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Basic Science
Pathology
10 notes available
1 Last Minute Review 2 Neuropathology Fundamentals 3 Embryology & Developmental Malformations 4 Neurocutaneous Syndromes (Phakomatoses) 5 CNS Tumors 6 Metabolic & Storage Diseases 7 Leukodystrophies 8 Mitochondrial Disorders 9 Neurotoxicology & Nutritional Deficiencies 10 Neurogenetics
Basic Science › Pathology

Neurogenetics

Neurogenetics

What You'll Learn

  • Autosomal dominant (AD): 50% offspring affected; one mutant allele sufficient; variable penetrance; male-to-male transmission possible (distinguishes from X-linked)
  • Autosomal recessive (AR): 25% affected offspring from two carrier parents; consanguinity increases risk; carriers are asymptomatic
  • X-linked recessive: males affected, females are carriers; NO male-to-male transmission; all daughters of an affected male are obligate carriers
  • Mitochondrial inheritance: maternal only — affected mother passes to all children; heteroplasmy and threshold effect determine phenotype
  • Trinucleotide repeat expansions: cause anticipation (earlier onset in successive generations); CAG repeats = polyglutamine = mostly AD; Friedreich ataxia (GAA) is the only common AR trinucleotide repeat disorder
  • Genomic imprinting: Prader-Willi = paternal deletion 15q11–13 (“P for Paternal, P for Prader”); Angelman = maternal deletion 15q11–13 (“A for Angelman, M for Maternal”)
  • Chromosomal microarray (CMA) is the recommended first-line genetic test for unexplained intellectual disability and autism; whole-exome sequencing (WES) is best for complex phenotypes
  • Huntington disease: CAG repeat in HTT on 4p16.3; normal ≤26 CAG; intermediate 27–35 (not pathogenic but may expand); reduced penetrance 36–39; fully penetrant ≥40; caudate atrophy; AD with anticipation (paternal transmission → larger expansions)
HighYield Pearls
  • Anticipation = larger repeat + earlier onset + worse severity in successive generations: classic for CAG (HD, SCA1/2/3/6/7, DRPLA, SBMA) and CTG (DM1); Friedreich (GAA) and FXS (CGG) generally do NOT show anticipation in the same way
  • HD CAG thresholds: ≤26 normal, 27–35 intermediate, 36–39 reduced penetrance, ≥40 fully penetrant; juvenile (Westphal) rigid-akinetic variant → paternal expansion; congenital DM1 → maternal transmission
  • FMR1 CGG repeats: >200 = full mutation (fragile X — ID + autism + large ears + macroorchidism + long face); premutation 55–200 → FXTAS in males (intention tremor + cerebellar ataxia + middle cerebellar peduncle T2 hyperintensity) and premature ovarian insufficiency in females
  • C9orf72 GGGGCC hexanucleotide expansion: most common familial cause of FTD AND ALS; AD; TDP-43 type B + p62 + dipeptide repeat protein (DPR) inclusions; bvFTD + psychiatric features common
  • Imprinting on 15q11–13: Prader-Willi = Paternal deletion (hypotonia + hyperphagia + obesity + hypogonadism + ID); Angelman = mAternal deletion / UBE3A (“happy puppet” — ataxia + laughter + seizures + ID)
  • Mitochondrial inheritance: maternal only, NO male-to-male transmission; heteroplasmy + threshold effect; MELAS (stroke-like + lactic acidosis + ragged-red fibers), MERRF (myoclonic epilepsy + RRF), LHON (subacute bilateral optic neuropathy in young males), KSS (PEO + pigmentary retinopathy + cardiac conduction block before age 20)
  • X-linked pearls: no male-to-male transmission; all daughters of affected male are obligate carriers; DMD/BMD (dystrophin), Fabry (α-galactosidase A), ALD (ABCD1 / VLCFA), OTC (hyperammonemia), Pelizaeus-Merzbacher (PLP1 dysmyelination)
  • CADASIL = NOTCH3 cysteine substitution (AD): recurrent subcortical lacunar strokes + confluent white-matter lesions (especially anterior temporal pole + external capsule) + migraine with aura + mood disturbance + early dementia
  • Friedreich ataxia: AR, intronic GAA expansion in FXN → frataxin loss → mitochondrial iron accumulation; gait ataxia + areflexia + upgoing toes + dorsal column loss + hypertrophic cardiomyopathy + diabetes + scoliosis + pes cavus
  • SMA (5q SMN1) genetic counseling: AR; SMN2 copy number is the major phenotype modifier; disease-modifying therapies now available (nusinersen, onasemnogene abeparvovec, risdiplam) — early diagnosis is critical
  • Predictive HD testing ethics: formal pre-test counseling required; respect the “right not to know”; presymptomatic testing of minors generally deferred for adult-onset disorders unless intervention is available; GINA (US) protects against health-insurance/employment discrimination but NOT life/disability insurance
  • First-line genetic test by indication: chromosomal microarray (CMA) remains important for CNV-heavy presentations such as ASD/ID/MCA, but ACMG now recommends exome or genome sequencing as a first- or second-tier test for pediatric congenital anomalies, developmental delay, or intellectual disability; targeted repeat testing for clinical suspicion of repeat disorders (HD, FXS, DM1, Friedreich, C9orf72); reanalyze ES/GS data over time as gene-disease knowledge expands
🔍 Quick ReferenceInheritance / mechanism · Repeat / mutation · Disease association
Inheritance / mechanism
  • Male-to-male transmission → autosomal dominant (rules out X-linked)
  • Maternal-only transmission — all children of an affected female inherit maternal mtDNA and are at risk, but clinical expression varies because of heteroplasmy and threshold effects; affected males do NOT transmit mtDNA disease → mitochondrial (MELAS, MERRF, LHON, KSS)
  • Skipped generations + consanguinity + carrier parents → autosomal recessive (Wilson, Friedreich, MLD, Krabbe, NCL)
  • No male-to-male transmission + obligate carrier daughters → X-linked (DMD/BMD, Fabry, ALD, OTC, Pelizaeus-Merzbacher)
  • Earlier onset + worse severity each generation → anticipation (CAG, CTG repeats)
  • Parent-of-origin–dependent phenotype → genomic imprinting (Prader-Willi / Angelman 15q11–13)
  • Paternal expansion bias → juvenile-onset → Huntington disease (Westphal variant)
  • Maternal expansion bias → congenital form → myotonic dystrophy type 1 (DM1)
Repeat / mutation type
  • CAG polyglutamine → HD, SCA1/2/3/6/7, DRPLA, SBMA (Kennedy)
  • CTG (DMPK 3′-UTR, chr 19) → myotonic dystrophy type 1
  • CCTG (CNBP/ZNF9 intron 1) → myotonic dystrophy type 2
  • GAA intronic (FXN) → Friedreich ataxia (AR; no classic anticipation)
  • CGG (FMR1 5′-UTR) → fragile X (>200) / FXTAS & POI (premutation 55–200)
  • GGGGCC hexanucleotide (C9orf72 intron 1) → familial FTD/ALS
  • GCN/GCG (PABPN1) → oculopharyngeal muscular dystrophy (OPMD)
  • NOTCH3 cysteine missense → CADASIL
  • PMP22 duplication (CMT1A) vs PMP22 deletion (HNPP) → demyelinating CMT vs tomaculous neuropathy
  • SMN1 homozygous deletion (5q13.2) → spinal muscular atrophy (SMN2 modifier)
Disease association / pearls
  • “Happy puppet” — laughter + ataxia + seizures + ID → Angelman (maternal 15q / UBE3A)
  • Neonatal hypotonia → hyperphagia + obesity + hypogonadism + ID → Prader-Willi (paternal 15q / SNRPN-SNORD116)
  • Long face + large ears + macroorchidism + ID + autism → fragile X (FMR1 full mutation)
  • Intention tremor + cerebellar ataxia + middle cerebellar peduncle T2 hyperintensity → FXTAS (FMR1 premutation)
  • Anterior temporal pole white-matter hyperintensities + recurrent lacunes + migraine → CADASIL (NOTCH3)
  • Caudate atrophy + chorea + psychiatric + saccadic abnormalities → Huntington disease
  • Bulbar weakness + gynecomastia + infertility + sensory neuropathy → SBMA / Kennedy disease (AR-CAG)
  • Hypertrophic cardiomyopathy + diabetes + scoliosis + areflexia with upgoing toes → Friedreich ataxia (GAA)
  • Frontal balding + cataracts + cardiac conduction block + myotonia + distal weakness → DM1 (CTG)
  • bvFTD + ALS + psychiatric prodrome + AD family history → C9orf72 (GGGGCC)
  • Stroke-like episodes + lactic acidosis + ragged-red fibers + maternal inheritance → MELAS
  • Subacute painless bilateral optic neuropathy in a young male, maternal family history → LHON
  • PEO + pigmentary retinopathy + cardiac conduction block onset <20 yo → Kearns-Sayre syndrome
  • Adult AD onset by 40s with APP triplication → Down syndrome (trisomy 21) → early Alzheimer disease
  • Valproate-induced fulminant hepatotoxicity in a child with epilepsy + neuropathy → POLG mutation (Alpers)
Central Dogma of Molecular Biology

DNA → RNA → Protein

  • Transcription: DNA → pre-mRNA in the nucleus; RNA polymerase II reads the template strand (3′ to 5′) and synthesizes mRNA (5′ to 3′)
  • RNA processing: 5′ cap + 3′ poly-A tail added; introns spliced out, exons joined to form mature mRNA
  • Translation: mRNA → protein at ribosomes; codons (3 nucleotides) specify amino acids; AUG = start codon (methionine); UAA, UAG, UGA = stop codons

Gene Structure

  • Promoter: upstream regulatory region; binding site for RNA polymerase and transcription factors
  • Exons: coding sequences that are retained in mature mRNA (“EXons are EXpressed”)
  • Introns: intervening noncoding sequences removed by splicing (“INtrons are IN the way”)
  • UTRs (untranslated regions): 5′-UTR and 3′-UTR — regulate mRNA stability, localization, and translation efficiency

Post-Translational Modifications

  • Glycosylation: addition of sugar moieties; important for protein folding and cell signaling
  • Phosphorylation: addition of phosphate group by kinases; key regulatory mechanism (e.g., tau hyperphosphorylation in Alzheimer disease)
  • Ubiquitination: tagging proteins with ubiquitin for proteasomal degradation (e.g., defective in Parkinson disease — parkin is an E3 ubiquitin ligase)
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