Hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP), otherwise known as familial spastic paraparesis or (historically) Strümpell-Lorraine syndrome, is a group of single gene conditions in which there is degeneration and/or abnormal development of the upper motor neurons in the pyramidal tract. HSP is broadly divided into two subgroups: pure (uncomplicated) and complex, depending on the presence or absence of additional findings.

Pure (uncomplicated) form HSP

Pure form HSP describes bilateral, symmetrical lower limb weakness and/or spasticity in the absence of other neurological symptoms. The main symptoms include:

• gradual leg weakness and/or stiffness;
• overactive bladder;
• erectile dysfunction; and
• mild impairment of vibration sensation in the lower extremities.

Most (90%) HSP diagnoses are pure HSP.

Note that gradual leg weakness and/or stiffness that occurs in early childhood may be non-progressive and resemble a spastic diplegic cerebral palsy. Symptoms that begin in later childhood are typically progressive with a variable course.

Complex HSP

Complex HSPs share the same features described above for pure HSP, but can include additional neurological and/or extra-neurological features, such as:

• cerebellar ataxia;
• epilepsy;
• intellectual difficulties;
• peripheral neuropathy;
• cognitive impairment/dementia;
• eye problems, such as retinopathy and optic neuropathy;
• ichthyosis;
• hearing loss; and/or
• difficulties with speech, swallowing and/or breathing.

About 10% of patients with HSP will have a complex form.

Age of onset, presenting symptoms and severity is variable for most HSP types, even within families.

HSP is a significant differential diagnosis for cerebral palsy. Genomic testing should be considered in all children in whom known risk factors for cerebral palsy are not present – for example, those with normal brain MRI, parental consanguinity and/or term delivery. The presence of additional phenotypes, including but not restricted to cognitive impairment, communication difficulties, retinopathy, growth restriction and progression of symptoms, should also trigger consideration of genomic testing in these patients.

There are over 80 genes in which variants are known to cause HSP. Traditionally, HSP was named by type as SPG (spastic paraplegia) and numbered sequentially, based on the order of genetic locus identification.

Inheritance can be autosomal dominant, autosomal recessive, X-linked or due to mitochondrial variation.

Dominant HSP

• Variants in the SPAST gene are the most common cause of autosomal dominant HSP (accounting for around 40% of cases), and most affected individuals and families have a pure (uncomplicated) pattern of involvement.
• Other genes associated with pure or complex HSP include KIF1A, KIF5A, REEP1 and ATL1. Variants in these genes are (relatively speaking) more commonly the cause of the condition in families in which an autosomal dominant pattern of inheritance has been identified.

Recessive HSP

• Biallelic SPG7 variants are an important cause of autosomal recessive HSP. Affected individuals may present with lower limb spasticity and have a pure (uncomplicated) course. Others may present with cerebellar ataxia as their first sign.
  • SPG7 is a mitochondrial-associated gene and the pattern of symptoms can reflect that. Other neurological or extra-neurological features may be present at diagnosis or develop later.
  • A small number of variants in SPG7 are relatively common in the UK population, and carrier status for SPG7-related conditions can be identified as an incidental finding when patients are investigated for HSP or ataxia. Carrier status is not associated with symptoms.
  • Heterozygous SPG7 common variants have been reported in association with several other neurological conditions; however, the relationship between them has not been confirmed. Presence of a single SPG7 variant is not considered to be diagnostic.
• In autosomal recessive forms of HSP, pathogenic variants in a number of other genes – including SPG11, SPG15, SACS and CYP7B1 – are more common, and are typically associated with a complex presentation or onset in childhood.

Note that this list is not exhaustive: many more HSP types and features occur. Careful attention to additional neurological and extra-neurological features can be helpful in the interpretation of any genetic variation identified through genomic testing.

• All modes of inheritance have been described in HSP.
• Autosomal dominant inheritance is the most common, reported in up to 75%–80% of HSP diagnoses. Non-penetrance of symptoms is reported in up to 10%–20% of those with an autosomal dominant HSP-related genetic variant. This may depend on the age at which they have been assessed, as age of symptom onset is highly variable.
  • Individuals affected by an autosomal dominant condition have one working copy of the gene, and one with a pathogenic variant.
  • The chance of a child inheriting the gene with the variant from an affected parent is 1 in 2 (50%).
• Autosomal recessive inheritance is reported in about 25%–30% of HSP diagnoses.
  • If both parents are carriers of an autosomal recessive condition, with each pregnancy there is a:
    • 1-in-4 (25%) chance of a child inheriting both gene copies with the pathogenic variant and therefore being affected;
    • 1-in-2 (50%) chance of a child inheriting one copy of the gene with the pathogenic variant and one normal copy, and therefore being a healthy carrier themselves; and
    • 1-in-4 (25%) chance of a child inheriting both normal copies and being neither affected nor a carrier.
• X-linked and mitochondrial HSPs are rare, reported in less than 1%–2% of diagnoses.
  • X-linked recessive conditions are usually only present in males.
  • Males with X-linked conditions cannot pass the variant on to their sons, but they always pass their affected X chromosome to their daughters. If the condition is recessive, their daughters will be carriers for the condition.
  • Female carriers of X-linked recessive conditions have a second, working copy of the gene and are therefore usually unaffected, or affected only mildly.
  • Sons of female carriers of X-linked recessive conditions have a 1-in-2 (50%) chance of being affected by the condition, and their daughters have a 1-in-2 (50%) chance of being carriers.
  • X-linked dominant conditions can affect both males and females.
• Approximately 40% of new diagnoses are sporadic.
• Due to the frequency of asymptomatic carriers, if examination of parents is normal, recessive inheritance is most likely. However, X-linked inheritance, autosomal dominant inheritance with reduced penetrance, mitochondrial inheritance with differing heteroplasmy and de novo variants should all be considered as possibilities prior to confirmatory testing.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.

• There is no specific treatment or cure for HSP.
• Management of children and adults with HSP is complex and should be delivered via a multidisciplinary team that includes neurologists, occupational therapists, physiotherapists and other specialty teams, depending on symptoms.
  • Medication to treat spasticity can be helpful in a proportion of individuals.
  • Physiotherapy does not slow disease progression, but can help to maintain function and avoid contractures.
  • Mobility aids (including wheelchairs) may be required by some, but not all, patients.
  • Driving may become challenging for individuals with HSP due to difficulty in controlling the pedals. Patients should be advised to contact the DVLA following their diagnosis.

For clinicians

• GeneReviews: Uncomplicated (pure) hereditary spastic paraplegia overview
  
• National Genomic Test Directory

References:

• Basu AP, Low K, Ratnaike T and others. ‘Genetic investigations in cerebral palsy‘. Developmental Medicine & Child Neurology 2025: volume 67, issue 2, pages 177–185. DOI: 10.1111/dmcn.16151
• Bellofatto M, De Michele G, Iovino A and others. ‘Management of hereditary spastic paraplegia: A systematic review of the literature‘. Frontiers in Neurology 2019: volume 10, article number 3. DOI: 10.3389/fneur.2019.00003
• Mackay-Sim A. ‘Hereditary spastic paraplegia: From genes, cells and networks to novel pathways for drug discovery‘. Brain Sciences 2021: volume 11, issue 3, page 403. DOI: 10.3390/brainsci11030403

For patients

• Contact: Familial spastic paraplegia
• The Hereditary Spastic Paraplegia Support Group