type 2 DM: Study based on disease-gene frequency model and the community-based prevalence data suggested a sibling recurrence ratio of 1.8–2.5 (Busfield, 2002). The life-time risk of developing the disease in offspring of one parent with type 2 DM is around 40%, greater if the mother is affected, and the risk rises to 70% if both the parents are affected (Ridderstrale & Groop, 2009). Thus, the empirical recurrence risks for first-degree relatives of type 2 DM are higher than those for type 1 DM. The increased risk of recurrence highlights the need for change in lifestyle and surveillance for early diagnosis. In addition to genetic contribution to DM, it has become obvious that the renal and retinal complications of DM also have genetic susceptibility and are currently an important research subject (Mishra et al., 2016). Though genetic variations are known for susceptibility to type 1 and 2 DM and are being explored in ongoing research works, genetic testing including HLA studies are currently not indicated in clinical settings.

To conclude, DM is a chronic debilitating illness with diverse etiologies. While type 1 and type 2 DM are well known and have a multifactorial inheritance, other monogenic forms of diabetes are often misdiagnosed as type 1 or 2 DM or remain underdiagnosed. Correct diagnosis with the help of molecular testing will aid in proper management and appropriate genetic counseling.

References