The diagnosis of hereditary spastic paraparesis (HSP) is based on the identification of a phenotype characterized as a slowly progressive, symmetric, spastic paraparesis in which the morbidity is largely related to impaired leg control rather than weakness, with or without recognition of other family members. The prevalence of dominantly inherited HSP, at least in Ireland, is estimated at 1.27/10⁵.¹ Like many of the disorders discussed in this text, the nosology of HSP is confounded by insights generated by molecular biology. The HSP phenotype is now recognized to result from mutations involving at least 50 different genetic loci and 18 identified genes (Table 7-1).² Despite the potential precision that a classification system based solely on gene location and gene product would provide, it remains an impractical bedside tool. Due to current limitations of genetic testing, a pragmatic classification system requires at least some consideration of clinical features. This chapter will attempt to provide a classification hybrid that addresses both clinical and genetic considerations (Table 7-1).

The concept of a hereditary disorder manifesting as spasticity of the lower extremities was initially championed by Seeligmüller, Strumpell, and Lorrain in the last quarter of the 19th century. It was envisioned as a singular entity with phenotypic variation.³ The classification system still utilized today was initially promoted by Anita Harding in 1981.⁴ She proposed a dominantly inherited HSP dichotomy in which type I was considered to reflect an early-onset phenotype with predominant, if not exclusive, upper motor neuron (UMN) features. In contrast, type II HSP referred to those with late onset in which weakness and presumed lower motor neuron (LMN) involvement overshadowed the UMN signs. In 1983, her classification system was expanded to encompass complicated as well as uncomplicated forms of the syndrome.⁵ Uncomplicated HSP still refers to a syndrome of spastic paraparesis in which cavus foot deformities and mild vibratory sense loss may occur as the only other associated features. Complicated HSP is defined by involvement of additional neurological and occasionally nonneurological systems as described below (Table 7-1).

In 1996, the nosology of HSP became at the same time both enhanced and complicated with discovery of the first disease producing mutation.³ The HSPs are currently genotypically catalogued by a numerical system based on the order of individual gene discovery. Each number is prefaced by the acronym SPG which stands for spastic paraplegia gene (Table 7-1). Unlike other classification systems, subheadings distinguishing dominant from other inheritance patterns are not utilized.

In virtually every case, the presenting symptoms relate to lower extremity spasticity which has a symmetric or near symmetric distribution. Symptom onset is typically recognized in the second or third decade but may become manifest as early as the first or as late as the seventh decade of life. Patients lose the ability to run or hop early in their course due to increased extensor tone in the lower extremities. Consequently the ability to fully flex the hip and the knee is impaired resulting in reduced stride length and difficulty running. Patients will describe dragging and stiffness of the legs and a tendency to trip on uneven ground. When observed, the legs may be noted to scissor or cross over each other due to increased adductor tone (Fig. 7-1). Circumduction (a rotational rather than linear advancement of the legs) is common in a compensatory attempt to avoid tripping. This risk results from a leg that is tonically extended at the hip and knee and from a tonic foot posture of inversion and plantar flexion (equinovarus posture). High-arched feet and hammer toe deformity are common but not invariable features of the illness. They are more likely to occur with disease onset in childhood at a time when the metatarsals remain malleable and vulnerable to the imbalance of forces produced by disproportionate involvement of specific muscle groups (Fig. 7-2).

HSP morbidity results in large part from the increased lower extremity extensor tone impairing lower extremity coordination. Lower motor neuron involvement may occur but is typically overshadowed by spasticity. If weakness occurs, it typically does so in a UMN pattern, with hip flexors, knee flexors, and foot dorsiflexors being typically weaker than their respective antagonists. Hyperreflexia of the lower extremities is universal, almost always accompanied by extensor plantar responses. Hyperreflexia of the upper extremities with Hoffman’s signs and reflex spread is common as well. Significant loss of upper extremity function associated with weakness, increased tone, or impaired coordination occurs infrequently in most genotypes and should lead to consideration of an alternative diagnosis.

Mild posterior column involvement may occur with vibratory sense loss and occasionally position sense loss in the toes. Rarely is it severe enough to produce significant sensory ataxia. A strikingly positive Romberg sign should once again lead to consideration of an alternative diagnosis. Urinary frequency, urgency, and urgency incontinence are common symptoms even in uncomplicated disease. Rectal urgency and incontinence and sexual dysfunction are uncommon.

There is a wide range of associated neurological and nonneurological symptoms that can occur in complicated forms of the disease. Recognition of these additional features may aid in the identification of a specific genotype (Table 7-1). Some of the more common associated features are amyotrophy of distal limb muscles that may result from either a motor neuronopathy (SPG3A, 4, 5, 9, 10, 11, 14, 15, 17, 20, 26, 30, 38, 39, 43, 41) or peripheral neuropathy (SPG2, 5, 25, 27, 30, 31, 36, the SPOAN syndrome, and the one recognized mitochondrial mutation producing a SPG phenotype).^2,6 Distal amyotrophy may initially affect either the hands or feet, hand-wasting and spastic paraparesis being referred to as Silver syndrome.^7,8 Ataxia, nystagmus, dysarthria, and other features of cerebellar dysfunction occur less frequently (SPG21). Extrapyramidal manifestations are relatively uncommon as well (SPG21, 35).^2,6,9,10 Cognitive changes may manifest as either mental retardation or dementia (SPG4, 11, 14, 15, 18, 21, 26, 27, 32, 35, 44, 45, 46, 47). A thin corpus callosum is a relatively common feature (SPG11, 18, 21, 35, 46, 47).^2,6,10,11 Seizures, deafness, cataracts, ichthyosis, ophthalmoparesis, ocular apraxia, retinal pigmentary degeneration, and optic atrophy with visual loss are some of the other potential associated features.^2,6,12