Genetic Disorders and Biochemical Pathology

Genetic Disorders and Biochemical Pathology Indian Medical PG Question 1: An infant presented with vomiting, malnutrition, blue eyes, blonde hair & fair skin. On investigation, Guthrie test was positive. All are true regarding this disease EXCEPT:

• A. Phenyl acetate positive in urine
• B. Mental retardation is present
• C. Hypopigmentation due to tryptophan deficiency (Correct Answer)
• D. Due to PAH enzyme defect

Genetic Disorders and Biochemical Pathology Explanation: ***Hypopigmentation due to tryptophan deficiency*** - The characteristic **hypopigmentation** (fair skin, blonde hair, blue eyes) in **phenylketonuria (PKU)** is due to **tyrosine deficiency**, not tryptophan deficiency. - **Phenylalanine hydroxylase (PAH)** deficiency leads to accumulation of phenylalanine, which cannot be converted to **tyrosine**. - **Tyrosine** is the precursor for **melanin synthesis** via the enzyme **tyrosinase**, so tyrosine deficiency results in decreased melanin production and hypopigmentation. *Phenyl acetate positive in urine* - In **phenylketonuria (PKU)**, **phenylalanine** accumulates and is shunted to alternative metabolic pathways, leading to the production and excretion of **phenylacetate, phenylpyruvate, and phenyllactate** in the urine. - The presence of these metabolites gives the urine a characteristic **mousey or musty odor**. *Mental retardation is present* - If **phenylketonuria (PKU)** is left untreated, the accumulation of **phenylalanine** is neurotoxic and leads to severe, **irreversible intellectual disability** and **developmental delay**. - Early detection through newborn screening (the **Guthrie test** detects elevated blood phenylalanine) and dietary phenylalanine restriction are crucial to prevent this outcome. *Due to PAH enzyme defect* - **Phenylketonuria (PKU)** is primarily caused by a deficiency in the enzyme **phenylalanine hydroxylase (PAH)**, which is responsible for converting phenylalanine to tyrosine. - This **autosomal recessive genetic disorder** leads to the accumulation of phenylalanine in the blood and tissues, causing the clinical manifestations.

Genetic Disorders and Biochemical Pathology Indian Medical PG Question 2: Which one of the following is an autosomal recessive disease?

• A. Retinitis pigmentosa
• B. Vitamin D resistant rickets
• C. Cystic fibrosis (Correct Answer)
• D. Neurofibromatosis

Genetic Disorders and Biochemical Pathology Explanation: ***Cystic fibrosis*** - **Cystic fibrosis** is caused by mutations in the **CFTR gene**, leading to defective chloride transport and thick, sticky mucus. - It is inherited in an **autosomal recessive pattern**, meaning an individual must inherit two copies of the mutated gene (one from each parent) to develop the disease. *Retinitis pigmentosa* - **Retinitis pigmentosa** is a group of inherited eye disorders, and while some forms are X-linked or autosomal dominant, a significant portion are also inherited in an **autosomal recessive pattern**. - However, it's not exclusively autosomal recessive, making cystic fibrosis a more definitive answer in this context. *Vitamin D resistant rickets* - **Vitamin D resistant rickets**, also known as **X-linked hypophosphatemic rickets**, is primarily inherited in an **X-linked dominant pattern**. - It is characterized by impaired renal phosphate reabsorption and skeletal abnormalities despite normal vitamin D levels. *Neurofibromatosis* - **Neurofibromatosis type 1 (NF1)** and **Neurofibromatosis type 2 (NF2)** are both inherited in an **autosomal dominant pattern**. - NF1 is characterized by **café-au-lait spots**, **neurofibromas**, and optical gliomas, while NF2 involves **bilateral vestibular schwannomas**.

Genetic Disorders and Biochemical Pathology Indian Medical PG Question 3: Which one of the following conditions can be screened during neonatal screening by biochemical tests?

• A. Congenital dislocation of hip
• B. Congenital rubella
• C. Chromosomal abnormalities
• D. Congenital hypothyroidism (Correct Answer)

Genetic Disorders and Biochemical Pathology Explanation: ***Congenital hypothyroidism*** - **Neonatal screening** for congenital hypothyroidism is a standard practice, using biochemical tests to measure **thyroid-stimulating hormone (TSH)** and **thyroxine (T4)** levels in dried blood spots. - Early detection and treatment prevent severe **intellectual disability** and developmental delays caused by thyroid hormone deficiency. *Congenital dislocation of hip* - This condition is primarily screened through **physical examination** (e.g., Ortolani and Barlow maneuvers) and imaging (e.g., ultrasound), not biochemical tests. - It involves a structural abnormality of the hip joint, not a metabolic or biochemical disorder. *Congenital rubella* - Diagnosis of congenital rubella involves detecting **rubella-specific IgM antibodies** or viral RNA, which are immunological/virological tests, not typical biochemical screening. - This is an infectious disease, not an inborn error of metabolism screened biochemically. *Chromosomal abnormalities* - Conditions like Down syndrome (Trisomy 21) are detected through **karyotyping** or **genetic tests**, which examine the number and structure of chromosomes. - While some biochemical markers are used in prenatal screening for chromosomal abnormalities (e.g., quad screen), direct neonatal screening for chromosomal abnormalities is not performed via general biochemical tests.

Genetic Disorders and Biochemical Pathology Indian Medical PG Question 4: Glutamine is increased in CSF, blood & urine WITHOUT elevated orotic acid in which defect:

• A. Arginase
• B. Argininosuccinate lyase deficiency
• C. CPS-I (Correct Answer)
• D. Arginosuccinate synthetase
• E. OTC

Genetic Disorders and Biochemical Pathology Explanation: ***CPS-I*** - A deficiency in **Carbamoyl Phosphate Synthetase I (CPS-I)** leads to a severe block in the **urea cycle**, resulting in profound hyperammonemia. - The elevated ammonia is then shunted to produce more **glutamine** (via glutamine synthetase), which serves as a detoxification mechanism but also causes high levels of glutamine in CSF, blood, and urine. *Arginase* - **Arginase deficiency** primarily leads to elevated **arginine** levels and mild to moderate hyperammonemia, but not typically a dramatic increase in glutamine due to the block occurring later in the cycle. - Clinical features include progressive spasticity, growth retardation, and intellectual disability. *Argininosuccinate lyase deficiency* - This deficiency causes accumulation of **argininosuccinate** in body fluids, which is a diagnostic marker, rather than primarily increased glutamine. - It presents with severe hyperammonemia, neurological symptoms, and often hepatomegaly. *Arginosuccinate synthetase* - A deficiency in **argininosuccinate synthetase** (also known as citrullinemia type I) leads to a buildup of **citrulline** and severe hyperammonemia. - While hyperammonemia can indirectly increase glutamine, the primary diagnostic marker is elevated citrulline, and the glutamine increase is not as pronounced or directly symptomatic as in CPS-I deficiency. *OTC* - **Ornithine Transcarbamylase (OTC) deficiency** is the most common urea cycle disorder and leads to severe hyperammonemia, accompanied by elevated **orotic acid** due to carbamoyl phosphate shunting to pyrimidine synthesis. - While hyperammonemia drives glutamine synthesis, the presence of elevated orotic acid is a key differentiator from CPS-I deficiency, which does not have increased orotic acid.

Genetic Disorders and Biochemical Pathology Indian Medical PG Question 5: Phenylketonuria is due to deficiency of:

• A. Phenylalanine (amino acid)
• B. Tyrosine
• C. Phenylalanine hydroxylase (PAH) (Correct Answer)
• D. None of the options

Genetic Disorders and Biochemical Pathology Explanation: ***Phenylalanine hydroxylase (PAH)*** - **Phenylketonuria (PKU)** is an inherited metabolic disorder caused by a deficiency of the enzyme **phenylalanine hydroxylase (PAH)**. - This enzyme is crucial for converting the amino acid **phenylalanine** into **tyrosine**, and its deficiency leads to an accumulation of phenylalanine in the body. - PKU follows an **autosomal recessive** inheritance pattern. *Phenylalanine (amino acid)* - While **phenylalanine** accumulates to toxic levels in PKU, it is the substrate, not the deficient component. - The disease stems from the body's inability to metabolize this amino acid due to the enzyme deficiency. *Tyrosine* - **Tyrosine** is the product of the reaction catalyzed by PAH, and its production is limited in PKU. - However, the deficiency of tyrosine is a secondary effect, not the primary cause of PKU. *None of the options* - This option is incorrect because the deficiency of **phenylalanine hydroxylase (PAH)** is precisely the cause of Phenylketonuria.

Genetic Disorders and Biochemical Pathology Indian Medical PG Question 6: Which one of the following is an autosomal dominant disorder?

• A. Cystic fibrosis
• B. Hereditary spherocytosis (Correct Answer)
• C. Sickle cell anemia
• D. G-6PD deficiency

Genetic Disorders and Biochemical Pathology Explanation: ***Hereditary spherocytosis*** - It is characterized by **autosomal dominant inheritance** [1], leading to the destruction of red blood cells. - Mutations in proteins that maintain the **red blood cell membrane** integrity result in spherocyte formation [1]. *Cystic fibrosis* - This condition follows a **autosomal recessive inheritance pattern**, requiring two copies of the mutated gene for disease manifestation. - It is caused by mutations in the **CFTR gene**, affecting chloride transport and leading to thick secretions. *G-6PD deficiency* - This disorder is inherited in an **X-linked recessive manner** [2], primarily affecting males and transmitted through carrier females. - Characterized by **hemolytic anemia** triggered by certain medications or infections, it does not follow dominant inheritance [2]. *Sickle cell anemia* - Sickle cell anemia is also an **autosomal recessive disorder** [3], meaning affected individuals must inherit two copies of the sickle cell gene. - It results in a mutation in the **HBB gene**, leading to the production of abnormal hemoglobin (HbS) [3].

Genetic Disorders and Biochemical Pathology Indian Medical PG Question 7: Sweaty feet odor in urine is seen in which condition?

• A. Phenylketonuria
• B. Isovaleric acidemia (Correct Answer)
• C. Alkaptonuria
• D. Maple syrup urine disease

Genetic Disorders and Biochemical Pathology Explanation: ***Isovaleric acidemia*** - This condition is characterized by a distinctive "sweaty feet" odor in body fluids, including urine, due to the accumulation of **isovaleric acid**. - It results from a deficiency in the enzyme **isovaleryl-CoA dehydrogenase**, which is crucial for leucine metabolism. *Phenylketonuria* - Patients with **phenylketonuria (PKU)** typically have a "mousy" or "musty" odor in their urine, not a sweaty feet smell. - This is due to the accumulation of **phenylalanine** and its metabolites. *Maple syrup urine disease* - This metabolic disorder is named for the characteristic sweet, maple syrup-like odor of the urine, which is distinctly different from a sweaty feet odor. - It is caused by a defect in the metabolism of **branched-chain amino acids (leucine, isoleucine, and valine)**. *Alkaptonuria* - This condition is known for urine that turns **dark brown or black** upon standing or when exposed to air, due to the oxidation of **homogentisic acid**. - It does not produce a sweaty feet odor.

Genetic Disorders and Biochemical Pathology Indian Medical PG Question 8: Which of the following is a sex-linked disorder?

• A. Hemophilia (Correct Answer)
• B. Neurofibromatosis
• C. Klinefelter's syndrome
• D. Thalassemia

Genetic Disorders and Biochemical Pathology Explanation: ***Hemophilia*** - Hemophilia is an **X-linked recessive disorder**, meaning the gene responsible is located on the X chromosome. - Males are predominantly affected because they have only one X chromosome, so a single copy of the mutated gene is sufficient to cause the disease. *Neurofibromatosis* - Neurofibromatosis is an **autosomal dominant disorder**, meaning a single copy of the mutated gene on a non-sex chromosome is enough to cause the condition. - It affects males and females equally and is characterized by tumors along nerves and skin changes. *Klinefelter's syndrome* - Klinefelter's syndrome is a **chromosomal disorder** resulting from an extra X chromosome in males (XXY), not a single gene mutation on a sex chromosome. - While it involves sex chromosomes, it's categorized as a **sex chromosome aneuploidy** rather than a sex-linked disorder in the traditional genetic sense. *Thalassemia* - Thalassemia is an **autosomal recessive disorder**, meaning it requires two copies of the mutated gene (one from each parent) on non-sex chromosomes to manifest. - It affects the production of hemoglobin and impacts males and females equally.

Genetic Disorders and Biochemical Pathology Indian Medical PG Question 9: The patient shown here is suffering from deficiency of which enzyme?

• A. Xanthine oxidase
• B. HGPRTase (Correct Answer)
• C. Glucose-6-phosphate dehydrogenase
• D. Adenosine deaminase

Genetic Disorders and Biochemical Pathology Explanation: ***HGPRTase*** - **HGPRTase deficiency** causes **Lesch-Nyhan syndrome** with characteristic **self-mutilation behavior**, choreoathetosis, and severe intellectual disability. - Clinical features include **orange sand-like crystals** in diapers due to hyperuricemia, **compulsive self-biting**, and **dystonia** as shown in the patient. *Adenosine deaminase* - **ADA deficiency** causes **SCID** with recurrent infections, lymphopenia, and failure to thrive in early infancy. - Clinical presentation focuses on **immunodeficiency** with chronic infections rather than neurological and behavioral abnormalities. *Xanthine oxidase* - **Xanthine oxidase deficiency** leads to **xanthinuria** with accumulation of xanthine causing kidney stones. - Patients present with **nephrolithiasis** and muscle pain but lack the neurological and self-destructive behaviors seen here. *Glucose-6-phosphate dehydrogenase* - **G6PD deficiency** causes **hemolytic anemia** triggered by oxidative stress from drugs, infections, or fava beans. - Features include **jaundice**, dark urine, and acute hemolysis but not the characteristic **neurological dysfunction** and **self-mutilation** of Lesch-Nyhan syndrome.

Genetic Disorders and Biochemical Pathology Indian Medical PG Question 10: What is the diagnosis in a patient who presents with nausea and vomiting, initially responds to intravenous glucose, but later develops increased blood glutamine and orotic acid levels?

• A. CPS-I deficiency
• B. Arginino succinate synthetase deficiency
• C. CPS-II deficiency
• D. Ornithine transcarbamoylase deficiency (Correct Answer)

Genetic Disorders and Biochemical Pathology Explanation: ***Ornithine transcarbamoylase deficiency*** - **Ornithine transcarbamoylase (OTC) deficiency** is an X-linked urea cycle disorder that leads to the accumulation of **carbamoyl phosphate**. - This excess carbamoyl phosphate is shunted into pyrimidine synthesis, resulting in increased **orotic acid** and **glutamine** levels, and symptoms like nausea and vomiting due to hyperammonemia. *CPS-I deficiency* - **Carbamoyl phosphate synthetase I (CPS-I) deficiency** also causes hyperammonemia but does not involve elevated **orotic acid**, as the pathway leading to pyrimidine synthesis is not overstimulated. - This deficiency would present with high ammonia and glutamine levels, but **normal or low orotic acid**. *Arginino succinate synthetase deficiency* - **Argininosuccinate synthetase deficiency** (citrullinemia) is characterized by very high plasma **citrulline** levels, which are not mentioned in this patient's presentation. - While it is a urea cycle disorder causing hyperammonemia, the diagnostic marker of elevated citrulline differentiates it from OTC deficiency. *CPS-II deficiency* - **Carbamoyl phosphate synthetase II (CPS-II)** is involved in *de novo* pyrimidine synthesis and is not part of the urea cycle. - A deficiency in CPS-II would typically lead to **pyrimidine starvation** rather than hyperammonemia or elevated orotic acid.

Genetic Disorders and Biochemical Pathology Flashcard 1 of 10

Question: Fabry s disease is inherited as _____ disorder.

Answer: X-linked recessive

Genetic Disorders and Biochemical Pathology Flashcard 2 of 10

Question: _____ occurs due to the inability to convert orotic acid to UMP due to a defect in the enzyme UMP synthase (pyrimidine synthesis)

Answer: Orotic aciduria

Genetic Disorders and Biochemical Pathology Flashcard 3 of 10

Question: _____ syndrome is a rare multisystem disorder of copper metabolism with features of both Wilsons and Menkes disease.

Answer: MEDNIK

Genetic Disorders and Biochemical Pathology Flashcard 4 of 10

Question: Treatment for phenylketonuria includes a diet low in _____ with supplemental tyrosine +/- tetrahydrobiopterin

Answer: phenylalanine

Genetic Disorders and Biochemical Pathology Flashcard 5 of 10

Question: Pearson syndrome is a mitochondrial inheritence disorder characterised by _____ insufficiency, pancytopenia and lactic acidosis

Answer: pancreatic

Genetic Disorders and Biochemical Pathology Flashcard 6 of 10

Question: Which epileptic syndrome has been associated with mutations in genes: ? _____

Answer: Juvenile myoclonic epilepsy

Genetic Disorders and Biochemical Pathology Flashcard 7 of 10

Question: The following symbol represents _____zygotic twins on a pedigree chart

Answer: di

Genetic Disorders and Biochemical Pathology Flashcard 8 of 10

Question: _____ disease is caused by a deficiency of the enzyme branching enzyme

Answer: Andersen

Genetic Disorders and Biochemical Pathology Flashcard 9 of 10

Question: The enzyme _____ is deficient in metachromatic leukodystrophy

Answer: arylsulfatase A

Genetic Disorders and Biochemical Pathology Flashcard 10 of 10

Question: _____ is characterized by a deficiency of the enzyme aldolase B

Answer: Hereditary fructose intolerance