Spastic Paraplegia 7

Clinical characteristics.

Spastic paraplegia 7 (SPG7) is characterized by insidiously progressive bilateral leg weakness and spasticity. Most affected individuals have decreased vibration sense and cerebellar signs. Onset is mostly in adulthood, although symptoms may start as early as age 11 years and as late as age 72 years. Additional features including ataxia (gait and limbs), spastic dysarthria, dysphagia, pale optic disks, ataxia, nystagmus, strabismus, ptosis, hearing loss, motor and sensory neuropathy, amyotrophy, scoliosis, pes cavus, and urinary sphincter disturbances may be observed.

Diagnosis/testing.

The diagnosis of SPG7 is established in a proband with typical clinical findings and biallelic pathogenic variants in SPG7 identified by molecular genetic testing.

Management.

Treatment of manifestations: Drugs that may reduce spasticity and muscle tightness include baclofen, tizanidine, dantrolene, and diazepam. Physical therapy and assistive walking devices often reduce contractures, provide support, and promote stability. Occupational therapy and speech therapy help with activities of daily living.

Surveillance: Annual neurologic evaluation to identify potential complications of spasticity, such as contractures.

Genetic counseling.

SPG7 is inherited in an autosomal recessive manner. Heterozygotes (carriers) are usually asymptomatic. Each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible if both pathogenic alleles have been identified in the family.

Suggestive Findings

Spastic paraplegia 7 (SPG7) should be suspected in individuals with the following:

• Insidiously progressive bilateral leg weakness
• Spasticity
• Decreased vibratory sense
• Cerebellar signs
• Neurologic examination demonstrating EITHER of the following:
  • A pure phenotype of spastic paraplegia with hyperreflexia, extensor plantar responses, and mildly impaired vibration sensation in the distal legs
  • A complicated phenotype of spastic paraplegia including optic neuropathy, progressive external ophthalmoplegia/ptosis slowed speech, swallowing difficulties, palatal tremor, subtle cognitive impairment, urinary urgency, ataxia, nystagmus, strabismus, decreased hearing, scoliosis, pes cavus, motor and sensory neuropathy, and amyotrophy [Brugman et al 2008, Salinas et al 2008, Warnecke et al 2010, Pfeffer et al 2014]
• Neuroimaging findings of cerebellar atrophy (MRI) or white matter changes as detected by diffusion tensor imaging in the frontal lobes, the corticospinal tracts, and the brain stem
• Family history consistent with autosomal recessive inheritance

Establishing the Diagnosis

The diagnosis of SPG 7 is established in a proband with typical clinical findings and identification of biallelic pathogenic variants in SPG7 by molecular genetic testing (see Table 1).

Note: A single SPG7 pathogenic variant (p.Leu78*) was identified in a proband with a pure HSP phenotype suggesting that heterozygosity for an SPG7 pathogenic variant may be sufficient to cause disease (i.e., autosomal dominant inheritance). However, this conclusion is challenged by the finding of unaffected p.Leu78* heterozygotes in other families as well as the possibility that the affected heterozygous individual had a second SPG7 pathogenic variant which was not detected due to testing limitations [Sánchez-Ferrero et al 2013].

Because the phenotype of SPG7 is indistinguishable from many other forms of hereditary spastic paraplegia, recommended molecular genetic testing approaches include use of a multigene panel or comprehensive genomic testing.

Note: Single-gene testing (sequence analysis of SPG7, followed by gene-targeted deletion/duplication analysis) is rarely useful and typically NOT recommended.

• A multigene panel that includes SPG7 and other genes of interest (see Differential Diagnosis) is most likely to identify the genetic cause of the condition at the most reasonable cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
  For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
• Comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is another good option. Exome sequencing is most commonly used; genome sequencing is also possible. Exome array (when clinically available) may be considered if exome sequencing is not diagnostic.
  For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.

Clinical Description

Spastic paraplegia 7 (SPG7) is characterized by insidiously progressive bilateral lower-limb weakness and spasticity. Most affected individuals have proximal or generalized weakness in the legs and impaired vibration sense.

Onset typically occurs in adulthood, around age 30-45 years, although symptoms may start as early as age 11 years and as late as age 72 years [De Michele et al 1998, McDermott et al 2001, Wilkinson et al 2004].

Presentation. The first sign is typically insidiously progressive bilateral leg weakness.

Additional features. Other signs and symptoms can be observed [Brugman et al 2008, Salinas et al 2008, Warnecke et al 2010, Almontashiri et al 2014, Pfeffer et al 2014] including the following:

• Cerebellar and motor signs
  • Ataxia (gait and limbs)
  • Spastic dysarthria
  • Dysphagia
• Ophthalmic findings
  • Pale optic disks
  • Nystagmus
  • Strabismus
  • Ptosis
• Hearing loss of conductive/neurosensory /mixed type
• Peripheral neuromuscular findings
  • Motor and sensory neuropathy
  • Amyotrophy
• Orthopedic issues
  • Scoliosis
  • Pes cavus
• Urinary sphincter disturbances

Progression. Severe disability of gait due to leg spasticity may develop as soon as eight years after onset of symptoms, and some individuals are confined to a wheelchair [Elleuch et al 2006, Schüle et al 2006].

Findings on Neuroimaging and Other Investigations

Neuroimaging

• In a few individuals, conventional cerebral MRI may show cerebellar (or, less frequently, cortical) atrophy [Salinas et al 2008, Hourani et al 2009, Warnecke et al 2010].
• White matter changes as detected by diffusion tensor imaging in the frontal lobes, the corticospinal tracts, and the brain stem are specific to SPG7.
• Spinal imaging studies are useful in the differential diagnosis to exclude other anomalies of the pontomedullary junction and of the cervical and dorsolumbar medulla.

Other investigations

• Spinal evoked potentials may reveal delayed prolongation of the central conduction time [Nielsen et al 2001].
• Electromyography with nerve conduction velocities may reveal axonal sensory motor neuropathy.
• Paired transcranial magnetic stimulation may show delayed prolongation of the central motor conduction time and motor threshold in some affected individuals in lower limb muscles [Warnecke et al 2010]. Intracortical inhibition appears normal in SPG7 [Nardone & Tezzon 2003].
• Optical coherence tomography is useful for detecting subclinical optic neuropathy [Klebe et al 2012].
• A battery of neuropsychological tests may reveal mild impairment of visuoconstructive and executive functions in some individuals [Warnecke et al 2010].
• Serum creatine kinase activity may be slightly above the normal range in some cases.
• Muscle biopsy has revealed the following:
  • Changes of denervation with partial reinnervation
  • Atrophic, angulated fibers, predominantly type II
  • Ragged-red fibers, which are positive for the histoenzymatic reaction to succinate dehydrogenase and negative for cytochrome c oxidase (COX, the complex IV of the mitochondrial respiratory chain), indicating an oxidative phosphorylation defect [Casari et al 1998, McDermott et al 2001, Wilkinson et al 2004, Tzoulis et al 2008].

Genotype-Phenotype Correlations

No genotype-phenotype correlations can be proposed based on published studies.

Prevalence

The prevalence of SPG7 is estimated at between 1:100,000 and 9:100,000 for most countries (www.orpha.net).

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with spastic paraplegia 7 (SPG7), the following evaluations are recommended if they have not already been completed:

• Ophthalmologic evaluation
• Hearing testing
• Urologic evaluation in case of bladder dysfunction
• Consultation with a clinical geneticist and/or genetic counselor

Evaluation by a multidisciplinary team that includes a general practitioner, neurologist, physical therapist, social worker, and psychologist should be considered.

Neuropsychological testing may be suggested.

Treatment of Manifestations

No specific drug treatments or cures for SPG7 exist.

Drugs to reduce spasticity and muscle tightness include baclofen, tizanidine, dantrolene, and diazepam – preferably administered one at a time.

Management of spasticity by intrathecal baclofen or intramuscular botulinum toxin injections may be an option in selected individuals [Kawano et al 2018].

A combination of physical therapy and assistive walking devices are often used to reduce contractures, provide support, and promote stability.

Occupational therapy and speech therapy are often helpful in managing activities of daily living.

Prevention of Secondary Complications

Because individuals with advanced disease are bedridden they are at major risk of aspiration pneumonia, urinary tract infections and pulmonary embolism; careful monitoring is recommended to help avoid these complications.

Surveillance

Annual neurologic evaluation can help identify potential complications of spasticity that develop over time (e.g., contractures).

Evaluation of Relatives at Risk

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

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.