X-linked Disorders Flashcards
Inheritance pattern of hypophosphatemic rickets
x-linked dominant; affects 1 in 20000
Clinical manifestations of hyposphatemic rickets
hypophosphatemia; short stature; bone deformity
Gene mutation of hypophosphatemic rickets and effects
Gene: PHEX. Regulates fibroblast growth factor; Inhibits the kidneys ability to reabsorb phosphate into the blood stream
Inheritance pattern of Fragile X syndrome
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
Clinical manifestations of Fragile X Syndrome
Intellectual disabilities; Dysmorphic features: large ears; long face. Macroorchidism; Autistic behavior; Social anxiety; Hand flapping/biting; Aggression
Gene mutation of Fragile X Syndrome
Gene: FMR1. Trinucleotide repeat disorder - CGG.
FMR1 associated conditions (2)
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)
Number of CGG repeats and disease manifestation in Fragile X syndrome
6-45: Normal. 46-55 Grey Zone. 56-200 Premutation. >200: Full mutation
Inheritance Pattern of Rett Syndrome
X linked Dominant; 1 in 10000 females; 95% new mutation rate
Clinical Manifestations of Rett Syndrome
Loss of normal movement and coordination; Acquired microcephaly; Loss of communication skills; Failure to thrive; Seizures; Abnormal hand movements
Gene mutation/function of Rett Syndrome
Gene: MECP2. Methyl CpG binding protein; Essential for the normal function of nerve cells
Inheritance pattern of Lesch-Nyhan Syndrom
X-linked recessive; 1 in 380000 affected
Clinical manifestations of Lesch-Nyhan Syndrome
Cerebral palsy; Cognitive and behavioral disturbances; Overproduction of uric acid; Self injury
Mutation and effect in Lesch-Nyhan Syndrome
Gene: HPRT1 (Hypoxanthine phosphoribosyltransferase 1). Recycling of purines
Inheritance pattern and examples of dystrophinopathies
X-linked recessive. Spectrum of muscle disease from mild to severe. Duchenne Muscular Dystrophy; Becker Muscular Dystrophy
Mutation in dystrophinopathies
Gene: DMD. Chr. Xp21-21.1. Dystrophin. Largest Human Gene
Clinical manifestations of duchenne muscular dystrophy
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
Clinical manifestations of becker muscular dystrophy
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
What is DMD-associated DCM?
Dilated cardiomyopathy presenting between 20 to 40 years of age; Early death; No skeletal muscle involvement; No Dystrophin in the myocardium
Inheritance pattern of Hemophilia A
X linked recessive; 1 in 4000 male births; 10% carrier females affected
Clinical manifestations of Hemophilia A
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
Mutation and effect in Hemophilia A
Gene: F8 on Chr. Xq28. Deficiency of Factor VIII; 22A inversion causes 50%
What do the majority of mitochondrial DNA produce?
Components of the respiratory chain
What is replicative segregation?
At cell division the multiple copies of mtDNA replicate and sort randomly among newly synthesized mitochondria. This could be normal DNA or mutated
Explain homoplasmy vs. heteroplasmy
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
What is the threshold effect?
When mitochondrial disease becomes clinically apparent after the number of affected mitochondria reaches a certain level
What type of tissues are typically affected by mitochondrial disease?
Tissues that rely heavily on oxidative phosphorylation: brain; retina; skeletal muscle; heart
Inheritance pattern of Kearns-Sayre Syndrome
Mitochondrial inheritance; 1-3 in 100000. Mostly caused by a somatic mutation
Clinical manifestations of Kearns-Sayre Syndrome
Triad: pigmentary retinopathy; progressive external opthalmoplegia; onset before age 20y. Cardiac conduction defects; ataxia; deafness; kidney problems
Mutation seen with Kearns-Sayre Syndrome
Single large deletion of mtDNA; Most common deletion removes twelve genes
What does MELAS stand for?
Mitochondrial Encephalomyopathy; Lactic Acidosis and Stroke like episodes
Inheritance pattern of MELAS
Mitochondrial inheritance; 1 in 300000. Low new mutation rate
Clinical manifestations of MELAS
Starts btwn age 2-10. Muscle weakness; Seizures; Repetitive stroke like episodes; Elevated lactic acidosis
Mutations seen with MELAS (5)
All on mitochondrial genes. MT-TL1 (80%); MT-ND1; MT-ND5; MT-TH; MT-TV
What does MERRF stand for?
Myoclonic Epilepsy with Ragged Red Fibers
Inheritance pattern with MERRF
Mitochondrial inheritance; 1 in 400000. Low new mutation rate
Clinical manifestations of MERRF
Muscle symptoms; Seizures; Ataxia; Dementia; Ragged red fibers
Mutation seen with MERRF
MT-TK in mitochondrial genes
Inheritance pattern of Leber Hereditary Optic Neuropathy
Mitochondrail inheritance; 1 in 30k-50k Europeans
Clinical manifestations of Leber Hereditary Optic Neuropathy
Bilateral subacute vision failure; occurs during young adulthood
Mutations seen with Leber Hereditary Optic Neuropathy
m.3460G>A; m.1178G>a; m.14484T>C. On mtDNA
