Continuum Myelopathies

Hereditary Myelopathies REVIEW ARTICLE

By Peter Hedera, MD, PhD C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
ABSTRACT
PURPOSE OF REVIEW: Hereditary myelopathies are very diverse genetic
disorders, and many of them represent a widespread neurodegenerative
process rather than isolated spinal cord dysfunction. This article reviews
various types of inherited myelopathies, with emphasis on hereditary
spastic paraplegias and spastic ataxias.
RECENT FINDINGS: The ever-growing number of myelopathy-causing genes

and broadening of phenotype-genotype correlations makes the molecular
diagnosis of inherited myelopathies a daunting task. This article
emphasizes the main phenotypic clusters among inherited myelopathies
that can facilitate the diagnostic process. This article focuses on newly
identified genetic causes and the most important identifying clinical
features that can aid the diagnosis, including the presence of a
characteristic age of onset and additional neurologic signs such as
leukodystrophy, thin corpus callosum, or amyotrophy.
SUMMARY: The exclusion of potentially treatable causes of myelopathy

remains the most important diagnostic step. Syndromic diagnosis can be CITE AS:
supported by molecular diagnosis, but the genetic diagnosis at present CONTINUUM (MINNEAP MINN)
does not change the management. Moreover, a negative genetic test 2018;24(2, SPINAL CORD DISORDERS):
523–550.
does not exclude the diagnosis of a hereditary myelopathy because
comprehensive molecular testing is not yet available, and many Address correspondence to
disease-causing genes remain unknown. Dr Peter Hedera, Department of
Neurology, Vanderbilt University
Medical Center, 465 21st Ave S,
6140 MRB III, Nashville, TN 37240,
peter.hedera@vanderbilt.edu.
INTRODUCTION
H
RELATIONSHIP DISCLOSURE:
ereditary myelopathies comprise a diverse group of Dr Hedera has received
neurodegenerative and neurometabolic disorders that were personal compensation as
historically defined according to signs and symptoms of spinal cord editor-in-chief of the Journal of
Parkinsonism and Restless Legs
dysfunction.1,2 Clinical manifestations of hereditary myelopathies Syndrome, as an editorial board
are similar to other causes of spinal cord dysfunction, with varying member of Neurology, and as a
degrees of motor and sensory deficits. However, the disease course is speaker for Ipsen and Teva
Pharmaceutical Industries Ltd.
characteristically chronic and slowly progressive, typical of a neurodegenerative Dr Hedera receives royalties
process. Hallmark pathologic changes in hereditary myelopathies are relatively from Elsevier and has provided
testimony as a treating clinician
stereotypical with a combination of diffuse axonal degeneration and secondary
in legal proceedings.
demyelination.3,4 Dying-back axonopathy and neurodegeneration are most
pronounced in the terminal segments of the longest axons. This accounts for a UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
preferential involvement of the distal representation of the dorsal columns in the USE DISCLOSURE :
cervical cord and the corticospinal tracts in the lumbar spinal cord. Thus, motor Dr Hedera reports no
and sensory signs in hereditary myelopathies predominantly affect the lower disclosure.
extremities, encompassing a syndrome of progressive spastic paraparesis with a © 2018 by the American Academy
variable range of weakness, deep tendon hyperreflexia, Babinski signs, bladder of Neurology.
CONTINUUMJOURNAL.COM 523
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

HEREDITARY MYELOPATHIES
hyperactivity, and dorsal column dysfunction. Dysmetria, if present, is typically

limited to the lower extremities because of damage of the spinocerebellar tracts
rather than widespread cerebellar dysfunction. Variable involvement of the
upper extremities with upper motor neuron signs can also be present, but a
fully developed spastic quadriparesis is rarely associated with the hereditary
myelopathies. Sensory spinothalamic tracts are infrequently affected, but coexisting
peripheral nervous system involvement is common in hereditary myelopathies.
Additional sensory loss due to concomitant peripheral neuropathy may be seen.
Many hereditary myelopathies actually represent a systemic process involving
additional brain structures rather than isolated axonal degeneration in the spinal
cord.5 It may be difficult to make a clinical distinction between myelopathies and
hereditary spinocerebellar ataxias because of variable axonal loss and the potential
for generalized spasticity in each.6 Abnormalities outside the central and peripheral
nervous system may also be present, and musculoskeletal changes or sensory
organ involvement are frequently encountered in some types of hereditary spastic
paraplegias (HSPs). However, the concept of hereditary myelopathies remains
useful to differentiate these conditions from other well-defined myelopathies, such
as those caused by compressive, vascular, and inflammatory etiologies.
Hereditary myelopathies can be categorized based on a combination of clinical,
genetic, and pathologic features.1,2,7,8 Although overlap exists, the most
commonly used clinical classification includes HSP, motor neuron disorders,
spastic ataxias (SPAXs), and metabolic leukodystrophies. HSP is considered a
prototypical example of a selective, length-dependent (distal) axonopathy.3,4 This
is one of the most genetically heterogeneous neurologic syndromes.8 However,
many types of HSP also overlap with neurometabolic disorders classified as
leukoencephalopathies with radiologic and pathologic evidence of demyelination
or hypomyelination.7 Motor neuron disorders include conditions with variable
involvement of upper and lower motor neuron degeneration, and considerable
overlap is seen with HSPs.2 The main distinguishing factor is typically a much less
favorable prognosis in motor neuron disease. SPAXs are distinguished by the
presence of cerebellar signs, such as nystagmus, dysarthria, and dysmetria
affecting the upper and lower extremities.9 Most of the HSPs, leukodystrophies,
and ataxias have identified disease-causing genes and are indeed defined by their
genotype rather than descriptive phenotype. However, the widespread use of
next-generation molecular diagnostics, including exome sequencing, reveal that
the clinical features of these conditions are rather fluid and often overlapping.
This article primarily focuses on HSP and SPAXs with an emphasis on recently
identified causes of diffuse spasticity. Lower motor neuron syndromes are
discussed only within the context of systemic neurodegeneration, and autosomal
recessive spinal muscular atrophy (SMA) caused by mutations in the survival
motor neuron 1 (SMN1 or telomeric SMN) is not reviewed in detail in this article.
HEREDITARY SPASTIC PARAPLEGIAS

The clinical hallmark of HSP is a gradual and progressive spastic weakness of the
lower extremities associated with variable degrees of impaired vibration sensation
and autonomic dysfunction with bladder and occasionally anal sphincter
hyperactivity.1,2 The rate of progression and overall severity varies from a mildly
spastic gait to wheelchair dependency and the development of secondary
complications from long-term spasticity. Despite recent advances in the understanding
of its pathophysiology, including axonal transport disruption, abnormal organelle
524 APRIL 2018

morphogenesis, impaired neuronal lipid homeostasis, or mitochondrial dysfunction, KEY POINTS
the treatment remains purely symptomatic and focuses on management of
● Clinical manifestations of
spasticity. Prevalence of HSP has been estimated between 1.27 and 9.6 per 100,000; hereditary myelopathies are
thus, these patients may be commonly encountered by practicing neurologists.10,11 similar to other causes of
All causes of HSP are considered a single-gene inherited disease without any spinal cord dysfunction.
known environmental influence. Mutations in more than 70 different
● The clinical course of
HSP-causing genes result in this stereotypical and otherwise undistinguishable
hereditary myelopathies
clinical phenotype.8 Syndromic diagnosis of HSP can be relatively is suggestive of a
straightforward in patients with a positive family history. The risk that other neurodegenerative process.
causes of acquired myelopathies (phenocopy) are also present in a single kindred
is very small, and unless atypical clinical features are present, many patients can ● Most hereditary
myelopathies embody
be diagnosed on clinical grounds alone. The diagnosis of HSP in apparently systemic neurodegeneration,
sporadic cases remains a diagnosis of exclusion. Targeted genetic testing not only involving additional brain
narrows the differential diagnosis but may also be cost effective when compared structures rather than
to the cost of an exhaustive evaluation for other treatable causes of myelopathy. isolated axonal degeneration
in the spinal cord.
Classification ● Clinical signs of hereditary

HSP is most commonly classified according to phenotypes and genotypes.7,8,12 myelopathies predominantly
Genetic classification is based on the mode of inheritance, with all three affect the lower extremities,
encompassing a syndrome
mendelian modes of inheritance (autosomal dominant, autosomal recessive, and
of progressive spastic
X-linked patterns) identified.8 Additionally, mutations in mitochondrial DNA paraparesis.
can also be associated with diffuse spasticity.
Autosomal dominant HSP is characterized by vertical inheritance with a ● Hereditary myelopathies
possibility of male-to-male transmission, 50% risk for offspring in each can be classified as hereditary
spastic paraplegias, spastic
successive generation, and equal frequency of the disease between males and ataxias, motor neuron
females.13 However, transmission of the disease to consecutive generations may diseases, or leukodystrophies.
not be apparent in small kindreds, especially when parents died young before
HSP could manifest clinically, were asymptomatic and thus unaware of the ● Hereditary spastic
paraplegia is characterized
disease, or did not develop the disease because of reduced penetrance.
by progressive spastic
Undisclosed adoption or false paternity are also possible causes of absent family weakness in the legs,
history. Another common explanation for the absent family history in autosomal impaired vibration sensation,
dominant HSP is a de novo mutation.14,15 Overall, it is estimated that one-fourth and bladder hyperactivity.
of patients with autosomal dominant HSP have de novo mutations and present
● Hereditary myelopathies
as sporadic disease. Thus, autosomal dominant HSP should be considered even in can be inherited as an
patients without a family history of a similar problem. autosomal dominant,
Autosomal recessive inheritance is supported by multiple affected children autosomal recessive, or
born to unaffected parents. Shared ancestry between parents increases the risk of X-linked condition.
autosomal recessive inheritance, but common types of autosomal recessive ● Hereditary spastic
HSP are frequently encountered in nonconsanguineous marriages. paraplegia is characterized
X-linked disorders affect males, and affected individuals may be identified in by interfamilial and
successive generations, suggesting autosomal dominant inheritance. Women intrafamilial variability.
who are carriers of mutated genes on the X chromosome may occasionally
manifest the disease if they have “unfavorable” lyonization; however, their
disease phenotype tends to be milder than in affected males. Autosomal recessive
and X-linked HSP may also present as apparently sporadic HSP, further
broadening the differential diagnosis of HSP.2,8
Clinical classification is based on the presence or absence of additional
neurologic signs, other than spastic weakness of the lower extremities.2,12
Isolated spastic paraparesis with a variable degree of weakness and impaired
vibration sensation encompass a syndrome of uncomplicated, or “pure,” HSP.

KEY POINTS Many patients with HSP develop complex clinical phenotypes. Some authors
advocate the classification with the term complex HSP, reserved for additional
● Hereditary spastic
paraplegia can be classified
neurologic signs, and the term complicated HSP, if non-neurologic signs such as
as uncomplicated with cataracts or skin ichthyosis are also present; however, this is not universally
isolated spastic weakness or accepted, and the terms complex and complicated HSP are used interchangeably in
complicated if additional this article. The most common additional neurologic signs associated with HSP
neurologic signs are present.
include: optic nerve atrophy, cerebellar ataxia, dystonia, deafness, retinitis
● Age of onset and pigmentosa, amyotrophy, peripheral neuropathy, pseudobulbar signs, absent or
associated clinical features hypoplastic corpus callosum, developmental delay (mental retardation), and
may suggest a specific adult-onset dementia.12,13 Complicated HSP is more common in autosomal
genetic type of autosomal recessive types of HSP. However, the distinction between uncomplicated and
dominant hereditary spastic
paraplegia. complicated HSP is becoming increasingly blurred with the growing recognition
of other subtle clinical features, such as dementia in autosomal dominant HSPs
● Definitive diagnosis of that were previously considered pure HSPs.
hereditary spastic paraplegia This clinical classification of HSP is further complemented by characterization
must be confirmed by
positive genetic testing.
based on the age of onset of gait difficulties. Patients with HSP have a broad age
range of disease onset, from infancy to the seventh decade.2,16,17 Although a
● Spastic gait type 3A significant intrafamilial variability exists, the age of onset may be helpful in
(SPG3A) is the main cause of determining the most likely genetic type of HSP, especially in patients with an
autosomal dominant
early-onset (younger than 10 years of age) autosomal dominant HSP. Moreover,
hereditary spastic paraplegia
with an early onset, and many patients with an early-onset autosomal dominant HSP tend to have slower
more than three-fourths progression of the disability, with the majority of patients maintaining an
of these patients have independent gait for several decades. Because of the lack of perceived
mutations in the ATL1 gene. deterioration, these patients may be misdiagnosed with cerebral palsy in the
absence of family history. Similarly, infantile-onset HSP is commonly associated
with a delayed acquisition of independent walking and should be distinguished
from perinatal encephalopathy or diplegic cerebral palsy. The progressive nature
of the gait disorder and spasticity usually helps to differentiate these two
conditions, but several cases have been reported of molecularly confirmed HSP
misdiagnosed as cerebral palsy.14,18
Progress in the molecular genetics of HSP now allows a molecularly proven
diagnosis in at least 75% of all patients with HSP employing clinically available
testing with HSP-focused panels of tests.19 The remaining patients have either
very rare genes, which are not a part of routine clinical testing, or have
yet-to-be-identified mutations. Single-gene testing may be more costly and time
consuming than panel testing and is more suitable for the diagnosis of additional
individuals at risk from pedigrees with a known disease-causing mutation.
Next-generation sequencing methods, coupled with progress in genomic
informatics, will likely streamline the molecular diagnosis in the future, and exome
and genome sequencing could become a routine way to establish the diagnosis.
Despite several uniform phenotypic characteristics of certain types of HSP,
the definitive diagnosis can be only achieved by genetic testing because of
significant genetic heterogeneity and overlapping phenotypic features of many
forms of HSP. Current genetic nomenclature uses classification based on the
order of identification of genetic loci, and SPG refers to spastic gait, followed by
the number in the historical order of identification of each genetic type of HSP.
The combination of genetic and premolecular era classification, which was
based on the mode of inheritance, age of onset, and uncomplicated (pure) or
complicated phenotype still provides a clinically useful framework, and the
author structures this article based on this model.
526 APRIL 2018

Autosomal Dominant Hereditary Spastic Paraplegia
Autosomal dominant HSP is the most common type of HSP and accounts for 75%
to 80% of all cases.
AUTOSOMAL DOMINANT HEREDITARY SPASTIC PARAPLEGIA WITH UNCOMPLICATED

PHENOTYPE AND EARLY AGE OF ONSET. Age of onset varies among the numerous
types of HSP, but onset in the first 2 decades of life is a typical feature of SPG3,
SPG12, and SPG72 (TABLE 7-1).8,16 SPG3A is the second most common type of
autosomal dominant HSP, accounting for approximately 10% to 15% of all
autosomal dominant HSP cases.13 However, it is the main cause of autosomal
dominant HSP with an early onset, and more than three-fourths of patients in
this category have mutations in the ATL1 (previously known as SPG3A) gene,
encoding atlastin-1 protein.16,20,21 The average age of onset in SPG3A is 4 years,
and more than 80% of affected individuals reported spastic gait before the end
of the first decade of life. The rate of progression is slow, and wheelchair
dependency or need for an assistive walking device is relatively rare. Most
patients with SPG3 have an uncomplicated motor phenotype and, in comparison
to other types of HSP, impaired vibration sensation and urinary bladder
Autosomal Dominant Pure Hereditary Spastic Paraplegia With Early-Onset TABLE 7-1
Disease
Mutated Gene/Protein
/Chromosomal
Location if Gene Age of
Genetic Type Unknown Onset Genetic Epidemiology Additional Clinical Features
SPG3 SPG3A/atlastin-1 Very early, 80% of early-onset autosomal Musculoskeletal problems,

average age dominant hereditary spastic peripheral neuropathy,
8 years paraplegia (HSP) and 10–15% of developmental delay in rare
all autosomal dominant HSP cases
SPG12 RTN2/reticulon 2 Before age 5% of early-onset autosomal Uncomplicated phenotype

of 20 years dominant HSP but overall rare
cause of HSP
SPG37 8p21.1-q13.3 Before age Only one family known Uncomplicated phenotype
of 20 years
SPG72 REEP2/receptor Very early, Only two families known Musculoskeletal problems, mild
accessory protein 2 average age postural tremor
4 years
SPG DNM2/dynamin 2 Before age Rare Mild dysarthria, allelic with

classification of 20 years Charcot-Marie-Tooth disease
not assigned type 2M and Charcot-Marie-
Tooth disease type B
SPG = spastic gait.

KEY POINT hyperactivity are less frequent findings.16,20,21 Additionally, these patients
commonly develop scoliosis and pes cavus deformities and need to be monitored
● SPG4 is the most common
type of autosomal dominant for orthopedic complications. Mutations in this gene may be rarely associated
hereditary spastic paraplegia, with adult-onset disease. Peripheral neuropathy has been occasionally reported,
accounting for almost 40% and this condition is allelic with hereditary sensory neuropathy type I, where
of all cases, but the age of only signs of peripheral nervous system involvement are present.22
onset is very variable.
SPG12 is much less common than SPG3A, and only a handful of families were
identified harboring mutations of the RTN2 gene (reticulon 2).23 The clinical
presentation is similar to SPG3A, but the course tends to be more aggressive, and
most patients develop wheelchair dependency in the fourth or fifth decade.
SPG72 was identified based on homology of the gene receptor accessory protein
2 (REEP2) to the REEP1 gene causing SPG31. Onset is before 5 years of age, and
no other identifiable neurologic abnormalities are present. Mutations in REEP2
may cause HSP as a dominant or recessive mutation.24 SPG37 is another
putative candidate for this type of HSP, but only one family was identified
using linkage analysis. The age of onset tends to be more variable, and
identification of other families is necessary for more definite clinical characterization.8
Mutations in DNM2 are another cause of this syndrome, but this condition
was not included in the SPG nomenclature.25
AUTOSOMAL DOMINANT HEREDITARY SPASTIC PARAPLEGIA WITH UNCOMPLICATED

PHENOTYPE AND PREDOMINANTLY ADULT AGE OF ONSET. This is a prototypical
spastic paraparesis with 11 known genes at present identified as a cause of this
type of HSP (TABLE 7-2).7,8 Considerable clinical overlap exists among different
types of autosomal dominant HSP. Significant interfamilial and intrafamilial
variability within the same genetic types do not allow reliable clinical
differentiation. Age of onset is also variable and may span from early childhood
to adulthood.8,14,26 However, in contrast to the subgroup of autosomal dominant
HSP with an early age of onset, no uniformity occurs in the age of onset. Genetic
epidemiology identified SPG4, caused by SPAST (spastin) mutations, as the most
common type, accounting for approximately 40% of all autosomal dominant
HSPs.8,13,26 Laboratory genetic testing for SPG4 should include both sequencing
and gene dosing methods because deletions within this gene are common.27 The
only other type of HSP that is relatively common is SPG31, which accounts for
about 5% of all autosomal dominant HSP cases.28 Other autosomal dominant
HSPs with a predominantly adult onset are relatively rare.
Most patients with SPG4 have a pure HSP phenotype, and individuals with
additional neurologic signs, such as ataxia or amyotrophy, are very rare. One
notable exception is the presence of cognitive decline. The estimates of dementia
incidence vary from zero to about 20%, and the dementia is usually mild, with a
neuropsychological profile resembling a frontal type of dementia.29 However,
age-related cognitive decline that does not meet criteria for dementia can be
detected in the vast majority of patients with SPG4, with signs of attention
deficit, executive disorders, and social cognition impairment. Although the
actual prevalence of dementia in SPG4 is still somewhat controversial, these
patients should be routinely screened for cognitive decline.
No distinctive features exist for other adult-onset pure HSPs. SPG6 and SPG8
tend to have a more aggressive course, with rapid progression leading to wheelchair
dependency.15,30 SPG31 has a broader range of onset, as early as the second decade,
but with most becoming symptomatic in their twenties and thirties.28 SPG31 has
528 APRIL 2018

Autosomal Dominant Pure Hereditary Spastic Paraplegia With TABLE 7-2
Predominantly Adult-Onset Disease
Mutated Gene/Protein
/Chromosomal Location Additional Clinical
Genetic Type if Gene Unknown Age of Onset Genetic Epidemiology Features
SPG4 SPAST/spastin Variable from 40% of autosomal dominant Cognitive decline and
infancy to seventh hereditary spastic dementia are common
decade paraplegia (HSP)
SPG6 NIPA1/nonimprinted gene Adulthood Rare (approximately 1% of Severe weakness and

in Prader-Willi syndrome/ autosomal dominant HSP) spasticity, rapidly
Angelman syndrome progressive
chromosome region 1
SPG8 WASHC5/strumpellin Adulthood Rare (approximately 1% of Some patients have

autosomal dominant HSP) severe deficits
SPG13 HSPD1/heat shock 60kD Adulthood Rare Mild distal

protein 1 amyotrophy
SPG19 9q33-q34 Adulthood Single family Slow progression
SPG31 REEP1/receptor accessory Variable from 4–6% Mild distal

protein 1 second to seventh amyotrophy
decades
SPG33 ZFYVE27/protrudin Adulthood Single family Pes cavus
SPG41 11p14.1-p11.2 Early adulthood Single family None
SPG42 SLC33A1/acetyl-coenzyme A Early adulthood Single family Slowly progressive,

transporter pes cavus
SPG73 CPTIC/carnitine Early adulthood Single family Mild distal

palmitoyltransferase IC amyotrophy
SPG classification PMCA4 (ATP2B4) Adulthood Single family None

not assigned
SPG = spastic gait.

mostly an uncomplicated phenotype other than mild distal amyotrophy. Mutations

in the REEP1 gene can also cause distal hereditary motor neuronopathy 5B.31
SPG42 and SPG73 are very rare, and each of them has been described in a single
family. Biallelic mutations in the SLC33A1/acetyl-coenzyme A transporter gene
are the cause of a recessive condition with congenital cataracts and hearing loss,
which are not seen in individuals carrying a single mutation causing SPG42.32
AUTOSOMAL DOMINANT HEREDITARY SPASTIC PARAPLEGIA WITH A COMPLICATED

PHENOTYPE. Although an occasional manifestation of a complex phenotype can
be seen in most types of autosomal dominant HSP, several genetic types of HSP
affect other parts of the central nervous system or extraneuronal tissues on a
regular basis (TABLE 7-3).
SPG9 is the only genetic type with a consistent complex phenotype among
autosomal dominant HSPs.8 It is caused by mutations in the aldehyde
dehydrogenase 18 family, member A1 (ALDH18A1) gene.33 Neurologic problems
include spastic weakness of the legs, motor neuronopathy that may resemble
amyotrophic lateral sclerosis (ALS), spastic dysarthria, and cerebellar ataxia, with
an average age of onset in the second decade. Systemic manifestations include
short stature with bone dysplasia, gastroesophageal reflux, hiatal hernia, and
cataracts. Two acronyms have been proposed for this syndrome, including
CMNSS (cataracts with motor neuronopathy, short stature, and skeletal
abnormalities) and SPACGR (spastic paraparesis with amyotrophy, cataracts, and
gastroesophageal reflux). The same gene is also associated with an autosomal
recessive type of HSP, designated as SPG9B, and the phenotype is more severe,
with developmental delay, microcephaly, and pronounced dysmorphic features.33
SPG10 is more variable in its clinical presentation, but more than half of these
patients have signs of sensorimotor axonal polyneuropathy with spastic
paraparesis.34 KIF5A mutation was also detected in one family with an isolated
polyneuropathy, classified as Charcot-Marie-Tooth disease type 2A.35 SPG10
accounts for about 1% to 2% of all autosomal dominant HSP cases and for almost
10% of complicated HSP. The clinical spectrum varies from pure HSP to a
complex HSP with ataxia, parkinsonism, retinitis pigmentosa, and hearing loss.
The age of onset is also variable, ranging from juvenile to adult onset.35,36
The combination of lower limb spasticity and prominent amyotrophy of
distal hand and foot muscles is commonly designated as Silver syndrome.37
Disproportionate atrophy of the thenar muscles with thumb weakness is a typical
clinical sign. This syndrome may be easily confused with motor neuron
disorders, but denervation of paraspinal and proximal muscles is not a feature
of Silver syndrome. SPG17, due to mutations in the BSCL2 (seipin) gene, is the
most common cause of Silver syndrome.38 Mutations in this gene may also be
associated with distal hereditary motor neuropathy type V phenotype (where
symptoms are limited to distal muscle weakness, and signs of pyramidal
tract lesions are very subtle and occur later in the course of the disease) or
Charcot-Marie-Tooth type 2 phenotype with a mild involvement of sensory
nerves and absent upper motor neuron signs. Silver syndrome is genetically
heterogeneous, and rare mutations in the SPG4, SPG3A, and SPG10 genes have
been reported in these patients.8
Mutations in the ATAD3A gene were previously identified in five unrelated
patients who had global developmental delay, hypotonia, optic atrophy, axonal
neuropathy, and hypertrophic cardiomyopathy.39 This same gene was found
530 APRIL 2018

mutated in one parent-child set, where the mother had juvenile-onset HSP and
polyneuropathy, and her son had been originally diagnosed with cerebral palsy
with hyperkinetic movements. Early-onset HSP with significant ataxia is seen in
patients with mutations in the TUBB4A/tubulin beta 4A class IVa gene.40
Coexisting cerebellar ataxia and radiologic signs of hypomyelination are
distinguishing features of this rare cause of spasticity.
Autosomal Recessive Hereditary Spastic Paraplegia

Autosomal recessive HSPs are very heterogeneous with an ever-growing list of
newly identified genes.7,8 Many new causes of autosomal recessive HSP are very
Autosomal Dominant Hereditary Spastic Paraplegia With Complicated TABLE 7-3

Phenotype
Mutated Gene/
Protein/Chromosomal
Location if Gene
Genetic Type Unknown Age of Onset Genetic Epidemiology Additional Clinical Features
SPG9 ALDH18A1/aldehyde Juvenile or Rare Cataracts, motor

dehydrogenase 18 early neuronopathy, short stature,
family, member A1 adulthood amyotrophy, cataracts,
gastroesophageal reflux
SPG10 KIF5A/kinesin 1 Juvenile or 1–2% of all autosomal dominant Sensorimotor neuropathy

adulthood hereditary spastic paraplegia
(HSP), 5–8% of all complicated
autosomal dominant HSP
SPG17 (Silver BSCL2/seipin Adulthood Rare Distal amyotrophy, motor

syndrome) neuropathy
SPG29 1p31.1-p21.1 Juvenile Single family Hearing loss, hiatal hernia,

neonatal hyperbilirubinemia
SPG36 1q23-q24 Adulthood Single family Demyelinating polyneuropathy
SPG38 4p16-p15 Adulthood Single family Silver syndrome, resembles

amyotrophic lateral sclerosis
SPG ATAD3A/ATPase Early onset Single family Amyotrophy, hyperkinetic

classification family AAA-domain movements
not assigned containing protein 3A
SPG TUBB4A/ tubulin beta Juvenile Rare Cerebellar ataxia, MRI

classification 4A class IVA evidence of hypomyelination,
not assigned allelic with autosomal
dominant dystonia 4
MRI = magnetic resonance imaging; SPG = spastic gait.

KEY POINTS rare and may be limited to a single family or even single patient. The frequency is
increased in populations with a higher degree of consanguinity. For example,
● Autosomal recessive
hereditary spastic
the prevalence of autosomal recessive HSP in Tunisia is reported to be as high as
paraplegias are genetically 5.75 per 100,000.41 More common types of autosomal recessive HSP can be
very heterogeneous and encountered in the general population. The genetic epidemiology of autosomal
account for 25% to 30% of recessive HSP is only emerging, but this mode of inheritance is estimated to
all cases of hereditary
account for 25% to 30% of all cases of HSP.10,13
spastic paraplegia.
In general, autosomal recessive HSPs tend to have an early age of onset and a
● Autosomal recessive complicated phenotype.2 However, several types of autosomal recessive HSP may
types of hereditary spastic also manifest as an uncomplicated HSP, and this article discusses this group
paraplegias tend to have an separately to provide a practical approach to the diagnosis. Neuroimaging of the
early age of onset and a
complex clinical picture with brain and spinal cord may be more helpful in these patients, and several types
additional neurologic signs. of autosomal recessive HSPs have signs of abnormal brain development, with
hypoplasia or absence of the corpus callosum being the most typical finding.1,42
The subgroup of HSP with corpus callosum hypoplasia also will be described
separately. Additional findings include white matter abnormalities, and several
autosomal recessive HSPs overlap with leukodystrophies.
AUTOSOMAL RECESSIVE HEREDITARY SPASTIC PARAPLEGIA WITH UNCOMPLICATED

PHENOTYPE. Mutations in the polypeptide 1, subfamily 1 of cytochrome P450
(CYP7B1) gene cause a relatively common type of autosomal recessive HSP,
SPG5A, which often can have an uncomplicated phenotype with onset in the
fourth or fifth decades (TABLE 7-4).43 The frequency of CYP7B1 mutations were
7.3% among autosomal recessive HSP and 3% among apparently sporadic pure
spastic paraplegia. Elevation of 27-hydroxycholesterol has been suggested as a
diagnostic test, but the definitive diagnosis requires molecular analysis.44
Neuroimaging of patients with SPG5A with a complex phenotype typically
demonstrates a widespread leukodystrophy; however, neuroimaging in patients
with pure HSP is unremarkable.45
SPG7 may account for approximately 5% of all autosomal recessive HSP
cases and 5% of apparently sporadic cases with pure HSP.46 It is caused by
mutations in the paraplegin gene (SPG7).47 Occasionally it has been associated
with autosomal dominant transmission of HSP, but this remains controversial.48
The phenotype can be pure in about 40% to 50% of these patients, and the rest
has a complex motor phenotype with dysarthria and cerebellar ataxia.46
Paraplegin mutations may be seen in otherwise pure cerebellar ataxia, and it
has been suggested that paraplegin mutations can explain 18% of apparently
sporadic ataxias.49
Other types of HSP from this subtype are quite rare. SPG48 has an adult onset,
while SPG59 has very early onset of pure HSP.50,51
AUTOSOMAL RECESSIVE HEREDITARY SPASTIC PARAPLEGIA WITH HYPOPLASIA OF

CORPUS CALLOSUM. Hypoplastic corpus callosum may be seen in several genetic
types of HSP, including dominant forms such as SPG3A and SPG4, although this
occurs rarely (TABLE 7-5).7,8 The frontal portion of the corpus callosum appears
thinned, but true agenesis is rare. Hypoplasia of the corpus callosum is
typically associated with enlarged ventricles. An additional MRI finding in SPG11
is increased white matter signal in the forceps minor area of the corpus callosum,
resembling “ears of the lynx.”52 The most common cause of this radiologic
finding is SPG11, which is caused by mutations in the spatacsin gene (SPG11)
532 APRIL 2018

Autosomal Recessive Hereditary Spastic Paraplegia With Possibly Pure TABLE 7-4
Phenotype
Mutated Gene/Protein/
Genetic Chromosomal Location
Type if Gene Unknown Age of Onset Genetic Epidemiology Additional Clinical Features
SPG5A CYP7B1/polypeptide 1, Juvenile to 7.3% of autosomal recessive Ataxia, polyneuropathy,
subfamily 1 of adulthood hereditary spastic paraplegia extrapyramidal signs, MRI signs of
cytochrome P450 (HSP) and 3% of apparently leukodystrophy in complex
sporadic HSP phenotype
SPG7 SPG7/paraplegin Juvenile or 5% of autosomal recessive HSP and Dysarthria, ataxia, optic atrophy,
adulthood 5% of apparently sporadic HSP supranuclear palsy
SPG25 6q23.3-q24.1 Adulthood Rare Familial disk herniation
SPG28 DDHD1/phosphatidic Childhood Rare Scoliosis

acid-preferring
phospholipase A1
SPG48 AP5Z1 adaptor related Adulthood Single family Urinary incontinence

protein complex 5 zeta-1
subunit
SPG59 USP8/ubiquitin specific Childhood Rare None

protease 8
MRI = magnetic resonance imaging; SPG = spastic gait.
Autosomal Recessive Hereditary Spastic Paraplegia With Hypoplasia of TABLE 7-5

the Corpus Callosum
Genetic Mutated
Type Gene/Protein Age of Onset Genetic Epidemiology Additional Clinical Features
SPG11 SPG11/ Childhood or 5% of autosomal recessive hereditary Developmental delay, optic atrophy,
spatacsin early adulthood spastic paraplegia (HSP) and 75% of ataxia, pseudobulbar signs,
HSP with developmental delay and polyneuropathy, levodopa-
hypoplasia of corpus callosum responsive parkinsonism
SPG15 ZFYVE26/ Childhood or 1–2% of all autosomal recessive HSP Developmental delay, optic atrophy,
spastizin early adulthood ataxia, central retinal degeneration,
polyneuropathy
SPG55 C12ORF65 Childhood Rare Developmental delay, visual loss,

polyneuropathy, arthrogryposis
SPG = spastic gait.

(CASE 7-1).53 It is not an exclusive feature of SPG11 because about 40% of patients
with SPG11 may have a normal-appearing corpus callosum. However, genetic
analysis among selected patients with HSP associated with developmental delay
and hypoplastic corpus callosum detected mutations in this gene in about 75% of
these patients.54 The complex phenotype in SPG11, other than cognitive deficits,
also includes optic atrophy, pseudobulbar signs, ataxia, polyneuropathy, and,
rarely, levodopa-responsive parkinsonism.55 SPG11 may seldom present as
pure HSP.
CASE 7-1 A 22-year-old man was evaluated for a long-standing history of abnormal
gait and developmental delay, complicated by new-onset behavioral
problems with outbursts of verbal and physical violence. His parents did
not report any perinatal problems, but his psychomotor development
was delayed. He had walked when he was 2 years old, and he acquired
speech around the same time. His walking was always abnormal, with a
tiptoed gait, and he was described as clumsy. His gait abnormalities had
been progressive, and he experienced multiple falls, leading to wheelchair
dependency at the age of 17.
His cognitive testing revealed a total IQ of 76, and he was enrolled in
special education programs. His family history was unremarkable, and
both parents and one brother were healthy.
Neurologic examination showed severe spasticity limited to the lower
extremities and deformities in his feet with high arches and hammer toes.
He had sustained clonus in both ankles and upgoing toes on both sides
with hyperactive deep tendon reflexes in the lower extremities. The rest
of his examination was unremarkable other than signs of mild
developmental delay.
His brain MRI showed a hypoplastic corpus callosum and increased
white matter signal in the forceps minor area of the corpus callosum,
resembling ears of the lynx (FIGURE 7-1). MRI of the cervical and thoracic
spine was unremarkable. Genetic testing for SPG11 was ordered, and he
was found to be compound heterozygote in the spatacsin gene, confirming
a diagnosis of SPG11.
COMMENT This patient presented with an isolated case of spastic paraparesis with
signs of developmental delay. Although the differential diagnosis for this
patient is wide, it is also consistent with a phenotype of complicated
hereditary spastic paraplegia (HSP). His imaging studies did not identify any
compressive cause of myelopathy and showed typical MRI findings that can
be seen in a subgroup of autosomal recessive HSP that includes SPG11.
Testing for a single gene is not typically recommended because it can be
time consuming, but, in this case, was driven by insurance restrictions. Given
the fact that SPG11 is the most common cause of this clinical and radiographic
presentation, this approach may be considered in these patients with
additional testing for other causes of HSP if the test for SPG11 is negative.
534 APRIL 2018

SPG15 caused by mutations in the ZFYVE26/spastizin gene is the second most
frequent cause of a hypoplastic corpus callosum.56 The typical SPG15 phenotype
is complex with similar features as SPG11.57 Its variant with central retinal
degeneration is known as Kjellin syndrome. Hypoplastic corpus callosum is also a
common feature of SPG55 caused by mutations in the C12ORF65 gene. In SPG55,
childhood-onset spasticity is accompanied by optic nerve atrophy with
progressive visual loss, developmental delay, peripheral axonal polyneuropathy,
and arthrogryposis.58
FIGURE 7-1
Corpus callosum imaging abnormalities of
hereditary spastic paraplegia in the patient in
CASE 7-1. A, Sagittal fluid-attenuated inversion
recovery (FLAIR) sequence brain MRI of a patient
with genetically confirmed spastic gait type 11
(SPG11) showing hypoplastic corpus callosum,
especially in the rostral segment (arrows). B,
Axial T2-weighted brain MRI of the same patient
demonstrating subtle increase of the white matter
signal in the forceps minor area of corpus callosum,
resembling ears of the lynx (arrows).

AUTOSOMAL RECESSIVE HEREDITARY SPASTIC PARAPLEGIA WITH COMPLICATED

PHENOTYPE OVERLAPPING WITH MOTOR NEURON DISORDERS. The hallmark of
motor neuron diseases is degeneration of both upper and lower motor neurons,
and considerable overlap exists with the HSPs (TABLE 7-6). Amyotrophy can be
present in many types of HSP, and Silver syndrome is one typical example.37 The
phenotype of SPG11 (spatacsin) is quite variable and is also an allelic condition
with the previously mapped type of autosomal recessive ALS type 5, which is an
otherwise indistinguishable form of juvenile-onset motor neuron disease with
onset before 25 years of age.57
TABLE 7-6 Autosomal Recessive Hereditary Spastic Paraplegia Overlapping With

Motor Neuron Disease
Age of Genetic Additional Clinical

Genetic Type Mutated Gene/Protein Onset Epidemiology Features
SPG20 (Troyer syndrome) SPART/spartin Juvenile Rare, mostly seen Distal amyotrophy, short
among Old Order stature, kyphoscoliosis,
Amish multiple limb contractures
SPG26 B4GALNT1/b-1,4-N- Juvenile Rare Amyotrophy, dysarthria,

acetylgalactosaminyl ataxia, developmental
transferase 1 delay, dystonia
SPG39 PNPLA6/neuropathy target Childhood Rare Amyotrophy, endocrine

esterase abnormalities with short
stature
SPG43 C19ORF12 Childhood Rare Amyotrophy, dysarthria,

multiple contractures
SPG62 ERLIN1 Childhood Rare Amyotrophy, ataxia
SPG68 FLRT1 Childhood Rare Amyotrophy, nystagmus,

optic atrophy
SPG classification not BICD2 Childhood Rare Amyotrophy, contractures

assigned
SPG classification not GRID2 Childhood Rare Amyotrophy, ataxia

assigned
Infantile-onset ascending ALS2/alsin Infantile to Rare 1:1,000,000 Quadriparesis,

spastic paralysis/ juvenile pseudobulbar palsy,
amyotrophic lateral amyotrophy
sclerosis type 2
SPG = spastic gait.
536 APRIL 2018

SPG20, also known as Troyer syndrome, is caused by mutations in the SPG20
gene encoding spartin protein.59 SPG20 was originally described in the Amish
community, but it can be found worldwide. Prominent distal amyotrophy and
slowly progressive spasticity are associated with a short stature, kyphoscoliosis,
and multiple limb contractures.60
SPG39, caused by mutations in the PNPLA6 gene encoding neuropathy target
esterase is very similar to Troyer syndrome, although many patients have no
skeletal abnormalities.61 A complex phenotype of this condition was previously
described as Laurence-Moon syndrome or Oliver-McFarlane syndrome, where
short stature is caused by multiple pituitary hormone deficiencies, including
growth hormone deficiency.62 Severe muscular atrophy is also a common feature
of SPG43, caused by mutations in the C19ORF12 gene. This is combined with
dysarthria and, in later stages, with multiple contractures.63 Another member of
this subgroup is SPG62, with mutations in the ERLIN1 gene, and amyotrophy is
commonly accompanied by cerebellar ataxia.51 SPG68 is caused by FLRT1
mutations, and amyotrophy is combined with nystagmus and optic atrophy.51
Progress in molecular diagnostics has connected several previously described
autosomal recessive syndromes with HSPs, although the currently used nomenclature
does not include these conditions as HSP. Biallelic mutations in the BICD2 gene cause
HSP with an early age of onset and severe amyotrophy that may suggest the diagnosis
of SMA.64 SMAs comprise a group of disorders characterized by progressive flaccid
weakness and muscle atrophy due to selective degeneration of the spinal cord lower
motor neurons; bulbar lower motor neurons can be also affected.65
Mutations in BICD2 may also be inherited in an autosomal dominant fashion,
and this type of HSP is allelic with autosomal dominant SMA type 2A, with an
early age of onset and contractures.64 GRID2 mutations is another cause of HSP
that may be confused with SMA, but the presence of cerebellar signs helps to
differentiate these two syndromes.66
Complicated autosomal recessive HSPs tend to manifest with more widespread
spasticity and may also affect the upper extremities or bulbar muscles. This
combination of clinical signs may be considered primary lateral sclerosis rather
than HSP, especially if the clinical involvement of dorsal columns is not apparent.67
The designation of primary lateral sclerosis is still somewhat controversial, with
some preferring to consider it a variant of ALS without clear involvement of
lower motor neurons. The most common criteria differentiating primary lateral
sclerosis from ALS require the absence of denervation 5 years since the onset of
spasticity.68 The vast majority of primary lateral sclerosis is considered a sporadic
condition with an average age of onset after 40 years and an asymmetric onset,
including a spastic monoparesis. However, infantile onset has been described, and
this condition is known as infantile-onset ascending spastic paralysis. This
condition may clinically resemble HSP, primary lateral sclerosis, or ALS because
signs of distal amyotrophy emerge in later stages of the disease. It was not
classified under the HSP system but is identical with ALS type 2. Recessive
mutations in the ALS2 (alsin) gene are the only known cause of this syndrome.69
Most patients develop severe pseudobulbar palsy with anarthria and severe dysphagia.
Paresis of horizontal gaze may be seen in patients with a long-term survival.
AUTOSOMAL RECESSIVE HEREDITARY SPASTIC PARAPLEGIA OVERLAPPING WITH

LEUKODYSTROPHIES. The pathologic substrate for diffuse spasticity varies, and
most myelopathies are caused by relatively selective axonal degeneration.

Additional causes may include abnormalities of myelin formation and

maintenance, and genetically based conditions are traditionally classified as
leukodystrophies. However, previous phenotypic classification of these disorders
was commonly based on the main symptom of spasticity and, thus, they were
also considered HSP (TABLE 7-7).7,8 This article reviews them with other
myelopathies, although it is possible that future classification schemes may not
consider these syndromes as myelopathies.
Neuroimaging of the spinal cord is typically not very helpful in the evaluation
of HSPs because it is unremarkable in the majority of patients, and the main
purpose of imaging is to exclude secondary causes, such as compressive lesions.
Paradoxically, brain imaging may be more useful because it can reveal several
potential abnormalities that may provide important diagnostic clues in this very
heterogeneous syndrome.1
Patients with SPG5A with CYP7B1 mutations who exhibit a complex
phenotype rather than pure HSP typically have a widespread leukodystrophy on
brain MRI.43,45 SPG26 caused by mutations in the B4GALNT1/b-1,4-N-
acetylgalactosaminyl transferase 1 gene causes a diffuse hypomyelination, and
spasticity is associated with ataxia and mild amyotrophy.70 White matter
changes with hypomyelination are also common in SPG35 caused by fatty acid
2-hydroxylase gene (FA2H) mutations.71 These patients have a high incidence of
seizures, parkinsonism, and dystonia. Iron accumulation in the basal ganglia is
also common and may account for the hypokinetic-rigid syndrome in these
patients.72 Homozygous mutations in the GJC2/connexin 47 gene are the cause of
SPG44, characterized by a complex phenotype that also includes febrile seizures,
deafness, and episodic spasms.73 SPG44 is allelic with autosomal recessive
hypomyelination leukodystrophy type 2, and a diffuse leukodystrophy with
hypoplastic corpus callosum are typical MRI findings. Mutations in the NT5C2
gene cause SPG45, which has similar clinical and radiologic findings as SPG44.74
Severe infantile encephalopathy with hypotonia evolving into severe
spasticity, profound mental retardation, and dysmorphic features is associated
with SPG47, SPG50, SPG51, and SPG52. These conditions are all caused by
mutations in different subunits of the adaptor-related protein AP4-complex.
These rare HSPs are clinically indistinguishable, but the diagnostic clue for all of
them is a stereotypical laughter with tongue protrusion and overall smiling
attitude.75,76 Other rare types of autosomal recessive HSP with white matter
disease are summarized in TABLE 7-7.
AUTOSOMAL RECESSIVE HEREDITARY SPASTIC PARAPLEGIA WITH COMPLICATED

PHENOTYPE. This section includes other types of autosomal recessive HSP that
may have variable signs from other subgroups, but they are not constantly
present to include them in other subgroups. Thus, this clinical clustering is not
absolute, and substantial clinical overlap exists (TABLE 7-8).
SPG18 is caused by mutations in the ERLIN2 gene.77 These patients develop
severe contractures with muscle atrophy. SPG21 is another prototypical
complicated HSP with ataxia, parkinsonism, polyneuropathy, and adult-onset
dementia. Mutations in the ACP33 gene encoding maspardin protein were first
identified among the Old Order Amish, where it was described as Mast
syndrome.78 SPG21 was later identified in different ethnic groups.
SPG46 is another complicated HSP with developmental delay, ataxia, hearing
loss, and polyneuropathy. Causative mutations are found in the GBA2 gene,
538 APRIL 2018

Autosomal Recessive Hereditary Spastic Paraplegia Overlapping With TABLE 7-7
Leukodystrophies
Genetic Age of Genetic

Type Mutated Gene/Protein Onset Epidemiology Additional Clinical Features
SPG26 B4GALNT1/b-1,4-N- Childhood Rare Amyotrophy, dysarthria, ataxia,

acetylgalactosaminyl developmental delay, dystonia
transferase 1
SPG35 FA2H/fatty acid 2-hydroxylase Childhood Rare Seizures, dystonia, parkinsonism with iron
accumulation in basal ganglia
SPG44 GJC2/connexin 47 Childhood Rare Febrile seizures, deafness, episodic spasms
SPG45 NT5C2 Childhood Rare Optic atrophy, nystagmus, strabismus
SPG47 AP4B1 Infancy Rare Severe mental retardation, facial

dysmorphism, seizures, stereotypical laughter
with tongue protrusion
SPG50 AP4M1 Infancy Rare Same as SPG47
SPG51 AP4E1 Infancy Rare Same as SPG47
SPG52 AP4S1 Infancy Rare Same as SPG47
SPG54 DDHD2 Infancy Rare Severe developmental delay, optic atrophy,

thin corpus callosum
SPG56 CYP2U1 Infancy Rare Severe developmental delay, dystonia,

polyneuropathy
SPG63 AMPD2 Infancy Rare Pure hereditary spastic paraplegia (HSP), short
stature, thin corpus callosum, white matter
changes may be mild
SPG64 ENTPD1 Infancy Rare Mild cognitive disability, behavioral

disturbances, white matter changes may be
mild
SPG67 PGAP1 Infancy Rare Severe developmental delay, tremor, agenesis

of corpus callosum, hypomyelination
SPG = spastic gait.

TABLE 7-8 Autosomal Recessive Hereditary Spastic Paraplegia With Complex

Phenotype
Age of Genetic
Genetic Type Mutated Gene/Protein Onset Epidemiology Additional Clinical Features
SPG18 ERLIN2 Childhood Rare Developmental delay, seizures,

contractures
SPG21 (Mast syndrome) ACP33/maspardin Childhood Rare Ataxia, adult-onset dementia and
parkinsonism, polyneuropathy
SPG30 KIF1A Childhood Rare Spastic ataxia
SPG46 GBA2/nonlysosomal Childhood Rare Developmental delay, ataxia,

glucosylceramidase hearing loss, polyneuropathy
SPG49 TECPR2 Childhood Rare Central apnea, severe

developmental delay, microcephaly,
dysmorphic features
SPG57 TFG Childhood Rare Optic atrophy, severe

polyneuropathy
SPG58 KIF1C Childhood Rare Spastic ataxia (spastic ataxia type 2

[SPAX2])
SPG60 WDR48 Infantile Rare Polyneuropathy, developmental

delay
SPG61 ERLIN1 Infantile Rare Polyneuropathy, acropathy
SPG70 MARS Infantile Rare Nephrotic syndrome,

polyneuropathy
Sjögren-Larsson ALDH3A2/fatty aldehyde Early Rare Ichthyosis, macular dystrophy,

syndrome dehydrogenase childhood leukoencephalopathy
Spastic paraplegia, optic KLC2/kinesin light chain 2 Childhood Rare Optic atrophy, neuropathy
atrophy, and neuropathy
(SPOAN)
SPG classification not KLC4/kinesin light chain 4 Childhood Rare Ataxia, multiple contractures,
assigned variable degree of leukodystrophy
SPG = spastic gait.
540 APRIL 2018

encoding the nonlysosomal glucosylceramidase.79 SPG49 is an especially severe
form because central apnea is the frequent cause of death in the first year of
life. Spasticity, severe developmental delay, microcephaly, and dysmorphic
features are caused by mutations in the TECPR2 gene.80 SPG57 is another rare
form caused by mutations in the TFG gene, and spasticity is accompanied by
optic atrophy and severe polyneuropathy.81 The dominant form of this disease is
known as hereditary motor and sensory neuropathy of Okinawa type.82
Polyneuropathy is a feature of additional rare types, such as SPG60, SPG61, and
SPG70.8,9 SPG61 is caused by mutations in the ERLIN1 gene, and severe mental
retardation and seizures are also common.51
Sjögren-Larsson syndrome is an autosomal recessive entity encompassing an
early childhood–onset of spasticity associated with macular dystrophy,
leukoencephalopathy, and ichthyosis, which is the most characteristic feature of
this disease.83 In spite of the development of a typical spastic paraparesis, this
syndrome, caused by mutations in ALDH3A2/fatty aldehyde dehydrogenase, is
not included in the SPG nomenclature.83
Disruption of kinesins, which are microtubule-based motor proteins, is an
important mechanism of HSPs, and SPG30 is caused by homozygous KIF1A
mutations.84 Spasticity is combined with ataxia, which overlaps with SPAXs. The
syndrome of spastic paraplegia, optic atrophy, and neuropathy (SPOAN) is
caused by mutations in the KLC2 (kinesin light chain 2) gene.85 Another member
of this family associated with spasticity disorder is KLC4, encoding the kinesin
light chain 4. Childhood-onset spasticity is complicated by cerebellar ataxia,
multiple contractures, and variable degrees of leukodystrophy.86 These two
entities were not included in the SPG system of classification, although,
undoubtedly, this is a form of complicated HSP with autosomal recessive
inheritance. Furthermore, a similar condition is caused by homozygous
mutations in the KIF1C gene with coexisting ataxia and spasticity. KIF1C-related
neurodegeneration has been classified as SPG58 or as autosomal recessive SPAX
type 2 (SPAX2).87,88 Other SPAXs are reviewed in the following section. These
examples support a need for a new classification of these conditions combining
phenotypic and genotypic features.
X-linked Hereditary Spastic Paraplegia

X-linked HSP is the rarest form of HSP with only 5 known loci on the X
chromosome and 3 identified genes so far (TABLE 7-9). X-linked HSP
predominantly affects males because they have a recessive X-linked or
intermediate inheritance, and female carriers rarely manifest a mild disease
related to skewed X chromosome inactivation.
SPG1 is also known as mental retardation, aphasia, shuffling gait, and
adducted thumbs (MASA) syndrome.89 The adducted thumbs are thought to be
caused by hypoplastic or absent extensor pollicis longus or brevis muscles. This
form of HSP is allelic with X-linked aqueductal stenosis and hydrocephalus,
because both of these disorders are caused by mutations in the L1CAM gene.89
The spastic paraplegia component is almost always complicated by other
features; corpus callosum hypoplasia, retardation, adducted thumbs, spastic
paraplegia, and hydrocephalus (CRASH) is an example. Obstructive
hydrocephalus is not the cause of spasticity as patients with successful shunt
surgery may still experience a progressive gait disorder caused by
neurodegeneration of the corticospinal tracts.

SPG2 is allelic with Pelizaeus-Merzbacher disease, but the spectrum of mutations

in the proteolipid protein 1 (PLP1) gene differs between these two disorders.90 HSP
may be pure in the initial stages of the disease, but most patients later develop
nystagmus, dysarthria, sensory disturbance, mental retardation, and optic atrophy.
MRI of the brain shows patchy leukodystrophy in many patients with SPG2.
SPG22 is the third X-linked form with a known genetic cause, and mutations
in the SLC16A2 gene have been identified in these patients. SPG22 is allelic with
Allan-Herndon-Dudley syndrome, characterized by severe mental retardation,
spasticity, ataxia, and dystonia.91 Endocrine abnormalities are also present, with
elevated T3 and thyroid-stimulating hormone (TSH) levels due to T3
insensitivity. Neuroimaging findings are consistent with hypomyelination.
SPASTIC ATAXIAS
Dysmetria, dysdiadochokinesis, scanning dysarthria, and oculomotor abnormalities
are signs of cerebellar disease or reflect disruption of cerebellar outflow circuits.
Neurodegenerative ataxias can be accompanied by additional neurologic
problems, including spasticity. The severity and frequency of spasticity varies
among various genetic types of ataxias.9 However, several inherited types of
neurodegenerative ataxias may occasionally present as myelopathies because of
severe spasticity affecting the lower extremities, and differentiating between
these entities is sometimes virtually impossible on clinical grounds alone.92
Spasticity may be a key clinical feature in a subset of inherited ataxias that are
classified as spastic ataxias (SPAXs) rather than spinocerebellar ataxias (SCAs)
(TABLE 7-10). Spasticity in SPAXs is an early sign, and other signs of ataxia may
TABLE 7-9 X-linked Hereditary Spastic Paraplegia
Mutated Gene/Protein/
Genetic Chromosomal Localization Age of Genetic
Type if Gene Unknown Onset Epidemiology Additional Clinical Features
SPG1 L1CAM Childhood Rare Mental retardation, adducted thumbs, corpus
callosum hypoplasia, aphasia, obstructive
hydrocephalus
SPG2 PLP1/proteolipid protein 1 Childhood Rare Nystagmus, optic atrophy, dysarthria, mental
retardation, leukodystrophy
SPG16 Xq11-q23 Infantile Rare Optic atrophy, aphasia, mental retardation,

dysmorphic features
SPG22 SLC16A2 Childhood Rare Severe mental retardation, spasticity, ataxia,

dystonia, endocrine abnormalities
hypomyelination
SPG34 Xq24-q25 Childhood Single family Pure phenotype
SPG = spastic gait.
542 APRIL 2018

be either subtle or absent in the early stages of the disease. It is a
heterogeneous group with both autosomal dominant and autosomal recessive
inheritance.9 SPAX1 is the only condition in this category with autosomal
dominant inheritance and an identified genetic cause.9,93 Several other
reported syndromes exist, including SPAX7 and spastic paraplegia, ataxia,
mental retardation (SPAR), but their genetic background remains unknown
and they are not discussed in this article. Isolated leg spasticity is a typical
presentation of SPAX1 during young adulthood followed by variable severity
of ataxia with dysarthria and dysphagia.93 Oculomotor abnormalities may
be overlooked in the early stages, making the diagnosis of SPAX difficult.
Identification of mutations in the VAMP1 gene is the only way to definitively
confirm the diagnosis.
SPAX2 overlaps with autosomal recessive SPG58 and was reviewed in the HSP
section.88 SPAX3 is another prototypical SPAX with the average age of onset
around 15 years, but the onset can vary from 2 to 59 years of age. All patients have
a spastic and ataxic gait with dysarthria, but nystagmus is present in less than
half of these patients. Mutations in the MARS2 gene are the only cause of SPAX3,
and the disease is mostly reported among French Canadians.94 SPAX4 is a rare
entity with only one family from the Old Order Amish background known.
Affected subjects exhibit spastic paraparesis with delayed gain of motor
milestones followed by signs of cerebellar ataxia. Homozygous mutation in the
MTPAP gene is the cause of SPAX4.95
Spastic Ataxias TABLE 7-10
Genetic Mutated Mode of

Type Gene/Protein Inheritance Age of Onset Genetic Epidemiology Additional Clinical Features
Spastic VAMP1 Autosomal Adulthood Rare Leg spasticity is presenting

ataxia type 1 dominant (fourth to fifth symptom, signs of ataxia occur
decade) later; dysarthria; cognitive
decline
Spastic KIF1C Autosomal Childhood Rare Spastic ataxia, overlaps with

ataxia type 2 recessive SPG58
Spastic MARS2 Autosomal Infantile Rare Spasticity, ataxia, dysarthria

ataxia type 3 recessive
Spastic MTPAP Autosomal Childhood Rare Spasticity, delayed motor

ataxia type 4 recessive development
Spastic AFG3L2 Autosomal Childhood Rare Spastic ataxia, myoclonic

ataxia type 5 recessive epilepsy
Spastic SACS/sacsin Autosomal Childhood 1:1932 in Quebec, Canada, Retinal striation,

ataxia type 6 recessive possibly 37% of all ataxias polyneuropathy
with young age of onset

KEY POINTS The potentially distinguishing clinical feature of SPAX5, caused by

homozygous or compound heterozygous mutations in the AFG3L2 gene, is the
● Spastic ataxias are
classified outside the
occurrence of myoclonic epilepsy.96 Typically, epilepsy is preceded by severe
classification scheme of spasticity, ataxia, and dystonia, encompassing a generic phenotype of SPAXs.
spinocerebellar ataxias. Rare patients who experience isolated progressive myoclonus without any ataxia
or spasticity have been reported.97 Single allele mutations in the AFG3L2 gene
● Spastic ataxias can be
cause autosomal dominant SCA23.98
inherited as autosomal
dominant or autosomal SPAX6, also known as autosomal recessive SPAX of Charlevoix-Saguenay,
recessive conditions. is caused by mutations in the SACS gene encoding the sacsin protein.99
Although it was originally identified among the French-Canadian population
● Prominent spasticity, of northeastern Quebec, it has been subsequently identified worldwide.100
which is commonly a
presenting feature, It may account for up to 37% of all ataxias with young onset. SPAX6 has an
distinguishes spastic ataxias early age of onset, and most patients never walk normally. Overall, it may be
from other types of easily confused with autosomal recessive HSP, and many patients resemble
cerebellar degeneration, patients with SPG20/Troyer syndrome; however, often subtle extraocular
but considerable clinical
overlap exists.
movement abnormalities suggest the diagnosis.101 An additional specific
clinical finding is retinal striation, resulting from prominent retinal nerves
obscuring the retinal blood vessels.
SCAs are degenerative ataxias involving the cerebellum as well as the
brainstem, spinal cord, and cerebrum. Although SCAs involve several systems in
the central nervous system, the distribution of the pathologic lesions is unique
to each degenerative ataxia. The estimated prevalence of autosomal dominant
SCAs can be up to 3.0 per 100,000 individuals worldwide.10,11 Prominent
spasticity caused by corticospinal tract involvement is particularly common in
SCAs types 1, 2, and 3, accounting for approximately 40% of all autosomal
dominant SCA.100 All three types of SCA are caused by the expansion of CAG
repeats, and expansion in successive generations may lead to genetic anticipation
with an earlier age of onset and more severe clinical phenotypes in children of
affected parents. Motor phenotypes vary considerably among SCAs, and SCA3,
also known as Machado-Joseph disease, is the most common condition that
clinically overlaps with HSP.102 Several patients with SCA3 who manifest only a
spastic gait without any obvious cerebellar signs have been diagnosed with
HSP rather than an SCA. The emergence of oculomotor abnormalities should
prompt the diagnosis of SCA rather than HSP, because cerebellar signs are
extremely rare in autosomal dominant HSP.92 Spasticity can be a feature of other
types of SCA, such as SCA8 and SCA17, and molecular diagnosis is necessary for
the definitive differentiation of HSP and SCA in these patients.
Friedreich ataxia is the most common autosomal recessive ataxia, with a
prevalence of 1 per 50,000 individuals.103 The most common disease-causing
molecular mechanism is a GAA trinucleotide repeat expansion in intron 1 of the
FXN (frataxin) gene. The disease-causing range of GAA repeats is quite broad,
ranging from 70 to more than 1000, and patients with a higher number of repeats
tend to have an earlier onset and more systemic complications, including
scoliosis, diabetes mellitus, and hypertrophic cardiomyopathy.103 Since the
discovery of the genetic basis of Friedreich ataxia, atypical and late-onset forms
of the disease have also been identified. Late-onset Friedreich ataxia is defined as
onset after 25 years of age and is usually caused by smaller GAA repeat
expansions or point mutations in the frataxin gene. Patients more often have
isolated lower limb spasticity and retained or even brisk reflexes, clinically
resembling spastic paraparesis (CASE 7-2).104 Compared to the classic Friedreich
544 APRIL 2018

ataxia, patients with the late-onset form tend to have a milder and more slowly
evolving disease with fewer non-neurologic manifestations of the disease.
CONCLUSION
Hereditary myelopathies are very diverse genetic disorders, and the exclusion of
potentially treatable causes remains the most important diagnostic step. Syndromic
A 35-year-old woman was evaluated for a long-standing history of CASE 7-2

abnormal gait. She had developed an abnormal gait around 10 years of age,
which progressively led to use of a cane 10 years later. Since that time her
symptoms had been relatively stable, and she had reported no other
problems other than mild urinary urgency. The rest of her history was
unremarkable. She had one unaffected sibling, and there was no
consanguinity between her parents.
Neurologic examination showed severe spasticity limited to the lower
extremities with hyperactive reflexes and upgoing toes. The rest of her
examination was normal. Her neuroimaging was unremarkable, and
genetic testing was negative for the most common causes of autosomal
dominant and autosomal recessive hereditary spastic paraplegia (HSP).
The patient later reported that one of her cousins had developed
progressive neurologic problems, and her description of the cousin
suggested ataxia rather than HSP. Genetic testing was expanded with
additional molecular testing focused on autosomal dominant and
autosomal recessive ataxias. This test revealed an abnormal intronic GAA
triplet expansion in the first intron of the frataxin gene with 355 and 630
repeats, confirming the diagnosis of Friedreich ataxia with an atypical
phenotypic presentation. Her cousin was also tested, and the same
diagnostic conclusion was reached. Two-dimensional cardiac echo was
ordered with normal results. Nerve conduction studies and EMG did not
show any signs of polyneuropathy.
This patient presented with spastic paraparesis, and both autosomal COMMENT
dominant and autosomal recessive causes were considered. The correct
diagnosis was reached only after the identification of a second-degree
relative with ataxia. The diagnosis of Friedreich ataxia is typically
established by the presence of cerebellar ataxia and spasticity with absent
reflexes due to axonal polyneuropathy. The availability of genetic testing
for Friedreich ataxia has expanded the known phenotypes of Friedreich
ataxia, and one subtype is pure HSP without any additional cerebellar signs
or signs of axonal polyneuropathy. These patients tend to have a lower
range of GAA repeats, but no obvious genotype/phenotype correlation has
been established. The diagnosis is very difficult to establish without any
additional diagnostic clues but is important for further management
because of the potential for developing cardiomyopathy or early diabetes
mellitus in Friedreich ataxia.

diagnosis can be supported by molecular diagnosis, but the genetic diagnosis does not
change the management, which remains purely symptomatic. Moreover, negative
genetic testing does not exclude this diagnosis because comprehensive molecular
testing is not yet available, and many disease-causing genes remain unknown.
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Hereditary Myelopathies REVIEW ARTICLE

RECENT FINDINGS: The ever-growing number of myelopathy-causing genes

SUMMARY: The exclusion of potentially treatable causes of myelopathy

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hyperactivity, and dorsal column dysfunction. Dysmetria, if present, is typically

HEREDITARY SPASTIC PARAPLEGIAS

524 APRIL 2018

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Classification ● Clinical signs of hereditary

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526 APRIL 2018

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AUTOSOMAL DOMINANT HEREDITARY SPASTIC PARAPLEGIA WITH UNCOMPLICATED

SPG3 SPG3A/atlastin-1 Very early, 80% of early-onset autosomal Musculoskeletal problems,

SPG12 RTN2/reticulon 2 Before age 5% of early-onset autosomal Uncomplicated phenotype

SPG DNM2/dynamin 2 Before age Rare Mild dysarthria, allelic with

SPG = spastic gait.

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AUTOSOMAL DOMINANT HEREDITARY SPASTIC PARAPLEGIA WITH UNCOMPLICATED

528 APRIL 2018

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SPG6 NIPA1/nonimprinted gene Adulthood Rare (approximately 1% of Severe weakness and

SPG8 WASHC5/strumpellin Adulthood Rare (approximately 1% of Some patients have

SPG13 HSPD1/heat shock 60kD Adulthood Rare Mild distal

SPG19 9q33-q34 Adulthood Single family Slow progression

SPG31 REEP1/receptor accessory Variable from 4–6% Mild distal

SPG33 ZFYVE27/protrudin Adulthood Single family Pes cavus

SPG41 11p14.1-p11.2 Early adulthood Single family None

SPG42 SLC33A1/acetyl-coenzyme A Early adulthood Single family Slowly progressive,

SPG73 CPTIC/carnitine Early adulthood Single family Mild distal

SPG classification PMCA4 (ATP2B4) Adulthood Single family None

SPG = spastic gait.

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mostly an uncomplicated phenotype other than mild distal amyotrophy. Mutations

AUTOSOMAL DOMINANT HEREDITARY SPASTIC PARAPLEGIA WITH A COMPLICATED

530 APRIL 2018

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Autosomal Recessive Hereditary Spastic Paraplegia

Autosomal Dominant Hereditary Spastic Paraplegia With Complicated TABLE 7-3

SPG9 ALDH18A1/aldehyde Juvenile or Rare Cataracts, motor

SPG10 KIF5A/kinesin 1 Juvenile or 1–2% of all autosomal dominant Sensorimotor neuropathy

SPG17 (Silver BSCL2/seipin Adulthood Rare Distal amyotrophy, motor

SPG29 1p31.1-p21.1 Juvenile Single family Hearing loss, hiatal hernia,

SPG36 1q23-q24 Adulthood Single family Demyelinating polyneuropathy

SPG38 4p16-p15 Adulthood Single family Silver syndrome, resembles

SPG ATAD3A/ATPase Early onset Single family Amyotrophy, hyperkinetic

SPG TUBB4A/ tubulin beta Juvenile Rare Cerebellar ataxia, MRI

MRI = magnetic resonance imaging; SPG = spastic gait.

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AUTOSOMAL RECESSIVE HEREDITARY SPASTIC PARAPLEGIA WITH UNCOMPLICATED

AUTOSOMAL RECESSIVE HEREDITARY SPASTIC PARAPLEGIA WITH HYPOPLASIA OF

532 APRIL 2018

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SPG25 6q23.3-q24.1 Adulthood Rare Familial disk herniation

SPG28 DDHD1/phosphatidic Childhood Rare Scoliosis

SPG48 AP5Z1 adaptor related Adulthood Single family Urinary incontinence

SPG59 USP8/ubiquitin specific Childhood Rare None

MRI = magnetic resonance imaging; SPG = spastic gait.

Autosomal Recessive Hereditary Spastic Paraplegia With Hypoplasia of TABLE 7-5

SPG55 C12ORF65 Childhood Rare Developmental delay, visual loss,

SPG = spastic gait.

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534 APRIL 2018