Maturity Onset Diabetes of the Young of eleven Chinese Children

doi:10.21203/rs.3.rs-3893249/v1

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Maturity Onset Diabetes of the Young of eleven Chinese Children

https://doi.org/10.21203/rs.3.rs-3893249/v1

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Objective

To identify characteristics of eleven children with Maturity Onset Diabetes of the Young (MODY) and reveal the correlation between phenotypes and genotypes for these patients.

Methods

We collected clinical characteristics including age at diagnosis, gender, clinical symptoms, physical examinations, development histories, laboratory data, and family histories, etc. Next-generation sequencing (NGS) panels were used to reveal the genetic variants for these patients.

Results

There were 6 male and 5 female patients in this study, age at diagnosis ranged from 5.1 to 14.5 years old, and body mass index (BMI) ranged from 18.1 kg/m² to 31.6 kg/m², 6 of them were overweight or obese. 13 mutations were identified from 11 patients in 8 genes: HNF4A and INSR (n = 1), GCK (n = 3), HNF1A (n = 2), PAX4 (n = 1), HNF1B (n = 2), BLK and ABCC8 (n = 1), and ABCC8 (n = 1). 2 patients obtained two mutations those could cause diabetes. Glutamate decarboxylase antibody (GADA) and islet associated antibody (IAA) were positive in the patient with PAX4-MODY. And clinical features of patients with the same MODY type were still different from each other. Insulin was used for patients with MODY 3, MODY 5, MODY 9, and 3 MODY 12 patients in this study.

Conclusion

Family history of hyperglycemia is not an exact clinical feature of every MODY, genetic sequencing should be applied for more patients with diabetes. The proportions of GCK-MODY were greater than others, and treatment for children with MODY is still challenging.

Maturity Onset Diabetes of the Young

genetic sequencing

therapy

Maturity-onset diabetes of the Young (MODY), the most common category of monogenic diabetes, results from a single or multiple defects in a single gene, normally associated with a secretory β-cell defect, accounting for approximately ~ 2.5% – 6.5% of pediatric diabetes (1). Fourteen subtypes related to 14 different genes of MODY were identified and are currently acknowledged. GCK, HNF1A, and HNF4A genes are responsible for at least 80% − 85% MODY cases (2). MODY is often misdiagnosed as type 1 (T1D) or type 2 (T2D) diabetes mellitus (3). Especially, in recent years, T2D has increased dramatically in children and adolescents throughout the world, coupled with high rates of overweight and obesity in young people (4, 5). Some researchers suspected that the early-onset T2D phenotype and monogenic diabetes appear nearly at the same time, which makes diagnosis of monogenic diabetes more insensitive (6).With rapid evolution of molecular diagnosis methods, genetic testing is both sensitive and specific for most MODYs. Although there are still debates for some genes like PAX4. A precise molecular diagnosis is essential because it leads to early diagnosis for their asymptomatic family members and allows optimal treatment of the patients. Like, most GCK-MODYs show a mild, asymptomatic, and stable fasting hyperglycemia usually requiring no specific medication (7). Sulfonylureas are effective except insulin for patients with HNF4A or HNF1A mutations (8). Mutations in the HNF1B is associated with pancreatic agenesis, renal abnormalities, genital tract malformations, and liver dysfunction, special therapy should be applied for these patients. But clinical manifestations of patients with same MODY differ from each other sometimes, so as treatment plans.

Patients

Clinical data was collected of 11 diabetic patients who admitted to the Pediatric Endocrinology Department of Tianjin Medical University General Hospital from January 2016 to July 2023. They didn’t have T1D or T2D specific features, or were diagnosed as atypical diabetes for more than one year. Data of these patients was obtained from medical records, including age at diagnosis, duration of the disease, clinical symptoms (such as polydipsia and polyuria and weight loss), diabetic ketosis or not, and family history encompassing at least three generations.

Genetic sequencing and analysis

Genetic sequencing methods included: 1. MODY capture chip: it contains 13 genes related to MODY1 ~ 13 (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, KCNJ11) and some other regions of more than 50 genes that may lead to monogenic diabetes. Direct sequencing was performed to compare with the reference sequence to find possible gene mutation. This method can’t detect small mutations in introns, and large gene deletions or repeated mutations may be missed on gene flanks. 2. High throughput sequencing: target sequencing capture combined with high-throughput sequencing technology to detect large deletion mutations.

The mutation prediction tools PolyPhen-2, SIFT, Mutation Taster and REVEL were used for silico mutation analysis. Known variants reported in the scientific literature were investigated on the Human Gene Mutation Database, Clinvar, Pubmed, and OMIM. Population data for known variants were investigated from the Exome Aggregation Consortium and 1000 Genomes Project Consortium (1000 Genomes) databases. Based on the 2015 standards and guidelines of the American College of Medical Genetics and Genomics (ACMG), variants were Classified as the following categories: pathogenic, likely pathogenic, variants of undetermined significance (VUS), likely benign, and benign(12).

Clinical features

There were 6 male and 5 female patients included in this study, and eight genes (HNF1A, INSR, GCK, HNF4A, HNF1B, PAX4, ABCC8, and BLK) were analyzed. Median age of these patients at diagnosis was 11.6 years old (5.1y − 14.8y). Median BMI was 21.3 kg/m², 6 of the patients were overweight or obese, and the overweight or obese were diagnosed with MODY 1, 3, 3, 5, 9, and 12. HbA1c arranged from 6.2–15.8%, the patients diagnosed with MODY 2 had lowest HbA1c. Glutamate decarboxylase antibody (GADA) and islet associated antibody (IAA) were positive in the patient with MODY 9, and the rest patients were negative for diabetes-associated autoantibodies at diagnosis. Patient 6 with MODY 3, patient 8 with MODY 5, patient 9 with MODY 9, and patients 10 with MODY 12 were found diabetic ketosis onset, HbA1c levels of these patients were all over 10%. Dyslipidemia appeared in 5 patients with MODY 1, 3, 3, 5, 5, and 12, acanthosis nigricans appeared in 3 patients with MODY 1, 5, and 9. Like reported, renal complications were seen in the two patients with MODY 5. Insulin was used for all these 13 patients at beginning, especially before precise molecular diagnosis, and treatments were modified in follow-up (Table 1).

Table 1

Clinical features of MODY patients
Patient	Subtype	Gender	Age at diagnosis	BMI	Obese or overweight	HbA1C(%)	Autoantibodies	Ketosis	Dyslipidemia	Specific features	Medication
P1	MODY1	M	11.6	22.6	Overweight	11.8	-	-	+	-	Metformin, sulfonylurea
P2	MODY2	M	6.9	14.7	-	6.2	-	-	-	-	-
P3	MODY2	F	5.1	14.6	-	7.7	-	-	-	-	-
P4	MODY2	M	7.7	15.1	-	6.5	-	-	-	-	-
P5	MODY3	F	9	21.3	Obese	6.8	-	-	-	Acanthosis nigricans	Insulin
P6	MODY3	F	11.7	20.7	Overweight	15.8	-	+	+	-	Insulin, metformin, sulfonylurea
P7	MODY5	M	14.5	18.1	-	9.3	-	-	+	Acanthosis nigricans;renal cysts	Insulin
P8	MODY5	F	14.5	31.6	Obese	12.3	-	+	+	Right renal hydronephrosis; acanthosis nigricans	Metformin
P9	MODY9	M	10.4	22.1	Overweight	11.6	GADA、IAA	+	-	Acanthosis nigricans	Insulin
P10	MODY12	F	13	23.6	Obese	11.7	-	+	+	-	Insulin, metformin
P11	MODY12	M	13.5	21.6	-	8.4	-	-	-	-	Sulfonylurea, metformin
BMI, body mass index; HbA1C, glycated hemoglobin A1c;

All patients underwent oral glucose tolerance tests (OGTT) in our department. During OGTT, the blood sugar of MODY 2 patients with GCK mutation increased slightly, while that of other patients increased significantly. Insulin didn’t respond well to the increase of blood sugar except patient 2 and patient 4 with MODY 2. And one severe obese MODY 5 girl (patient 8) had obvious sustained hyperinsulinemia. The fluctuation of C-peptide was consistent to insulin change (Fig. 1).

Mutations analysis

Genetic sequencing was applied for the 11 patients in this study, 13 variants were detected within seven genes. A patient may have more than one mutation in the same or different genes. Patient 1 had missense mutations within HNF4A and INSR at the same time, patient 10 had missense mutations within BLK and ABCC8 at the same time. The rest 9 patients had one variant related to MODY for each. Only c. 2819 C > T of INSR and c. 89 C > A of BLK had not been reported previously. Based on the ACMG guidelines, 46.2% (6/13) of these mutations were assessed as pathogenic, 23.1% (3/13) were likely pathogenic, 23.1% (3/13) were assessed as VUS (Table 2), and7.7% (1/13) were benign. 10 of all the 11 patients inherited the mutations from parents except patient 3 with MODY 2. 9 patients had diabetic family history within 3 generations (Fig. 2).

Table 2

Genetic testing results of MODY
Patient	Gene	Type	cDNA change	Amio acid change	ACMG classification	dbSNP database record
P1	HNF4A	Missense	c.1031T > C	I344T	Likely pathogenic	rs777332317
P1	INSR	Missense	c.2819C > T	T940I	Likely pathogenic	Novel
P2	GCK	Missense	c.571C > T	R191W	pathogenic	rs1085307455
P3	GCK	Deletion	Exon 8–10		pathogenic	-
P4	GCK	Missense	c.704T > C	M235T	pathogenic	rs193922323
P5	HNF1A	Frameshift	c.872dupC	G292Rfs*25	pathogenic	rs587776825
P6	HNF1A	Missense	c.932C > A	A311D	pathogenic	rs757574765
P7	HNF1B	Deletion	Exon 1–9		pathogenic	-
P8	HNF1B	Splicing	c.1534 + 10C > T		VUS	rs368168569
P9	PAX4	Missense	c.490C > A	R164W	VUS	-
P10	ABCC8	Missense	c. 1412 C > T	A471V	VUS	rs780283224
P10	BLK	Missense	c. 89 C > A	A30D	benign	Novel
P11	ABCC8	Missense	c.4166T > G	L1389R	Likely pathogenic	-
VUS: Variants of Undetermined Significanc

MODY cases are still often misdiagnosed now days. Traditional criteria of MODY, such as diabetes before 25 years old, non-insulin therapy and family history of diabetes, lack of T1D and T2D characters identifies only small part of MODY cases, is not sufficient in clinical practice (9). Such as, obesity was considered as evidence of T2D with polygenic background. However, the overweight and obesity rate of young people is increasing all over the world, causing a challenge to distinguish MODY from T2D, obesity alone should not preclude genetic testing in young persons with hyperglycemia and insulin therapy is in need for many MODYs (1). Some variants in HNF1A, HNF1B and HNF4A may also be associated with T2D and obesity (10, 11). In our study 6 patients were overweight or obese, including three patients with HNF1A and HNF4A mutations. But the BMI of two MODY 5 patients with HNF1B mutations were extremely different from each other. Andrew T, et al. (12) pointed out that lacks of clinical criterion, cost of genetic testing, and specialists’ emphasis on treatment rather than diagnosis were the major barriers for precision medication to MODY.

MODY 1 diabetes caused by HNF4A gene mutation is less common than HNF1A (MODY 3). These two types variants carriers tend to have hyperglycemia at the same age, and phenotypically familiar (3). The transcription factor HNF4A is expressed primarily in the liver, pancreas and kidney, where it regulates the expression of genes required for glucose transport and metabolism. About half of HNF4A gene variants carriers have macrosomia and 15% of variants carriers have transient neonatal hypoglycemia (13). Patient 1 was diagnosed MODY 1 diabetes at 11.5 years old with birth weight 4500g, but unclear of neonatal hypoglycemia or not. He was treated metformin and sulfonylureas after diagnosis. The mutation was inherited from his mother, who was treated with metformin and acarbose to control blood sugar.

MODY 3, the most common type MODY, is charactered by impaired insulin secretion after glucose stimulation due to mutation in HNF1A gene with autosomal dominant inheritance pattern. The transcription factor HNF1A is expressed in the liver, kidney, intestine and pancreatic β-cells. Fasting blood glucose is normal in the early stage, ketosis is rare because residual insulin secretion can last for many years, and glucose intolerance might be evident during adolescence or early adulthood (14). These patients present glycosuria from very beginning due to impaired renal tubular transport of glucose. 63% HNF1A mutation carriers develop diabetes before 25 years of age, 79% before 35 years-old and 96% before 55 years-old (15). In our study, a girl with MODY 3 (patient 5) was diagnosed diabetes at 9 years-old, her father was diagnosed at 15 years-old and her grandfather was diagnosed at 48 years-old. Patient 6 with MODY 3 was diagnosed diabetes at 11.7 years-old, her mother and grandmother were both found diabetes younger than 30 years-old. HNF1A mutations are associated with an increased frequency of cardiovascular disease and microvascular complications, careful glucose control is needed for MODY 3 patients (16).

MODY 3 and MODY 1 patients should be treated with diet control from beginning due to marked postprandial hyperglycemia after high carbohydrate food (14). Low-dose sulfonylureas is sufficient for MODY 3 and MODY 1 adult patients to control blood sugar and avoid hypoglycemia (17). But for patient 6 with MODY 3, blood sugar fluctuated severely and insulin secretion was extremely low, insulin supplement was needed to stabilize blood sugar. And patient 5 was young, insulin was also used to control blood sugar. Lipid metabolism disorder is also common for MODY 3 and MODY 1, which need appropriate diet control for these children.

MODY 2 is another common MODY, clinical manifestations are asymptomatic, mild, non-progressive fasting hyperglycemia and slight increase during OGTT. Genetic tests showed a high percentage of de novo variants (24%) in GCK genes, and negative family history of hyperglycemia should not be excluded from gene evaluation (18). GCK mutations altered the set-point of insulin secretion (19). HbA1c is usually 5.6–7.6%, and fasting glucose is always 5.5–8.5 mmol/L. 75.8% of patients had a level of 2h-postprandial blood sugar below 11.1 mmol/L, and the increments of blood glucose were 2.82 ± 2.03 mmol/L during OGTT (20). Multiple studies showed MODY 2 patients do not require antihyperglycemic medication except during pregnancy. And diet control can slightly reduce blood glucose levels and improve the glucose tolerance curve (21). Consistent with previous reports, patient 2, 3 and 4 with GCK gene mutations, showed slight increase in HbA1c, fasting glucose. Only patient 4 was treated with metformin for first two months due to hyperinsulinemia, and withdrawed after genetic diagnosis.

A diabetic child with multi-system extrapancreatic features is suspected to be monogenic disorder (22). Most MODY 5 patients with HNF1B mutations may have renal developmental disorders, like renal cysts, renal dysplasia and genital-tract malformations, hyperuricemia may also occur (23–25). Therefore, diabetic patient with HNF1B mutation were also described as renal cysts and diabetes (RCAD) syndrome, typically develops during adolescence and early adulthood. Patient 7 and patient 8 were both diagnosed MODY 5 in adolescence, patient 7 was found bilateral renal cysts, and patient 8 is found hydronephrosis. The variant of patient 8 had been reported previously (26). MODY 5 patients have variable phenotypes even within family with the same HNF1B variant, absence of the pancreatic body or tail is highly indicative in patient with renal cysts (27). Hepatic insulin resistance is another feature for MODY 5 patients (28, 29). Patient 7 had normal body size and normal insulin level, but patient 8 was severe obese with serious hyperinsulinemia and obvious acanthosis nigricans revealing insulin resistance. It is difficult to distinguish from T2D.

The paired homeodomain transcriptional factor, PAX4, function as a transcription repressor and plays a crucial role in pancreatic β cell function, development, regeneration (30), and represses the transcriptional activity of insulin and glucagon promoters (31, 32). Inactivation of PAX4 causes a lack of mature β and δ cells, resulting in impaired inability to produce sufficient insulin and growth inhibitory hormone, leading to diverse phenotypes (33). Missense mutation of PAX4 c.490C > A, p.Arg164Trp was identified from patient 5, which has been reported as MODY 9 before (34). But the patient in our study presented elevated blood glucose, polydipsia, polyuria with low insulin level, just like T1D. What is more important, autoimmune antibodies, glutamate decarboxylase antibody (GADA) and insulin antibody (IAA)were positive at diagnosis. Polymorphisms and mutations in PAX4 were also associated with T1D and T2D in various ethnic groups, like German, Swiss, Chinese, and Japanese (35, 36). There is overlap between T1D, T2D and PAX4-MODY.

ABCC8 gene mutations can cause dysfunction in ATP-sensitive potassium channels, resulting in MODY 12, which was first described by Bowman (37). Diverse clinical manifestations present with MODY 12, including overweight or obese, but always normal lipid metabolism. Activating mutations in the ABCC8 gene cause diabetes with decreased insulin secretion and inactivating mutations usually cause hyperinsulinemia and hypoglycemia in infancy. 4 patients with ABCC8 missense mutations were found hyperglycemia at adolescence. Patient 10 was macrosomia once but unaware of hypoglycemia or not in infancy, and she was also obese at diagnosis with dyslipidemia and nonalcoholic fatty liver disease. And she was found diabetic ketoacidosis at first, with high HbA1c levels 12.2%. Occasionally, all these mutations of ABCC8 gene were missense and inherited from their mothers.

Despite a missense mutation in ABCC8 gene, a mutation of BLK, c.C89A, p.Ala30Asp was also detected from patient 10. B-lymphocyte kinase (BLK) encodes a tyrosine receptor protein that stimulates β-cells to produce and secrete insulin and is essential for thymopoiesis in immature T cells, that may be responsible for MODY 11. But not all carriers of BLK pathogenic variants exhibit diabetes, there is still debates whether patients carrying BLK variants can be diagnosed MODY (38). And analysis of p.Ala30Asp used PolyPhen-2, SIFT and Mutation Taster tools showed it was benign, tolerated, and polymorphism. Thus, the patient was diagnosed MODY 12 finally.

The incidence of MODY is higher than thought. Treatment for patients diagnosed with MODY is obvious different from T1D or T2D. More evidences should be found to connect the phenotypes and genotypes for MODYs, and genetic findings could provide instructions for treatments. For all MODYs, insulin therapy is needed sometimes, especially for pregnant. For young children with MODYs, insulin therapy is applied more often than adults, because contraindications of oral anti-glucose drugs and difficult excise and diet control. Genetic family screening and personalized medical care should be applied for more cases with abnormal glucose metabolism.

Ethical Approval

The Ethical Committee of Tianjin Medical University General Hospital approved this study (approval number: IRB2023-WZ-211) and waived the informed consent requirement because the data were gathered from electronic medical records, and the participants’ identities were anonymized.

Funding

This article was funded by Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-068C, TJWJ2022XK008) and General hospital Clinical research project (22ZYYLCCG03).

Availability of data and materials

All data analyzed has been supplied in this manuscript.

Author Contribution

Shifeng Ma, Rui Li, and Xiaoxiao Liu wrote the main manuscript text. Xinyi Han, Sihan Sheng and Yilin Li prepared figures and tables. Rongxiu Zheng designed the study and paticipated in writing manuscript text. All authors reviewed the manuscript.

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No competing interests reported.

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Maturity Onset Diabetes of the Young of eleven Chinese Children

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Genetic sequencing and analysis

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Mutations analysis

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