X-linked Disorders

Question 1

Inheritance pattern of hypophosphatemic rickets

Answer 1

x-linked dominant; affects 1 in 20000

Question 2

Clinical manifestations of hyposphatemic rickets

Answer 2

hypophosphatemia; short stature; bone deformity

Question 3

Gene mutation of hypophosphatemic rickets and effects

Answer 3

Gene: PHEX. Regulates fibroblast growth factor; Inhibits the kidneys ability to reabsorb phosphate into the blood stream

Question 4

Inheritance pattern of Fragile X syndrome

Answer 4

x-linked dominant; affects 1 in 2500-4000 males. 1 in 7k-8k females. Anticipation and maternal transmission bias. Most common cause of inherited developmental delay

Question 5

Clinical manifestations of Fragile X Syndrome

Answer 5

Intellectual disabilities; Dysmorphic features: large ears; long face. Macroorchidism; Autistic behavior; Social anxiety; Hand flapping/biting; Aggression

Question 6

Gene mutation of Fragile X Syndrome

Answer 6

Gene: FMR1. Trinucleotide repeat disorder - CGG.

Question 7

FMR1 associated conditions (2)

Answer 7

Fragile X Associated Tremor Ataxia Syndrome(FXTAS)(White matter lesions and intention tremor; gait ataxia); FMR1 related Primary Ovarian Insufficiency (Cessation of menses b4 age 40)

Question 8

Number of CGG repeats and disease manifestation in Fragile X syndrome

Answer 8

6-45: Normal. 46-55 Grey Zone. 56-200 Premutation. >200: Full mutation

Question 9

Inheritance Pattern of Rett Syndrome

Answer 9

X linked Dominant; 1 in 10000 females; 95% new mutation rate

Question 10

Clinical Manifestations of Rett Syndrome

Answer 10

Loss of normal movement and coordination; Acquired microcephaly; Loss of communication skills; Failure to thrive; Seizures; Abnormal hand movements

Question 11

Gene mutation/function of Rett Syndrome

Answer 11

Gene: MECP2. Methyl CpG binding protein; Essential for the normal function of nerve cells

Question 12

Inheritance pattern of Lesch-Nyhan Syndrom

Answer 12

X-linked recessive; 1 in 380000 affected

Question 13

Clinical manifestations of Lesch-Nyhan Syndrome

Answer 13

Cerebral palsy; Cognitive and behavioral disturbances; Overproduction of uric acid; Self injury

Question 14

Mutation and effect in Lesch-Nyhan Syndrome

Answer 14

Gene: HPRT1 (Hypoxanthine phosphoribosyltransferase 1). Recycling of purines

Question 15

Inheritance pattern and examples of dystrophinopathies

Answer 15

X-linked recessive. Spectrum of muscle disease from mild to severe. Duchenne Muscular Dystrophy; Becker Muscular Dystrophy

Question 16

Mutation in dystrophinopathies

Answer 16

Gene: DMD. Chr. Xp21-21.1. Dystrophin. Largest Human Gene

Question 17

Clinical manifestations of duchenne muscular dystrophy

Answer 17

Progressive muscular weakness proximal > distal; Calf hypertrophy; Dilated cardiomyopathy; CK levels 10x normal; Onset before the age of 5; Wheelchair bound before 13; Death in 30s; Absence of Dystrophin

Question 18

Clinical manifestations of becker muscular dystrophy

Answer 18

Progressive muscular weakness proximal > distal; Dilated cardiomyopathy; CK levels 5x normal; Later onset; Wheelchair bound after 16; Death in 40s; Abnormal quantity or quality of Dystrophin

Question 19

What is DMD-associated DCM?

Answer 19

Dilated cardiomyopathy presenting between 20 to 40 years of age; Early death; No skeletal muscle involvement; No Dystrophin in the myocardium

Question 20

Inheritance pattern of Hemophilia A

Answer 20

X linked recessive; 1 in 4000 male births; 10% carrier females affected

Question 21

Clinical manifestations of Hemophilia A

Answer 21

Blood disorder where blood fails to clot appropriately due to a deficiency of Factor VIII; Spontaneous bleeds into joints/muscles/intracranial; Excessive bruising; Prolonged bleeding after injury or incision; Delayed wound healing; Royal family

Question 22

Mutation and effect in Hemophilia A

Answer 22

Gene: F8 on Chr. Xq28. Deficiency of Factor VIII; 22A inversion causes 50%

Question 23

What do the majority of mitochondrial DNA produce?

Answer 23

Components of the respiratory chain

Question 24

What is replicative segregation?

Answer 24

At cell division the multiple copies of mtDNA replicate and sort randomly among newly synthesized mitochondria. This could be normal DNA or mutated

Question 25

Explain homoplasmy vs. heteroplasmy

Answer 25

Homoplasmy refers to a cell that has a uniform collection of mtDNA - either completely normal or completely mutant. Heteroplasmy is when a cell has some mutant mtDNA and some normal. This effects penetrance and expressivity

Question 26

What is the threshold effect?

Answer 26

When mitochondrial disease becomes clinically apparent after the number of affected mitochondria reaches a certain level

Question 27

What type of tissues are typically affected by mitochondrial disease?

Answer 27

Tissues that rely heavily on oxidative phosphorylation: brain; retina; skeletal muscle; heart

Question 28

Inheritance pattern of Kearns-Sayre Syndrome

Answer 28

Mitochondrial inheritance; 1-3 in 100000. Mostly caused by a somatic mutation

Question 29

Clinical manifestations of Kearns-Sayre Syndrome

Answer 29

Triad: pigmentary retinopathy; progressive external opthalmoplegia; onset before age 20y. Cardiac conduction defects; ataxia; deafness; kidney problems

Question 30

Mutation seen with Kearns-Sayre Syndrome

Answer 30

Single large deletion of mtDNA; Most common deletion removes twelve genes

Question 31

What does MELAS stand for?

Answer 31

Mitochondrial Encephalomyopathy; Lactic Acidosis and Stroke like episodes

Question 32

Inheritance pattern of MELAS

Answer 32

Mitochondrial inheritance; 1 in 300000. Low new mutation rate

Question 33

Clinical manifestations of MELAS

Answer 33

Starts btwn age 2-10. Muscle weakness; Seizures; Repetitive stroke like episodes; Elevated lactic acidosis

Question 34

Mutations seen with MELAS (5)

Answer 34

All on mitochondrial genes. MT-TL1 (80%); MT-ND1; MT-ND5; MT-TH; MT-TV

Question 35

What does MERRF stand for?

Answer 35

Myoclonic Epilepsy with Ragged Red Fibers

Question 36

Inheritance pattern with MERRF

Answer 36

Mitochondrial inheritance; 1 in 400000. Low new mutation rate

Question 37

Clinical manifestations of MERRF

Answer 37

Muscle symptoms; Seizures; Ataxia; Dementia; Ragged red fibers

Question 38

Mutation seen with MERRF

Answer 38

MT-TK in mitochondrial genes

Question 39

Inheritance pattern of Leber Hereditary Optic Neuropathy

Answer 39

Mitochondrail inheritance; 1 in 30k-50k Europeans

Question 40

Clinical manifestations of Leber Hereditary Optic Neuropathy

Answer 40

Bilateral subacute vision failure; occurs during young adulthood

Question 41

Mutations seen with Leber Hereditary Optic Neuropathy

Answer 41

m.3460G\>A; m.1178G\>a; m.14484T\>C. On mtDNA