Lysosomal Flashcards
I Cell Disease (MUCOLIPIDOSIS II)
Defect: Lysosomal storage disease – absence M6P protein tag (due to
defected N- acetylglucosamine phosphotransferase in cis golgi)
Mode of Inheritance: Autosomal recessive
Mechanism: The absence of M6P tag results in almost all hydrolytic enzymes secreted extracellularly, rather than being sent to lysosomes to function in degradation!undigested substrates (glycolipids/glycoproteins/GAGs) accumulate in inclusion bodies Characteristics: progressive disease; high levels of acid hydrolases in the blood; skeletal abnormalities, coarse facial features, restricted joint movement, psychomotor retardation, enlarged spleen, liver, & heart valves, death due to CHF or RTI, life expectancy ~10 years Key Words: absence of M6P, lysosomal storage disease, waste products in inclusion bodies, coarse facial features, enlarged liver/spleen, death CHF
Pseudo-Hurler Polydystrophy (MUCOLIPIDOSIS III)
Defect: Lysosomal storage disease - partial dysfunction of N-acetylglucosamine phosphotransferase in cis golgi
Mode of Inheritance: Autosomal recessive
Mechanism: Mild form of I Cell Disease in which pt has partial function of N- acetylglucosamine phosphotransferase!some enzymes are tagged with M6P and get to lysosomes but not enough
Characteristics: later onset than I Cell, survival into adulthood
Hurler Syndrome (MPS IH)
Defect: Lysosomal storage disease - deficiency in alpha-L-iduronidase
Mode of Inheritance: Autosomal recessive
Mechanism: Deficient alpha-L-iduronidase!accumulation of 2 types of GAGs: dermatan sulphate & heparan sulphate
Characteristics: progressive; physical & mental deterioration, hepatosplenomegaly, skeletal deformity, coarse facial features, hirsutism, corneal clouding; death before 10 Key Words: alpha-L-iduronidase, dermatan sulphate & heparan sulphate, hepatosplenomegaly, coarse facial features, skeletal deformity, hirsutism, corneal clouding
Scheie & Hurler-Scheie Syndrome (MPS IS & MPS HIS)
Defect: Lysosomal storage disease - Residual alpha-L-iduronidase Mode of Inheritance: Autosomal recessive
Mechanism: Mild form of Hurler Syndrome so partial breakdown of GAGs Characteristics: Milder form of Hurler Syndrome
Hunter Syndrome (MPS II)
Defect: Lysosomal storage disease - deficiency of iduronodate sulphatase
Mode of Inheritance: X-linked recessive
Mechanism: Deficient iduronodate sulphatase!accumulation of dermatan
sulphate & heparan sulphate (GAGs)
Characteristics: Similar to Hurler, BUT – later presentation (2-4 years old) and milder course, surviving into mid 30s, no corneal clouding
Key words: iduronodate sulphatase, no corneal clouding
**BE ABLE TO DISTINGUISH FROM HURLER - hunter needs to see to aim for the X
Sanfilippo Syndrome (MPS III)
Defect: Lysosomal storage disease - defect in heparan sulphate (GAG) degradation
by other enzymes (type A-D)
Mode of Inheritance: Autosomal recessive
Mechanism: Accumulation of heparan sulfate
Characteristics: normal development until 1-2 years!progressive mental retardation & behavioral disturbance (aggressive, destructive), hearing loss, death late teens/early 20s Key words: aggressive behavior, similar to Hurler
[Note: Hurler is the most severe MPS, but children with Sanfilippo live longer with more severe behavioral problems]
Morquio Syndrome (MPS IV)
Defect: Lysosomal storage disease - defective degradation of keratan sulphate (GAG) Mode of Inheritance: Autosomal recessive
Mechanism: Accumulation of GAG
Characteristics: normal IQ, short stature, pectus carinatum (pigeon chest), aortic regurgitation!cardiomegaly, deafness, weakness
Key words: short, pectus carinatum, normal IQ; Often mistaken for skeletal dysplasia rather than lysosomal storage disease
Maroteaux-Lamy Sydrome (MPS VI)
Defect: Deficient arylsulphatsae B (do not need to memorize for Block III) Mode of Inheritance: Autosomal recessive
Mechanism: Accumulation of GAG
Characteristics: Similar to Hurler, but with normal IQ, corneal opacification Key words: Similar to Hurler with normal IQ
Sly Syndrome (MPS VII)
Defect: Deficient beta-glucoronidase (do not need to memorize for Block III) Mode of Inheritance: Autosomal recessive
Mechanism: Accumulation of GAG
Characteristics: wide variability in severity; different mutations
Chediak-Higashi Syndrome
Defect: Mutation CHS1/LYST (lysosomal trafficking regulatory protein involved in
vesicle fusion)
Mode of Inheritance: Autosomal recessive
Mechanism: Mutated CHS1/LYST: delayed fusion of phagosome with lysosome
in leukocytes & granular defects in NK cells ! recurrent infections; granular defects in platelets!coag. defects; autophagocytosis of melanosomes in melanocytes!albinism Characteristics: Recurrent infections (life threatening), hypopigmentation, mild coagulation defects, varying neurological problems; Treatment = BMT (hematologic & immune defects)
Key words: CHS1/LYST, phagocytosis, autophagocytosis, recurrent infections
Guacher Disease
Defect: Glucocerebroside (sphingolipid)
Mode of Inheritance: Autosomal recessive
Mechanism: Accumulation of glucocerebroside (sphingolipid); mostly occurs in macrophages Characteristics: Similar symptoms to other lysosomal storage diseases, but GAGs are not affected
