Clinical characteristics: Spastic paraplegia 4 (SPG4; also known as SPAST-HSP) is characterized by insidiously progressive bilateral lower-limb gait spasticity. More than 50% of affected individuals have some weakness in the legs and impaired vibration sense at the ankles. Sphincter disturbances are very common. Onset is insidious, mostly in young adulthood, although symptoms may start as early as age one year and as late as age 76 years. Intrafamilial variation is considerable.
Diagnosis/testing: The diagnosis of SPAST-HSP is established in a proband with characteristic clinical features and a heterozygous pathogenic variant in SPAST identified by molecular genetic testing.
Management: Treatment of manifestations: Antispastic drugs for leg spasticity; anticholinergic antispasmodic drugs for urinary urgency; regular physiotherapy to stretch spastic muscles and prevent contractures. Consideration of botulinum toxin and intrathecal baclofen when oral drugs are ineffective and spasticity is severe and disabling. Urodynamic evaluation in order to initiate treatment when sphincter disturbances become a problem.
Surveillance: Evaluation every 6-12 months to update medications and physical rehabilitation.
Genetic counseling: SPAST-HSP is inherited in an autosomal dominant manner with age-related, nearly complete penetrance and is characterized by significant intrafamilial clinical variability. Most individuals diagnosed with SPAST-HSP have an affected parent. The proportion of cases caused by a de novo pathogenic variant is low. Each child of an individual with SPAST-HSP has a 50% chance of inheriting the pathogenic variant. Prenatal testing and preimplantation genetic testing are possible if a pathogenic SPAST variant has been identified in an affected family member. Because of variable clinical expression, results of prenatal testing cannot be used to predict whether an individual will develop SPAST-HSP and, if so, what the age of onset, clinical course, and degree of disability will be.
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