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Hereditary Spastic Paraplegias (HSP) - Strümpell-Lorrain Syndrome

Hereditary Spastic Paraplegia (HSP) represents a heterogeneous group of inherited neurodegenerative diseases (prevalence 0.1-9.6/100,000), characterized by the progressive degeneration of the corticospinal tracts. The cardinal symptoms are progressive spasticity and weakness of the lower limbs, sphincter disturbances, and lower back pain (pure forms), which may be associated with other neurological/multisystemic signs and symptoms (complex forms). Currently, over 80 distinct genetic conditions are known, with autosomal dominant, autosomal recessive, and X-linked inheritance patterns. Regarding the age of onset, two peaks are recognized: at 2 years and 40 years of age.

HSPs are caused by mutations in over 80 genes involved in the length-dependent axonal degeneration of the corticospinal tracts. Among these, the main ones are SPG4 (SPAST, the most common form, representing 40% of autosomal dominant forms), SPG3A (ATL1, autosomal dominant infantile onset), SPG7 (the most frequent autosomal recessive form, often associated with ataxia), and SPG11 (a complex autosomal recessive form). Among the most important pathogenic mechanisms are: axonal transport deficits, endoplasmic reticulum dysfunction, mitochondrial impairment, alterations in lipid metabolism, and autophagy deficits. The result is the selective retrograde degeneration of the longest axons, which in turn leads to progressive spasticity in the lower limbs.

  • Primary Motor Symptoms:

    • Lower Limb Spasticity: prevalent in the extensor muscles (quadriceps, gastrocnemius) with gradual progression.

    • Muscle Weakness: most affected muscles are the iliopsoas, hamstrings, and tibialis anterior.

    • Gait Alterations: “scissoring” spastic gait, circumduction, toe-walking, instability with fall risk.

  • Neurological Signs:

    • Hyperreflexia: brisk tendon reflexes in the lower limbs, clonus, bilateral Babinski sign.

    • Sensory Alterations: mild impairment of proprioception (statokinetic sense), reduced vibration sense (pallesthesia), possible distal tactile sensory involvement in the lower limbs.

  • Sphincter Disturbances:

    • Bladder Dysfunction: urinary urgency (frequent early symptom), urgency/overflow incontinence, urinary retention, recurrent infections.

    • Bowel Disorders: constipation is most common; fecal incontinence is less frequent.

  • Pure HSP (90% of cases): limited symptoms characterized by lower limb spasticity and weakness, sphincter disturbances, slight reduction in vibration sense; slow progression and better prognosis.

  • Complex HSP (10% of cases): characterized by atypical neurological symptoms including:

    • Cognitive Involvement: variable intellectual disability, progressive dementia, behavioral disorders.

    • Cerebellar Symptoms: ataxia, dysmetria, nystagmus, dysarthria.

    • Peripheral Neuropathy: symmetrical distal sensory-motor involvement.

    • Ophthalmic Manifestations: early cataracts, retinopathy, optic neuropathy.

    • Epilepsy.

  • Major Clinical Criteria: bilateral lower limb spasticity, mild muscle weakness, hyperreflexia, bilateral Babinski sign.

  • Supporting Criteria: Mendelian family history, slow and inexorable progression, lack of response to symptomatic treatments.

  • Brain and Spinal Cord MRI: motor cortex atrophy, white matter alterations, spinal cord atrophy, T2-FLAIR hyperintensity of the lateral columns, thin corpus callosum (typical of SPG11/SPG15).

  • Electrophysiology: normal or mildly reduced motor conduction velocities, reduced sensory conduction velocities (in forms with neuropathy), central conduction delay in MEPs (motor evoked potentials), alterations of sensory pathways in SSEPs (somatosensory evoked potentials).

  • Definitive Genetic Diagnosis: multi-gene panels, Whole Exome Sequencing (WES) when panels are negative, MLPA for deletions/duplications, segregation analysis.

  • Most Commonly Tested Genes: SPG4 (SPAST – 40% of autosomal dominant forms), SPG3A (ATL1 – early onset), SPG7 (autosomal recessive forms with ataxia), SPG11 (complex forms).

  • Differential Diagnosis: multiple sclerosis, leukodystrophies, primary lateral sclerosis (PLS), spinocerebellar ataxia (SCA), vitamin deficiencies, spinal canal stenosis.

Available therapies

  • Anti-spasticity Therapies:

    • Oral Medications: baclofen 10–80 mg/day (GABA-B agonist), tizanidina 2–24 mg/day (lower sedation), diazepam 2–10 mg/day (nocturnal spasms).

    • Injectable Therapies: intramuscular botulinum toxin (focal spasticity, every 3–4 months), phenol/alcohol nerve blocks (duration 6–12 months).

    • Intrathecal Baclofen: implantable pump, 50–1200 mcg/day, indicated for severe generalized spasticity.

  • Sphincter Disturbances:

    • Bladder Dysfunction: antimuscarinics (oxybutynin, tolterodine), beta-3 agonists (mirabegron), intermittent catheterization.

    • Bowel Disorders: laxatives (macrogol), prokinetics, dietary changes.

  • Multidisciplinary Rehabilitation:

    • Physiotherapy: stretching of spastic muscles, strengthening of weak muscles, gait retraining, aquatic exercises.

    • Occupational Therapy: functional assessment, adaptive aids, compensatory strategies.

    • Orthotics and Assistive Devices: AFO (Ankle-Foot Orthosis) for drop foot, KAFO (Knee-Ankle-Foot Orthosis) for knee instability, orthopedic shoes, mobility aids (canes, walkers).

  • Surgical Interventions:

    • Orthopedic Surgery: tenotomies for tendon lengthening, tendon transfers, osteotomies for deformity correction.

    • Neurosurgery: selective dorsal rhizotomy, myelotomies (selected cases), spinal cord stimulation (experimental).

Research in progress

  • Development of gene therapies using AAV vectors for specific gene delivery
  • CRISPR/Cas9 gene editing for mutation correction
  • Neuroprotectors: antioxidants, microtubule stabilizers, autophagy modulators
  • Neurotrophic factors to support axonal survival
  • Precision medicine with genetic stratification for gene-specific therapies
  • Experimental models: patient
  • Specific iPSCs, 3D neural tissue organoids

Reference laboratory

Contacts and informations

Email/Ph: malattieneuromuscolari@policlinico.mi.it

Patient Associations:

Specialist Resources:

  • OMIM: Online Mendelian Inheritance in Man
  • GeneReviews: revisioni clinico-genetiche HSP
  • ClinVar: database varianti genetiche
  • European HSP Registry: collaborazione europea pazienti
  • Global HSP Registry: iniziativa internazionale