Better Diseases

Sphingolipidoses

Lipid storage disorders from impaired sphingolipid degradation, causing lipid accumulation

Niemann-Pick disease

Sphingolipidosis; sphingomyelinase deficiency; sphingomyelin accumulates

Fabry disease

Sphingolipidosis (impaired sphingolipid degradation, lipid accumulation)

Krabbe disease

Sphingolipidosis (impaired sphingolipid degradation, lipid accumulation)

Gaucher disease

Sphingolipidosis; glucocerebrosidase deficiency; glucosylceramide accumulates

Tay-Sachs disease

Sphingolipidosis; hexosaminidase A deficiency; GM2 ganglioside accumulates

Metachromatic leukodystrophy

Sphingolipidosis (impaired sphingolipid degradation, lipid accumulation)

Neonatal respiratory distress syndrome (RDS)

Insufficient pulmonary surfactant, particularly dipalmitoylphosphatidylcholine (DPPC)

Scurvy

Collagen disorder; vitamin C deficiency impairs collagen hydroxylation in the RER

Menkes disease

Collagen disorder; ATP7A copper transporter mutation; decreased lysyl oxidase activity

Osteogenesis imperfecta

Collagen disorder; type I/II collagen mutations; defective triple helix

Ehlers-Danlos syndrome

Collagen synthesis, processing, or structural defects; also grouped with fibrillin-related disorders

Alport syndrome

Type IV collagen mutation; defective basement membrane

Supravalvular aortic stenosis (SVAS)

Elastin mutation causing narrowing of the aorta

Emphysema

Destruction of lung connective tissue and alveolar walls; associated with alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin deficiency

Misfolded protein; reduced lung protection against neutrophil elastase; accumulates in liver cells; causes emphysema and liver damage

Marfan syndrome

FBN1 (fibrillin) mutation; defective elastic fiber microfibrils; weakened elastic fibers

Mucopolysaccharidoses (MPS)

Lysosomal storage disorders caused by defective glycosaminoglycan (GAG) degradation

Hunter syndrome (MPS II)

Iduronate sulfatase deficiency

Hurler syndrome (MPS II)

Alpha-L-iduronidase deficiency; severe form of MPS I; dermatan sulfate and heparan sulfate accumulate

Hurler-Scheie syndrome (MPS I)

Alpha-L-iduronidase deficiency; intermediate MPS I phenotype

Scheie syndrome (MPS I)

Milder MPS I phenotype (alpha-L-iduronidase deficiency)

Morquio syndrome (MPS IV)

Mucopolysaccharidosis type IV

Maroteaux-Lamy syndrome (MPS VI)

N-acetylgalactosamine-4-sulfatase deficiency

Sly syndrome (MPS VII)

Mucopolysaccharidosis type VII

MPS IX

Hyaluronidase deficiency

Mucolipidosis VII

Listed in the defective-enzyme table; beta-glucuronidase deficiency

Epidermolysis bullosa simplex (EBS)

Keratin mutations (KRT5 and KRT14); compromised epithelial cell integrity; skin blistering

Emery-Dreifuss muscular dystrophy (EDMD)

Laminopathy; emerin mutation (X-linked) or LMNA mutation (autosomal dominant); also nesprin-1; muscle wasting and early joint contractures

Limb-girdle muscular dystrophy

Laminopathy; LMNA (lamin A) mutation

Familial partial lipodystrophy (Dunnigan type)

Laminopathy; LMNA mutation; abnormal fat distribution

Dilated cardiomyopathy

LMNA (lamin A) mutation; weakened heart muscle

Hutchinson-Gilford progeria syndrome (HGPS)

LMNA mutation producing abnormal lamin A (progerin); premature aging

Charcot-Marie-Tooth disease (CMT)

Associated with lamins, neurofilaments, kinesins, and connexins (connexins lower priority)

Alexander disease

GFAP (glial fibrillary acidic protein) disorder

Amyotrophic lateral sclerosis (ALS)

Neurofilament disorder (Lou Gehrig's disease)

Cardiomyopathy (desmin)

Desmin disorder

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17)

Tau disorder

Alzheimer's disease

Tau (abnormal phosphorylation, paired helical filaments, neurofibrillary tangles) and amyloid-beta (amyloid plaques)

Hereditary spherocytosis

Spectrin and ankyrin disorder causing hemolytic anemia

Dilated cardiomyopathy with woolly hair and keratoderma

Mutations in desmoplakin (DSP), desmocollin 2 (DSC2), and plakoglobin (PKG)

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D)

Desmosomal protein mutations: plakophilin 2, desmocollin 2, desmoglein 2, desmoplakin, plakoglobin

Hypertrophic cardiomyopathy

NOT caused by desmosomal mutations; associated with sarcolemmal protein defects

Laminopathy

Disease caused by mutations in nuclear lamins or lamina-associated proteins (LMNA mutation -> abnormal lamin A -> disrupted nuclear lamina and organization)

MELAS

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; mtDNA mutations; affects brain, muscle, heart

Kearns-Sayre syndrome (KSS)

Mitochondrial DNA defects; eye muscles and heart

Leigh syndrome

Subacute necrotizing encephalomyopathy; mitochondrial dysfunction affecting the developing nervous system

MERRF

Myoclonic epilepsy with ragged-red fibers; mitochondrial dysfunction

Leber hereditary optic neuropathy (LHON)

mtDNA mutations; progressive optic neuropathy

Heteroplasmy

Mix of mutant and normal mtDNA in a cell; influences disease severity

Threshold expression

Mitochondrial disease symptoms appear when the proportion of mutant mitochondria is high enough

Zellweger spectrum disorders

Mutations in peroxins (PEX proteins); defective peroxisome assembly

X-linked adrenoleukodystrophy (X-ALD)

Peroxisomal disorder; impaired very-long-chain fatty acid (VLCFA) metabolism

Creutzfeldt-Jakob disease (CJD)

Prion disease; PrPc converts to misfolded PrPsc; transmissible spongiform encephalopathy

Kuru

Prion disease (PrPsc)

Bovine spongiform encephalopathy (BSE)

Prion disease in cattle

Scrapie

Prion disease in sheep

Cystic fibrosis

CFTR ΔF508 misfolding; recognized by ER quality control and targeted for degradation (ERAD)

UPR

Unfolded protein response; increases chaperone production and adjusts ER activity

ERAD

ER-associated degradation; removes misfolded proteins via ubiquitination and degradation

Acetaminophen toxicity

CYP450 metabolism generates toxic metabolite NAPQI

Ethanol metabolism (excess)

CYP2E1; activates microsomal ethanol-oxidizing system

Statin metabolism and grapefruit

Grapefruit inhibits CYP3A4, interfering with statin metabolism; contributes to muscle wasting

I-cell disease (Mucolipidosis II)

UDP-N-acetylglucosamine-1-phosphotransferase deficiency; lysosomal enzymes not tagged with mannose-6-phosphate and are misdirected

Pompe disease (type II glycogen storage disease)

Lysosomal acid alpha-glucosidase (acid maltase) deficiency; glycogen accumulates in lysosomes

Familial breast cancer (BRCA1)

Breast and ovarian cancer; DNA repair, especially double-strand breaks

Familial breast cancer (BRCA2)

Breast, ovarian, pancreatic cancer, melanoma; DNA repair, especially double-strand breaks

Li-Fraumeni syndrome

TP53 (p53); sarcomas, breast cancer, leukemias, brain tumors; p53 is a transcription factor for apoptosis and cell-cycle arrest

Lynch syndrome (hereditary nonpolyposis colorectal cancer)

MSH2 and MLH1; DNA mismatch repair; colorectal, endometrial, ovarian, bladder cancers, glioblastoma

Familial adenomatous polyposis (FAP)

APC gene; regulates beta-catenin levels and cell adhesion; colorectal cancer, duodenal and gastric tumors

Familial retinoblastoma

RB1; retinoblastoma and osteosarcoma; cell-cycle regulation

Hereditary retinoblastoma

One defective RB1 copy inherited, only one more somatic hit needed; often bifocal; presents in children

Sporadic retinoblastoma

Both RB1 copies need somatic mutations; usually unifocal; described in adults

Knudson's two-hit hypothesis

Both copies of a tumor-suppressor gene must be inactivated; retinoblastoma is the example

RB function

Inhibits E2F and restricts cell-cycle entry; loss removes the cell-cycle brake

Loss of heterozygosity (LOH)

Loss of the remaining functional allele

Haploinsufficiency

One functional copy does not make enough protein to maintain normal tumor-suppressor activity

Dominant-negative effect

Mutant protein interferes with the normal protein; p53 is the example

HPV

Cervical cancer; small circular double-stranded DNA virus

HBV

Liver cancer; partially double-stranded DNA virus

HCV

Liver cancer and some lymphomas; single-stranded RNA flavivirus

EBV

Burkitt lymphoma and nasopharyngeal carcinoma; double-stranded DNA herpesvirus

KSHV

Kaposi's sarcoma and lymphomas; double-stranded DNA herpesvirus

Rous sarcoma virus (RSV)

Sarcomas; RNA retrovirus; carries v-src oncogene encoding a transforming tyrosine kinase

Merkel cell polyomavirus (MCV)

Merkel cell skin cancer; double-stranded DNA virus

SV40

Mesothelioma, brain tumors, osteosarcoma, non-Hodgkin lymphoma; double-stranded DNA virus

t(8;14)

Ig enhancer activates c-MYC; Burkitt lymphoma

t(14;18)

Ig enhancer activates BCL-2; follicular B-cell lymphoma

inv(11)

Increased cyclin D1 expression; parathyroid adenoma

t(9;22)

BCR-ABL fusion protein; CML and ALL

t(15;17)

PML-RAR fusion protein; acute promyelocytic leukemia (APL)

Regulatory-region rearrangement vs coding-region rearrangement

Regulatory: increased production of a normal protein. Coding: abnormal fusion protein

RAS (K-RAS, N-RAS, H-RAS)

Pancreatic, thyroid, colorectal, lung, liver, bladder, kidney cancers; melanoma; leukemias

BRAF

Melanoma; colon carcinoma

EGFR

Lung carcinomas

ERBB2 / HER2

Breast and ovarian carcinomas

MYC

Burkitt lymphoma

N-MYC

Neuroblastoma; lung carcinoma

L-MYC

Lung carcinoma

PDGFR

Chronic myelomonocytic leukemia; gastrointestinal stromal tumors (GIST)