Single gene defects part 1 and 2 Flashcards
what are some inheritance patterns of single gene disorders ?
autosomal dominant autosomal recessive x linked dominant x linked recessive y linked mitochondrial
Hereditary Motor & Sensory Neuropathy
autosomal dominant
duplication of 1.5 Mb of 17p
peripheral myelin protein 22 (PMP-22)
Pathology of HMSN
overproduction of PMP 22 which prevents schwann cell proliferation
associated with Charcot-Marie-tooth disease
Neonatal catastrophe
feeding problems tachypnea lethargy and hypotonia progress to seizure and coma appear "septic" secondary metabolic abnormalities
Hepatic disease is characterized by
Jaundice hepatomegaly bleeding and bruising (coagulopathy) hepatocellular dysfunction hypoglycemia hyperammonemia
indicator of Metabolic acidosis
vomiting, poor feeder
failure to thrive
tachypnea
metabolic decompensation with mild illness
apparent intolerance of certain food types
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
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
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
50% of Homocystinuria is responsive to
B6
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)
Neurofibromatosis
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 …
enzymes
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
Consanguinity
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 dermatitis
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
galactosemia
organic acidemias
examples of Neonatal Hepatic disease
galactosemia
tyrosinemia
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
homocystinuria
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
