# Clinical Cases: Molecular Genetics and Mutations ## Case 1: Huntington Disease (Trinucleotide Repeat Expansion) ### Clinical Image ![Huntington Disease MRI](case_01_image.jpg) *Source: [Radiopaedia - Huntington disease](https://radiopaedia.org/articles/huntington-disease) - CC BY-NC-SA 3.0* ### Case Presentation A 42-year-old man presents with his wife who reports 2 years of progressive personality changes, involuntary movements, and cognitive decline. She describes him as increasingly irritable and impulsive, with difficulty at work. Physical examination reveals chorea (rapid, involuntary, irregular movements) affecting his face, trunk, and limbs, along with motor impersistence (inability to maintain tongue protrusion). Cognitive testing shows executive dysfunction. His father died at age 50 from "dementia" after years in a psychiatric facility. MRI brain shows bilateral caudate atrophy with enlarged frontal horns of the lateral ventricles, giving a characteristic "boxcar" appearance. Genetic testing reveals 45 CAG repeats in the HTT gene (normal <36, pathogenic >39), confirming Huntington disease. The genetic counselor explains anticipation: his father likely had fewer repeats with later onset, and any children have 50% risk of inheriting the expanded allele. The repeats tend to expand further during paternal transmission, potentially causing earlier onset in the next generation. He is referred to a movement disorder specialist for symptomatic treatment (tetrabenazine for chorea) and to psychiatric services for mood management. Presymptomatic testing is discussed for his adult children. ### Key Learning Points - Huntington disease is caused by CAG repeat expansion in HTT encoding huntingtin protein; the polyglutamine tract becomes toxic when expanded, causing selective neurodegeneration in the striatum - Trinucleotide repeat disorders show anticipation (earlier onset in successive generations) because repeats tend to expand during DNA replication, particularly in spermatogenesis; juvenile HD is typically inherited from the father - Genetic testing requires careful counseling because the result is predictive and there is no disease-modifying treatment; guidelines recommend testing only after age 18 with appropriate genetic counseling --- ## Case 2: Prader-Willi Syndrome (Genomic Imprinting) ### Clinical Image ![Prader-Willi Syndrome](case_02_image.jpg) *Source: [Wikipedia - Prader-Willi syndrome](https://en.wikipedia.org/wiki/Prader%E2%80%93Willi_syndrome) - CC BY-SA 3.0* ### Case Presentation A 5-year-old boy is referred for evaluation of obesity and developmental delay. His mother reports that as a newborn he was very floppy and had difficulty feeding, requiring a feeding tube for several months. Around age 2, he developed insatiable appetite and began gaining weight rapidly despite dietary restriction. He has mild intellectual disability and behavioral problems including tantrums. Physical examination reveals central obesity, small hands and feet, almond-shaped eyes, and small genitalia (hypogonadism). Genetic testing reveals a deletion of the paternal chromosome 15q11-13 region. The geneticist explains genomic imprinting: certain genes are expressed only from the maternal or paternal copy, with the other silenced by epigenetic modifications. The genes in this region that cause Prader-Willi syndrome are normally expressed only from the paternal chromosome; when the paternal copy is deleted, there is no functional expression because the maternal copy is imprinted (silenced). Interestingly, deletion of the same region on the maternal chromosome causes a completely different syndrome (Angelman syndrome) because different genes in the region are maternally expressed. Management includes strict dietary control, growth hormone therapy, and behavioral interventions. ### Key Learning Points - Genomic imprinting creates parent-of-origin effects: certain genes are expressed only from maternal or paternal alleles, with the other copy epigenetically silenced - Prader-Willi syndrome results from loss of paternally-expressed genes at 15q11-13 (deletion, uniparental disomy, or imprinting defect); Angelman syndrome results from loss of maternally-expressed genes in the same region - The same chromosomal deletion causes different diseases depending on the parent of origin, demonstrating that genetic diseases can depend on more than just the DNA sequence --- ## Case 3: Fragile X Syndrome (X-Linked with CGG Repeat Expansion) ### Clinical Image ![Fragile X Syndrome](case_03_image.jpg) *Source: [Wikipedia - Fragile X syndrome](https://en.wikipedia.org/wiki/Fragile_X_syndrome) - CC BY-SA 3.0* ### Case Presentation A 3-year-old boy is referred for evaluation of developmental delay and speech regression. He spoke his first words at 12 months but has since lost language skills and now has only 10 single words. He exhibits repetitive behaviors, poor eye contact, and hand flapping, raising concern for autism spectrum disorder. Physical examination reveals a long face, prominent ears, and macroorchidism (large testes) is noted. His maternal grandfather has a progressive tremor and balance problems. Genetic testing reveals >200 CGG repeats in the 5' UTR of the FMR1 gene, confirming fragile X syndrome. The genetic counselor explains: normal individuals have <55 repeats; premutation carriers (55-200 repeats) have normal intelligence but may develop fragile X-associated tremor/ataxia syndrome (FXTAS) in later life, particularly males, explaining the grandfather's symptoms. Full mutations (>200 repeats) occur when premutation alleles expand during maternal transmission, causing methylation and silencing of FMR1. The loss of FMRP protein (which regulates synaptic plasticity) causes the cognitive and behavioral features. Testing reveals his mother carries a premutation, explaining how she is unaffected but transmitted a full mutation to her son. The family is referred to early intervention services. ### Key Learning Points - Fragile X syndrome results from CGG repeat expansion (>200) in the 5' UTR of FMR1; massive expansion causes DNA methylation and gene silencing, eliminating FMRP protein expression - Premutation carriers (55-200 repeats) are at risk for fragile X-associated tremor/ataxia syndrome (FXTAS) and, in females, premature ovarian insufficiency; the premutation can expand to full mutation during female meiosis - The inheritance pattern is complex: unaffected carrier females can have affected sons; the phenotype is worse in males due to hemizygosity (only one X chromosome)