HEREDITARY SPASTIC PARAPLEGIA

Hereditary Spastic Paraplegia — progressive lower limb spasticity caused by 80+ different genes, where molecular diagnosis distinguishes treatable mimics from true HSP and predicts whether the disease will remain pure or develop complex features.

Whole genome sequencing evaluates all 80+ HSP genes simultaneously — SPG4 (SPAST), SPG3A (ATL1), SPG7 (paraplegin), and the full genetic landscape — replacing the sequential single-gene testing that delays diagnosis by years.

SPAST
SPG4
ATL1
SPG3A
SPG7

About this condition

Hereditary Spastic Paraplegia

Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by progressive length-dependent degeneration of the corticospinal tract, producing lower limb spasticity and weakness. Over 80 genetic loci (SPG1 through SPG80+) and their corresponding genes have been identified, with autosomal dominant, autosomal recessive, and X-linked inheritance patterns. The most common form is SPG4 (SPAST gene, encoding spastin), accounting for approximately 40% of autosomal dominant HSP cases. Combined prevalence of all HSP forms is approximately 2-10 per 100,000.

HSP is classified as 'pure' (uncomplicated — spasticity and weakness limited to the lower limbs, with or without urinary urgency and mild sensory loss) or 'complex' (complicated — spasticity plus additional neurological features such as ataxia, peripheral neuropathy, cognitive impairment, thin corpus callosum, epilepsy, or optic atrophy). The distinction between pure and complex HSP has major prognostic implications: pure HSP typically allows independent ambulation for decades, while complex HSP may include progressive cognitive decline, wheelchair dependence, and shortened life expectancy.

HSP is frequently misdiagnosed. The differential includes primary progressive multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), vitamin B12 deficiency, copper deficiency, spinal cord compression, dopa-responsive dystonia, and structural myelopathy. Many HSP patients undergo years of investigation — MRI brain and spine, lumbar puncture, evoked potentials, NCS/EMG — without a definitive diagnosis. Molecular confirmation through comprehensive genetic testing ends the diagnostic odyssey, provides accurate prognosis (pure vs. complex trajectory), enables genetic counseling for family members, and excludes treatable mimics.

SPG7 (paraplegin) is a common cause of recessive HSP that frequently presents with cerebellar ataxia — it is increasingly recognized as one of the most common genetic ataxias and should be considered in any adult with progressive spastic ataxia.

Gene locus: SPAST/SPG4 (2p22.3), ATL1/SPG3A (14q22.1), SPG7 (16q24.3), plus 80+ additional loci

With 80+ causative genes, sequential single-gene testing is impractical. WGS evaluates the complete HSP genetic landscape in one test — ending diagnostic odysseys that average 5-10 years for rare HSP subtypes.

Ending the diagnostic odyssey — average HSP diagnostic delay is 5-10 years, during which treatable mimics may be missed

HSP patients typically undergo years of neurological investigation before receiving a molecular diagnosis. During this period, treatable conditions that mimic HSP — dopa-responsive dystonia (GCH1), B12/copper deficiency, structural myelopathy, primary progressive MS — may be under-investigated because the clinical picture is attributed to 'possible HSP.' Whole genome sequencing either confirms HSP with a specific gene identification (providing prognosis and reproductive counseling) or excludes HSP, redirecting investigation toward potentially treatable conditions.

SPG4 (SPAST) exon deletions account for 20% of SPG4 cases — invisible to standard sequencing

Approximately 20% of SPG4 pathogenic alleles are multi-exon deletions or duplications in SPAST — structural variants that are not detectable by standard exon sequencing or Sanger sequencing. A patient with autosomal dominant pure HSP who tests negative on SPAST sequencing may actually carry a SPAST deletion. Whole genome sequencing detects both sequence variants and copy number variants from the same data, identifying the complete spectrum of SPAST pathogenic alleles in a single test without requiring separate MLPA analysis.

Hereditary Spastic Paraplegia — progressive lower limb spasticity caused by 80+ different genes, where molecular diagnosis distinguishes treatable mimics from true HSP and predicts whether the disease will remain pure or develop complex features.

Hereditary Spastic Paraplegia

With 80+ causative genes, sequential single-gene testing is impractical. WGS evaluates the complete HSP genetic landscape in one test — ending diagnostic odysseys that average 5-10 years for rare HSP subtypes.

Ending the diagnostic odyssey — average HSP diagnostic delay is 5-10 years, during which treatable mimics may be missed

SPG4 (SPAST) exon deletions account for 20% of SPG4 cases — invisible to standard sequencing

Others in Neurological

One test. A lifetime of answers.