An 18-month-old girl is brought to the pediatrician’s office for failure to thrive and developmental delay. The patient’s mother says she has not started speaking and is just now starting to pull herself up to standing position. Furthermore, her movement appears to be restricted. Physical examination reveals coarse facial features and restricted joint mobility. Laboratory studies show increased plasma levels of several enzymes. Which of the following is the underlying biochemical defect in this patient?

Failure of mannose phosphorylation

Congenital lack of lysosomal formation

Inappropriate protein targeting to endoplasmic reticulum

Inappropriate degradation of lysosomal enzymes

A 4-week-old infant is brought to the physician by his mother because of blood-tinged stools for 3 days. He has also been passing whitish mucoid strings with the stools during this period. He was delivered at 38 weeks' gestation by lower segment transverse cesarean section because of a nonreassuring fetal heart rate. He was monitored in the intensive care unit for a day prior to being discharged. His 6-year-old brother was treated for viral gastroenteritis one week ago. The patient is exclusively breastfed. He is at the 50th percentile for height and 60th percentile for weight. He appears healthy and active. His vital signs are within normal limits. Examination shows a soft and nontender abdomen. The liver is palpated just below the right costal margin. The remainder of the examination shows no abnormalities. Test of the stool for occult blood is positive. A complete blood count and serum concentrations of electrolytes and creatinine are within the reference range. Which of the following is the most appropriate next step in management?

Continue breastfeeding and advise mother to avoid dairy and soy products

Perform stool antigen immunoassay

Perform an air enema on the infant

Assess for IgA (anti‑)tissue transglutaminase antibodies (tTG)

Stop breastfeeding and switch to soy-based formula

A 4-month-old boy is brought to the emergency department by his mother because of lethargy and vomiting since he woke up 1 hour ago. The mother says that he last breastfed the previous evening and slept through the night for the first time. His family recently immigrated from Bolivia. His temperature is 38.7°C (101.2°F). Physical examination shows dry mucous membranes and enlarged, reddened tonsils. Serum studies show: Glucose 42 mg/dL Ketones 0.2 mg/dL N = < 1 mg/dL AST 40 U/L ALT 60 U/L Ammonia 80 μ/dL (N=15–45) Which of the following enzymes is most likely deficient in this patient?

Medium-chain acyl-CoA dehydrogenase

Galactose-1-phosphate uridyltransferase

Lysosomal acid α-1,4- glucosidase

A 6-month-old boy is referred to a geneticist after he is found to have persistent hypotonia and failure to thrive. He has also had episodes of what appears to be respiratory distress and has an enlarged heart on physical exam. There is a family history of childhood onset hypertrophic cardiomyopathy, so a biopsy is performed showing electron dense granules within the lysosomes. Genetic testing is performed showing a defect in glycogen processing. A deficiency in which of the following enzymes is most likely to be responsible for this patient's symptoms?

Lysosomal alpha 1,4-glucosidase

Mucopolysaccharidoses for USMLE Step 1: High-Yield Biochemistry Lessons

MPS Basics - GAGs Gone Wrong

Pathophysiology: A group of lysosomal storage diseases caused by deficient enzymes that degrade glycosaminoglycans (GAGs).
Accumulation: Leads to GAGs building up in lysosomes, causing multisystem cellular damage.
Major GAGs Involved:
- Dermatan sulfate
- Heparan sulfate
- Keratan sulfate
- Chondroitin sulfate

⭐ All mucopolysaccharidoses are autosomal recessive, except for Hunter syndrome, which is X-linked recessive.

MPS Syndromes - A Rogues' Gallery

Syndrome (MPS Type)	Deficient Enzyme	Accumulated GAG(s)	Key Clinical Features
Hurler (MPS I-H)	α-L-iduronidase	Heparan sulfate, Dermatan sulfate	- Severe course - Corneal clouding - Gargoylism, Dysostosis multiplex - Hepatosplenomegaly - Developmental delay
Scheie (MPS I-S)	α-L-iduronidase	Heparan sulfate, Dermatan sulfate	- Mild course - Corneal clouding - Stiff joints, Aortic valve disease - Normal intelligence & lifespan
Hurler-Scheie (I-H/S)	α-L-iduronidase	Heparan sulfate, Dermatan sulfate	- Intermediate phenotype - Corneal clouding - Mild/no intellectual disability - Dysostosis multiplex
Hunter (MPS II)	Iduronate-2-sulfatase	Heparan sulfate, Dermatan sulfate	- X-linked Recessive - NO corneal clouding - Aggressive behavior, ID - Dysostosis multiplex - 📌 Hunters see clearly (no corneal clouding) and aim for the X (X-linked).
Sanfilippo (MPS III)	4 different enzymes (A-D) involved in Heparan sulfate degradation	Heparan sulfate	- Severe CNS involvement - Mild somatic features - Progressive intellectual disability, aggression, hyperactivity
Morquio (MPS IV)	Galactose-6-sulfatase (A) or β-galactosidase (B)	Keratan sulfate, Chondroitin-6-sulfate	- Severe skeletal dysplasia (short trunk dwarfism) - Normal intelligence - Corneal clouding - Atlanto-axial instability

Diagnosis & Management - Clues & Cures

Enzyme Replacement Therapy (ERT): Regular infusions to replace the deficient lysosomal enzyme, improving somatic but not typically CNS symptoms.
Hematopoietic Stem Cell Transplantation (HSCT): Standard of care for severe MPS I (Hurler) if performed before age 2.5. Can preserve neurocognition.
Supportive/Symptomatic Care: Multidisciplinary approach for cardiac, airway, and orthopedic issues.

⭐ Hunter syndrome (MPS II) is X-linked recessive, distinguishing it from the other autosomal recessive MPS types. 📌 Mnemonic: "Hunters aim for the X."

Core defect: Deficient lysosomal enzymes for glycosaminoglycan (GAG) degradation, leading to accumulation.

Inheritance pattern: All are autosomal recessive except for the X-linked Hunter syndrome.

Clinical features: Coarse facial features (gargoylism), dysostosis multiplex, and hepatosplenomegaly are common.

Hurler syndrome (MPS I): Caused by α-L-iduronidase deficiency; presents with corneal clouding.

Hunter syndrome (MPS II): Caused by iduronate-2-sulfatase deficiency; distinguished by NO corneal clouding.

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