Genetic Disorders and Biochemical Pathology Practice Questions

Q: Enzyme replacement therapy is available for all of the following conditions except:

Sanfilippo disease. **Explanation:** The correct answer is **Sanfilippo disease (Mucopolysaccharidosis III)**. The primary challenge in Enzyme Replacement Therapy (ERT) for Lysosomal Storage Disorders (LSDs) is the **Blood-Brain Barrier (BBB)**. Intravenously administered enzymes are large molecules that cannot cross the BBB to reach the Central Nervous System (CNS). * **Sanfilippo disease** is characterized predominantly by severe, progressive neurological deterioration and cognitive decline. Because the pathology is almost exclusively within the CNS, standard systemic ERT is ineffective. While research into intrathecal delivery is ongoing, there is currently no FDA-approved ERT for Sanfilippo syndrome. * **Gaucher’s disease (Type 1):** This was the first LSD treated with ERT (Imiglucerase). It targets systemic manifestations like hepatosplenomegaly and cytopenia. * **Pompe disease:** Treated with Alglucosidase alfa, which targets the accumulation of glycogen in cardiac and skeletal muscle. * **Fabry disease:** Treated with Agalsidase alfa/beta to manage systemic complications like renal failure and cardiovascular issues. **NEET-PG High-Yield Pearls:** 1. **Gaucher Disease:** Most common LSD; characterized by "crumpled tissue paper" appearance of macrophages. 2. **Pompe Disease:** The only glycogen storage disease (Type II) that is also a lysosomal storage disorder (Acid maltase deficiency). 3. **Sanfilippo Syndrome:** Caused by a deficiency in enzymes required to break down **Heparan sulfate**. 4. **I-Cell Disease:** Caused by a failure of mannose-6-phosphate tagging, leading to enzymes being secreted extracellularly rather than reaching lysosomes.

Q: A 6-year-old mentally retarded male patient presents with hepatosplenomegaly, coarse facial features, corneal clouding, a large tongue, prominent forehead, joint stiffness, short stature, and skeletal dysplasia. What is the diagnosis?

Hurler’s Disease. ### Explanation The clinical presentation describes a classic case of **Hurler’s Disease (MPS IH)**, the most severe form of Mucopolysaccharidosis. It is caused by a deficiency of the lysosomal enzyme **$\alpha$-L-iduronidase**, leading to the accumulation of dermatan sulfate and heparan sulfate. **Why Hurler’s Disease is Correct:** The presence of **corneal clouding** combined with mental retardation, hepatosplenomegaly, and skeletal deformities (dysostosis multiplex) is the pathognomonic triad for Hurler’s. The "coarse" facial features (gargoylism) and macroglossia are due to the progressive deposition of glycosaminoglycans (GAGs) in various tissues. **Analysis of Incorrect Options:** * **Hunter Disease (MPS II):** Clinically similar to Hurler’s but distinguished by the **absence of corneal clouding** and an **X-linked recessive** inheritance (Hurler is Autosomal Recessive). Patients often exhibit aggressive behavior. * **Natowicz Syndrome (MPS IX):** A very rare deficiency of hyaluronidase. It typically presents with periarticular soft tissue masses and short stature, but lacks the severe systemic and corneal involvement seen here. * **Maroteaux-Lamy Syndrome (MPS VI):** While it features corneal clouding and skeletal dysplasia, **intellectual ability is typically normal**. The mental retardation in this case points specifically toward Hurler’s. **High-Yield NEET-PG Pearls:** * **Enzyme Defect:** $\alpha$-L-iduronidase (Hurler) vs. Iduronate sulfatase (Hunter). * **Inheritance:** All MPS are Autosomal Recessive except Hunter (X-linked). * **Urine Test:** Positive for increased GAGs (Dermatan and Heparan sulfate). * **Zebra Bodies:** Characteristic inclusion bodies seen on electron microscopy in MPS. * **Memory Aid:** "The **Hunter** needs clear eyes to see the **X** (X-linked) on the target" (No corneal clouding in Hunter).

Q: Sweat chloride levels are typically observed to be in which of the following states in patients with cystic fibrosis?

Increased. **Explanation:** **Cystic Fibrosis (CF)** is an autosomal recessive disorder caused by a mutation in the **CFTR (Cystic Fibrosis Transmembrane Conductance Regulator)** gene. This gene encodes a chloride channel that functions differently depending on the tissue type. 1. **Why the answer is Increased:** In the **sweat glands**, the CFTR protein is responsible for the **reabsorption** of chloride from the primary secretion back into the ductal cells. Sodium follows chloride to maintain electrical neutrality. In CF, the defective CFTR protein prevents this reabsorption. Consequently, high amounts of sodium and chloride remain in the sweat, leading to the characteristic **increased sweat chloride levels** (typically >60 mmol/L). 2. **Why other options are wrong:** * **Decreased/No change:** These are incorrect because the fundamental defect in CF sweat glands is the inability to remove chloride from the lumen, making the sweat hypertonic compared to healthy individuals. * **May increase or decrease:** While sweat chloride levels can vary based on the specific mutation (genotype), they are consistently **elevated** in symptomatic CF patients. They do not decrease below normal physiological levels. **High-Yield Clinical Pearls for NEET-PG:** * **Gold Standard Diagnosis:** The **Pilocarpine Iontophoresis Sweat Test** remains the investigation of choice. * **Diagnostic Threshold:** Sweat chloride **≥60 mmol/L** on two separate occasions is diagnostic. * **False Positives:** Conditions like adrenal insufficiency, untreated hypothyroidism, and malnutrition can sometimes cause elevated sweat chloride. * **The "Salty Baby" Sign:** Parents often report a salty taste when kissing the child, which is a classic clinical clue. * **Contrast with Lungs:** In the respiratory tract, CFTR failure leads to decreased chloride secretion and increased sodium/water reabsorption, resulting in thick, dehydrated mucus.

Q: A 5-day-old child presents with intractable seizures and generalized rashes. Blood examination shows hyperammonemia and lactic acidosis. What is the probable diagnosis?

Organic aciduria. ### Explanation The clinical presentation of a neonate with **intractable seizures**, **hyperammonemia**, and **lactic acidosis** is classic for **Organic Aciduria** (e.g., Methylmalonic acidemia, Propionic acidemia). **1. Why Organic Aciduria is Correct:** Organic acidurias are metabolic disorders characterized by the accumulation of organic acids in blood and urine. * **Lactic Acidosis:** The accumulation of toxic metabolites inhibits the pyruvate dehydrogenase complex, leading to secondary lactic acidosis. * **Hyperammonemia:** High levels of organic acids inhibit the first step of the urea cycle (N-acetylglutamate synthase), leading to elevated ammonia levels. * **Clinical Clues:** The presence of **generalized rashes** (often erythematous or desquamating) and **intractable seizures** in the first week of life are hallmark signs of these metabolic crises. **2. Why Other Options are Incorrect:** * **Mitochondrial Encephalopathy (MELAS):** While it causes lactic acidosis and seizures, it rarely presents with significant hyperammonemia or skin rashes in the first 5 days of life. * **Phenylketonuria (PKU):** Presents later with developmental delay and "mousy odor." It does **not** cause acute hyperammonemia or lactic acidosis. * **Urea Cycle Enzyme Deficiencies (UCDs):** While UCDs cause severe hyperammonemia and seizures, they typically present with a **normal or low anion gap** and **no lactic acidosis**. The pH is usually alkalotic (respiratory alkalosis) due to hyperventilation triggered by ammonia. **High-Yield Clinical Pearls for NEET-PG:** * **Differentiating Point:** Hyperammonemia + Ketosis/Acidosis = **Organic Aciduria**. * **Differentiating Point:** Hyperammonemia + Respiratory Alkalosis = **Urea Cycle Disorder**. * **Sweet/Fruity Odor:** Isovaleric acidemia ("sweaty feet" odor). * **Initial Management:** Stop protein intake, start IV glucose, and consider peritoneal dialysis/hemodialysis to remove ammonia.

Q: Amyloid precursor protein is cleaved by ______ and ________ in Alzheimer's disease?

β secretase , γ secretase. ### Explanation **Concept Overview:** Alzheimer’s disease is characterized by the accumulation of **Amyloid-beta (Aβ) plaques** in the brain. These plaques are derived from the **Amyloid Precursor Protein (APP)**, a transmembrane protein. The fate of APP depends on which enzymes cleave it, following either a non-amyloidogenic or an amyloidogenic pathway. **Why Option C is Correct:** In the **amyloidogenic pathway** (pathological), APP is first cleaved by **β-secretase** (BACE1), releasing a soluble fragment and leaving a C-terminal fragment in the membrane. This is followed by cleavage by **γ-secretase** (presenilin complex). This sequential cleavage releases the **Aβ peptide** (specifically Aβ42), which is prone to aggregation, forming the neurotoxic plaques seen in Alzheimer’s. **Analysis of Incorrect Options:** * **Options A, B, and D:** These involve **α-secretase**. In the **non-amyloidogenic pathway** (physiological), α-secretase cleaves APP within the Aβ domain itself. This prevents the formation of the Aβ peptide and instead produces soluble APPα, which is considered neuroprotective. Therefore, any pathway involving α-secretase does not lead to the pathology of Alzheimer's. **NEET-PG High-Yield Pearls:** * **Presenilin 1 & 2:** Mutations in these genes (components of γ-secretase) are the most common cause of **Early-onset Familial Alzheimer’s Disease**. * **Trisomy 21 (Down Syndrome):** The gene for APP is located on **Chromosome 21**. This explains why patients with Down Syndrome develop Alzheimer’s pathology prematurely (by age 40). * **ApoE4:** The ε4 allele of Apolipoprotein E is the strongest genetic risk factor for late-onset sporadic Alzheimer’s. * **Histology:** Look for **Extracellular** Amyloid plaques and **Intracellular** Neurofibrillary tangles (composed of hyperphosphorylated **Tau protein**).

Q: What is true about Fragile X syndrome?

Involves a triplet nucleotide repeat sequence. **Explanation:** **Fragile X Syndrome (FXS)** is the most common cause of inherited intellectual disability and the second most common genetic cause of intellectual disability after Down syndrome. **1. Why Option A is Correct:** Fragile X syndrome is a classic example of a **Trinucleotide Repeat Expansion disorder**. It is caused by the expansion of the **CGG repeat** in the 5' untranslated region of the ***FMR1* gene** located on the X chromosome. * **Normal:** 200 repeats. This expansion leads to **hypermethylation** of the promoter region, effectively silencing the gene and resulting in a deficiency of the Fragile X Mental Retardation Protein (FMRP), which is essential for normal brain development. **2. Why Other Options are Incorrect:** * **Option B:** While the name "Fragile X" comes from the appearance of a "broken" or constricted site on the X chromosome when cultured in folate-deficient medium, there is no actual **chromosomal breaking** or instability in vivo. It is a gene mutation, not a breakage syndrome like Fanconi anemia. * **Option C:** FXS follows an **X-linked dominant** inheritance pattern with variable expressivity (anticipation), not mitochondrial inheritance. * **Option D:** "Centrochrome" is not a standard biological term relevant to this pathology. **High-Yield Clinical Pearls for NEET-PG:** * **Clinical Triad:** Intellectual disability, **Macroorchidism** (enlarged testes, post-pubertal), and long face with large everted ears. * **Genetics:** Shows **Anticipation** (severity increases in successive generations) and the **Sherman Paradox**. * **Diagnosis:** PCR or Southern Blot (to detect repeat size). * **Behavioral:** Highly associated with Autism Spectrum Disorder (ASD) and ADHD.

Q: Which condition is caused by a deficiency of fibrillin 1?

Marfan syndrome. **Explanation:** **Marfan syndrome** is an autosomal dominant connective tissue disorder caused by a mutation in the **FBN1 gene** located on chromosome 15q21. This gene encodes **fibrillin-1**, a glycoprotein that serves as a major structural component of extracellular microfibrils. These microfibrils provide a scaffold for elastin deposition and regulate **TGF-β (Transforming Growth Factor beta)** signaling. A deficiency leads to weakened connective tissue and excessive TGF-β activation, resulting in the characteristic skeletal, ocular, and cardiovascular manifestations. **Analysis of Incorrect Options:** * **Ehlers-Danlos syndrome:** This is a heterogeneous group of disorders primarily caused by defects in the synthesis or structure of **fibrillar collagen** (e.g., Type V collagen in the Classical type, Type III in the Vascular type), not fibrillin. * **Osteogenesis imperfecta:** Also known as "brittle bone disease," it is most commonly caused by mutations in the genes encoding **Type I collagen** (COL1A1 and COL1A2). * **Angelman syndrome:** This is a neurogenetic disorder caused by the loss of function of the **UBE3A gene** on chromosome 15 (maternal inheritance/imprinting), unrelated to structural proteins or connective tissue. **High-Yield Clinical Pearls for NEET-PG:** * **Cardiovascular:** The most common cause of death is **Aortic Root Dilatation** leading to aortic dissection or aneurysm. Mitral Valve Prolapse (MVP) is also frequent. * **Ocular:** Characterized by **Ectopia lentis** (dislocation of the lens), typically **upward and outward** (superior subluxation). * **Skeletal:** Tall stature, arachnodactyly (long fingers), pectus excavatum, and a high-arched palate. * **Mnemonic:** Marfan = **M**utation in **F**ibrillin-1 on chromosome **15** (Fifteen/Fibrillin).

Q: A child presents with hypotonia and seizures, confirmed to be cerebrohepatorenal syndrome. Which of the following is accumulated in the brain in cerebrohepatorenal syndrome?

Long chain fatty acid. **Explanation:** **Cerebrohepatorenal syndrome**, also known as **Zellweger Syndrome**, is the most severe form of peroxisomal biogenesis disorders. It is caused by mutations in *PEX* genes, which are essential for the normal assembly and function of peroxisomes. **Why the correct answer is right:** Peroxisomes are the primary site for the **$\beta$-oxidation of Very Long Chain Fatty Acids (VLCFA)**—fatty acids with 22 or more carbons. In Zellweger syndrome, the absence of functional peroxisomes leads to a failure in breaking down these lipids. Consequently, **VLCFAs (specifically C24 and C26)** accumulate in the blood and tissues, particularly the brain (causing demyelination and seizures) and the liver (causing hepatomegaly and jaundice). **Why the incorrect options are wrong:** * **A. Glucose:** Glucose metabolism occurs primarily in the cytosol and mitochondria. While hypoglycemia can occur in liver failure, glucose does not "accumulate" as a pathological hallmark of this syndrome. * **C. Triglycerides:** These are stored in adipose tissue and processed via lipolysis. Their accumulation is characteristic of conditions like Wolman disease or simple steatosis, not peroxisomal disorders. * **D. Lactic acid:** Lactic acidosis is a hallmark of mitochondrial disorders (e.g., MELAS) or defects in the Pyruvate Dehydrogenase complex, not peroxisomal biogenesis. **High-Yield Clinical Pearls for NEET-PG:** * **Triad of Zellweger:** Hypotonia (floppy baby), Seizures, and Hepatomegaly. * **Dysmorphism:** Look for a high forehead, large anterior fontanelle, and "stippled epiphyses" (chondrodysplasia punctata) on X-ray. * **Biochemical Marker:** Elevated plasma levels of **VLCFA** is the definitive diagnostic test. * **Prognosis:** Usually fatal within the first year of life.

Question 1

Enzyme replacement therapy is available for all of the following conditions except:

Accepted Answer

Sanfilippo disease

Answer

Gaucher's disease

Answer

Pompe disease

Answer

Fabry disease

Question 2

A 6-year-old mentally retarded male patient presents with hepatosplenomegaly, coarse facial features, corneal clouding, a large tongue, prominent forehead, joint stiffness, short stature, and skeletal dysplasia. What is the diagnosis?

Accepted Answer

Hurler’s Disease

Answer

Hunter Disease

Answer

Natowicz syndrome

Answer

Maroteaux-Lamy syndrome

Question 3

Sweat chloride levels are typically observed to be in which of the following states in patients with cystic fibrosis?

Accepted Answer

Increased

Answer

Decreased

Answer

No change

Answer

May increase or decrease

Question 4

Calcification of the intervertebral disc is present in which of the following conditions?

Accepted Answer

Ankylosing spondylitis

Answer

Maple syrup urine disease

Answer

Homocystinuria

Answer

Achondroplasia

Question 5

A 5-day-old child presents with intractable seizures and generalized rashes. Blood examination shows hyperammonemia and lactic acidosis. What is the probable diagnosis?

Accepted Answer

Organic aciduria

Answer

Mitochondrial encephalopathy with lactic aciduria

Answer

Phenylketonuria

Answer

Urea cycle enzyme deficiency

Question 6

Amyloid precursor protein is cleaved by ______ and ________ in Alzheimer's disease?

Accepted Answer

β secretase , γ secretase

Answer

α secretase , γ secretase

Answer

α secretase , β secretase

Answer

β secretase , α secretase

Question 7

What is true about Fragile X syndrome?

Accepted Answer

Involves a triplet nucleotide repeat sequence

Answer

Characterized by chromosomal breaking

Answer

Caused by a mitochondrial mutation

Answer

Absence of a centrochrome

Question 8

Which condition is caused by a deficiency of fibrillin 1?

Accepted Answer

Marfan syndrome

Answer

Ehlers-Danlos syndrome

Answer

Osteogenesis imperfecta

Answer

Angelman syndrome

Question 9

A child presents with hypotonia and seizures, confirmed to be cerebrohepatorenal syndrome. Which of the following is accumulated in the brain in cerebrohepatorenal syndrome?

Accepted Answer

Long chain fatty acid

Answer

Glucose

Answer

Triglycerides

Answer

Lactic acid

Question 10

A child presented with deranged developmental milestones and hyperactivity, later developed self-mutilating behavior and hair-pulling behavior, and died a few years later. Which enzyme deficiency is most likely implicated?

Accepted Answer

Hypoxanthine-guanine phosphoribosyltransferase (HGPT)

Answer

Phenylalanine hydroxylase

Answer

Adenosine deaminase

Answer

Hexosaminidase A

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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