Genetic Disorders and Biochemical Pathology Practice Questions

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.

Q: Which chromosomal compliment is associated with Turner syndrome?

Turner syndrome. **Explanation:** **Turner Syndrome (45, XO)** is the correct answer. It is a form of gonadal dysgenesis caused by the complete or partial absence of one X chromosome in females. This occurs most commonly due to **nondisjunction** during paternal meiosis. The lack of the second sex chromosome leads to the characteristic "streak ovaries" and a deficiency in estrogen. **Analysis of Incorrect Options:** * **Edward Syndrome (Trisomy 18):** This is an autosomal chromosomal disorder characterized by an extra copy of chromosome 18. Key features include "rocker-bottom" feet, micrognathia, and clenched fists with overlapping fingers. * **Patau Syndrome (Trisomy 13):** This involves an extra copy of chromosome 13. It presents with severe midline defects such as holoprosencephaly, cleft lip/palate, and polydactyly. * **Klinefelter Syndrome (47, XXY):** This is a male chromosomal disorder where there is at least one extra X chromosome. It presents with testicular atrophy, gynecomastia, and a tall, eunuchoid body habitus. **High-Yield Clinical Pearls for NEET-PG:** * **Most common cause of primary amenorrhea:** Turner Syndrome. * **Cardiovascular associations:** Bicuspid aortic valve (most common) and Coarctation of the aorta. * **Physical findings:** Webbed neck (cystic hygroma), short stature, and widely spaced nipples (shield chest). * **Renal anomaly:** Horseshoe kidney. * **Biochemical profile:** Elevated LH and FSH (Hypergonadotropic hypogonadism) due to lack of feedback inhibition from estrogen.

Q: Phenylketonuria is inherited in which pattern?

Autosomal recessive. **Explanation:** **Phenylketonuria (PKU)** is a classic example of an **Autosomal Recessive (AR)** disorder. It is primarily caused by a deficiency of the hepatic enzyme **Phenylalanine Hydroxylase (PAH)**, or less commonly, its cofactor **Tetrahydrobiopterin (BH4)**. In AR inheritance, an individual must inherit two mutated alleles (one from each carrier parent) to manifest the disease. This pattern is typical for most inborn errors of metabolism involving enzyme deficiencies, as a single functional gene (in heterozygotes) usually produces enough enzyme to maintain normal metabolic function. **Analysis of Incorrect Options:** * **Autosomal Dominant (AD):** These disorders typically involve structural proteins (e.g., Marfan syndrome) or receptors (e.g., Familial Hypercholesterolemia). A single mutant allele is sufficient to cause the phenotype. * **X-linked Dominant:** These are rare (e.g., Alport syndrome, Vitamin D-resistant rickets) and affect both males and females, often being more severe in males. * **X-linked Recessive:** These primarily affect males (e.g., Hemophilia, G6PD deficiency). PKU affects both sexes equally, ruling out X-linked inheritance. **High-Yield Clinical Pearls for NEET-PG:** * **Biochemical Hallmark:** Accumulation of Phenylalanine and its metabolites (Phenylpyruvate, Phenyllactate, Phenylacetate) in blood and urine. * **Clinical Presentation:** Intellectual disability, **"Mousy/Musty" body odor**, microcephaly, and hypopigmentation (due to decreased melanin synthesis). * **Diagnosis:** Guthrie Test (bacterial inhibition assay) or Tandem Mass Spectrometry (TMS) for newborn screening. * **Management:** Lifelong restriction of dietary Phenylalanine; Tyrosine becomes an **essential amino acid** for these patients.

Question 1

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 2

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 3

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 4

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 5

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 6

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 7

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 8

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

Question 9

Which chromosomal compliment is associated with Turner syndrome?

Accepted Answer

Turner syndrome

Answer

Edward syndrome

Answer

Patau syndrome

Answer

Klinefelter syndrome

Question 10

Phenylketonuria is inherited in which pattern?

Accepted Answer

Autosomal recessive

Answer

Autosomal dominant

Answer

X-linked dominant

Answer

X-linked recessive

Genetic Disorders and Biochemical Pathology — MCQs

Genetic Disorders and Biochemical Pathology — MCQs

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