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Clinical Case Studies in Biochemistry :
BIOMOLECULES-
[case studies illustrating the clinical relevance of biomolecule metabolism]
Carbohydrate Metabolism Disorders
Case 1: The Unquenchable Thirst and Rapid Weight Loss 🥤📉 ● Patient Presentation: Mark, a 15-year-old male, is brought to the emergency department by his parents due to a 3-week history of excessive thirst (polydipsia), frequent urination (polyuria), significant unexplained weight loss (15 lbs), and persistent fatigue. Over the last 24 hours, he has become increasingly lethargic, with deep, rapid breathing and a fruity odor on his breath. ● History: Mark was previously healthy with no significant medical history. No family history of similar conditions. He recently had a viral flu-like illness. ● Clinical Examination Findings: Dehydrated, tachycardic, Kussmaul respirations (deep, sighing breathing). Fruity breath odor. Abdominal tenderness. Reduced skin turgor. ● Laboratory Investigations: ○ Random Blood Glucose: 650 mg/dL (Normal: 70-140 mg/dL) ○ Urine Ketones: ++++ (Strongly positive) ○ Arterial Blood Gas (ABG): pH 7.15 (Normal: 7.35-7.45), PCO_2 25 mmHg (Normal: 35-45 mmHg), HCO_3^- 10 mEq/L (Normal: 22-28 mEq/L) \rightarrow Metabolic acidosis with respiratory compensation. ○ Serum Electrolytes: Hyponatremia, Hyperkalemia (initially, may become hypokalemic with treatment). ○ HbA1c: 11.5% (Normal: <5.7%) ○ C-peptide: Very low (Indicates low endogenous insulin production) ○ Islet cell antibodies/GAD antibodies: Positive ● Diagnosis: Type 1 Diabetes Mellitus with Diabetic Ketoacidosis (DKA) ● Biochemical Correlation: Autoimmune destruction of pancreatic β-cells leads to absolute insulin deficiency. Without insulin, glucose cannot enter cells for energy, leading to hyperglycemia. The body shifts to excessive lipolysis and fatty acid oxidation, producing ketone bodies (acetoacetate, β-hydroxybutyrate, acetone) causing ketosis and metabolic acidosis. The fruity breath is due to acetone. Kussmaul breathing is a compensatory mechanism for acidosis. ● Discussion Points for Course:
- Explain the biochemical basis of polyuria, polydipsia, and polyphagia in uncontrolled diabetes.
- Detail the pathway of ketone body synthesis and its regulation.
- How does insulin normally regulate glucose, fat, and protein metabolism?
- Discuss the principles of DKA management (insulin, fluids, electrolytes). Case 2: The Sleepy Infant with an Enlarged Liver 👶💤 ● Patient Presentation: A 4-month-old infant, Emily, is brought to the pediatrician due to poor feeding, lethargy, and episodes of jitteriness, especially a few hours after feeds. Her parents also noticed her abdomen seems distended.
● History: Full-term birth, uneventful neonatal period. Exclusively breastfed initially, recently started on formula. Symptoms worsened after formula introduction. No family history of metabolic disorders. ● Clinical Examination Findings: Hepatomegaly (markedly enlarged liver), mild hypotonia. Jittery during examination. Doll-like facies. ● Laboratory Investigations: ○ Fasting Blood Glucose: 35 mg/dL (Normal for age: >50-60 mg/dL) \rightarrow Severe hypoglycemia. ○ Lactate: Elevated (e.g., 5 mmol/L; Normal: <2 mmol/L) \rightarrow Lactic acidosis. ○ Uric Acid: Elevated. ○ Triglycerides and Cholesterol: Elevated. ○ Liver Function Tests: Mildly elevated transaminases. ○ Glucagon Challenge Test: Minimal to no rise in blood glucose. ○ Liver Biopsy (if performed): Shows accumulation of glycogen and fat. Enzyme assay reveals deficient glucose-6-phosphatase activity. ● Diagnosis: Von Gierke's Disease (Glycogen Storage Disease Type Ia) ● Biochemical Correlation: Deficiency of glucose-6-phosphatase , an enzyme crucial for the final step of both gluconeogenesis and glycogenolysis (converting glucose-6-phosphate to free glucose). This prevents the liver from releasing glucose into the bloodstream, leading to severe fasting hypoglycemia. Accumulated glucose-6-phosphate is shunted into glycolysis (producing excess pyruvate and lactate, causing lactic acidosis ), pentose phosphate pathway (producing excess ribose-5-phosphate, leading to increased purine synthesis and hyperuricemia ), and triglyceride synthesis (causing hyperlipidemia and fatty liver). Hepatomegaly is due to glycogen accumulation. ● Discussion Points for Course:
- Why is glucose-6-phosphatase essential for maintaining blood glucose homeostasis?
- Explain the biochemical pathways leading to lactic acidosis and hyperuricemia in this condition.
- How does the defect impact gluconeogenesis vs. glycogenolysis?
- Discuss the dietary management principles for GSD Type Ia (e.g., continuous feeds, cornstarch). Case 3: The Adult Onset of Blood Sugar Concerns 🍬 ● Patient Presentation: David, a 52-year-old overweight office manager, presents for a routine health check-up. He reports feeling more tired than usual and experiencing increased thirst and occasional blurred vision over the past year, which he attributed to stress and aging. ● History: Sedentary lifestyle, diet high in processed foods and sugary drinks. Family history of diabetes (mother and older brother). BMI 31 kg/m². Blood pressure 145/ mmHg. ● Clinical Examination Findings: Acanthosis nigricans (dark, velvety patches of skin) observed on the neck and axillae. Otherwise, unremarkable. ● Laboratory Investigations: ○ Fasting Blood Glucose: 145 mg/dL (Normal: <100 mg/dL; Prediabetes: 100- mg/dL; Diabetes: ≥126 mg/dL) ○ HbA1c: 7.2% (Normal: <5.7%; Prediabetes: 5.7-6.4%; Diabetes: ≥6.5%) ○ Lipid Profile: Triglycerides 250 mg/dL (High), HDL cholesterol 35 mg/dL (Low).
Lipid Metabolism Disorders
Case 5: The Young Man with Chest Pain and Skin Lesions 💔💛 ● Patient Presentation: Michael, a 30-year-old man, presents to the emergency department with severe, crushing chest pain radiating to his left arm, ongoing for 2 hours. He also mentions having yellowish, firm nodules on his Achilles tendons and elbows for several years. ● History: Father died of a heart attack at age 40. Michael has never had his cholesterol checked. He smokes half a pack of cigarettes daily. ● Clinical Examination Findings: Diaphoretic, anxious. Xanthomas (firm, yellowish nodules) on Achilles tendons and extensor tendons of the hands. Corneal arcus (whitish ring around the cornea) noted. ECG shows ST-segment elevation consistent with an acute myocardial infarction. ● Laboratory Investigations: ○ Lipid Profile (fasting, if available from previous records or drawn later): ■ Total Cholesterol: 450 mg/dL (Normal: <200 mg/dL) ■ LDL Cholesterol: 380 mg/dL (Optimal: <100 mg/dL) ■ HDL Cholesterol: 30 mg/dL (Desirable: >40-60 mg/dL) ■ Triglycerides: 180 mg/dL (Normal: <150 mg/dL) ○ Cardiac Enzymes (Troponin I/T): Markedly elevated. ○ Genetic testing (later): May reveal mutation in the LDL receptor gene. ● Diagnosis: Familial Hypercholesterolemia (FH) presenting with Acute Myocardial Infarction ● Biochemical Correlation: An autosomal dominant genetic disorder most commonly caused by mutations in the LDL receptor gene. This leads to impaired clearance of LDL particles from the circulation by the liver. Consequently, LDL cholesterol levels are significantly elevated from birth, leading to premature and aggressive atherosclerosis (plaque buildup in arteries). Xanthomas are cholesterol deposits in tendons and skin. Corneal arcus is also a sign of hyperlipidemia. ● Discussion Points for Course:
- Describe the structure and function of LDL particles and the LDL receptor.
- How does a defective LDL receptor lead to high LDL cholesterol levels?
- Explain the link between high LDL cholesterol and atherosclerosis.
- Discuss the treatment strategies for FH (statins, PCSK9 inhibitors, lifestyle). Case 6: The Infant Who Fails to Thrive and Develops Neurological Problems 🧠📉 ● Patient Presentation: A 9-month-old infant, Lisa, presents with failure to thrive, progressive loss of developmental milestones (e.g., stopped babbling, lost ability to sit unsupported), and an enlarged abdomen. ● History: Parents are first cousins (consanguineous marriage). Normal birth and early development until around 6 months. ● Clinical Examination Findings: Marked hepatosplenomegaly, hypotonia, cherry-red spot on macula (ophthalmic exam). Global developmental delay. ● Laboratory Investigations: ○ Complete Blood Count: May show anemia and thrombocytopenia (due to hypersplenism). ○ Bone Marrow Aspiration: Presence of "Gaucher cells" (lipid-laden macrophages with a characteristic "crinkled paper" or "onion skin" appearance of cytoplasm).
○ Enzyme Assay (in leukocytes or cultured skin fibroblasts): Deficient activity of β-glucocerebrosidase (acid β-glucosidase). ○ Genetic testing: Confirms mutations in the GBA gene. ● Diagnosis: Gaucher Disease (Type 1, Non-Neuronopathic, or could be Type 2/3 if severe neurological signs early) (The cherry-red spot can be seen in other sphingolipidoses like Tay-Sachs, but Gaucher cells are specific). ● Biochemical Correlation: An autosomal recessive lysosomal storage disorder caused by deficiency of the enzyme β-glucocerebrosidase. This enzyme is responsible for the breakdown of the sphingolipid glucocerebroside (glucosylceramide). Deficiency leads to the accumulation of glucocerebroside within the lysosomes of macrophages, forming Gaucher cells. These cells infiltrate various organs, primarily the spleen, liver, and bone marrow, leading to hepatosplenomegaly, bone disease, and cytopenias. Neurological involvement occurs in Types 2 and 3. ● Discussion Points for Course:
- What are sphingolipids and what is their general function?
- Explain the role of lysosomes and lysosomal enzymes.
- Describe the pathophysiology of how glucocerebroside accumulation leads to clinical manifestations.
- Discuss enzyme replacement therapy (ERT) for Gaucher disease. Case 7: The Lethargic Baby After a Minor Illness 🤒😴 ● Patient Presentation: An 18-month-old boy, Tom, is brought to the emergency room with severe lethargy, vomiting, and unresponsiveness. His mother reports he had a mild cold and poor appetite for the past two days and was found very sleepy this morning. ● History: Previously healthy, developmentally normal. No specific dietary restrictions. ● Clinical Examination Findings: Unresponsive to stimuli, shallow breathing, mild hepatomegaly. No signs of dehydration. ● Laboratory Investigations: ○ Blood Glucose: 25 mg/dL (Severe hypoglycemia) ○ Urine Ketones: Negative or trace (Inappropriately low for the degree of hypoglycemia \rightarrow hypoketotic hypoglycemia ) ○ Serum Ammonia: Normal to mildly elevated. ○ Liver Function Tests: Elevated AST, ALT. ○ Plasma Acylcarnitine Profile (via tandem mass spectrometry): Elevated C6, C8, C10 acylcarnitines (medium-chain). ○ Urine Organic Acids: Dicarboxylic aciduria (e.g., adipic, suberic, sebacic acids). ○ Enzyme assay or genetic testing: Confirms deficiency of Medium-Chain Acyl-CoA Dehydrogenase (MCAD). ● Diagnosis: Medium-Chain Acyl-CoA Dehydrogenase (MCAD) Deficiency ● Biochemical Correlation: An autosomal recessive disorder of fatty acid β-oxidation. MCAD enzyme is responsible for dehydrogenating medium-chain fatty acyl-CoAs (6- carbons). Deficiency impairs the breakdown of these fatty acids for energy, especially during periods of fasting or increased metabolic stress (like illness). This leads to:
- Hypoglycemia: Reduced gluconeogenesis (as β-oxidation provides ATP and acetyl-CoA which allosterically activates pyruvate carboxylase).
- Hypoketonemia: Impaired ketogenesis (as β-oxidation provides the acetyl-CoA substrate for ketone body synthesis). The body attempts to metabolize fatty acids via alternative pathways (omega-oxidation), leading to dicarboxylic aciduria. Accumulated medium-chain acylcarnitines are toxic.
48 hours of life. ● History: Full-term, normal delivery. No family history of neonatal deaths or metabolic disorders. ● Clinical Examination Findings: Very lethargic, hypotonic, hypothermic. Rapid, shallow breathing progressing to apnea. Seizures observed. ● Laboratory Investigations: ○ Plasma Ammonia: Markedly elevated (e.g., >500 μmol/L; Normal: <50 μmol/L in neonates after 48h, <100 μmol/L before). ○ Arterial Blood Gas (ABG): Respiratory alkalosis initially (due to hyperventilation stimulated by ammonia), may progress to metabolic acidosis. ○ Plasma Amino Acid Analysis: May show elevated glutamine and alanine, and low citrulline (depending on the specific enzyme defect, e.g., in OTC deficiency). Orotic acid in urine may be elevated in OTC deficiency. ○ Liver Function Tests: Often normal initially. ○ Enzyme assay or genetic testing: To identify the specific urea cycle enzyme defect (e.g., Ornithine Transcarbamylase - OTC deficiency is most common and X-linked). ● Diagnosis: Urea Cycle Disorder (e.g., Ornithine Transcarbamylase (OTC) Deficiency) ● Biochemical Correlation: Urea cycle disorders are inherited defects in one of the enzymes or transporters required for the urea cycle , which detoxifies ammonia (a byproduct of amino acid catabolism) by converting it to urea in the liver. A defect leads to hyperammonemia , which is highly neurotoxic, causing cerebral edema, seizures, coma, and death if not treated promptly. Different enzyme defects result in specific patterns of amino acid and intermediate accumulation. For instance, in OTC deficiency, carbamoyl phosphate accumulates and enters the pyrimidine synthesis pathway, leading to increased orotic acid production. ● Discussion Points for Course:
- Outline the steps and enzymes of the urea cycle.
- How does ammonia exert its neurotoxic effects?
- Why is a low-protein diet critical in managing urea cycle disorders?
- Discuss acute (e.g., dialysis, nitrogen scavengers like sodium benzoate/phenylacetate) and long-term management strategies. Case 10: The Baby with Sweet-Smelling Urine and Neurological Decline 🍁👶 ● Patient Presentation: A 10-day-old infant, Maria, is brought in with poor feeding, vomiting, increasing lethargy, and a distinctive sweet, "maple syrup" or "burnt sugar" odor in her urine and earwax. ● History: Born at term after an uneventful pregnancy. Symptoms started around day 5 of life. ● Clinical Examination Findings: Lethargic, hypotonic, episodes of opisthotonos (arching of the back) and abnormal limb movements. Poor suck reflex. ● Laboratory Investigations: ○ Plasma Amino Acid Analysis: Markedly elevated levels of branched-chain amino acids (BCAAs): leucine, isoleucine, and valine , and their corresponding α-ketoacids. Alloisoleucine (pathognomonic) is present. ○ Urine Organic Acid Analysis: Elevated levels of branched-chain α-ketoacids (e.g., α-ketoisocaproate, α-keto-β-methylvalerate, α-ketoisovalerate) and their byproducts.
○ Newborn Screening: Would detect elevated BCAAs. ○ Enzyme assay (in leukocytes or fibroblasts): Deficient activity of the branched-chain α-ketoacid dehydrogenase (BCKAD) complex. ● Diagnosis: Maple Syrup Urine Disease (MSUD) ● Biochemical Correlation: An autosomal recessive disorder caused by a deficiency in the branched-chain α-ketoacid dehydrogenase (BCKAD) complex. This multi-enzyme complex is required for the oxidative decarboxylation (second step) in the catabolism of the essential branched-chain amino acids: leucine, isoleucine, and valine. Accumulation of these BCAAs and their corresponding α-ketoacids is neurotoxic, leading to cerebral edema, encephalopathy, and progressive neurological damage. The characteristic odor is due to sotolone, a metabolite of isoleucine. ● Discussion Points for Course:
- What are the metabolic fates of leucine, isoleucine, and valine?
- Explain the composition and function of the BCKAD complex. How is it regulated?
- Discuss the biochemical basis of neurotoxicity in MSUD, particularly the role of leucine.
- Describe the principles of dietary management (restriction of BCAAs) and the need for emergency protocols during illness.
Nucleic Acid Metabolism Disorders
Case 11: The Man with Excruciatingly Painful, Swollen Big Toe 🦶💥 ● Patient Presentation: John, a 55-year-old overweight man, presents to his primary care physician with a sudden onset of severe pain, redness, warmth, and swelling in his right great toe (metatarsophalangeal joint). The pain started abruptly overnight and is so intense that even the touch of a bedsheet is unbearable. ● History: He reports a similar, milder episode a year ago that resolved on its own. He enjoys a diet rich in red meat and seafood and consumes alcohol (beer) regularly. He is also on a diuretic (hydrochlorothiazide) for hypertension. ● Clinical Examination Findings: Right great toe is erythematous, swollen, warm, and exquisitely tender to palpation. Limited range of motion. No signs of trauma. ● Laboratory Investigations: ○ Serum Uric Acid: 10.5 mg/dL (Normal: Men 3.5-7.2 mg/dL; Women 2.6-6.0 mg/dL) \rightarrow Hyperuricemia. ○ Erythrocyte Sedimentation Rate (ESR) and C-Reactive Protein (CRP): Elevated (inflammatory markers). ○ Synovial Fluid Analysis (if arthrocentesis performed): Presence of negatively birefringent, needle-shaped monosodium urate (MSU) crystals under polarized light microscopy. High white blood cell count, predominantly neutrophils. ● Diagnosis: Acute Gouty Arthritis (Gout) ● Biochemical Correlation: Gout is a metabolic disorder characterized by hyperuricemia and the deposition of monosodium urate (MSU) crystals in joints and soft tissues. Uric acid is the final breakdown product of purine metabolism in humans (from adenine and guanine). Hyperuricemia can result from:
- Overproduction of uric acid: Due to increased purine synthesis, high dietary purine intake, or increased cell turnover (e.g., myeloproliferative disorders, chemotherapy).
- Underexcretion of uric acid: Due to renal impairment or certain medications (e.g.,
for neurological and behavioral issues)?
Disorders Involving Multiple Biomolecule Types / Complex Regulation
Case 13: The Adult with Abdominal Pain, Neuropathy, and Dark Urine 🍷☀ ● Patient Presentation: A 28-year-old woman, Clara, presents with recurrent episodes of severe, colicky abdominal pain, nausea, and vomiting. During these episodes, she also experiences muscle weakness, paresthesias (tingling) in her hands and feet, anxiety, and confusion. She notes that her urine turns dark reddish-brown when left standing, especially if exposed to sunlight. ● History: Episodes often triggered by stress, certain medications (e.g., barbiturates, sulfonamides), alcohol, or fasting. Family history of similar episodic illnesses. ● Clinical Examination Findings: During an acute attack: Tachycardia, hypertension, mild abdominal tenderness without rebound. Neurological exam may show peripheral neuropathy (decreased sensation, weakness) and altered mental status. Skin may show photosensitivity. ● Laboratory Investigations (during an acute attack): ○ Urine: Markedly elevated levels of porphobilinogen (PBG) and δ-aminolevulinic acid (ALA). Urine may turn dark red/purple upon standing due to oxidation of porphobilinogen to porphobilin. ○ Serum Electrolytes: Hyponatremia may be present. ○ Erythrocyte Porphobilinogen Deaminase (PBGD, also known as Hydroxymethylbilane Synthase) activity: Reduced (typically ~50% of normal in heterozygotes, but can be normal in some latent cases or during an attack if enzyme is induced). ○ Genetic testing: Confirms mutation in the HMBS gene. ● Diagnosis: Acute Intermittent Porphyria (AIP) ● Biochemical Correlation: An autosomal dominant disorder of heme biosynthesis , caused by a partial deficiency of the enzyme porphobilinogen deaminase (PBGD). Heme is a crucial component of hemoglobin, myoglobin, and cytochromes (involved in electron transport – lipid and carbohydrate energy metabolism link). The deficiency leads to accumulation of the neurotoxic porphyrin precursors ALA and PBG in the nervous system and other tissues, particularly when the pathway is induced (e.g., by drugs that induce cytochrome P450 synthesis, increasing heme demand). The exact mechanisms of neurotoxicity are complex but involve direct effects of ALA/PBG and heme deficiency in neural tissues. Abdominal pain is visceral neuropathy. ● Discussion Points for Course:
- Outline the heme biosynthesis pathway and the role of PBGD.
- How does a deficiency in this enzyme lead to the accumulation of ALA and PBG but not photosensitivity (as seen in some other porphyrias)?
- Explain the concept of enzyme inducibility and how certain drugs can precipitate attacks.
- Discuss management of acute attacks (e.g., hemin infusion, glucose loading) and prevention strategies. Case 14: The Child with Spontaneous Fractures and Blue Sclerae 뼈🦴👁 ● Patient Presentation: Leo, a 5-year-old boy, is brought to the orthopedic clinic due to his third long bone fracture in the past two years, all occurring with minimal trauma. His parents also note that the whites of his eyes have a distinct blueish tint. He has a history
of easy bruising and some hearing loss. ● History: Multiple fractures since infancy. Delayed motor milestones. Family history of similar problems (mother has mild form). ● Clinical Examination Findings: Blue sclerae, dentinogenesis imperfecta (discolored, brittle teeth), joint hypermobility, short stature for age. Signs of recent and healed fractures. Audiometry confirms conductive or mixed hearing loss. ● Laboratory Investigations: ○ Serum Calcium, Phosphate, Alkaline Phosphatase: Usually normal (to rule out rickets or other bone mineral disorders). ○ Vitamin D levels: Usually normal. ○ Skin Biopsy for fibroblast culture and collagen analysis (specialized test): May show abnormalities in type I collagen synthesis or structure (e.g., reduced production, abnormal electrophoretic mobility). ○ Genetic testing: Identification of mutations in COL1A1 or COL1A2 genes, which encode the α1 and α2 chains of type I collagen. ● Diagnosis: Osteogenesis Imperfecta (OI) - Type I (most common and mildest classical form described) ● Biochemical Correlation: A group of genetic disorders characterized by bones that break easily. Most forms are caused by mutations affecting the synthesis or structure of type I collagen , the major structural protein of bone, tendon, skin, sclera, and dentin. ○ Type I OI is typically due to mutations leading to reduced quantity of normal type I collagen (e.g., a null allele in COL1A1 ). ○ More severe forms (Types II, III, IV) often involve mutations causing abnormal structure of collagen molecules (e.g., glycine substitutions in the triple helical domain), which interfere with collagen fibril formation and stability. The defect in collagen (a protein) leads to impaired bone matrix formation, resulting in fragile bones. Blue sclerae occur because the underlying choroidal veins are visible through the abnormally thin sclera, which is also rich in type I collagen. ● Discussion Points for Course:
- Describe the structure of type I collagen (triple helix, amino acid composition like Gly-X-Y repeats).
- How do different types of mutations in collagen genes lead to varying severities of OI?
- Explain the biochemical basis for blue sclerae and dentinogenesis imperfecta.
- Discuss the multidisciplinary management of OI (orthopedic, physical therapy, bisphosphonates). Case 15: The Adult with Progressive Neurological Deterioration and Liver Disease After a Viral Infection 🧠 hepatocytes: 🔥 ● Patient Presentation: A 22-year-old college student, Brian, presents with acute onset of confusion, slurred speech, tremors in his hands, and jaundice. This began about a week after recovering from a flu-like illness. His roommate notes recent personality changes and clumsiness. ● History: Previously healthy. No significant alcohol or drug use. Family history is non-contributory initially, but further questioning reveals a distant cousin died young from "liver problems." ● Clinical Examination Findings: Jaundice, Kayser-Fleischer rings (golden-brown rings at the periphery of the cornea, seen on slit-lamp examination). Hepatomegaly (may be tender). Asterixis ("flapping tremor"), dysarthria, ataxia, cognitive impairment.
