Metabolic disorders in biochemistry.pptx

Metabolic disorders

1. METABOLIC DISORDERS Group 9 Abhinav(49) Dikshant (30) Nauman(68) Hariom(41)
Ajay(51) Bharti(35) Ojas(71) Aditya(101) Akhil(6) Sindhu(31) Rafaqat (61) Priyanshu (84) Sahil(93) MENTOR- DR. JAGAT

2. GENERALIZED VIEW OF METABOLISM Metabolism It refers to the sum of all chemical reactions that occur in living organisms, including digestion, absorption and the transportation of substances into different cells. Textbook of biochemistry 10 th edition (revised reprint) -DM Vasudevan SAHIL NAWAZ CHOUDHURY (93)

3. CANCER METABOLISM GONE AWRY: HOW BIOCHEMISTRY FUELS CANCER SAHIL NAWAZ CHOUDHURY (93)

4. CARCINOGENESIS Carcinogenesis is the process by which normal cells are "transformed" to cancer cells. Multiple events lead to carcinogenesis including mutations, epigenetic events, and abnormal cell division. Uncontrolled cell division is one of the hallmarks of cancer. SAHIL NAWAZ CHOUDHURY (93) Reference: Resveratrol nanoformulation for cancer prevention and therapy Siddiqui et al. Annals of the New York Academy of Sciences · June 2015

5. WARBURG EFFECT Warburg effect is a metabolic shift observed in cancer cells where they favour process of anaerobic glycolysis over oxidative phosphorylation. But their metabolism is often referred to aerobic glycolysis or Warburg effect This phenomenon is observed because HIF(Hypoxia Inducing Factor) is over expressed in cancer cell, which activates catabolism of glucose The oxidative phosphorylation occurring in mitochondria of cancer cells also help in its growth. SAHIL NAWAZ CHOUDHURY (93)

6. ABBREVIATIONS: PTKs - protein tyrosine kinases; PI3K, phosphatidylinositol-3-kinase; S6K, ribosomal protein S6 kinase; ALD, aldolase; PGK, phosphoglycerate kinase; ENO, enolase; PKM, pyruvate kinase M. Other HIF-1-regulated glycolytic enzymes that are not shown: glucosephosphate isomerase, phosphofructokinase L, triosephosphate isomerase, glyceraldehyde-3-phosphate dehydrogenase, and phosphoglyceromutase .  SAHIL NAWAZ CHOUDHURY (93) HIF-1: upstream and downstream of cancer metabolism Gregg L. Semenza et al Curr Opin Genet Dev. 2010

7. PROPOSED BENEFITS High rate of ATP production High levels of lactate High levels of Lactate keeps a lower pH favouring invasion and metastasis Lactate-induced MRP1 expression contributes to metabolism-based etoposide resistance in non-small cell lung cancer cells - PMC (nih.gov) Qi Dong et al Cell Commun Signal 2020 A GSTP1-mediated lactic acid signaling promotes tumorigenesis through the PPP oxidative branch - PMC (nih.gov) Yandi Sun et al Cell Death Dis 2023  SAHIL NAWAZ CHOUDHURY (93)

8. EFFECT ON ENZYMES Many cancer cells are shown to delete different enzyme producing genes or whole metabolic pathways This is because cancer cells prefer to thrive in minimal enzymes E.g. deletion of asparagine synthetase (aspartate to asparagine) SAHIL NAWAZ CHOUDHURY (93)

9. ALTERATION IN ENERGERTICS There is a shift in the redox state of the cells. It is attributed to a pseudohypoxic phenotype. The TCA cycle is said to be "truncated" in cancer cells, because the high flux of intermediates out of the pathway prevents it from acting as a true cycle. SAHIL NAWAZ CHOUDHURY (93)

10. GLUTATHIONE S TRANSFERASE (GST) Glutathione S-transferases (GSTs) are a family of enzymes that play a complex role in cancer. GSTs and Detoxification: GSTs are phase II detoxification enzymes that attach glutathione (GSH) to harmful substances, making them water-soluble for excretion. This detoxification process helps protect cells from damage caused by carcinogens and other toxins. GSTs and Cancer Risk: Certain GST polymorphisms, genetic variations, can influence cancer risk. Deficiencies of GSTM & GSTT might reduce an individual's ability to detoxify carcinogens, potentially increasing cancer risk. GSTs and Chemoresistance: Cancer cells can exploit GSTs to develop resistance to chemotherapy drugs. SAHIL NAWAZ CHOUDHURY (93)

11. ISOENZYMES GSTs are divided into several isoenzymes, each with slightly different functions and substrate specificities. Some of the major GST isoenzymes include: GST Alpha (GSTA): Involved in detoxifying carcinogens and environmental pollutants. GST Mu (GSTM): Plays a role in metabolizing certain drugs and toxins. GST Pi (GSTP): Helps detoxify herbicides and insecticides. GST Theta (GSTT): Contributes to the detoxification of various toxins and carcinogens. SAHIL NAWAZ CHOUDHURY (93)

12. DIAGNOSIS History and symptoms Screening tests Imaging tests Biopsy Biomarkers SAHIL NAWAZ CHOUDHURY (93)

13. SAHIL NAWAZ CHOUDHURY (93) Biomarkers for cancer are measurable substances or changes in the body that can indicate the presence of cancer or its progression. These can include: Proteins : Such as prostate-specific antigen (PSA) for prostate cancer, CA-125 for ovarian cancer, and HER2 for breast cancer. Genetic Markers : Mutations in specific genes like BRCA1 and BRCA2, which are linked to breast and ovarian cancers. Tumor Markers : These are substances produced by cancer cells, like carcinoembryonic antigen (CEA) for colorectal cancer. Blood Cell Counts : Abnormalities in blood cell counts can indicate certain types of cancer, like leukemia. Hormones : Hormone levels can indicate certain types of cancers, like elevated levels of cortisol in adrenal cancer. Imaging Biomarkers : These are obtained through imaging tests like CT scans or MRIs, showing characteristics of tumors.

14. SAHIL NAWAZ CHOUDHURY (93)

15. SAHIL NAWAZ CHOUDHURY (93)

16. BIOCHEMICAL INSIGHTS INTO PORPHYRIA NAME : DIKSHANT SUNIL POHREGAONKAR ROLL NO.:- 30

17. CASE STUDY Patient Presentation: A 35-year-old male presents to the emergency department complaining of severe abdominal pain, nausea, and constipation for the past two days. He reports a history of intermittent episodes of similar symptoms over the past few years, often triggered by fasting or certain medications. On examination, the patient appears anxious and is experiencing diffuse abdominal tenderness upon palpation. Clinical History: The patient mentions that his symptoms typically improve with intravenous glucose administration and hydration. He denies any recent alcohol consumption but reports taking over-the-counter pain relievers for a headache a few days prior to the onset of symptoms. Family history is notable for similar symptoms in his sister and aunt. Diagnostic Workup: Laboratory investigations reveal elevated levels of urinary porphobilinogen (PBG) and delta-aminolevulinic acid (ALA), suggestive of -----------------. Further genetic testing confirms a diagnosis -----------------------------. NAME : DIKSHANT SUNIL POHREGAONKAR ROLL NO.:- 30

18. PORPHYRIA DEFINITION :- Defects in Heme synthesis. Accumulation and increased excretion of porphyrins. Inherited or acquired. NAME : DIKSHANT SUNIL POHREGAONKAR ROLL NO.:- 30

19. PORPHYRIA Acute hepatic porphyria Acute intermittent porphyria Hereditary coproporphyria Variegate porphyria Chronic hepatic porphyria Congenital erythropoietic porphyria Erythropoietic porphyria Porphyria cutanea tarda NAME : DIKSHANT SUNIL POHREGAONKAR ROLL NO.:- 30

20. HEME SYNTHESIS GLYCINE + SUCCINYL-CoA ALA-synthase Delta amino levulinic acic ALA-dehydratase Porphobilinogen PBG-deamise UPG-III-cosynthase Uroporphyrinogen UPG-decarboxylase Coprophyrinogen CPG-oxidase Protoporphyrinogen PPG-oxidase Protoporphyrin Heme synthase Heme Acute intermittent porphyria Congenital erythropoietic porphyria Porphyria cutanea tarda Hereditary coproporphyria Porphyria variegata Hereditary protoporphyria NAME : DIKSHANT SUNIL POHREGAONKAR ROLL NO.:- 30

21. Features of important types of Porphyrias ACUTE INTERMITTENT PORPHYRIA Autosomal dominant Most common No photosensitivity CONGENITAL ERYTHROPOIETIC PORPHYRIA Autosomal recessive Photosensitivity Erythrodontia PORPHYRIA CUTANEA TARDA Autosomal dominant Second most common Photosensitivity NAME : DIKSHANT SUNIL POHREGAONKAR ROLL NO.:- 30

22. CAUSES OF PORPHYRIA MOST of the forms are genetically inherited Autosomal dominant Autosomal recessive SOME are acquired forms Heavy alcohol use Smoking Viral infections (HIV, hepatitis C) NAME : DIKSHANT SUNIL POHREGAONKAR ROLL NO.:- 30

23. Features of important types of Porphyrias HEREDITARY COPROPORPHYRIA Autosomal dominant Milder photosensitivity HEREDITARY PROTOPORPHYRIA Autosomal dominant Protoporphyrin increased in plasma, RBC’s and feces RBC’s show fluorescence. NAME : DIKSHANT SUNIL POHREGAONKAR ROLL NO.:- 30

24. QUESTIONS 1. Which of the following enzymes is deficient in acute intermittent porphyria (AIP)? A) Uroporphyrinogen decarboxylase B) Porphobilinogen deaminase (delta-aminolevulinic acid dehydratase) C) Ferrochelatase D) Coproporphyrinogen oxidase 2. Which of the following triggers is commonly associated with exacerbations of porphyria symptoms? A) High carbohydrate diet B) Excessive alcohol consumption C) Regular exercise D) Antihypertensive medications

25. QUESTIONS 3. What is the primary biochemical defect in acute porphyrias such as acute intermittent porphyria (AIP)? A) Accumulation of delta-aminolevulinic acid (ALA) and porphobilinogen (PBG) B) Deficiency of heme synthase C) Overproduction of heme D) Increased urinary excretion of uroporphyrinogen 4. Which of the following is NOT a common symptom of acute porphyria attacks? A) Severe abdominal pain B) Neurological symptoms (e.g., peripheral neuropathy, seizures) C) Photosensitivity D) Joint pain and arthritis 5. Which of the following treatments is most appropriate for managing an acute porphyria attack? A) Blood transfusion B) Intravenous glucose administration C) Nonsteroidal anti-inflammatory drugs (NSAIDs) D) Cholecystectomy

26. ONGOING RESEARCHES Strategies to address dysregulated or dysfunctional steps within the heme development pathway are in development. (Antonio Fontanellas 1, Matías A Ávila) Advances in the understanding of the molecular bases and pathogenesis of porphyrias. (2019 European Association for the Study of the Liver. Published by Elsevier B.V.) NAME : DIKSHANT SUNIL POHREGAONKAR ROLL NO.:- 30

27. GAUCHER’S DISEASE By Sindhu Donapati Roll no.31

28. Sindhu Donapati Roll no. 31

29. Inborn lipid metabolism disorder Autosomal recessive Affects mainly spleen and liver Enzyme deficient: Beta-glucosidase Sindhu Donapati Roll no. 31

30. Sindhu Donapati,Rollno.31

31. It is mainly of 3 types involving the deficiencies of GBA1 GBA2 and GBA3 enzyme Deficiencies Type 1: 90% prevalence Affects platelets and often characterised by repeated bruising Fatigue and low platelet count Type 2: Fatal and affects neonates by 3 to 6 months after birth Not more than 2 years of life Type 3: Eye movement disorders, bone disorders , seizures Sindhu Donapati Roll no. 31

32. However, in all the three types , Liver enlarges by 2 to 3 times its original size and the spleen enlarges by nearly 15 times its actual size Diagnosis is confirmed by blood tests by enzyme assay of Beta glucosidase in Peripheral leucocytes Sindhu Donapati Roll no. 31

33. Sindhu Donapati Roll no. 31

34. Research and Progression in Gaucher Disease Exposure to excess bioactive glycosphingolipids appears to affect hematopoiesis and the balance of osteoblast and osteoclast numbers and activity Lab studies in mice with symptoms of Gaucher disease types 2 and 3 show that decreasing the function of a protein called RIPK3 improved symptoms Researches are going on for the compounds which can reduce glucocerebroside content altogether in the brain Use of chaperone reagents into consideration Sindhu Donapati Roll no. 31

35. Phenylketonuria A genetic disorder K.Abhinav Roll number 49

36. Pathway of tyrosine synthesis This reaction is catalysed by the enzyme Phenylalanine hydrolyase Essential cofactor tetrahydrobioptrin K.Abhinav Roll number 49

37. What is PKU Inherited disorder Affects phenylalanine processing K.Abhinav Roll number 49

38. Types of PKU Mainly 5 types 1 is PAH dependent while 2,3 are dihydrobiopterin Synthease,4,5 are dependent on biopterin availability K.Abhinav Roll number 49

39. Cause of PKU Caused due to mutated gene for PAH enzyme Gene affected->gene for cofactor tetrahydrobioptrin (BH4) or PAH enzyme Located on->chromosome 12 K.Abhinav Roll number 49

40. Biochemical basis of PKU Malfunction of PAH(Phenylalanine hydroxylase) Causes decrease in tyrosine which is essential for neurotransmitters Excess phenylalanine crosses the blood-brain barrier and causes damage to the brain K.Abhinav Roll number 49

41. K.Abhinav Roll number 49

42. Diagnosis of PKU Newborn screening test Blood test K.Abhinav Roll number 49

43. Treatment of PKU Lifelong special diet Foods to avoid->high protein foods like meat,eggs,cheese Low-phenylalanine formula Medical monitoring K.Abhinav Roll number 49

44. Long term management of PKU Regular blood test Dietary counseling Support groups K.Abhinav Roll number 49

45. New Developments In the field of PKU FDA has recently approved the drug saproterin (Kuvan) [1] Gene therapy has also been approved for treatment of PKU [2] [1] Dubois EA, Cohen AF. Sapropterin . Br J Clin Pharmacol . 2010 Jun;69(6):576-7. doi : 10.1111/j.1365-2125.2010.03643.x. PMID: 20565448; PMCID: PMC2883749. [2] Grisch -Chan HM, Schwank G, Harding CO, Thöny B. State-of-the-Art 2019 on Gene Therapy for Phenylketonuria. Hum Gene Ther . 2019 Oct;30(10):1274-1283. doi : 10.1089/hum.2019.111. Epub 2019 Sep 9. PMID: 31364419; PMCID: PMC6763965. K.Abhinav Roll number 49

46. FATTY LIVER Ajay Roll no 51

47. Case study A patient was operated for intestinal obstruction and had continuous gastric aspiration for 3 days. Blood pH – 7.55, pCO2 – 50 mm Hg, plasma bicarbonate – 30 mEq/L, serum sodium – 130 mmol/L, serum potassium – 2.9 mmol/L,serum chloride – 95 mmol/Lm Ajay Roll no 51

48. What is a fatty liver Fatty liver disease is also known as hepatic steatosis An inbuilt increasing fat in the liver is known as fatty liver Very common in India more than 10 million cases are registered in India per year It's actually there are no symptoms for the fatty liver eating excess calories make fat in liver Ajay Roll no 51

49. Types of fatty liver diseases Fatty liver is categorized into three stages they are Simple steatosis(grade 1) Non alcoholic steatohepatic (NASH) Advanced fibrosis or cirrhosis (grade 3) Ajay Roll no 51

50. Grade 1 disease Grade 1 fatty liver, also known as mild fatty liver or simple fatty liver, may not cause any noticeable symptoms in most people. However, some people might experience the following signs and symptoms: Fatty liver disease can be asymptomatic until it advances to cirrhosis. Symptoms may include upper right abdominal pain or fullness. Other symptoms can include loss of appetite, nausea, and weight loss. Yellowing of the skin and eyes (jaundice) may also be present. Swelling in the abdomen and legs (oedema) can occur. Extreme tiredness, confusion, and weakness can also be symptoms of fatty liver disease.1 Ajay Roll no 51

51. Grade 2 disease Huge amounts of fat are deposited “inside” the liver in grade 2 fatty liver. The liver cells store this material as microscopic droplets. Grade 2 fatty liver when the amount of fat in the liver accounts for 10-25% Signs and Symptoms of Fatty Liver Grade 2 Lack of appetite. Weight-loss. Vomiting. Legs and abdomen appear swollen. The feeling of exhaustion and debility Ajay Roll no 51

52. Grade 3 disease Grade 3 fatty liver disease means a person has a large percentage of fat deposited in their liver. Grade 3 NAFLD occurs when a person's liver contains a percentage of fat greater than 66% and severe inflammation symptoms of grade 3 fatty liver disease? weight loss. edema (fluid buildup that causes swelling in the legs) weakness. nausea. loss of appetite. Ajay Roll no 51

53. Ajay Roll no 51

54. GLYCOGEN STORAGE DISEASES Akhil Gudladona Roll no. 6

55. What are Glycogen Storage Diseases Glycogen Storage Diseases or GSDs are inborn errors of carbohydrate metabolism that result in abnormal storage of glycogen Clinical onset of GSDs can range from neonatal life to adulthood. Depending on the specific type, GSDs can result from a failure to convert glycogen into energy and/or a toxic glycogen accumulation The common element in all GSDs is the failure to use or store glycogen

56. Normal Synthesis And Storage of Glycogen After a meal, the glucose level in plasma increases and stimulates the storage of excess glucose in cytoplasmic glycogen. The liver contains the highest percent of glycogen by weight, about 10% Muscles can store about 2% by weight. since the total muscle mass is greater than liver mass, the total mass of glycogen in the muscle is about twice that of the liver

57. ETIOLOGY The etiology of GSDs is best understood by following the metabolic events leading to the synthesis (glycogenesis) and degradation of glycogen (glycogenolysis). Glycogen synthesis is, in part, accomplished by the enzyme glycogen synthase (GS).

58. GSD Type 0a There are two distinct forms of glycogen synthase, one in the liver encoded by the GYS2 gene and one in skeletal muscle encoded by the GYS1 gene. Both forms of GS work by linking (alpha-1,4 links) a glucose monomer to the growing glycogen polymer. The absence or malfunction of liver glycogen synthase due to mutations in the GYS2 gene will prevent glycogen from being synthesized in the liver. This is the cause of GSD type 0a.

59. Von Gierke Disease(GSD Type 1a) GSDs type I results from genetic disorders in the metabolism of glucose-6-phosphatase. GSD type Ia (also called von Gierke disease) is caused by mutations in the G6PC gene This causes decreased production of Glucose 6 phosphatase ultimately leading to Gycogen Storage Disease

60. Fanconi-Bickel disease Fanconi-Bickel disease is a rare GSD caused by a GLUT2 deficiency It occurs due to a mutation in the SLC2A2 gene. GLUT2 deficiency results in a failure to export glucose, an increased intracellular glucose level, and reduced glycogen degradation This leads to increased glycogen storage and hepatomegaly.

61. GSD Type 3 or CORI’S DISEASE GSD type III is caused by mutations in the AGL gene This results in either a nonfunctional Glycogen debranching enzyme (GSD type IIIa or type IIIb) or a Glycogen debranching with reduced function (GSD type IIIc and IIId).

62. GSD Type 2 or POMPE’S Disease GSD type II is unique among GSDs because it is also classified as a lysosomal storage disease Lysosomal storage diseases are caused by a missing or nonfunctional lysosomal enzyme. In the case of GSD II, this enzyme is lysosomal acid alpha-glucosidase encoded by the gene GAA This enzyme breaks down glycogen into glucose for use as a cellular energy source. Mutation in the GAA gene results in the toxic accumulation of glycogen in lysosomes

63. Classification Of GSDs

64. Treatment Of GSDs Currently, there is no cure for any GSD, and most treatments attempt to alleviate signs/symptom Key goals are to treat or avoid hypoglycemia, hyperlactatemia, hyperuricemia, and hyperlipidemia Some GSDs like GSD type II can now be treated with enzyme replacement therapy (ERT), Liver transplantation should be considered for patients with certain GSDs with progressive hepatic forms that have progressed to hepatic malignancy or failure.

65. Aditya Shetkar 101

66. Understanding the Biochemical Mechanisms of ADA-SCID -Hariom Gautam (41)

67. Introduction Ada is an enzyme expressed in variety of tissues, but highest activity is in lymphocytes. ADA plays a crucial role in the breakdown of adenosine obtained from food and in the turnover of nucleic acids within tissues. It is essential for the development and maintenance of the immune system in humans. Hariom Gautam (41) Reference:Osmosis by Elsevier

68. Autosomal Recessive Inheritance Hariom Gautam (41) ADA Protein Structure The active site contains a zinc ion, which is coordinated by specific amino acid residues. Zinc is the only cofactor necessary for ADA activity. The substrate, adenosine, is stabilized and bound to the active site by nine hydrogen bonds. Reference:Donald Voet –Biochemistry (4 th edition)

69. Role of ADA Adenosine Deaminase (ADA2) : ADA2  is an enzyme that plays a crucial role in  purine metabolism . Its primary function is to catalyze the  deamination  of  adenosine (Ado)  and  deoxyadenosine ( dAdo ) . Deamination  involves the removal of an  amino group  from the adenosine or deoxyadenosine molecule. The reaction results in the conversion of Ado to  inosine  and dAdo to  deoxyinosine . These can be further metabolized to yield uric acid. Hariom Gautam (41)

70. Disruption of normal metabolic pathway In ADA-deficient individuals, there is a marked depletion of T, B, and NK lymphocytes. It is called combined immunodeficiency as both humoral and cellular immunity are impaired. This deficiency can cause higher risk for infections leading to scid (severe combined immunodeficieny ) Hariom Gautam (41)

71. Reference:Flinn AM, Gennery AR. Adenosine deaminase deficiency: a review. Orphanet J Rare Dis. 2018 Hariom Gautam (41)

72. Clinical Implications : Deficiency of ADA2  disrupts this essential purine metabolic pathway. Accumulation of adenosine and deoxyadenosine occurs due to impaired deamination. Elevated levels of these nucleosides can lead to various clinical manifestations, including systemic vasculitis, early-onset stroke, bone marrow failure, and immunodeficiency. Hariom Gautam (41)

73. Therapeutic Approaches : Hematopoietic stem cell transplantation (HSCT)  remains a critical treatment for ADA-SCID (severe combined immunodeficiency due to ADA deficiency). The choice of donor source significantly impacts survival rates. Hariom Gautam (41) Reference: Autoimmune Dysregulation and Purine Metabolism in Adenosine Deaminase Deficiency- ; Aisha et al 2012- Frontiers in Immunology

74. Future Advances and Research Emerging therapies for ADA-SCID : Focus : Novel approaches beyond gene therapy and HCT, including small molecules and gene editing Uchida N, Yanagi M, Hamada H. Physical Enhancement? Nanocarrier? Current Progress in Transdermal Drug Delivery. Nanomaterials (Basel). 2021 Clinical and immunological outcomes of ADA-SCID patients treated with gene therapy : Study : Follow-up of ADA-SCID patients treated with gene therapy. Results : Sustained immune reconstitution, improved quality of life, and reduced infections Kuo, C.Y., Garabedian , E., Puck, J. et al. Adenosine Deaminase (ADA)–Deficient Severe Combined Immune Deficiency (SCID) in USIDNet Hariom Gautam (41)

75. Cystinurea Ojas Solanke Roll no. 71

76. Introduction to Cystinuria Cystinuria is a monogenic disease characterized by recurrent nephrolithiasis often starting in childhood. Cystinuria is caused by mutations in genes encoding proximal tubule dibasic amino acid transporter which facilitates reabsorption of cysteine, ornithine, lysine, and arginine from tubular fluid. This reabsorption defect leads to very high urinary excretion of dibasic amino acids including cysteine. Although these amino acids generally have good solubility, cysteine can dimerize to form cystine that has poor water solubility at physiological urine pH and cause recurrent stones. Patients with cystinuria are at increased risk for chronic kidney disease (CKD) and potentially renal failure. Thus, lifelong preventive medical treatment is often necessary in majority of the patients. Sadiq, Sanober & Cil, Onur. (2022). Cystinuria: An Overview of Diagnosis and Medical Management. Turkish Archives of Pediatrics. 57. 377-384. 10.5152/TurkArchPediatr.2022.22105. name: Ojas Solanke roll no: 71

77. Etiology of Cystinuria The cysteine transporter is a heterodimer composed of 2 subunits. The heavy subunit rBAT is encoded by SLC3A1, and the light subunit b(0,+)AT is encoded by SLC7A9. The defects in this transporter cause impaired reabsorption of cysteine that results in hyperexcretion of cystine in the urine greater than 300 mg/day.Cystine has poor solubility at physiological urine pH and its solubility dramatically increases in alkaline urine. At pH 7, cystine solubility is ~250 mg/L which increases to 500 and 1000 mg/L at pH of 7.5 and 8, respectively. Urine volume and pH are the key determinants of cystine solubility, whereas dietary protein and sodium intake are important determinants of urinary cystine excretion. Knoll T, Zöllner A, Wendt-Nordahl G, Michel MS, Alken P. Cystinuria in childhood and adolescence: recommendations for diagnosis, treatment, and follow-up. Pediatr Nephrol. 2005 Jan;20(1):19-24 Name: ojas solanke Roll no 71

78. Genetic cause Cystinuria typically has autosomal recessive inheritance. Cysteine transporter is a dibasic amino acid transporter consisting of 2 subunits: neutral and basic amino acid protein rBAT encoded by SLC3A1 and b(0,+)AT amino acid transporter encoded by SLC7A9. Cystinuria is classified into 3 types A, B, and AB based on the genetic abnormality. Type A patients have SLC3A1 mutations, type B patients have SLC7A9 mutations, and type AB patients have mutations in both SLC3A1 and SLC7A9. Type A cystinuria is inherited autosomal recessively and heterozygous carriers typically have normal cystine excretion. Type B cystinuria is generally inherited autosomal recessively; however, autosomal dominant inheritance with incomplete penetrance was also reported. Although very rare, type AB cystinuria patients have heterozygous mutations in both SLC3A1 and SLC7A9. Earlier studies generally showed no differences in disease severity between type A and B patients. Interestingly, some studies reported that type AB patients generally have a mild phenotype although it may be difficult to make any conclusions since this type is very rarely seen. Sadiq, Sanober & Cil, Onur. (2022). Cystinuria: An Overview of Diagnosis and Medical Management. Turkish Archives of Pediatrics. 57. 377-384. 10.5152/TurkArchPediatr.2022.22105. Name: Ojas Solanke Roll no: 71

79. Autosomal Recessive Conditions Cystinuria typically follows an autosomal recessive pattern of inheritance, which means that an individual must inherit two copies of the mutated gene (one from each parent) to develop the condition. Individuals who inherit only one copy of the mutated gene are carriers of the condition but do not usually experience symptoms . Leslie SW, Nazzal L. Renal Calculi (Cystinuria, Cystine Stones) [Updated 2019 May 6]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2019 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470527 Name: Ojas Solanke Roll no: 71

80. Clinical Presentation Clinical manifestations of cystinuria are similar to any patient with obstructive urolithiasis including flank pain, loin pain, gross hematuria, vomiting, or fever. Symptoms can be more variable in children and include microscopic or gross hematuria, dysuria, recurrent abdominal pain, and recurrent urinary tract infections. In small children, symptoms can be vague or non-specific such as irritability, vomiting, and unmotivated crying.Patients with non-obstructive stones can be asymptomatic, and in these patients, stones can be detected incidentally during imaging tests. Sadiq, Sanober & Cil, Onur. (2022). Cystinuria: An Overview of Diagnosis and Medical Management. Turkish Archives of Pediatrics. 57. 377-384. 10.5152/TurkArchPediatr.2022.22105. Name: Ojas Solanke Roll no: 71

81. Diagnosis And Laboratory Testing The condition is most often diagnosed after an episode of kidney stones. Testing the stones after they are removed shows that they are made of cystine. Unlike calcium-containing stones, cystine stones do not show up well on plain x-rays. Tests that may be done to detect these stones and diagnose the condition include: 24-hour urine collection Abdominal CT scan, or ultrasound Intravenous pyelogram (IVP) Urinalysis Elder JS. Urinary lithiasis. In: Kliegman RM, St. Geme JW, Blum NJ, Shah SS, Tasker RC, Wilson KM, eds. Nelson Textbook of Pediatrics. 21st ed. Philadelphia, PA: Elsevier; 2020:chap 562. Name: Ojas Solanke Roll no:71

82. Complications Renal colic Renal colic is a condition that causes moderate to severe pain as a result of the movement of a kidney stone down the ureter towards the bladder. This pain is usually reported in the lower back and is commonly concentrated to one side as the stone is moving down a ureter on one side. Although the pain typically begins in the lower back, often progresses down towards the groin as the stone moves. Recurrent UTIs Individuals affected by cystinuria are more likely to suffer from infections of the urinary tract as compared to other members of the general population. Some of the common symptoms of a urinary tract infection (UTI) include: Frequent urge to pass urine Pain or burning on urination Cloudy urine with a pungent smell Back pain In severe cases, the UTI can spread beyond the bladder and into the kidneys, thus causing more severe symptoms such as fever, nausea, and vomiting to arise. Katz G, Pras E, Landau EH, Shapiro A, Pode D. [Cystinuria and urolithiasis]. Harefuah. 1995 Jul;129(1-2):12-5, 79. Hebrew. PMID: 7557700. Name:Ojas Solanke Roll no. 71

83. Hydronephrosis Hydronephrosis involves a blockage of the ureter, usually as a result of a stone lodged in the area, and causes the urine to flow back up into the kidney. This affects the function of the kidney, as the organ becomes enlarged and the area is also prone to infection. Signs of hydronephrosis may include: Abdominal pain Increased frequency of urination Pain on urination Nausea and vomiting Fever Kidney damage While the kidneys can often regain their previous function with the removal of the stone that has been blocking the ureter, kidney function, in rare cases, can be irreversibly damaged. Damage to the urinary tract can lead to recurrent infections and blockages in the area that may require reparative surgery, which can also cause scar tissue to develop. Over time, this can lead to renal insufficiency or renal disease. Katz G, Pras E, Landau EH, Shapiro A, Pode D. [Cystinuria and urolithiasis]. Harefuah. 1995 Jul;129(1-2):12-5, 79. Hebrew. PMID: 7557700. Name:Ojas Solanke Roll no: 71

84. Research and Future Directions Cystinuria is a condition where kidneys can't remove certain chemicals. UCSF is studying how a medicine called SGLT2 inhibitors affects this issue. The study is in its early stages. Current cystinuria research is focused on methods of monitoring disease activity, novel drug therapies and genotype–phenotype studies. The future of research is collaboration at a national and international level, facilitated by groups such as the Rare Kidney Stone Consortium and the UK Registry of Rare Kidney Diseases. Wollaston, W. On cystic oxide: a new species of urinary calculus. Philos. Trans. R. Soc. Lond. 100, 223–230 (1810). Name: Ojas Solanke Roll no: 71

85. Mitochondrial diseases Bharati Gaikwad Roll no.35

86. What are Mitochondrial diseases? Mitochondrial disorders are caused by defects in mitochondria that affects oxidative phosphorylation muscular and neurological problems are common features Other common symptoms Impaired vision Hearing loss Cardiac arrhythmias Diabetes and stunted growth Bharati Gaikwad Roll no.35 S, Hirano M, Koga Y, McFarland R, Suomalainen A, Thorburn DR, Zeviani M, Turnbull DM. Mitochondrial diseases. Nat Rev Dis Primers. 2016 Oct 20;2:16080. doi: 10.1038/nrdp.2016.80. PMID: 27775730.

87. Why does mitochondrial DNA mutate? Mitochondrial DNA acquires mutations at 6 to 7 times the rate of nuclear DNA because: It lack protective histones. It is in close proximity to the electron transport chain, exposing it to high concentrations of free radicals, which can damage the nucleotides. > It lack DNA repair mechanisms, which results in mutant tRNA, RNA, and protein transcripts. Bharati Gaikwad Roll no.35 Molnar MJ, Kovacs GG. Mitochondrial diseases. Handb Clin Neurol. 2017;145:147-155. doi: 10.1016/B978-0-12-802395-2.00010-9. PMID: 28987165.

88. Primary mitochondrial disorders caused by germline mutations in mtDNA and/or nDNA genes that encode either OXPHOS structural proteins or mitochondrial proteins of the complex machinery needed to carry out the OXPHO Secondary mitochondrial disorders secondary mitochondrial disorders (SMD) are elicited by mutations in other genes not related to OXPHOS. Can only be inherited Can be inherited or acquired Bharati Gaikwad Roll no.35 SOURCE :- Bottani E, Lamperti C, Prigione A, Tiranti V, Persico N, Brunetti 2020 Nov

89. Biochemical basis of mitochondrial diseases caused primarily by the impairment of oxidative phosphorylation (OXPHOS). Mitochondrial function is under the control of two genomes; the mitochondrial genome ( mtDNA ) and the nuclear genome ( nDNA ) mitochondrial genome is a small, circular DNA molecule that encodes 13 proteins of the OXPHOS machinery, 22 mitochondrial tRNA ( mt-tRNA ), and 2 mitochondrial rRNAs ( mt-rRNA ). Primary mutations of the mtDNA include point mutations The pathogenicity of mtDNA mutations is further complicated by heteroplasmy Bharati Gaikwad Roll no.35

90. Mitochondrial Myopathy The main symptoms of mitochondrial myopathy are Muscle fatigue Exercise intolerance Weakness Difficulty in swallowing Slurred speech progressive external ophthalmoplegia Bharati Gaikwad Roll no.35 Mark Tarnopolsky, in Mitochondrial Case Studies , 2016

91. Mitochondrial encephalomyopathy the main symptoms of mitochondrial encephalomyopathy are Vision loss Migraines,headaches and seizures Hearing loss Ataxia Bharati Gaikwad Roll no.35 Schapira AH. Mitochondrial disease. Lancet. 2006 Jul 1;368(9529):70-82. doi: 10.1016/S0140-6736(06)68970-8. PMID: 16815381.

92. Types of mitochondrial disorders Barth syndrome genetic disorder of lipid metabolism that primarily affects boys and men. Symptoms Reduced muscle tone ( hypotonia ) Muscle weakness and fatigue Delayed growth Methylglutaconic aciduria Bharati Gaikwad Roll no.35 Schapira AH. Mitochondrial disease. Lancet. 2006 Jul 1;368(9529):70-82. doi: 10.1016/S0140-6736(06)68970-8. PMID: 16815381.

93. Leigh syndrome Leigh syndrome (also known as (MILS, or maternally inherited Leigh syndrome) usually begins in between the age of three months and two years. Rarely, it can occur in teenagers and adults. Symptoms of Leigh syndrome usually progress rapidly, and may include loss of appetite, vomiting, irritability, loss of head control and motor skills, continuous crying, and seizures. As the disorder progresses, symptoms also may include generalized weakness, lack of muscle tone, and episodes of lactic acidosis (a buildup of lactic acid in the body), which can lead to problems with breathing and kidney function. Bharati Gaikwad Roll no.35 Schapira AH. Mitochondrial disease. Lancet. 2006 Jul 1;368(9529):70-82. doi: 10.1016/S0140-6736(06)68970-8. PMID: 16815381.

94. Diagnosis of mitochondrial diseases Enzymatic analysis of the OXPHOS complexes, and the genetic analysis of the mtdna . Targeted ndna sequencing approach Muscle Biopsy Presence of cytochrome C oxidase (COX, complex iv)-negative fibers as detected by the sequential COX/SDH histochemistry Bharati Gaikwad Roll no.35 Schapira AH. Mitochondrial disease. Lancet. 2006 Jul 1;368(9529):70-82. doi: 10.1016/S0140-6736(06)68970-8. PMID: 16815381.

95. DIABETES MELLITUS PRIYANSHU KHAITAN ROLL NO-84

96. WHAT IS DIABETES? Diabetes is a metabolic disorder due to absolute or relative deficiency of insulin .It can be of 2 types 1.Diabetes type I 2.Diabetes type II Type I Type II Age of onset Childhood( upto 20 yr ) >30 yr age group Prevalence 10-20% 80-90% Defect Insulin defiency due to pancreatic destruction Decreased production or resistance to Insulin Weight Normal or low obese Genetic predeposition less Very strong Autoantibodies Commonly found Rare Complications Ketoacidosis Hyperosmolar state Treatment Only insulin effective Oral hypoglycemic drugs/insulin Priyanshu khaitan roll-84

97. METABOLIC CHANGES Insulin deficiency Leads to increase in blood glucose levels and decrease in intracellular glucose levels Increase gluconeogenesis Increase glycogenolysis Increase lipolysis Increase blood glucose Increase in fatty acid and glycerol Lead to increase in ketone bodies PRIYANSHU KHAITAN ROLL NO 84

98. Connolly D.  et al.  Metabolic, structural and biochemical changes in diabetes and the development of heart failure.  Diabetologia   65 , 411–423 (2022).

99. CLINICAL PRESENTATION OF DIABETES 1.Polyuria Frequent urination due to increase in blood sugar beyond renal threshold (180mg ) which leads to appearance of Glucose in urine that attarcts water with it leading to more urine formation 2.Polyphagia Cells have decreased uptake of glucose and this stimulates the hunger centres of brain leading to polyphagia 3.Polydypsia Due to polyuria more water is required leading to polydipsia PRIYANSHU KHAITAN ROLL NO-84

100. BIOCHEMISTRY TESTS FOR DIABETES DIAGNOSIS Glucose test- 1.Fasting glucose level test normal levels-less than 99mg/dl prediabetic-100-125mg/dl diabetic->126mg/dl 2.Glucose tolerance test- drinking a glucose containing liquid and blood sugar level is measured after 2 hrs Normal levels-140mg/dl Prediabetic-140-199mg/dl Diabetic->200mg/dl 3.Random blood sugar test Measuring blood sugar at any time sugar level of 200mg/dl or higher is a diabetes indicator. 4.HbA1C test Measuring average blood sugar level over past 2-3 months Normal-below 5.7% Prediabetic-5.7-6.4% Diabetic->6.5% PRIYANSHU KHAITAN ROLL NO.-84

101. DIABETIC COMPLICATIONS 1 .Diabetic ketoacidosis 2.Retinopathy 3.Diabetic foot-due to neuropathy in cutaneous sensory nerves of legs 4.Delay in wound heeling 5.Nephropathy due to glucose more than renal threshold 6.Neuropathy 7.Hyperosmolar state-it is life threatening condition due to hyperincrease in blood glucose causing drawing of water from cells of body. PRIYANSHU KHAITAN ROLL NO 84

102. FABRY’S DISEASE RAFAQAT HUSSAIN Roll No-61

103. Introduction to Fabry's Disease Fabry's disease is a rare genetic disorder that results from the buildup of a fatty substance called globotriaosylceramide (Gb3) in the body's cells. It is an X-linked condition, meaning it primarily affects males, but females can also be carriers and exhibit symptoms. Symptoms of Fabry's disease can vary widely and may include pain, skin lesions, kidney problems, and heart issues. RAFAQAT HUSSAIN Roll No-61

104. Genetic Cause of Fabry's Disease Fabry's disease is caused by mutations in the GLA gene, which provides instructions for making an enzyme called alpha-galactosidase A. Mutations in the GLA gene lead to a deficiency in alpha-galactosidase A, resulting in the accumulation of Gb3 in various tissues and organs. The inheritance pattern of Fabry's disease follows an X-linked recessive pattern, with affected males inheriting the mutated gene from their mothers. RAFAQAT HUSSAIN Roll No-61

105. Diagnosis of Fabry's Disease Fabry's disease can be diagnosed through genetic testing to identify mutations in the GLA gene. Other diagnostic tests may include blood tests to measure levels of alpha-galactosidase A and Gb3, as well as imaging studies to assess organ damage. Early diagnosis of Fabry's disease is crucial to prevent complications and initiate appropriate treatment. RAFAQAT HUSSAIN Roll No-61

106. Treatment Options for Fabry's Disease Enzyme replacement therapy (ERT) is a common treatment for Fabry's disease, providing the missing alpha-galactosidase A enzyme to help break down Gb3. Chaperone therapy is another treatment approach that aims to stabilize the mutated enzyme and improve its function. Symptomatic management, such as pain relief medications, blood pressure control, and kidney support, may also be part of the treatment plan for Fabry's disease. RAFAQAT HUSSAIN Roll No-61

107. Prognosis and Complications of Fabry's Disease Without treatment, Fabry's disease can lead to serious complications, including kidney failure, heart disease, and stroke. Early diagnosis and appropriate treatment can help improve outcomes and quality of life for individuals with Fabry's disease. Regular monitoring and management of symptoms and complications are essential for long-term care and prognosis in Fabry's disease. RAFAQAT HUSSAIN Roll No-61

108. Research and Future Directions Ongoing research is focused on developing new treatment approaches for Fabry's disease, including gene therapy and novel enzyme replacement strategies. Improved understanding of the molecular mechanisms underlying Fabry's disease may lead to targeted therapies and personalized treatment options. Collaboration between researchers, healthcare providers, and patient advocacy groups is essential to advance knowledge and improve outcomes for individuals with Fabry's disease. RAFAQAT HUSSAIN Roll No-61

109. Tay Sachs Dis ease Nauman Bin Bashir Roll No.:-68

110. Introduction Tay Sachs Disorder is a rare genetic disorder. It is caused by a mutation in the HEXA gene. The mutation leads to the accumulation of gangliosides in the brain. Nauman Bin Bashir Roll No.:-68

111. Inheritance Pattern Tay Sachs Disorder is inherited in an autosomal recessive manner. Both parents must be carriers of the mutated gene for a child to be affected. Carriers have one normal and one mutated HEXA gene. Nauman Bin Bashir Roll No.:-68

112. Pathogenesis The HEXA gene encodes for the enzyme hexosaminidase A (Hex A). Hex A is responsible for breaking down a specific type of ganglioside. In Tay Sachs, the lack of functional Hex A leads to the accumulation of gangliosides in nerve cells. Nauman Bin Bashir Roll No.:-68 © Solovyeva VV et al. 2018 New Approaches to Tay -Sachs Disease Therapy. Frontiers in Physiology

113. Ganglioside Accumulation Gangliosides accumulate in the lysosomes of nerve cells. This accumulation disrupts normal cell function. Nerve cells become swollen and dysfunctional, leading to neurodegeneration. Nauman Bin Bashir Roll No.:-68

114. Clinical Manifestations Infants with Tay Sachs typically appear normal at birth. Symptoms usually appear around 6 months of age. Progressive neurodegeneration leads to developmental regression and eventual death. Nauman Bin Bashir Roll No.:-68

115. Diagnosis Genetic testing can identify mutations in the HEXA gene. Enzyme assays can measure Hex A activity in the blood. Prenatal testing can be done through chorionic villus sampling or amniocentesis. Nauman Bin Bashir Roll No.:-68

116. Research and Future Perspectives Ongoing research aims to develop potential treatments for Tay Sachs Disorder. Gene therapy and enzyme replacement therapy are being explored. Early detection and intervention may improve outcomes for affected individuals. Nauman Bin Bashir Roll No.:-68

117. References National Institute of Neurological Disorders and Stroke. Tay-Sachs Disease Information Page. https://www.ninds.nih.gov/Disorders/All-Disorders/Tay-Sachs-Disease-Information-Page. National Tay-Sachs & Allied Diseases Association. About Tay-Sachs Disease. https://ntsad.org/. Kaback, M. M. (2001). Tay-Sachs disease—carrier screening, prenatal diagnosis, and the molecular era. The Anatomical Record, 265(1), 1-6.