Hereditary spastic paraplegia (HSP) is a clinically and genetically heterogeneous disorder commonly characterized by progressive spasticity in the lower limbs, but not necessarily associated with motor deficit. HSP is sometimes referred to as Familial Spastic Paraplegia and Strumpell-Lorrain syndrome, and is independent of ethnicity. HSP is typically categorized into two classifications: uncomplicated and complicated, according to the presence of associated clinical features such as cerebellar symptoms, neuropathy, severe amyotrophy, retinal abnormalities, mental retardation, to mention only the most frequent presentations.^1-2 The most common form of HSP is uncomplicated (or pure), which refers to patients who present with lower extremity spasticity variably associated with weakness, deep sensory loss and bladder disturbance. Patients who present with these signs in addition to other neurological deficits are typically classified as complicated (or complex) HSP. It is believed that complicated HSP accounts for 10% of all cases, while uncomplicated HSP accounts for 90% of cases.³

HSP is categorized by both clinical presentation and inheritance pattern. Three genetic classifications of HSP have been identified: X-linked, autosomal recessive, and autosomal dominant. In cases with positive family histories, diagnosis of HSP may be more straightforward, but as autosomal dominant, autosomal recessive, and X-linked transmission have been reported, it is sometimes difficult to establish the pattern of inheritance. To date, nine loci have been mapped for dominant forms, six for recessive (including Charlevoix-Saguenay ataxia or ARSACS), and three for X-linked forms⁴ (Table 1). Five genes associated with HSP have been identified, L1CAM (SPG1), PLP (SPG2), sacsin (Charlevoix Saguenay ataxia), paraplegin (SPG7) and spastin (SPG4).⁵

Spastin/SPG4, the only gene known to cause the uncomplicated autosomal dominant form of HSP, was recently identified⁷ and has been reported in approximately 100 families. Importantly, Spastin/SPG4 appears to account for at least 40% of all the uncomplicated (pure) autosomal dominant forms,⁵ which makes molecular analyses for this form very informative. This is particularly important, as the phenotype of SPG4 is heterogeneous, and may not even be exclusively uncomplicated: cognitive disturbances and late-onset dementia have been associated with SPG4.^8-9 Phenotype-genotype association revealed that SPG4 patients could not be distinguished from other forms of HSP solely on the basis of the clinical features.⁸ Further, inheritance of Spastin/SPG4 is associated with both reduced penetrance (not all who inherit the mutation will develop the disease) and variable expressivity (affected family members may show different levels of severity). These two characteristics of SPG4/Spastin contribute to the wide clinical inter- and intra-familial heterogeneity.^10,11,12

The Spastin/SPG4 gene, like paraplegin — which is associated with autosomal recessive HSP — encodes a protein of the AAA family. These proteins are involved in a great variety of heterogeneous cellular processes, which makes the prediction of Spastin/SPG4's function very difficult. About 69 different mutations in Spastin/SPG4 have been described to date, adding extensive allelic heterogeneity to the clinical variability. The mutations appear to result in loss of function of the protein. Svenson and others (2001) proposed a model of haploinsufficiency where the function of spastin would be highly dependent on the concentration of functional versus mutant protein.¹³ This would account for the wide clinical heterogeneity.

The few existing neuropathological studies of uncomplicated HSP have shown isolated axonal degeneration of the distal parts of the longest motor and sensory axons, namely the crossed and uncrossed corticospinal tracts, the fasciculi gracili, and the spinocerebellar tracts.² However, the pathophysiology of these disorders is not yet understood.

The main symptom of autosomal dominant HSP is spasticity in the lower limbs, usually described by patients as stiffness of gait. The most common symptom in children is walking on their toes (dorsiflexion), or trembling of the knees and/or ankles. Age of onset is highly variable; HSP has been reported at infancy and as late as the eighth decade.¹⁴ Neurologic examinations of HSP patients reveal hyperreflexia in the lower limbs and sometimes in the upper limbs, extensor plantar responses, increased muscle tone while walking (whereas the tonus may be normal at rest). Impaired vibration sense in the ankle and mild distal dysmetria in the upper limbs may also be noted. Sphincter disturbance, mostly urinary urgency, but also urinary and anal incontinence, as well as disturbed sexual function, may also be reported. Symptoms worsen gradually, but tend to progress slower in early-onset compared to late-onset forms (after 35 years).¹⁴

Currently, it is believed that three in every 100,000 people are affected with HSP.³ Typically, the diagnosis of HSP is made clinically, and may be very difficult without a family history. Indeed, in non-familial cases, HSP is diagnosed by exclusion. It is extremely important to exclude: structural spinal cord disorders (particularly cervical/lumbal spondylosis); inflammatory, infectious and metabolic diseases (among others: multiple sclerosis, vitamin B12 deficiency, adrenoleukodystrophy) which may present as spastic paraparesis; as well as other neurodegenerative diseases which, at onset, may mimic HSP (e.g., ataxia with pyramidal signs, motor neuron disease or dopa-responsive dystonia). Typical investigation procedures may include cerebral, cervical and thoracolumbar MRI, CSF analysis, EMG, evoked potentials, vitamin B12, vitamin E and VLCFA assays.

HSP is a progressive and disabling disease for which there is no pharmaceutical treatment or cure. However, symptoms of HSP patients (spasticity, muscle weakness, urinary dysfunction) are often treated with oral and intrathecal baclofen and oral dantrolene, which have been reported to provide some improvement, especially for those diagnosed in the early stages of their illnesses. The management of increased muscle tone associated with spasticity can also be treated with pharmaceutical agents such as Zanaflex®.¹⁵ In addition to the neurochemical approach, other symptomatic treatments are available for HSP patients, such as physical therapies (strengthening, stretching, aerobic), surgical therapy, and alternative therapies including dietary regimes.

The genetic characterization of Spastin/SPG4 has allowed the recent development of molecular assays to detect mutations that cause approximately 40% of uncomplicated HSP.⁵ Though there is no known cure for HSP, as noted above, there is a reported association between early diagnosis and a better treatment response. In addition, a definitive molecular diagnosis is helpful to:

1. Alleviate the affected individual's anxiety, caused by having an undiagnosed disorder
2. Provide information regarding the prognosis for the individual's particular disease (i.e., whether or not children may remain ambulatory with the proper physical therapy)
3. Provide information regarding genetic counseling and family planning

Testing HSP patients for Spastin/SPG4 can make it possible to confirm diagnoses not only in patients with unambiguous symptoms, but also in those with complex symptoms. Asymptomatic testing may also be possible, though it may raise ethical issues similar to those raised by testing for other neurodegenerative disorders such as Huntington's disease.

A woman with no medical history consulted at the age of 40 years because of difficulty walking, due to "stiffness of both legs" that had begun insidiously several months earlier and appeared to be progressively increasing. Examination revealed increased muscle tone and a mild proximal motor deficit in the lower limbs, hyperreflexia in lower and upper limbs, with clonus of the ankles and a positive Hoffmann sign and extensor plantar reflex, and slightly impaired vibration sense in the ankles. She had no sphincter disturbances. Her parents were alive and healthy and so were her three children, but she mentioned a 79-year-old aunt with increasing walking difficulties that had worsened since the age of 63, who was now unable to walk at all. Thorough investigations excluded structural, inflammatory, metabolic and infectious etiologies. Because of the possibility of HSP, the asymptomatic family members were then examined. Brisk reflexes and an extensor plantar response were found in her 74-year-old mother and in her eldest sister, aged 54. Her other sister, aged 49, had no signs at examination. Two of her children were also examined. The eldest, a 24-year-old man, presented no signs, whereas the daughter, aged 20, had brisk reflexes and extensor plantar reflexes. Molecular analysis revealed a mutation in the Spastin/SPG4 gene in the patient, her mother, her two sisters, and the two children who had been examined. Further family studies revealed the presence of the mutation in the aunt and three of her six children, who already had mild walking difficulties with onset at 9, 30 and 45 years, respectively.

1 2 3 4 5 Your understanding of the disease or condition How you will diagnose patients with this disorder How you will explain the disease or condition to patients and their families None of the above Breaking news in genetics Dementias Epilepsy Mitochondrial disorders Movement disorders Multiple sclerosis Neuromuscular disorders Pediatric disorders

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