Neurodegenerative Disorders — MCQs
A child presents with bone pain and hepatosplenomegaly, indicative of Gaucher's disease. A trephine biopsy and aspirate show the following finding. Which of the following is the most likely enzyme deficient in this condition?
Which of the following is characterized by denervation atrophy of the muscles?
Branched-chain ketoaciduria is due to a deficiency of which enzyme?
A 45-year-old man presents to the clinic for evaluation of weakness in his arms and legs. The symptoms started gradually, and are now more noticeable and interfering with his ability to work as an electrician. On physical examination, the cranial nerves are normal, but there is weakness of his left handgrip and right leg quadriceps with loss of muscle bulk. There are obvious fasciculations over the left forearm and right thigh. Tone is increased in the arms and legs and the reflexes are brisk. Which of the following is the most likely diagnosis?
What is the metabolic abnormality associated with Zellweger syndrome?
A 6-year-old presents with developmental delay, musty body odor, and fair skin. Lab tests show high phenylalanine levels. What is the most appropriate management?
Which of the following statements about Niemann-Pick disease is false?
A 10-month-old child with coarse facies is referred for developmental delay. On examination, hepatosplenomegaly was noted. WBC N-acetylglucosamine-1-phosphotransferase activity was absent. The X-ray is shown below. What is the diagnosis?
A child born with microcephaly, chorioretinitis, and intracranial calcification. Most likely diagnosis is:
What is the commonest cause of obstructive hydrocephalus in children?
Neurodegenerative Disorders Indian Medical PG Practice Questions and MCQs
Question 1: A child presents with bone pain and hepatosplenomegaly, indicative of Gaucher's disease. A trephine biopsy and aspirate show the following finding. Which of the following is the most likely enzyme deficient in this condition?
- A. Hexosaminidase
- B. Glucocerebrosidase (Correct Answer)
- C. Sphingomyelinase
- D. Alpha 1,4-glucosidase
Explanation: ***Correct: Glucocerebrosidase*** - The clinical presentation of **bone pain**, **hepatosplenomegaly**, and the characteristic histological finding of **lipid-laden macrophages** (Gaucher cells) with a **crinkled paper** appearance in the bone marrow aspirate are highly suggestive of **Gaucher's disease**. - **Gaucher's disease** is caused by a deficiency of the lysosomal enzyme **glucocerebrosidase**, leading to the accumulation of **glucocerebroside**. *Incorrect: Hexosaminidase* - Deficiency of **hexosaminidase A** is associated with **Tay-Sachs disease**, which presents with neurological degeneration but typically **lacks hepatosplenomegaly** and bone pain. - The histological findings in Tay-Sachs disease would show neuronal storage of **GM2 gangliosides**, not Gaucher cells. *Incorrect: Sphingomyelinase* - Deficiency of **sphingomyelinase** causes **Niemann-Pick disease**, characterized by hepatosplenomegaly, neurological involvement, and interstitial lung disease, but the storage cells (foam cells) have a **foamy appearance** due to sphingomyelin accumulation, not the "crinkled paper" appearance of Gaucher cells. - While there is organomegaly, the distinct **histological features** in the image rule out Niemann-Pick disease. *Incorrect: Alpha 1,4-glucosidase* - Deficiency of **alpha 1,4-glucosidase** (acid maltase) causes **Pompe disease** (Glycogen Storage Disease Type II), which primarily affects muscle and liver with **glycogen accumulation**. - Pompe disease does not typically present with the same type of **bone pain** or the characteristic **Gaucher cells** seen in the image.
Question 2: Which of the following is characterized by denervation atrophy of the muscles?
- A. Werdnig-Hoffman disease (Correct Answer)
- B. Carnitine palmityl transferase deficiency
- C. McArdle disease
- D. Pompe disease
Explanation: ***Werdnig-Hoffman disease*** - This is a severe form of **spinal muscular atrophy (SMA)**, characterized by the degeneration of **anterior horn cells** in the spinal cord [1]. - The loss of motor neurons leads to **denervation atrophy** of skeletal muscles, resulting in profound weakness and hypotonia [1], [2]. *Carnitine palmityl transferase deficiency* - This is a **fatty acid oxidation disorder** that primarily affects muscle energy metabolism. - It causes muscle pain, weakness, and **rhabdomyolysis** during sustained exercise, but not denervation atrophy. *McArdle disease* - Also known as **glycogen storage disease type V**, this condition is caused by a deficiency in **myophosphorylase**. - It results in exercise intolerance, muscle cramps, and myoglobinuria, but the muscle damage is metabolic, not from denervation. *Pompe disease* - This is a **lysosomal storage disorder** caused by a deficiency of **acid alpha-glucosidase (GAA)**. - It leads to the accumulation of glycogen in lysosomes, causing muscle weakness, cardiomyopathy, and respiratory failure, but the muscle pathology is due to lysosomal dysfunction, not denervation. **References:** [1] Kumar V, Abbas AK, et al.. Robbins and Cotran Pathologic Basis of Disease. 9th ed. Peripheral Nerves and Skeletal Muscles, pp. 1239-1240, 1247-1248. [2] Cross SS. Underwood's Pathology: A Clinical Approach. 6th ed. Common Clinical Manifestations Of Central And Peripheral Nervous System Disease, pp. 730-731.
Question 3: Branched-chain ketoaciduria is due to a deficiency of which enzyme?
- A. Branched-chain α-ketoacid dehydrogenase (Correct Answer)
- B. Methylmalonyl-CoA mutase
- C. Fumarylacetoacetate hydrolase
- D. α-ketoacid dehydrogenase
Explanation: ***Branched-chain α-ketoacid dehydrogenase*** - **Branched-chain ketoaciduria**, also known as **Maple Syrup Urine Disease (MSUD)**, is caused by a deficiency in the **branched-chain α-ketoacid dehydrogenase (BCKDH)** enzyme complex. - This enzyme complex is crucial for the oxidative decarboxylation of **branched-chain α-keto acids**, which are metabolites of the essential amino acids **leucine**, **isoleucine**, and **valine**. *α-ketoacid dehydrogenase* - This is a general term for enzymes that catalyze the oxidative decarboxylation of α-keto acids. - While **BCKDH** is a type of α-ketoacid dehydrogenase, stating **"α-ketoacid dehydrogenase"** alone is too broad and not specific enough to the metabolic pathway affected in MSUD. *Methylmalonyl-CoA mutase* - A deficiency in **methylmalonyl-CoA mutase** causes **methylmalonic acidemia**, a distinct inherited metabolic disorder. - This enzyme is involved in the metabolism of **valine**, **isoleucine**, **methionine**, and **threonine**, converting methylmalonyl-CoA to succinyl-CoA. *Fumarylacetoacetate hydrolase* - A deficiency in **fumarylacetoacetate hydrolase** is responsible for **tyrosinemia type 1 (hepatorenal tyrosinemia)**. - This enzyme is involved in the final step of **tyrosine degradation**, leading to the accumulation of toxic metabolites like fumarylacetoacetate and succinylacetone.
Question 4: A 45-year-old man presents to the clinic for evaluation of weakness in his arms and legs. The symptoms started gradually, and are now more noticeable and interfering with his ability to work as an electrician. On physical examination, the cranial nerves are normal, but there is weakness of his left handgrip and right leg quadriceps with loss of muscle bulk. There are obvious fasciculations over the left forearm and right thigh. Tone is increased in the arms and legs and the reflexes are brisk. Which of the following is the most likely diagnosis?
- A. tabes dorsalis
- B. amyotrophic lateral sclerosis (ALS) (Correct Answer)
- C. amyotonia congenita
- D. myotonic muscular dystrophy
Explanation: ***amyotrophic lateral sclerosis (ALS)*** - The combination of **upper motor neuron (UMN)** signs (increased tone, brisk reflexes) and **lower motor neuron (LMN)** signs (weakness, muscle bulk loss, fasciculations) [1], [3] in the absence of sensory or cognitive deficits is characteristic of **ALS**. [1] - **ALS** typically presents with progressive, asymmetrical weakness that eventually affects multiple muscle groups, consistent with the patient's worsening symptoms. [1], [2] *tabes dorsalis* - **Tabes dorsalis** is a complication of **syphilis** affecting the dorsal columns and posterior roots, leading to **sensory ataxia**, lancinating pains, and **absent reflexes**. - It does not typically present with the combined UMN and LMN signs, or **fasciculations**, observed in this patient. [3] *amyotonia congenita* - **Amyotonia congenita** is a historical term for a heterogeneous group of conditions primarily presenting as **severe hypotonia** and **muscle weakness at birth**, often associated with **floppy infant syndrome**. - It is a congenital condition and does not match the adult-onset, progressive weakness with both UMN and LMN features described. *myotonic muscular dystrophy* - **Myotonic muscular dystrophy** is characterized by **muscle weakness**, **myotonia** (delayed muscle relaxation), and often **multisystem involvement** (e.g., cataracts, cardiac conduction defects). - While it causes weakness and muscle wasting, the prominent **fasciculations**, brisk reflexes, and the specific combination of UMN and LMN signs differentiate it from this presentation. [1], [3]
Question 5: What is the metabolic abnormality associated with Zellweger syndrome?
- A. Accumulation of long-chain fatty acids
- B. Accumulation of short-chain fatty acids
- C. Accumulation of very long-chain fatty acids (Correct Answer)
- D. Accumulation of medium-chain fatty acids
Explanation: ***Accumulation of very long-chain fatty acids*** - **Zellweger syndrome** is a peroxisomal biogenesis disorder, meaning that peroxisomes, which are responsible for the **beta-oxidation** of very long-chain fatty acids (VLCFAs), are absent or dysfunctional. - The inability to break down **VLCFAs** leads to their accumulation in various tissues, causing significant neurological and systemic dysfunction. *Accumulation of long-chain fatty acids* - While peroxisomes can contribute to the metabolism of some **long-chain fatty acids (LCFAs)**, their primary role in this context is with **VLCFAs**. - **Mitochondria** are the main organelles responsible for the beta-oxidation of most LCFAs. *Accumulation of short-chain fatty acids* - **Short-chain fatty acids (SCFAs)** are primarily produced by gut bacteria and are metabolized in the mitochondria and other cellular compartments. - Their accumulation is not characteristic of **Zellweger syndrome**. *Accumulation of medium-chain fatty acids* - **Medium-chain fatty acids (MCFAs)** are primarily metabolized in the **mitochondria** and do not typically accumulate in Zellweger syndrome. - Disorders affecting MCFA metabolism usually point to different enzyme deficiencies, such as **MCAD deficiency.**
Question 6: A 6-year-old presents with developmental delay, musty body odor, and fair skin. Lab tests show high phenylalanine levels. What is the most appropriate management?
- A. Low-phenylalanine diet (Correct Answer)
- B. Avoidance of ascorbic acid
- C. Vitamin D supplementation
- D. High-protein diet
- E. Tetrahydrobiopterin (BH4) supplementation
Explanation: ***Low-phenylalanine diet*** - The patient's symptoms (developmental delay, musty body odor, fair skin) and high **phenylalanine levels** are classic for **phenylketonuria (PKU)**. - Management primarily involves a strict **low-phenylalanine diet** to prevent further neurological damage. - This is the **cornerstone of PKU management** and must be initiated as early as possible. *Tetrahydrobiopterin (BH4) supplementation* - While **BH4 (sapropterin)** can be beneficial in some patients with **BH4-responsive PKU** (a subset of PKU cases), it is not first-line management. - BH4 testing is performed after diagnosis, but dietary restriction remains the primary treatment. - Not all PKU patients respond to BH4, and it's used as an adjunct, not a replacement for dietary management. *Avoidance of ascorbic acid* - **Ascorbic acid** (vitamin C) is generally not contraindicated in PKU and does not impact phenylalanine metabolism. - This intervention is not relevant to the management of PKU. *Vitamin D supplementation* - While vitamin D supplementation might be necessary for general health, especially in children with restricted diets, it is not the primary treatment for **phenylketonuria (PKU)**. - It does not directly address the elevated phenylalanine levels. *High-protein diet* - A **high-protein diet** would exacerbate the condition, as proteins are a major source of phenylalanine. - This would lead to even higher phenylalanine levels and worsen the symptoms of PKU.
Question 7: Which of the following statements about Niemann-Pick disease is false?
- A. Due to deficiency of sphingomyelinase.
- B. CNS symptoms are present in type A.
- C. Type B Niemann-Pick disease is characterized by severe neurological symptoms. (Correct Answer)
- D. Histiocytes show PAS positive inclusions, and Type A is more severe.
Explanation: ***Type B Niemann-Pick disease is characterized by severe neurological symptoms.*** - This statement is **false** because **Type B Niemann-Pick disease** generally presents with **visceral involvement** (e.g., hepatosplenomegaly, lung disease) with **minimal to no neurological symptoms**. - **Severe neurological symptoms** are characteristic of **Type A Niemann-Pick disease**, which involves widespread CNS degeneration and a more rapidly progressive course. *Due to deficiency of sphingomyelinase.* - This statement is **true**. - Niemann-Pick disease (Types A and B) is caused by a deficiency of the enzyme **acid sphingomyelinase**, leading to the accumulation of sphingomyelin within lysosomes, particularly in macrophages. *CNS symptoms are present in type A.* - This statement is **true**. - **Type A Niemann-Pick disease** is the most severe form and is characterized by significant **neurodegeneration** in addition to visceral involvement. - Patients typically present with **developmental regression**, **ataxia**, and **spasticity** due to extensive sphingomyelin deposition in the central nervous system. *Histiocytes show PAS positive inclusions, and Type A is more severe.* - This statement is **true**. - The characteristic "foam cells" (lipid-laden macrophages/histiocytes) found in tissues of Niemann-Pick patients stain positive with **periodic acid–Schiff (PAS)** due to accumulated sphingomyelin. - **Type A Niemann-Pick disease** is indeed the most severe form, with a rapidly progressive course and early fatality, usually by early childhood.
Question 8: A 10-month-old child with coarse facies is referred for developmental delay. On examination, hepatosplenomegaly was noted. WBC N-acetylglucosamine-1-phosphotransferase activity was absent. The X-ray is shown below. What is the diagnosis?
- A. I cell disease (Correct Answer)
- B. MPS type II
- C. Proteus syndrome
- D. Larsen syndrome
Explanation: ***I cell disease*** - **I-cell disease** (Mucolipidosis II) is characterized by **coarse facial features**, developmental delay, hepatosplenomegaly, and **skeletal abnormalities** (dysostosis multiplex) seen on X-ray, which are consistent with the image. - The absence of **N-acetylglucosamine-1-phosphotransferase (GlcNAc-1-phosphotransferase)** activity leads to misrouting of lysosomal enzymes, resulting in accumulation of mucolipids within cells. *MPS type II* - **MPS type II** (Hunter syndrome) also presents with coarse facies, developmental delay, and hepatosplenomegaly, and can show skeletal abnormalities. - However, the enzymatic defect is in **iduronate sulfatase**, not GlcNAc-1-phosphotransferase, and the clinical course tends to be slightly milder than I-cell disease, particularly in early infancy. *Proteus syndrome* - **Proteus syndrome** is characterized by **overgrowth of tissues**, asymmetric growth, and various tumors, not by the specific metabolic defect or typical pattern of skeletal changes described. - It does not involve absent GlcNAc-1-phosphotransferase activity. *Larsen syndrome* - **Larsen syndrome** primarily involves **skeletal abnormalities**, such as joint dislocations (especially knees, hips, and elbows), flattened facial appearance, and clubfoot. - It does not feature the same metabolic defect (absent GlcNAc-1-phosphotransferase activity) or the prominent coarse facial features and hepatosplenomegaly seen in the patient.
Question 9: A child born with microcephaly, chorioretinitis, and intracranial calcification. Most likely diagnosis is:
- A. Congenital syphilis
- B. Toxoplasmosis (Correct Answer)
- C. Rubella
- D. Trypanosomiasis
Explanation: ***Toxoplasmosis*** - The classic triad of **chorioretinitis**, **hydrocephalus** (or microcephaly), and **intracranial calcifications** is a hallmark of congenital toxoplasmosis. - **Intracranial calcifications** in toxoplasmosis are characteristically **diffuse and scattered** throughout the brain parenchyma (unlike CMV which causes periventricular calcifications). - **Microcephaly** results from central nervous system damage and inflammation. - Other features may include seizures, hepatosplenomegaly, and jaundice. *Congenital syphilis* - Characterized by manifestations such as **hepatosplenomegaly**, **bone abnormalities** (e.g., osteochondritis), rash, and rhinitis. - While it can cause CNS involvement, the specific triad of chorioretinitis and intracranial calcifications is not typical. *Rubella* - The classic congenital rubella syndrome triad includes **sensorineural hearing loss**, ocular defects (e.g., **cataracts**, **glaucoma**), and **congenital heart defects** (e.g., patent ductus arteriosus, pulmonary artery stenosis). - Although it can cause microcephaly, chorioretinitis and prominent intracranial calcifications are not characteristic features. *Trypanosomiasis* - Congenital trypanosomiasis (e.g., Chagas disease) can cause **cardiomyopathy**, **megaviscera** (megaesophagus, megacolon), and neurological symptoms. - It does not typically present with the described triad of chorioretinitis and intracranial calcifications.
Question 10: What is the commonest cause of obstructive hydrocephalus in children?
- A. Acqueductal stenosis (Correct Answer)
- B. Aquaductal gliosis
- C. Subarachnoid hemorrhage
- D. Tubercular meningitis
Explanation: **Explanation:** **1. Why Aqueductal Stenosis is Correct:** Aqueductal stenosis is the narrowing of the **Aqueduct of Sylvius** (which connects the third and fourth ventricles). It is the most common cause of **congenital obstructive (non-communicating) hydrocephalus** in infants and children. It can be caused by developmental narrowing, septa formation, or X-linked inheritance (Bickers-Adams syndrome). Because the blockage occurs within the ventricular system, CSF cannot reach the subarachnoid space, leading to proximal ventricular dilatation. **2. Analysis of Incorrect Options:** * **Aqueductal Gliosis:** This is usually a **secondary** process resulting from intrauterine infections (like Toxoplasmosis or CMV) or post-hemorrhagic scarring. While it causes obstruction, primary developmental stenosis is statistically more common. * **Subarachnoid Hemorrhage (SAH):** This typically causes **communicating (non-obstructive) hydrocephalus**. The blood products interfere with the absorption of CSF at the level of the arachnoid villi, rather than blocking the internal flow within the ventricles. * **Tubercular Meningitis (TBM):** TBM is the most common cause of **acquired** hydrocephalus in developing countries. However, it usually results in communicating hydrocephalus due to thick basal exudates blocking the subarachnoid space. **3. NEET-PG High-Yield Pearls:** * **Bickers-Adams Syndrome:** X-linked recessive aqueductal stenosis characterized by hydrocephalus, adducted thumbs, and intellectual disability. * **Clinical Sign:** "Setting-sun" eye phenomenon (downward gaze palsy due to pressure on the midbrain tectum). * **Diagnostic Choice:** MRI is the gold standard to visualize the level of obstruction. * **Treatment:** Endoscopic Third Ventriculostomy (ETV) is often preferred over shunting for aqueductal stenosis.
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