Genetics

Question 1

Down syndrome- common with harsh, holosystolic murmur, flat facial profile, protruding tongue, upslanting palpabrae fissures, and small ears

Most commonly due to maternal nondisjunction

Answer 1

Note that 5% of DS pts is due to Robertsonian translocation

Question 2

Huntingtin causes transcriptional repression (silencing) by increasing histone deaceylation, silencing the genes needed for neuronal survival (So you can tx with histone deacetylase inhibitors)

Question 3

Vascular occlusion

A 3 day old girl with perssitent bilious emesis, no blood, the infant appears dehydrated

HR highly elevated and BP normal-ish

laparotomy shows a normal appearing duodenum, the absence of a large sement of the jejunum and ileum, and the remainder the of the distal ileum winding around a small vascular stalk

Answer 3

Bilious emesis (below 2nd part of duodenum)- DDx is midugt volvulus, which is a surgical emergency and must be excluded definitely. Other causes include intestinal steneosis and atresia

The absence of a segment of jejunum and ileum confirms the intestinal atresia (The most common cause of non-duodenal intestinal atresia is a vascular accident in utero that leads to decreased intestinal perfusion and ischemia of the respective segment of bowel. This leads to narrowing, or in the most severe cases, complete obliteration of the intestinal lumen.

In the case that the superior mesenteric artery, or another major intestinal artery, is occluded, large segments of bowel can be entirely underdeveloped. Classically, the affected area of bowel assumes a spiral configuration and is described to have an “apple peel” like appearance; this is accompanied by lack of a dorsal mesentery. Ileal atresia can also result as a complication of meconium ileus)

)

Question 4

Duodenal atresia- due to failure of recanalization at 8-10 weeks gestation. presents with bilious or nonbilious emesis and associated with Down syndrome

Answer 4

Jejunum/ileum atresia- due to vascular injury, presents with bilious emesis and abdominal distension and associated with gastroschisis

Colonic atresia- cause unknown, presents with constipation and abdominal distension and assoicated with Hirschspurng disease

Question 5

Apple peel atresia occurs when the SMA is obstructed

The result is a blind-ending proximal jejunum, a length of absent bowel and mesentery, and a terminal ileum spiraled around an ileocolic vessel

Question 6

Turner Syndrome- associated with congenital coarctation of the aorta, which typically affects the region of the aorta just distal to the left subclavian artery.

Severe coarctation usually presents during infancy with differential cyanosis affecting the lower limbs as long as the ductus arteriosus remains patnet. On ductus closure, these neonates can develop signs of heart failure or shock

Answer 6

Moderate steneosis often presents in childhood or adolescence with sympotms of lower extremity claudication (e.g. pain and cramping with exercise), BP discrepancy bettwen the upper and lower extremities and delayed/diminshed femoral pulses

Question 7

Ataxia telangiectasia is an AR disorder marked by cerebellar atrophy leading to ataxia within the first yr of life

Pts also have severe immunodeficiency with repeated sinopulmonary infections

Increased risk of cancer because of defective DNA repair processes

Answer 7

Ataxia-telangiectasia is marked by DNA hypersensitivity to ionizing radiation

Question 8

Holoencephalopathy- presents with closely set eyes (hypotelorism), cleft palate/lip and a midline mass consistent with a proboscis

fused cerebral hemispheres with an absent forebrain fissue and a signle intracranial ventricle (due to incomplete divison of the forebrain into 2 hemispheres)

Commonly due to genetic (trisomy 13, sonic hedgehog mutation), or maternal alcohol use

Example of a developmental field defect, which is when an initial embryonic disturbance leads to multiple malformations by disrupting the development of adjacent tissues and structures

Answer 8

Cleavage of the prosencephalon into the telencephalon and diencephalon normally occurs at 5 weeks gestation

Question 9

Deformations are fetal structural anomalies that occur due to extrinsic mechanical forces- pressure by the uterus is one of the most common sources

Question 10

Hardy-Weinberg Eqn

Note that for RARE autosomal recessive disorders, p~=1, so the probabilty of being a carrier approximates to 2x frequency of the mutant allele, or 2q

Question 11

Niemann-Pick Disease- AR disorder common among Ashkenazi Jews and is marked by sphingomyelinase deficiency

Sphingomyelin accumulation within lysosomes results in cells that appear enlarged, foamy, and vacuolated on EM. These cells accumulate in the liver and spleen and cause HSM

Answer 11

Progressive nuronal accumulation is resposnible for hypotonia and neurologic degeneration (loss of developmental milestones)

Retinal accumulation leads to a cherry red spot similar to retinal vein occlusion

Death will occur at a very (3-5 yo) young age

Question 12

Fragile X syndrome is the most common inherited cause of intellectual diability. Physical findings include maccroorchidism and dysmorphic features

Nueropsychiatric disorders include developmental delay, ADHD, and autism

FXS is caused by a mutation of fragile X mental retardation (FMR1) gene on the long arm of the X chromosome, which normally has 5-55 CGG trinucleotide repeats and can potentially expand during meiosis in oocytes. Full mutation = 200+ CGG repeats, which causes FMR1 hypermethylation. NDA methylation inactivates FMR1 (confirm with Southern blot testing)

Question 13

Tay Sachs is a AR neurodegenerative disorder commonly seen in Aschkenawi Jews caused by B-hexosaminidase A-deficiency which results in accumulation of the cell membrane glycolipid GM2 ganglioside within lysosomes

Affects infants typically have normal development in the first few months of life, followed by progressive neurologic deterioration with clinical features including weakness, hypotonia, developmental regression, seizures, blindness, and spasticity

Physical exam will show macropcephaly and an abnormal startle reflex with acoustic stimuli

Answer 13

Tay Sachs
The center of the fovea appears bright red (cherry red) and is surrounded by a white macule as a halo

Pts usually die by 2-5 years old

Question 14

PKU (AR) is due to mutation in phenylalanine hydroxylase and presents with intellectual disability, gait or posture issues, and a musty body odor

Question 15

What are some common medical conditions with polygenic inehritance?

Answer 15

Androgenetic alopecia

Epilepsy

Glaucoma

HTN

Ischemic heart disease

Schizophrenia

Type II DM

Question 16

The most common type of hair loss in males and females in androgenetic alopecia (male pattern baldness), driven by hormonal and genetic factors.

Polygenic inheritence with varying expressivity, with key sites being the short arm of chromosome 20, and possibly X and Y chromosomes

Question 17

Mitochondria contain their own DNA (mtDNA) that exists as small circular chromosomes. Each mitochondrian contains 1-10 copies of maternally dervied mtDNA. As a result, diseases arising from mutations in mtDNA are transmitted from the mother to all of her offspring.