J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.69.2.150 on 1 August 2000. Downloaded from 150 J Neurol Neurosurg Psychiatry 2000;69:150–160 REVIEW Hereditary spastic paraparesis: a review of new developments CJ McDermott, K White, K Bushby, PJ Shaw Hereditary spastic paraparesis (HSP) or the reditary spastic paraparesis will no doubt Strümpell-Lorrain syndrome is the name given provide a more useful and relevant classifi- to a heterogeneous group of inherited disorders cation. in which the main clinical feature is progressive lower limb spasticity. Before the advent of Epidemiology molecular genetic studies into these disorders, The prevalence of HSP varies in diVerent several classifications had been proposed, studies. Such variation is probably due to a based on the mode of inheritance, the age of combination of diVering diagnostic criteria, onset of symptoms, and the presence or other- variable epidemiological methodology, and wise of additional clinical features. Families geographical factors. Some studies in which with autosomal dominant, autosomal recessive, similar criteria and methods were employed and X-linked inheritance have been described. found the prevalance of HSP/100 000 to be 2.7 in Molise Italy, 4.3 in Valle d’Aosta Italy, and 10–12 Historical aspects 2.0 in Portugal. These studies employed the In 1880 Strümpell published what is consid- diagnostic criteria suggested by Harding and ered to be the first clear description of HSP.He utilised all health institutions and various reported a family in which two brothers were health care professionals in ascertaining cases aVected by spastic paraplegia. The father was from the specific region. Polo et al in 1991 said to be “a little lame”, suggesting autosomal reported a higher prevalence of 9.6/100 000 in 13 dominant transmission.1 Both Strümpell and Cantabria, Spain. In their report only hospital Lorrain added similar cases to the literature in records were used to ascertain cases, although subsequent years.23 Shortly after these land- many secondary cases were identified by mark descriptions, numerous reported cases of examining all at risk relatives. HSP appeared in the literature. However, http://jnnp.bmj.com/ Pratt, who considered the presence of addi- Clinical features tional neurological features to be incompatible PURE HEREDITARY SPASTIC PARAPARESIS with the original descriptions, labelled many of Criteria which have been suggested for the these as HSP plus syndromes.4 Early reviews of diagnosis of pure HSP are included in table 1. these and other cases attempted to identify Most patients present with diYculty walking or “pure” cases as had been described by Strüm- gait disturbance, noticed either by themselves pell. However, the definition of “pure” varied or a relative. In those with childhood onset, a 5–8 Department of among authors. It was Harding in 1981 who, delay in walking is not uncommon. Other on September 23, 2021 by guest. Protected copyright. Neurology, Ward 11, after detailed clinical evaluation of 22 families, symptoms include stiVness of legs, urinary dis- Royal Victoria suggested criteria for classifying HSP into pure turbance, and premature wear on footwear. Up Infirmary, Newcastle and complicated forms which have since been to 25% of aVected patients are asymptomatic, upon Tyne NE1 4LP, 9 UK adopted and are discussed below. Further emphasising the often benign nature of the dis- CJ McDermott subdivision of pure HSP was also suggested by ease and the importance of careful clinical PJ Shaw Harding based on the age of onset of the evaluation of families included in genetic stud- disease. It was found that families could be ies. The age of onset can be from infancy to the Department of Human separated into two groups, one with onset eighth decade.9 The marked interfamilial vari- Genetics K Bushby before 35 years (type I) and the other with ation in age of onset was one of the early point- onset after 35 years (type II). There seemed to ers to genetic heterogeneity in this condition. Department of be clinical diVerences between the groups, with This variation may also be partly due to Neurology, Manchester the type I patients having a slow and variable diYculty in ascertaining an exact date of onset, Royal Infirmary, course compared with the more rapidly evolv- particularly in older patients who have had the Manchester UK ing type II, in which muscle weakness, urinary disease for decades, or may reflect other as yet K White symptoms, and sensory loss were more unknown genetic or enviromental modifying 9 Correspondence to: marked. Neither of these classifications are factors. Dr CJ McDermott ideal, with many families not easily fitting the The cardinal abnormalities on examination [email protected] criteria. As is the case in other hereditary neu- of patients with pure HSP include spasticity, Received 31 August 1999 rodegenerative disorders, the unravelling of the hyperreflexia, and extensor plantar responses, Accepted 3 December 1999 molecular genetic mechanisms underlying he- with weakness of a pyramidal distribution in www.jnnp.com J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.69.2.150 on 1 August 2000. Downloaded from Hereditary spastic paraparesis 151 Table 1 Suggested diagnostic criteria for pure hereditary sphincter involvement is unusual in HSP, spastic paraparesis and clinical features that would alert the although Schetlens et al did report a family in clinician to possible alternative diagnoses which faecal urgency and incontinence were Clinical features present and Schwarz had earlier described a man similarly aZicted. In both reports urinary Obligatory Family history 23 24 Progressive gait disturbance symptoms were also present. Sexual dys- Spasticity of lower limbs function has only been described in one family. Hyperreflexia of lower limbs It occurred about 10–15 years after the onset of Extensor plantar responses Common Paresis of lower limbs disease, and so the patient’s reproductive Sphincter disturbances capacity was not dramatically aVected. The Mild dorsal column disturbance problem in aVected males consisted of erectile Pes cavus 25 Hyperreflexia of upper limbs failure with retained capacity to ejaculate. Mild terminal dysmetria Mild muscle wasting is well recognised al- Loss of ankle jerks though uncommon in HSP. When present it is Uncommon Paresis of upper limbs Distal amyotrophy found in distal muscles in the lower limbs, usu- Diagnostic alerts Paresis greater than spasticity ally the small muscles of the foot and tibialis Prominent ataxia Prominent amyotrophy anterior. It is more common in patients who 915 Prominent upper limb involvement have had the disease for over 10 years. If Peripheral neuropathy muscle wasting is prominent and present early Asymmetry Retinal pigmentation in the course of the disease, the diagnosis Extrapyramidal signs should be reconsidered. Upper limb involve- ment is relatively uncommon and usually con- sists of mild hyperreflexia, which may be the lower limbs. The lower limb spasticity is the present early in the disease. A trace of terminal prominent finding on examination, particularly dysmetria may also be found in the upper in the hamstrings, quadriceps, and ankles. This limbs, but more florid cerebellar signs are not pattern of hypertonicity is responsible for the seen. There are occasional reports of mild dis- classic gait with the aVected person demon- tal muscle atrophy but more marked involve- strating circumduction and toe walking. Mus- ment of the upper limbs with spasticity, cle weakness when present is seen in iliopsoas, weakness, or amyotrophy is not usually seen in tibialis anterior and, to a lesser extent, the pure HSP.9 hamstrings. A characteristic feature of HSP, Important negative findings on examination which has been stressed by several authors, is are normal cranial nerve function and no the marked discrepancy between the often evidence of corticobulbar tract involvement. severe spasticity and only mild or absent mus- The possible involvement of the autonomic cle weakness.814 This is demonstrated by the nervous system in HSP has not been systemati- patient with HSP who is wheelchair bound due cally studied, although Cartlidge and Bone, to spasticity but on manual muscle testing has when reporting on the finding of sphincter dis- normal power. turbance in patients with HSP considered Other features which some authors have involvement of the autonomic nervous system included under the umbrella of pure HSP in three patients and performed a battery of 17 include: mild sensory abnormalities in the autonomic function tests which were normal. http://jnnp.bmj.com/ lower limbs, absent ankle jerks, pes cavus, uri- The prognosis and severity of HSP varies nary symptoms, mild ataxia in the upper limbs, between families and, to a lesser extent, within and mild distal muscle wasting.9 15–18 This more the same family, although life expectancy is inclusive approach seems to be validated by the normal. Several authors have supported the multisystem involvement suggested by para- observation by Harding that in early onset HSP clinical investigations and neuropathological (<35 years), disease progression is slow with findings. Sensory impairment is seen in 10%- most patients remaining ambulant through 65% of cases of pure HSP and is found more most of their lives, and with only a small on September 23, 2021 by guest. Protected copyright. commonly, but not exclusively, in patients with proportion becoming confined to a wheelchair longstanding disease. It usually consists of in elderly life. This contrasts with many cases of diminished vibration sense and, less often, late onset HSP (>35 years), in whom disease diminished joint position sense in the extremi- progression can be rapid, with most patients ties of the lower limbs.91516 In most patients losing the ability to walk in their 60s and nerve conduction studies are normal.9151920 70s.91620 This suggests that the abnormalities found on examination are due to a central axonopathy COMPLICATED HEREDITARY SPASTIC PARAPARESIS rather than peripheral nerve involvement.