Trinucleotide repeat (TNR) disorders

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Four you need to know for the USMLE:

1. Fragile X (CGG; FraGile X)
2. Huntington disease (CAG; AGreat Hunter)
3. Friedreich ataxia (GAA; AtaxiA)
4. Myotonic dystrophy (CTG; MyoTonic)

TNR diseases demonstrate anticipation, which is an ↑ in the # of codon repeats with each successive generation. The # of repeats directly correlates with the severity of the condition and inversely correlates with age of onset. ↑ repeats = ↑ severity of condition + ↓ age of onset USMLE will tell you, e.g., a guy with Huntingon develops features at age 32, and that his dad had similar findings starting in his 40s. Answer = anticipation. Not super complicated.

Huntington disease

Caused by CAG repeat expansion

• Huntington disease is an AD disorder of the huntingtin gene on chromosome 4 (although the disease is spelled Huntington, the gene is huntingtin).
• Knowing specifically that it is AD and on chromosome 4 is one of the highest yield points for genetics on the Step 1.
• Disease presents when the CAG (AGreat Hunter) repeats are >40. 36-39 is considered premutation, with anticipation almost certainly leading to disease in the next generation.

Choreoathetosis and cognitive decline are the hallmark clinical features

• Chorea = fast, jerky movements.
• Athetosis = slow, writhing movements.
• Progressive dementia/cognitive decline generally ensues from the 30s or 40s onward, depending on # of CAG repeats.

USMLE wants you to know where in the brain is affected

• Choose caudate nuclei and putamen as the areas of the brain that are affected.
• There is also dilatation/widening of the anterior horns of the lateral ventricles.

Most common cause of death is (weirdly) pneumonia

• The leading cause of death is pneumonia secondary to aspiration from ↓ muscle coordination.

USMLE loves turning Huntington disease into an ethics scenario

If a patient requests genetic testing because he or she has a parent with known Huntington disease, you DO NOT do testing right away. Genetic counseling is mandatory beforehand. Huntington disease demonstrates complete penetrance. If the patient has 40 or more repeats, there is 100% chance he or she will develop the disease.

Neutrotransmitter irregularities are HY

• The USMLE might also tell you a patient with progressive dementia died and brain biopsy reveals protein strands with long glutamine repeats.
• The CAG codon codes for glutamine, so you need to remember CAG = glutamine.
• Hormonally, the disease is characterized by increased dopamine and decreased GABA and acetylcholine.
• The decreased GABA is very high-yield.

For Huntington, choose ↓ GABA   |  ↓ ACh   |  ↑ Dopamine

Treatment for Huntingon

• The disease is incurable but can be palliated with amine-depleting drugs, such as tetrabenazine and reserpine.
• Both of these drugs inhibit VMAT (vesicular monoamine transporter).
• VMAT is necessary for the packaging of catecholamines into vesicles and their subsequent release into the synaptic cleft.
• If VMAT is inhibited, free, unprotected dopamine within the presynaptic cleft is degraded by monoamine oxidase.
• Typical antipsychotics (e.g., haloperidol) are also used in the treatment of Huntington-associated psychosis.

Fragile X syndrome

Caused by CGG repeat expansion

• The disease gets its name because of X-chromosome fragility when CGG (FraGile) repeats exceed 200.
• The increased number of repeats causes gene methylation, which is identified when karyotyping is performed on leukocytes in a folate- and thymidine-deficient medium.
• Disease is X-linked recessive, not dominant. If a female has mild clinical features, it’s due to skewed lyonization (X-inactivation).

Physical presentation is very HY for the Step

• Most salient characteristics in any USMLE question are large, everted ears, long jaw, and macroorchidism (large testes).
• Be on the lookout for a boy (X-linked) with a long, narrow head and big ears who has intellectual impairment.
• There is also joint laxity, scoliosis, and pes planus (flat-footedness).

USMLE is tricky when contrasting fetal alcohol syndrome (FAS) with Fragile X

• Fetal alcohol syndrome is the most common cause of mental retardation overall. Most important characteristic in any vignette is a long, smooth, flat philtrum.
• If the USMLE gives you a boy with ↓ IQ who has large, everted ears and any change to his philtrum, the answer is FAS, not Fragile X.

The USMLE is known to be very difficult with FAS questions. The vignette might sound entirely like Fragile X, but if they mention somewhat incidentally that the philtrum is flat, long, or smooth, choose FAS, not Fragile X.

Myotonic dystrophy

Caused by CTG repeat expansion

• Myotonic dystrophy is an AD disease on chromosome 19, with an expansion of CTG (MyoTonic dystrophy).
• This leads to abnormal expression of a myotonin-protein kinase, a type of serine-threonine kinase.

Presentation is generally easy on the USMLE

• Characterized by sustained muscle contraction, muscle wasting, baldness, cataracts, and testicular atrophy.
• The key feature is the sustained muscle contraction, where the individual will demonstrate an inability to relax his or her muscles.
• This shows up in questions as an extra-long handshake or not being able to let go of the golf club or doorknob.

Friedreich ataxia

Caused by GAA repeat expansion

• Friedreich ataxia is an AR disorder on chromosome 9, with an expansion of GAA (Friedreich AtaxiA).
• USMLE wants you to know the gene is called frataxin. Do NOT confuse this with Fragile X, which is the FMR1 gene.

HY findings

• May present with cardiomyopathy. Sources differ as to whether hypertrophic or dilated is more common. But the USMLE will give you a clear presentation as to which one they’re referring to.
• If hypertrophic, the patient will have a severely thickened LV and (often) an S4 heart sound; there will be diastolic dysfunction (↑ diastolic filling pressure + preserved ejection fraction). If dilated, there will be a lateralized apex beat / apical impulse, a dilated cardiac silhouette, and an S3 heart sound.
• Early-onset T2DM is a notable feature.
• Kyphoscoliosis and pes cavus (high-arched foot) are HY.
• The disorder is characterized by (obviously) ataxia, Babinski reflexes, dysarthria, and hammer toes (contraction deformity of toes).

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