Robbins Pathology Chapter 5

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exon

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a nucleic acid sequence that is represented in the mature form of an RNA molecule either after portions of a precursor RNA (introns) have been removed

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intron

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nucleotide sequence within a gene that is removed by RNA splicing

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Point mutation that leads to an inappropriate "stop"

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nonsense mutation

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point mutation that subs in a "pretty close" AA

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conservative missense mutation

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point mutation that swaps in an aa which causes significant protein change

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nonconservative missense mutation

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change in the number of nucleotides

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frameshift. multiple of three can be okay, otherwise it will lead to a missense or nonsense mutation

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miRNA function?

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micro RNA act to stop protein transcription

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penetrance

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proportion of individuals with the mutation who exhibit clinical symptoms

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how many genes do we have

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20-30K (similar to small animals). Can be used to make ~100K proteins

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Familial hypercholesterolemia is caused by a

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loss of function mutation in the LDL receptor

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hereditary spherocytosis results from a

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loss of function mutation involving a key structural protein (alpha-spectrin) that forms the normal cytoskeleton elements of the red cell membrane. Causes RBCs to get grabbed by spleen

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mutant allele in hereditary spherocytosis is classified as a ___________ _________. What does this mean?

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dominant negative (aka antimorph) which are dominant mutations that act in opposition to normal gene activity

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what does 'dominant negative' mean?

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dominant mutation that acts in opposition to normal gene activity

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what kind of gene mutation is involved in huntington's chorea?

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autosomol dominant, delayed expression, gain of function

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Incomplete penetrance and variable expressivity are phenomena associated only with autosomal ______ inheritance

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Incomplete penetrance and variable expressivity are phenomena associated only with dominant inheritance

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wilson disease

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autosomol recessive. accumulation of toxic copper in liver/tissues/eyes (Kayser fleisher rings).

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which is more common x-linked recessive or dominant?

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x-linked recessive are more common (most common disease type in humuns)

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what kind of disease is agammaglobulinemia

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x-linked recessive disease

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mosaicism results because of

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x-inactivation (variable expression….. Penetrance)

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what causes porphyria?

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single-gene enzyme defects. Caused by defect in enzyme in production of heme

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achondroplasia

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mutation in Fibroblast growth factor receptor (FGFR). Abnormal development of cartilage in the long bones.

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thalassemia

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inherited autosomal recessive disease which results in reduced rate of synthesis or no synthesis of one of the globin chains that make up hemoglobin

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ehlers-danlos syndromes

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genetic defect in the synthesis or structure of fibrillar collagen

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most clinically significant type of ehlers-danlos?

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vascular type. They can have spontaneous rupture of arteries or bowel

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cause of vitamin d-resistant rickets?

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Vitamin D receptor (VDR) is mutated such that it has complete or partial loss of function. Causes hypocalcemia and rickets. Most common in middle east

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lysosomal storage disease

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group of diseases with multiple types. All effect lysosomal trafficing.

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MPS

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mucopolysaccharidoses. Rare autosomal recessive lysosomal storage disease affects multiple organs/tissues. Not enough or nonfuctioning enzymes for breakdown of Glycosaminoglycans.

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Hurler's Syndrome

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MPS 1

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definition of Complex multigenic disorder

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occur when many polymorphisms, each with a modest effect and low penetrance are inherited.

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polymorphism

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a genetic variant that has at least 2 alleles and occurs in at least 1% of the population

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chromosomal disorders

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change in number or structure of one or more chromosome

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causes of aneuploidy

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nondisjunction & anaphase lag

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anaphase lag

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can happen during mitosis or meiosis. Chromomes fail to separate

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Familial hypercholesterolemia is caused by a

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single gene mutation in LDL receptor (19p)

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gaucher disease

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recessive mutation of glucocerebrosidase which cause an accumulation of glucocerebroside (usually in WBCs).

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gaucher disease. describe Type I.

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Type I is non-neural with onset in childhood or early adult.

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turner syndrome

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monosomy x. susceptible to coarctation of the aorta and bicuspid aortic valve.

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xanthoma

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They are cutaneous manifestations of lipidosis in which there is an accumulation of lipids in large foam cells within the skin

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corneal arcus

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white or gray ring around the cornea. Caused by hypercholesterolemia

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what tell-tale cells do you see in xanthomas? (microscopically)

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foamy macrophages and cholesterol crystals

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what pattern of inheritance is in familial hypercholesterolemia?

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autosomal dominant

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how come macrophages can ingest LDL in soft tissues?

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macrophages have scavenger LDL receptors. Different than the messed up LDL receptor

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most common causes of chronic hepatic fibrosis?

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infection (hep-c), alcohol abuse, non-alcoholic steatohepatitis associated with metabolic syndrome, Autoimmune disease

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varices

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dialated veins (usually people mean esophageal varices)

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why does hepatic fibrosis cause esophageal varices?

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fibrosis causes blood to back up in portal vein which puts increased pressure on veins in stomach and esophagus

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sclerotherapy

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forcing clots in esophageal varices (endoscopic)

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what color is cytoplasm in foamy macrophages?

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clear

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inheritance of gucher disease?

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autosomal recessive

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number one symptom of gaucher disease?

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hepatosplenomegaly (followed by bone lesions, gaucher cells, many others)

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type A aortic dissection?

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dissection that is very high on aorta

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What is problem in Loeys-Dietz syndrome?

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a recently-discovered autosomal dominant genetic syndrome which has many features similar to Marfan syndrome, but which is caused by mutations in the genes encoding TGF-beta receptor

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cardio vascular changes in monosomy X

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Turner syndrome has CV anomolies in 20-30% of cases. 10% coarctation of aorta. 16% have bicuspid aortic valve (has association with aortic wall abnormalities). Aortic stenosis

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what is dr gryzbicki's favorite tumor in the whole wide world?

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teratoma (neoplasms composed of disorganized tissues from germ cell layers)

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kleinfelter cause?

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multiple x chromosomes.

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kleinfelter is at increased risk of?

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breast cancer, extragonadal germ cell tumors, autoimmune diseases

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what percent of the human genome encodes proteins?

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less than 2%

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two most common forms of DNA variations in the human genome?

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- single nucleotide polymorphisms - copy number variations

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CNV

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copy number variations are structural rearrangements of the genome such as deletions, duplications, inversions, and translocations

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epigenetics

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heritable changes in gene expression that are not caused by alterations in DNA sequence

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explain activation of miRNA? (looking for two key enzyme names)

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- pre-miRNA is exported to cytoplasm - Dicer "cuts" it into miRNA (still double stranded) - miRNA separates (to single strand) - miRNA joins RISC (RNA induced silencing complex) - RISC complex cuts or blocks mRNA

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difference between miRNA and siRNA?

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siRNA is introduced into the cell whereas miRNA come from nucleus. Both need Dicer/RISC

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estimated 50% of spontaneous abortuses are because of?

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chromosomal abnormality

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What is meant by "Mendelian disorder"

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disorder where there is a single gene mutation and a high penetrance

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what kind of mutation is involved in sickle cell anemia?

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nonconservative missense mutation. A single amino acid substitution affects the beta-globin chain of hemoglobin. CAC to CDC (glutamic acid to valine)

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beta0-thalassemia

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CAG to UAG (glutamic acid to stop codon) on beta-globin causes premature termination of beta-globin which is degraded. Severe anemia

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Almost all trinucleotide-repeat mutations involve what nucleotides?

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C and G

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mutations at several genetic loci that produce the same trait

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genetic heterogeneity

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a single gene that leads to many end effects

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pleiotropism

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give an example of a pleiotropic disease

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sickle cell disease. One gene mutation causes the primary sickeling, but also splenic, organ and bone problems

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what is the term used to explain the range of problems that can occur in neurofibromatosis type 1?

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variable expressivity

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why don't mutations in genes that encode enzymes not manifest in autosomal dominant patterns?

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because there are two copies of the gene for the enzyme (one on each chromosome). You'd still get half (enough) of the enzyme

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what kind of (non-enzyme) proteins are affected in autosomal dominant disorders?

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1. those involved in regulation of metabolic pathways (example: LDL receptor in familial hypercholesterolemia) 2. structural proteins

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example of gain of function disease?

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Huntington Disease. the trinucleotide repeatmutation gives rise to an abnormal protein (huntingtin) that is toxic to neurons. This explains why even heterozygotes are affected

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Huntington disease (Autosomal dominant or recessive?)

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Autosomal dominant

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Neurofibromatosis (Autosomal dominant or recessive?)

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Autosomal dominant

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Myotonic dystrophy (Autosomal dominant or recessive?)

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Autosomal dominant

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Tuberous sclerosis (Autosomal dominant or recessive?)

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Autosomal dominant

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Polycystic kidney disease (Autosomal dominant or recessive?)

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Autosomal dominant

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Familial polyposis coli (Autosomal dominant or recessive?)

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Autosomal dominant

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Phenylketonuria (Affected protein type / protein name / Molecular lesion?)

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Enzyme. Phenylalanine hydroxylase Splice-site mutation: reduced amount

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Tay-Sachs (Affected protein type / protein name / Molecular lesion?)

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Enzyme. Hexosaminidase Splice-site mutation or frameshift without stop: reduced amount

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Severe combined immunodeficiency (Affected protein type / protein name / Molecular lesion?)

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Enzyme. Adenosine deaminase. Point mutations: abnormal protein with reduced activity

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Emphysema and liver disease (Affected protein type / protein name / Molecular lesion?)

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Enzyme Inhibitor alpha1-antitrypsin Missense mutation: impaired secretion from liver to serum

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Familial hypercholesterolemia (Affected protein type / protein name / Molecular lesion?)

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Receptor Low-density lipoprotein receptor Deletions, point mutations: reduction of synthesis, transport to cell surface, or binding to low density lipoprotein

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Vitamin D-resistant rickets (Affected protein type / protein name / Molecular lesion?)

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Receptor. Vitamin D receptor Point mutations: failure of normal signaling

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Alpha-Thalassemia (Affected protein type / protein name / Molecular lesion?)

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Oxygen transport Hemoglobin Deletions: reduced amounts

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Beta-Thalassemia (Affected protein type / protein name / Molecular lesion?)

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Oxygen transport Hemoglobin Deletions: Defective mRNA processing: reduced amount

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Sickle cell anemia (Affected protein type / protein name / Molecular lesion?)

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Oxygen transport Hemoglonin Point mutations: abnormal structure

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Cystic fibrosis (Affected protein type / protein name / Molecular lesion?)

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Ion Transport Cystic fibrosis transmembrane conductance regulator Deletions and other mutations: nonfunctional or misfolded proteins

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Osteogenesis imperfecta (Affected protein type / protein name / Molecular lesion?)

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Structural (extracellular) Collagen Deletions or point mutations cause reduced amount of normal collagen or normal amounts of defective collagen

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Ehlers-Danlos (Affected protein type / protein name / Molecular lesion?)

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Structural (extracellular) Collagen Deletions or point mutations cause reduced amount of normal collagen or normal amounts of defective collagen

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Marfan Syndrome (Affected protein type / protein name / Molecular lesion?)

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Structural (extracellular) Fibrillin Missense mutations

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Duchenne/Becker muscular dystrophy (Affected protein type / protein name / Molecular lesion?)

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Structural (cell membrane) Dystrophin Deletion with reduced synthesis

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Hereditary spherocytosis (Affected protein type / protein name / Molecular lesion?)

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Structural (cell membrane) Spectrin, ankyrin, or protein 4.1 Heterogeneous

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Hemophilia A (Affected protein type / protein name / Molecular lesion?)

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Hemostasis Factor VIII Deletions, insertions, nonsense mutations, and others: reduced synthesis or abnormal factor VIII

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Hereditary retinoblastoma (Affected protein type / protein name / Molecular lesion?)

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Growth regulation Rb Protein Deletions

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Neurofibromatosis type 1 (Affected protein type / protein name / Molecular lesion?)

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Growth regulation Neurofibromin Heterogeneous

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galactosemia. What is wrong? What happens?

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deficiency of galactose-1-phosphate uridyltransferase leads to accumulation of galactose and consequent tissue damage

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what does alpha1-antitrypsin do? What happens if defective?

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protects tissues from neutrophil elastase. In its absence, neutrophil elastase is free to break down elastin, which contributes to the elasticity of the lungs, resulting in respiratory complications such as emphysema and COPD

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Autosomal Recessive

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Congenital adrenal hyperplasia (Autosomal dominant or recessive or X-linked?)

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Autosomal Recessive

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Alkaptonuria (Autosomal dominant or recessive or X-linked?)

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Autosomal Recessive

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Neurogenic muscular atrophies (Autosomal dominant or recessive or X-linked?)

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Autosomal Recessive

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Friedreich ataxia (Autosomal dominant or recessive or X-linked?)

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Autosomal Recessive

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Spinal muscular atrophy (Autosomal dominant or recessive or X-linked?)

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Autosomal Recessive

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All sex linked disorders are _______ and almost all are ________

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all sex linked orders are X-LINKED and almost all are RECESSIVE

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why is there no Y linked inheritance

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males with mutations affecting y-linked genes are usually infertile

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Duchenne muscular dystrophy (Autosomal dominant or recessive or X-linked?)

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X-linked Recessive

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Hemophilia A (Autosomal dominant or recessive or X-linked?)

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X-linked Recessive

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Hemophilia B (Autosomal dominant or recessive or X-linked?)

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X-linked Recessive

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Chronic granulomatous disease (Autosomal dominant or recessive or X-linked?)

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X-linked Recessive

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Glucose-6-phosphate dehydrogenase deficiency (Autosomal dominant or recessive or X-linked?) and what does it do?

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X-linked Recessive. Predisposes red cell hemolysis in patients receiving certain types of drugs.

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Agammaglobulinemia (Autosomal dominant or recessive or X-linked?)

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X-linked Recessive

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Wiskott-Aldrich syndrome (Autosomal dominant or recessive or X-linked?)

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X-linked Recessive

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Diabetes insipidus (Autosomal dominant or recessive or X-linked?)

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X-linked Recessive

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Lesch-Nyhan Syndrome (Autosomal dominant or recessive or X-linked?)

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X-linked Recessive

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Fragile-X syndrome (Autosomal dominant or recessive or X-linked?)

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X-linked Recessive

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Tay-Sachs disease. Risk factor?

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Ashkenazi Jew

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Phenylketonuria (Affected protein type / protein name / Molecular lesion?)

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Enzyme. Phenylalanine hydroxylase Splice-site mutation: reduced amount

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Tay-Sachs (Affected protein type / protein name / Molecular lesion?)

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Enzyme. Hexosaminidase Splice-site mutation or frameshift without stop: reduced amount

Front 121

Severe combined immunodeficiency (Affected protein type / protein name / Molecular lesion?)

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Enzyme. Adenosine deaminase. Point mutations: abnormal protein with reduced activity

Front 122

Emphysema and liver disease (Affected protein type / protein name / Molecular lesion?)

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Enzyme Inhibitor alpha1-antitrypsin Missense mutation: impaired secretion from liver to serum

Front 123

Familial hypercholesterolemia (Affected protein type / protein name / Molecular lesion?)

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Receptor Low-density lipoprotein receptor Deletions, point mutations: reduction of synthesis, transport to cell surface, or binding to low density lipoprotein

Front 124

Vitamin D-resistant rickets (Affected protein type / protein name / Molecular lesion?)

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Receptor. Vitamin D receptor Point mutations: failure of normal signaling

Front 125

Alpha-Thalassemia (Affected protein type / protein name / Molecular lesion?)

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Oxygen transport Hemoglobin Deletions: reduced amounts

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Beta-Thalassemia (Affected protein type / protein name / Molecular lesion?)

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Oxygen transport Hemoglobin Deletions: Defective mRNA processing: reduced amount

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Sickle cell anemia (Affected protein type / protein name / Molecular lesion?)

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Oxygen transport Hemoglonin Point mutations: abnormal structure

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Cystic fibrosis (Affected protein type / protein name / Molecular lesion?)

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Ion Transport Cystic fibrosis transmembrane conductance regulator Deletions and other mutations: nonfunctional or misfolded proteins

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Osteogenesis imperfecta (Affected protein type / protein name / Molecular lesion?)

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Structural (extracellular) Collagen Deletions or point mutations cause reduced amount of normal collagen or normal amounts of defective collagen

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Ehlers-Danlos (Affected protein type / protein name / Molecular lesion?)

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Structural (extracellular) Collagen Deletions or point mutations cause reduced amount of normal collagen or normal amounts of defective collagen

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Marfan Syndrome (Affected protein type / protein name / Molecular lesion?)

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Structural (extracellular) Fibrillin Missense mutations

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Duchenne/Becker muscular dystrophy (Affected protein type / protein name / Molecular lesion?)

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Structural (cell membrane) Dystrophin Deletion with reduced synthesis

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Hereditary spherocytosis (Affected protein type / protein name / Molecular lesion?)

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Structural (cell membrane) Spectrin, ankyrin, or protein 4.1 Heterogeneous

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Hemophilia A (Affected protein type / protein name / Molecular lesion?)

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Hemostasis Factor VIII Deletions, insertions, nonsense mutations, and others: reduced synthesis or abnormal factor VIII

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Hereditary retinoblastoma (Affected protein type / protein name / Molecular lesion?)

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Growth regulation Rb Protein Deletions

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Neurofibromatosis type 1 (Affected protein type / protein name / Molecular lesion?)

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Growth regulation Neurofibromin Heterogeneous

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galactosemia. What is wrong? What happens?

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deficiency of galactose-1-phosphate uridyltransferase leads to accumulation of galactose and consequent tissue damage

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what does alpha1-antitrypsin do? What happens if defective?

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protects tissues from neutrophil elastase. In its absence, neutrophil elastase is free to break down elastin, which contributes to the elasticity of the lungs, resulting in respiratory complications such as emphysema and COPD

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what is primaquine?

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antimalarial drug.

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if someone has an adverse reaction to primaquine, what disease do they likely have?

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G6PD

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FBN1 Mutation leads to? (Disease and pathogenesis)

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Marfan syndrome results from an inherited defect in an extracellular glycoprotein called fibrillin-1. fibrillin is the major component of microfibrils in the ECM

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FBN2 mutation leads to?

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congenital contractural arachnodactyly. An autosomal dominant disorder characterized by skeletal abnormalities

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Tests have shown that anti-________ antibodies may be able to stop the vascular progression of marfan syndrome

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Normal microfibrils sequester TGF-beta thereby keeping it inactive. In Marfans, if you have no (or bad) microfibrils you'll get excessive TGF-beta.

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dolichocephalic

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means "long headed". A symptom of Marfan's syndrome

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what eye finding can be used to diagnose Marfans?

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ectopia lentis: bilateral subluxation or dislocation (usually outward and upward) of the lens

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Alport Syndrome

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caused by mutations in collagen biosynthesis. Prevent proper production or assembly of type IV collagen, which is an important structural component of basement membranes in the kidney, inner ear, and eye.

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Epidermolysis bulosa

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Mutation in collagen that causes the epidermis to be poorly attached to the dermis

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List 4 diseases that stem from mutations affecting collagen

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Ehlers-Danlos
Osteogenesis Imperfecta
Alport syndrome
Epidermolysis bullosa

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what is the ultimate problem in familial hypercholesterolemia? (clinical signs?)

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atherosclerosis. Also causes xanthomas and arcus corneae

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niemann pick disease type c

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NPC1 & NPC2 are needed to transport cholesterol through a hepatocyte. This disease is a disorder of NPC1/2 and causes a buildup of cholesterol

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three consequences of intracellular cholesterol

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1. Suppresses the synthesis of LDL receptors (less will come in)
2. cholesterol activates acyl-coenzyme A (cholesterol acyltransferase) which esterifies and stores cholesterol
3. Cholesterol suppresses cholesterol synthesis by inhibiting enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA)

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how do statins work?

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they supress the activity of HMG CoA reductase (less cholesterol is synthesized in the hepatocyte, so more LDL receptors are made)

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what is one drug class that can work in familial hypercholesterolemia?

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statins. Supress synthesis of cholesterol

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Mannose-6-phosphate groups

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serve as an “address label” that is recognized by specific rectors on the inner golgi. Lysosomal enzymes bind these receptors and are thereby segregated from other secretory proteins

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what does tay-sachs look like microscopically?

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neurons are ballooned with cytoplasmic vacoules, each representing a markedly distended lysosome filled with gangliosides

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cherry red spot on the macula means you have what disease?

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GM2 Gangliosidosis (Tay-Sachs disease is the most common of the three)

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list the 3 types of GM2 gangliosidosis

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Tay-Sachs disease
Sandhoff disease
GM2 gangliosidosis variant AB