Genetics Flashcards
What are the characteristics of multifactorial inheritance (predisposing/susceptibility genes) related to diabetes mellitus?
- Greater # genes in parents-> greater probability of affected child
- Recurrence risk higher when more than 1 family member affected
- Risk incr w/ severity of malformation!
- *Difference in sex ratio: less frequently affected sex will more often transmit to more frequently affected sex; fewer susceptibility genes are required in the most often affected sex
Explain the difference in lifetime risks of developing diabetes for relatives of different relatedness
Risk to relatives declines w/ incr. remote degrees of relationship
Compare and contrast type 1 diabetes mellitus (non-insulin dependent), type 2 diabetes mellitus (insulin dependent) and gestational diabetes (GM)
Type 1:
- Onset insulitis early, atrophy, fibrosis, Beta-cell depletion)
- Ketoacidosis
- 30-50% twin concordance
- HLA-DQ and DR linkage
- NO family history (not genetic)
Type 2:
- Onset > age 30
- Obese
- Normal or incr. insulin (insulin resistance)
- No anti-islet Ab, ketoacidosis uncommon, no insulitis
- Focal atrophy and amyloid deposits w/ mild beta cell depletion
- 90-100% twin concordance (genetic)
- NO HLA assoc.
- Family history!
GM:
- Resolves after delivery
- Sign b/t 24-28 wks
- MC symptom is fatigue! (lack of glucose)
Define a single nucleotide polymorphism (SNP) and how it is used for identifying susceptibility of diabetes
Genes linked to diabetes increase susceptibility of different types of DM (doesn’t cause it though)
Explain how SNPs can be used for other diseases
HNF4 SNPs have overlap between Type 2 DM and MODY!
Type 2 >30 overweight
MODY <25 normal
Also SNPS overlap between type 2 DM and Gestational DM!
Define the types of MODY and types of proteins involves in this disease
11 genes cause MODY
MODY 1: HNF-4a (TF–>LOF)
MODY 2: Glucokinase (Phos->LOF)
MODY 3: HNF-1a (TF–>LOF)
HNF=hepatic nuclear factor
What are the most common forms of MODY?
- MODY 3 (MC): Glucose 5x normal
- MODY 2: Glucose 2x normal, B cell secretes less insulin and the liver increases glucose production, hexokinase still OK though!
If one event occurs, a second event occurs. If DM occurs in one MZ twin, it occurs 30-50% of the time in the second twin (type 1) or 90-100% of the time (type 2)
Concordance
- Onset <25
- Normal weight
- Autosomal dominant
- No insulin resistance
- Beta-cell fx impaired
Maturity Onset of Diabetes of the Young (MODY)
-Underdx but high normal glucose that can’t be explained.
TQ
________=1st step of glycogenesis and glycolysis, inhib by G6P
Hexokinase is NOT inhibited by G6P
Glucokinase
receives glucose through GLUT2
Name the dz associated:
Glucokinase
Transcription factors
Glucokinase: MODY 2
TF: MODY 3 & MODY 1
What are a few harms to the fetus in a mother with GDM?
Before 20 wks? after?
- Before 20 wks: slows fetal growth
- After 20 wks: Excessive fat deposition–>macosomia (baby over 9 lbs)
- Altered organ development and maturation: hepatosplenomegaly, cardiomegaly small colon syndrome, feeding intolerance, vomiting, distention
- Hyperglycemia impairs cortisol surge–>altered fetal lung and organ maturation prior to birth–>decr neonatal intestinal motility
TQ
Risk of malformations in babies is higher when maternal _____ exceeds ___% before 16 weeks gestation
HbA1C
9.3%
What are some malformations that occur with high maternal HbA1c?
- Caudal regression (MC)
- Situs inversus
- Renal anomalies
- Cardiac anomalies
- Anal/rectal atresia
- Anencephaly
- Spina bifida
What are some issues the baby may have at birth when the mother is diabetic?
Newborns may be hypoglycemic bc of elevated insulin–>
Inadequate glucose to brain–>
Mental retardation and failure to thrive–>
Incr risk for breathing issues, obesity, *type 2 DM, perinatal mortality, neurologic damage!
What are some increased risks for neonatal hypoglycemia?
- Decreased substrate
- Incr glucose utilization
- Hyperinsulinemia (DM mom)
- Endocrinopathies
What are some diabetic maternal risks post pregnancy?
- 50% risk of developing T2DM
- 67% risk of developing GDM in later pregnancies especially if baby was >9lbs or congenital malformations
- Infants: Incr risk of T2DM later in life
21-year old primigravid woman,was first seen at 22weeks’ gestation. She began working at a factory six-weeks ago and began receiving insurance benefits. Her medical history was unremarkable. She is 5’5” and reports a pre- pregnancy weight of about 145 lbs. She has a HbA1c 9.91% on presentation. Imaging showed a fetus with normal amniotic fluid volume with significant abnormalities. At 23 weeks’ gestation the woman had a miscarriage.
- Detailed exam revealed which of the following?
A. Hypoplastic pelvis
b. Lumbrosacral a genesis
C. Flexion contraction of lower ribs D. Missing ribs
E. Caudal regression
2. Which is best explanation of poor development? A. Poor prenatal B. Gestational DM C. Inhalation of hazards D. Obesity E. Undiagnosed MODY
3. What might also occur in this fetus? A. anal atresia B. Downs C. miscarriage D. Polydactyl E. SIDS  4. Significance of Hb1Ac?
- E (caudal regression)
- B (GDM)
- A (Anal atresia)
- GDM
A non-obese (BMI20) 18-year-old is diagnosed with diabetes and treated with low-dose biphasic lispro before breakfast and dinner. The patient has never experienced hypoglycemic crises or ketoacidosis. Acanthosis nigricans are absent and tests for glutamic acid decarboxylase antibodies are negative. During pregnancy the patient’s mother developed gestational diabetes but was not overweight prior to or since pregnancy.
Non-obese 18 yo with diabetes tx with lispro before bfast and din. Mom had GM. AB negatives
- Which of the following is most likely assoc between mothers diabetes and the development of diabetes in this pt?
a. Genetic
B. Fam hx
C. Maternal elevated insulin D. Preterm delivery
2. Which increased risks for neonatal hypo is most likely assoc with this pt A. Hyperinsulinemia B. Decr substrate C. Incr glucose utilization D. Hypothyroid E.Adrenal insufficiency
3. Which of the following is the pts mom at risk for? A. Chronic renal failure B. Infertility C.Type 1 DM D.Tupe 2 DM E.Weight gain
- C (maternal elevated insulin)
- A (hyperinsulinemia)
- D (Type 2 DM)
An infant born at 38 weeks’ gestation to a 35-year-old female,who had no prenatal care following 15 weeks gestation when pregnancy was confirmed, was admitted to the hospital 2 days after birth for irritability and refusal to feed. The mother reported being very tired during pregnancy but no other symptoms of concern. The child weighed 4050 g at birth. Blood glucose was 10 mg/dL (normal

40-20 mg/dL at term) and glucose was delivered through an umbilical catheter. At 3 hours, two seizures occurred that lasted 20-30 seconds each, and glucose was increased. Over the next 24 hours the child remained stable. Glucose levels normalized and the infant was released.
1. Which of the following is most likely consideration? A. Gestational diabetes b. Gluccokinase def C.Type 1 DM D. MODY 3 E.Type 2 DM
2. Had prenatal care been avail to the mother, which elevated lab value would be of concern for congenital malformations? A. HbA1c B. Glucose C. Insulin D. Glucagon E. Hematocrit
- A (GDM)
TQ 2. A (HbA1C)
