Hereditary Spastic Paraplegia

Introduction and Overview

This chapter focuses on the clinically and genetically heterogeneous neurodegenerative disorders known as hereditary spastic paraplegias (HSPs), emphasizing those that may begin in childhood. The primary feature of these diseases is bilateral leg spasticity when walking. ^, Specifically, this results from progressive pathology within axons in the corticospinal tracts and the dorsal columns of the spinal cord.

The evaluation of gait disturbances is a core diagnostic skill in neurology that involves careful history taking, neurological examination, and lesion localization. Many neurological conditions adversely affect motor function and interfere with gait. For example, diseases causing ataxia, dystonia, chorea, or parkinsonism can all affect gait. In this chapter, the emphasis is on inherited diseases producing progressively worsening spasticity, typically bilateral and symmetric, with childhood onset.

Spasticity affecting gait in children is most often acquired and generally does not fall under the classification of movement disorders. Most young children with a spastic gait have a static problem caused by complications of prematurity (germinal matrix hemorrhage, periventricular leukomalacia), pre- or peri-natal hypoxic ischemic encephalopathy, CNS infection, early life trauma, or congenital brain anomalies. ^, This constellation of etiologies often falls under the descriptive term, Cerebral Palsy (See Chapter 21 ). In the vast majority of these cases, neuroimaging will show brain abnormalities corresponding to the neurological deficits.

Acute or subacute clinical presentations of gait disorders are potential neurological emergencies and, due to their more rapid time course, are seldom in the differential diagnosis of HSPs. The history and comprehensive examination would lead to neuroanatomic localization, followed with decisions about diagnostic procedures such as spinal cord imaging.

Chronic, progressive clinical presentations of spasticity and abnormal gait support the possibility of an HSP, although other diagnoses should still be considered. The task is more straightforward in HSPs involving degeneration of long tracts of the spinal cord only, historically termed “pure HSP” or “uncomplicated HSP.” Complex or syndromic HSPs involve additional neurological manifestations such as cognitive impairment, epilepsy, dystonia, ataxia, muscle wasting, or polyneuropathy. Often there is overlap with complex HSPs also meeting criteria in classification systems used for other degenerative and metabolic diseases.

Definitions of Spasticity and Hypertonia

Hypertonia designates the observation by an examiner of elevated resistance to passive stretch across a joint when the patient is examined in the resting state. Spasticity is a form of hypertonia where the examiner perceives that the resistance increases at faster speed of stretch and differs depending on the direction of joint movement. There is often a “catch,” a point at which the resistance increases rapidly once the joint reaches a certain angle or the passive movement reaches a certain speed.

Clinical Characteristics—Phenomenology of Spastic Paraplegia in Children

Spasticity is nearly always associated with hyperreflexia, clonus, and extensor plantar response (Babinski sign). It is generally straightforward for a clinician to identify that a gait is abnormal. However, characterizing the specific difficulties requires experience and careful observation. Even with experience, based on visual or kinematic features, it can be difficult to differentiate spastic, dystonic, ataxic, orthopedic, antalgic, and functional gaits, particularly as movement disorder presentations may be mixed, combining multiple features. Therefore, it is instructive to consider how other primary phenomenologies can mimic spastic paraplegias as well as how to differentiate these clinically. It is also important to recognize that diseases classified as spastic paraplegias may also have pathophysiological involvement in other brain regions.

Localization and Pathophysiology

HSPs predominantly result from disease localizing to the longest corticospinal tract axons. Pathological studies show degeneration of terminal portions of the long descending corticospinal tracts and ascending dorsal columns. In simple HSPs, the constellation of findings, as discussed in the prior section, localize to the spinal cord. Sensory loss may be mild or absent, but there should not be sensory loss at a segmental level. Clinicians should consider the possibility of a lesion to the spinal cord and use a detailed neurological examination to estimate how likely an acquired spinal process is. In complex HSP, the neurological localization is more diffuse.

Many pathophysiological mechanisms have been implicated through careful study of the large number of causative genes. ^{, , , ,} The most prominent mechanisms involve disruptions in:

• 1.

  Endoplasmic reticulum shaping and organelle interactions

• 2.

  Lipid droplet metabolism

• 3.

  Axonal Transport

• 4.

  Endosomal trafficking

• 5.

  Mitochondrial function

• 6.

  Myelin production

The most common HSPs share involvement in genes encoding proteins that shape and stabilize the tubular endoplasmic reticulum which extends through axons. These proteins also make connections with adjacent mitochondria and organelles. Lipid droplets are intracellular lipid bodies that function in lipid metabolism and other processes in axons and elsewhere. They are surrounded by a phospholipid and protein monolayer which is disrupted in several HSPs. Axonal transport refers to cytoskeletal transport machinery including neuronal microtubules and motor proteins. Endosomal trafficking involves varied processes important for trophic signaling and cell survival including retrograde transport of endocytosed molecular “cargo” toward the cell body. ^, Ultimately, future treatments may emerge based on shared pathophysiological mechanisms. ^{, ,}

Diseases and Disorders

Although the number of identified genetic spastic paraplegias has surpassed 70, HSPs remain a rare diagnosis overall, particularly for pediatric neurologists. This is partly because many of these diseases progress slowly, and their overt symptoms are not noted until adulthood. Childhood onset may be suggested by lack of interest or skill in sports, for example, preceding a clinical presentation in adulthood.

As in other movement disorder disease categories, HSP phenotypes overlap with other categories, including spastic ataxias and spinocerebellar ataxias. The high number of HSPs identified has resulted in advocacy for a gene-based classification system (“HSP- gene ”), rather than the traditional consecutive numbering system (“SPGn”). Genetic discoveries have resulted in identification of individuals with shared genotypes but phenotypes that fit into different disease categories with “expanding spectrum of genotype X ” the rule rather than the exception. A common diagnostic strategy, based on high overlap between different genetic etiologies as well as high intragenic and intrafamilial variability, involves testing using the largest possible commercially available diagnostic panels for HSPs. Another suggested strategy is to test for the most common diagnoses first, within the observed inheritance pattern, and then expand the search if necessary. New mutations, progress in characterizing variants of unknown significance, and the possibility of benign variants mean that it remains important for clinicians to carefully consider specific features, even though the importance of that strategy for guiding targeted gene testing has diminished.

Careful history including age of onset and family history, plus neurological and general examinations should broadly guide the diagnostic evaluation. For example, having a particular inheritance pattern can limit the diagnostic possibilities. In children, the most common childhood onset, autosomal dominantly inherited spastic paraplegias are HSP- SPAST /SPG4, HSP- ATL1 /SPG3, and HSP- REEP1 /SPG31. The most common with autosomal recessive inheritance are HSP- KIAA1840 /SPG11and HSP- ZFYVE26 /SPG15, both of which have a complicated phenotype with cognitive impairment and thin corpus callosum, and HSP- CYP7B1 /SPG5. These are discussed in greater detail below.

The prognosis of childhood onset cases demonstrates some patterns corresponding to inheritance pattern. In a large European case series of children and adults with HSP, just under half of pediatric cases had autosomal dominant inheritance. Children with autosomal dominant HSPs had slower progression of disease than adults. However, children with autosomal recessive HSPs, which also have more complicated features such as cognitive impairment and ataxia, often have more rapid progression and severity.

In this chapter, the HSPs are presented by mode of inheritance. Clinical features, genetics, and pathophysiology are presented in the text for the more common, childhood-onset HSPs. More comprehensive lists are presented in tables.