Neurogenetics
Neurogenetics
What Do You Need to Know?
- 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)
🚩 Don’t Miss — Test-Day Priorities
- 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
🔍 Buzzwords & Pathognomonic FindingsInheritance / 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)
Types of Mutations
Classification of Mutations
| Mutation Type | Description | Example |
|---|---|---|
| Silent | Nucleotide change but same amino acid (codon degeneracy) | No clinical effect |
| Missense | Single nucleotide change → different amino acid | Sickle cell disease (Glu → Val); CADASIL (NOTCH3 cysteine mutations) |
| Nonsense | Single nucleotide change → premature stop codon | Duchenne muscular dystrophy (truncated dystrophin) |
| Frameshift | Insertion or deletion NOT a multiple of 3 → shifts reading frame | Duchenne (out-of-frame deletion) vs. Becker (in-frame deletion) |
| In-frame insertion/deletion | Insertion or deletion of 3n nucleotides; reading frame preserved | Becker muscular dystrophy (shortened but partially functional dystrophin) |
| Splice-site mutation | Disrupts intron-exon boundary → abnormal mRNA splicing | Some forms of SMA, familial dysautonomia (IKBKAP) |
| Trinucleotide repeat expansion | Dynamic mutation; repeat length increases across generations | Huntington (CAG), Fragile X (CGG), Friedreich ataxia (GAA) |
| Chromosomal deletion | Loss of a chromosome segment | DiGeorge (22q11.2 deletion), Williams (7q11.23) |
| Chromosomal duplication | Extra copy of a chromosome segment | CMT1A (PMP22 duplication) |
| Gene fusion | Two genes fused by translocation or deletion | BCR-ABL in CML; KIAA1549-BRAF in pilocytic astrocytoma |
Functional Consequences of Mutations
- Loss of function: reduced or absent protein function; most AR diseases (both alleles must be affected)
- Gain of function: protein acquires new or enhanced activity; typically AD (e.g., Huntington — toxic polyglutamine expansion)
- Dominant negative: mutant protein interferes with normal protein function; one bad copy poisons the complex (e.g., some collagen disorders, p53 mutations)
- Haploinsufficiency: one functional copy insufficient to maintain normal function; AD mechanism (e.g., NF1 — 50% neurofibromin is not enough)
Board Pearl
Duchenne vs. Becker dystrophy — the reading frame rule: Duchenne = out-of-frame (frameshift) deletion → no functional dystrophin → severe. Becker = in-frame deletion → shortened but partially functional dystrophin → milder. This is one of the most commonly tested mutation-type concepts on boards.
Patterns of Inheritance
| Pattern | Key Features | Board-Relevant Examples |
|---|---|---|
| Autosomal dominant | 50% offspring affected; vertical transmission; male-to-male transmission possible; variable penetrance and expressivity; de novo mutations common | Huntington, NF1, NF2, TSC, myotonic dystrophy, CADASIL, most SCAs, CMT1A |
| Autosomal recessive | 25% affected offspring; horizontal transmission (siblings affected); carriers asymptomatic; consanguinity ↑ risk; typically loss-of-function mutations | Friedreich ataxia, Wilson disease, SMA, most metabolic diseases, ataxia-telangiectasia |
| X-linked recessive | Males affected; carrier females usually asymptomatic; NO male-to-male transmission; affected father → all daughters are carriers, no sons affected | Duchenne/Becker, Kennedy disease (SBMA), Fragile X, Fabry disease, adrenoleukodystrophy |
| X-linked dominant | Affects both sexes; often lethal in males; affected females show variable expression due to X-inactivation | Rett syndrome (MECP2), incontinentia pigmenti (IKBKG), Aicardi syndrome (presumed X-linked dominant; gene not yet identified) |
| Mitochondrial | Maternal inheritance only (mtDNA-encoded disorders); affected mother → all children at risk; affected father → no children affected; heteroplasmy (variable mutation load); threshold effect. Caveat: many mitochondrial diseases (e.g., POLG, most Leigh syndrome) are nuclear-encoded and follow Mendelian (often AR) inheritance. | MELAS, MERRF, LHON, Kearns-Sayre, NARP |
| Genomic imprinting | Gene expression depends on parent of origin; same chromosomal deletion → different disease depending on which parent it came from | Prader-Willi: paternal 15q11–13 deletion (~70%), maternal UPD (~25%), imprinting defect (~5%). Angelman: maternal 15q11–13 deletion (~70%), paternal UPD (~5%), imprinting defect (~5%), UBE3A mutation (~10%) |
Board Pearl
Male-to-male transmission EXCLUDES X-linked inheritance. If a pedigree shows an affected father with an affected son, the disease must be autosomal (dominant or recessive), not X-linked. This is one of the most commonly tested pedigree interpretation rules.
Board Pearl
Prader-Willi vs. Angelman — same deletion, different parent: Both classically involve deletion of 15q11–13, but several mechanisms exist. Prader-Willi: paternal 15q11–13 deletion (~70%), maternal UPD (~25%), imprinting defect (~5%) → hypotonia, obesity, hypogonadism, intellectual disability (“P for Paternal, P for Prader”). Angelman: maternal 15q11–13 deletion (~70%), paternal UPD (~5%), imprinting defect (~5%), UBE3A mutation (~10%) → severe intellectual disability, seizures, happy demeanor, ataxic, stiff, jerky gait with arm flapping (historically “happy puppet syndrome”) (“A for Angelman, M for Maternal”).
Genetic Testing Modalities
| Test | Resolution | Detects | Key Indications |
|---|---|---|---|
| Karyotype | ~5 Mb | Aneuploidies, large structural rearrangements (translocations, large deletions) | Down syndrome, Turner, Klinefelter; balanced translocations |
| FISH | ~100 Kb–5 Mb | Targeted detection of known deletion/duplication using fluorescent probe | DiGeorge (22q11.2), Prader-Willi/Angelman (15q11–13); confirmatory test |
| Chromosomal microarray (CMA/SNP array) | ~5–10 Kb | Copy number variants (microdeletions/duplications); loss of heterozygosity (LOH); cannot detect balanced translocations | First-line test for unexplained intellectual disability, autism, multiple congenital anomalies |
| Single-gene sequencing | Single nucleotide | Point mutations, small insertions/deletions in one specific gene | When a specific gene is suspected (e.g., HTT for Huntington) |
| Gene panel | Single nucleotide | Mutations in multiple genes related to a phenotype | Epilepsy panel, neuropathy panel, ataxia panel; cost-effective for defined phenotypes |
| Whole-exome sequencing (WES) | Single nucleotide | ~1.5% of genome (all exons); captures ~85% of disease-causing mutations | Complex/undiagnosed phenotypes; parent-child trios increase diagnostic yield (~25–40%) |
| Whole-genome sequencing (WGS) | Single nucleotide | Entire genome including noncoding regions, structural variants | Most comprehensive; identifies intronic variants and structural variants missed by WES; increasingly entering clinical practice (NHS Genomic Medicine Service, US rare-disease and pediatric ICU programs, cancer profiling), though cost, interpretation burden, and reimbursement still limit routine first-line use |
| Repeat-primed PCR / triplet-repeat PCR / Southern blot | Repeat sizing | Sizes trinucleotide and other repeat expansions; Sanger sequencing cannot size large repeats | HD, Fragile X, Friedreich ataxia, DM1/DM2, SCAs |
| Methylation-specific PCR / methylation testing | CpG methylation | Detects abnormal methylation at imprinted loci or expanded CGG | First-line for Prader-Willi/Angelman (detects ~99%); confirms Fragile X full mutation methylation status |
| MLPA (multiplex ligation-dependent probe amplification) | Single exon / copy number | Exonic deletions/duplications missed by sequencing | DMD, SMN1, PMP22 (CMT1A/HNPP), hereditary cancer panels |
Board Pearl
Chromosomal microarray (CMA) is the recommended first-line genetic test for children with unexplained intellectual disability, autism spectrum disorder, or multiple congenital anomalies — NOT karyotype. CMA has ~15–20% diagnostic yield vs. ~3% for karyotype. However, CMA cannot detect balanced translocations or low-level mosaicism — karyotype is still needed for these.
Trinucleotide Repeat Disorders
Overview
- Trinucleotide repeats are dynamic mutations — repeat length tends to increase in successive generations
- Anticipation: longer repeats → earlier onset and more severe disease in each generation
- CAG repeats (coding region) → polyglutamine (polyQ) tract → typically gain-of-function toxicity; mostly AD
- GAA repeats (intronic) → loss of function (reduced transcription); Friedreich ataxia is AR
- CGG/CTG repeats (UTR/noncoding) → variable mechanisms (RNA toxicity, methylation, silencing)
High-Yield Trinucleotide Repeat Table
| Disease | Repeat | Gene / Protein | Locus | Inheritance | Key Features |
|---|---|---|---|---|---|
| Huntington disease | CAG | HTT / huntingtin | 4p16.3 | AD | Normal ≤26 CAG; intermediate 27–35 (not pathogenic but may expand); reduced penetrance 36–39; fully penetrant ≥40; caudate atrophy; chorea, psychiatric, dementia; paternal anticipation |
| Fragile X syndrome | CGG | FMR1 / FMRP | Xq27.3 | X-linked | >200 = full mutation (methylation → silencing); most common inherited cause of intellectual disability; long face, large ears, macroorchidism |
| Fragile X premutation | CGG | FMR1 | Xq27.3 | X-linked | Intermediate/gray zone: 45–54 CGG (unstable but not associated with FXTAS/FXPOI); premutation 55–200 repeats; FXTAS in older males (tremor, ataxia, white matter lesions); premature ovarian insufficiency (POI) in females |
| Friedreich ataxia | GAA | FXN / frataxin | 9q21.11 | AR | Only common trinucleotide repeat that is AR; Normal 5–33 GAA; borderline 34–65; pathogenic ≥66 (typical 600–1200); larger expansions correlate with earlier onset and cardiomyopathy. Spinocerebellar ataxia + hypertrophic cardiomyopathy + diabetes; dorsal column & spinocerebellar tract degeneration; absent reflexes + extensor plantar responses; scoliosis, pes cavus, optic atrophy, sensorineural hearing loss, loss of joint position/vibration sense (dorsal column) |
| Myotonic dystrophy type 1 (DM1) | CTG | DMPK | 19q13.32 | AD | Multisystem: myotonia, distal weakness, cataracts, cardiac conduction defects, frontal balding, testicular atrophy, insulin resistance; maternal anticipation → congenital DM1 |
| SCA1 | CAG | ATXN1 | 6p22.3 | AD | Cerebellar ataxia + pyramidal signs + neuropathy |
| SCA2 | CAG | ATXN2 | 12q24.12 | AD | Cerebellar ataxia + slow saccades (distinguishing feature) |
| SCA3 (Machado-Joseph) | CAG | ATXN3 | 14q32.12 | AD | Most common SCA worldwide; ataxin-3 (ATXN3) on 14q32; bulging eyes, dystonia, spasticity, peripheral neuropathy, faciolingual fasciculations/myokymia, parkinsonism, restless legs syndrome |
| SCA6 | CAG | CACNA1A | 19p13.13 | AD | Pure cerebellar ataxia; small CAG expansion (≥20 CAG; pathogenic 20–33) in CACNA1A; mechanism involves calcium channel dysfunction; minimal/absent anticipation; late onset; very slowly progressive |
| SCA7 | CAG | ATXN7 | 3p14.1 | AD | Cerebellar ataxia + retinal degeneration (pigmentary maculopathy) — unique among SCAs |
| DRPLA | CAG | ATN1 | 12p13.31 | AD | Ataxia + chorea + seizures + dementia; more common in Japanese population |
| Kennedy disease (SBMA) | CAG | Androgen receptor (AR) | Xq12 | X-linked recessive | X-linked; CAG expansion in androgen receptor (AR) gene; normal 9–36, pathogenic ≥38 CAG; gain-of-function polyQ mechanism (like other CAG disorders); bulbospinal muscular atrophy; proximal weakness, bulbar involvement, tongue fasciculations; subclinical androgen insensitivity (testicular atrophy, gynecomastia, infertility) accompanies bulbar/limb LMN findings; sensory neuropathy; slowly progressive |
| SCA17 | CAG | TBP (TATA-binding protein) | 6q27 | AD | Ataxia + dementia + parkinsonism + chorea (HD-like phenotype) |
| OPMD (oculopharyngeal muscular dystrophy) | GCN/GCG | PABPN1 | 14q11.2 | AD | Normal 10 repeats, AD pathogenic 12–17; adult-onset ptosis + dysphagia + proximal weakness; intranuclear filamentous inclusions |
| Myotonic dystrophy type 2 (DM2) | CCTG (tetranucleotide) | CNBP / ZNF9 | 3q21 | AD | Proximal > distal weakness; less severe than DM1; no congenital form; cataracts; mild myotonia |
| FCMTE / BAFME | TTTCA / TTTTA (pentanucleotide) | SAMD12 (BAFME1) and others | 8q24 (BAFME1) | AD | Cortical myoclonus + tremor + epilepsy |
| C9orf72 ALS-FTD | GGGGCC (hexanucleotide) | C9orf72 | 9p21.2 | AD | Large GGGGCC repeat expansions are pathogenic; exact thresholds and intermediate categories are laboratory-dependent (avoid a single hard cutoff); most common genetic cause of ALS-FTD |
Board Pearl
Friedreich ataxia is the ONLY common trinucleotide repeat disorder that is autosomal recessive. All other major trinucleotide repeat diseases are AD or X-linked. The GAA expansion in frataxin (intronic) causes loss of function — unlike CAG (polyglutamine) disorders which are gain-of-function. Classic triad: ataxia + cardiomyopathy + diabetes. Exam finding: absent deep tendon reflexes + extensor plantar responses (combined dorsal column and corticospinal tract disease).
Clinical Pearl — Anticipation by Parent of Origin
The parent who transmits the larger expansion varies by disease: Huntington disease — paternal transmission causes greater expansion (spermatogenesis has more cell divisions); Myotonic dystrophy type 1 — maternal transmission causes greater expansion (congenital DM1 is almost always maternally inherited — floppy baby, respiratory failure, facial diplegia). Fragile X — maternal transmission expands premutation to full mutation (no male-to-full transmission because the premutation does not expand during spermatogenesis).
Non-Trinucleotide Repeat Genetic Neurologic Diseases
Key Board-Relevant Genetic Diseases
| Disease | Inheritance | Gene / Protein | Locus | Key Features |
|---|---|---|---|---|
| Alzheimer disease (early-onset familial) | AD | APP / amyloid precursor protein | 21q21.3 | Onset <65 years; Down syndrome patients (trisomy 21) have extra APP copy → early Alzheimer |
| Alzheimer (early-onset) | AD | PSEN1 / presenilin-1 | 14q24.2 | Most common cause of early-onset familial AD; most aggressive; onset 30s–50s |
| Alzheimer (early-onset) | AD | PSEN2 / presenilin-2 | 1q42.13 | Rarest cause of familial AD; Volga-German families |
| Alzheimer (risk factor) | Risk allele | APOE ε4 | 19q13.32 | Strongest genetic risk factor for late-onset AD; ~3× risk for one ε4 allele; ~8–12× risk for two ε4 alleles (varies by population/study); ε2 is protective |
| CADASIL | AD | NOTCH3 | 19p13.12 | Recurrent subcortical strokes + migraine with aura + white matter disease + dementia; granular osmiophilic material (GOM) on skin biopsy |
| Wilson disease | AR | ATP7B | 13q14.3 | Copper accumulation; Kayser-Fleischer rings, hepatic disease, dystonia/tremor, psychiatric symptoms |
| CMT1A | AD | PMP22 duplication | 17p12 | Most common CMT; demyelinating neuropathy; pes cavus, stork legs; duplication → overexpression of PMP22 |
| CMT1B | AD | MPZ / myelin protein zero | 1q23.3 | Demyelinating neuropathy; similar to CMT1A but less common |
| HNPP | AD | PMP22 deletion | 17p12 | Hereditary neuropathy with liability to pressure palsies; recurrent compressive neuropathies; deletion (vs. duplication in CMT1A) |
| Duchenne / Becker MD | X-linked recessive | DMD / dystrophin | Xp21.2 | Duchenne = absent dystrophin (frameshift); Becker = reduced/truncated dystrophin (in-frame) |
| Spinal muscular atrophy (SMA) | AR | SMN1 | 5q13.2 | Loss of SMN1; severity inversely correlated with SMN2 copy number; nusinersen (antisense oligonucleotide), onasemnogene (gene therapy), risdiplam (oral) |
| Parkinson disease — LRRK2 | AD (reduced penetrance) | LRRK2 (dardarin) | 12q12 | Most common monogenic cause of PD; common G2019S mutation; clinically indistinguishable from idiopathic PD |
| Parkinson disease — GBA | AR (Gaucher); heterozygote = PD risk | GBA (glucocerebrosidase) | 1q21 | Strongest genetic risk factor for PD; AR mutations cause Gaucher disease; heterozygous carriers have ~5× PD risk |
| Channelopathies & ion-channel disorders | ||||
| Benign familial neonatal seizures | AD | KCNQ2 (Kv7.2; also KCNQ3) | Self-limited neonatal seizures days 2–7 of life; Na channel blockers (CBZ, PHT) paradoxically effective. KCNQ2-DEE is severe variant. | |
| GEFS+ (generalized epilepsy with febrile seizures plus) | AD | SCN1B (also SCN1A, GABRG2) | Febrile seizures persisting beyond age 6 plus afebrile generalized seizures; spectrum with Dravet (SCN1A LOF, more severe). | |
| GLUT1 deficiency syndrome | AD (mostly de novo) | SLC2A1 (GLUT1) | Early-onset seizures, movement disorder, microcephaly; low CSF glucose (CSF:serum ratio <0.45); treat with ketogenic diet. | |
| Episodic ataxia type 1 (EA1) | AD | KCNA1 (Kv1.1) | Brief (seconds-minutes) ataxia + myokymia; triggered by startle/exertion; respond to phenytoin/carbamazepine/acetazolamide. | |
| Episodic ataxia type 2 (EA2) / FHM1 / SCA6 | AD | CACNA1A (Cav2.1, P/Q-type) | One gene, three phenotypes. EA2 = longer attacks (hours), downbeat nystagmus, acetazolamide-responsive; FHM1 = hemiplegic migraine; SCA6 = small CAG expansion, slowly progressive ataxia. | |
| Hyperkalemic periodic paralysis / paramyotonia congenita | AD | SCN4A (Nav1.4) | HyperKPP = brief (minutes-hour) episodes triggered by K+/cold/rest after exertion; paramyotonia = cold-induced paradoxical myotonia worse with exercise. | |
| Hypokalemic periodic paralysis | AD | CACNA1S (most common) or SCN4A | Long attacks (hours-day), triggered by carbohydrate meals/rest after exercise; serum K+ low during attack; acetazolamide, K supplementation. | |
| Myotonia congenita (Thomsen / Becker) | AD (Thomsen) or AR (Becker) | CLCN1 (chloride channel) | "Warm-up" myotonia; muscle stiffness improving with repeated activity; mexiletine first-line. | |
| Central core disease + malignant hyperthermia susceptibility | AD | RYR1 (ryanodine receptor 1) | Floppy infant + proximal weakness + scoliosis + MH susceptibility; CACNA1S is another MH gene; treat MH crisis with dantrolene. | |
| Metabolic / leukodystrophic | ||||
| Menkes disease ("kinky hair") | X-linked recessive | ATP7A (copper transporter) | Low ceruloplasmin and serum copper; pili torti; seizures, hypothermia, FTT; early SC copper histidine may help. | |
| Pelizaeus-Merzbacher disease | X-linked recessive | PLP1 (proteolipid protein) | Hypomyelinating leukodystrophy; nystagmus from birth, stridor, spasticity, ataxia; "tigroid" myelin pattern. | |
| Dopa-responsive dystonia (Segawa) | AD | GCH1 (GTP cyclohydrolase 1) most common; AR forms with TH or SR deficiency | Childhood-onset dystonia with diurnal variation (worse evening) and dramatic levodopa response; no long-term motor complications. Always trial levodopa in young-onset dystonia. | |
| Familial amyloid polyneuropathy (hATTR) | AD | TTR (transthyretin); also apoA1, gelsolin | Adult-onset length-dependent painful sensorimotor neuropathy + autonomic + cardiomyopathy; treat with tafamidis, patisiran, inotersen, vutrisiran. | |
| OTC deficiency | X-linked | OTC (ornithine transcarbamylase) | Most common urea cycle disorder; episodic hyperammonemia → encephalopathy/coma, often after high-protein meals or catabolic stress; respiratory alkalosis. | |
| Tumor-predisposition / phakomatoses (partial list) | ||||
| Von Hippel-Lindau (VHL) | AD | VHL (tumor suppressor) | CNS + retinal hemangioblastomas (cerebellum and spinal cord), clear-cell RCC, pheochromocytoma, pancreatic NETs. | |
| Sturge-Weber syndrome | NOT inherited — somatic mosaic | Somatic GNAQ R183Q mutation (chromosome 9q21) | Common board trap: SWS is a somatic mosaic mutation, not Mendelian. Port-wine stain V1, leptomeningeal angiomatosis, glaucoma, seizures, hemiparesis. | |
| Miller-Dieker syndrome | Contiguous gene deletion (17p13.3) | Includes PAFAH1B1 (LIS1) and YWHAE | Classic (Type I) lissencephaly + facial dysmorphism + severe DD/seizures. | |
| Rett syndrome | X-linked dominant | MECP2 (Xq28) | Classically affects females; males are rare but can survive with somatic mosaicism, 47,XXY, or atypical/hypomorphic MECP2 variants. Developmental regression at 6–18 mo, hand wringing/stereotypies, autistic regression. Trofinetide (Daybue) FDA-approved 2023. | |
| Familial schizophrenia | AD (rare; mostly polygenic) | DISC1 disrupted by t(1;11)(q42;q14.3) balanced translocation in a Scottish family | Classic example of a translocation-associated neuropsychiatric disorder. | |
| Down syndrome | Trisomy 21 (~95% nondisjunction; ~3–5% Robertsonian translocation; ~1–2% mosaicism) | Whole chromosome 21 | Most common cause of intellectual disability; early-onset AD (APP on chromosome 21); congenital heart disease; AML M7 (megakaryoblastic). | |
Board Pearl
CMT1A = PMP22 duplication; HNPP = PMP22 deletion — same gene, opposite dosage. Both are on chromosome 17p12. CMT1A (too much PMP22) causes chronic demyelinating neuropathy. HNPP (too little PMP22) causes episodic compressive neuropathies. This reciprocal duplication/deletion from unequal crossing over is a classic board question.
Chromosomal Disorders with Neurologic Manifestations
| Disorder | Karyotype | Key Neurologic Features | Other Features |
|---|---|---|---|
| Down syndrome | Trisomy 21 | Intellectual disability; early-onset Alzheimer disease (APP gene on Ch 21 → amyloid overproduction); infantile spasms; increased seizure risk | Cardiac defects (AV canal), atlantoaxial instability, hypothyroidism, duodenal atresia, leukemia |
| Edwards syndrome | Trisomy 18 | Severe intellectual disability; neural tube defects | Clenched fists (overlapping fingers), rocker-bottom feet, cardiac defects; most die within first year |
| Patau syndrome | Trisomy 13 | Holoprosencephaly; severe intellectual disability; midline facial defects (cleft lip/palate, cyclopia) | Polydactyly, cardiac defects, cutis aplasia; most die within first year |
| Turner syndrome | 45,X | No intellectual disability; visuospatial processing deficits; social cognition difficulties | Short stature, webbed neck, shield chest, coarctation of aorta, streak gonads |
| Klinefelter syndrome | 47,XXY | Learning difficulties (language-based); mild intellectual disability in some | Tall stature, gynecomastia, hypogonadism, infertility |
| DiGeorge / 22q11.2 deletion | del(22)(q11.2) | Learning disability; psychiatric illness (~25% develop schizophrenia); velopharyngeal insufficiency | Cardiac defects (conotruncal), hypocalcemia (absent parathyroids), T-cell deficiency (thymic aplasia), cleft palate |
| Williams syndrome | del(7)(q11.23) | Intellectual disability with relative strength in verbal/social skills (“cocktail party personality”); visuospatial deficits | Elfin facies, supravalvular aortic stenosis, hypercalcemia; deletion includes elastin gene |
| Cri-du-chat syndrome | del(5p) | Severe intellectual disability; high-pitched cat-like cry (due to laryngeal abnormality) | Microcephaly, wide-set eyes, low-set ears |
Clinical Pearl — Down Syndrome and Alzheimer Disease
Virtually all patients with Down syndrome develop Alzheimer neuropathology (amyloid plaques and neurofibrillary tangles) by age 40, due to lifelong overproduction of amyloid-beta from the extra copy of APP on chromosome 21. Clinical dementia onset is typically in the 50s. This is one of the strongest pieces of evidence supporting the amyloid hypothesis of Alzheimer disease.
Genetic Counseling Concepts
Key Terminology
- Penetrance: proportion of individuals with a given genotype who express the phenotype
- Complete penetrance (100%) = all carriers show disease (e.g., Huntington with >40 repeats)
- Reduced penetrance = some carriers never develop clinical disease (e.g., BRCA1, Huntington 36–39 repeats)
- Expressivity: range of phenotypic severity among individuals who express the genotype
- Variable expressivity = same mutation → different severity (e.g., NF1 — some have mild café-au-lait spots only, others have severe plexiform neurofibromas)
- Anticipation: earlier onset and/or increased severity in successive generations; hallmark of trinucleotide repeat disorders
- De novo mutations: new mutations not present in either parent; no family history does NOT exclude a genetic disease (e.g., ~50% of NF1, ~2/3 of TSC are de novo)
- Variants of uncertain significance (VUS): genetic variant detected on sequencing with insufficient evidence to classify as pathogenic or benign; do NOT use for clinical decision-making; may be reclassified over time
- Pleiotropy: single gene affecting multiple organ systems (e.g., myotonic dystrophy — muscle, heart, eyes, endocrine)
- Genetic heterogeneity:
- Locus heterogeneity: same phenotype caused by mutations in different genes (e.g., CMT caused by >80 different genes)
- Allelic heterogeneity: same phenotype caused by different mutations in the same gene
- Mosaicism:
- Somatic mosaicism — postzygotic mutation in a subset of cells (e.g., NF1, TSC, McCune-Albright)
- Germline (gonadal) mosaicism — mutation confined to gonadal cells; explains recurrence in DMD/TSC/OI despite normal parental somatic testing
- Hardy-Weinberg equilibrium: p² + 2pq + q² = 1; assumes random mating, no mutation/migration/selection; for a rare AR disease with disease prevalence q², carrier frequency ≈ 2q
- Pre-implantation genetic diagnosis (PGD): IVF + embryo biopsy (single cell or trophectoderm) + targeted testing for a known monogenic disorder in the family; selects unaffected embryos for transfer
Heteroplasmy and Threshold Effect (Mitochondrial)
- Heteroplasmy: coexistence of mutant and wild-type mtDNA within the same cell
- Threshold effect: clinical disease manifests only when the proportion of mutant mtDNA exceeds a tissue-specific threshold (typically 60–90%)
- Tissues with highest energy demand (brain, muscle, heart) are most vulnerable → explains CNS and muscle predominance in mitochondrial diseases
- Mitotic segregation: during cell division, mtDNA distributes unevenly to daughter cells → explains variable expression even within the same family
Clinical Pearl — Genetic Testing in Neurologic Practice
When a VUS is reported, clinicians should not use it to confirm a diagnosis or guide treatment. Family segregation studies (testing affected and unaffected relatives) can help reclassify VUS over time. The yield of whole-exome sequencing in undiagnosed neurologic disease is approximately 25–40% when performed as a parent-child trio, compared to ~25% for proband-only testing.
Quick Reference — High-Yield Neurogenetics Summary
Inheritance Pattern Quick-Recall
| Inheritance | Distinguishing Clue | Board-Favorite Examples |
|---|---|---|
| AD | Vertical transmission; 50% affected; male-to-male OK | Huntington, NF1/2, TSC, CADASIL, most SCAs, CMT1A, myotonic dystrophy |
| AR | Horizontal (siblings); 25% affected; consanguinity | Friedreich ataxia, Wilson, SMA, most leukodystrophies, Tay-Sachs |
| X-linked recessive | Males only; NO male-to-male; carrier mothers | Duchenne/Becker, Kennedy (SBMA), Fragile X, Fabry, ALD |
| X-linked dominant | Often male-lethal; affected females | Rett, incontinentia pigmenti, Aicardi (presumed X-linked dominant; gene not yet identified) |
| Mitochondrial | Maternal only; variable severity | MELAS, MERRF, LHON, Kearns-Sayre |
| Imprinting | Parent-of-origin matters | Prader-Willi (paternal), Angelman (maternal) |
Trinucleotide Repeat Quick-Recall
| Repeat | Location | Mechanism | Diseases |
|---|---|---|---|
| CAG | Coding (exon) | Polyglutamine → gain of function; toxic aggregation | Huntington, SCAs (1, 2, 3, 6, 7), DRPLA, Kennedy (SBMA) |
| CGG | 5′-UTR | Methylation → gene silencing (full mutation); RNA toxicity (premutation) | Fragile X syndrome; FXTAS (premutation) |
| CTG | 3′-UTR | RNA toxicity (CUG-repeat RNA sequesters MBNL1) | Myotonic dystrophy type 1 (DM1) |
| GAA | Intronic | Impaired transcription → loss of function (reduced frataxin) | Friedreich ataxia (the ONLY common AR trinucleotide repeat disorder) |
References
- Ropper AH, Samuels MA, Klein JP, Prasad S. Adams and Victor’s Principles of Neurology. 12th ed. McGraw Hill; 2023.
- Aminoff MJ, Greenberg DA, Simon RP. Clinical Neurology. 11th ed. McGraw Hill; 2022.
- Nussbaum RL, McInnes RR, Willard HF. Thompson & Thompson Genetics in Medicine. 8th ed. Elsevier; 2016.
- Bird TD. Hereditary Ataxia Overview. In: Adam MP, et al., editors. GeneReviews. University of Washington, Seattle; 2023.
- Paulson H. Repeat expansion diseases. Handb Clin Neurol. 2018;147:105–123.
- Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749–764.
- Durr A. Autosomal dominant cerebellar ataxias: polyglutamine expansions and beyond. Lancet Neurol. 2010;9(9):885–894.
- Pandolfo M. Friedreich ataxia: the clinical picture. J Neurol. 2009;256(Suppl 1):3–8.
- Darras BT. Spinal muscular atrophies. Pediatr Clin North Am. 2015;62(3):743–766.
- Biesecker LG, Green RC. Diagnostic clinical genome and exome sequencing. N Engl J Med. 2014;370(25):2418–2425.
Continue reading — sign in
The full note has more clinical pearls, tables, and board-focused tips. Free account, no fee.