Fiche de révision : Genetic Mutations and Syndromes

📋 Course Outline

1. Genetic Mutation Fundamentals
2. Inheritance Patterns and Mutation Types
3. Alagille Syndrome
4. McCune–Albright Syndrome
5. Primary Ciliary Dyskinesia
6. Treacher Collins Syndrome

📖 1. Genetic Mutation Fundamentals

🔑 Key Concepts & Definitions

• Genetic mutation : A permanent alteration of the DNA sequence that can produce a clinically significant syndrome.

★ Must-know

📌 Germ-cell mutations can be inherited, whereas somatic-cell mutations arise in body cells and may result from environmental factors such as radiation.

Further detail

• Genetic mutations can participate in physiologic and pathologic processes, including evolution, immune-system development, and cancer.

• Major complications of genetic mutations include spontaneous abortion, severe organ defects such as tetralogy of Fallot and renal dysplasia, visual or hearing disturbances, growth deficiency, intellectual disability, and cancer.

💡 Memory Hook

DNA alteration → altered protein or gene expression → disease

📖 2. Inheritance Patterns and Mutation Types

📝 Essential Points

• A point mutation substitutes one DNA base and may be a transition between two purines or two pyrimidines, or a transversion between a purine and a pyrimidine.

• Silent mutations encode the same amino acid, missense mutations encode a different amino acid, and nonsense mutations create an early stop codon that can produce a nonfunctional protein.

• Deletions remove DNA bases, insertions add DNA bases, splice-site mutations alter mRNA splicing, and frameshift mutations shift the reading frame.

• Mendelian disorders result from a single gene mutation with large effects, chromosomal disorders involve numerical or structural chromosome abnormalities, and complex multigenic disorders involve genes that increase disease risk without independently causing disease.

• Autosomal dominant inheritance requires one mutated copy, autosomal recessive inheritance requires both copies, X-linked mutations are not transmitted from father to son, Y-linked mutations pass from father to son, codominant alleles both affect the same trait, and mitochondrial mutations show maternal inheritance.

📖 3. Alagille Syndrome

🔑 Key Concepts & Definitions

• Alagille syndrome : An autosomal dominant disorder causing liver, skeletal, ocular, cardiac, and renal defects, also called arteriohepatic dysplasia or Alagille–Watson syndrome.

★ Must-know

• About 95% of Alagille syndrome cases involve the JAG1 gene on chromosome 20p12, while NOTCH2 mutations on chromosome 1p13 are associated with renal malformations.

• Loss of intrahepatic bile ducts in Alagille syndrome causes chronic cholestasis with increased conjugated bilirubin, liver enzymes, and cholesterol and may progress to cirrhosis or liver failure.

Further detail

• Characteristic Alagille features include butterfly-shaped or hemivertebrae, a triangular face with prominent forehead and hypertelorism, short stature, peripheral pulmonary artery stenosis or tetralogy of Fallot, renal dysplasia, and ocular abnormalities such as embryotoxon.

• Treatment of Alagille syndrome includes ursodeoxycholic acid with cholestyramine, rifampin, or naltrexone, nutritional support, biliary diversion or liver transplantation, and surgical repair of significant heart defects.

📖 4. McCune–Albright Syndrome

🔑 Key Concepts & Definitions

• McCune–Albright syndrome : Characterized by fibrous dysplasia, hyperfunctioning endocrinopathy, and unilateral café-au-lait skin spots.

★ Must-know

• A postzygotic mutation in GNAS1 on chromosome 20q13.1–13.2 causes somatic mosaicism and abnormal Gs alpha protein signaling through the G-protein, cyclic AMP, and adenylate cyclase pathway.

• Fibrous dysplasia commonly affects the skull base and proximal femur, with radiographs showing expansile lytic lesions, cortical thinning, a ground-glass appearance, and a possible shepherd’s-crook deformity of the proximal femur.

• Endocrine manifestations include hyperthyroidism, Cushing’s syndrome, growth-hormone excess, renal phosphate wasting, and precocious puberty.

Further detail

• Bisphosphonates can reduce pain in fibrous dysplasia but do not stop disease progression, while endocrine medications treat the associated hormone excesses.

💡 Memory Hook

Fibrous dysplasia → endocrinopathy → café-au-lait spots

📖 5. Primary Ciliary Dyskinesia

🔑 Key Concepts & Definitions

• Primary ciliary dyskinesia : A congenital autosomal recessive disease in which defective ciliary motility impairs mucociliary clearance and decreases fertility.

★ Must-know

• Immotile or abnormally moving cilia cause recurrent respiratory infections, chronic rhinosinusitis, bronchiectasis, and impaired movement of fallopian-tube cilia and sperm flagella.

• Kartagener syndrome is the combination of situs inversus, chronic sinusitis, and bronchiectasis occurring in primary ciliary dyskinesia.

Further detail

• Mutations in DNAH5 and DNAI1 affect axonemal outer dynein arms, while mutations in RSPH4A and RSPH9 affect radial spokes.

• Diagnosis can include reduced or absent nasal nitric oxide, spirometry showing obstruction, genetic testing, high-speed video microscopy, transmission electron microscopy, and confirmation from cultured immotile cilia.

📌 Treatment includes antibiotics, nebulized hypertonic saline, mucolytic agents, nasal saline and intranasal glucocorticoids, daily chest physiotherapy, vaccination, smoking cessation, and polyp removal when required.

💡 Memory Hook

Immotile cilia → poor clearance → recurrent infections

📖 6. Treacher Collins Syndrome

🔑 Key Concepts & Definitions

• Treacher Collins syndrome : A severe genetic disorder of craniofacial development, also called mandibulofacial dysostosis or Franceschetti–Zwahlen–Klein syndrome.

★ Must-know

• A TCOF1 mutation on chromosome 5q32 causes treacle-protein insufficiency, impaired ribosome biogenesis, neuroepithelial apoptosis, reduced neural crest cells, and first- and second-branchial-arch anomalies.

• Treacher Collins syndrome is autosomal dominant with variable penetrance, and approximately 60% of cases are spontaneous.

• Typical findings include mandibular and zygomatic hypoplasia, retrognathia, downslanting eyelids, lower-eyelid coloboma, malformed external and middle ears, cleft or high-arched palate, and dental abnormalities.

Further detail

• Management may require reconstructive surgery, tracheostomy for severe neonatal airway obstruction, glossopexy, correction of cleft palate or choanal atresia, gastrostomy, hearing aids, and speech therapy.

💡 Memory Hook

Treacle deficiency → neural crest loss → craniofacial hypoplasia

📊 Synthesis Tables

Inheritance Pattern Comparison

Syndrome Defining Features