deck 1 baby nelson Flashcards
What is the most common type of congenital malformations?
multifactorial inherited conditions - 20%
other types are single gene mutations (6%) of children, chromosomal disorders (7.5%), unusual pattern of inheritance (2-3%), exposure to teratogens (6%)
How much of the human genome (DNA) codes for proteins?
<25 of the genome
human genetic material has 3.1 billion bases
the rest of the DNA is called junk DNA
Types of mutations - most common?
point mutation is the most common - change in a single DNA base
Types of point mutation:
1. changes a codon and the amino acid - missense mutation
2. Nonsense mutation - changes the codon to a stop codon, transcription stops prematurely
(frameshift is the other type of mutation, causes a shift and leads to premature stop codon)
What is penetrance?
complete penetrance - everyone who carries a mutation for an AD disorder shows signs of that disorders
incomplete penetrance - some people who are obligate carriers of a mutation known to cause an AD may not show clinical signs of the disorder (and others might show symptoms)
What is variable expressivity?
same gene can show a wide range of manifestations of the clinical disease
A child with achondroplasia is born to two parents without achondroplasia, how is that possible for an autosomal dominant condition?
spontaneous mutation
approximately 80% of patients with achondroplasia have a spontaneous mutation in the FGFR3 gene
can be associated with advanced paternal age >35 years
What are 3 diseases that are associated with mutation in fibroblast growth factor receptor 3 (FGFR 3) mutation
achondroplasia
thanatophoric dysplasia
Crouzon syndrome
nonsyndromic craniosnostosis
What are the features of achondroplasia
cause: defect in carilage-derived bone, most common skeletal dysplasia in humans
short stature, macrocephaly, flat mid face with a prominent forehead
rhizomelic shortening of the limbs (i.e. disproportional shortening of the proximal limb)
infancy: hydrocephalus and central apnea from narrowing of the foramen magnum, and compression of the brainstem may happen and present as life-threatening in infancy
Childhood: bowing of the legs - unequal growth of tibia and fibula , dental malocclusion, OSA< hearing loss
Adults: compression of nerve roots and sciatica
**normal life spans and normal intelligence
How to diagnose achondroplasia?
characteristic X ray findings
molecular testing - if difficult to diagnose or if want prenatal diagnosis
Prenatal diagnosis: molecular testing from amnio or CVS
Name some common autosomal dominant diseases (table 47-1 in Baby Nelson)
achondroplasia thanatophoric dysplasia Crouzon syndrome Nonsyndromic craniosynostosis NF1 NF2 Huntington Myotonic Dystrophy Marfan syndrome Hereditary angioneurtoci edema (C-1 esterase inhibitor)
What are 5 rules of autosomal dominant inheritance
- trait in every generation
- each chip of an affected parent has a one in two chance of being affected
- males and females are equally affected
- male to male transmission occurs
- traits generally involve mutations in genes that code for regulatory or structural proteins (collagen)
Neurofibromatosis type 1 - name the features/diagnostic criteria
quite common 1/3500
Cafe au lait spots >5 that are 0.5 mm in prepuberty or >1.5 mm in puberty
Axillary Freckling
Neurofibromas (plexiform)
F
Optic Glioma
Osseous changes (ie sphenoid dysplasia)
Lisch Nodules
Complications of NF-1: learning disability, scoliosis, seizures, cerebral vasculature abnormalities
can also get optic nerve gliomas, astrocytomas of brain and spinal cord, malignant peripheral nerve tumours
Life expectance - reduced by 10-15 years
malignancy most common cause of death
AD but spontaneous mutations in 30-50% of cases
NF-2 -
much less common than NF-1
tumor suppressor bgene - so results in neurologic eye and skin lesions, multiple intracranial and spinal tumours - i.e. bilateral acoustic schwannomas, schwannomas of other cranial and spinal nerves, meningioma and glioma
cataracts
skin plaque like lesions, sC nodules and cutaneous schwannomas
Marfan syndrome - findings
Skeletal findings: tal, thin body habits, Spider like fingers and toes , Sternal abnormalities - excavatum/carinatum, scoliosis, pes planus, joint laxity
Eye findings: high myopia (can lead to retinal degeneration), ectopia lentos
Cardiac findings: progressive dilation of the aortic root, aortic insufficiency followed by aortic dissection is a common complication
How is Tay-Sachs Disease inherited?
Autosomal recessive inheritance
What are some examples of X linked conditions where some heterozygous carrier females can show some manifestations
colour-blindness
Duchenne MD
hemophilia
**some skewed X chromosome inactivation
What are rules of autosomal recessive inheritance
- trait in siblings, not in their parents or their offspring
- on average 25% of the siblings of the pro band are affected (at the time of conception, each sibling has a 25% chance of being affected)
- normal sibling has a 2/3 chance of being a carrier (heterozygote)
- mens and females are likely to be affected equally
- rare traits likely to be associated with consanguinity
- traits involve mutations in genes that code for enzymes (i.e. phenylalanine hydroxylase-deficient in PKU) are associated with serious illness and shortened life span
Provide some examples of AR diseases
CAH
PKU (lots of different mutations) - women with high phenylalanine during pregnancy, babies have brain damage
CF
Friederich Ataxia (does NOT show anticipation)
Gaucer disease -
Sickle cell disease
X linked recessive inheritance rules
- *most X linked diseases are recessive - so males are more likely to be affected
1. incidence higher in males than in females
2. trait from carrier females (who may show mild expression of the gene) to half of their sons (more severely affected)
3. each son of a carrier female has a one in two chance of being affected
4. Transmitted from affected males (trait) to all of their daughters, it is NEVER transmitted father to son
5. the trait may skip generations - can be passed through multiple carrier females
examples of autosomal recessive inheritance
muscular dystrophy (Duchenne) hemophilia A
Name some examples of X linked recessive diseases
- fragile X - females may have some expression
- Duchenne muscular dystrophy
- hemophilia A - factor VII deficiency
- Colour blindness
- Adrenoleukodystrophy - long chain fatty acid coA
- G6PD - but again females can have some expressivity
What are some examples of X linked dominant inheritance
- X linked vitamin D resistance rickets - hypo phosphatemic rickets - kidney can’t reabsorb phosphate
- Incontinentia pigmentia - affected sons die in utero, females, variable involvement
- Rett syndrome - mutations in MECP2 gene, normal at birth, later develop microcephaly and developmental regression
50% have seizures
hand washing posture - by 2 years of age
lethal in males
What are some examples of multifactorial disorders?
aka polygenic inheritance - multifactorial - genetic and environmental
cleft lip and palate, spina bifida
adult disorders: asthma, atherosclerosis, diabetes, cancer
true or false - pyloric stensois has a inherited component
true - it does
