EPIDEMIOLOGY

HSP affects individuals of all ethnic groups and ancestries without particular ethnic predilection. The prevalence of HSP has been estimated in Ireland (1.27 per 100,000),⁵ Italy (2.7 per 100,000),⁶ and Spain (9.6 per 100,000).⁵

GENETIC CLASSIFICATION: MODE OF INHERITANCE AND HSP LOCUS

There are autosomal dominant, autosomal recessive, and X-linked forms of HSP, each of which is genetically heterogeneous: Many different, separate gene mutations cause clinically similar, often indistinguishable syndromes of lower extremity spastic weakness). HSP genetic loci are designated SPG (spastic gait) and numbered 1 through 28 in order of their discovery (Table 69-1).

TABLE 69-1 Hereditary Spastic Paraplegia (HSP) Loci

CLINICAL CLASSIFICATION: “UNCOMPLICATED” AND “COMPLICATED” HSP

Classifying HSP as complicated or uncomplicated is useful for research purposes because it enables analysis of homogenous cohorts. Uncomplicated HSP (also known as known as “nonsyndromic” or “pure” HSP) refers to the syndrome of insidiously progressive (or, in the case of early childhood onset, essentially nonprogressive) spastic leg weakness, frequently accompanied by urinary urgency and mildly impaired vibration sensation in the distal lower extremities. Complicated forms of HSP are inherited syndromes in which the predominant feature of spastic paraparesis is accompanied by other neurological or systemic abnormalities (such as mental retardation, ataxia, peripheral neuropathy, deafness, cataracts, and muscle atrophy), in addition to lower extremity spastic weakness.

Classifying HSP as uncomplicated or complicated is also important for prognosis. Families with “uncomplicated” HSP (e.g., HSP caused by SPG4/spastin gene mutation) are not at risk of having offspring with “complicated” HSP. The converse is not always true, however. Families with some forms of “complicated” HSP (e.g., SPG7 or SPG10 HSP caused by paraplegin or kinesin heavy chain [KIF5A] gene mutations, respectively)^7,8 may have offspring affected with either “uncomplicated” or “complicated” HSP.

Controversies in HSP classification arise as the knowledge of the HSPs expands. For example, seizures, cognitive impairment, and ataxia⁹ have been reported in patients with the most common form of dominantly inherited HSP (SPG4, caused by SPG4/spastin gene mutation), generally considered prototypical of uncomplicated HSP.^10–14 Further studies to determine the frequency of “extraspinal” features in otherwise uncomplicated HSP are needed.

NEUROPATHOLOGY: DISTAL AXON DEGENERATION INVOLVING LONGEST MOTOR AND SENSORY FIBERS IN THE CENTRAL NERVOUS SYSTEM

Postmortem studies of uncomplicated HSP reveal relatively selective axonal degeneration involving terminal portions of corticospinal tracts (maximal in the thoracolumbar region) and dorsal column fibers (maximal in cervicomedullary region).^15–20 Spinocerebellar fibers are involved to a lesser extent. Myelin loss is considered secondary to primary axonal degeneration. Decreased numbers of cortical motor neurons and anterior horn cells have been reported.^18,19 Peripheral nerves and dorsal root ganglia are normal in uncomplicated HSP.¹⁹

Axonal degeneration in uncomplicated HSP thus involves the distal ends of the longest motor (corticospinal tracts) and sensory (dorsal column) fibers in the central nervous system (CNS). In this regard, uncomplicated HSP may be considered a “CNS homologue” of Charcot-Marie-Tooth disease type 2, in which distal motor and sensory axon degeneration is limited to the peripheral nervous system. To extend this analogy, it is noteworthy that one type of HSP (SPG10) is caused by mutation in KIF5A,⁸ whereas mutations in another kinesin (KIF1B) cause Charcot-Marie-Tooth disease type 2A1.²¹

EMERGING CONCEPTS OF HSP PATHOGENESIS

The molecular mechanisms underlying axon degeneration for most types of HSP are poorly understood. Nonetheless, the discovery of many HSP genes is generating new concepts about the pathophysiology of HSPs.¹⁶ Thus far, 28 HSP loci and 11 HSP genes have been discovered (see Table 69-1). The functions of most of these HSP proteins have not been fully elaborated; however, as a group, HSP genes (and their respective proteins) appear highly diverse. This diversity of HSP genes (and their proteins) suggests that axonal degeneration in various genetic types of HSP may be caused by diverse, primary biochemical disturbances.²² A tentative biochemical classification of HSP is emerging. It is likely that these disparate biochemical disturbances converge into one or more common pathways.

SYMPTOMS: SPASTIC GAIT AND URINARY URGENCY

Developmental milestones are normal. Prenatal, perinatal, and postnatal periods are uneventful, and developmental milestones are attained normally in uncomplicated HSP. Although the age at which walking begins is not delayed, affected individuals’ persistent toe-walking may be the first sign of early-onset HSP.

The predominant symptom of HSP is abnormal gait caused by bilateral lower extremity spasticity and weakness. This may begin at any age, from infancy through old age. Spastic gait caused by HSP that begins in infancy may be essentially nonprogressive and mimic spastic diplegic cerebral palsy. In contrast, lower extremity spasticity that begins in later childhood through adulthood usually worsens insidiously. It is common for symptoms of lower extremity spasticity to be worse in cold weather, after exertion, and in the evening. Urinary urgency is common and is occasionally an early symptom.

NEUROLOGICAL EXAMINATION: UPPER MOTOR NEURON SIGNS IN THE LEGS; IMPAIRED VIBRATION SENSATION IN THE TOES

Examination of individuals with uncomplicated HSP reveals signs of upper motor neuron deficits in the lower extremities: bilateral, approximately symmetrical, lower extremity spasticity and weakness; pathological hyperreflexia; and extensor plantar responses (plantar responses are occasionally flexor in obviously affected patients). Spasticity is noted particularly in the hamstring, Achilles, and adductor tendons. Weakness is noted particularly in the iliopsoas, hamstring, and tibialis anterior muscles.

Although all patients with HSP have lower extremity spasticity, the degree of weakness is variable. Some patients have lower extremity spasticity but normal muscle strength. Although Harding^19,54 used the variable proportion of weakness and spasticity (along with age at symptom onset) to classify HSP as type I (greater spasticity than weakness) and type II (significant weakness), this classification is not widely used because estimates of the relative contributions of weakness versus spasticity are qualitative and because some genetic types of HSP may manifest as both type I and type II.

Vibration sensation in the toes is often mildly impaired in uncomplicated HSP. Distal lower extremity vibratory impairment may not manifest for several years, but when present, this is a helpful diagnostic sign. When not attributed to other disorders (such as peripheral neuropathy or cervical spondylosis), impaired vibration sensation in the toes helps to distinguish HSP’s motor (corticospinal tract) and sensory (dorsal column) patterns of involvement from primary lateral sclerosis (involvement of upper motor neurons with sparing of dorsal columns).⁵⁵ Although vibratory sense may be mildly impaired in HSP, severe dorsal column disturbance is not typical of uncomplicated HSP and would prompt a search for other disorders (including Friedreich’s ataxia, subacute combined degeneration, and tertiary syphilis).

SYNDROME VARIABILITY

Some genetic forms of HSP represent unique clinical syndromes (e.g., spastic paraplegia associated with distal muscle wasting caused by SPG20/spartin and SPG17/BSCL2 gene mutations that cause autosomal recessive Troyer’s syndrome and autosomal dominant Silver’s syndrome, respectively). Other genetic forms of HSP may be clinically indistinguishable (e.g., uncomplicated SPG4, SPG8, and SPG6 HSP).

Within a given genetic type of HSP (such as SPG4 HSP caused by spastin gene mutation), there may be significant clinical variability. Part of this variability may result from the effects of different mutations.⁵⁷ For example, whereas SPG4 HSP (caused by spastin mutation) is usually uncomplicated, ataxia in addition to spastic paraplegia has been reported in a family with SPG4 mutation GLN490Stop.⁹

Significant variability between affected patients who share the same HSP gene mutation reflects the influence of modifying genetic and possibly environmental factors. One source of modifying genes is polymorphisms in HSP genes themselves. Recently, Svenson and associates analyzed benign SPG4/spastin polymorphisms (S44L and P45Q) and showed that L44 and Q45 are each associated with a striking decrease in age at onset in the presence of the pathogenic mutations in SPG4/spastin’s adenine-adenine-adenine domain.⁵⁸

LABORATORY STUDIES, NEUROIMAGING, AND NEUROPHYSIOLOGICAL EVALUATION

These tests are useful for excluding other disorders and for characterizing the pattern of neurological involvement (and thus classifying HSP as uncomplicated or one of the complicated forms). Genetic testing, discussed later, is useful for confirming the clinical diagnosis of HSP.

Extensive neurodiagnostic evaluations are not always indicated for every affected patient in large families with definite HSP. The extent of neuroimaging and neurophysiological studies is guided by the certainty of the diagnosis in the patient’s first-degree relatives and the patient’s symptoms, neurological findings, and manner of progression. Extensive neurodiagnostic studies to rule out alternative or coexisting disorders are performed for any individual with atypical signs, symptoms, or clinical course.

Neuroimaging is important for ruling out alternative disorders, including multiple sclerosis, leukodystrophies, and structural abnormalities affecting the brain or spinal cord (see “Differential Diagnosis” section). Whereas brain magnetic resonance imaging in uncomplicated HSP is usually normal, those of complicated forms of HSP may reveal syndrome-specific abnormalities, such as thin corpus callosum in autosomal recessive SPG11 HSP (e.g., Casali et al⁶³) and cerebral or cerebellar abnormalities in autosomal recessive SPG7 HSP. Magnetic resonance imaging of the thoracic spinal cord often demonstrates atrophy in uncomplicated HSP.^9–11,64

Electromyographic nerve conduction studies usually yield normal results in uncomplicated HSP. Such studies are useful in ruling out other disorders (such as amyotrophic lateral sclerosis, Friedreich’s ataxia, Machado-Joseph disease). Such study results are usually normal in uncomplicated HSP.^51,52,65 Exceptions have been reported, however, including peripheral neuropathy in some patients with SPG4 HSP caused by spastin frameshift mutation 906delT⁵³ and axonal neuropathy associated with SPG3A HSP caused by atlastin mutation R495W.⁶⁶ Subclinical sensory neuropathy in otherwise uncomplicated HSP has been described.^67,68 Several types of complicated HSP are associated with peripheral neuropathy (see Table 69-1).

Somatosensory evoked potentials may demonstrate dorsal column impairment in uncomplicated HSP. Whereas somatosensory evoked potentials recorded from lower extremities often show delayed conduction, somatosensory evoked potentials recorded from the upper extremities are usually normal.^52,69–72 This finding may help distinguish patients with autosomal recessive, uncomplicated HSP (and those with uncomplicated spastic paraplegia who do not have a family history of the disorder) from patients in an early stage of primary lateral sclerosis (in whom vibration sensation and dorsal column function are normal).⁵⁵

Cortical evoked potentials provide a useful measurement of corticospinal tract conduction velocity. Studies of patients with uncomplicated HSP often reveal reduced conduction velocity and amplitude when cortical evoked potentials are recorded from the lower extremities.^73–76 In contrast, cortical evoked potentials recorded from cervical spinal segments are usually normal or show only mildly reduced conduction velocity.⁷⁵