Week 3 Flashcards
Osteogensis Imperfecta is caused by what type of mutation + MoI?
mutation: in the gene COL1A1 or COL1A2 (encoding for the proα1(I) and proα2(I) chains of type I collagen)
MoI: Autosomal dominant
Osteogensis Imperfecta Type I CF?
1) Up to 100 fractures
2) no short stature
3) blue sclera
4) may have hearing loss
*Classic non-deforming (Type I)
Osteogenesis Imperfecta Type II CF?
1) Dark sclera
2) Rib fractures
3) Sever short stature
4) deforemed extremities
5) small thorax
6) Undermineralised skull
*Perinatal lethal (Type II)
CF of Type III Osteogenesis imperfecta
- Fractures at birth
- Progressive deformity
- Marked short stature
- Blue sclera
- Frequent hearing loss
- Dentinogenesis imperfecta
* Progressively deforming (Type III)
Osteogensis Imperfecta Type IV CF?
– Multiple fractures
– Mild to moderate deformity
– Variable short stature
– Normal to grey sclerae
* Common variable (Type IV)
what type of mutations cause mild, non-deforming Osteogenesis Imperfecta?
*Type I
loss of function mutations in the COLA1 gene (nonsense, frameshift, splicing abnormalities)
* results in the reduction of available proα1
What type of mutations cause sever cases of Osteogenesis Imperfecta?
*Type II-IV
Missense mutations in *COLA1A1/2 gene
*Have a dominant negative effect
CF of the Classical type of Ehlers-Danlos Syndrome
1) Skin:
– Hyperextensible skin (and hyperelastic)
– Fragile skin with abnormal wound healing
(e.g. dermal splitting over pressure points, widened and atrophic scars)
– Tendency to bruise (with staining)
– Fleshy lesions over knees and elbows
2) Joint hypermobility
MoI + Gene mutation of the Classical type of Ehlers-Danlos Syndrome
MoI: AD
mutation : COL5A1, COL5A2
* Variable expressivity
MoI of Hypermobility type Ehlers-Danlos Syndrom
AD
(unknown mutation type)
CF of Hypermobility type Ehlers-Danlos Syndrome
- Joint hypermobility
- Subluxations (dislocations)
- Chronic pain and degenerative joint disease
- Skin (normal or slightly hyperextensible)
- Mild aortic root dilatation
* least severe type
MoI + mutation gene of Vascular type Ehlers-Danlos Syndrome
MoI: AD
Mutation in: COL3A1 gene (Type III collagen)
* **Genotype/ phenotype correlations **
CF of Vascular type Ehlers-Danlos Syndrome
- Thin, translucent skin
- Typical facial features:
– Thin, narrow nose, prominent eyes - Fragility of:
– Arteries
– Intestines
– Uterus
* Severe type
MoI + Mutation gene of Kyphoscoliotic Ehlers-Danlos Syndrome
MoI: AR
Mutation: in PLOD1 gene
* Rare condition
CF of Kyphoscoliotic EDS
- Hypotonia and significant delay in motor milestones
- Fragile sclerae (risk of rupture of globe)
- Fragile skin, joint laxity
MoI+ Mutant gene in Mrafan Syndrome
MoI: AD (CT disorder)
Mutation: in FBN1 gene , 15q11 (fibrilin gene)
CF of Marfan syndrome?
– Ectopia lentis (lens displacement)
– Aortic root dilatation*
– Systemic score (use table, 7 or more)
* Marfan syndrome
FBN1 mutations are app.:
—- % inherited
—- % de novo
– 75% inherited
– 25% de novo
* No definitive genotype/ phenotype correlation
* Variable expressivity
Instability of triplet repeats is a type of ———— mutation
insertion
* slipping mispairing during DNA replication
The 2 types of triplet repeat mutations+ disorders
1) Expansion in the coding part
– encoded protein has gained a new function (e.g.
Huntington, most types of Spinocerebellar Ataxias, Kennedy disease)
2) Expansion in the non-coding part
– Disturbs protein expression/ function (e.g. Fragile
X syndrome- UTR, Friedreich’s ataxia- intron)
– RNA assumes new function (e.g. Myotonic
dystrophy 1 - UTR, Myotonic dystrophy 2 - intron)
In Huntington disease, Age of onset correlates w/ number of repeats.
– Adult onset: —- repeats
– Juvenile onset: —— repeats
– Adult onset: up to 55 repeats
– Juvenile onset: > 60 repeats
In Huntington disease Anticipation is observed. However, more commonly in [Paternal/maternal] transmission
Paternal
CF of Fragile X-syndrome
1) Intellectual disability
2) Dysmorphic features: long face, prominant chin and ears
3) Joint laxity (“loose joints”)
4) Large testes after puberty
MoI of Fragile X-syndrome+ Mutant gene
MoI: Gain of Fxn (In frame insertion) , X-linked recessive (M>F)
Mutation: in FMR1 gene
( CGG repeats in the untranslated region (UTR) of exon1 of the FMR1 gene)
*Fragile X-syndrome
Normal CGG allele repeats?
5-44 repeates
*Fragile X-syndrome
intermediate alleles of CGG repeats
45-54 repeats
– Not pathogenic but may expand into premutation if
passed on by females
premutation allele for Fragile X-syndrome
55-200 CGG repeates
– Associated with risk for FXTAS and POI
– May expand into full mutation if passed on by females
Full muation allele for Fragile X-Syndrome
> 200 CGG repeats
- Causes Fragile X syndrome (males affected more severely than women)
CF of Fragile X tremor/ ataxia syndrome (FXTAS)
– Progressive ataxia and intention tremor
– Late onset
CF of Fragile X-associated Primary Ovarian Insufficiency (POI)
Menopause before the age of forty
CF of Myotonic Dystrophy type 1 (DM1)
1) muscle weakness (Hypotonia), Myotonia
2) Cataracts
3) Endocrine multiple disorders
4) Cardiac Conduction defecs
5) Intellectual disability
6) Ptosis, facial wekness
*Hypotonaia may lead to respiratory compromise (failure)
*Myotonic Dystrophy
MoI of DM1 + mutation
MoI: AD (Anticipation mostly in materanl inheritance)
mutation: CTG repeat expansion at the DMPK gene (untranslated regoin)
* Myotonic Dystrohy Type 1
Normal CTG repeats
5-34 repeats
premutation (intermediate) alleles causing DM1
35-49 CTG repeats
– Asymptomatic but can expand in subsequent generations
Full penetrance (full mutation) alleles for DM1
> 50 CTG repeats
– Larger repeats correlate with earlier onset and increased severity (e.g. more than 1000 repeats with congenital disease)
Anticipation is Observed in Myotonic Dystrophy Type 1. However, it is mostly observed in [Paternal/Maternal] inheritance
Maternal
Clinical syndromes w/ Copper/ Iron regulation
1) Wilson disease
2) Haemochromatosis
Channelopathies CF ?
1) Nervous (epilepsy, ataxia, blindness, deafness)
2) Cardiac (Arrythmias, sudden cardiac arrest)
3) Respiratory - CF
————–: disease casued by defects in ion channels (e.g, CF)
channelopathies
MoI of Cystic fibrosis+ gene affected?
MoI: AR
Mutation: in the CFTR gene
(reduced Cl- and HCO-3 transport)
* genotype/ phenotype relates to the pancreatic function
CF of CF?
1) Airways and sinuses:
– Recurrent bronchitis, sinusitis
– Progressive obstructive airway disease
– Recurrent infections
2) Gastrointestinal:
– Pancreatic insufficiency and malabsorption
– Meconium ileus
– Pancreatic/ chronic hepatic disease
3) Sweat gland abnormalities (hyponatraemic
dehydration)*
4) Azoospermia (abnormal vas deferens)
– Congenital Absence of Vas Deferens (CAVD) is described as a distinct phenotype/ condition at the mild end of CF spectrum
* Mutation
CF Class #: abnormal channel activation (gating)
CLASS III
* mutation
CF Class # : abnormal Chloride conductivity
CLASS IV
CF Class #: reduced stability (increased turnover
CLASS VI
CF Class #: non-coding mutations lead to reduced synthesis
CLASS V
CF Class # : abnormal CFTR processing (e.g. F508del)
CLASS II
CF Class #: nonsense/ frameshift mutations (e.g. G542X)
CLASS I
MoI+ Mutation in Wilson disease
MoI: AR
Mutation: in the ATP7B gene (Excessive Copper metabolism)
CF of Wilson disease
1) Hepatitis, hepatic failure, chronic disease
2) Movement disorders
3) Depression
4) Copper deposition in the cornea- Kayser-Fleischer rings
Diagnosis of Wilson disease:
Copper analysis show [low/high] serum copper and ceruloplasmin
Low
MoI + mutation of Hereditary Haemochromatosis
MoI : AR, reduced penetrance
Mutation: in the HFE gene (high iron levels)
CF of Haemochromatosis
1) Joint pain
2) skin pigmentation
3) Cardiomyopathy
4) DM
*liver Cirrhosis is a complication as the disease progresses
LAb Diagnosis of Haemochromatosis?
elevated transferriniron saturation and ferritin concentration
Clincial case
- 17-year-old male
- ‘Marfanoid’ habitus
- Distinctive features (prominent lips)
- Unusual tongue lesions
- Family history of cancer (Phaeochromocytoma, Thyroid cancer)
Syndrome+ MoI +Mutation
* Marfanoid habitus –> symptoms resembling those of Marfan syndrome
Syndrome : Multiple Endocrine Neoplasia Type 2 (MEN2B)
MoI: AD
Mutation: Activating mutation of RET
MEN2A/B or both syndroms
- Oncogenesis
- Medullary thyroid carcinoma (A, B)
- Phaeochromocytoma (A, B)
- Parathyroid adenoma/ hyperplasia (A)
- Mucosal neuromas (B)
- Ganglioneuromatosis of GI tract (B)
