Single gene defects part 1 and 2 Flashcards Preview

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Flashcards in Single gene defects part 1 and 2 Deck (60):
0

Hereditary Motor & Sensory Neuropathy

autosomal dominant
duplication of 1.5 Mb of 17p
peripheral myelin protein 22 (PMP-22)

1

what are some inheritance patterns of single gene disorders ?

autosomal dominant
autosomal recessive
x linked dominant
x linked recessive
y linked
mitochondrial

2

Pathology of HMSN

overproduction of PMP 22 which prevents schwann cell proliferation
associated with Charcot-Marie-tooth disease

3

Neonatal catastrophe

feeding problems
tachypnea
lethargy and hypotonia
progress to seizure and coma
appear "septic"
secondary metabolic abnormalities

4

Hepatic disease is characterized by

Jaundice
hepatomegaly
bleeding and bruising (coagulopathy)
hepatocellular dysfunction
hypoglycemia
hyperammonemia

5

indicator of Metabolic acidosis

vomiting, poor feeder
failure to thrive
tachypnea
metabolic decompensation with mild illness
apparent intolerance of certain food types

6

what characterizes a storage disease?

hepatosplenomegaly
somatic dysmorphism
skeletal/joint dysplasia
ophthalmologic signs
thickened skin/loss of elasticity
nonimmune fetal hydrops
progressive, degenerative course
developmental regression

7

what are characteristics of neurologic syndrome?

altered muscle tone and reflexes, not focal
ataxia
seizure disorder, particularly if progressive
developmental delay
movement disorder
altered state of consciousness

8

what are some tools for diagnosing inborn errors?

basic chemistries, glucose, anion gap
blood ammonia levels
liver function tests
blood lactate and pyruvate levels
urinalysis
plasma and urine amino acids
urine organic acids
tissue enzymology
DNA mutational analysis

9

50% of Homocystinuria is responsive to

B6
vitamin supplementation

10

what are some Drug therapy strategies?

limit accumulation of toxic metabolites
encourage waste nitrogen excretion
supplement poorly transported nutrient
enzyme replacement

11

what are some characteristics of metabolic disorders?

imbalance in body's biochemistry
autosomal recessive inheritance
variable incidence
lifelong disorders
chronic disease or chronic with acute decompensation
variable treatment options

12

what problems could be the issue with IEM in which the issue is the enzyme?

-accumulation of substance A
-deficiency of substance B
-both accumulation of sub A and deficiency of sub B

13

What is peripheral myelin protein-22?

encodes PMP 22 which arrests schwann cell division
duplication of the gene results in dosage effect and interruption of myelin stability
results from inappropriate crossing over and more frequently during male gametogenesis

14

HMSN Type 1

classification is based on motor nerve conduction velocities
most common
reduced nerve conduction and nerve demyelination

15

HMSN Type 2

normal nerve conduction but axonal degeneration

16

what are some symptoms of HMSN?

characterized by slowly progressing distal muscle weakness and wasting
associated with Charcot Marie Tooth disease and Peroneal muscular atrophy
weakness and wasting onset 10-30 yrs
spread to upper limbs and tremors evident
foot high arch and toes curl (hammertoe)

17

Neurofibromatosis

Autosomal dominant
due to mutation (deletion, insertion, duplications, point mutations) of neurofibromin (Nf1) gene 17q
50% due to new mutations

18

Neurofibromin (Nf1)

down regulates Ras activity through GTPase action (tumor suppressor gene)

19

clinical manifestations of Neurofibromatosis

Cafe au lait spots - small pigmented skin lesions and small soft fleshy benign tumors
Axillary/truncal freckling, large head and Lisch nodules (raised pigmented spots of iris)
1/3 cases result in non verbal learning disorder
Most are normal while other develop epilepsy, CNS tumor or scoliosis

20

clinical diagnostic criteria for NF

six or more cafe au lait spots - if pt is older the spots should be larger
two or more neurofibromas of any type or one plexiform neurofibroma
freckling in the axilla or inguinal regions
optic glioma
two or more Lisch nodules

21

what is difficult about diagnosing Nf1?

each family typically has a unique mutation making testing complex and labor intensive
95% of pts over the age of 8 yrs who carry Nf-1 gene will have detectable Lisch Nodules on slit lamp ophthamologic

22

what is the genetic basis of Marfan syndrome?

autosomal dominant
due to mutation (missense with dominant negative effect resulting in decreased fibrillin) of type 1 fibrillin gene (15q21)

23

Type 1 fibrillin

coating of ECM protein, elastin
can bind inactive transforming growth factor beta and holds in inactive state
mutated fibrillin cannot retain TGF-b thus ECM proteases activate leading to excess active TGF-b and promotion of inflammation

24

Marfan Syndrome

disorder of fibrous connective tissue
affected pts are tall, reduced upper to lower segment body ratio, scoliosis, long limbs, spider like fingers, cardiovascular abnormalities
Aortic aneurysm is life threatening
dilation rate can be reduced by b-adrenergic blockade

25

what are some of the skeletal major and minor criteria for Marfan syndrome?

Four should be present
arm span to height ratio is greater than 1.05
hypermobility of wrist and thumbs
pectus carinatum
pectus excavatum requiring surgery
High arched plate with dental crowding
medial displacement of medial malleolus causing pes planus
facial features

26

what are some the major and minor ocular criteria for dx of Marfans?

Ectopia lentis
flat cornea
hypoplastic iris

27

what are some cardiovascular criteria for dx of Marfan syndrome?

dilatation of ascending aorta
dissection of the ascending aorta
mitral valve prolapse

28

Patients with Marfanoid habitus should also be screened for?

Homocystinuria - treatable inborn error of homocystine metabolism

29

Briefly describe the phases of clinical trials

phase 1 - finding optimal dose, route of administration and side effects
phase 2 - looks at the effect of the treatment for the disease
phase 3 - large study to see if treatment is better than standard treatment
phase 4 - approved drugs; long term side effects

30

Duchenne Muscular Dystrophy

Progressive muscle weakness - clumsy/awkward walking on tiptoes
due to tight heel cord, weak muscles in front leg leading to footdrop
muscle weakness progresses from feet to abdomen to shoulders
unable to walk by age 10
mild to mod intellectual impairment
death by 20yrs to pneumonia or heart failure

31

Pathogenesis of DMD

deletion of dystrophin gene
dystrophin is for the connection of muscle fibers to the ECM
absence allows excess Ca to penetrate the sarcolemma leading to increased oxidative stress and damage to sarcolemma
muscle fibers undergo necrosis and replaced by adipose or connective tissue

32

Losartan treatment

TGF beta blocking drug
in mice with Marfan syn it results in normal aortic development
in DMD mice, it helps to halt progression of the disease

33

Fragile X syndrome

Most common cause of inherited learning disability
involves presence of a fragile X locus
with increasing number of CGG copies of FMR-1 gene instability increases and associated with development and functioning of cerebral neurons

34

Clinical features of Fragile X

High forehead
large ears
long face
prominent jaw
learning difficulties
Autistic phenotype

35

Rett's syndrome

99% mutations de novo
X linked dominant
normal development until 6-18 mo then decelerated head growth and development and loss of acquired skills (speech and motor skills)

36

Pathology of Rett's syndrome

Loss of function mutations of MECP2 gene on X chromosome
-MECP2 encodes nuclear protein which binds methylated DNA and recruits histone deacetylases to methylated DNA. Appears to be important for maintaining neuronal interactions
-assumed to be responsible for global gene silencing

37

Clinical features of Rett's syndrome

affected females have small brains, cortical/cerebellar atrophy w/o neuronal loss
Austistic phenotype
altered or no speech or motor skills
males have severe encephalopathy

38

what is a metabolic disorder?

disease due to imbalance in body's biochemistry
autosomal recessive in most cases
lifelong disorders

39

Most Inborn errors in metabolism are related to defects in ...

enzymes
enzyme complexes
enzyme receptors
enzyme cofactors

40

if there is an issue with the Enzyme, the problem could be ...

-an accumulation of the starting materials
-a deficiency in the product
-an accumulation of the starting materials and a deficiency of the product

41

Consanguinity

increases the risk of inheriting inborn errors of metabolism

42

clinical Characteristics of PKU

phenylpyruvic acid in the urine
mental retardation
abnormal gait and stance
"mousy" odor
dermatitis

43

Pathology of PKU

abnormal levels of PHE prevent the normal transport of other AA, particularly TYR across the BBB
resulting in disruption of neurotransmitter synthesis and protein synthesis
brain cells are abnormal and myelination is defective

44

Treatments for PKU

Diet restriction - adequately treated patients do not develop mental
Kuvan (sapropterin dihydrochloride) is an enzyme cofactor and oral form of tetrahydrobiopterin (BH4) works with phenylalanine hydroxylase to metabolize Phe. Reduces blood Phe levels in pts with BH4 responsive PKU

45

How is newborn screening done for PKU?

in 1961, inhibitory assay of Phe with bacillus, with Phe the inhibition is overcome
in 1965, fluorometric method utilizes filter paper blood spots
currently, tandem mass spectroscopy is used

46

Maternal PKU

High plasma PHE acts as fetal teratogen
fetuses have microcephaly, mental retardation, and growth retardation
small % have heart defects, dysmorphic facial features
fetal abnormalities correlate with maternal PKU levels
most detrimental in the first trimester

47

what are the major clinical presentations of IEMs?

Neonatal catastrophe
Hepatic disease
Metabolic acidosis
Neurologic syndrome
storage disease
typically occur in infant/child that was normal at birth

48

Neonatal catastrophe seen in

urea cycle defects
galactosemia
organic acidemias

49

examples of Neonatal Hepatic disease

galactosemia
tyrosinemia
neonatal hemachromatosis

50

examples of Infant/child hepatic disease

wilson disease
fatty acid oxidation defects
Alpha 1 antitrypsin

51

Examples of Neonate metabolic acidosis

fatty acid oxidation defects
propionic and methylmalonic acidemia

52

examples of infant/child metabolic acidosis

"later onset" forms of above
biotinidase deficiency

53

Examples of Neonate neurologic syndrome

urea cycle defects
organic acidemia
mitochondrial OXPHOS defects

54

Diseases Examples of Infant/Child neurologic syndromes

undiagnosed PKU
homocystinuria
Mito OXPHOS defects

55

Disease examples of neonate storage diseases

Mucopolysacchariosis type VII
Niemann-Pick, type A

56

What is the general approach to treating Metabolic disorders?

dietary adjustments
vitamin supplementation
drug therapies
organ transplantation
proposed therapies

58

Disorders where organ transplantation is a treatment option?

Mucopolysaccharidosis - bone marrow
Hereditary tyrosinemia - liver
Urea cycle defects - liver

59

What are some general qualities of single-gene disorders?

Gene alteration results in disease
No environmental influence
Rare events; collectively common

60

What are some general qualities of polygenic disorders?

Multiple gene alterations establish disease susceptibility
Environmental triggers induce/active disease