Major acquired and inherited connective tissue diseases Flashcards
What 2 features are expressed by a genetic connective tissue disease?
Functions of proteins expressed
Where involved proteins are expressed in the genome
Why is therapy of connective tissue diseases usually guided by genotype instead of phenotypic effects, even though many conditions are defined by clinical features?
Phenotypic effects are highly variable and originate from a specific mutation, so it is easier to look at gene that has become mutated
Are rarer forms of a connective tissue disease caused by the same gene as the common forms of that disease?
Rarer forms of connective tissue diseases can be caused by mutation of other genes as well as the characteristic gene mutations
Give 2 benefits of molecular understanding of the genetic causes of connective tissue diseases?
Informs appropriate surveillance and prophylactic intervention
What gene mutates to cause Marfan syndrome, and how many types of mutations are there?
FBN1/fibrillin-1 mutations produce defective elastic fibres, over 1800 different mutations (most missense) reported
Give 8 examples of clinical features of Marfan syndrome?
Tall, long hands/feet and arm span that exceeds height, cardiovascular effects, high arched palate, long thin digits, upwards lens dislocation, myopia (near objects clear, far away blurry), hyperextensible joints
How many types of mutations affect collagen fibres, and what determines which type of connective tissue is affected?
1000s of mutations that affect many different tissues, but impact depends on where gene mutation is expressed
What are the most and least common mutations of genes that code for collagen fibres?
Most common mutations are single-base substitutions, less common are premature stop codon that causes haploinsufficiency
What 2 gene mutations occur, and what effect do they have on collagen to cause Osteogenesis Imperfecta?
COL1A1 and COL1A2 mutations produce defective type 1 collagen fibres
Why is Osteogenesis Imperfecta also called ‘brittle bone’ disease?
bone predominantly contains type 1 collagen fibres, but these are defective so the bone is more fragile in OI
How do gene mutations usually change the structure of procollagen so that the type 1 collagen fibres are defective, in OI?
Common mutations cause glycine to be replaced with larger AA so that procollagen triple helix structure is loosely intertwined
Are all OI cases caused by mutation of COL1A1 and COL1A2 genes?
No, some OI cases caused by mutation of other genes that regulate collagen assembly/function
Describe the severity of type I Osteogenesis Imperfecta and the mutation that it is commonly caused by?
mildest, most common form that occurs when mutations cause quantitative defect/haploinsufficiency: half of normal amount of type 1 collagen produced
Give 2 examples of clinical features of type I/mild OI?
Bones very fracture-prone
thin sclera allows blue choroid underneath to be seen
Describe the severity of type II/perinatal lethal osteogenesis imperfecta, and the type of mutation that it is usually caused by?
most severe form that occurs when mutations cause qualitative defect resulting in abnormal type 1 collagen produced
Give 5 clinical features of type II/perinatal lethal OI?
Very fragile bones cause intracranial fractures
severe breathing difficulties
severe osteopenia
skull osteomalacia
long bone and rib deformities
What gene mutation causes skeletal development abnormalities, and explain this process in terms of how the collagen is affected?
COL2A1 mutations cause defective type 2 collagen production, which predominantly makes up cartilage that is replaced by bone in endochondral ossification, affecting skeletal development
Give 6 clinical features of skeletal development abnormalities?
Short stature
enlarged joints
spinal curvature
early arthritis
cleft palate
vision and hearing defects
Give 3 examples of conditions that can be caused by COL2A1 mutation expressing defective type 2 collagen and resulting in skeletal development abnormalities?
hypochondrogenesis, type 2 achondrogenesis, some stickler syndrome cases
What 3 gene mutations cause Alport syndrome, what type of collagen is affected and where is this collagen predominantly found?
COL4A3, COL4A4, COL4A5 mutations cause defective type 4 collagen, which is a major component of basement membrane
Give 3 clinical features of Alport syndrome?
CKD
Hearing loss
Eye abnormalities
What is the incidence of Alport syndrome?
Incidence is 1 in 5000-10,000
What gene mutation leads to the most common form of Alport syndrome, and what percentage of all cases does this form make up?
Most common form (85%) due to COL4A5 mutations
Why is Alport syndrome a more severe disease in men than women?
X-linked disease, so men have more severe disease as they only have mutated gene copy, but women can be carriers
eg. renal failure more likely in men
What types of gene mutations occur in Stickler syndrome, and what kind of collagen fibres do these affect?
Mutations in type IX/9 or type XI/11 collagen, which are essential for type 2 collagen fibre formation
How many variants are there of the gene mutation that causes Stickler syndrome to be expressed?
There are at least 5 variants:
type I - COL2A1 mutations (75% of cases)
type II - COL11A1
type III - COL11A2 (non-ocular)
type IV - COL9A1 (recessive)
type V - COL9A2 (recessive)
Give 4 clinical features of Stickler syndrome?
Causes flattened facial features
eye and ear problems
affected joints such as congenitally enlarged knees, wrists
cleft palate
How many forms are there of Ehlers Danlos syndrome, and what gene mutations are they caused by?
At least 13 different forms, caused by mutation of one of at least 19 genes, including COL3A1, COL5A1, COL5A2 and the EDS forms present with overlapping symptoms and variable presentation
Why can the correct form of Ehlers Danlos syndrome be difficult to diagnose based on clinical presentation only?
EDS forms present with overlapping symptoms and variable presentation
What is the gene mutation that causes Type III/hypermobile EDS, what is the characteristic clinical feature and what is its incidence?
Caused by unknown gene defect
presents as benign hypermobility (very flexible joints)
incidence is 1 in 10,000-15,000
What 2 gene mutations cause Type I/II/classic EDS, what are the 2 characteristic clinical features and what is its incidence?
Mutation of COL5A1/COL5A2 producing null allele, which is normally expressed in skin and other tissues that express type I collagen
presents as stretchy skin that scars and bruises easily, hypermobile joints
incidence is 1 in 20,000
What gene mutation causes Type IV/vascular EDS, what are the 3 characteristic clinical features and what is its incidence?
Caused by COL3A1 mutations which are expressed in blood vessels and skin
presents as bruising, varicose veins, arterial rupture and organ rupture due to fragile skin and blood vessels
incidence in 1 in 200,000
