What is Hereditary Spastic Paraplegia?
Hereditary Spastic Paraplegia (HSP) is a broad group of genetic, degenerative disorders characterised by impaired walking due to spasticity and weakness of the legs. The primary features of HSP are spasticity and weakness with the proportions varying from individual to individual. Symptoms generally worsen over time, though by how much and how fast is highly variable. Diagnosis is primarily by clinical neurological examination and testing as there are similarities with a number of other disorders. Genetic testing for HSP is now widely available. The detection rate of HSP mutations is in the 50–60% range with state-of-the-art next-generation whole exome sequencing.
Also known as
Hereditary Spastic Paraplegia (HSP) is also called Familial Spastic Paraplegia or Paraparesis (FSP) and Strumpell-Lorraine Syndrome, as well as other less commonly used names including Spastic Paraplegia, Hereditary Charcot-Disease, Spastic Spinal Paralysis, Diplegia Spinalis Progressiva, French Settlement Disease, Troyer syndrome, and Silver syndrome. Hereditary Spastic Paraplegia is the most common name used in the USA, UK and Australia.
Prevalence
The disease has been reported in nearly every country. Frequency estimates vary widely (from 0.5 to 12 people per 100,000 of population) and are an estimate or approximation as highly reliable data are not available. Based on what we consider to be the most applicable evidence on prevalence, a rate of 7.4/100,000 of population is applied. No significant differences in prevalence relating to gender have been found in most population studies, however in at least one larger study, prevalence in males was found to be slightly higher. Average age of symptom onset is 24 years old. There is also juvenile onset HSP which can show up in children of any age and tends to be associated with more severe symptoms as well as a larger range of symptoms, including affecting the upper limbs and sometimes sight, speech, swallowing and cognition.
Extrapolated to the Australian population, this translates to about 1,775 people with HSP, with over 500,000 globally. Every 3 weeks in Australia a child is born with an HSP mutation.
Being rare, it is a low profile disease globally, largely unknown in the general population, and receiving little, though significantly increasing, medical research attention over recent years. With current estimates of the number of rare diseases over 7,000 (80% of which are genetic) most rare disease organisations and support groups find themselves in similar situations to ours.
Worldwide, HSP is thought to be under-diagnosed as mild cases, which go undiagnosed, exist. Around 15% of people with HSP mutations, quoted in some places as high as 25%, never show symptoms. Misdiagnosis – commonly as Multiple Sclerosis, Cerebral Palsy or Primary Lateral Sclerosis – is not uncommon, while some HSP diagnoses prove to be incorrect. Overall, total numbers with HSP are likely to be underestimated.
Symptoms
HSP is most commonly characterised by muscle stiffness, spasm and weakness in the legs. Most frequent onset is in early adulthood (2nd to 4th decade) but can be as late as the 50’s or even later for some. A lesser onset peak is in children under 6 years old. Onset symptoms are commonly the occasional stumble, trip or fall while walking due to foot dragging and the toes catching. An awkward gait also develops. Some reflexes may become exaggerated and the arches of the feet may increase in height.
Whilst the HSP-associated genetic variant occurring in any particular extended family is very highly likely to be exactly the same, what is known as phenotypic variation can be huge*. Variation in the phenotype in a family may occur in factors such as:
- age of onset – in the one family with the same mutation, it is not uncommon to have examples of early onset in infancy or the teens of mild symptoms and late onset in adults in their 40s, 50s or even older
- symptom profile (gait features and characteristics; which muscles are weak and which muscles are spastic; the relativity of weakness vs spasticity overall for an individual – in some HSPers, muscle weakness is dominant, while in others spasticity is dominant; presence or absence of bladder and/or bowel continence issues, cognitive impairment, speech impairment, hearing impairment or abnormalities with the eyes)
- rate of disease progression/degeneration.
Examples of HSP gait
Here are two video examples of HSP gait – the first shows members of the HSP community in Queensland, Australia who were videoed walking during a gait pattern study of HSP. The second video is from Norway. The title roughly translates to ‘HSP movement patterns’.
Progression of the disease often results in the need for a cane or walker and more severe cases ultimately require a wheelchair. A wide variety of symptoms are observed across cases and over time given the degenerative nature of the disease. Now that so many gene mutations have been identified as causing HSP, it may explain some of the variation in both symptoms and severity between cases. The majority of individuals with HSP have a normal life expectancy.
Less common symptoms include urinary urgency. Even less commonly, the upper limbs and voice can be affected, particularly in severe, early onset cases. In rare, ‘complicated’ forms it can be accompanied by other neurological symptoms including optic neuropathy and retinopathy (eye diseases), dementia, cognitive impairment, ataxia (lack of muscle control), icthyosis (skin disorder), peripheral neuropathy (commonly tingling or numbness in hands or feet) and deafness. Severe pain sometimes also occurs. Many other diseases can also possibly complicate the symptoms of HSP if present.
* What are genotypes and phenotypes?
The distinction between genotype and phenotype is the difference between someone’s heredity, the set of genes they carry, i.e. their genotype, and what that set of genes produces, i.e. their physical and other characteristics or phenotype.
Physical characteristics (phenotype) are determined by the set of genes (genotype) someone has.
Physical characteristics include appearance, development and behaviour. Examples include height; eye, skin and hair colour; body shape and size. Phenotype also includes characteristics that can be observed or measured such as levels of hormones, blood type and behaviour.
Phenotype is determined as well as by environmental influences on the genes. Identical twins, who have identical genotypes, eventually develop some differences because each twin will encounter different environmental influences as they develop and age.