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Hereditary Spastic Paraplegia: Clinical Principles and Genetic Advances John K. Fink, MD1 1 Department of Neurology, University of Michigan; Ann Arbor

Veterans Affairs Medical Center, Ann Arbor, Michigan

Address for correspondence J.K. Fink, MD, 5013 Taubman Biomedical Science Research Building, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200 (e-mail: jkfi[email protected]).

Abstract Keywords

► ► ► ►

spastic paraplegia hereditary spinal cord genetic

Hereditary spastic paraplegia (HSP) refers to inherited disorders in which spastic gait is either the only feature or is a major syndrome feature. There are more than 70 genetic types of HSP. Neuropathological studies, albeit limited to only a few genetic types of HSP, have identified axon degeneration involving the distal ends of the corticospinal tracts and fasciculus gracilis fibers. In this review, the author highlights the clinical and genetic features of HSP.

Clinical Features, Differential Diagnosis, and Management Spastic gait, lower extremity hyperreflexia, and some degree of spasticity are present in all subjects with hereditary spastic paraplegia (HSP). Beyond these features, marked clinical variability makes it difficult to make generalizations that apply to all HSP types and patients. Age-of-symptom onset ranges from infancy through late adulthood. Gait disturbance ranges from a subtle, nondisabling, forward-shifted heel strike to frank spastic paraplegia requiring wheelchair dependence. Lower extremity spasticity (particularly affecting hamstrings, quadriceps, gastrocnemius-soleus, and adductor muscles) may be mild or severe and associated with tendon contractures. Lower extremity spasticity is often but not always accompanied by lower extremity weakness. When present, lower extremity weakness affects primarily iliopsoas, hamstrings, and tibialis anterior muscles, and ranges from mild to severe. Although symptoms may begin asymmetrically, over time (within a couple of years) both legs are similarly affected. Urinary bladder disturbance is frequent, occasionally an early symptom, and typically manifests as urinary urgency and less commonly as urinary retention. External sphincter disturbance may impair defecation. Mild reduction of distal vibratory sensation is a common, but not constant feature. Subtly decreased vibration sensation in the toes, in the absence of evidence suggesting peripheral neuropathy, suggests underlying mild dorsal column involvement, a common feature of HSP.

Issue Theme Neurogenetics; Guest Editor, Ali Fatemi, MD

Inherited lower extremity spasticity and weakness (uncomplicated HSP) may be associated with additional neurologic abnormalities (complicated HSP), which in various types of HSP, may include nonprogressive intellectual disability, dementia, peripheral neuropathy, ataxia, extrapyramidal disturbance, distal muscle wasting, cataracts, or optic neuropathy. Marked clinical variability often occurs between different genetic types of HSP, as well as between individuals with the same genetic type of HSP (e.g., not all patients with SPG7 HSP have ataxia and not all patients with SPG11 HSP have cognitive impairment). Furthermore, there may be significant variability in the age-of-symptom onset, severity, and presence of additional neurologic features between individuals in the same family who share precisely the same HSP gene mutation. Although some genetic types of HSP usually cause uncomplicated syndromes (e.g., SPG4 or SPG3A HSP) and other genetic types usually cause complicated syndromes (e.g., SPG7 or SPG11), there is wide variability, with many genetic types manifesting as either complicated or uncomplicated HSP syndromes. Indeed, complicated and uncomplicated HSP syndromes may occur in a given family in which affected family members share the same gene mutation (but presumably differ in their modifying genes). The course of HSP is also variable. When symptoms begin in early childhood, they may not worsen significantly over many years and decades. Such patients may resemble those with spastic diplegic cerebral palsy. Later-onset symptoms generally worsen slowly over many years. Anecdotal

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DOI http://dx.doi.org/ 10.1055/s-0034-1386767. ISSN 0271-8235.

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Semin Neurol 2014;34:293–305.

Hereditary Spastic Paraplegia: Clinical Principles and Genetic Advances experience indicates that after several years of slow, steady worsening of gait, many individuals appear to reach a clinical plateau, after which the rate of worsening is similar to that attributable to age and the degree of exercise. Onset and progression of symptoms over days to months is not typical of HSP and suggests an additional or alternative disorder. Collectively and individually, various genetic types of HSP exhibit extremely wide clinical variability, including age-ofsymptom onset, severity, course, presence and degree of weakness, and occurrence of other neurologic signs. This variability provides important insights into the molecular mechanisms that underlie HSP. Clinical variation between patients with different genetic types of HSP indicates that the degree and selectivity with which corticospinal tracts (and dorsal column fibers to a lesser extent) are impaired is related to the underlying molecular abnormality. Similarly, variation in clinical signs between patients with the same genetic type of HSP (e.g., SPG4) who differ in the precise mutation location (genotype–phenotype correlation) indicates that the degree and selectivity of corticospinal tract impairment is related to either the amount of residual activity of the involved HSP protein, to disturbance in specific functional domains of this protein, or to both. Significant clinical variability between members of the same family who share the same HSP gene mutation indicates the importance of modifying factors, including other genes and potentially nongenetic factors such as exercise, diet, and cardiovascular fitness. Among the more than 70 genetic types of HSP, only a few have been described in more than a dozen families. For example, the range of clinical features of SPG3A, SPG4, and SPG11, among the most common types of HSP, is relatively well understood because many patients with these relatively common types of HSP have been described. In contrast, the majority of genetic types of HSP have been described in only one to several families. The range of clinical features for these genetic types of HSP is not well known, nor is it known if features reported from index cases depend on the particular mutation(s) identified.

Differential Diagnosis Differential diagnosis of HSP (►Table 1) includes structural abnormalities of the brain and spinal cord (e.g., cervical spondylosis leading to compressive cervical myelopathy and tethered cord syndrome); leukodystrophy (Krabbe disease, metachromatic leukodystrophy, adrenomyeloneuropathy, B12 deficiency, primary progressive multiple sclerosis), infectious disorders (e.g., human immunodeficiency virus and tropical spastic paraplegia due to HTLV1), other motor neuron disorders (amyotrophic lateral sclerosis [ALS] and primary lateral sclerosis in particular), other degenerative neurologic disorders whose symptoms include upper motor neuron impairment (e.g., Friedreich ataxia, spinocerebellar ataxia type 3, spinal cord arteriovenous malformations), and environmental toxins (e.g., hypocupremia from denture cream-related hyperzincemia). The differential diagnosis of spasticity depends on the ageof-symptom onset, course of the disorder (relatively static, worsening over months, worsening over many years), the Seminars in Neurology

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occurrence of the disorder in first-degree relatives, and importantly, on the presence or absence of additional neurologic deficits. As noted above, HSP onset after early childhood is associated with insidious worsening. As a “clinical pearl,” HSP is unlikely if patients can date the onset of symptoms to a particular month or event (e.g., “symptoms began during Labor Day picnic”), or if there is marked worsening within 6 to 12 months. Symptom onset and progression in HSP are so insidious that typically it is difficult to date symptom onset more accurately than to a 1- to 3-year interval. Diagnostic difficulties arise primarily when (1) there is no family history of similar disorder and nongenetic conditions cannot be excluded; (2) genetic testing cannot be afforded or is incomplete; (3) there are coexistent conditions (e.g., diabetic neuropathy, cervical myelopathy, or prematurity); (4) there are significant additional neurologic or neuroimaging abnormalities (such as evidence of central nervous system [CNS] white matter disturbance); and (5) when symptom duration is too short (e.g., < 5 years) to exclude emergence of syndrome-specific signs of other disorders (e.g., lower motor neuron signs indicating ALS or emergence of corticobulbar muscle or upper extremity involvement in primary lateral sclerosis).

Genetic Testing Analysis of large panels (e.g., 53 genes) by next-generation sequencing permits confirmation of diagnosis in most patients with a family history of affected first-degree relatives. Nonetheless, next-generation sequencing of panels of HSP genes is not complete, in part because it does not include all HSP genes, and because it may not effectively identify all gene copy variants, including exon deletions (known to cause 10% of SPG4 HSP). In practice, it is recommended to begin testing with a large panel of HSP genes by next-generation sequencing, and if no mutation is identified, for dominantly inherited patients, to specifically follow-up with SPG4 exon deletion analysis. Exon deletion analysis for selected other HSP genes is performed in research laboratories and is not widely available. Genetic testing is most useful to confirm a clinical diagnosis of HSP. It is important that genetic testing results be interpreted in light of the clinical context. Clinical diagnosis of HSP can be confirmed by the identification of a potentially pathogenic HSP gene variation in a patient with signs and symptoms consistent with HSP and for whom alternative or coexisting disorders have been excluded. Much less diagnostic certainty is provided when genetic testing identifies an HSP gene variant of unknown clinical significance, or when a potentially pathogenic HSP gene variation is discovered in a patient whose clinical syndrome does not conform to HSP. Genetic test results for HSP can be applied to genetic counseling and prenatal and preimplantation genetic diagnosis. This application of HSP gene test results must consider the mode of inheritance, degree of genetic penetrance, and strength of evidence indicating the likely pathogenicity of the identified HSP gene variation. Although genetic penetrance is age-dependent and high (estimated to be 90% for SPG3A and SPG4 HSP), genetic penetrance is not well established for

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Category

Example

Recommended diagnostic studies for patients with progressive spastic paraparesis

Structural abnormality of the brain and spinal cord

Tethered cord syndrome; spinal cord compression from degenerative spondylosis or neoplasm

MRI of entire neuroaxis in children and brain; cervical and thoracic spinal cord in adults

Leukodystrophy

B12 deficiency, multiple sclerosis, adrenomyeloneuropathy, Krabbe disease, metachromatic leukodystrophy, mitochondrial disorder

B12, methylmalonic acid, serum very long chain fatty acids, β galactosidase, arylsulfatase, serum lactate and pyruvate; cerebrospinal fluid analysis for immunoglobulin index and oligoclonal bands as indicated by clinical and neuroimaging findings

Infectious diseases

Tropical spastic paraplegia due to HTLV1 infection (which may be familial) and pachymeningitis from tertiary syphilis

HIV, HTLV1, syphilis serology

Other motor neuron disorders

Amyotrophic lateral sclerosis, primary lateral sclerosis, distal hereditary motor neuropathy

Serial electromyography (to exclude amyotrophic lateral sclerosis) is recommended for the first 3–5 y of adult-onset progressive spastic paraparesis

Other degenerative neurologic disorders

Friedreich ataxia (which may have spasticity rather than areflexia)22 spinocerebellar ataxia type III (Machado-Joseph disease), spinal cord arteriovenous malformation

Friedreich ataxia and SCA3 gene analysis

Environmental toxins

Hypocupremia (e.g., from denture cream-related hyperzincemia), lathyrism, konzo, cycad poisoning, and organophosphate-induced delayed neuropathy

Serum copper, serum zinc

Other

Spastic diplegic cerebral palsy, dopa-responsive dystonia, stiff person syndrome

A 2-wk trial of low-dose levodopa-carbidopa is generally recommended for children with the appearance of spastic gait.

Abbreviations: HIV, human immunodeficiency virus; MRI, magnetic resonance imaging. Source: Modified from Fink JK. The hereditary spastic paraplegias. In: Rosenberg R, ed. Molecular and Genetic Basis of Neurologic and Psychiatric Disease. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014.

most types of HSP. Genetic counseling must also note that at least two forms of HSP (SPG7/paraplegin1–3 and SPG724) can be transmitted as either an autosomal recessive or an autosomal dominant disorder.

Management Presently, there are no specific treatments to prevent, halt, or reverse the pathologic processes that underlie HSP. Many (but not all) HSP patients who engage in regular physical exercise report improvement in endurance, improved walking ability, and less pain. Based on this anecdotal experience, we recommend that patients with HSP participate in a program of exercise every day that changes over time and that is sustained indefinitely. We recommend that patients consult a physiatrist and physical therapist to design a program to strengthen (particularly core muscles, iliopsoas, hamstring, and tibialis anterior muscles) and facilitate stretching, balance, and speed. Complex, context-based exercises (such as walking in a pool, sit-stand-sit, and stair climbing) are rec-

ommended in addition to isolated muscle strengthening and strengthening. Medications to reduce spasticity (such as Lioresal, Dantrolene) may be helpful in patients who do not have marked weakness. Intrathecal Lioresal has benefited selected patients (those without marked weakness for whom trial doses have unequivocally demonstrated improved ability to walk). Botulinum toxin may be useful to reduce selected spasticity, particularly in the hamstrings and adductors. Treatment of urinary urgency (e.g., with oxybutynin) is often needed. Ankle-foot-orthotic devices may help reduce toe-dragging.

Neuropathology Post mortem studies in HSP demonstrate axon degeneration involving lateral corticospinal tracts, and consistently but to a much lesser extent, fasciculus gracilis fibers. Degeneration is most severe at the distal ends of these axons (in the thoracic spinal cord for corticospinal tracts and in the cervicomedullary region for fasciculus gracilis fibers).5–12 Spinal cord axon Seminars in Neurology

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Table 1 Differential diagnosis of hereditary spastic paraplegia

Hereditary Spastic Paraplegia: Clinical Principles and Genetic Advances

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Table 2 Genetic types of hereditary spastic paraplegia, their encoded proteins, and clinical syndromes Autosomal recessive HSP SPG5 270800

CYP7B1

Uncomplicated or complicated by axonal neuropathy, distal or generalized muscle atrophy, and white matter abnormalities on MRI

23–29

SPG7 602783

Paraplegin

Uncomplicated or complicated: Variably associated with mitochondrial abnormalities on skeletal muscle biopsy and dysarthria, dysphagia, optic disc pallor, axonal neuropathy, and evidence of vascular lesions, cerebellar atrophy, or cerebral atrophy on cranial MRI

30,31

SPG11 604360

Spatacsin (KIAA1840)

Uncomplicated or complicated: Spastic paraplegia variably associated with thin corpus callosum, mental retardation, upper extremity weakness, dysarthria, and nystagmus; may have Kjellin syndrome: Childhood-onset, progressive spastic paraplegia accompanied by pigmentary retinopathy, mental retardation, dysarthria, dementia, and distal muscle atrophy; juvenile, slowly progressive ALS reported in subjects with SPG11 HSP; 50% of autosomal recessive HSP is considered to be SPG11

32,33

SPG14 605229

Unknown

Single consanguineous Italian family, 3 affected subjects, onset age 30 y; Complicated spastic paraplegia with mental retardation and distal motor neuropathy (sural nerve biopsy was normal)

34

SPG15 270700

Spastizin/ZFYVE26

Complicated: Spastic paraplegia variably associated with associated with pigmented maculopathy, distal amyotrophy, dysarthria, mental retardation, and further intellectual deterioration (Kjellin syndrome)

35,36

SPG18 611225

Endoplasmic reticulum, lipid raft associated protein 2 (ERLIN2)

Two families described with spastic paraplegia complicated by mental retardation and thin corpus callosum. ERLIN2 mutations also identified in patients with juvenile primary lateral sclerosis

37,38 39

SPG20 607211

Spartin

Complicated: Spastic paraplegia associated with distal muscle wasting (Troyer syndrome)

40–44

SPG21 248900

Maspardin

Complicated: Spastic paraplegia associated with dementia, cerebellar and extrapyramidal signs, thin corpus callosum, and white matter abnormalities (Mast syndrome)

45

SPG23 270750

Unknown

Complicated: Childhood-onset HSP associated with skin pigment abnormality (vitiligo), premature graying, characteristic facies; Lison syndrome

46

SPG24 607584

Unknown

Complicated: Childhood onset HSP variably complicated by spastic dysarthria and pseudobulbar signs

47

SPG25 608220

Unknown

Consanguineous Italian family, 4 subjects with adult-onset (30–46 y) back and neck pain related to disk herniation and spastic paraplegia; surgical correction of disk herniation ameliorated pain and reduced spastic paraplegia. Peripheral neuropathy also present.

48

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SPG26 609195

Unknown

Single consanguineous Bedouin family with 5 affected subjects. Complicated: Childhood onset (between 7 and 8 y), progressive spastic paraparesis with dysarthria and distal amyotrophy in both upper and lower limbs; nerve conduction studies were normal; mild intellectual impairment, normal brain MRI

49

SPG27 609041

Unknown

Complicated or uncomplicated HSP. Two families described. In 1 family (7 affected subjects) uncomplicated spastic paraplegia began between ages 25 and 45 y. In the second family (3 subjects described), the disorder began in childhood and included spastic paraplegia, ataxia, dysarthria; mental retardation, sensorimotor polyneuropathy, facial dysmorphism, and short stature

50,51

SPG28 609340

DDHD1

Uncomplicated: Pure spastic paraplegia, onset in infancy, childhood, or adolescence, either as an uncomplicated spastic paraplegia syndrome; or variable associated with axonal neuropathy, distal sensory loss, and cerebellar eye movement disturbance

52,53

SPG29 609727

Unknown

Uncomplicated HSP, childhood onset

SPG30 610357

KIF1A

Complicated: Spastic paraplegia, distal wasting, saccadic ocular pursuit, peripheral neuropathy, mild cerebellar signs

SPG32 611252

Unknown

Mild mental retardation, brainstem dysraphia, clinically asymptomatic cerebellar atrophy

SPG35 612319

Fatty acid 2-hydroxylase (FA2H)

Childhood onset (6–11 y), spastic paraplegia with extrapyramidal features, progressive dysarthria, dementia, seizures. Brain white matter abnormalities and brain iron accumulation; an Omani and a Pakistani kindred reported.

55–57

SPG39 612020

Neuropathy target esterase (NTE)

Complicated: Spastic paraplegia associated with wasting of distal upper and lower extremity muscles

58

SPG43 615043

C19orf12

Two sisters from Mali, symptom onset 7 and 12 y, progressive spastic paraplegia with atrophy of intrinsic hand muscles and dysarthria (1 sister)

59

SPG44 613206

Gap junction protein GJA12/GJC2, also known as connexin47 (Cx47)

Allelic with Pelizeaus-Merzbacher-like disease (PMLD, early-onset dysmyelinating disorder with nystagmus, psychomotor delay, progressive spasticity, ataxia). GJA/GJC2 mutation I33M causes a milder phenotype: Late-onset (first and second decades), cognitive impairment, slowly progressive, spastic paraplegia, dysarthria, and upper extremity involvement. MRI and MR spectroscopy imaging consistent with a hypomyelinating leukoencephalopathy

60

SPG45 613162

Unknown

Single consanguineous kindred from Turkey, 5 subjects described: Affected subjects had mental retardation, infantile-onset lower extremity spasticity and contractures, 1 subject with optic atrophy, 2 subjects with pendular nystagmus; MRI in 1 subject was normal.

61

SPG46 614409

Unknown

Dementia, congenital cataract, ataxia, thin corpus callosum

62

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Hereditary Spastic Paraplegia: Clinical Principles and Genetic Advances

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SPG47 614066

AB4B1

Two affected siblings from consanguineous Arabic family with Early-childhood-onset slowly progressive spastic paraparesis, mental retardation, and seizures; 1 subject had ventriculomegaly; the other subject had thin corpus callosum and periventricular white matter abnormalities

63

SPG48 613647

KIAA0415

Analysis of KIAA0415 gene in 166 unrelated spastic paraplegia subjects (38 recessive, 64 dominant, 64 “apparently sporadic”) and control subjects revealed homozygous mutation in 2 siblings with late-onset (6th decade) uncomplicated spastic paraplegia; and heterozygous mutation in 1 subject with apparently sporadic spastic paraplegia.

64

SPG49 615031

TECPR2

Five subjects from three apparently unrelated families (Jewish Bukharian ancestry) had infantile-onset hypotonia, developmental delay with severe cognitive impairment, dysmorphic features (short stature, brady-microcephaly, oral, facial, dental, nuchal abnormalities). Spastic, ataxic, rigid gait developed in childhood; additional features included gastroesophageal reflux, recurrent apneic episodes, mild dysmorphic features. Two subjects had epilepsy and MRI of 2 subjects showed thin corpus callosum and cerebellar atrophy.

65

SPG50 612936

AP4M1

Five subjects from one consanguineous Moroccan family exhibited infantile-onset, nonprogressive spastic quadriplegic with severe cognitive impairment; variably associated with adducted thumbs. Ventriculomegaly, white matter abnormalities, and variable cerebellar atrophy noted on neuroimaging. Neuroaxonal abnormalities, gliosis, and reduced myelin noted on postmortem examination.

66,67

SPG51 613744

AP4E1

Two siblings from a consanguineous Palestinian Jordanian family and 2 siblings from a consanguineous Syrian family exhibited microcephaly, hypotonia, psychomotor delay, spastic tetraplegia, marked cognitive impairment with severe language impairment, and facial dysmorphic features; abnormal MRI (showing atrophy and diffuse white matter loss). Seizures were variably present.

67–69

SPG52 614067

AP4S1

Five subjects from a consanguineous Syrian kindred exhibited delayed motor development and severe cognitive impairment. Neonatal hypotonia was followed by progressive spastic gait with contractures. Dysmorphic features included short stature, microcephaly, and facial abnormalities

69–71

SPG53 614898

VSP37A

Nine subjects from two Arab Moslem families exhibited developmental delay, progressive lower extremity spasticity, and subsequently progressive upper extremity involvement associated with skeletal dysmorphism (kyphosis and pectus carinatum); mild-to-moderate cognitive impairment; and variable hypertrichosis and impaired vibration sensation.

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SPG54 615033

DDHD2

Affected subjects reported from 4 unrelated families exhibited psychomotor delay, cognitive impairment, progressive spasticity (onset before age 2 y), thin corpus callosum, and periventricular white matter abnormalities. Additional clinical features include foot contractures, dysarthria, dysphagia, strabismus, and optic hypoplasia.

37,73

SPG55 615035

C12ORF65

Two Japanese brothers from consanguineous parents exhibited early-onset spastic paraplegia variably associated with reduced visual acuity (with central scotoma and optic atrophy), reduced upper extremity strength and dexterity, lower extremity muscle atrophy, and motor sensory neuropathy.

74 75

SPG56 615030

CYP2U1

Five unrelated families were reported with earlychildhood-onset spastic paraplegia, variable upper extremity involvement, upper extremity dystonia, cognitive impairment, thin corpus callosum, brain white matter disturbance, axonal neuropathy, and basal ganglia calcifications.

53

SPG57 602490

Trk-fused gene (TFG)

Two siblings with early-childhood onset spastic paraplegia, optic atrophy (at age 2.5 y), and wasting of hand and leg muscles due to axonal-demyelinating sensorimotor neuropathy; normal intelligence

76

SPG58 611302

KIF1C

Spastic-ataxia. Subjects are described from 4, unrelated consanguineous kindreds. Following normal development, progressive ataxia began between ages 1 and 17 y and was associated with lower extremity spasticity that was nonprogressive. MRI in 1 subject showed some evidence of demyelination of posterior limb of internal capsule and occipital cortex, and cerebellar and cortical atrophy in another unrelated subject. Subjects in 1 family had short stature and microcephaly. Subjects in another family had chorea, developmental delay, and cognitive impairment.

19,77

SPG59 603158

USP8

Uncomplicated spastic gait reported in 2 subjects from one consanguineous family. Toe-walking noted at age 20 mo. When examined in late childhood, subjects were ambulatory with spastic gait.

19

SPG60 612167

WDR48

Early-childhood-onset gait impairment associated with increased lower extremity muscle tone and reflexes, nystagmus, peripheral neuropathy, and mild learning disability.

19

SPG61 616685

ARL6IP1

Two affected subjects are reported from 1 consanguineous family, with onset at age 14 mo. Subjects were nonambulatory at ages 11 and 12 y. Examination demonstrated increased patellar and absent ankle deep tendon reflexes, diffuse motor and sensory neuropathy with loss of digits and acromutilation, and normal intelligence.

19

SPG62

ERLIN1

Two affected subjects from 1 consanguineous family are reported. Symptom onset (toe-walking) at ages 2 and 3 y; spastic gait described at ages16 and 20 y. Subjects were ambulatory despite having flexion contractures at the knees. Cognition was normal. One subject had absent lower extremity reflexes.

19

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Hereditary Spastic Paraplegia: Clinical Principles and Genetic Advances

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SPG63 615686

AMPD2

Two affected subjects from 1 consanguineous family are reported: Delayed walking milestone, ambulatory with scissoring gait, and normal cognition. One subject had periventricular white matter and corpus callosum abnormalities.

19

SPG64 615683

ENTPD1

Two affected subjects from 1 consanguineous family are reported with childhood-onset complicated spastic paraplegia. Symptom onset between ages 3 and 4 y; examination showed lower extremity spasticity, hyperreflexia, amyotrophy (1 subject), microcephaly, aggressiveness, and delayed puberty.

19

SPG65 (same disorder is SPG45)

NT5C2

Consanguineous kindred from Turkey with 5 subjects described: Affected subjects had mental retardation, infantile-onset lower extremity spasticity and contractures, 1 subject with optic atrophy, 2 subjects with pendular nystagmus; MRI in 1 subject was normal. Four additional families reported with infantile-onset spasticity, thin or dysplastic corpus callosum, and learning difficulty.

19,61

SPG66 610009

ARSI

One affected subject from a consanguineous family is described with early childhood onset of abnormal gait. At 3.5 y, the subject was not ambulatory, had lower extremity spasticity but was areflexic, and had severe sensorimotor polyneuropathy, corpus callosum and cerebellar hypoplasia, colpocephaly, and borderline intelligence.

19

SPG67 611655

PGAP1

Two affected subjects from 1 consanguineous family are described: Onset in infancy with global delay, abnormal hand movements, spasticity, borderline intelligence (1 subject). MRI scan was abnormal, showing prominent cortical sulci in 1 subject and corpus callosum agenesis, vermis hypoplasia, and defective myelination in 1 subject

19

SPG68 604806

FLRT1

Two affected subjects from 1 consanguineous family are described: Early-childhood-onset gait impairment with hyperreflexia (patellar clonus), but no spasticity; nystagmus; optic atrophy; foot drop; peripheral neuropathy; normal brain MRI; and normal intelligence.

19

SPG69

RAB3GAP2

One subject from a consanguineous family is described: Infantile-onset, global developmental delay, lower extremity spasticity, dysarthria, deafness, cataract, and intellectual impairment.

19

SPG70 156560

MARS

Four subjects from one consanguineous family are described: Infantile-onset, delayed motor milestones, lower extremity spasticity, amyotrophy, borderline intelligence

19

SPG71 615635

ZFR

One affected subject from a consanguineous family is described with symptom onset at age 1 y. At age 3 y, had lower extremity spasticity and flexion contractures at the knees. Brain MRI showed thin corpus callosum; normal intelligence

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SPG72 615625

REEP2

Uncomplicated spastic paraplegia manifesting as childhood onset (infancy to age 8 y) toe walking or progressive spastic gait. Two of 10 subjects had upper extremity spasticity. Cognition, speech, and vision were normal. REEP2 mutations may cause both autosomal dominant HSP (due to heterozygous mutation), or autosomal recessive HSP due to compound heterozygote mutations.

4

603513

GAD1

Four siblings in a consanguineous Pakistani family with spastic cerebral palsy, and moderate to severe mental retardation

78 79 80

“SPOAN” syndrome 609541

Unknown

Complicated spastic paraplegia associated with optic atrophy, neuropathy (SPOAN)

81

256840

Epsilon subunit of the cytosolic chaperonin-containing t-complex peptide-1 (Cct5)

Complicated spastic paraplegia associated with mutilating sensory neuropathy

82,83

SPG1 303350

L1 cell adhesion molecule (L1CAM)

Complicated: Associated with mental retardation, and variably, hydrocephalus, aphasia, and adducted thumbs

84

SPG2 300401

Proteolipid protein

Complicated: Variably associated with MRI evidence of CNS white matter abnormality; may have peripheral neuropathy

85–88

SPG16 300266

Unknown

Uncomplicated or complicated: Associated with motor aphasia, reduced vision, nystagmus, mild mental retardation, and dysfunction of the bowel and bladder

89,90

SPG22 300523

Monocarboxylate transport 8 (MCT8)

Complicated (Allan-Herndon-Dudley syndrome): Congenital onset, neck muscle hypotonia in infancy, mental retardation, dysarthria, ataxia, spastic paraplegia, abnormal facies

91–93

Uncomplicated, onset 12–25 y

94

Adult onset, progressive spastic paraplegia, mild to severe symptoms, variably associated with axonal neuropathy, late-onset dementia, and cardiomyopathy

95

X-linked HSP

SPG34 300750 Maternal (mitochondrial) inheritance HSP No SPG designation

Mitochondrial ATP6 gene

Abbreviations: ALS, amyotrophic lateral sclerosis; CNS, central nervous system; HIV, human immunodeficiency virus; HSP, hereditary spastic paraplegia; MRI, magnetic resonance imaging. Source: Used by permission from Fink JK. The hereditary spastic paraplegias. In: Rosenberg R, ed. Molecular and Genetic Basis of Neurologic and Psychiatric Disease. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014.

degeneration may cause atrophy of cervical and thoracic segments.13–17 Demyelination of degenerating corticospinal tracts and fasciculus gracilis fibers is considered to be secondary to underlying axon degeneration and not a primary process. These observations form the basis for the central dogma that HSP is due to length-dependent, distal degeneration of motor (corticospinal tract) and sensory (fasciculus gracilis fibers) axons. In this regard, HSP may be viewed as a CNS equivalent of Charcot-Marie-Tooth type 2, a clinically and genetically heterogeneous group of disorders marked by length-dependent, distal axon degeneration of peripheral motor and sensory nerves. It is prudent to recognize, however, that the lengthdependent, CNS-limited, distal motor sensory axon degener-

ation generalization, though accurate for a few genetically defined types of HSP (e.g., SPG4), may not apply equally to types of HSP for which there are no neuropathological descriptions for the vast majority of genetic types of HSP. Furthermore, the concept that HSP reflects selective vulnerability of very long CNS axons (corticospinal tracts and fasciculus gracilis fibers) does not explain all neurologic involvement in HSP (such as dementia in SPG4 HSP, ataxia in SPG7 HSP, and optic neuropathy in SPG7 HSP). Although demyelination in SPG4 appears to be secondary to axon degeneration, it is noted that many genetic types of HSP have significant brain white matter abnormalities (►Table 2), raising the possibility that for some types of HSP, myelin abnormalities may be causal and not secondary to axon degeneration. Finally, the generalization that motor sensory Seminars in Neurology

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Hereditary Spastic Paraplegia: Clinical Principles and Genetic Advances

Hereditary Spastic Paraplegia: Clinical Principles and Genetic Advances

Fink

Table 3 Examples of hereditary spastic paraplegia proteins participating in shared cellular-molecular functions Cellular-molecular process

Representative types of HSP and mutant genes

Axon transport

SPG30/KIF1A, SPG4/Spastin, SPG58/KIF1C

Disturbance in ER morphology

SPG12/Reticulon 2, SPG3A/Atlastin, SPG4/Spastin, SPG31/REEP1, SPG72/REEP2

Mitochondrial abnormality

SPG13/chaperonin 60/heat shock protein 60, SPG7/paraplegin, mitochondrial ATP6

Primary myelin abnormality

SPG2/Proteolipid protein, SPG42/Connexin 47, SGP17/BSCL2 (Seipin), CcT5

Abnormal protein conformation leading to ER-stress response, ER protein degradation disturbance

SPG8/Strumpellin, SPG62/ERLIN1, SPG18/ERLIN2

Disturbance in vesicle formation and membrane trafficking including selective uptake of proteins into vesicles

SPG47/AP4B1, SPG48/KIAA0415, SPG50/AP4M1, SPG51/AP4E1, SPG52/AP4S1, SPG53/VPS37A,

Disturbance of lipid metabolism

SPG28/DDHD1, SPG54/DDHD2, SPG39/NTE, SPG56/CYP2U1, SPG35/ FA2H, Sjögren-Larsson/FALDH

Purine nucleotide metabolism

AMPD2, ENTPD1, and NT5C2 are involved in purine nucleotide metabolism

Abbreviations: ER, endoplasmic reticulum; HSP, hereditary spastic paraplegia. Source: Modified from Fink JK. The hereditary spastic paraplegias. In: Rosenberg R, ed. Molecular and Genetic Basis of Neurologic and Psychiatric Disease. 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2014.

axon degeneration is limited to the long CNS axons must be reconciled with the fact that peripheral motor or motor sensory neuropathy occurs in nearly two dozen genetic forms of HSP (►Table 2).

Molecular Mechanisms Underlying Hereditary Spastic Paraplegia The 58 discovered HSP genes can be categorized into one or more of the following cellular and molecular pathways: axon transport, control of endoplasmic reticulum morphology, mitochondrial function, myelination, protein folding and degradation, vesicle transport and membrane trafficking, lipid metabolisms, and purine nucleotide metabolism (see ►Table 3 for representative examples and18–20 for additional examples and references). It is not known if these primary cellular-molecular abnormalities disturb a shared biochemical process for which distal corticospinal axons are particular vulnerable.

Summary Hereditary spastic paraplegia is an extremely large and diverse group of disorders that share the primary clinical feature of lower extremity spasticity, often accompanied by lower extremity weakness. Neuropathological studies reveal axon degeneration that is maximal at the distal ends of corticospinal tracts (in the thoracic region) and fasciculus gracilis fibers (in the cervicomedullary region). Many genetic types of HSP are associated with additional neurologic involvement, such as ataxia, peripheral neuropathy, and cognitive impairment. Whereas various genetic types of Seminars in Neurology

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“uncomplicated” HSP may not be distinguishable by clinical parameters alone, syndrome-specific neurologic or systemic findings may help diagnose various “complicated” types of HSP. More than 70 genetic types of HSP have been discovered. The 58 discovered HSP genes participate in diverse biochemical pathways, including axon transport, control of endoplasmic reticulum morphology, mitochondrial function, myelination, protein folding and degradation, vesicle transport and membrane trafficking, lipid metabolisms, and purine nucleotide metabolism. Genetic testing can diagnose the majority of patients with HSP. Nonetheless, HSP is a clinical diagnosis for most, and requires careful exclusion of alternate and coexisting disorders. The differential diagnosis includes treatable disorders (e.g., B12 deficiency, cervical spondylosis, dopa-responsive dystonia, multiple sclerosis), as well as disorders whose prognosis is quite different than HSP (e.g., ALS and primary lateral sclerosis). Treatment for HSP includes medications to reduce muscle spasticity and urinary urgency, and patientspecific rehabilitation to improve and maintain balance, cardiovascular fitness, and lower extremity strength, flexibility, and speed.

Acknowledgments This research is supported by the National Institutes of Health (5 R01 NS069700), the Department of Veterans Affairs (Merit Review Award), the Spastic Paraplegia Foundation, the Geriatric Research Education and Clinical Center of the Ann Arbor Veterans Affairs Medical Center, the Paul and Lois Katzman Family, the Susan Parkinson Foundation, the Peter Sills Foundation, and the generosity of

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