Inborn Errors of Galactose Metabolism (I.E.G.M.)

Inborn Errors of Galactose Metabolism (I.E.G.M.) are rare genetic conditions that affect how the body processes a sugar called galactose (a simple sugar found in milk and dairy products). Normally, the body uses three main enzymes (special proteins that speed up chemical reactions) in the Leloir pathway to change galactose into glucose, which our cells use for energy. In I.E.G.M., one of these enzymes does not work properly or is missing. As a result, galactose and related substances build up in the body. This buildup is toxic (poisonous) and can harm the liver, eyes, brain, kidneys, and other organs if not recognized and treated early.

Inborn errors of galactose metabolism, collectively known as galactosemias, are rare genetic disorders in which the body cannot properly process the simple sugar galactose. Galactose is a key component of lactose, the sugar found in milk and many dairy products. When enzymes of the Leloir pathway (the series of chemical steps that convert galactose into glucose) are missing or impaired, galactose and its byproducts accumulate in tissues, causing damage to the liver, brain, eyes, and other organs WikipediaCleveland Clinic.

Early detection—usually through newborn screening—and prompt dietary management are vital to prevent life-threatening complications such as E. coli sepsis, hepatic failure, and irreversible neurological damage. Long-term complications may include cataracts, speech and learning difficulties, premature ovarian insufficiency, and reduced bone density WikipediaNational Organization for Rare Disorders.

I.E.G.M. are autosomal recessive disorders (each child must inherit a faulty gene from both parents to be affected). Although they are rare—classic galactosemia occurs in about 1 in 30,000 to 60,000 births in Western countries—they are included in most newborn screening programs because early detection and a strict diet can prevent the most serious damage. Cleveland Clinic

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Types of Inborn Errors of Galactose Metabolism

There are three main types of I.E.G.M., each caused by a different enzyme that does not work properly.

Type I: Classic Galactosemia

Classic Galactosemia occurs when the GALT enzyme (galactose-1-phosphate uridylyltransferase) fails to work. This enzyme normally converts galactose-1-phosphate into UDP-galactose. In Type I, the faulty GALT enzyme leads to a rapid buildup of galactose-1-phosphate in the liver, brain, kidneys, and other tissues. Babies usually feel fine at birth but soon develop serious problems such as

• Liver damage (the liver becomes inflamed and grows too large)

• Jaundice (yellowing of the skin and eyes)

• Cataracts (cloudy spots in the lenses of the eyes)

• Sepsis (blood infection, often by E. coli)

• Hypoglycemia (low blood sugar)

• Bleeding (because of low clotting factors)

• Poor weight gain and failure to thrive

• Seizures and cerebral edema (brain swelling)

If untreated, Type I can be life-threatening in the first weeks of life. Even with treatment, long-term issues such as speech delays, learning disabilities, poor coordination, and ovarian failure in girls can occur. EyeWikiNCBI

Type II: Galactokinase Deficiency

In Type II Galactokinase Deficiency, the GALK1 enzyme (galactokinase) cannot convert galactose into galactose-1-phosphate. As a result, galactose builds up and is turned into galactitol, which collects in the lenses of the eyes and forms cataracts usually within the first weeks or months of life. Unlike Type I, babies with Type II often have no other serious problems besides eye changes. Early removal of galactose from the diet stops cataract formation. Cleveland ClinicWikipedia

Type III: Epimerase Deficiency

Type III Galactose Epimerase Deficiency affects the GALE enzyme (UDP-galactose 4-epimerase), which normally helps convert UDP-galactose back into UDP-glucose. Type III can range from mild cases (mostly affecting red and white blood cells) to severe forms that look like classic galactosemia (with liver disease, cataracts, and brain involvement). Severity depends on how much GALE activity remains in the body. Cleveland Clinic

Clinical and Duarte Variants

Besides the three main types, some people have variant forms:

• Clinical Variant Galactosemia: A milder form of Type I, often seen in certain populations (e.g., some African groups). Babies still risk feeding problems and liver issues but may escape newborn screening unless carefully monitored. NCBI

• Duarte Variant: A partial GALT deficiency where enzyme activity is reduced but not absent. Usually these individuals stay healthy without symptoms, though they may benefit from brief dietary changes early in life.

Types of Galactosemia

Galactosemias are classified by the specific enzyme defect in the Leloir pathway:

1. Classic Galactosemia (Type I)
   Caused by deficiency of galactose-1-phosphate uridylyltransferase (GALT). Infants present within days of birth with jaundice, vomiting, lethargy, and hepatomegaly. Without treatment, mortality approaches 75%. Diagnosis is via newborn screening and enzyme assays. Wikipedia

2. Galactokinase Deficiency (Type II)
   Due to lack of galactokinase (GALK), leading primarily to galactitol buildup in the lens and early cataract formation. Infants are otherwise usually healthy. A galactose-restricted diet prevents cataracts if started early. Wikipedia

3. Epimerase Deficiency (Type III)
   From impaired UDP-galactose-4-epimerase (GALE) activity. Severity ranges from benign red blood cell–limited deficiency to a generalized form causing liver failure, hearing loss, cognitive deficits, and ovarian failure. Management relies on dietary restriction, but endogenous galactose synthesis can still cause symptoms. Wikipedia

4. Mutarotase Deficiency (Type IV)
   A newly described defect in galactose mutarotase (GALM), the enzyme that interconverts α- and β-galactose. Presents with mild hypergalactosemia and occasional cataracts; long-term outcomes remain under study. ScienceDirect

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Causes of Inborn Errors of Galactose Metabolism

Below are twenty different mechanisms and genetic changes that can lead to faulty enzymes in the galactose pathway. Each “cause” is a way the gene or enzyme can be affected, leading to I.E.G.M.

1. Missense Mutation – A single DNA “letter” change causes one amino acid in the enzyme to be wrong, so the enzyme does not work.

2. Nonsense Mutation – A DNA change creates a premature “stop” signal in the enzyme’s code, making it too short to function.

3. Frameshift Mutation – A small insertion or deletion of DNA letters shifts the “reading frame,” scrambling the entire enzyme.

4. Splice-Site Mutation – Errors in the gene’s “cutting and pasting” signals lead to missing or extra pieces in the messenger RNA.

5. Large Deletion – A section of the gene is missing, so the enzyme is never made.

6. Gene Duplication – Extra copies of parts of the gene can interfere with normal enzyme function.

7. Promoter Mutation – Damage in the “on/off switch” region makes the cell produce far less enzyme.

8. Gene Inversion – A chunk of DNA flips around in the gene, disrupting its code.

9. Compound Heterozygosity – Two different mutations (one on each copy of the gene) combine to cause disease.

10. Homozygous Mutation – The same harmful mutation is inherited from both parents.

11. Uniparental Disomy – Both copies of the gene come from one parent, increasing chance of two faulty copies.

12. Gene Imprinting Error – Faulty “imprinting” can silence one gene copy, leaving only the defective one active.

13. Mosaicism – Some cells carry the mutation and others do not, leading to variable enzyme levels.

14. Epigenetic Silencing – Chemical tags on the DNA shut off the gene without changing its code.

15. Consanguinity – Parents related by blood are more likely to both carry the same rare faulty gene.

16. Population Founder Effect – In small communities founded by a few individuals, certain mutations can become common.

17. Spontaneous New Mutation – A DNA change occurs for the first time in a parent’s sperm or egg.

18. Regulatory RNA Defect – Abnormal microRNA or other regulatory molecules reduce enzyme production.

19. Mitochondrial Dysfunction – Although enzymes are cytosolic, energy shortfalls can worsen symptoms by reducing enzyme folding.

20. Transcription Factor Defect – A faulty protein that normally boosts enzyme gene activity leaves cells with too little enzyme.

Each of these genetic or molecular events can independently or together reduce one of the key enzymes—GALT, GALK1, or GALE—causing I.E.G.M.

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Symptoms of Inborn Errors of Galactose Metabolism

When galactose and related substances build up in the body, they cause a range of signs (things a doctor sees) and symptoms (things a patient or parent notices). Here are fifteen common features:

1. Poor Feeding – Babies refuse milk or formula (they feel full or nauseated) because their bodies cannot handle the sugar.

2. Vomiting – The gut reacts badly to galactose, causing frequent spit-ups or vomiting.

3. Diarrhea – Loose, watery stools occur when the intestines cannot absorb or process galactose properly. American Liver Foundation

4. Jaundice – Yellow tint in skin and eyes from liver stress (bilirubin buildup).

5. Hepatomegaly – The liver becomes large and tender as it tries to filter toxic galactose-1-phosphate.

6. Failure to Thrive – Babies do not gain weight or grow at normal rates.

7. Lethargy – Lack of energy; babies sleep more and react less to stimuli.

8. Hypotonia – Low muscle tone; babies appear “floppy.”

9. Irritability – Babies cry more and seem uncomfortable or fussy. MedlinePlus

10. Seizures – Repeated muscle jerks or staring spells due to brain irritation.

11. Cataracts – Clouding of the eye lenses from galactitol buildup, leading to blurry vision.

12. E. coli Sepsis – Severe blood infection, often caused by Escherichia coli, due to immune weakness and gut bacteria leakage. EyeWiki

13. Renal Dysfunction – Kidney injury or failure when toxic chemicals accumulate in the kidneys.

14. Bleeding Diathesis – Easy bruising or bleeding because the liver makes fewer clotting factors.

15. Developmental Delays – Speech, learning, balance, or motor skill delays even with treatment, due to early brain injury. EyeWikiNCBI

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Diagnostic Tests for Inborn Errors of Galactose Metabolism

Early diagnosis is critical. Tests fall into five categories: Physical Exam, Manual Tests, Lab & Pathological Tests, Electrodiagnostic Tests, and Imaging Tests.

Physical Exam

1. General Appearance Check – Observation of skin color, alertness, and feeding behavior.

2. Liver Palpation – Feeling the abdomen for an enlarged, tender liver (hepatomegaly).

3. Neurological Exam – Checking muscle tone (for hypotonia), reflexes, and responsiveness.

Manual Tests

4. Reducing Sugar Test – A drop of urine is mixed with a special solution; if it “reduces” the solution, galactose is present.

5. Clinitest – A handheld tablet test that changes color when reducing sugars (like galactose) are in the urine.

Lab & Pathological Tests

6. Blood Galactose-1-Phosphate Level – Measures toxic sugar compound in red blood cells. NCBI

7. RBC GALT Enzyme Activity – Checks how well the GALT enzyme works in red blood cells. NCBI

8. RBC GALK1 Enzyme Activity – Measures galactokinase function in red blood cells. NCBI

9. GALE Enzyme Activity – Tests UDP-galactose 4-epimerase function in blood or skin cells.

10. Genetic Testing (GALT) – DNA analysis for mutations in the GALT gene. NCBI

11. Genetic Testing (GALK1) – DNA sequencing of the GALK1 gene for mutations. Wikipedia

12. Genetic Testing (GALE) – DNA analysis for variants in the GALE gene.

13. Newborn Screening – Heel-prick blood spot tested for enzyme activity or reducing substances.

Electrodiagnostic Tests

14. Electroencephalogram (EEG) – Records brain electrical activity to check for seizure patterns.

15. Nerve Conduction Study (NCS) – Evaluates how well nerves send signals, since chronic buildup may affect nerves.

Imaging Tests

16. Abdominal Ultrasound – Sound wave imaging to view liver size, texture, and gallbladder health.

17. Magnetic Resonance Imaging (MRI) – Detailed pictures of the liver or brain to assess damage.

18. Head CT or MRI – Checks for brain swelling or structural changes from early injury.

19. Slit-Lamp Eye Exam – Uses a special microscope to look for early cataract formation in the lens.

20. Liver Biopsy (Pathology) – A tiny tissue sample examined under a microscope to see liver cell damage.

Non-Pharmacological Treatments

Most management strategies for galactosemia are non-drug interventions focused on diet, supportive therapies, and monitoring.

1. Lactose- and Galactose-Restricted Diet
   Complete elimination of lactose-containing foods (cow’s milk, breast milk) prevents acute toxicity from galactose buildup. Mechanism: removes exogenous galactose source. Wikipedia

2. Soy-Based and Elemental Formulas
   Infants receive formula free of lactose. Purpose: ensure adequate nutrition without galactose exposure.

3. Dietary Counseling by a Metabolic Dietitian
   Personalized meal planning to maintain growth and nutritional balance while avoiding hidden galactose (e.g., in legumes, certain pharmaceuticals).

4. Regular Monitoring of Growth and Development
   Frequent assessments allow early detection of delays, enabling timely intervention.

5. Bone Density Surveillance
   Dual-energy X-ray absorptiometry (DEXA) scans monitor for osteoporosis risk; early physical therapy can promote bone strength.

6. Physical Therapy
   Improves muscle tone and motor skills in children with hypotonia or coordination issues.

7. Occupational Therapy
   Enhances fine motor skills and daily living activities for patients with developmental delays.

8. Speech and Language Therapy
   Addresses speech deficits and language delays common in treated patients.

9. Early Educational Support
   Individualized education plans support cognitive challenges and learning disabilities.

10. Psychological Counseling
    Helps patients and families cope with chronic disease stressors.

11. Genetic Counseling
    Educates families on inheritance patterns, recurrence risk, and prenatal testing options.

12. Newborn Screening Programs
    Universal screening ensures early diagnosis and treatment initiation.

13. Regular Ophthalmologic Exams
    Early detection of cataracts; guides timely ophthalmic interventions.

14. Audiology Evaluations
    Monitors for sensorineural hearing loss, especially in GALE deficiency.

15. Liver Function Testing
    Serum liver enzymes and ultrasound monitor hepatic health.

16. Neurological Assessments
    Detects tremors, ataxia, or other neuro symptoms for early rehabilitation.

17. Endocrine Follow-Up
    Monitors ovarian function in females; may prompt hormone evaluation.

18. Bone Health Education
    Encourages weight-bearing activities and appropriate vitamin intake.

19. Family Support Groups
    Provide community resources and shared experiences.

20. Telehealth Consultations
    Maintain frequent follow-up for remote or resource-limited families.

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Drug Treatments

While dietary therapy remains the mainstay, several pharmacological agents are under study or used to manage complications:

1. Epalrestat (Aldose Reductase Inhibitor)

   • Class: ARI

   • Dosage: 50–150 mg orally three times daily

   • Time: With meals

   • Purpose & Mechanism: Inhibits aldose reductase, reducing galactitol accumulation in lens and other tissues Wikipedia.

   • Side Effects: Gastrointestinal upset, headache

2. Govorestat (AT-007)

   • Class: Experimental ARI

   • Dosage: 300 mg once daily (under trial)

   • Purpose & Mechanism: Potent ARI in Phase III trials; lowers galactitol and may improve neurological outcomes Wikipedia.

   • Side Effects: Mild transient liver enzyme elevation

3. Ranirestat (in clinical trials)

   • Class: ARI

   • Dosage & Time: Trial-dependent dosing

   • Purpose & Mechanism: Similar to epalrestat; under investigation for better tissue penetration Wikipedia.

   • Side Effects: Under evaluation

4. Fidarestat (in clinical trials)

   • Class: ARI

   • Dosage & Time: Trial schedule

   • Mechanism: Reduces sorbitol/galactitol formation; efficacy under study Wikipedia.

5. Estrogen Replacement Therapy

   • Class: Hormone Therapy

   • Dosage: 0.625 mg conjugated estrogens daily

   • Purpose & Mechanism: Prevents osteoporosis from premature ovarian failure ScienceDirect.

   • Side Effects: Nausea, breast tenderness

6. Progesterone Supplementation

   • Class: Hormone Therapy

   • Dosage: 200 mg micronized progesterone daily (added cyclically)

   • Purpose: Protects endometrium in estrogen users

7. Alendronate

   • Class: Bisphosphonate

   • Dosage: 70 mg once weekly

   • Purpose & Mechanism: Improves bone density by inhibiting osteoclast activity

8. Ampicillin

   • Class: β-lactam antibiotic

   • Dosage: 50 mg/kg IV every 6 h (neonatal sepsis)

   • Purpose: Empiric treatment for E. coli sepsis risk

   • Side Effects: Rash, diarrhea

9. Gentamicin

   • Class: Aminoglycoside antibiotic

   • Dosage: 5 mg/kg IV once daily

   • Purpose: Synergistic therapy for gram-negative sepsis

   • Side Effects: Nephrotoxicity, ototoxicity

10. JAG101 Gene Therapy (experimental)

    • Class: AAV-mediated gene therapy

    • Dosage: Single IV infusion (preclinical data)

    • Purpose & Mechanism: Delivers functional GALT gene to liver and brain; restores enzyme activity and lowers toxic metabolites Jaguar Gene Therapy.

    • Side Effects: Under safety evaluation

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Dietary Molecular & Herbal Supplements

Adjunct supplements may support cellular health and mitigate oxidative stress:

1. N-Acetylcysteine (600 mg 2×/day)

   • Function: Antioxidant precursor to glutathione

   • Mechanism: Scavenges free radicals

2. Vitamin E (400 IU/day)

   • Function: Lipid-soluble antioxidant

   • Mechanism: Prevents membrane lipid peroxidation

3. Vitamin C (500 mg 2×/day)

   • Function: Water-soluble antioxidant

   • Mechanism: Regenerates oxidized vitamin E

4. Alpha-Lipoic Acid (300 mg/day)

   • Function: Mitochondrial antioxidant

   • Mechanism: Chelates metals, regenerates antioxidants

5. Coenzyme Q10 (100 mg/day)

   • Function: Electron transport chain support

   • Mechanism: Reduces oxidative damage

6. Omega-3 Fish Oil (1 g/day EPA/DHA)

   • Function: Anti-inflammatory

   • Mechanism: Modulates eicosanoid pathways

7. Curcumin (500 mg 2×/day)

   • Function: Anti-inflammatory antioxidant

   • Mechanism: Inhibits NF-κB signaling

8. Resveratrol (100 mg/day)

   • Function: Polyphenol antioxidant

   • Mechanism: Activates SIRT1, reduces ROS

9. Green Tea Extract (250 mg/day)

   • Function: Catechin-based antioxidant

   • Mechanism: Scavenges free radicals

10. Probiotic Blend

    • Function: Gut microbiome support

    • Mechanism: May reduce endogenous galactose production

11. L-Carnitine (500 mg 2×/day)

    • Function: Mitochondrial energy shuttle

    • Mechanism: Enhances fatty acid oxidation

12. Magnesium Citrate (200 mg/day)

    • Function: Cofactor in glucose metabolism

    • Mechanism: Stabilizes ATP production

13. Zinc (15 mg/day)

    • Function: Antioxidant enzyme cofactor

    • Mechanism: Supports superoxide dismutase

14. Silymarin (200 mg 2×/day)

    • Function: Liver protectant

    • Mechanism: Stabilizes hepatocyte membranes

15. Milk Thistle Extract

    • Function: Hepatoprotective

    • Mechanism: Reduces liver inflammation

Regenerative & Stem Cell Drugs

Emerging therapies aim to restore enzyme function or regenerate damaged tissues:

1. JAG101 (AAV9-GALT Vector)

   • Dosage: Single IV dose in trials

   • Mechanism: One-time gene replacement restores GALT activity Jaguar Gene Therapy.

2. Ex Vivo GALT-Gene-Edited Hematopoietic Stem Cells

   • Dosage: Autologous transplant

   • Mechanism: Corrected cells engraft and produce enzyme

3. Mesenchymal Stem Cell Infusion

   • Dosage: 1×10^6 cells/kg IV

   • Mechanism: Paracrine support for liver regeneration

4. CRISPR-Cas9 GALT Correction (experimental)

   • Dosage: Preclinical protocols

   • Mechanism: Direct editing of patient fibroblasts

5. Hepatocyte Transplantation

   • Dosage: 1×10^8 cells/kg portal infusion

   • Mechanism: Supplies functional enzyme in liver

6. Small-Molecule Chaperones

   • Dosage & Time: Under investigation

   • Mechanism: Stabilize mutant enzyme folding

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Surgeries

Surgical interventions address organ-specific complications:

1. Cataract Extraction

   • Procedure: Lens removal with intraocular lens implant

   • Why: Restores vision lost to galactitol-induced cataract formation

2. Cochlear Implantation

   • Procedure: Electrode placement in inner ear

   • Why: Treats sensorineural hearing loss in GALE deficiency

3. Liver Transplantation

   • Procedure: Orthotopic transplant

   • Why: In severe hepatic failure unresponsive to diet

4. Port-A-Cath Placement

   • Procedure: Central venous catheter insertion

   • Why: Facilitates IV therapies (antibiotics, gene therapy vectors)

5. Ovarian Transplantation (experimental)

   • Procedure: Autologous or donor tissue graft

   • Why: Potential future option for ovarian insufficiency

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 Preventive Strategies

Proactive measures to reduce disease burden:

1. Universal Newborn Screening

2. Prenatal Genetic Testing

3. Carrier Screening in High-Risk Populations

4. Preconception Genetic Counseling

5. Early Dietary Intervention at Birth

6. Regular Ophthalmic and Auditory Surveillance

7. Bone Health Monitoring from Childhood

8. Vaccination to Prevent Sepsis (e.g., Hib, Pneumococcus)

9. Infection-Control Measures in Neonates

10. Family Education on Emergency Signs

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When to See a Doctor

Seek immediate medical attention if any of these occur:
persistent jaundice beyond two weeks of life; vomiting, diarrhea, or feeding refusal; unexplained lethargy or hypotonia; signs of sepsis (fever, irritability); cataract development; any growth or developmental delays.

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What to Eat and What to Avoid

• Eat: Soy-based products, rice drinks, most fruits, vegetables, meats, grains (careful with labeling).

• Avoid: Cow’s milk, breast milk, dairy products (cheese, yogurt), lactose-containing medications, certain legumes (lupin), and foods processed with whey or casein.

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Frequently Asked Questions

1. What causes galactosemia?
   A mutated gene inherited from both parents leads to missing enzymes in the galactose breakdown pathway, causing toxic buildup of galactose and its derivatives Wikipedia.

2. How is galactosemia diagnosed?
   Through newborn heel-prick blood tests measuring galactose and enzyme activities, often confirmed by genetic testing.

3. Can breastfed infants be diagnosed early?
   Yes—since breast milk contains lactose, symptoms appear quickly, prompting screening results and dietary changes.

4. Is treatment lifelong?
   Yes, a galactose-free diet and regular monitoring are lifelong requirements to prevent complications.

5. Can patients tolerate small amounts of galactose?
   Classic galactosemia patients must strictly avoid galactose, while some GALE or GALM deficiency patients may tolerate minimal amounts under supervision.

6. Will a lactose-free diet prevent all complications?
   Diet prevents acute toxicity but may not fully eliminate long-term issues like ovarian insufficiency or neurological symptoms.

7. Is gene therapy available?
   Experimental therapies (e.g., JAG101) are in preclinical or early clinical stages; not yet widely available.

8. Can adults with mild forms develop symptoms later?
   Some carriers or mild GALE/GALK deficiency individuals may develop cataracts or subtle neurological issues in adulthood.

9. What is the life expectancy?
   With early detection and strict diet, many live into adulthood, though some long-term complications may persist.

10. Are there support groups?
    Yes—organizations like the Galactosemia Foundation offer resources for families and patients.

11. Can pregnancy be safe for women with galactosemia?
    With good metabolic control, many women have successful pregnancies, though ovarian failure risk remains high.

12. Are there any new drugs on the horizon?
    Aldose reductase inhibitors (e.g., govorestat) and gene therapies are under development.

13. Does galactosemia affect the immune system?
    Primary issue is sepsis risk in infancy; beyond that, no major chronic immune deficiency.

14. Can siblings be tested before birth?
    Yes—via chorionic villus sampling or amniocentesis if parents are known carriers.

15. How often should follow-up occur?
    At least quarterly in early childhood, then biannually or annually as the child grows, with more frequent visits if complications arise.

Disclaimer: Each person’s journey is unique, treatment plan, life style, food habit, hormonal condition, immune system, chronic disease condition, geological location, weather and previous medical  history is also unique. So always seek the best advice from a qualified medical professional or health care provider before trying any treatments to ensure to find out the best plan for you. This guide is for general information and educational purposes only. Regular check-ups and awareness can help to manage and prevent complications associated with these diseases conditions. If you or someone are suffering from this disease condition bookmark this website or share with someone who might find it useful! Boost your knowledge and stay ahead in your health journey. We always try to ensure that the content is regularly updated to reflect the latest medical research and treatment options. Thank you for giving your valuable time to read the article.

The article is written by Team RxHarun and reviewed by the Rx Editorial Board Members

Last Updated: August 07, 2025.