Clinical Guidance

Recently, after analyzing a cohort of more than 500 individuals with SPAST-HSP, showed that missense variants were associated with an earlier age of onset (by 10 years), when compared to truncating variants. This finding provides an explanation for the bimodal age of onset distribution typical of SPAST-HSP. It is important to note that age at onset and clinical severity are highly variable for a given variant, even in the same family. The observed difference in age of onset between related individuals ranged from 27 years to 69 years . Furthermore, two family members with the same variant can have in one case a pure spastic paraparesis and in the other a complex disease. For example, reported wide phenotypic variability with the p.

Source: GeneReviews — "Spastic Paraplegia 4"

Penetrance

Penetrance is age dependent and mostly complete in individuals with SPAST-HSP. It is estimated to be 85% by age 45 years and complete at 70 years . It should be emphasized that age dependence is explained partly by variability in age at onset and partly by the difficulty in determining the precise age of onset; thus, neurologic examination is important. Penetrance is greater if pyramidal signs as well as spastic gait are considered: approximately 6% of individuals who have a SPAST variant are completely asymptomatic on examination; approximately 20% have abnormal signs when examined, but no awareness of being affected. Penetrance may be sex dependent.

Source: GeneReviews — "Spastic Paraplegia 4"

Diagnostic Criteria

Suggestive Findings

Spastic paraplegia 4 (SPG4; also known as SPAST-HSP) should be suspected in individuals with the following:

• Characteristic clinical symptoms of insidiously progressive bilateral leg stiffness affecting gait with or without spasticity at rest and mild proximal weakness, often accompanied by urinary urgency

• Neurologic examination demonstrating corticospinal tract deficits affecting both legs (spastic weakness, hyperreflexia, and extensor plantar responses). Mildly impaired vibration sensation in the ankles is present in the majority of individuals.

• Family history consistent with autosomal dominant inheritance, or exclusion of other causes of spastic paraplegia in simplex cases (i.e., a single occurrence in a family)

Source: GeneReviews — "Spastic Paraplegia 4"

Differential Diagnosis

See Hereditary Spastic Paraplegia Overview for a review of the differential diagnosis. SPAST-HSP is the most frequently occurring form of autosomal dominant hereditary spastic paraplegia, accounting for an estimated 40% of AD-HSP . Because SPAST is the most commonly involved gene in AD-HSP, it is the first and most relevant gene to be tested. The other main types of autosomal dominant pure spastic paraplegia to consider are SPG3A, SPG31, and SPG10. With the exceptions of SPG3A, SPG31, and SPG10, no significant differences have been established between SPG4 and other types of pure dominant spastic paraplegia.

Table 2.

Other Types of Autosomal Dominant Pure Spastic Paraplegia (AD-HSP) to Consider in the Differential Diagnosis of SPAST-HSP

Source: GeneReviews — "Spastic Paraplegia 4"

Management Guidelines

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 4 (SPAST-HSP), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:

Source: GeneReviews — "Spastic Paraplegia 4"

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Source: GeneReviews — "Spastic Paraplegia 4"

Surveillance Guidelines

Specialized outpatient evaluations are suggested every six to 12 months to update medications and physical rehabilitation.

Source: GeneReviews — "Spastic Paraplegia 4"