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| You will get asked a lysosomal storage disease question on your real USMLE. Memorizing the respective enzyme deficiencies and accumulated substrates is mandatory if you want anything 240s or higher. Gaucher could even be considered 220s truthfully. |
For starters, the USMLE obsesses over which of these conditions are autosomal recessive (AR) vs X-linked recessive (XR).
Make a point to remember that Fabry disease and Hunter syndrome are both XR. The rest are AR.
| For whatever magical reason, the USMLE cares that you know Fabry and Hunter are XR. |
Fabry disease = ↓ α-galactosidase A enzyme= ↑ ceramide trexhoside substrate = XR
The classic presentation on the Step1 is burning pain in the extremities in the setting of kidney or heart problems. Fairly straightforward.
Sometimes they’ll also mention red, non-blanching macules/papules between the umbilicus and knees (angiokeratomas). If they mention any of those findings within the context of a lysosomal storage disease → Fabry disease.
Gaucher disease = ↓ glucocerebrosidase (glucosylceramidase) = ↑ glucocerebroside (glucosylceramide) = AR
The one feature that sets Gaucher apart from the other lysosomal storage diseases is that it causes aseptic necrosis of the femur with bone crisis. If they mention a lysosomal storage disease and then any type of presentation suggesting bone problems, Gaucher is the answer.
The USMLE also loves to mention that macrophages are found to have a “crinkly” or “crumpled tissue paper” appearance. Hepatosplenomegaly, vertebral collapse, anemia, thrombocytopenia and bone infarction are traditional findings.
| How do you treat Gaucher disease? Imiglucerase = recombinant glucocerebrosidase. Not hard, but was asked in a question somewhere. |
The following two I’m grouping together for a reason:
Tay-Sach disease = ↓ hexosaminidase A = ↑ GM2 ganglioside = AR
Niemann-Pick disease = ↓ sphingomyelinase = ↑ sphingomyelin = AR
| Cherry red spot on the macula is seen in BOTH Tay-Sach and Niemann-Pick disease on USMLE Step1. But only Niemann-Pick will have hepatosplenomegaly. The way to remember this is: Niemann-Pick is a longer name than Tay-Sach, and hepatosplenomegaly is a long word, so that’s the one that has HSM. Simple yet revolutionary, I know. |
So in the event that there’s an infant with neuronal degeneration + a cherry-red macula:
| Is hepatosplenomegaly present? No, there’s no HSM → Tay-Sach disease
Is hepatosplenomegaly present? Yes, HSM present → Niemann-Pick disease |
Occasionally, they will also mention foam cells, which are lipid-laden macrophages.
| “Foam” and “Niemann” both have an “m”. |
Metachromatic leukodystrophy = ↓ arylsulfatase A = ↑ cerebroside sulfate = AR
Mention of color change or staining in a lysosomal storage disease question = metachromatic leukodystrophy.
This condition tends to present with overall CNS and PNS demyelination. The vignette may also mention ataxia. The USMLE tends to mention that an infant with neurological dysfunction was found to have macrophages that appeared brown when stained with toluidine blue. Or an infant with neurological dysfunction was found to have macrophages that appeared purple when stained with cresyl violet. Apparently cerebroside sulfate can appear these colors when stained. Not HY, but I mention this disease anyway for the sake of completion and because it inevitably shows up in Qbanks.
Krabbe disease ↓ galactocerebrosidase (galactosylceramidase) = ↑ galactocerebroside (galactosylceramide) + psychosine = AR
| Similar sounding:Fabry = α-galactosidase A deficiency
Krabbe = galactocerebrosidase deficiency Krabbe and galactocerebrosidase both have a b |
USMLE vignettes mention developmental delay and peripheral neuropathy in an infant with optic atrophy. The question might also mention that the infant was found to have globoid cells with linear inclusions inside macrophages. The term “globoid cell” is synonymous with Krabbe disease on Step1.
| USMLE question writers like to see that you can differentiate Hurler vs Hunter syndromes. |
As said before, Hunter syndrome and Fabry disease are both XR. That means if you’re ever confronted with the genetics of Hurler vs Hunter syndrome:
“Hunters can shoot the target (X) with their arrows.” Therefore Hunter must be the one that’s XR, and Hurler AR.
Hurler syndrome = ↓ α-L-iduronidase = ↑ heparan sulfate + dermatan sulfate = AR
Hurler syndrome presents with clouded corneas, gargoyle-like facies, stridor (due to airway obstruction), frequent ear infections, valvular lesions and hepatosplenomegaly.
Hunter syndrome = ↓ iduronate sulfatase = ↑ heparan sulfate + dermatan sulfate = XR
Hunter syndrome presents generally as a milder version of Hurler and without clouded corneas. Remember, not only can hunters see their target (XR), but because they can literally see it, they don’t have clouded corneas.
| Does the infant have clouded corneas? Yes, has clouded corneas → Hurler syndrome (AR)
Does the infant have clouded corneas? No, does not have clouded corneas. → Hunter syndrome (XR) |
I-cell disease = ↓ mannose-6-phosphate production = AR
Don’t worry about the enzyme deficiency for I-cell disease. They just want you to know it’s a syndrome that presents in a child as coarse facial features and stiff joints, where there’s decreased ability to phosphorylate the 6th position on mannose.
This phosphorylation leads to failure to target hydrolases to the lysosomes. Therefore in this disease, if the vignette is obviously I-cell disease, the answer might be: increased lysosomal hydrolases in the plasma.
| An important factoid for I-cell disease is that whilst it’s technically a lysosomal storage disease, the failure of M6P production occurs in the Golgi apparatus. If they ask you the organelle associated with I-cell disease, the answer is Golgi, not lysosomes! |
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