Classic Genetic Disorders

Trinucleotide repeat expansions

Shared behavior. In these four disorders an unstable three-base repeat lengthens as it passes through the germline, so all show anticipation — earlier onset and more severe disease in successive generations. Mnemonic "Try hunting for my fried eggs": Huntington (CAG), Myotonic dystrophy (CTG), Friedreich ataxia (GAA), Fragile X (CGG).

Huntington disease. The CAG expansion adds a polyglutamine tract to huntingtin. GABAergic neurons of the caudate die, so the caudate atrophies and the lateral ventricles enlarge. Neurotransmitter pattern: ↓GABA, ↓ACh, ↑dopamine. Memory aid: CAG = Caudate, Anticipation, Glutamine.

Fragile X syndrome. The CGG expansion triggers hypermethylation that silences FMR1. It is the most common inherited cause of intellectual disability; Down syndrome is the most common genetic cause overall. Premutation carriers (intermediate repeat lengths) risk primary ovarian insufficiency and fragile X–associated tremor/ataxia syndrome (FXTAS).

Friedreich ataxia. Frataxin handles iron inside mitochondria; its loss injures neurons and cardiomyocytes. Hypertrophic cardiomyopathy is the usual cause of death.

Marfan syndrome

Defect. Autosomal dominant FBN1 mutation (chromosome 15) produces defective fibrillin-1, the glycoprotein scaffold on which elastin is laid down.

Findings. Tall stature with long extremities, arachnodactyly, hyperflexible joints, pectus deformity, upward lens subluxation, and mitral valve prolapse. Cystic medial degeneration of the aorta causes aortic root dilation and dissection — the main threat to life, classically a tall young man with sudden chest and back pain.

Lens direction: Marfan dislocates up and out; homocystinuria (marfanoid habitus plus intellectual disability and thrombosis) dislocates down and in.

Neurocutaneous syndromes

Common thread. NF1, NF2, tuberous sclerosis, and von Hippel-Lindau are autosomal dominant tumor-suppressor disorders that combine skin or eye findings with nervous system and visceral tumors.

NF1. Loss of neurofibromin, a GTPase-activating protein, leaves RAS switched on. Penetrance is essentially complete, but expressivity varies widely within families.

Tuberous sclerosis. Hamartin and tuberin normally restrain mTOR signaling, so their loss seeds hamartomas in many organs, with marked variable expressivity. Ash-leaf spots plus cardiac rhabdomyoma plus seizures in an infant point to tuberous sclerosis.

Von Hippel-Lindau. The VHL protein normally targets hypoxia-inducible factor for degradation; losing it mimics constant hypoxia.

Autosomal trisomies and prenatal screening

Down syndrome (trisomy 21). The most common trisomy among live births and the most common genetic cause of intellectual disability. Most cases arise from meiotic nondisjunction, whose risk rises with advanced maternal age; a minority result from Robertsonian translocation or mosaicism. Associations: duodenal atresia ("double bubble," bilious vomiting), Hirschsprung disease, AV septal (endocardial cushion) defect, early-onset Alzheimer disease (extra APP gene on chromosome 21), and increased ALL and AML risk.

Maternal serum AFP. Elevated AFP points to an open neural tube defect or an abdominal wall defect (after excluding wrong dates or multiple gestation). Low AFP occurs in Down and Edwards syndromes.

Chromosome 15 imprinting

Prader-Willi vs Angelman. Both involve the imprinted 15q region, where only one parent's copy is active. Prader-Willi results from loss of the paternal genes: neonatal hypotonia and poor feeding, then hyperphagia and obesity, hypogonadism, and intellectual disability. Angelman results from loss of the maternal gene UBE3A: ataxia, seizures, and inappropriate laughter (the "happy puppet"). Either can arise from a deletion or from uniparental disomy — maternal disomy gives Prader-Willi, paternal disomy gives Angelman.

Prader-Willi = Paternal loss; Angelman = mAternal loss.