Clinical Cases of Proteins

Dr Ashish Anjankar

Case Scenario 1:

A 6-month-old infant is brought to the pediatric clinic with complaints of delayed milestones, irritability, and a musty odour in the urine. On examination, the baby has fair skin, blond hair, and blue eyes. The paediatrician suspects an inborn error of metabolism and orders blood tests, which reveal elevated levels of phenylalanine.

  1. State the probable diagnosis.
  2. Explain the affected metabolic reaction in the above condition.
  3. Describe the disorder under the clinical features with biochemical basis, diagnosis and Management.

Answer:

  1. Phenylketonuria
  2. Phenylketonuria is an autosomal recessive disorder caused by a deficiency of the enzyme phenylalanine hydroxylase (PAH), which converts phenylalanine to tyrosine. In the absence of PAH activity, phenylalanine accumulates and is converted into phenylketones, which are neurotoxic.
  3. Clinical Features with Biochemical basis
    • Intellectual disability due to toxic effects on brain development.
    • Delayed milestones and developmental delay.
    • Seizures and irritability.
    • Hypopigmentation: fair skin, hair, and blue eyes due to decreased melanin synthesis.
    • Musty or mousy odor of urine due to phenylacetate.
    • If untreated, leads to severe mental retardation and behavioral issues.

Diagnosis:

      • Newborn screening using Guthrie bacterial inhibition test or tandem mass spectrometry.
      • High blood phenylalanine levels (>20 mg/dL).
      • Ferric chloride test (historical): gives green color with phenylketones in urine.

Management:

      • Lifelong dietary restriction of phenylalanine (low-protein diet).
      • Tyrosine supplementation as it becomes essential.

Case Scenario 2:

A 55-year-old male presents with complaints of fatigue, swelling in the lower limbs, and shortness of breath, especially when lying flat. He has a history of poorly controlled hypertension and type 2 diabetes mellitus. On examination, he has peripheral edema and elevated blood pressure (160/100 mmHg).

Laboratory Findings:

  • Serum creatinine: 3.5 mg/dL
  • Blood urea nitrogen (BUN): 60 mg/dL
  • Serum albumin: 3.0 g/dL
  • Urinalysis: Proteinuria, Hematuria
  1. What is the most likely diagnosis in this patient?
  2. Explain the biochemical pathway leading to the formation of the compound elevated in this case and which is the end product of protein metabolism.
  3. Briefly describe the metabolic disorders associated with this compound.

Answer:

  1. Diagnosis:

The most likely diagnosis is chronic kidney disease (CKD), possibly progressing to uremia, based on elevated serum creatinine and BUN, along with proteinuria, hematuria, and a history of hypertension and diabetes mellitus.

2. Biochemical Pathway – Formation of Urea:

    • Urea is the main nitrogenous end product of protein metabolism.
    • Proteins are broken down into amino acids, which undergo deamination to produce ammonia (NH₃).
    • Ammonia is toxic and is converted into urea via the urea cycle (ornithine cycle) in the liver.

Key Steps:

    1. Ammonia + CO₂ → Carbamoyl phosphate
    2. Carbamoyl phosphate + Ornithine → Citrulline
    3. Citrulline + Aspartate → Argininosuccinate
    4. Argininosuccinate → Arginine + Fumarate
    5. Arginine → Urea + Ornithine (cycle continues)

 

3. Metabolic Disorders of Urea Cycle:

    • Uremia: Accumulation of urea in the blood due to renal failure
    • Inherited urea cycle disorders: Hyperammonemia I & II, Citrullinemia, Arginosuccinic Acidaemia, Hyperargininemia

Case Scenario 3:

A mother brings her infant to the clinic with the complaint that the diapers are stained dark, and the urine turns black on standing. The urine tests show it is positive for reducing substances with Benedict’s test, but negative with glucose oxidase test. Ferric chloride test gives a purple-black color. Blood glucose and uric acid levels are normal.

  1. What is the most probable diagnosis?
  2. Name the enzyme deficient in this condition and describe the biochemical basis.
  3. Mention the clinical features and diagnostic tests for this disorder.

Answers:

  1. The most likely diagnosis is Alkaptonuria, a rare inherited metabolic disorder.
  2. Deficient Enzyme and Biochemical Basis:
    • Enzyme Deficiency: Homogentisate oxidase, an enzyme involved in the degradation of tyrosine.
    • Biochemical Basis:
      • Normally, tyrosine is broken down to fumarate and acetoacetate.
      • In alkaptonuria, due to homogentisate oxidase deficiency, homogentisic acid (HGA) accumulates.
      • HGA is excreted in urine, which darkens upon standing due to oxidation and polymerization.
      • HGA also deposits in connective tissues, leading to ochronosis.

3 Clinical Features and Diagnosis:

Clinical Features:

    • Dark-colored urine that turns black on standing.
    • Ochronosis: bluish-black pigmentation of ear cartilage, sclera, and skin.
    • Arthritis: especially of spine and large joints in adulthood.
    • No significant symptoms in early childhood except dark urine.

Diagnosis:

    • Urine tests:
      • Positive Benedict’s test (due to homogentisic acid, a reducing substance).
      • Negative glucose oxidase test (rules out glucose).
      • Ferric chloride test: purple or black color.
    • Detection of homogentisic acid in urine by chromatography.

Case Scenario 4:

A 7-year-old boy is brought to the pediatric clinic with complaints of frequent infections and delayed wound healing. Family history reveals a genetic disorder affecting collagen synthesis. The child has hypermobile joints, stretchy skin, and easy bruising. A connective tissue disorder is suspected.

a. Describe the four levels of structural organization of proteins.
b. What type of protein structure is primarily affected in collagen-related disorders? Explain.
c. Mention one disease caused by structural abnormalities in collagen and its molecular basis.

Answer:

a. Four Levels of Structural Organization of Proteins:

    1. Primary Structure:
      • Linear sequence of amino acids linked by peptide bonds.
      • Determines the protein’s unique properties and function.
    2. Secondary Structure:
      • Local folding into α-helices and β-pleated sheets.
      • Stabilized by hydrogen bonds between peptide backbone atoms.
    3. Tertiary Structure:
      • Three-dimensional folding of the polypeptide chain.
      • Stabilized by interactions like hydrogen bonds, disulfide bonds, hydrophobic interactions, and ionic bonds.
      • Determines the functional shape of globular proteins.
    4. Quaternary Structure:
      • Association of two or more polypeptide chains (subunits).
      • Example: Hemoglobin with two alpha and two beta chains.

 

b. Protein Structure Affected in Collagen Disorders:

    • Primarily the secondary and quaternary structures.
    • Collagen has a unique triple helical structure, stabilized by:
      • Repeating Gly-X-Y sequences (X and Y often being proline and hydroxyproline).
      • Hydrogen bonding and cross-linking between chains.
    • Any disruption in this sequence or post-translational modifications can affect collagen stability.

c. Example of Disease – Ehlers-Danlos Syndrome (EDS):

    • Cause: Defects in collagen structure or processing enzymes (e.g., lysyl hydroxylase deficiency).
    • Molecular Basis: Impaired cross-linking of collagen fibers → weak connective tissue.
    • Clinical Features: Hyperextensible skin, joint hypermobility, fragile blood vessels, poor wound healing

Case Scenario 5:

A 4-year-old child is brought to the clinic with complaints of chronic diarrhea, abdominal distension, and failure to gain weight. The child also shows signs of muscle wasting and irritability. The diet history reveals sufficient protein intake. Stool examination shows bulky, foul-smelling stools. A deficiency in protein digestion or absorption is suspected.

a. Describe the normal process of protein digestion and absorption.
b. What could be the possible disorder affecting protein digestion in this child? Explain its biochemical basis.
c. Mention any two other disorders of protein digestion and their key features.

Answer:

a. Normal Process of Protein Digestion and Absorption:

    • Stomach:
      • Pepsinogen, secreted by chief cells, is activated to pepsin by HCl.
      • Pepsin begins protein digestion by breaking peptide bonds.
    • Small Intestine:
      • Pancreas secretes trypsinogen, chymotrypsinogen, proelastase, and procarboxypeptidases.
      • Trypsin, activated by enterokinase, activates other enzymes.
      • These enzymes break proteins into dipeptides and amino acids.
    • Absorption:
      • Amino acids, di- and tri-peptides are absorbed via active transport in the small intestine.

b. Possible Disorder and Biochemical Basis:

    • Likely diagnosis: Cystic fibrosis or protein-losing enteropathy, but most suggestive here is exocrine pancreatic insufficiency (e.g., in Cystic Fibrosis).
    • Biochemical Basis:
      • Lack of pancreatic enzyme secretion leads to incomplete digestion of proteins.
      • Proteins remain undigested in the intestine → malabsorption, steatorrhea, and nutritional deficiencies despite adequate intake.

c. Two Other Disorders of Protein Digestion:

    1. Kwashiorkor:
      • Protein deficiency despite adequate calories.
      • Features: Edema, fatty liver, muscle wasting.
    2. Hartnup Disease:
      • Defective transport of neutral amino acids (e.g., tryptophan) in intestine and kidneys.
      • Features: Pellagra-like symptoms due to niacin deficiency.

Case Scenario 6:

A 6-year-old child is brought to the dermatology clinic with very fair skin, white hair, and light-colored eyes. The parents report that the child has poor vision, is sensitive to sunlight, and often gets sunburns even with short sun exposure. Family history reveals that a distant relative had similar features since birth. Ophthalmologic examination shows nystagmus and photophobia. A genetic disorder affecting melanin production is suspected.

a. What is the probable diagnosis? Describe the types and biochemical basis of this condition.
b. Explain the role of the key enzyme involved in melanin synthesis and its deficiency in this disorder.
c. List the clinical features and complications associated with this condition.

Answer:

a. Probable Diagnosis and Biochemical Basis:

    • Probable diagnosis: Albinism , particularly Oculocutaneous albinism (OCA)
    • Types:
      • Type I: Due to mutation in the tyrosinase gene.
      • Type II–IV: Involve defects in other proteins like OCA2, TYRP1, SLC45A2, affecting melanin transport or processing.
    • Biochemical Basis:
      • Melanin is synthesized from tyrosine via a series of enzymatic reactions.
      • Defects in this pathway → absent or reduced melanin in skin, hair, and eyes.
      • Especially in Type I albinism, the enzyme tyrosinase is deficient or inactive.

b. Role of Key Enzyme (Tyrosinase):

    • Tyrosinase catalyzes:
      1. Tyrosine → DOPA
      2. DOPA → Dopaquinone, which eventually leads to melanin formation.
    • Deficiency of tyrosinase → interruption in melanin synthesis → hypopigmentation.

c. Clinical Features and Complications:

    • Clinical Features:
      • Pale skin, white or light hair, light-colored irises.
      • Photophobia, nystagmus, and reduced visual acuity.
      • Sun sensitivity and frequent sunburns.
    • Complications:
      • Increased risk of skin cancers due to lack of melanin protection.
      • Visual impairment from underdeveloped retinal pigmentation and misrouting of optic nerves.

Case Scenario 7:

A 45-year-old man presents with complaints of fatigue, loss of appetite, and yellowish discoloration of the eyes. He has a history of chronic alcohol use. On examination, he shows signs of jaundice and hepatomegaly. Laboratory investigations reveal elevated levels of AST (SGOT) and ALT (SGPT). A liver function test suggests hepatocellular injury.

a. What is transamination? Name the key enzymes and coenzyme involved in this process.
b. Explain the biochemical significance of transamination reactions.
c. Why are AST and ALT elevated in liver damage? What is their clinical relevance?

Answer:

a. Definition and Enzymes:

    • Transamination is the process of transfer of an amino group (-NH₂) from an amino acid to an α-keto acid, usually α-ketoglutarate, forming a new amino acid (typically glutamate) and a new keto acid.
    • Enzymes: Aminotransferases (transaminases)
      • Alanine transaminase (ALT): Alanine + α-ketoglutarate ⇌ Pyruvate + Glutamate
      • Aspartate transaminase (AST): Aspartate + α-ketoglutarate ⇌ Oxaloacetate + Glutamate
    • Coenzyme: Pyridoxal phosphate (PLP), derived from vitamin B6.

b. Biochemical Significance:

    • Transamination allows:
      • Interconversion of amino acids and keto acids, helping in amino acid metabolism.
      • Collection of amino groups as glutamate, which then undergoes oxidative deamination to release ammonia for urea synthesis.
      • Synthesis of non-essential amino acids.
    • It is a reversible reaction and does not release free ammonia directly, making it a safer process in the body.

c. Clinical Relevance of AST and ALT:

    • AST (Aspartate transaminase) and ALT (Alanine transaminase) are found mainly in liver cells.
    • ALT is more liver-specific, while AST is also found in cardiac and skeletal muscle.
    • In liver cell damage (e.g., hepatitis, alcoholic liver disease), these enzymes are released into the bloodstream, causing elevated serum levels.
    • They are used as markers of liver function:

 

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