Spasticity and hereditary spastic paraplegia

Progressive lower-limb spasticity with hyperreflexia, extensor plantar responses, and a stiff scissoring gait. In adults, often years of "trouble running" or "stiff legs" before formal diagnosis. In children, the differential overlaps spastic diplegic cerebral palsy heavily, and a treatable mimic missed here gets relabeled CP for a lifetime. Hereditary spastic paraplegia (HSP) is the umbrella genetic diagnosis, but the most important clinical job is not "which SPG number." It's "is this a treatable disorder I am about to miss?"

Three axes structure the work-up:

1. Pure vs complicated. Pure HSP: spasticity is the dominant or only feature. Complicated HSP: spasticity plus ID, peripheral neuropathy, optic atrophy, cerebellar signs, retinopathy, or extrapyramidal features. The presence of any complication changes the differential dramatically.
2. Age of onset. Childhood (always rule out treatable mimics + dopa-responsive dystonia + cerebral palsy mimics), adolescent / young adult (HSP gene panel becomes high-yield), late adult (consider acquired causes too: cervical myelopathy, B12, primary lateral sclerosis, HTLV-1, copper).
3. Inheritance pattern. AD most common in adult-onset pure HSP (SPAST leads the list); AR more common in childhood and complicated HSP; X-linked rare but classic (L1CAM, PLP1).

These are the diagnoses where missing the call has the highest cost.

• Dopa-responsive dystonia (Segawa) (GCH1): lower-limb dystonia with diurnal variation often misread as spastic diplegia. Even minor evening worsening or morning improvement should trigger a trial of low-dose L-DOPA in every child with progressive lower-limb spasticity. Dramatic response over days-weeks.
• X-linked adrenoleukodystrophy / adrenomyeloneuropathy (ABCD1): AMN is the adult form, classically an adult male with progressive spastic paraparesis, sphincter dysfunction, adrenal insufficiency. Female carriers can develop AMN-like myelopathy in midlife. Check VLCFAs in every undiagnosed adult-onset spastic paraparesis, and adrenal function alongside (untreated primary adrenal insufficiency is fatal).
• Cerebrotendinous xanthomatosis (CYP27A1): progressive spasticity + ataxia + dementia + tendon xanthomas + juvenile cataracts + chronic diarrhea. Treatable with chenodeoxycholic acid, dramatic if started before extensive CNS damage. Cholestanol level is the screening test.
• Arginase deficiency (ARG1, urea cycle): the late-onset urea cycle disorder that presents as progressive spastic diplegia with cognitive decline, NOT acute hyperammonemia. Plasma amino acids show elevated arginine; ammonia may be normal between episodes. Treatable with low-protein diet and ammonia scavengers.
• Cobalamin C deficiency and other cobalamin metabolism defects (MMACHC, MTRR, MTR, MMADHC): spasticity, optic atrophy, neuropathy, hemolytic anemia, megaloblastic anemia. Treatable with B12 (hydroxocobalamin), betaine, folate. Plasma homocysteine + MMA + amino acids screens.
• Biotinidase deficiency: seizures, alopecia, dermatitis, lactic acidosis, hearing loss, optic atrophy, ± spasticity. Treatable with biotin; on newborn screen.
• Vitamin B12 deficiency (acquired): subacute combined degeneration. Always check B12 + MMA + homocysteine in any new myelopathy.
• GLUT1 deficiency (SLC2A1): paroxysmal exercise-induced spasticity / dystonia with low CSF glucose. Ketogenic diet.

Pure HSP (AD, most common)

• SPG4 (SPAST, spastin): the single most common cause of AD pure HSP overall. Adult onset, slowly progressive, lower-limb spasticity dominant, minimal upper-limb or bulbar involvement.
• SPG3A (ATL1, atlastin): classic childhood-onset AD pure HSP.
• SPG31 (REEP1): AD pure HSP.
• SPG6 (NIPA1): AD pure HSP.

Complicated HSP (often AR, often childhood-onset)

• SPG7 (SPG7, paraplegin, AR): spasticity + cerebellar ataxia + optic atrophy. One of the most common AR complicated HSPs.
• SPG11 (SPG11, spatacsin, AR): thin corpus callosum on MRI (a classic finding), spasticity, ID, peripheral neuropathy, parkinsonism. SPG15 (ZFYVE26) phenotype overlaps (Kjellin syndrome with retinopathy).
• SPG30 (KIF1A): AR with cerebellar and cognitive involvement.
• SPG2 (PLP1, X-linked): allelic with Pelizaeus-Merzbacher; mild end of the PLP1 spectrum.

Childhood and "spastic CP look-alike" presentations

When a child presents with bilateral lower-limb spasticity:

• If there is no clear perinatal injury, no static encephalopathy, and especially if there is progression over months, it is not cerebral palsy. Pursue the work-up.
• If there is even subtle diurnal variation, trial L-DOPA.
• If there is sphincter dysfunction, optic atrophy, or peripheral neuropathy, the disorder is complicated HSP or one of the treatable mimics above.

1. Brain and full spine MRI. Distinguish HSP (often subtle or normal) from compressive myelopathy, leukodystrophy, and structural lesions. Thin corpus callosum → SPG11. Periventricular white matter → leukodystrophy. Cervical cord compression → not HSP.
2. VLCFAs and adrenal function (ACTH-stim cortisol) in any unexplained spastic paraparesis. Cheap, fast, life-saving.
3. Trial of L-DOPA in every child or adolescent with progressive spastic diplegia (4-6 weeks at low dose).
4. Plasma amino acids (arginase deficiency screening: elevated arginine).
5. Cholestanol (CTX).
6. B12, MMA, homocysteine (acquired and inherited cobalamin disorders); biotinidase activity if features fit.
7. Copper, ceruloplasmin if features suggest Wilson disease.
8. Targeted gene testing or HSP gene panel when treatable causes are excluded and phenotype fits.
9. EMG / NCS if mixed UMN/LMN signs (consider ALS, primary lateral sclerosis, peripheral neuropathy + UMN syndromes).
10. HTLV-1 serology in endemic-region exposure with adult tropical spastic paraparesis.