Cellular/molecular

Question 1

Syndrome Lesch-Nyhan

Answer 1

Pathophysiologie:

1. Déficit HGPRT (voie de sauvetage des purines)
2. Impossibilité de convertir guanine -> GMP et hypoxanthine -> IMP
3. Augmentation de la production d’acide urique et de synthèse des purines de novo
4. X-linked recessive

Symptômes: 
H yperuricemia
G out
P issed off (aggression, self-mutilation)
R etardation (intellectual disability)
Dys T onia

Tx : Allopurinol et febuxostat (inhibe xanthine oxidase)

Question 2

Adenosine deaminase (ADA) deficiency

Answer 2

Pathophysiologie:
déficit dégradation adénosine -> augmentation dATP -> toxicité lymphocytes

Étiologie majeure de Severe Combined ImmunoDeficiency

Question 3

Anémie falciforme

Answer 3

Pathophysiologie:
1. Mutation ponctuelle faux-sens glutamic acid with valine

Avantage sélectif contre le paludisme
Autosomal récessif

Question 4

Xeroderma pigmentosum

Answer 4

Defect in nucleotide excision repair (G1 phase mostly) for mutations secondary to UV exposure

Question 5

Lynch syndrome (HNPCC : hereditary nonpolyposis colorectal cancer)

Answer 5

Defect in mismatch repair (G2 phase mostly)

Question 6

Osteogenesis imperfecta

Answer 6

Multiple gene defect possible. Most common COL1A1 (chromosome 17) + COL 1A2 (chromosome 7)
Mostly autosomal dominant. Multiple types (6).
Pathogenesis : problems forming triple helix in collagen synthesis cycle.
Affects mostly Type I collagen
Sx :
-Multiple fractures with minimal trauma
-Blue sclerae
-Dentiogenesis imperfecta
-Hearing loss

Question 7

Scurvy

Answer 7

Vitamin C -> necessary for hydroxylation of proline and lysine residues in collagen synthesis.
Deficiency leads to :
-Fatigue, emotional change
-Dyspnea
-Bone pain, myalgia
-easy bruising and petechiae, poor wound healing
-Gum disease (gingivitis)

Question 8

Ehlers-Danlos Disease

Answer 8

Pathogenesis : problems with cleavage of procollagen or cross-linking in collagen synthesis.
Multiple types. Most common : hypermobility type. Classical type mutation COL5A1 or COL5A2 in type V collagen. Vascular type (uncommon) -> deficit in type III collagen.
Inheritance and severity vary. Autosomal dominant or recessive.
Sx : hyperextensible skin, tendency to bleed, hypermobile joints (dislocation), berry and aortic aneurysms, organ rupture

Question 9

Menkes disease

Answer 9

Pathogenesis : defective Menkes protein (ATP7A) -> impaired copper absorption and transport -> reduces activity of lysyl oxidase (copper is cofactor) -> problems with cross-linking in collagen synthesis. 
X-linked recessive disease. 
Sx: 
-brittle (fragile) + kinky (crépu) hair
-Growth retardation
-hypotonia

Question 10

Kartagener syndrome

Answer 10

Pathogenesis: defect in dynein arm (retrograde transport to microtubule : from + to -, so “back to nucleus”)
Sx :
-Reduced fertility man + woman (immobile sperm + dysfonctional fallopian tube)
-Raises risk of ectopic pregnancy
-Bronchiectasie
-Chronic/recurrent sinusitis + ear infection
-situs inversus
-conductive hearing loss

Question 11

Proteasome defect

Answer 11

Linked to some cases of Parkinson disease

Question 12

Peroxisomal diseases

Answer 12

Pathogenesis : peroxisome necessary for catabolism of very-long chain fatty acids (b-oxydation), AA, ethanol, branched-chain fatty acid -> deficit synthesis of plasmalogens (phospholipid important for myelin) -> neurologic disorder

1. Zellweger syndrome : hypotonia, seizures, hepatomegaly, early death
2. Refsum disease : scaly (écailles) skin, ataxia, cataract/night blindness, shortening 4th toe, epiphyseal dysplasia

Question 13

Marfan syndrome

Answer 13

Pathogenesis : defective fibrillin (glycoprotein forming sheath around elastin).
FBN1 mutation on chromosome 15
Autosomal dominant disorder
Sx :
-Tall with long extremities
-pectus carinatum (carène, more specific) or excavatum (entonnoir)
-hypermobile joints
-arachnodactyly (long + tapering fingers and toes)
-cystic medial necrosis of Ao
-Aortic incompetence, Ao dissection
-Floppy mitral valve
-Subluxation of lenses (upward and temporally)

Question 14

Alpha1-antitrypsin deficiency

Answer 14

Pathogenesis: alpha1-antitrypsin inhibit elastase which breaks down elastin which gives elastic properties to skin, lung, large arteries, etc… -> deficit = more elastase = less elastin
Sx:
-cause of emphysema and cirrhosis (hepatic fibrosis secondary to its accumulation)
-also associated with some cancers and other diseases