Hereditary spastic paraplegia
Hereditary spastic paraplegia refers to a group of inherited disorders that cause stiffness and weakness in the legs. There may be additional examination findings in some affected people, depending on the underlying genetic cause.
Overview
Hereditary spastic paraplegia (HSP), otherwise known as familial spastic paraparesis, hereditary spastic paraplegia, Strümpell-Lorraine syndrome or (historically) spastic paraplegia, is a group of single gene disorders in which there is degeneration, or abnormal development, of the upper motor neurons in the pyramidal tract. This group is broadly divided into two subgroups: pure (uncomplicated) or complex, depending on the presence or absence of additional findings.
Clinical features
Pure (uncomplicated) form hereditary spastic paraplegia
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 beginning in later childhood are typically progressive with a variable course.
Complex hereditary spastic paraplegia
Complex HSPs share the same features as described above for pure HSP in addition to other 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.
Genomics
- There are over 80 genes that are known to cause HSP. Traditionally, HSP was named by type as SPG (spastic paraplegia) and numbered sequentially based upon the order of genetic locus identification.
- Inheritance can be autosomal dominant, autosomal recessive, X-linked or due to mitochondrial variation.
- 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) more commonly the cause of the condition in families where an autosomal dominant pattern of inheritance has been identified.
- 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 either spasticity or cerebellar ataxia as their first sign and go on to develop other neurological or extra-neurological features.
- SPG7 is a mitochondrial-associated gene and the pattern of symptoms can reflect that. 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. Those with carrier status are not expected to be symptomatic.
- In autosomal recessive forms of HSP, pathogenic variants in a number of other genes – including SPG11, SPG15, SACS and CYP7B1 – are relatively more common and typically associated with a complex presentation.
- This list is not exhaustive and many more HSP types and features occur. Careful attention to additional neurological and extra-neurological features can be very helpful to the interpretation of any genetic variation identified through genomic testing.
Inheritance and genomic counselling
- All modes of inheritance have been described in HSP.
- Autosomal dominant inheritance is most common and is reported in up to 75%–80% of HSP diagnoses. Non-penetrance of symptoms is reported in up to 10%–20% of autosomal dominant HSP-related gene carriers. This may depend on the age at which they have been assessed as age of onset of symptoms is highly variable.
- Autosomal recessive inheritance is reported in approximately 25%–30% of HSP diagnoses. X-linked and mitochondrial HSPs are rare, reported in less than 1%–2% of HSP diagnoses. 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. But X-linked inheritance, autosomal dominant inheritance with reduced penetrance, mitochondrial inheritance with differing heteroplasmy, or a de novo variant should all be considered as possibilities prior to confirmatory testing.
Management
- There is no specific treatment or cure for HSP.
- Management of children and adults with HSP is complex and should be delivered via a multi-disciplinary 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 people with HSP due to difficulty in controlling the pedals. Patients should be advised to contact the DVLA following their diagnosis.
Resources
For clinicians
References:
- 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, article number 403. DOI: 10.3390/brainsci11030403