GeneticsTier 1Medical Sciences concept

Trinucleotide repeat disorders (myotonic dystrophy, Fragile X, Huntington's, Friedreich's ataxia) and genetic anticipation

Core concept

Anticipation = earlier onset and greater severity in successive generations
- Mechanism: the repeat is unstable in meiosis and expands on transmission
- Longer repeat -> earlier onset and more severe disease (inverse correlation)
Three mechanistic classes, and the class predicts the inheritance and the phenotype
- Coding CAG -> polyglutamine -> toxic protein gain of function (HD, SCAs, SBMA)
  - Expansion favoured in paternal transmission - sperm undergo many more mitoses
- Non-coding expansion -> RNA gain of function or loss of function
  - DM1 - CTG in the DMPK 3'UTR: CUG-repeat RNA foci sequester MBNL1 and upregulate CELF1 -> spliceopathy (insulin receptor, CLCN1 chloride channel -> myotonia, cardiac troponin T)
  - Fragile X - CGG in the FMR1 5'UTR: >200 repeats -> hypermethylation -> transcriptional silencing -> loss of FMRP
  - Friedreich ataxia - GAA in intron 1 of FXN: heterochromatin silencing -> frataxin deficiency
- Loss of function is recessive; gain of function is dominant
Anticipation is a property of unstable repeats, not of dominant inheritance in general - do not invoke it for a Mendelian point mutation

Key detail

	Gene / locus	Repeat	Inheritance	Normal / premutation / full	Expanding parent
Huntington	HTT, 4p16.3	CAG (coding)	AD	<27 / 27-35 intermediate, 36-39 reduced penetrance / >=40	Paternal
Myotonic dystrophy 1	DMPK, 19q13, 3'UTR	CTG	AD	<35 / 35-49 / >=50 (>1000 = congenital)	Maternal for congenital
Fragile X	FMR1, Xq27.3, 5'UTR	CGG	X-linked	<45 / 55-200 premutation / >200 full	Maternal only
Friedreich ataxia	FXN, 9q21, intron 1	GAA	AR	<33 / - / 66-1300	No anticipation
DM2	CNBP/ZNF9, 3q21	CCTG	AD	-	Minimal anticipation, no congenital form
SCA 1/2/3/6/7/17, DRPLA	various	CAG	AD	-	Paternal
SBMA (Kennedy)	AR, Xq12	CAG	X-linked	-	-
ALS/FTD	C9orf72	GGGGCC hexanucleotide	AD	-	Commonest genetic cause of both

Phenotype discriminators

HD - chorea + behavioural/psychiatric change often precedes motor + subcortical dementia; caudate atrophy, "box-car" ventricles; loss of striatal GABAergic medium spiny neurons (indirect pathway first -> chorea)
- Juvenile (Westphal) variant - >60 repeats, paternal transmission, rigid-akinetic + seizures, not choreiform
DM1 - distal weakness, grip myotonia and percussion myotonia, frontal balding, ptosis, cataracts (posterior subcapsular, iridescent), conduction block and sudden death, insulin resistance, testicular atrophy, dysphagia, hypersomnolence, low IgG
- DM2 is proximal and spares the face - "PROMM"
- Cardiac conduction disease drives mortality; annual ECG regardless of muscle symptoms
Fragile X - commonest inherited intellectual disability; long face, large ears, macro-orchidism post-pubertal, autism, joint laxity
- Premutation carriers are not normal: FXTAS (males >50 - ataxia, intention tremor, MCP sign on MRI) and FXPOI (premature ovarian insufficiency in ~20% of female carriers)
Friedreich - onset <25, gait and limb ataxia, absent knee and ankle jerks with extensor plantars, dorsal column loss (positive Romberg), dysarthria, pes cavus, scoliosis, optic atrophy, deafness
- Hypertrophic cardiomyopathy in ~2/3 - the usual cause of death; diabetes in ~10-30%
- Pathology: dorsal root ganglion cell loss, dorsal columns, spinocerebellar and corticospinal tracts
- Nerve conduction: motor velocity preserved (>40 m/s) with small or absent SNAPs - an axonal sensory neuronopathy, not demyelination

Clinical relevance

Testing - standard PCR fails to amplify large expansions and will read as a false homozygous normal; use triplet-repeat-primed PCR or Southern blot for DM1 and Fragile X
Predictive testing for HD is a formal multi-session counselling protocol; not performed on asymptomatic minors; consider insurance and family implications before the sample is taken
Reproductive options - preimplantation genetic testing, prenatal diagnosis, donor gametes; DM1 mothers must be counselled about congenital DM1 (hypotonia, talipes, respiratory failure, ~40% mortality)
Anaesthetic risk in DM1 - exquisite sensitivity to opioids and induction agents, delayed recovery, post-op respiratory failure, arrhythmia; avoid depolarising blockade
Therapy
- HD chorea - tetrabenazine, deutetrabenazine, valbenazine (tetrabenazine causes depression and suicidality - screen); antipsychotics for chorea plus behaviour
- AMT-130 (AAV microRNA lowering mutant huntingtin, intrastriatal) reported ~75% slowing at 3 years and is under regulatory review - first potential disease-modifying therapy; not yet approved
- Friedreich - omaveloxolone (Nrf2 activator) approved for age >=16; monitor LFTs and BNP
- DM1 - mexiletine for disabling myotonia, pacemaker/ICD for conduction disease, modafinil for hypersomnolence
- Fragile X - supportive; no approved disease-modifying agent

Correlations

Movement disorders - chorea, cerebellar disorders
Myopathy, acquired and genetic; channelopathies and myotonia
Cardiomyopathy - hypertrophic (Friedreich), conduction disease (DM1)
Intellectual disability and autism genetics
Premature ovarian insufficiency
Motor neurone disease and FTD - C9orf72
Genetic counselling, predictive testing and preimplantation diagnosis

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