Diseases in human genetics

1. β-Thalassemia

Gene / Chromosome: HBB gene, chromosome 11

Inheritance: Autosomal recessive

Pathophysiology: Reduced or absent β-globin → excess α-globin → hemolysis & ineffective erythropoiesis

Clinical types:

  * Trait (minor): heterozygous, mild anemia

  * Intermedia: moderate anemia, may not need transfusion

  * Major: homozygous, severe anemia, transfusion-dependent

Clinical features: Anemia, growth retardation, bone deformities, hepatosplenomegaly

Diagnosis: CBC, Hb electrophoresis, genetic testing

Management: Transfusions, iron chelation, bone marrow transplant, genetic counseling

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2. Sickle Cell Anemia

Gene / Mutation: HBB gene, chromosome 11; Glu→Val at codon 6

Inheritance: Autosomal recessive

Pathophysiology: HbS polymerizes → RBCs sickle → hemolysis, vaso-occlusion

Clinical features: Hemolytic anemia, jaundice, pain crises, hemarthrosis, stroke, splenic sequestration, chronic organ damage (kidney, eye, bone)

Acute crises: Pain, stroke, acute chest syndrome, priapism

Chronic complications: Chronic anemia, gallstones, leg ulcers, osteonecrosis, delayed growth

Diagnosis: Blood smear, Hb electrophoresis, genetic testing

Management: Hydroxyurea, transfusions, infection prophylaxis, supportive care, bone marrow transplant

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3. G6PD Deficiency

Gene / Chromosome: G6PD gene, X chromosome

Inheritance: X-linked recessive

Pathway: Pentose phosphate pathway

Function: Produces NADPH → maintains reduced glutathione → protects RBCs from oxidative stress

Pathophysiology: Deficiency → low NADPH → low GSH → RBC oxidative damage → hemolysis

Triggers: Fava beans, drugs (primaquine, sulfonamides), infections

Clinical features: Hemolytic anemia, jaundice, neonatal hyperbilirubinemia

Diagnosis: Low G6PD enzyme activity, Heinz bodies, genetic testing

Management: Avoid triggers, supportive care, phototherapy for neonatal jaundice

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4. Phenylketonuria (PKU)

Gene / Enzyme: PAH gene → phenylalanine hydroxylase

Inheritance: Autosomal recessive

Pathophysiology: Phenylalanine cannot convert to tyrosine → accumulation → neurotoxicity

Clinical features: Intellectual disability, myelination defect, low brain weight, hypopigmentation, seizures

Dietary restrictions: Avoid phenylalanine & aspartame

Diagnosis: Newborn screening (Guthrie test), plasma phenylalanine, genetic testing

Management: Low phenylalanine diet, tyrosine supplementation, early intervention

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5. Maple Syrup Urine Disease (MSUD)

Gene / Enzyme: BCKDHA, BCKDHB, DBT → branched-chain α-keto acid dehydrogenase complex

Inheritance: Autosomal recessive

Pathophysiology: Defective BCKD → accumulation of leucine, isoleucine, valine → ketoacidosis → neurotoxicity

Clinical features: Sweet maple syrup odor urine, poor feeding, vomiting, lethargy, seizures, coma

Diagnosis: Newborn screening, blood BCAA elevation, urine organic acids, genetic testing

Management: Restriction of branched-chain amino acids, special formulas, thiamine supplementation

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6. Alkaptonuria

Gene / Enzyme: HGD gene → homogentisate oxidase

Inheritance: Autosomal recessive

Pathophysiology: Deficiency → homogentisic acid accumulation → oxidizes → black urine, tissue deposition

Clinical features: Dark urine on standing, ochronosis (eyes, ears, cartilage), arthritis

Diagnosis: Elevated urinary homogentisic acid, genetic testing

Management: Low phenylalanine/tyrosine diet, supportive care

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7. Lactose Intolerance

Gene / Enzyme: LCT gene → lactase / β-galactosidase

Inheritance: Autosomal recessive (primary congenital form)

Pathophysiology: Lactase deficiency → lactose undigested → osmotic diarrhea, fermentation by gut bacteria → bloating, gas

Clinical features: Diarrhea, abdominal pain, bloating, gas

Diagnosis: Lactose hydrogen breath test, lactose tolerance test, genetic testing

Management: Lactose-free diet, lactase enzyme supplements, probiotics

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8. Tay-Sachs Disease

Gene / Enzyme: HEXA → β-hexosaminidase A

Inheritance: Autosomal recessive

Pathophysiology: Deficiency → GM2 ganglioside accumulates in neurons → neurodegeneration

Clinical features: Normal at birth → developmental delay, hypotonia, seizures, cherry-red spot, early death

Diagnosis: Enzyme assay, genetic testing

Management: Supportive care

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9. Hereditary Spherocytosis (HS)

Genes: ANK1, SLC4A1, SPTA1, SPTB

Inheritance: Mostly autosomal dominant, some recessive

Pathophysiology: Defective RBC membrane → spherocytes → trapped in spleen → hemolysis

Clinical features: Fatigue, jaundice, hepatosplenomegaly, gallstones

Diagnosis: Blood smear, osmotic fragility, EMA binding, genetic testing

Management: Folic acid, splenectomy for severe cases

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10. Von Willebrand Disease (vWD)

Gene / Chromosome: vWF, chromosome 12

Inheritance: Mostly autosomal dominant, type 3 recessive

Pathophysiology: ↓ vWF → impaired platelet adhesion, ↓ Factor VIII stabilization

Types:

  * Type 1: partial quantitative deficiency (85%)

  * Type 2: qualitative defect (protein dysfunctional)

  * Type 3: almost complete absence

Clinical features: Mucocutaneous bleeding, menorrhagia, prolonged bleeding

Diagnosis: vWF antigen, ristocetin cofactor activity, Factor VIII activity, genetic testing

Management: DDAVP (type 1), vWF concentrates, antifibrinolytics

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11. Hemophilia A

Gene / Factor: F8 → Factor VIII

Inheritance: X-linked recessive

Pathophysiology: ↓ Factor VIII → impaired intrinsic coagulation → prolonged bleeding

Clinical features: Hemarthrosis, hematuria, soft tissue, intracranial bleeding

Diagnosis: Prolonged aPTT, normal PT, Factor VIII assay, genetic testing

Management: Factor VIII replacement, gene therapy (experimental)

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12. Hemophilia B (Christmas Disease)

Gene / Factor: F9 → Factor IX

Inheritance: X-linked recessive

Pathophysiology: ↓ Factor IX → impaired intrinsic coagulation → prolonged bleeding

Clinical features: Mild/moderate/severe bleeding, hemarthrosis, hematuria, intracranial bleeding

Diagnosis: Prolonged aPTT, Factor IX assay

Management: Factor IX replacement, prophylaxis in severe cases

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13. Gaucher Disease

Gene / Enzyme: GBA → glucocerebrosidase

Inheritance: Autosomal recessive

Pathophysiology: Glucocerebroside accumulates in macrophages → Gaucher cells → spleen, liver, bone, CNS

Types:

  * Type 1: non-neuronopathic, childhood-adulthood

  * Type 2: acute neuronopathic, infancy

  * Type 3: chronic neuronopathic, childhood

Clinical features: Hepatosplenomegaly, pancytopenia, bone pain/fractures

Diagnosis: Enzyme assay, genetic testing, bone marrow

Management: ERT, substrate reduction therapy, supportive care

14. Albinism

Enzyme / Gene: Tyrosinase (TYR gene) → OCA1, OCA2, TYRP1 (OCA3), CHS1 (Chediak-Higashi), HPS (Hermansky-Pudlak), OA1 (X-linked ocular albinism)

Inheritance: Autosomal recessive (except OA1)

Pathophysiology: ↓ melanin → impaired pigmentation and retinal development

Clinical features: Pallor, photophobia, low visual acuity, nystagmus, strabismus, sun sensitivity

Diagnosis: Clinical features, genetic testing

Management: Sun protection, visual aids, manage associated syndromes, genetic counseling

Urea Cycle Disorders — Detailed Subtopic List

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1. Ornithine Transcarbamoylase (OTC) Deficiency

Gene / Enzyme: OTC gene → Ornithine transcarbamoylase

Inheritance: X-linked recessive

Pathophysiology:

  * Ornithine cannot convert to citrulline

  * Block in mitochondrial urea cycle

  * **Hyperammonemia** → neurotoxicity

Clinical features:

  * Neonatal lethargy, vomiting, poor feeding

  * Seizures, coma, hypotonia

  * Respiratory alkalosis

  * Males severely affected; females heterozygotes mild or variable

Diagnosis: Elevated plasma ammonia, low citrulline, elevated urinary orotic acid, genetic testing

Management: Nitrogen scavengers (sodium benzoate, sodium phenylacetate), protein restriction, citrulline supplementation, liver transplant in severe cases

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2. Carbamoyl Phosphate Synthetase 1 (CPS1) Deficiency

Gene / Enzyme: CPS1 gene → Carbamoyl phosphate synthetase 1

Inheritance: Autosomal recessive

Pathophysiology:

  * CPS1 cannot convert ammonia + bicarbonate → carbamoyl phosphate

  * First step block in urea cycle

  * Severe neonatal hyperammonemia

Clinical features: Lethargy, vomiting, poor feeding, seizures, coma, respiratory alkalosis

Diagnosis: Elevated plasma ammonia, low citrulline, genetic testing, normal urinary orotic acid

Management: Dialysis, nitrogen scavengers, protein restriction, liver transplant

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3. N-Acetylglutamate Synthase (NAGS) Deficiency

Gene / Enzyme: NAGS gene → N-acetylglutamate synthase

Inheritance: Autosomal recessive

Pathophysiology:

  * NAGS deficiency → ↓ NAG → CPS1 inactive

  * First step block in urea cycle

  * Hyperammonemia

Clinical features: Neonatal lethargy, vomiting, seizures, hypotonia, coma

Diagnosis: Elevated plasma ammonia, low citrulline, genetic testing, normal urinary orotic acid

Management: N-carbamylglutamate (Carbaglu®)**, nitrogen scavengers, protein restriction, liver transplant

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## **4. Argininosuccinate Synthetase (ASS) Deficiency — Citrullinemia Type I**

* **Gene / Enzyme:** ASS1 gene → Argininosuccinate synthetase

* **Inheritance:** Autosomal recessive

* **Pathophysiology:**

  * Citrulline cannot convert to argininosuccinate

  * Hyperammonemia

* **Clinical features:** Neonatal lethargy, poor feeding, vomiting, seizures, hypotonia, coma

* **Diagnosis:** Elevated plasma ammonia, high plasma citrulline, genetic testing

* **Management:** Nitrogen scavengers, protein restriction, arginine supplementation, liver transplant

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## **5. Argininosuccinate Lyase (ASL) Deficiency — Argininosuccinic Aciduria**

* **Gene / Enzyme:** ASL gene → Argininosuccinate lyase

* **Inheritance:** Autosomal recessive

* **Pathophysiology:**

  * Argininosuccinate cannot convert → arginine + fumarate

  * Hyperammonemia, accumulation of argininosuccinate

* **Clinical features:** Lethargy, vomiting, seizures, developmental delay, hypotonia

* **Diagnosis:** Elevated plasma ammonia, elevated plasma argininosuccinate, genetic testing

* **Management:** Nitrogen scavengers, arginine supplementation, protein restriction, liver transplant

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## **6. Arginase Deficiency — Hyperargininemia**

* **Gene / Enzyme:** ARG1 gene → Arginase

* **Inheritance:** Autosomal recessive

* **Pathophysiology:**

  * Arginine cannot convert → urea + ornithine

  * Mild hyperammonemia

  * Arginine accumulation → neurotoxicity

* **Clinical features:** Late-onset spasticity, developmental delay, growth retardation, occasional seizures

* **Diagnosis:** Mildly elevated plasma ammonia, elevated plasma arginine, genetic testing

* **Management:** Protein restriction, arginine-limited diet, nitrogen scavengers if severe, liver transplant in severe cases

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### ✅ High-Yield Summary / Exam Tips for UCDs

* **Hyperammonemia** → neurotoxicity, lethargy, seizures, coma

* **Inheritance patterns:**

  * X-linked: OTC deficiency

  * Autosomal recessive: CPS1, NAGS, ASS, ASL, Arginase

* **Diagnostic metabolites:**

  * OTC: ↑ ammonia, ↑ urinary orotic acid

  * CPS1/NAGS: ↑ ammonia, normal orotic acid

  * ASS: ↑ citrulline

  * ASL: ↑ argininosuccinate

  * Arginase: ↑ arginine

* **Management principle:** Reduce nitrogen load (diet, scavengers), supplement deficient intermediates, liver transplant for severe neonatal forms

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# 🧬 Inborn Errors of Metabolism (IEM)

### 1️⃣ Definition

**IEM** are **genetic disorders** caused by **mutations in genes encoding enzymes, transporters, or cofactors**, leading to **abnormal metabolism** of carbohydrates, amino acids, lipids, or other molecules.

* Usually **autosomal recessive**

* Can also be **X-linked recessive** in some cases

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### 2️⃣ Mechanism

* **Gene mutation** → defective enzyme → metabolic pathway blocked

* Two main consequences:

  1. **Accumulation of toxic substrate** (cannot be processed)

  2. **Deficiency of essential product** (cannot be produced)

**Example:**

* **Phenylketonuria (PKU)** → defective phenylalanine hydroxylase → phenylalanine accumulates → brain toxicity

* **G6PD deficiency** → defective NADPH production → oxidative stress → hemolysis

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### 3️⃣ Clinical Features

* Depend on the **metabolic pathway affected**

* Common signs:

  * **Neurological issues** (seizures, developmental delay)

  * **Jaundice / hemolysis**

  * **Growth retardation**

  * **Characteristic odors or urine color** (e.g., MSUD, alkaptonuria)

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### 4️⃣ Diagnosis

* **Biochemical testing** → measure metabolites in blood/urine

* **Enzyme assays** → measure activity of specific enzymes

* **Genetic testing** → identify mutations in relevant genes

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### 5️⃣ Treatment / Management

* **Dietary restrictions** (e.g., PKU → low phenylalanine diet)

* **Enzyme replacement therapy** (for lysosomal storage disorders)

* **Gene therapy** (emerging)

* **Supportive care** for complications

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### ✅ Exam-ready short answer

**Inborn errors of metabolism (IEM) are genetic disorders caused by enzyme or transporter defects that disrupt normal metabolism, leading to toxic accumulation of substrates or deficiency of products.**