A 19-year-old man is admitted for the third time with a stroke-like episode, this time with right hemianopia and headache. MRI shows a cortical lesion in the left occipital lobe that does not fit any arterial territory. He is short, has hearing loss, and his fasting blood lactate is 4.8 mmol/L (reference 0.5-2.2). What would a muscle biopsy most likely show?

Ragged red fibres on Gomori trichrome

Absent dystrophin on immunostaining

Perifascicular atrophy of muscle fibres

Rimmed vacuoles with inclusions

Lysosomal storage and mitochondrial disorders

16 NEET-PG practice questions on Lysosomal storage and mitochondrial disorders, part of Biochemistry. The first 16 are below; the first 5 with answers and explanations (tap Show answer after you have chosen), the rest in Learn with a free account.

Question 1 · Medium
A 7-month-old girl has poor feeding, failure to thrive and loss of milestones. She has a protuberant abdomen with marked hepatosplenomegaly, and fundoscopy shows a cherry-red spot. Bone marrow aspirate shows many large macrophages with foamy, vacuolated cytoplasm. What is the most likely diagnosis?
1. AKrabbe disease
2. BTay-Sachs disease
3. CNiemann-Pick disease type A
4. DGaucher disease type 1
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Answer: C · Niemann-Pick disease type A
Infantile neurodegeneration with massive hepatosplenomegaly, a cherry-red spot and foamy (lipid-laden) macrophages points to Niemann-Pick disease type A. Deficient acid sphingomyelinase leads to sphingomyelin storage in macrophages and neurons. Children usually die in early childhood. Enzyme activity in leucocytes or SMPD1 gene testing confirms the diagnosis and allows prenatal diagnosis in later pregnancies.
- A: Krabbe disease causes irritability, spasticity and globoid cells in the brain without organomegaly.
- B: Tay-Sachs disease has a cherry-red spot but no hepatosplenomegaly.
- D: Type 1 Gaucher disease spares the nervous system and shows tissue-paper, not foamy, macrophages.
Question 2 · Easy
A 5-year-old boy is brought to the paediatric genetics clinic with coarse facial features, a hoarse voice, stiff finger joints, hepatosplenomegaly and hyperactive, aggressive behaviour. His corneas are clear on slit-lamp examination. His mother's brother had a similar illness. Urine shows excess dermatan sulfate and heparan sulfate. Which enzyme is deficient?
1. AArylsulfatase A
2. BGalactocerebrosidase
3. CIduronate-2-sulfatase
4. DAlpha-L-iduronidase
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Answer: C · Iduronate-2-sulfatase
Hunter syndrome (mucopolysaccharidosis type II) is the only X-linked mucopolysaccharidosis, so it affects boys and passes through carrier mothers, as in this family. Deficient iduronate-2-sulfatase causes dermatan and heparan sulfate to accumulate, giving coarse features, joint stiffness and organomegaly. Clear corneas and aggressive behaviour help separate it from Hurler syndrome, which causes corneal clouding. Enzyme replacement (idursulfase) is available.
- A: Arylsulfatase A deficiency is metachromatic leukodystrophy, a demyelinating disease without coarse features.
- B: Galactocerebrosidase deficiency is Krabbe disease, with globoid cells in the brain, not mucopolysacchariduria.
- D: Alpha-L-iduronidase deficiency is Hurler syndrome: autosomal recessive with corneal clouding.
Question 3 · Medium
A 21-year-old man has had burning pain in his hands and feet since childhood, worse with fever, exercise and hot weather. He sweats very little. There are clusters of dark red, non-blanching papules around the umbilicus and on the scrotum, whorl-like corneal opacities, and urine protein is 2+. His maternal uncle died of kidney failure at 45. Which substance accumulates in his tissues?
1. AGlobotriaosylceramide
2. BGalactocerebroside
3. CSulfatide
4. DGlucocerebroside
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Answer: A · Globotriaosylceramide
Painful acroparaesthesia, hypohidrosis, angiokeratomas in the bathing-trunk area, cornea verticillata and proteinuria are typical of Fabry disease. Deficient alpha-galactosidase A causes globotriaosylceramide (Gb3) to accumulate in vascular endothelium, kidney, heart and nerves. It is X-linked, so it passes through the maternal line, and men develop kidney failure, cardiomyopathy and strokes in mid-adult life. Enzyme replacement (agalsidase) or the oral chaperone migalastat is used.
- B: Galactocerebroside accumulates in Krabbe disease, an infantile leukodystrophy.
- C: Sulfatide accumulates in metachromatic leukodystrophy, a demyelinating disease.
- D: Glucocerebroside accumulates in Gaucher disease, with splenomegaly and bone disease.
Question 4 · Medium
A 19-year-old man is admitted for the third time with a stroke-like episode, this time with right hemianopia and headache. MRI shows a cortical lesion in the left occipital lobe that does not fit any arterial territory. He is short, has hearing loss, and his fasting blood lactate is 4.8 mmol/L (reference 0.5-2.2). What would a muscle biopsy most likely show?
1. AAbsent dystrophin on immunostaining
2. BPerifascicular atrophy of muscle fibres
3. CRimmed vacuoles with inclusions
4. DRagged red fibres on Gomori trichrome
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Answer: D · Ragged red fibres on Gomori trichrome
Recurrent stroke-like episodes outside vascular territories, lactic acidosis, short stature and deafness in a young person suggest MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes). Muscle fibres with clumps of abnormal mitochondria under the sarcolemma stain red with modified Gomori trichrome (ragged red fibres), and many fibres are cytochrome oxidase-negative. Most cases are due to the m.3243A>G mutation in a mitochondrial tRNA gene, which can be detected in blood or urine cells. L-arginine is often used during acute episodes.
- A: Absent dystrophin is Duchenne muscular dystrophy, not a mitochondrial disease.
- B: Perifascicular atrophy is the hallmark of dermatomyositis.
- C: Rimmed vacuoles are seen in inclusion body myositis of older adults.
Question 5 · Easy
A 24-year-old man from Pune has had a dragging feeling in the left upper abdomen for two years and episodes of severe bone pain in the thighs. The spleen is palpable 12 cm below the costal margin. Hb 9.8 g/dL, platelets 62,000/µL. Bone marrow shows large macrophages with a fibrillary cytoplasm resembling crumpled tissue paper. Deficiency of which enzyme is most likely?
1. AAlpha-galactosidase A
2. BGlucocerebrosidase
3. CSphingomyelinase
4. DHexosaminidase A
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Answer: B · Glucocerebrosidase
Massive splenomegaly, cytopenias from hypersplenism, bone crises and 'crumpled tissue paper' macrophages (Gaucher cells) are typical of type 1 (non-neuronopathic) Gaucher disease. Deficient glucocerebrosidase (acid beta-glucosidase) leaves glucocerebroside inside the lysosomes of macrophages of the spleen, liver and marrow. It is the commonest lysosomal storage disease, inherited as autosomal recessive. Diagnosis is confirmed by low enzyme activity in leucocytes or by GBA gene testing.
- A: Alpha-galactosidase A deficiency (Fabry) causes painful neuropathy, angiokeratomas and renal disease.
- C: Sphingomyelinase deficiency (Niemann-Pick) gives foamy, vacuolated macrophages, not tissue-paper cells.
- D: Hexosaminidase A deficiency (Tay-Sachs) is a neurodegenerative disease without organomegaly.
Question 6 · Easy
A 23-year-old man has had painless loss of central vision, first in the right eye and two months later in the left. Genetic testing confirms Leber hereditary optic neuropathy due to a mitochondrial DNA point mutation. He asks whether his future children could inherit the mutation. What is the correct answer?
1. AHalf of his sons will inherit it
2. BNone of his children will inherit it
3. COnly his daughters will inherit it
4. DAll of his children will inherit it
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Question 7 · Hard
A 17-year-old girl has had drooping of both eyelids for three years and now cannot move her eyes fully in any direction, without double vision. Fundoscopy shows salt-and-pepper pigmentary retinopathy. She was brought to casualty after two fainting spells. The ECG shows complete heart block with a ventricular rate of 34/min. Muscle biopsy later shows ragged red fibres. What is the next best step in management?
1. AOral beta-blocker therapy
2. BPermanent pacemaker implantation
3. CHigh-dose intravenous steroids
4. DOral coenzyme Q10 alone
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Question 8 · Medium
A 15-year-old girl from Bengaluru with type 1 Gaucher disease has a spleen 10 cm below the costal margin, platelets 48,000/µL, frequent nosebleeds and two episodes of bone crisis this year. She has no neurological signs. Which is the most appropriate specific treatment?
1. AOral hydroxyurea
2. BTotal splenectomy
3. CEnzyme replacement with imiglucerase
4. DAgalsidase beta infusions
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Question 9 · Medium
A 2-year-old girl has coarse facial features, a large tongue, noisy breathing, a gibbus at the thoracolumbar junction, hepatosplenomegaly and developmental delay. Slit-lamp examination shows cloudy corneas in both eyes. Urine shows excess dermatan sulfate and heparan sulfate. Which enzyme is most likely deficient?
1. AGalactose-6-sulfatase
2. BIduronate-2-sulfatase
3. CAlpha-L-iduronidase
4. DN-acetylgalactosamine-4-sulfatase
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Question 10 · Medium
A 10-year-old boy treated with intravenous gentamicin for a urinary infection develops severe bilateral hearing loss after only three doses, with normal renal function and drug levels. His mother and her sister also became deaf after aminoglycoside injections in childhood. Which mechanism best explains this susceptibility?
1. AMutant mitochondrial rRNA that binds the drug
2. BDeficient G6PD causing oxidative cell damage
3. CPseudocholinesterase deficiency prolonging action
4. DSlow acetylator status reducing drug clearance
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Question 11 · Medium
A 14-month-old boy has coarse facial features, marked gingival hyperplasia, restricted joint movement and developmental delay. Activities of several lysosomal enzymes are very low in his cultured fibroblasts but are markedly raised in his plasma. Which step of protein processing is defective?
1. AAdding mannose-6-phosphate to enzymes
2. BAdding sialic acid in the trans-Golgi
3. CUbiquitin tagging for proteasome breakdown
4. DRemoving the signal peptide in the ER
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Question 12 · Medium
A 22-year-old engineering student has had painless, rapid loss of central vision in both eyes over three months, one eye after the other. The discs were hyperaemic early on, and now show temporal pallor. MRI brain and orbits is normal. Mitochondrial DNA testing shows the m.11778G>A mutation. Which component of the respiratory chain is affected?
1. AComplex I (NADH dehydrogenase)
2. BComplex V (ATP synthase)
3. CComplex II (succinate dehydrogenase)
4. DComplex IV (cytochrome oxidase)
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Question 13 · Medium
A 34-year-old woman with sensorineural hearing loss and type 2 diabetes is mildly affected by a mitochondrial DNA mutation. Her 14-year-old son, who carries the same mutation, is short, has had two stroke-like episodes and has a raised blood lactate. Her other son carries it but has no symptoms. Which phenomenon best explains the different severity within this family?
1. AAnticipation
2. BGenomic imprinting
3. CHeteroplasmy
4. DUniparental disomy
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Question 14 · Hard
A 3-year-old girl with developmental regression, raised CSF lactate and a POLG gene mutation is brought to the PICU in convulsive status epilepticus. She has received two doses of intravenous lorazepam, and the seizures continue. Which antiseizure drug should be avoided as the next agent?
1. AFosphenytoin
2. BSodium valproate
3. CLevetiracetam
4. DPhenobarbitone
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Question 15 · Medium
An 8-month-old boy is brought to the paediatric OPD because he no longer sits or reaches for toys, skills he had at 6 months. He startles violently at ordinary sounds, has poor head control and a large head. Fundoscopy shows a cherry-red spot at both maculae. Consider four statements: 1. The substance stored in his neurons is GM2 ganglioside. 2. Marked hepatosplenomegaly is expected. 3. The deficient enzyme is hexosaminidase A. 4. Both parents are most likely carriers. Which statements are correct?
1. A3 and 4 only
2. B2 and 4 only
3. C1 and 3 only
4. D1, 3 and 4 only
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Question 16 · Hard
A 6-year-old boy has coarse facial features, stiff joints, hepatosplenomegaly, umbilical hernia and pebbly ivory-coloured skin lesions over both scapulae. His cognitive development is slipping and he is hyperactive. A paediatric resident makes four statements: 1. The disorder is X-linked recessive. 2. Dense corneal clouding is an early feature. 3. Urine shows excess dermatan sulfate and heparan sulfate. 4. The deficient enzyme is iduronate-2-sulfatase. Which statements are correct?
1. A2, 3 and 4 only
2. B1 and 4 only
3. C1, 3 and 4 only
4. D1, 2, 3 and 4
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Lysosomal storage and mitochondrial disorders

A 7-month-old girl has poor feeding, failure to thrive and loss of milestones. She has a protuberant abdomen with marked hepatosplenomegaly, and fundoscopy shows a cherry-red spot. Bone marrow aspirate shows many large macrophages with foamy, vacuolated cytoplasm. What is the most likely diagnosis?

A 15-year-old girl from Bengaluru with type 1 Gaucher disease has a spleen 10 cm below the costal margin, platelets 48,000/µL, frequent nosebleeds and two episodes of bone crisis this year. She has no neurological signs. Which is the most appropriate specific treatment?

A 14-month-old boy has coarse facial features, marked gingival hyperplasia, restricted joint movement and developmental delay. Activities of several lysosomal enzymes are very low in his cultured fibroblasts but are markedly raised in his plasma. Which step of protein processing is defective?

A 3-year-old girl with developmental regression, raised CSF lactate and a POLG gene mutation is brought to the PICU in convulsive status epilepticus. She has received two doses of intravenous lorazepam, and the seizures continue. Which antiseizure drug should be avoided as the next agent?