Diseases! Flashcards
Ashkenazi Jewish descent lysosomal storage diseases
GTP:
Gaucher disease
Tay-Sachs disease
Niemann-Pick disease type A
autosomal recessive
X-linked lysosomal storage diseases
Danon, you are a Fabulous Hunter! (X)
Danon (X-linked dominant)
Fabry
Hunter’s
Tay-Sachs disease
- autosomal recessive
- beta-hexosaminidase A deficiency –> accumulation of GM2 ganglioside –> progressive neurodegeneration
- cherry-red macula, blindness, delayed development, seizures
- no hepatosplenomegaly
- whorled configurations within lysosomes (onion-skin layers of membranes)
Sandhoff’s disease
- similar to Tay-Sachs disease, also due to deficiency in beta-hexosaminidase A/B –> accumulated GM2 ganglioside
- YES hepatosplenomegaly
Niemann-Pick disease
- autosomal recessive
- deficincy in sphingomyelinase –> sphingomyelin accumulation in cell membrane
- progressive neurologic deterioration, cherry-red macula, lungs affected, hepatosplenomegaly
- foam cells
Gaucher disease
- autosomal recessive
- deficiency in beta-glucocerebrosidase –> accumulation of glucocerebroside
- Erlenmayer flask distal femur, hepatosplenomegaly, blood abnormalities (anemia, thrombocytopenia), lung disease
- macrophages with wrinkled paper appearance
Fabry disease
- X-linked recessive
- deficiency in alpha-galactosidase A –> accumulation of globotriaosylceramide (aka ceramide trihexoside, a glycolipid)
- angiokeratomas (small red dots), hypohidrosis, dysesthesia (pinprick pain), neuropathy, GI problems, hearing problems
Danon disease
- X-linked dominant
- deficiency in lysosome-associated membrane protein 2 (LAMP-2) –> accumulation of cytoplasmic debris and glycogen
- cardiomyopathy, skeletal myopathy, mental retardation
Hunter disease
Mucopolysaccharidosis (MPS) Type II
- X-linked recessive
- deficiency in iduronate-2-sulphatase (I2S) –> accumulation of dermatan sulfate, heparan sulfate
- progressive deterioration, coarse facial features, enlarged tongue, hearing loss, abnormal dentition, skeletal deformities, clawed hands, hepatosplenomegaly, cardiomyopathy, severe short stature
- NO corneal clouding
Hurler disease
Mucopolysaccharidosis (MPS) Type I
- autosomal recessive
- deficiency in alpha-L-iduronidase –> accumulation of dermatan sulfate, heparan sulfate
- umbilical/inguinal hernas often present at birth
- progressive deterioration, dwarfism, hepatosplenomegaly, coarse facial features, skeletal deformities, large tonge
- YES corneal clouding
Farber disease
Farber lipogranulomatosis
- autosomal recessive
- deficiency in acid ceramidase –> accumulation of ceramide
- hoarse voice/weak cry, lipogranulomas (small lumps of fat under skin), swollen and painful joints with progressive joint deformities
- breathing problems, hepatosplenomegaly, developmental delay
Krabbe disease
globoid cell leukodystrophy
- autosomal recessive
- deficiency in beta-galactosylceramidase –> accumulation of galactosylceramide (galactocerebroside)
- irritability, failure to thrive, progressive muscle weakness, slowed mental/physical development, hearing loss, vision loss, seizures
- abnormal presence of globoid cells
Metachromatic Leukodystrophy
- autosomal recessive
- Cerebroside sulfate accumulation in neural and non-neural tissue → progressive demyelination of the central and peripheral nervous system
- Motor regression and developmental delay, ataxia, optic nerve atrophy → loss of vision, flaccid paralysis followed by spastic paralysis
I-Cell disease
mucolipidosis II
- autosomal recessive
- deficiency in N-acetylglucosamine-1-phosphotransferase –> accumulation of oligosaccharides, glycosaminoglycans, lipids (mannose phosphate)
- hypotonia, developmental delay, limited mobility, clubfeet, thickened skin, short hands/fingers, gingival hypertrophy
- heart valve abnormailities, repeated respiratory infections
Patau syndrome
- trisomy 13
- low birth weight, cleft lip/palate, hypotelorism (decreased distance between eyes), CNS anomaly, polydactyly, rocker bottom feet
Edwards syndrome
- triosmy 18
- low birth weight, prominent occiput, tightly clenched fists with overlapping fingers, clubfoot, rocker bottom feet, heart defects, CNS abnormalities
Down syndrome
- trisomy 21
- hypotonia, characteristic facial features, developmental delay, heart/GI defects
Turner syndrome
- monosomy X (45, X)
- short stature, amenorrhea, lack of secondary sexual development, infertility, learning disabilities
Klinefelter syndrome
- 47,XXY
- small testes, infertility, gynecomastia (overdevelopment of breast tissue in males), tall stature, hearing problems, learning disabilities
DiGeorge syndome
- 22q11.2 microdeletion
- craniofacial anomalies, intellectual disability, immunodeficiency, heart defects, absence of parathyroids/thymus
Williams syndrome
- 7q11.23 deletion
- low birth weight, mild-moderate intellectual disability, distinctive facial features, cardiovascular problems, friendly outgoing personality
Cri du chat syndrome
- microdeletion of the short arm at chromosome 5 (46,XX,5p- or 46,XY, 5p‑)
- Cat-like high-pitched crying in affected infants, congenital heart defects (e.g., VSD) microcephaly, intellectual disability (moderate to severe), single palmar crease, dysmorphic facial features
Prader-Willi syndrome
- 15q11.2-q13 deletion on paternal chromosome OR maternal uniparental disomy
- neonatal hypotonia, obesity, excessive eating habits, small hands/feet, short stature, hypogonadism, intellectual disability
Prader misses his papa
Angelman syndrome
- 15q11.2-q13 deletion on maternal chromosome OR paternal uniparental disomy OR UBE3A gene mutations
- distinct facial appearance, short stature, severe intellectual disability, spasticity, seizures
Angel misses her mama
Fragile X syndrome
- CGG repeat expansion in 5’UTR of FMR1 gene
- X-linked dominant
- moderate intellectual disability, long narrow face with large ears, macrocephaly, macroorchidism (abnormally large testes), flexible joints
Fragile X has X-tra large ears, testes, dominant
fragile, CGG repeat
Friedreich ataxia
- GAA repeat expansion in intron of FXN gene
- autosomal recessive
- unsteady movements, impaired sensory functions, hesitant/slurred speech, heart disease, diabetes
ataxia, GAA repeat
Huntington disease
- CAG repeat expansion in exon of HD(HTT) gene
- autosomal dominant with paternal transmission bias
- motor abnormalities, personality changes, gradual loss of cognition
Hunting cags
myotonic dystrophy 1
- CTG repeat expansion in 3’UTR of DMPK gene
- autosomal dominant
- muscle wasting/weakness, myotonia, facial features, cardiac conduction defects, hormonal changes, cataracts
Rett syndrome
- mutations in MECP2 gene
- X-linked dominant
- language/communication problems, brain function problems, loss of purposeful hand use (hand wringing, washing, clapping), slow growth, microcephaly
Rett, hand wringing
Ehler-Danlos syndrome
- pathogenic mutations in at least 20 genes
- most common: classical form caused by variants of COL5A1 or COL5A2 genes
- classical form is autosomal dominant
- hypermobility, hypotonia, highly elastic and fragile skin, easy bruising, unusual scarring, pseudotumors, ocular defects
Marfan syndrome
- mutations in FBN1 (fibrillin) gene
- autosomal dominant
- tall and slender, elongated fingers/toes, loose joints, vision problems, risk of aortic aneurysm
Osteogenesis imperfecta
- collagen 1 gene mutation
- defective collagen synthesis: blue sclera, bone fractures, osteoporosis
Von Gierke disease
- Mechanism: glucose-6-phosphatase
- Symptoms/Features: Lactic acidosis, severe hypoglycemia that does not resolve until carb intake, hyperuricemia, impaired growth (liver issues)
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Pompe disease
- Mechanism: acid α-glucosidase; acid maltase
- Symptoms/Features: All organs affected, but especially the muscles. Excess glycogen in lysosomes. Normal blood sugar. Enlarged liver and heart. Progressive muscle weakness and heart problems in severe forms.
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Cori disease
Mechanism: glycogen debranching enzyme
Symptoms/Features: Enlarged liver, growth delay, fasting hypoglycemia that resolves over time, abnormal glycogen structure (short branches), progressive muscle weakness
Andersen disease
Mechanism: glycogen branching enzyme
Symptoms/Features: Growth delay, progressive cirrhosis, enlarged liver, mypoathy. Death by age 5 usually.
McArdle disease
Mechanism: muscle glycogen phosphorylase
Symptoms/Features: Muscle weakness and cramping after exercise (from birth), rhabdomyosis. Usually a relatively benign, chronic condition.
Hers disease
Mechanism: liver glycogen phosphorylase
Symptoms/Features: Liver enlargement, hypoglycemia that resolves over time, developmental delay.
Tarui disease
Mechanism: muscle phosphofructokinase
Symptoms/Features: Exercise-induced muscle cramps, developmental delay, hemolytic anemia in some.
Pyruvate dehydrogenase complex deficiency
Mechanism: pyruvate dehydrogenase complex (PDC)
Symptoms/Features: Congenital lactic acidosis due to pyruvate not being converted to acetyl CoA and being shunted to lactate instead. Neurodegeneration, muscle spasticity, early death in neonatal onset form.
Treatment: dietary restriction of carbohydrate, supplementation with thiamine
Beriberi disease
Mechanism: thiamine
Symptoms/Features: Damage to peripheral nervous system: pain in limbs, muscle weakness, abnormal skin sensation. Heart enlargement with inadequate cardiac output.
Notes: related to malnutrition, occasionally seen in alcoholics
Wernicke-Korsakoff syndrome
Mechanism: thiamine
Symptoms/Features: Wernicke’s encephalopathy, confusion, changes in vision
Notes: found in chronic alcoholism or other conditions that impair thiamine absorption
Leigh disease
Mechanism: pyruvate carboxylase
Symptoms/Features: Subacute necrotizing encephalomyelopathy, early-onset progressive neurodegenerative diosrder. Includes mild-to-moderate lactic acidemia. Progressive loss of mental and movement abilities, typically results in death within a couple of years usually due to respiratory failure.
PFK1 deficiency
Mechanism: phosphofructokinase 1
Symptoms/Features: Exercise intolerance: muscle cramps, weakness, fatigue. Myopathy: muscle weakness and wasting. Rhabdomyolysis, hemolytic anemia, enlarged liver, elevated creatine kinase.
Pyruvate kinase deficiency
Mechanism: pyruvate kinase
Symptoms/Features: Hemolytic anemia, jaundice due to bilirubin release from RBC destruction, pale skin, lethargy, easy fatigue, enlarged spleen. Spiculated RBCs.
GLUT1 deficiency
Mechanism: GLUT1
Symptoms/Features: Seizures, headaches and neurological symptoms, microcephaly, anemia
Primary carnitine deficiency; carnitine uptake defect (CUD)
Mechanism: L-carnitine transporter OCTN2
Symptoms/Features: Metabolic decompensation in infancy: hypoketotic hypoglycemia, hepatomegaly. Childhood myopathy involving heart and skeletal muscles. Fatigability in adulthood.
Treatment: carnitine supplementation and low fat diet, avoidance of LCFA
CACT; CPT1; CPT2 deficiencies
Mechanism: carnitine acylcarnitine translocase;
carnitine palmitoyl-transferase I;
carnitine palmitoyl-transferase II
Symptoms/Features: Hypoketotic hypoglycemia, hyperammonemia, hepatomegaly, cardiomyopathy, myoglobinuria
Treatment: high-carb diet that is low in fat; carnitine supplementation
MCAD deficiency
Mechanism: medium chain acyldehydrogenase
Symptoms/Features: Liver dysfunction due to inability to oxidize medium chain fatty acids. Dicarboxylic acids from omega-oxidation increase. Hypoketotic hypoglycemia due to impairment of gluconeogenesis in liver. Hyperammonemia.
Treatment: frequent carb intake
LCAD deficiency
Mechanism: long chain acyldehydrogenase
Symptoms/Features: Damage to liver, heart, retina, muscles. Hyperammonemia.
Propionic acidemia
Mechanism: proprionyl CoA carboxylase
Symptoms/Features: Early neonatal period: progressive encephalopathy and damage to heart and liver, seizures, developmental delays
Treatment: strict dietary regime, biotin supplementation
Methylmalonic aciduria
Mechanism: methylmalonyl CoA mutase;
defects in B12 metabolism
Symptoms/Features: Infants become ill on protein feeding and develop lethagy, failure to thrive, muscular hypotnia, respiratory distress, vomiting, dehydration
Treatment: protein restriction
Zellweger syndrome
Mechanism: peroxisome biogenesis
Symptoms/Features: Primarily affects liver and brain. Usually fatal by age 1. Profound hypotonia, feeding problems, profound mental retardation, seizures, hearing/vision loss, liver and kidney disease, chondrodyplasia punctata (scattered calcification at end of long bones and knee). Distinctive facial features: flattened face, broad nasal bridge, high forehead.
Adrenoleukodystrophy
Mechanism: ABC, ABCD1 transporters (VLFCA)
Inheritance Pattern: X-linked
Symptoms/Features: Progressive neurodegenerative decline, leading to a vegetative state without treatment. Loss of vision, behavior disturbances, lethal at young age. Affects nervous system (myelin) and adrenal cortex.
Treatment: Lorenzo’s oil
Refsum disease
Mechanism: phytanic acid alpha-oxidation
Symptoms/Features: Retinitis pigmentosa, cerebellar ataxia, polyneuropathy
Treatment: avoid plant FA
Complex III inhibition
Mechanism: ETC Complex III inhibition:
antimycin or mutations
Inheritance Pattern: homozygous recessive
Symptoms/Features: Growth retardation, amino aciduria, cholestasis, iron overload, lactic acidosis, early death.
Complex IV inhibition
Mechanism: ETC Complex IV inhibition:
cyanide, carbon monoxide, sodium azide
Symptoms/Features: Irreversible inhibition of ETC; death.
Uncoupling agents
Mechanism: ETC uncoupling agents:
dinitrophenol (DNP), FCCP
Symptoms/Features: Heat: sweating, fever. Dizziness, nausea.
Leber’s hereditary optic neuropathy
Mechanism: NADH:CoQ Oxidoreductase (Complex I) mutation
Inheritance Pattern: mtDNA
Symptoms/Features: Blindness that strikes in midlife.
Methemoglobinemia
Mechanism: elevated levels of methemoglobin:
can be inherited (congenital) or acquired (exogenous oxidizing drugs)
Symptoms/Features: Chocolate-brown colored arterial blood. Cyanosis, shortness of breath, mental status changes, headache, fatigue, exercise intolerance, dizziness, loss of concsiousness.
Treatment: methylene blue dye
Sickle cell disease (NORD)
Mechanism: Hemoglobin A –> Hemoglobin S (point mutation)
- increased 2,3-diphosphoglycerate (DPG) levels in HbS, leads to decreased O2 affinity ==> RBCs unload O2 and sickle when deoxygenated
Inheritance Pattern: homozygous recessive
Symptoms/Features: Sickling of RBCs. Painful episodes of vaso-occlusive crisis, spleenic crisis, aplastic crisis, sequestration crisis, hemolytic crisis, acute chest syndrome.
Treatment: Hydroxyurea (increase HbF), blood transfusions, blood marrow trasnplants, avoiding cold temperatures.
Alpha/Beta thalassemia
Mechanism: Alpha: HbH, HbBart
Beta: HbF, HbA2
Symptoms/Features: Microcytic anemia (small RBCs), susceptible to iron overload, increased risk of infection, bone deformities, enlarged spleen.
Treatment: Avoiding iron overload, iron chelators, blood transfusions, bone marrow transplants.
Patau syndrome
Mechanism: Trisomy 13
Symptoms/Features: Low birth weight, cleft lip/palate, hypotelorism, severe CNS anomaly, polydactyly, rocker bottom feet, renal anomalies.
Notes: >90% of affected infants die within 1 year.
Edwards syndrome
Mechanism: Trisomy 18
Symptoms/Features: Low birth weight, prominent occiput, tightly clenched fists with overlapping fingers, clubfoot, rocker bottom feet, CNS anomalies, heart defects
Notes: >90% of affected infants die within 1 year.
Down syndrome
Mechanism: Trisomy 21
Symptoms/Features: Hypotonia, characteristic facial features, developmental delay, heart/GI defects, increased risk of childhood respiratory infection and leukemia, adults at risk of early onset Alzheimer disease
Turner syndrome
Mechanism: Monosomy X (45, X)
Symptoms/Features: Short stature, amenorrhea, lack of secondary sexual development, infertility, coarctation of aorta, lymphedema at birth, webbing of neck, learning disabilities
Klinefelter syndrome
Mechanism: 47, XXY
Symptoms/Features: Small testes, infertility, gynecomastia, tall stature, hearing problems, learning disabilities
DiGeorge syndrome
Mechanism: 22q11.2 microdeletion
Symptoms/Features: Craniofacial anomalies, intellectual disability, immunodeficiency, heart defects, absence of parathyroids and thymus
Williams syndrome
Mechanism: 7q11.23 deletion
Symptoms/Features: Low birth weight, mild to moderate intellectual/learning disability, distinctive facial features (broad forehead, small chin), cardiovascular problems, friendly outgoing personality
Prader-Willi syndrome
Mechanism: 15q11.2-q13 deletion on paternal chromosome or materinal uniparental disomy
Symptoms/Features: Neonatal hypotonia, obesity, excessive and indiscriminate eating habits, small hands and feet, short stature, hypogonadism, intellectual disability
Angelman syndrome
Mechanism: 15q11.2-q13 deletion on maternal chromosome or parental uniparental disomy or UBE3A gene mutations
Symptoms/Features: distinct facial appearance, short stature, severe intellectual disability, spasticity, seizures
Fragile X syndrome
Mechanism: CGG repeat expansion in 5’UTR of FMR1 gene
Inheritance Pattern: X-linked
Symptoms/Features: Moderate intellectual disability, long narrow face with large ears, macrocephaly, macro-orchidism, flexible joints
Notes: Most common heritable form of moderate intellectual disability
Friedreich ataxia
Mechanism: GAA repeat expansion in intron of FXN gene
Inheritance Pattern: autosomal recessive
Symptoms/Features: unsteady movements, impaired sensory functions, hesitant/slurred speech, heart disease, diabetes
Tuberculoid leprosy
Mechanism: Mycobacterium leprae infection
Symptoms/Features: low infectivity; granulomas and local inflammation, peripheral nerve damage; normal serum immunoglobulin levels, normal T-cell responsiveness
proper Th1 response
Lepromatous leprosy
Mechanism: Mycobacterium leprae infection
Symptoms/Features: high infectivity; organisms show florid growth in macrophages; disseminated infection in bone, cartilage, diffuse nerve damage; hypergammaglobulinemia, low/absent T-cell responsiveness
improper Th2 response
Hunter disease (MPS II)
Mechanism: Iduronate-2-sulphatase deficiency
Inheritence pattern: X-linked recessive
Symptoms/Features: Progressive deterioration, coarse facial features, enlarged tongue, hearing loss, abnormal dentition, dysostosis multiplex, joint stiffness, contractures leading to clawing of the hands, hepatosplenomegaly, cardiomyopathy, severe short stature
Kwashiorkor
Mechanism: protein deficient diet
Symptoms/Features: skin lesions, pitting edema (decreased albumin), subcutaneous fat preserved, enlarged fatty liver, lethargy, absent/mild muscle wasting, poor appetite
insufficient protein in diet = lack of protein synthesis in liver
Marasmus
Mechasism: protein and caloric deficient diet
Symptoms/Features: tissue and muscle wasting, subcutaneous fat not preserved, alert and irritable, voracious appetite
