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 10th edition (revised
reprint)
-DM Vasudevan
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.
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:
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
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
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
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
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)
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
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
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
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
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
47. 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
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
65. 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.
77. 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
Reference:Osmosis by
78. Autosomal
Recessive
Inheritance
Hariom Gautam
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 (4th
79. Role of ADA
1.Adenosine Deaminase (ADA2):
1.ADA2 is an enzyme that plays a crucial role
in purine metabolism.
2.Its primary function is to catalyze
the deamination of adenosine
(Ado) and deoxyadenosine (dAdo).
3.Deamination involves the removal of
an amino group from the adenosine or
deoxyadenosine molecule.
4.The reaction results in the conversion of
Ado to inosine and dAdo to deoxyinosine.
5.These can be further metabolized to yield
uric acid.
Hariom Gautam
80. 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 Hariom Gautam
81. Reference:Flinn AM, Gennery AR.
Adenosine deaminase deficiency: a review.
Orphanet J Rare Dis. 2018
ADA Deficiency
Accumulation of Adenosine
Conversion to
Ribonucleotides/Deoxyribonucleotides
Inhibition of Ribonucleotide
Reductase (by dATP)
Prevents Deoxyribose-Containing
Nucleotide Production
Cell Division Impairment because
of decreased DNA synthesis.
Severe Combined
Immunodeficiency (SCID)
Decreased T Cells, B Cells, NK
Cells
Untreated ADA Deficiency: Fatal
Infections
Hariom Gautam
82. 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
83. 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
Reference: Autoimmune
Dysregulation and Purine
Metabolism in Adenosine
Deaminase Deficiency-; Aisha
et al 2012- Frontiers in
Immunology
84. Future Advances and Research
Emerging therapies for ADA-SCID:
o Focus: Novel approaches beyond gene therapy and HCT, including small
molecules and gene editing
oUchida 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
86. 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
87. 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
88. 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 Solank
89. 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
90. 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
91. 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
92. 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
93. 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
94. 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
96. 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.
97. 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.
98. 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
99. 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
100. Mitochondrial Myopathy
• The main symptoms of mitochondrial myopathy are
• Muscle fatigue
• Exercise
intolerance
• Weaknes
s
• Difficulty in
swallowing
• Slurred speech
• progressive external
ophthalmoplegia
Bharati Gaikwad
Roll no.35
Mark Tarnopolsky, in Mitochondrial Case Studies, 2016
101. Mitochondrial encephalomyopathy
the main symptoms of mitochondrial
encephalomyopathy are
• Vision
loss
• Migraines,headaches and seizures
• Hearing
loss
• Ataxi
a
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.
102. 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.
103. 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.
104. 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.
106. 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
107. 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
108. Connolly D. et al. Metabolic, structural and biochemical
changes in diabetes and the development of heart
failure. Diabetologia 65, 411–423 (2022).
109. 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
110. 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%
111. 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
113. 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
114. 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
115. 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
116. 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
117. 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
118. 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
120. 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
121. 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
123. 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
124. 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
125. 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
126. 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
127. 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.
