Clinical characteristics: Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by progressive bilateral and mostly symmetric spasticity and weakness of the legs. Compared to other forms of autosomal dominant hereditary spastic paraplegia (HSP), in which diminished vibration sense (caused by degeneration of the corticospinal tracts and dorsal columns) and urinary bladder hyperactivity are present in all affected individuals, these findings occur in a minority of individuals with SPG3A. The average age of onset is four years. More than 80% of reported individuals manifest spastic gait before the end of the first decade of life. Most persons with early-onset ATL1-HSP have a "pure" ("uncomplicated") HSP; however, complicated HSP with axonal motor neuropathy and/or distal amyotrophy with lower motor neuron involvement (Silver syndrome phenotype) has been observed. The rate of progression in ATL1-HSP is slow, and wheelchair dependency or need for a walking aid (cane, walker, or wheelchair) is relatively rare.
Diagnosis/testing: The diagnosis of ATL1-HSP is established in a proband with suggestive findings and almost exclusively a heterozygous pathogenic variant in ATL1 identified by molecular genetic testing. Note: The exceptions are two families with biallelic ATL1 pathogenic variants.
Management: Treatment of manifestations: Treatment is symptomatic. Medical treatment of spasticity may begin with oral baclofen or tizanidine, followed by chemodenervation with botulinum A or B toxins if oral antispasticity medications are not tolerated. Intrathecal baclofen pump may be considered for those who improve on oral baclofen but have significant systemic adverse effects. Medical therapy should be combined with intensive physical therapy focused on stretching and strengthening exercises that may help delay or minimize muscle tendon contractures, scoliosis, and foot deformities. Distal weakness (typically affecting foot dorsiflexion) can be ameliorated by ankle-foot orthoses. Urinary urgency can be treated with anticholinergic antispasmodic drugs.
Surveillance: No consensus exists regarding the frequency of clinical follow-up visits, but reevaluation once or twice yearly to identify and treat new complications is recommended.
Agents/circumstances to avoid: Dantrolene, as it can induce irreversible weakness, adversely affecting mobility.
Genetic counseling: ATL1-HSP is almost exclusively inherited in an autosomal dominant manner. More than 95% of individuals diagnosed with SPG3A have an affected parent; the proportion of individuals with ATL1-HSP caused by a de novo pathogenic variant is currently unknown. Each child of an individual with ATL1-HSP has a 50% chance of inheriting the pathogenic variant. Once the ATL1 pathogenic variant has been identified in a family member with autosomal dominant ATL1-HSP, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
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