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Genetic Diseases
Unit 1: Genetic Diseases: Cause, Symptoms, Population/Inheritance, Treatment

Additional Biochemistry Flashcards




Alzheimer's Disease
  • Cause: formation of amyloid plaques in cerebral cortex leads to neurodegeneration. ẞ-Amyloid proteins are cleaved from Amyloid Precursor Proteins, a normal neuronal component.
    • SNPs in APP modulate susceptibility to cleavage of ẞ-Amyloid.
  • Population/Inheritance: Can be familial (<1%)
  • Symptoms: memory loss, dementia, personality change.
    • Brain on autopsy: shrinkage of cerebral cortex & hippocampus, enlarged ventricles. Characteristic “tangling” and damage of cells
Androgen Insensitivity Syndrome (AIS)

  • Cause: males lack androgen receptor (AR), so they cannot respond to any testosterone produced.
    • Patients make testosterone, but can’t respond to it
  • Population/ Inheritance:
    • X-linked (so males only)
  • Symptoms:
    • males identified early on as girls (develop female sexual characteristics)
    • Usually not diagnosed until they fail to menstruate as teens.
  • Treatment:
    • Symptomatic management only: sex assignment, genitoplasty, gonadectomy in relation to tumor risk, hormone replacement therapy, and genetic and psychological counseling.
    • Methods to correct a malfunctioning androgen receptor protein that result from an AR gene mutation are not currently available.
DiGeorge/ velocardiofacial syndrome
  • Cause: microdeletion at 22q11.2
    • deletions span about 3 Mb and >20 genes
    • unaffected alleles are functional, but not sufficient
    • symptoms reflect importance of gene dosage (copy number)
    • Haploinsufficience - single haploid does not express enough protein
  • Symptoms:
    • puffy/ hooded eyelids
    • retrognathia (posterior placement of chin)
    • bulbous nose
    • protuberant ears
    • usually score lower IQs (50-80), but good language
Fragile X Syndrome
  • Cause:
    • CGG repeat expansion at 5’ end of Fragile X Gene. (G4 structures)
    • Fragile X gene encodes a protein FMR1 (Fragile X MR 1)
  • Population / Inheritence:
    • Second most frequent cause of “intellectual disability”
    • X-linked dominant - all males are affected due to a single copy of X, females show variable impact since one copy of X chromosome is inactivated in each cell.
      • variable penetrance
    • Note that degree of symptoms is related to the number of CGG repeats.
  • Symptoms:
    • Prominent ears (one or both), long face, High-arched palate, Hyperextensible finger joints, Double-jointed thumbs, Flat feet, soft skin, Larger testes in men after puberty (postpubescentmacroorchidism), Low muscle tone


Huntington Disease
  • Cause: expansion of CAG repeat within the HD gene, which encodes the Huntingtin protein (Htt). This causes buildup of mutant protein (mHtt)  in the brain and subsequent neuronal death.
  • Population/Inheritance:
    • Autosomal dominant, more common in persons of european descent
    • Number of CAG repeats accounts for about 60% of the variation of the age of the onset of symptoms. The remaining variation is attributed to environment and other genes that modify the mechanism of HD. 36–40 repeats result in a reduced-penetrance form of the disease, with a much later onset and slower progression of symptoms. With very large repeat counts, HD has full penetrance and can occur under the age of 20, when it is then referred to as juvenile HD, akinetic-rigid, or Westphal variant HD. This accounts for about 7% of HD carriers.
  • Symptoms:
    • Usually appear around 35-45 years of age. The earliest symptoms are a general lack of coordination and an unsteady gait. As the disease advances, uncoordinated, jerky body movements become more apparent, along with a decline in mental abilities and behavioral andpsychiatric problems. Physical abilities are gradually impeded until coordinated movement becomes very difficult. Mental abilities generally decline intodementia. Complications such aspneumonia,heart disease, and physical injury from falls reduce life expectancy to around twenty years after symptoms begin.
Huntington Disease Phenocopy
  • Cause: expansion of repeats within the coding region of the PRNP gene, as opposed to the HD gene affected in Huntington Disease proper.
  • Symptoms:
    • According to study guide, the symptoms essentially overlap with Huntington’s Disease.
Kennedy Disease
  • AIS variant
  • Cause: expansion of CAG repeat in exon 1 of the gene for androgen receptor. Causes decreased receptor response.
  • Population/ Inheritance:
    • X-linked recessive: females can act as carriers, and only males are directly affected.
  • Symptoms: form of Androgen Insensitivity Syndrome
    • Also accompanied by late-onset neurodegeneration.
    • Can be misdiagnosed as ALS (amyotrophic lateral sclerosis / Lou Gehrig’s Disease).
Microduplication at 22q11.2
  • Cause: microduplicaiton at 22q11.2
    • Duplication spans about 4 Mb
    • Endpoints are not identical among affected
    • There are multiple repeats that contribute to instability in this region
  • Symptoms:
    • superior placement of eyebrows
    • widely spaced eyes
    • flaring eyebrows
    • mild retrognathia (jaw slightly posterior)
    • long narrow face



Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) [2-5]

  • Cause: mutations in mitochondrial DNA, maternal inheritance.
  • Symptoms: muscle weakness and pain, recurrent headaches, loss of appetite, vomiting. Stroke-like episodes prior to 40, resulting in vision loss, impaired movement, dementia.
  • Treatment: None, high rate of morbidity and mortality.
Muscular Dystrophy
  • Cause:  large deletion in dystrophin gene
    • protein important for making interdigitated actin/myosin in the muscle
    • linear relationship between amount of protein and wellness, a bit of protein is better than none
  • Population/ Inheritance:
    • Severe MD (Duchenne) due to nonsense codon in an exon
      • mutation causes exon skipping, then NMD
      • X-linked
      • Prevalence: 1:3000 according to slides
    • Becker MD: milder, can be ameliorated somewhat
      • caused by nonsense mutation (different exon from severe MD), which causes the affected exon to be skipped
      • make a dystrophin -1 exon
      • get a full-length protein with an internal deletion -> just effective enough
      • Prevalence: 1:30000 global
  • Treatment: potential for treatment with antisense RNA


Myotonic Dystrophy
  • Cause: expansion of CTG repeat ain the DMPK gene, which encodes a myosin kinase expressed in skeletal muscle.
  • Population/Inheritance:
    • Autosomnal dominant and anticipatory:
    • The gene is located on the long arm ofchromosome 19.[7]
    • The number of repeats varies greatly, but the average number in a healthy person is between 5 and 37. The repeat size of an individual with DM1 will become larger usually duringgametogenesis or early embryonic development. Individuals with larger expansions have an earlier onset of the disorder and a more severephenotype.
  • Symptoms: myotonia, including disabling weakness, especially in jaw and facial muscles, drooping eyelids, weakness in hands and lower legs, as well as cognitive impairment.

Osteogenesis Imperfecta

Type I


Symptoms: MILD. blue sclera, near normal height, fractures, hearing loss

Cause: Null COL1A1 allele (dominant)

  • Decreased amt. of normal protein:
  • Mutations in COL1A1 that lead to decreased amounts of normal collagen cause the mild phenotype seen in type I OI.
  • Normally, 2:1 ration of A1 to A2 chains. This disease shows decreased amount of pro-alpha1 chains, so can still make normal amt. of pro-alpha2 chains -> decreased amt. of normal collagen.

Osteogenesis Imperfecta

Type II


Symptoms: Lethal perinatal.
severe bone compression, soft calvarium, blue sclerae, perinatal death

Cause: COL1A1, COL1A2
(new in family/ de novo - some parents are mosaic, can be transmitted more than once)

  • Structural abnormality:
  • Mutations that disrupt the formation of the normal type I collagen triple helix cause the lethal phenotype seen in type IIA OI

Osteogenesis Imperfecta

Type III


Symptoms: Severe, non-lethal.
very short, marked and progressive deformity, blue or normal sclerae, DI (abnormality of dentin in teeth), often non-ambulatory

Cause: COL1A1, COL1A2
(often new in family/de novo)

  • Structural abnormality:
  • COL1A1 and COL1A2 mutations that result in structural protein defects cause moderate

Osteogenesis Imperfecta

Type IV


Symptoms: Moderate.
normal sclerae, mild-moderate short stature, fractures, DI, bone deformity

Cause: COL1A1, COL1A2 (dominant)

Structural abnormality:
COL1A1 and COL1A2 mutations that result in structural protein defects


Osteogenesis Imperfecta

Type VII


Symptoms: severe to lethal


CRTAP (autosomal recessive)

Defect in post-translational modification.
Cartilage-associated protein (CRTAP, gene located at 3p22) deficiency.
Type I collagen with normal primary structure, but excess post-translational modification of the alpha chain helical regions


Osteogenesis Imperfecta




severe to lethal


LEPRE1 (autosomal recessive)

Defect in post-translational modification.
Prolyl-3-hydroxylase-1 (P3H1) is encoded by leprecan-like 1, LEPRE1, located at 1q34. Mutations in LEPRE1 cause OI type VIII

Phenylketonuria (PKU)

  • Cause: Mutation in gene encoding phenylalanine hydroxylase. Body cannot convert phenylalanine into tyrosine.
  • Result: Phenylalanine accumulates in blood, can lead to mental retardation, possibly albinism?
  • Treatment: Dietary restriction of protein, with good results.
Prader-Willi Syndrome
  • Cause: Classic example of genomic imprinting (for boards) - genes are expressed differently depending on which parent they come from
    • Copy number variation (CNV), microdeletion syndrome: deletion of multiple genes at or near 15p12, 7 genes missing or not expressed
    • not always complete penetrance - variability of syndromes
  • Symptoms: neonates exhibit profound hypotonia -> may cause axphyxia, poor sucking, failure to thrive, distinctive cry and facial features.
    • after overcoming feeding difficulties in the first year of life, patients become hyperphagic and obese
    • death around 25-30, usually from diabetes or heart disease



Prion diseases

Transmissible Spongiform Encephalopathies (TSEs)



  • Conformationally altered form of a protein found in normal cells.
  • Mutation in PRNP gene results in mutated PrP protein, which is insoluble and forms amyloid deposits.
  • These deposits seed further conversion to insoluble form. The deposits in the brain interfere with neurological function.

Symptoms: depression, insomnia, dementia, weight loss, wasting

Transmission: familial, sporadic, or infection

Listed human prion diseases: Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler syndrome (GSS), fatal familial insomnia, sporadic fatal insomnia, kuru (infection through cannibalism), variant bovine spongiform encephalopahty (vBSE) aka mad cow disease (infection through ingestion of contaminated beef)

Rheumatoid Arthritis
  • Cause: form of autoimmunity, the causes of which are still incompletely known
  • Population: women 3 times more susceptible than men
    • 1% of world population (onset typically age 40-50)
  • Symptoms: chronic, systemic inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints. Substantial loss of functioning and mobility if not adequately treated.
  • Treatment: glucocorticoids, high dose aspirin
Rubinstein-Taybi Syndrome

  • Cause: haploinsufficiency (only one allele is working) in CREBBP, a HAT
    • No CREBBP = not viable
    • Issue of TRANSCRIPTION -> Activator is only HALF working
    • CREBBP is a HAT (histone acetyletransferase), which acetylates histone and other proteins, which frees DNA for gene transcription
    • CREB Binding Protein is a protein that binds to CREB, which subsequently binds to specific sequences throughout the genome
    • CREB activates transcription of DNA by binding to co-activators. Co-activators respond to cytoplasmic cAMP levels, relayed to nucleus.
    • The interactions between CREB and co-activators are implicated in development as well as mental disability, gluconeogenesis, cancer, and cocaine addiction.
  • Population/ Inheritance: Autosomal dominant
  • Symptoms:
    • Unusual and recognizable faces (eyes, nose, palate) (lopsided, wide-set eyes) (head is a bit small for the body) (nose is a bit too large for the face)
    • Broad thumbs and broad first toes
    • Small height, poor bone growth, small head, overweight
    • Cryptochidism in males (failure of one or both testicles to descend)
    • Mental disability, short attention span, poor coordination
Sickle Cell Disease
  • Cause: single amino acid substitution
    • multiple forms, all lead to “sickling” of RBC’s, leading to circulatory problems.
    • Single letter change in beta-globin molecule : HbS  caused by mutation in B chain at position 6, from Glutamate to Valine (aka “E6V”).
      • Glutamate is highly charged (tends to be on outside of protein); uncharged AAs like Valine tend to be on the inside of the protein. Placing Valine on the outside makes the protein fold inappropriately, distorting the shape of the RBC
    • mutations at other sites can also cause “sickling”
  • Population/Inheritance: autosomal recessive genetic blood disorder with incomplete dominance
    • occurs more commonly in people (or their descendants) from parts of tropical and sub-tropical regions where malaria is or was common
  • Cause: deficiency in synthesis of globin genes due to aberrant RNA splicing.
  • Symptoms: anemia
  • Population/Inheritance:
    • Autosomal recessive.
    • More common in individuals who live in (or whose ancestors lived in) areas with endemic malaria -> north Africa, Italy. Carrier frequency can vary (20-40%)
  • Benefits: Can cause decreased effectiveness of malaria parasite (Plasmodium). Parasite replicates in RBCs during one stage of its life cycle; mutations in globin impair replication. When recessive, mutation provides protection against malaria that can compensate for their deleterious effect on RBC funciton.
  • Treatment:
    • Iron chelation, blood transfusion
    • Prevention: Carrier detection (genetic screening either premarital [Iran] or pre-natal [Cyprus)
Williams-Beuren Syndrome
  • Cause: microdeletion: 7q12, about 25 genes deleted
  • Symptoms:
    • distinctive “elfin” facial appearance, cheerful demeanor, sociability, ease with strangers
    • unpredictable negative outbursts and a predisposition to violent outbursts
    • intellectual disability, paradoxically accompanied by excellent language skills and love of music
    • cardiovascular problems including supravalvular aortic stenosis and transient hypercalcemia
Xeroderma Pigmentosum
  • Cause: deficiency in one of 7 XP alleles in the NER (nucleotide excision repair) pathway (which corrects damage on a single strand DNA - repair of UV damage)
  • Symptoms: freckles, dry and scaly skin, hypopigmentation, cutaneous atrophy.
    • Eventually, premalignant actinic keratoses form in sun-damaged areas.
    • 45% of patients developed basal cell or squamous cell carcinomas by 8 years of age, with 97% of the lesions occurring on the face, head, or neck
  • Population/Inheritance: autosomal recessive.
    • Incidence: 1:250,000
    • Gene Frequency: 1:200
    • 6x more common in Japanese people
  • Treatment: out of sun, totally covered by sunscreen at all times. (not completely effective)
Aplastic anemia

  • Cause: mutations and polymorphisms in hTERT (telomerase gene)
    • failure of bone marrow to produce hematopoietic cells
  • Symptoms: failure to produce red cells, platelets and lymphocytes
Dyskeratosis goncentia
  • Cause:
    • Autosomal dominant: 3q21-28; heritable deletion (hTERC) in telomerase RNA
    • X-linked: defect in dyskerin; dyskerin protein interacts with snoRNAs for rRNA modification (pseudouridylation)
    • Telomere lengths in affected individuals are SHORTER than in normals
  • Symptoms: alopecia; leukoplakia (precancerous oral lesions); abnormal skin pigmentation; nail dystrophy; fibrosis of the lung; cirrhosis of the liver; hypogonadism; failure to produce blood cells
  • Population/Inheritance: 2 types: autosomal dominant or x-linked
Werner Syndrome
  • Cause: deficiency in WRN helicase (protein that helps to CAP the telomere; unwinds G4 DNA to promote replication)
    • impaired replication of telomeres, gradually erode
    • WRN -/- cells: G4 DNA impairs replication -> telomeres shorten
  • Symptoms: Accelerated aging in 2nd decade; genomic instability; graying, baldness, cataracts, diabetes, fat redistribution; sarcomas (usually very rare); early death (50s-60s)
  • Population/Inheritance: autosomal recessive
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