1.18 Neuromuscular Disease & Fragile X Spectrum
Key Takeaways
DMD is typically out-of-frame DMD variants with absent dystrophin; BMD is often in-frame with residual dystrophin—both are X-linked and require carrier cardiomyopathy surveillance counseling
Myotonic dystrophy type 1 shows CTG anticipation in DMPK; congenital DM1 is almost always maternally transmitted
SMA is AR SMN1-related; SMN2 copy number modifies severity and informs prognosis counseling alongside modern disease-modifying therapies
FMR1 CGG categories (normal, intermediate, premutation, full mutation) map to FXS, FXTAS, and FXPOI with distinct counseling agendas
Neuromuscular and Fragile X stems reward precise inheritance language: X-linked dystrophinopathy carriers, AD CTG expansion risk, AR SMA residual risk, and X-linked Fragile X transmission rules
1.18 Neuromuscular Disease & Fragile X Spectrum
Quick Answer: DMD/BMD = X-linked DMD (frame shift → DMD; in-frame → BMD) + carrier heart surveillance; DM1 = DMPK CTG anticipation (congenital = maternal); SMA = biallelic SMN1 loss, SMN2 copies modify severity; Fragile X = FMR1 CGG tiers → FXS / FXTAS / FXPOI.
These conditions are Domain 1C staples because they combine classic phenotypes with inheritance traps genetic counselors must explain without oversimplification.
Duchenne & Becker Muscular Dystrophy
Pathogenic variants in DMD (Xp21) disrupt dystrophin. Inheritance is X-linked. The reading-frame rule is the highest-yield molecular teaching point:
| Condition | Typical molecular theme | Clinical tempo |
|---|---|---|
| Duchenne (DMD) | Out-of-frame deletions/duplications or nonsense → little/no dystrophin | Early childhood proximal weakness, calf pseudohypertrophy, Gowers sign, loss of ambulation in childhood (historic natural history), cardiomyopathy, respiratory decline |
| Becker (BMD) | Often in-frame deletions → truncated but partially functional dystrophin | Later onset, milder skeletal course, still significant cardiomyopathy risk |
Carrier Counseling (Do Not Skip)
Manifesting or non-manifesting female carriers can have elevated CK, mild weakness, and—critically—dilated cardiomyopathy. Exam stems that stop at “carriers are asymptomatic” are wrong. Cascade testing of maternal relatives, CK/cardiac surveillance referrals for carriers, and reproductive options (including prenatal/PGT discussions) are core GC tasks.
Germline mosaicism: A mother of an isolated affected son with negative leukocyte testing for the familial variant may still have recurrence risk due to germline mosaicism—quote empiric residual risk rather than absolute zero.
CK tip: Markedly elevated CK in a boy with proximal weakness supports dystrophinopathy workup (genetic testing ± muscle biopsy historically). Female relatives with high CK need carrier evaluation.
Myotonic Dystrophy Type 1 (DM1)
DM1 is caused by a CTG trinucleotide repeat expansion in the DMPK 3′ UTR. Inheritance is autosomal dominant with anticipation (increasing expansion and earlier/more severe disease in successive generations).
| Feature | Counseling anchor |
|---|---|
| Multisystem phenotype | Myotonia, distal weakness, cataracts, arrhythmias/conduction block, endocrine issues, cognitive/behavioral features variable |
| Anticipation | Expansions can enlarge intergenerationally—especially through maternal transmission for very large alleles |
| Congenital DM1 | Severe neonatal hypotonia, respiratory insufficiency, talipes; almost always maternally transmitted large expansions |
| Testing | PCR may miss huge expansions—Southern blot / specialized methods needed for full characterization |
Exam trap: Do not confuse DM1 (CTG DMPK) with DM2 (CCTG CNBP), which has less congenital anticipation narrative. For CGC Domain 1C, DM1 anticipation + congenital maternal transmission is the tested pearl.
Cardiac conduction disease makes preoperative counseling and cascade family cardiac screening part of the GC conversation even when the consult started as “muscle stiffness.”
Spinal Muscular Atrophy (SMA)
5q SMA is typically biallelic pathogenic variants in SMN1 (most commonly homozygous exon 7 deletion). Inheritance is autosomal recessive. A nearly identical paralog, SMN2, produces limited full-length SMN protein; SMN2 copy number inversely correlates with severity on average (more copies → milder phenotypes), though modifiers exist.
| SMA type (classic) | Onset theme | SMN2 tendency |
|---|---|---|
| Type 1 (Werdnig-Hoffmann) | Infantile, never sits, historically high early mortality | Often 2 copies |
| Type 2 | Sits, does not walk independently | Intermediate |
| Type 3 (Kugelberg-Welander) | Walks, later progressive weakness | Higher copy numbers more often |
| Type 4 | Adult onset | Highest copy numbers |
Counseling points for the exam:
- Carrier testing must account for [2+0] silent carriers (two SMN1 copies on one allele, none on the other)—standard dosage carrier screens can be falsely reassuring; residual risk counseling matters.
- Newborn screening and early therapy (e.g., nusinersen, onasemnogene abeparvovec, risdiplam—know that disease-modifying options exist and timing matters) change the prognostic script families heard historically.
- Partners of known carriers need carrier screening with residual-risk explanation.
Fragile X Spectrum (FMR1 CGG Repeats)
Fragile X–associated disorders arise from CGG repeat expansion in the FMR1 5′ UTR, with methylation silencing at full mutation sizes. Categories (approximate clinical teaching ranges used on exams):
| Category | Approx. CGG repeats | Primary counseling phenotype |
|---|---|---|
| Normal | ~5–44 | Not associated with FXS/FXTAS/FXPOI |
| Intermediate (gray zone) | ~45–54 | Generally stable-ish; small expansion risk—context-specific counseling |
| Premutation | ~55–200 | FXTAS (late-onset tremor/ataxia, more in males), FXPOI (female ovarian insufficiency), anxiety/other neuropsychiatric risks; can expand to full mutation in offspring (especially maternal transmission) |
| Full mutation | >200 (with methylation) | Fragile X syndrome (FXS): ID, autism features, long face/large ears/macroorchidism post-puberty in males; females variable due to X-inactivation |
Transmission Rules Genetic Counselors Must State Clearly
- Full-mutation FXS is X-linked: males with full mutation are typically more severely affected; females vary.
- Premutation mothers can transmit expanded alleles that become full mutations—size and sex-of-parent effects matter; maternal premutations are the classic route to FXS children.
- Premutation fathers transmit the premutation to all daughters (who then may expand in the next generation) but typically do not transmit to sons (X-linked).
- Do not tell a premutation carrier she “has Fragile X syndrome.” She needs FXPOI/FXTAS risk counseling and reproductive expansion risk—not an FXS diagnosis.
| Spectrum condition | Who | Counseling focus |
|---|---|---|
| FXS | Full mutation | Developmental supports, cascade testing, reproductive options |
| FXTAS | Premutation (esp. older males) | Neurology referral, family cascade for reproductive-age relatives |
| FXPOI | Premutation females | Fertility timeline, reproductive endocrinology, reproductive options, expansion risk to offspring |
Integrating Neuromuscular + Fragile X Stems
When a vignette mixes hypotonia and developmental delay, sort by tempo and extras:
| Clue | Lean toward |
|---|---|
| Calf hypertrophy, huge CK, X-linked pedigree | Dystrophinopathy |
| Grip myotonia, cataracts, AD anticipation, congenital hypotonia with maternal DM1 | DM1 |
| Symmetric proximal weakness, tongue fasciculations, AR, SMN1 del | SMA |
| Large ears, ID/autism, maternal ID or FXPOI, CGG testing | Fragile X |
Always end with cascade testing strategy and—when relevant—cardiac (DMD carriers, DM1) or reproductive endocrine (FXPOI) referrals. These conditions illustrate Domain 2 anticipation/penetrance concepts with Domain 1 phenotypes.
A 5-year-old boy has proximal weakness, Gowers sign, and CK of 15,000. DMD gene testing shows an out-of-frame exon deletion. Which statement about his mother is most accurate for genetic counseling?
As an obligate non-carrier by definition, she needs no cardiac evaluation
If she carries the familial variant, she may still require cardiomyopathy surveillance even if skeletal muscles seem strong
Dystrophinopathies are autosomal recessive, so maternal testing is unnecessary
Out-of-frame variants cause Becker muscular dystrophy, so carrier risks are negligible
Which statement best captures anticipation in myotonic dystrophy type 1?
CTG expansions in DMPK can increase across generations, and congenital DM1 is almost always transmitted by an affected or expansion-carrying mother
Anticipation occurs only with paternal transmission of SMN1 deletions
DM1 is autosomal recessive, so anticipation means earlier sibling onset only
Congenital DM1 is typically caused by FMR1 full mutations rather than DMPK CTG expansions
Parents of an infant with SMA type 1 are both SMN1 deletion carriers. How should SMN2 copy number be used in counseling?
SMN2 copy number is irrelevant once SMN1 deletions are confirmed
SMN2 copies cause disease only when SMN1 is normal
Higher SMN2 copy number generally correlates with milder SMA phenotypes and informs prognosis discussions alongside therapy options
SMN2 testing replaces the need for parental carrier testing
A 32-year-old woman has a 90 CGG FMR1 allele and irregular menses with elevated FSH. Which counseling package best fits her repeat category?
Full-mutation Fragile X syndrome diagnosis with immediate special-education planning for herself
No reproductive concerns because premutation alleles cannot expand
Intermediate gray-zone allele with no association to ovarian insufficiency
Premutation-associated FXPOI risk counseling plus discussion of expansion risk to offspring and cascade family testing
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