Spastic Paraplegia 3a

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) have 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.

Suggestive Findings

Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) should be suspected in individuals with the following clinical findings and family history.

Clinical findings

• Early age of onset, from infancy to ten years (average age: 4 years)
• Progressive bilateral and mostly symmetric lower-extremity weakness and spasticity resulting from axonal degeneration of the corticospinal tracts
• Diminished vibration sense caused by impairment of dorsal columns
• Urinary bladder hyperactivity

Family history consistent with autosomal dominant inheritance, including affected males and females in multiple generations and simplex cases (i.e., a single occurrence in a family). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

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 (see Table 1). Note: The exceptions are two families with biallelic ATL1 pathogenic variants.

Note: Identification of a heterozygous ATL1 variant of uncertain significance does not establish or rule out a diagnosis of ATL1-HSP.

Molecular genetic testing approaches can include a combination of gene-targeted testing (multigene panel) and comprehensive genomic testing (exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of ATL1-HSP has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

Spastic paraplegia 3A (SPG3A; also known as ATL1-HSP) is characterized by slowly progressive bilateral and mostly symmetric spasticity and weakness of the legs, and with a variable degree of diminished vibration sense (caused by degeneration of the corticospinal tracts and dorsal columns) and urinary bladder hyperactivity. The average age of onset is four years; more than 80% of affected individuals manifest spastic gait before age ten years. The rate of progression is slow; wheelchair dependency or need for an assistive walking device is relatively rare.

Most persons with early-onset ATL1-HSP have a "pure" or "uncomplicated" hereditary spastic paraplegia (HSP) phenotype. However, complex HSP phenotypes with axonal motor neuropathy and/or distal amyotrophy (like that observed in the Silver syndrome phenotype) have also been reported [Scarano et al 2005, Ivanova et al 2007, Salameh et al 2009]. In complicated forms with spastic quadriparesis, involvement of bulbar muscles can result in dysphagia and dysarthria [Yonekawa et al 2014].

Findings also seen in ATL1-HSP can include pes cavus deformities and scoliosis, possibly attributable to the early age of onset.

Other phenotypes observed in the spectrum of ATL1-HSP include the following:

• Adult-onset ATL1-HSP. Although it has been suggested that ATL1-HSP is a neurodevelopmental rather than a neurodegenerative disorder, identification of individuals with adult-onset ATL1-HSP argues strongly against this hypothesis [Sauter et al 2004, Zhu et al 2006]. Persons with adult-onset ATL1-HSP also tend to experience slower disease progression.
• Hereditary sensory neuropathy type ID (HSN1D), an axonal form of autosomal dominant hereditary motor and sensory neuropathy distinguished by prominent sensory loss that leads to painless injuries. A pathogenic ATL1 missense variant was identified in a single family with HSN1D, in whom other known causative genes had been excluded [Guelly et al 2011, Leonardis et al 2012]. Two additional ATL1 variants were identified in 115 unrelated individuals with the HSN1D phenotype [Guelly et al 2011].
• Clinical presentation with a pure autonomic failure followed by the development of spastic paraplegia was reported in one individual with a novel pathogenic ATL1 splice site variant in exon 2 [Shin et al 2014]. Whether this represents an allelic condition or an atypical presentation of ATL1-HSP remains to be elucidated.
• Clinical presentation mimicking a severe neonatal-onset cerebral palsy with quadriparesis was reported in an individual with a de novo ATL1 pathogenic variant [Yonekawa et al 2014]. The individual also experienced abnormal speech and swallowing with pseudobulbar palsy. Electrophysiologic studies showed axonal polyneuropathy.

Findings not universally seen in ATL1-HSP compared to other forms of autosomal dominant HSP include the following [Dürr et al 2004]:

• Hyperreflexia of the upper extremities
• Impairment of vibration sensation at the ankles
• Urinary bladder hyperactivity

Genotype-Phenotype Correlations

No specific genotype-phenotype correlations have been reported; however:

• Early-onset disease has been associated with missense variants around the GTPase binding domain.
• Late-onset disease has been associated with frameshift variants in the C terminus that result in premature truncation of the protein, as well as some missense variants in the GTPase binding domain [Tessa et al 2002, Sauter et al 2004].

Penetrance

Overall, penetrance of pathogenic variants is high (~80%-90%) [Dürr et al 2004]. In many familial cases, individuals with a heterozygous ATL1 pathogenic variant had a normal neurologic examination even at an advanced age, arguing against significant age-dependent penetrance [Dürr et al 2004].

The lowest penetrance, 30%, was reported for the p.Arg415Trp heterozygous pathogenic variant detected in three affected individuals but also in nine unaffected family members [D'Amico et al 2004]. Reduced penetrance of this variant was also observed in additional families in which mostly females were unaffected, suggesting (incorrectly) X-linked inheritance [Varga et al 2013].

Prevalence

Prevalence of autosomal dominant (AD) HSP has been estimated at 0.5-5:100,000 [McMonagle et al 2002, Ruano et al 2014].

SPG3A is the third most common cause of AD HSP in all age groups. Metanalysis of epidemiologic studies suggested that SPG3A accounts for about 5% of all AD HSP, with an estimated prevalence of 0.025-0.25:100,000 [Erfanian Omidvar et al 2019]. This estimated frequency of SPG3A is lower than previously reported, at 10%-15% of all AD HSP [Fink et al 1996].

SPG3A, the most common cause of early onset of AD HSP before age ten years, accounts for 40% of AD HSP in this age group [Dürr et al 2004].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 3A (SPG3A; also known as ATL1-HSP), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Treatment for spasticity, distal weakness, and urinary bladder dysfunction (the primary manifestations of ATL1-HSP) is symptomatic. See Table 4.

Management by multidisciplinary specialists including a physiatrist, physical therapist, and speech therapist is recommended.

Surveillance

There is no consensus regarding the frequency of clinical follow-up visits, but routine reevaluations are warranted (see Table 5).

Agents/Circumstances to Avoid

Dantrolene should be avoided in persons who are ambulatory as it may induce irreversible weakness, which can adversely affect overall mobility.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

The use of regional anesthesia, such as spinal or epidural anesthesia, during delivery in women with ATL1-HSP and spinal cord involvement has traditionally been avoided due to the theoretic risk of exacerbating the degree of weakness and spasticity. However, several instances of successful regional anesthesia in individuals with hereditary spastic paraplegia have been reported [Thomas et al 2006, Ponsonnard et al 2017].

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. Note: There may not be clinical trials for this disorder.