Single gene defects part 1 and 2 Flashcards Preview

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

Hereditary Motor & Sensory Neuropathy

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


what are some inheritance patterns of single gene disorders ?

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


Pathology of HMSN

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


Neonatal catastrophe

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


Hepatic disease is characterized by

bleeding and bruising (coagulopathy)
hepatocellular dysfunction


indicator of Metabolic acidosis

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


what characterizes a storage disease?

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


what are characteristics of neurologic syndrome?

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


what are some tools for diagnosing inborn errors?

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


50% of Homocystinuria is responsive to

vitamin supplementation


what are some Drug therapy strategies?

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


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


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


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


HMSN Type 1

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


HMSN Type 2

normal nerve conduction but axonal degeneration


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)



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


Neurofibromin (Nf1)

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


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


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


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


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)


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


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


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


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

Ectopia lentis
flat cornea
hypoplastic iris


what are some cardiovascular criteria for dx of Marfan syndrome?

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


Patients with Marfanoid habitus should also be screened for?

Homocystinuria - treatable inborn error of homocystine metabolism


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


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


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


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


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


Clinical features of Fragile X

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


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)


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


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


what is a metabolic disorder?

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


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

enzyme complexes
enzyme receptors
enzyme cofactors


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



increases the risk of inheriting inborn errors of metabolism


clinical Characteristics of PKU

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


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


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


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


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


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


Neonatal catastrophe seen in

urea cycle defects
organic acidemias


examples of Neonatal Hepatic disease

neonatal hemachromatosis


examples of Infant/child hepatic disease

wilson disease
fatty acid oxidation defects
Alpha 1 antitrypsin


Examples of Neonate metabolic acidosis

fatty acid oxidation defects
propionic and methylmalonic acidemia


examples of infant/child metabolic acidosis

"later onset" forms of above
biotinidase deficiency


Examples of Neonate neurologic syndrome

urea cycle defects
organic acidemia
mitochondrial OXPHOS defects


Diseases Examples of Infant/Child neurologic syndromes

undiagnosed PKU
Mito OXPHOS defects


Disease examples of neonate storage diseases

Mucopolysacchariosis type VII
Niemann-Pick, type A


What is the general approach to treating Metabolic disorders?

dietary adjustments
vitamin supplementation
drug therapies
organ transplantation
proposed therapies


Disorders where organ transplantation is a treatment option?

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


What are some general qualities of single-gene disorders?

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


What are some general qualities of polygenic disorders?

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