Defects in Enzymes
Lysosomal Storage Diseases
Lysosomal enzymes catalyze the breakdown of complex macromolecules.
Autophagy: breakdown of intracellular organelles
Synthesis of a catalytcally inactive enzyme but that cross-reacts with immunoassays so normal levels of enzyme are detected.
Defects in post-translational processing of the enzymes (e.g. addition of mannose-6-phosphate "marker": enzyme secreted instead of ending in lysosome)
Lack of an enzyme activator or protector protein
Lack of a substrate activator protein
Lack of a transport protein required for egress of digested material out of lysosome
Long-chain complex proteoglycans abundant in ground substance of connective tissue. All except Hunter's are AR. Progressive disorders characterized by involvement of multiple organs including liver, spleen, heart and blood vessels. Most associated with coarse facial features, clouding of the cornea, joint stiffness and mental retardation, HSM, skeletal deformities, valvular lesions and subendothelial arterial deposits, particularly in coronary arteries. MI impt cause of death.
Hereditary deficiency of one of the enzymes involved in the synthesis or degradation of glycogen.
Myopathic forms: , muscle phosphofructokinase (Type VII)
Deficiency of a-glucosidase (acid maltase):
Brancher glycogenosis: (Type IV) lack of branching enzyme with widespread deposition of abnormal glycogen in brain, heart, skeletal muscle and liver.
Defects in Proteins that Regulate Cell Growth
Hair color, eye color, skin color, height and intelligence.
Diabetes Mellitus, obesity, cleft lip or palate, congenital heart disease, coronary heart disease, hypertension, gout, pyloric stenosis.
The risk of inheriting a multifactorial disorder is greater in sibs of pts. having severe expression of the disorder.
Concordance for identical twins is 20-40%
If one child is affected, 7% risk for next child; if two, 9%.
46 chromosomes. 46,XX female; 46,XY male.
Arrest mitosis in metaphase with colchicine and stain chromosomes. Giemsa stain: G banding. Resolution improved by getting cells in prophase.
p: short arm (petit); q: long arm.
Regions numbered 1,2,3 from centromere outward.
Limits to karyotyping: applicable only to cells that are dividing.
FISH: flouresence labelled probes recognize chromosome-specific sequences, or demonstarte subtle microdeletions.
Euploid. . any exact multiple of haploid.
Aneuploid . chromosome # is not an exact multiple of 23.
Nondisjunction def. homologous pairs of chromosomes fail to disjoin at first meiotic division or the two chromatids fail to separate at either the second meiotic division or at somatic mitotic divisions. This results in two aneuploid cells.
Anaphase lag def. one homologous chromosome is left behind and is excluded from cell nucleus in meiosis or mitosis. This results in one normal cell and in one cell with monosomy.
Mosaicism def. two or more populations of cells in the same individual.
Mosaicism affected the sex chromosomes is fairly common. e.g. 45X/47,XXX mosaic (phenotype: )
Chromosomal breakage: structural change in chromosomes followed by loss or rearrangement of material:
(e.g. , , )
Bench-to-bedside plans for fragile X syndrome are severely limited by the lack of validated outcome measures. The reviewed candidate biomarkers are at early stages of validation and deserve further investigation.
What causes Fragile X Syndrome | Fragile X Association …
A biomarker is a measurable and quantifiable biological characteristic that can serve as an indicator of healthy or pathological processes. For example, HDL and LDL are biomarkers for cardiovascular health and autoantibodies are biomarkers for autoimmune disease. Biomarkers are extremely useful in evaluating the clinical benefit of pharmaceutical interventions. A good biomarker assay will be sensitive, specific, rapid, simple to perform, inexpensive and applicable to easily obtained sample material. There is an urgent need to develop such biomarkers for fragile X syndrome (FXS).