SMA & Duchenne – High-Yield Review Notes

Spinal Muscular Atrophy (SMA)

• Genetics / protein
– Autosomal-recessive $SMN1$ deletion ➔ ↓ SMN protein (vital for motor-neuron survival)
– Disease severity ≈ $\text{SMN2}$ copy # ( $2$ = non-sitters, $3$ = sitters, $4+$ = walkers; exceptions exist)

• Diagnosis
– Gold standard = targeted DNA test (homozygous $SMN1$ loss + copy count)
– Newborn screening now universal in USA; confirmatory test still required

• Disease types & presentation
– Lower-motor-neuron signs: ↓ tone, absent DTRs, tremor, Gower manoeuvre, wide-based gait
– Type III (ambulatory) often loses walking in early adolescence unless treated

• Disease-modifying therapies
– Nusinersen (Spinraza®) – intrathecal, exon-7 inclusion
– Onasemnogene (Gene Tx) – single IV AAV9
– Risdiplam (Evrysdi®) – oral splicing modifier
– Apitegromab (anti-myostatin mAb) → ↑ muscle bulk (monthly IV)

• Orthopaedics / bone health
– Hip dysplasia → varus-derotation + pelvic osteotomies
– Progressive scoliosis; fusion delayed until near puberty; decision to fuse to pelvis depends on ambulation
– Osteoporosis from non-weight-bearing + weak muscle pull; multiple low-energy fractures
– Serial casting now recommended (consensus guideline) to address ankle contracture if family will maintain splints/AFOs

• PT / outcome tools
– Revised Hammersmith (RHS): tracks sitter/stander/walker change; $\ge18$ = 2 y walking reserve; $\le9$ ≈ loss ≤1 y
– Time Function Tests & 6-min walk (fatigability minute 1 vs 6)
– Goals: preserve trunk control, standing (power-chair stander), self-transfers, respiratory excursion

Duchenne Muscular Dystrophy (DMD) / Dystrophinopathies

• Genetics / pathophysiology
– X-linked recessive; $\approx1/3500$ male births
– Absent dystrophin ➔ membrane instability → muscle necrosis → fat/fibrosis
– Becker = in-frame mutation (partial protein)

• Clinical clues
– Onset $2–4\,y$: frequent falls, stair & run difficulty, no jump, Gower sign, calf pseudohypertrophy
– CK usually >10\,000\,\text{IU/L} (pathognomonic scale)
– Cognitive/behavioural comorbidity (speech delay, ASD, OCD) due to brain dystrophin isoforms

• Treatment landscape
– Glucocorticoids: Prednisone / Deflazacort; newer $\text{Vamorolone}$ (fewer growth-bone adverse effects)
– Exon-skipping PMOs (e.g.
$\Delta45$ eligible) – weekly IV; 2nd-gen agents in trial
– AAV micro-dystrophin gene therapy (Sarepta, Pfizer trials); single IV
– HDAC-inhibitor “Juvenestat” – ↓ fibrosis, ↑ strength; oral

• Key functional assessments
North Star Ambulatory Assessment (NSAA, $0{-}34$):
– Score $\ge27$ ➔ decline ≈ $8$ pts/yr
– $18$ = ≥2 y walking left; $13$ ≈ ≤2 y; $9$ ≈ ≤1 y
– Record item times (e.g.
rise-from-floor) for sensitivity
Rise-from-floor (timed): >30\,s → loss ambulation ≤12 m; <5\,s predicts stability
Six-min walk: monitor fatigue (Δ distance minute 1 vs 6) & therapy response
Performance Upper Limb ( Pool 2.0 ): shoulder → elbow → hand domains for non-walkers; entry graded by Brooks scale

• Surgery / orthotics
– Spinal fusion standard once curve >40^{\circ}; fuse to pelvis only if non-ambulatory (sacral fixation restricts pelvic tilt required for stand/transfers)
– Post-fusion: expect temporary dip in function, most regain baseline within $\approx12$ m when on DMT
– AFOs rarely used (add weight, alter compensatory lordosis)

• Female carriers
– $50\%$ risk to sons; carriers may have proximal weakness or cardiomyopathy ➔ surveillance

Rehab & Clinical Pearls

• Standing (frame/power chair) → ↑ bone density, ↓ contracture, peer-level eye contact, bowel/bladder & respiration benefit
• Gravity always wins – emphasise core, proximal strengthening, adaptive seating/lateral supports
• Monitor for fatigue: allow full trial time; document qualitative changes (e.g.
smaller trunk-lean, fewer hand assists)
• Prepare families early for mobility transitions; use objective cut-offs to time equipment, home mods, transfer training
• Keep detailed genotype + treatment history in all notes (e.g.
“presymptomatic $3$-copy SMA treated day $3$ risdiplam + gene-therapy day $21$”) for downstream therapists