Which one of the following diseases is classified as an autosomal dominant disorder?

Maturity onset diabetes of the young

Glucose-6 phosphate dehydrogenase deficiency

A patient presents with an X-ray showing cardiomegaly, along with symptoms of hypotonia, macroglossia, hepatomegaly, and floppy baby syndrome. The X ray of the infant is shown below. What is the most likely diagnosis?

Transposition of great arteries

Which of the following statements about Niemann-Pick disease is false?

Type B Niemann-Pick disease is characterized by severe neurological symptoms.

Due to deficiency of sphingomyelinase.

CNS symptoms are present in type A.

Histiocytes show PAS positive inclusions, and Type A is more severe.

An 8-month-old infant is brought in with poor feeding, lethargy, hypotonia, and hepatomegaly. Labs reveal hypoglycemia and metabolic acidosis. Which condition is most likely?

Hereditary fructose intolerance

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency

Lysosomal Storage Diseases for USMLE Step 1: High-Yield Psychiatry Lessons

LSDs Overview - Tiny Trash Troubles

Definition: Group of ~70 inherited metabolic disorders. Caused by defects in lysosomal enzymes or essential proteins, leading to lysosomal dysfunction.
Pathophysiology: Specific enzyme deficiency → progressive accumulation of undigested macromolecules (e.g., sphingolipids, mucopolysaccharides, glycogen) within lysosomes → cellular engorgement, organomegaly, and widespread systemic damage.
Inheritance: Mostly Autosomal Recessive (AR).

⭐ Most LSDs are Autosomal Recessive. Notable X-linked Recessive exceptions include Fabry Disease and Hunter Syndrome (MPS II).

MPS Disorders - Sugar Storage Saga

MPS Type	Enzyme Def.	Accum. GAG(s)	Features	Inh.
IH	α-L-iduronidase	H, D $SO_4$	Coarse facies, cornea, dysostosis, CNS↓	AR
II	Iduronate sulfatase	H, D $SO_4$	Coarse facies, NO cornea, dysostosis, aggression	XR
III	Heparan N-sulfatase	H $SO_4$	Severe CNS↓, mild somatic	AR
IV	Gal-6-sulfatase	K, C-6 $SO_4$	Skeletal (short trunk), normal IQ, cornea	AR
VI	Arylsulfatase B	D $SO_4$	Coarse facies, cornea, dysostosis, normal IQ	AR
VII	β-glucuronidase	H, D, C $SO_4$	Variable: hydrops, HSM, dysostosis	AR

⭐ Hunter (MPS II): X-linked, NO corneal clouding (vs Hurler).

Sphingolipidoses - Fatty Brain Breakdown

Disease	Enzyme Deficient	Accumulated Substrate	Key Features	Inheritance
Tay-Sachs	Hexosaminidase A	GM2 ganglioside	Cherry-red spot, neurodegeneration, onion-skin lysosomes. 📌 Tay-SaX lacks heXosaminidase A.	AR
Niemann-Pick (Type A/B)	Sphingomyelinase	Sphingomyelin	Cherry-red spot (Type A), HSM, foam cells.	AR
Gaucher	Glucocerebrosidase	Glucocerebroside	HSM, pancytopenia, bone crises, Gaucher cells (crumpled tissue paper). 📌 Gaucher - Glucocerebrosidase.	AR
Fabry	α-galactosidase A	Ceramide trihexoside	Peripheral neuropathy, angiokeratomas, renal failure.	XLR
Krabbe	Galactocerebrosidase	Galactocerebroside, psychosine	Peripheral neuropathy, optic atrophy, globoid cells.	AR
Metachromatic Leukodystrophy	Arylsulfatase A	Sulfatides	Demyelination (central & peripheral), ataxia, dementia.	AR

⭐ Cherry-red spot on macula is seen in Tay-Sachs disease and Niemann-Pick disease type A.

Other Notable LSDs - Rare & Remembered

Pompe Disease (GSD Type II)
- Enzyme: Acid $\alpha$-glucosidase
- Substrate: Glycogen (lysosomal)
- Key: Massive cardiomegaly, profound hypotonia, hepatomegaly. "Floppy infant".
I-cell Disease (Mucolipidosis II)
- Enzyme: N-acetylglucosamine-1-phosphotransferase
- Substrate: Lysosomal enzymes mis-targeted (↑ in plasma)
- Key: Coarse facies, skeletal dysplasia, gingival hyperplasia, developmental delay.
- ⭐ I-cell disease: Deficiency of N-acetylglucosamine-1-phosphotransferase leads to mis-targeting of lysosomal enzymes.
Wolman Disease
- Enzyme: Acid lipase
- Substrate: Cholesterol esters, triglycerides
- Key: Bilateral adrenal calcification, hepatosplenomegaly, FTT, early death.
Cholesterol Ester Storage Disease (CESD)
- Enzyme: Acid lipase (milder)
- Substrate: Cholesterol esters, triglycerides
- Key: Hepatomegaly, hyperlipidemia, cirrhosis; later onset_

LSDs Dx & Rx - Spot & Support

Dx: Clinical suspicion → Enzyme assays / Genetic tests (confirmatory, PND). Newborn screening (some LSDs).
Rx: ERT, SRT, HSCT, Chaperones. Supportive care crucial. Gene therapy investigational.

⭐ ERT is available for several LSDs (e.g., Gaucher, Fabry, Pompe, MPS I, II, VI) but often has limited efficacy for CNS manifestations due to the blood-brain barrier.

High‑Yield Points - ⚡ Biggest Takeaways

LSDs: Enzyme defects lead to lysosomal substrate accumulation.

Gaucher disease: Most common; glucocerebrosidase deficiency; crumpled tissue paper cells, hepatosplenomegaly.

Tay-Sachs disease: Hexosaminidase A defect; cherry-red spot, neurodegeneration, no hepatosplenomegaly.

Niemann-Pick disease: Sphingomyelinase deficiency; foam cells, cherry-red spot, marked hepatosplenomegaly.

Fabry disease: X-linked recessive; α-galactosidase A defect; angiokeratomas, peripheral neuropathy, renal failure.

Mucopolysaccharidoses (MPS): Defective glycosaminoglycan (GAG) breakdown; e.g., Hurler syndrome (corneal clouding), Hunter syndrome (X-linked, no corneal clouding).

Pompe disease: Acid α-glucosidase (acid maltase) defect; cardiomegaly, profound hypotonia, muscle weakness.

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Lysosomal Storage Diseases