Lysosomal storage diseases

Lysosomal storage diseases US Medical PG Question 1: An 18-month-old boy is brought in by his parents for a routine check-up. The parents state that the patient still has not had any language development, and they are concerned about developmental delay. Of note, they have also noticed that the patient’s facial features have changed significantly in the last year. The patient also seems to have trouble visually focusing on objects or on the television. On exam, the patient's temperature is 98.2°F (36.8°C), blood pressure is 108/72 mmHg, pulse is 86/min, and respirations are 14/min. Of interest, the patient has not increased much in length or weight in the past 3 months. He is now in the 25th percentile for weight but is in the 90th percentile for head circumference. The patient does not appear to have any gross or fine motor deficiencies. Of note, he has coarse facial features that were not previously noted, including a long face, prominent forehead, and protruding eyes. The patient has corneal clouding bilaterally. At rest, the patient keeps his mouth hanging open. After extensive workup, the patient is found to have 2 mutated copies of the IDUA gene, with no production of the protein iduronidase. Which of the following is the likely mutation found in this disease?

• A. Interstitial deletion
• B. Silent mutation
• C. Missense mutation
• D. Chromosomal translocation
• E. Nonsense mutation (Correct Answer)

Lysosomal storage diseases Explanation: ***Nonsense mutation*** - A **nonsense mutation** leads to the formation of a **premature stop codon**, resulting in a truncated, non-functional protein, which aligns with the total absence of iduronidase. - This type of mutation can severely impair protein function, leading to the severe phenotype described with **Hurler syndrome**, which is caused by a complete lack of **alpha-L-iduronidase** activity due to mutations in the *IDUA* gene. *Interstitial deletion* - An **interstitial deletion** involves the loss of a segment of a chromosome; while it can cause genetic disorders, it typically results in the **complete absence of a gene** or multiple genes, not specific protein truncation from a gene sequence. - Though a deletion in the *IDUA* gene could cause Hurler syndrome, the specific finding of **no production of the protein iduronidase** suggests a point mutation affecting protein synthesis rather than a large chromosomal deletion. *Silent mutation* - A **silent mutation** is a change in a single nucleotide that does not alter the **amino acid sequence** of the protein due to the redundancy of the genetic code. - This type of mutation would **not cause any change** in protein function or expression, as seen in this patient with complete absence of iduronidase. *Missense mutation* - A **missense mutation** involves a change in a single nucleotide that results in a **different amino acid** being incorporated into the protein. - While a missense mutation can impair protein function, it typically results in a **partially functional** or altered protein, not the complete absence of protein product as described. *Chromosomal translocation* - A **chromosomal translocation** involves the rearrangement of parts between non-homologous chromosomes. - While translocations can lead to genetic disorders by disrupting gene function or dosage, they are less likely to cause a **complete absence of a specific enzyme** unless the translocation directly disrupts the gene's coding region or regulatory elements in a way that prevents any transcription or translation.

Lysosomal storage diseases US Medical PG Question 2: A 2-year-old boy is brought to the emergency department by his parents because of fever and recurrent episodes of jerky movements of his extremities for the past 6 hours. Pregnancy and delivery were uncomplicated, and development was normal until the age of 1 year. The parents report that he has had gradual loss of speech, vision, and motor skills over the past year. During this time, he has been admitted to the hospital three times because of myoclonic seizures. Physical examination shows hypertonicity of the upper and lower extremities. Fundoscopic examination shows pallor of the optic disc bilaterally. An MRI of the brain shows brain atrophy and hyperintensity of the periventricular and subcortical areas. Two days after admission, the patient dies. Histopathologic examination of the brain shows aggregation of globoid cells and loss of glial cells. The patient’s condition was most likely caused by a deficiency of which of the following enzymes?

• A. β-Galactocerebrosidase (Correct Answer)
• B. β-Glucocerebrosidase
• C. Arylsulfatase A
• D. Sphingomyelinase
• E. β-Hexosaminidase A

Lysosomal storage diseases Explanation: ***β-Galactocerebrosidase*** - The clinical presentation, including the **rapid neurodegeneration** (loss of speech, vision, motor skills), **hypertonicity**, **optic disc pallor**, brain atrophy, and periventricular/subcortical hyperintensities on MRI, is highly consistent with **Krabbe disease**. - The classic histopathologic finding of **globoid cells** (macrophages filled with undigested galactocerebroside) and **loss of glial cells** in the brain are pathognomonic for Krabbe disease, which is caused by a deficiency of **β-galactocerebrosidase**. *β-Glucocerebrosidase* - Deficiency of β-glucocerebrosidase causes **Gaucher disease**, which typically involves **hepatosplenomegaly**, **bone crises**, and **pancytopenia**. - While some forms have neurological involvement, the characteristic globoid cells and rapid neurodegeneration seen here are not typical for Gaucher disease. *Arylsulfatase A* - Deficiency of arylsulfatase A leads to **metachromatic leukodystrophy (MLD)**, which also presents with **progressive neurological deterioration**, motor regression, and demyelination. - However, MLD is characterized by the accumulation of **sulfatides** in white matter and detection of **metachromatic granules** in nerves and urine, not globoid cells. *Sphingomyelinase* - Deficiency of sphingomyelinase causes **Niemann-Pick disease**, which is characterized by **hepatosplenomegaly**, **cherry-red spots** in the macula (in type A), and foam cells in various tissues. - The neurological symptoms and brain pathology in this child are not consistent with Niemann-Pick disease. *β-Hexosaminidase A* - Deficiency of β-hexosaminidase A causes **Tay-Sachs disease**, which presents with **progressive neurodegeneration**, **cherry-red spots** in the macula, and **exaggerated startle response**. - While it causes loss of motor skills and vision, the severe demyelination with periventricular hyperintensities and globoid cells are not features of Tay-Sachs disease (which primarily involves ganglioside accumulation).

Lysosomal storage diseases US Medical PG Question 3: A deficiency in which of the following lysosomal enzymes is inherited in a pattern similar to a deficiency of iduronate sulfatase (Hunter syndrome)?

• A. Sphingomyelinase
• B. Glucocerebrosidase
• C. Galactocerebrosidase
• D. Alpha-L-iduronidase
• E. Alpha-galactosidase A (Correct Answer)

Lysosomal storage diseases Explanation: ***Alpha-galactosidase A*** - A deficiency in **alpha-galactosidase A** causes **Fabry disease**, which, like Hunter syndrome (iduronate sulfatase deficiency), is inherited in an **X-linked recessive** pattern. - Both conditions primarily affect males, with carrier females potentially exhibiting milder symptoms. *Sphingomyelinase* - A deficiency in sphingomyelinase leads to **Niemann-Pick disease types A and B**, which are inherited in an **autosomal recessive** pattern. - This mode of inheritance differs from the X-linked pattern of Hunter syndrome. *Glucocerebrosidase* - A deficiency in glucocerebrosidase causes **Gaucher disease**, inherited in an **autosomal recessive** pattern. - This is a common lysosomal storage disorder, but its inheritance pattern is distinct from X-linked disorders. *Galactocerebrosidase* - A deficiency in galactocerebrosidase causes **Krabbe disease (globoid cell leukodystrophy)**, which is inherited in an **autosomal recessive** pattern. - Krabbe disease is a severe neurodegenerative disorder, but its genetic transmission is not X-linked. *Alpha-L-iduronidase* - A deficiency in **alpha-L-iduronidase** causes **Hurler syndrome (MPS I)**, which is inherited in an **autosomal recessive** pattern. - While both Hunter and Hurler syndromes are mucopolysaccharidoses, their genetic inheritance patterns are different.

Lysosomal storage diseases US Medical PG Question 4: A 22-year-old man presents to the physician due to a progressively worsening weakness and an increasingly large abdomen. He notes that he eats well and is fairly active; however, his abdomen has become increasingly protuberant. He also complains of easy bruisability. His medical history is not significant and he takes no medications. Physical examination reveals hepatomegaly and splenomegaly. Several bruises can be seen on the inside of his arms and legs. His skin has a yellowish tinge to it. Laboratory testing shows the following: Hematocrit 25% Erythrocyte count 2.5 x 106/mm3 Thrombocyte count 25,000/mm3 A bone marrow biopsy shows a crinkled-paper appearance to the macrophages. Which of the following enzymes is most likely deficient in this patient?

• A. Arylsulfatase A
• B. Sphingomyelinase
• C. α-galactosidase
• D. Hexosaminidase
• E. β-glucosidase (Correct Answer)

Lysosomal storage diseases Explanation: ***β-glucosidase*** - The patient's symptoms (hepatosplenomegaly, easy bruisability, anemia, thrombocytopenia) and the characteristic **crinkled-paper appearance of macrophages** on bone marrow biopsy are pathognomonic for **Gaucher disease**. - **Gaucher disease** is an autosomal recessive lysosomal storage disorder caused by a deficiency of the enzyme **β-glucosidase** (also known as glucocerebrosidase), leading to the accumulation of glucocerebroside. *Arylsulfatase A* - Deficiency of **arylsulfatase A** causes **metachromatic leukodystrophy**, characterized by progressive demyelination and neurological symptoms, not the hematological and visceral findings seen here. - While it is also a lysosomal storage disorder, the clinical presentation and specific cell morphology are distinct. *Sphingomyelinase* - Deficiency of **sphingomyelinase** leads to **Niemann-Pick disease**, which shares some features with Gaucher disease, such as hepatosplenomegaly. - However, the characteristic cell found in Niemann-Pick disease is a lipid-laden macrophage with a **foamy appearance**, not a "crinkled-paper" appearance. *α-galactosidase* - Deficiency of **α-galactosidase A** causes **Fabry disease**, an X-linked lysosomal storage disorder. - Symptoms include episodic pain, acroparesthesias, angiokeratomas, and renal/cardiac involvement, which are not described in this patient. *Hexosaminidase* - Deficiency of **hexosaminidase A** causes **Tay-Sachs disease**, a lysosomal storage disorder primarily affecting the central nervous system. - It is characterized by progressive neurodegeneration, developmental delay, and a **cherry-red spot** on the retina, without the hepatosplenomegaly or characteristic macrophages seen in this case.

Lysosomal storage diseases US Medical PG Question 5: A 1-year-old boy is brought to his pediatrician for a follow-up appointment. He was recently diagnosed with failure to thrive and developmental delay. His weight is 7 kg (15.4 lb), height is 61 cm (24 in), and head circumference is 42 cm (16.5 in). The patient’s father had a younger sister who suffered from mental and physical delay and died at a very young age. The patient was able to raise his head at the age of 7 months and began to sit alone only recently. He babbles, coos, and smiles to other people. On presentation, his blood pressure is 75/40 mm Hg, heart rate is 147/min, respiratory rate is 28/min, and temperature is 36.4°C (97.5°F). He has a coarse face with small deep orbits, proptotic eyes, big lips, and gingival hyperplasia. His skin is pale with decreased elasticity. His lung and heart sounds are normal. Abdominal examination reveals diminished anterior abdominal wall muscle tone and hepatomegaly. Muscle tone is increased in all groups of muscles on both upper and lower extremities. The physician becomes concerned and performs testing for the suspected hereditary disease. A blood test shows increased lysosomal enzyme concentration in the serum and decreased N-acetylglucosamine-1-phosphotransferase (GlcNAc phosphotransferase) activity within the leukocytes. Which of the statements listed below describes the mechanism of the patient’s condition?

• A. The lysosomal enzymes are secreted from the cells instead of being targeted to lysosomes because of lack of mannose phosphorylation on N-linked glycoproteins. (Correct Answer)
• B. There is impaired hydrolysis of GM2-ganglioside, which accumulates in the cytoplasm.
• C. Due to enzyme deficiency, glycogen is extensively accumulated within the hepatocytes.
• D. The patient’s symptoms are due to dysfunctional metabolism of sphingomyelin, which accumulates within the lysosomes.
• E. The symptoms result from defective glycolysis, which results in a total energy deficiency.

Lysosomal storage diseases Explanation: ***The lysosomal enzymes are secreted from the cells instead of being targeted to lysosomes because of lack of mannose phosphorylation on N-linked glycoproteins.*** - This describes **I-cell disease (mucolipidosis II)**, a lysosomal storage disorder characterized by a deficiency of **N-acetylglucosamine-1-phosphotransferase**. - Without this enzyme, mannose residues on lysosomal enzymes cannot be phosphorylated, preventing their proper targeting to lysosomes and leading to their secretion into the bloodstream. *There is impaired hydrolysis of GM2-ganglioside, which accumulates in the cytoplasm.* - This mechanism describes **Tay-Sachs disease**, which is caused by a deficiency in B-hexosaminidase A. - While Tay-Sachs also causes developmental delay, the clinical features and biochemical findings (specifically the lysosomal enzyme activity levels in serum and leukocytes) do not match those of the described patient. *Due to enzyme deficiency, glycogen is extensively accumulated within the hepatocytes.* - This mechanism describes **glycogen storage diseases**, such as Von Gierke disease (type I) or Pompe disease (type II). - While Pompe disease is a lysosomal storage disorder, the enzymatic defect involves **acid alpha-glucosidase** and leads to glycogen accumulation primarily in muscles and heart, not related to N-acetylglucosamine-1-phosphotransferase deficiency. *The patient’s symptoms are due to dysfunctional metabolism of sphingomyelin, which accumulates within the lysosomes.* - This mechanism describes **Niemann-Pick disease**, caused by a deficiency in **sphingomyelinase**. - While it is a lysosomal storage disease with hepatosplenomegaly and developmental delay, the specific enzymatic defect and the coarse facial features do not align with the patient's presentation and lab results. *The symptoms result from defective glycolysis, which results in a total energy deficiency.* - Defective glycolysis would lead to issues with cellular energy production, causing symptoms such as muscle weakness and fatigue. - However, this mechanism does not explain the specific clinical features like coarse facies, gingival hyperplasia, hepatomegaly, or the characteristic enzymatic defect seen in I-cell disease.

Lysosomal storage diseases US Medical PG Question 6: A medical student is studying digestive enzymes at the brush border of the duodenum. He isolates and inactivates an enzyme in the brush border that has a high affinity for the pancreatic proenzyme trypsinogen. When the enzyme is inactivated, trypsinogen is no longer converted to its active form. Which of the following is the most likely underlying mechanism of this enzyme?

• A. Attachment of a carbohydrate to a side chain
• B. Phosphorylation of an amino acid side chain
• C. Carboxylation of a glutamate residue
• D. Cleavage of a propeptide from an N-terminus (Correct Answer)
• E. Conjugation of ubiquitin to lysine residue

Lysosomal storage diseases Explanation: ***Cleavage of a propeptide from an N-terminus*** - The enzyme described is **enteropeptidase (also known as enterokinase)**, which is located in the **duodenal brush border**. - Enteropeptidase's primary function is to activate **trypsinogen** by cleaving a small **N-terminal hexapeptide**, converting it into its active form, **trypsin**. *Attachment of a carbohydrate to a side chain* - This process is known as **glycosylation** and can affect protein folding, stability, and recognition, but it's not the primary mechanism by which brush border enzymes like enteropeptidase activate zymogens. - While some enzymes are glycosylated, inactivation of this mechanism would not halt trypsinogen activation in this specific enzymatic pathway. *Phosphorylation of an amino acid side chain* - **Phosphorylation** is a common post-translational modification that regulates enzyme activity by adding a phosphate group, often to serine, threonine, or tyrosine residues. - While important for many cellular signaling pathways and enzyme regulation, it is not the mechanism by which enteropeptidase activates trypsinogen. *Carboxylation of a glutamate residue* - **Carboxylation** typically involves the addition of a carboxyl group, notably important for blood clotting factors (e.g., vitamin K-dependent carboxylation). - This modification is not involved in the activation of pancreatic proenzymes by brush border enzymes in the duodenum. *Conjugation of ubiquitin to lysine residue* - **Ubiquitination** is a process that tags proteins for degradation by the proteasome or can regulate protein function and localization. - This is a mechanism for protein turnover and regulation, not for the activation of a proenzyme like trypsinogen.

Lysosomal storage diseases US Medical PG Question 7: A 40-year-old male with Down syndrome is brought to your clinic by his mother. She reports that over the past few months he has started having difficulty managing his daily routine at his assisted-living facility and no longer seems like himself. She says that last week he wandered away from the facility and was brought back by police. Additionally, he has stopped taking his regular antiepileptic medication, and she is concerned that he might have a seizure. TSH is checked and is normal. Which of the following is most likely to be responsible for this man's current presentation?

• A. Premature degradation of a protein
• B. Abnormal protein metabolism (Correct Answer)
• C. Hormone deficiency
• D. Nutritional deficiency
• E. Expansion of trinucleotide repeats

Lysosomal storage diseases Explanation: ***Abnormal protein metabolism*** - Individuals with **Down syndrome (trisomy 21)** are at a significantly higher risk of developing early-onset **Alzheimer's disease** due to an extra copy of the **APP gene** on chromosome 21. - **Amyloid Precursor Protein (APP)** metabolism is altered, leading to excessive production and aggregation of **beta-amyloid plaques**, which is a hallmark of Alzheimer's pathology and causes the cognitive decline observed. *Premature degradation of a protein* - This option points to a general protein issue but doesn't specifically address the **pathophysiology of Alzheimer's** in Down syndrome, which is primarily about abnormal production and aggregation, not premature degradation. - While protein degradation pathways are involved in neurodegenerative diseases, the core problem in Alzheimer's relates to the **accumulation of misfolded proteins**. *Hormone deficiency* - The patient's **TSH is normal**, ruling out **hypothyroidism**, which can cause cognitive changes and is more common in Down syndrome. - While other hormonal imbalances could affect cognitive function, the significant and progressive decline described is more consistent with a **neurodegenerative process** than a general hormone deficiency. *Nutritional deficiency* - While nutritional deficiencies can certainly impact cognitive function and behavior, the patient's age, underlying condition (**Down syndrome**), and the specific pattern of progressive decline strongly suggest a **neurodegenerative cause** rather than a primary nutritional deficiency. - There is no specific information in the vignette to point toward a nutritional deficiency. *Expansion of trinucleotide repeats* - **Trinucleotide repeat expansion disorders** (e.g., Huntington's disease, Fragile X syndrome) cause a variety of neurological and psychiatric symptoms. - However, the patient's presentation in the context of Down syndrome is characteristic of **early-onset Alzheimer's disease**, which is not caused by trinucleotide repeat expansion.

Lysosomal storage diseases US Medical PG Question 8: An 8-month-old female infant from a first-degree consanguineous couple was brought to the physician because the mother noticed abnormalities in the growth of her child as well as the different lengths of her child's legs. The infant had gingival hyperplasia, restricted movement in both shoulders, a prominent, pointed forehead, and enophthalmos with a slight opacity in both corneas. A blood test revealed 10 fold higher than normal levels of the following enzymes: N-acetyl-ß-glucosaminidase, ß-glucuronidase, ß-hexosaminidase A, and alkaline phosphatase. Which of the following is most likely deficient in this patient?

• A. Lysosomal alpha-1,4-glucosidase
• B. Glucose-6-phosphate dehydrogenase
• C. N-acetyl-glucosamine-1-phosphotransferase (Correct Answer)
• D. Glucocerebrosidase
• E. Alpha-galactosidase A

Lysosomal storage diseases Explanation: ***N-acetyl-glucosamine-1-phosphotransferase*** - The clinical presentation with **gingival hyperplasia**, **restricted joint movement**, **skeletal abnormalities** (growth abnormalities, leg length discrepancy, prominent forehead), and **corneal opacity** with elevated lysosomal enzymes (N-acetyl-ß-glucosaminidase, ß-glucuronidase, ß-hexosaminidase A) is highly characteristic of **I-cell disease** (mucolipidosis II). - I-cell disease is caused by a deficiency in **N-acetyl-glucosamine-1-phosphotransferase**, an enzyme crucial for phosphorylating mannose residues on lysosomal enzymes, tagging them for delivery to lysosomes. Without this tag, lysosomal enzymes are secreted extracellularly, leading to their accumulation in the blood and their deficiency within lysosomes, causing the clinical features. *Lysosomal alpha-1,4-glucosidase* - Deficiency of **lysosomal alpha-1,4-glucosidase** causes **Pompe disease (glycogen storage disease type II)**, which is characterized by **cardiomegaly**, hypotonia, and liver involvement, but typically does not present with the skeletal dysplasias, gingival hyperplasia, or corneal clouding seen in this patient. - While it is a lysosomal storage disorder, the specific clinical features and panel of elevated enzymes differ significantly from this case. *Glucose-6-phosphate dehydrogenase* - Deficiency of **glucose-6-phosphate dehydrogenase (G6PD)** causes **G6PD deficiency**, an X-linked disorder leading to **hemolytic anemia** in response to oxidative stress (e.g., fava beans, certain drugs, infections). - It does not present with the systemic skeletal, connective tissue, and corneal abnormalities described, nor does it involve elevated lysosomal enzyme levels. *Glucocerebrosidase* - Deficiency of **glucocerebrosidase** causes **Gaucher disease**, which presents with **hepatosplenomegaly**, bone crises, pancytopenia, and sometimes neurological involvement. - While it is a lysosomal storage disorder, the clinical features (e.g., absence of gingival hyperplasia, corneal opacity, or specific skeletal dysplasias like restricted joint movement) and the pattern of elevated enzymes do not match the patient's presentation. *Alpha-galactosidase A* - Deficiency of **alpha-galactosidase A** causes **Fabry disease**, an X-linked lysosomal storage disorder characterized by **neuropathic pain**, **angiokeratomas**, renal failure, and cardiac involvement. - The clinical picture of Fabry disease does not include gingival hyperplasia, prominent skeletal abnormalities, or the specific pattern of elevated lysosomal enzymes observed in this patient.

Lysosomal storage diseases US Medical PG Question 9: A 47-year-old homeless man is brought to the emergency department by police, who found him sleeping by the side of the street. He is somnolent and confused and is unable to give a reliable history. His medical history is unobtainable. Vital signs include: temperature 36.9°C (98.4°F), blood pressure 112/75 mm Hg, and pulse 85/min. Physical examination reveals that he has severe truncal ataxia and horizontal gaze palsy with impaired vestibulo-ocular reflexes. Muscle stretch reflexes and motor strength are normal. He has no sensory deficits. Which of the following best represents the most likely etiology of this patient’s condition?

• A. Miller-Fisher syndrome
• B. Vitamin B1 deficiency (Correct Answer)
• C. Vitamin B12 deficiency
• D. Delirium tremens
• E. Ethylene glycol intoxication

Lysosomal storage diseases Explanation: ***Vitamin B1 deficiency*** - The patient's **somnolence, confusion, truncal ataxia, and horizontal gaze palsy** are classic symptoms of **Wernicke encephalopathy**, which is caused by acute **thiamine (vitamin B1) deficiency**. - This condition is common in individuals with **alcohol use disorder** or malnutrition, as the patient's homeless status suggests. *Miller-Fisher syndrome* - This is a rare variant of **Guillain-Barré syndrome** characterized by the triad of **ataxia, areflexia, and ophthalmoplegia**. - While ophthalmoplegia and ataxia are present, the patient's **normal muscle stretch reflexes** and lack of significant **motor weakness** make this diagnosis less likely. *Vitamin B12 deficiency* - Leads to **subacute combined degeneration** of the spinal cord, causing **ataxia, paresthesias, weakness, and loss of proprioception and vibratory sensation**. - The acute presentation with **gaze palsy** and the absence of sensory deficits or significant motor weakness make this less probable. *Delirium tremens* - Typically occurs due to **severe alcohol withdrawal** and presents with **agitation, hallucinations, tremors, and autonomic instability** (e.g., fever, tachycardia, hypertension). - The patient's presentation of somnolence, confusion, ataxia, and gaze palsy is not typical for delirium tremens. *Ethylene glycol intoxication* - Can cause **neurological symptoms** like altered mental status and ataxia, and in severe cases, ophthalmoplegia due to **cranial nerve involvement**. - However, it is also associated with **acute kidney injury, metabolic acidosis with a high anion gap, and calcium oxalate crystaluria**, none of which are indicated in the provided information.

Lysosomal storage diseases US Medical PG Question 10: A 6-month-old infant male is brought to the emergency department with a 1-hour history of vomiting and convulsions. He was born at home and had sporadic prenatal care though his parents say that he appeared healthy at birth. He initially fed well; however, his parents have noticed that he has been feeding poorly and is very irritable since they moved on to baby foods. They have also noticed mild yellowing of his skin but assumed it would go away over time. On presentation, he is found to be very sleepy, and physical exam reveals an enlarged liver and spleen. The rest of the physical exam is normal. Which of the following enzymes is most likely functioning abnormally in this patient?

• A. Aldolase B (Correct Answer)
• B. Galactokinase
• C. Lactase
• D. Fructokinase
• E. Gal-1-phosphate uridyl transferase

Lysosomal storage diseases Explanation: ***Aldolase B*** - The symptoms of vomiting, irritability, jaundice, hepatosplenomegaly, and poor feeding in an infant after starting baby foods strongly suggest **hereditary fructose intolerance (HFI)**. - HFI is caused by a deficiency in **Aldolase B**, which is responsible for cleaving **fructose-1-phosphate** into dihydroxyacetone phosphate and glyceraldehyde in the liver, kidney, and small intestine. *Galactokinase* - A deficiency in **galactokinase** causes **galactosemia type II**, characterized primarily by **cataracts** from birth, with milder symptoms compared to classic galactosemia. - It does not typically present with the severe liver failure, vomiting, and convulsions seen in this patient. *Lactase* - **Lactase deficiency** causes **lactose intolerance**, presenting with gastrointestinal symptoms like bloating, gas, and diarrhea, particularly after consuming milk products. - It does not typically cause the systemic symptoms of liver dysfunction, vomiting, convulsions, or jaundice experienced by this infant. *Fructokinase* - A deficiency in **fructokinase** causes **essential fructosuria**, which is a **benign, asymptomatic** metabolic disorder. - Fructose accumulates in the urine but does not lead to the severe clinical manifestations such as vomiting, convulsions, or liver enlargement. *Gal-1-phosphate uridyl transferase* - A deficiency in **Gal-1-phosphate uridyl transferase** causes **classic galactosemia**, which would also present with vomiting, feeding difficulties, jaundice, and hepatosplenomegaly. - However, classic galactosemia symptoms appear upon ingestion of **lactose** (from breast milk or formula), typically much earlier than the introduction of baby foods containing fructose.

Lysosomal storage diseases Flashcard 1 of 7

Question: _____ is a lysosomal storage disease caused by frameshift mutations.

Answer: Tay-Sachs

Lysosomal storage diseases Flashcard 2 of 7

Question: What substrate accumulates in the lysosomes of a patient with Gaucher disease? _____

Answer: Glucocerebroside

Lysosomal storage diseases Flashcard 3 of 7

Question: Which lysosomal storage disease is characterized by a cherry red spot on the macula and hepatosplenomegaly? _____

Answer: Niemann Pick disease

Lysosomal storage diseases Flashcard 4 of 7

Question: Describe, in general, the lysosomal storage diseases.

Answer: Diverse group of diseases resulting from defects in lysosomal enzymes, characterized by an accumulation of abnormal metabolic products within cells.

Lysosomal storage diseases Flashcard 5 of 7

Question: Pompe's disease (GSD type II)

Answer:

Extra Information: heart, liver, muscle manifestations, esp. cardiomegaly; early deathARlysosomal α-1,4-glucosidase (acid maltase)mnemonic: Very Bad Carbohydrate Metabolism (the glycogen storage diseases in order)

Lysosomal storage diseases Flashcard 6 of 7

Question: Where does mannose-6-phosphate tagging occur?

Answer: Golgi

Lysosomal storage diseases Flashcard 7 of 7

Question: A mannose-6-phosphate tag targets proteins for where?

Answer: lysosome