Review Article

Hereditary
Address correspondence
to Dr Peter Hedera,
Department of Neurology,
Vanderbilt University,
465 21st Avenue South,
6140 MRB III, Nashville,
TN, 37232, peter.hedera@
Myelopathies
vanderbilt.edu.
Peter Hedera, MD, PhD, FACMG
Relationship Disclosure:
Dr Hedera has received a
grant from NIH/NINDS.
Unlabeled Use of ABSTRACT
Products/Investigational
Use Disclosure:
Hereditary myelopathies comprise a diverse group of disorders whose signs and
Dr Hedera reports symptoms include progressive spasticity, limb ataxia without additional cerebellar
no disclosure. signs, impaired vibration and positional sensation, and a variable degree of neurogenic
Copyright * 2011, weakness, all suggesting spinal cord impairment. Recent progress in the understanding
American Academy of
Neurology. All rights of hereditary myelopathies has revealed that many are systemic processes with wide-
reserved. spread axonal degeneration. However, the concept of hereditary myelopathies remains
clinically helpful in differentiating hereditary myelopathies from other potentially
treatable myelopathies. In this article, hereditary myelopathies are divided into four
categories: hereditary spastic paraplegias, motor neuron disorders, spinocerebellar and
spastic ataxias, and metabolic disorders, including leukodystrophies.

Continuum Lifelong Learning Neurol 2011;17(4):800–815.

INTRODUCTION Recent progress in the elucidation of

Hereditary myelopathies comprise a di-
verse group of neurodegenerative and
neurometabolic disorders that are his-
torically defined based on their clinical
presentation indicating predominant
spinal cord dysfunction. Clinical symp-
toms and signs that suggest spinal cord
pathology include the following:
& Progressive and gradual spasticity
and weakness mostly limited
to the lower extremities with
variable involvement of the
upper extremities caused by
neurodegeneration of the
pyramidal tracts (syndrome of
spastic paraparesis or paraplegia)
& Limb ataxia without oculomotor
abnormalities and dysarthria
caused by neurodegeneration
of the spinocerebellar tracts
& Impaired vibration and positional
sensation reflecting the
involvement of dorsal columns
& Flaccid weakness and hypotonia
caused by selective degeneration
of lower motor neurons
molecular and genetic mechanisms of
these disorders has revealed that many
myelopathies actually represent a sys-
temic process with a widespread central
or peripheral nervous system pathology.
Despite this new understanding, the con-
cept of hereditary myelopathies remains
conceptually useful because they often
need to be differentiated from other
well-defined myelopathies, such as those
caused by compressive, vascular, and in-
flammatory etiologies.
Classification of hereditary myelopa-
thies is currently based on a combination
of clinical, genetic, and pathologic fea-
tures. Although some overlap exists, the
most commonly used categorization rec-
ognizes four major groups: hereditary
spastic paraplegias (HSPs), motor neuron
disorders, spinocerebellar and spastic
ataxias, and metabolic disorders, including
leukodystrophies. HSP is considered a
prototypical example of selective, length-
dependent (distal) axonopathy. Motor
neuron disorders include conditions with
variable involvement of upper and lower

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motor degeneration and have consider-
able overlap with HSPs; however, the
prognosis of HSP and motor neuron
disorder differs, and the precise classifica-
tion may facilitate future care. Ataxias with
an isolated spasticity are typically diag-
nosed by molecular (genetic) testing, and
these patients have a somewhat atypical
presentation of genetic ataxias; however,
their correct diagnosis is important be-
cause of the need to manage other clinical
problems commonly associated with
inherited ataxias. Finally, clinical presenta-
tion of neurometabolic disorders may also
be limited to the syndrome of myelopathy
rather than diffuse involvement of the
KEY POINT
CNS. These disorders also may be asso- h Hereditary myelopathies
ciated with additional clinical problems comprise four entities:
that need to be actively identified and hereditary spastic
managed, such as adrenal insufficiency. paraplegias, motor
This article reviews these four major neuron disorders,
types of hereditary myelopathies. It will spinocerebellar and
not specifically focus on other genetic spastic ataxias, and
conditions with variable presentations metabolic disorders.
that can also include a syndrome of spas-
tic paraparesis (including a spastic gait
variant of Alzheimer disease with prese-
nilin 1 mutations), levodopa-responsive
dystonia (Segawa disease), or mitochon-
drial disorders. These conditions are
included in Table 5-1 on differential diag-
nosis of hereditary myelopathies.

TABLE 5-1 Differential Diagnosis of Hereditary Myelopathies

Distinctive Features From

Cause of Myelopathy Hereditary Myelopathies
Structural spinal cord Radiculopathy
abnormalities
Sensory level
Multiple sclerosis Remitting/relapsing course
Optic neuritis
Infectious myelopathies Constitutional symptoms
Mitochondrial disorders Vision and hearing loss
Short stature
Hypertrophic cardiomyopathy
Migraine headaches
Metabolic myelopathies Systemic manifestation
(other than those reviewed (hematologic problems)
in this article)
Alzheimer disease variant Development of dementia of
Alzheimer disease type
Segawa disease Diurnal variation of gait
(levodopa-responsive dystonia) disorder
Diplegic form of cerebral palsy Perinatal history
Static course
Diagnostic Evaluation
Neuroimaging (MRI)
Spinal angiogram in vascular causes
MRI
CSF analysis
Evoked potentials
CSF analysis
Human T-cell lymphotropic virus type I and
HIV serologies
Lactic acidosis
Ragged red fibers and other abnormalities of
oxidative phosphorylation on muscle biopsy
Genetic analysis
Vitamin B12 and methylmalonic acid levels
Copper levels (zinc levels if hyperzincemia is
cause of copper deficiency)
Presenilin 1 genetic analysis
PET scan
Amyloid imaging
Challenge with levodopa
Genetic analysis
Neuroimaging

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 Hereditary Myelopathies

KEY POINT
h Hereditary spastic
paraplegia is
characterized by
progressive spastic
weakness in the legs,
impaired vibration
sensation, and
bladder hyperactivity.
HEREDITARY SPASTIC
PARAPLEGIA
HSP is one of the most genetically heter-
ogeneous neurodegenerative syndromes,
with more than 50 genes resulting in a
quite stereotypical and mostly indis-
tinguishable clinical phenotype.1 The
clinical hallmark of HSP is a gradual and
progressive spastic weakness of the
lower extremities that is associated with
variable degrees of impaired vibration
sensation and autonomic dysfunction
with bladder and occasionally anal
sphincter hyperactivity. The prevalence
of HSP has been estimated to be be-
tween 1.27 and 9.6 per 100,000. Thus,
these patients are relatively commonly
encountered by practicing neurologists.2
Stumbling caused by difficulties with
foot dorsiflexion is typically the present-
ing symptom of spastic gait and usually
progresses into a characteristic scissor-
ing gait. Some individuals are unaware of
the disease and describe their gait as a
typical familial trait; therefore, if possi-
ble, it is preferable to examine several
first-degree relatives of patients who do
not report positive family history of gait
disorder. Spastic paraparesis is mostly
symmetrical, but many patients report a
slightly asymmetric onset, and, even in
an advanced disease, they perceive one
leg as worse than the other. More pro-
nounced asymmetry of spastic parapare-
sis usually warrants further investigation
to exclude structural and compressive
causes, even in patients with a positive
family history; however, spastic mono-
paresis affecting only one leg can occur
in patients with neurodegenerative
HSP, although this is rare. Spasticity is
more prominent than weakness, which
initially tends to be limited to distal leg
muscles; proximal muscle strength is
impaired in more advanced stages of
the disease. More profound proximal
weakness, especially early in the course
of the disease, should prompt a search
for an alternative diagnosis. Spasticity
examination sometimes shows relatively
mild resistance to passive stretch,
whereas walking accentuates its degree
dramatically. Untreated spasticity may
result in severe spasticity at rest and can
include contractures and wheelchair de-
pendency. Examination of upper extrem-
ities may reveal mild hyper-reflexia with
additional pyramidal signs (Troemner
and Hoffman signs), but other hallmarks
of pyramidal involvement, most notably
loss of dexterity, will be absent.
The age of disease onset in patients
with HSP ranges from infancy to the
seventh decade.3 Even though signifi-
cant intrafamilial variability exists, the
age of onset may be helpful in deter-
mining the most likely genetic type of
HSP. For example, SPG3A (SPG refers
to spastic gait and 3A refers to the order
of identification of this genetic locus),
which is caused by mutations in the
atlastin GTPase 1 gene, ATL1, accounts
for most early-onset (less than 10 years
of age) autosomal dominant (AD) HSP.
Infantile onset is commonly associated
with a delayed acquisition of indepen-
dent walking and must be distinguished
from perinatal encephalopathy (diplegic
form of cerebral palsy [CP]). The pro-
gressive nature of the gait disorder
and spasticity usually helps to differentiate
these two conditions, but several cases
with molecular diagnoses of HSP have
been misdiagnosed as CP.4 Overall, the
rate of progression varies considerably
among different genetic types of HSP
and within families. Patients diagnosed
with HSP should be counseled about
the progressive nature of the disease,
even though the lack of a phenotype-
genotype correlation makes more accu-
rate prognosis difficult.5 However, the
diagnosis of HSP with a determined ge-
netic type can facilitate the discussion
about the disease prognosis in some
cases. For example, early-onset SPG3A is
characterized by very slow disability pro-
gression, with most patients maintaining

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independent gait even after several de-
cades of the disease; hence, SPG3A may
be confused with CP because of lack
of perceived deterioration. Contrary to
this, the most frequent age of onset of
SPG6 is in early adulthood, and essen-
tially every patient becomes wheelchair
dependent 10 to 15 years after disease
onset.
Based on the additional neurologic
signs present, HSP can be clinically clas-
sified as uncomplicated or complicated.5
Isolated leg spasticity and weakness with
a variable degree of impaired vibration
sensation, in which neurologic signs are
limited to the dysfunction of cortico-
spinal tracts and dorsal columns, point
to a syndrome of uncomplicated or
‘‘pure’’ HSP. Patients with HSP who de-
velop complex clinical phenotypes with
more widespread neurologic signs than
those seen in pure HSP are classified as
having complicated HSP. Some authors
advocate for the term ‘‘complex HSP’’
to be reserved for HSP with additional
neurologic signs and for the term ‘‘com-
plicated HSP’’ to be used for HSP with
additional non-neurologic signs, such as
cataracts or skin ichthyosis. This is not
universally accepted, however, and the
terms complex HSP and complicated
HSP are used interchangeably in this
article. The most common additional
neurologic signs associated with HSP
include optic nerve atrophy, ataxia, dys-
tonia, deafness, retinitis pigmentosa,
amyotrophy, peripheral neuropathy,
pseudobulbar signs, absent or hypo-
plastic corpus callosum (CC), mental re-
tardation, and adult-onset dementia.
Complicated HSP is more common in
autosomal recessive (AR) types of HSP.
However, the distinction between un-
complicated and complicated HSP is
becoming more difficult because of the
increasing recognition of overlapping
clinical features. SPG4 is the most com-
mon type of AD HSP, with most patients
having pure HSP; however, dementia has
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KEY POINTS
been recently identified as a common h Hereditary spastic
feature of these patients, and patients paraplegia is
with adult-onset AD HSP should be characterized by
screened for signs of cognitive decline. interfamilial and
Clinical classification of HSP is com- intrafamilial variability
plemented by genetic classification, and and can be classified
all three mendelian modes of inheri- as uncomplicated
tance, AD, AR, and X-linked, have been (isolated spastic
reported.6 AD HSP accounts for 75% to weakness) or
80% of all cases of HSP and is charac- complicated (if
additional neurologic
terized by vertical inheritance with
signs are present).
examples of male-to-male transmission,
a 50% risk for offspring in each succes- h Hereditary spastic
sive generation, and equal frequency of paraplegia can be
inherited as autosomal
the disease between males and females.
dominant, autosomal
However, transmission of the disease
recessive, or X-linked.
to consecutive generations may not be
apparent in small kindreds, especially
when parents die before HSP manifests
clinically, are asymptomatic and thus un-
aware of the disease, or do not develop
the disease because of reduced pene-
trance. Another common explanation
for the absent family history in AD HSP
is a de novo mutation (Case 5-1). Over-
all, it is estimated that one-quarter of
patients with HSP caused by mutations
in AD genes have apparently sporadic
disease for these reasons, and the
possibility of AD HSP cannot be dis-
missed even if family history of HSP is
lacking. AR inheritance is supported by
multiple affected children born to unaf-
fected parents. Shared ancestry be-
tween parents increases the risk of AR
inheritance, but common types of AR
HSP are frequently encountered in
nonconsanguineous marriages. X-linked
disorders affect males, and affected
individuals may be identified in succes-
sive generations, suggesting AD inher-
itance. Women 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 it is in affected males.
AR and X-linked HSP may also present
as apparently sporadic HSP, further
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 Hereditary Myelopathies

KEY POINT
h Diagnosis of hereditary
spastic paraplegia can
be established based on
positive family history.
The diagnosis in
apparently sporadic
patients is a diagnosis of
exclusion; genetic
testing in apparently
sporadic cases can
be diagnostic.
broadening the differential diagnosis
of HSP.
Syndromic diagnosis of HSP can be
relatively straightforward in patients
with a clear family history. The risk of
phenocopies in a single kindred is very
small, and, unless atypical clinical fea-
tures are present, many patients can be
diagnosed on clinical grounds alone.
The diagnosis of HSP in apparently
sporadic cases remains a diagnosis of
exclusion, even though genetic testing
may narrow differential diagnosis (see
Case 5-1). Table 5-1 summarizes the
most important alternative diagnostic
considerations and the most appropri-
ate diagnostic tests. Only symptomatic
therapy is available and is the same as
for acquired myelopathies.
Overview of the Most
Common Types of Hereditary
Spastic Paraplegia
The progress in the molecular genetics
of HSP now allows molecularly based
diagnosis in at least 75% of all patients
with HSP; the remaining patients have
HSP caused by as-yet-unidentified genes.
Furthermore, phenotype-genotype anal-
ysis of the most common types of HSP
has markedly broadened the scope of
motor and nonmotor presentations,
making it difficult to specifically deter-
mine the mutated gene without actual

Case 5-1
A 44-year-old woman was evaluated for a 25-year history of progressive gait disorder resulting in
wheelchair dependency for the last 10 years. She was in her usual state of health until about the age
of 19, at which time she noticed unsteady gait and leg cramps. This was rapidly progressive with
multiple falls, and she required a walker 5 years after the onset, followed by inability to walk 10 years
later. None of her first- or second-degree relatives had similar problems. Her previous workup
included repeated MRI studies of the whole neuraxis, two lumbar punctures with CSF analysis,
somatosensory- and visual-evoked potential studies, biochemical assays of B12 and E vitamins, human
T-cell lymphotropic virus type I antibodies, muscle biopsy, and repeated EMG and nerve conduction
studies. All these tests were essentially normal. Hereditary spastic paraplegia (HSP) was not
considered, but several other diagnoses were postulated, including primary progressive multiple
sclerosis, for which she was treated with 1 year of interferon beta therapy without any clinical benefit.
She failed multiple oral medications for spasticity.
Her examination showed severe spasticity limited to the lower extremities with sustained ankle
clonus and upgoing toes bilaterally, diminished vibration sensation from the ankles with normal
examination of other sensory modalities, and muscle weakness 3/5 distally and 4/5 proximally. The
rest of her neurologic examination was normal. She was accompanied by both parents and
their examinations did not show any signs of corticospinal dysfunction. Genetic testing for
autosomal dominant (AD) HSP was ordered, and a disease-causing mutation in the non-imprinted
Prader-Willi/Angelman syndrome 1 gene, NIPA1 (SPG6), was detected. Additional testing
of both parents with confirmed paternity confirmed the de novo nature of this mutation. An
intrathecal baclofen pump was implanted with good clinical benefit.
Comment. This clinical scenario demonstrates that AD HSP needs to be included in the
differential diagnosis after compressive and demyelinating causes and common biochemical
abnormalities (vitamin B12 and E deficiency) are excluded, even in patients without any evidence
for a genetic disorder. The case also illustrates the role of genetic testing in the management
of these patients. Presently, a confirmed diagnosis of HSP does not change the management
of the disease, and some neurologists do not order the genetic tests for this reason. However,
establishing the molecular diagnosis early may actually be cost-effective because other
conditions do not need to be excluded, and the results can provide important diagnostic and
therapeutic guidance.

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genetic testing. However, the combi-
nation of genetic and preYmolecular
era classification, which was based on
the mode of inheritance, age of onset,
and phenotype (uncomplicated or com-
plicated), still provides a clinically useful
framework for the clinical approach to
patients with HSP. The most common
and important types of HSP are re-
viewed here.
Autosomal dominant hereditary
spastic paraplegia with early age of
onset and uncomplicated phenotype.
Early onset of a disease is typically de-
fined as onset before 20 years of age,
and adult onset is typically defined as
onset after 20 years of age. This is clearly
an arbitrary categorization, but most
patients with early-onset AD HSP man-
ifest initial signs of the disease before 10
years of age, which may be a more ap-
propriate cutoff age for the early-onset
category. More than one-half of patients
in this category have mutations in the
ATL1 gene (previously known as SPG3A;
encoding atlastin-1 protein).7 SPG3A is
the second most common type of AD
HSP, accounting for approximately 10%
to 15% of all AD HSP cases and 40% of
all AD HSP patients without mutations
in the spastin gene, SPAST (encoding
spastin protein).6
The average age of onset in SPG3A is
4 years, and more than 80% of reported
individuals manifest spastic gait before
the end of the first decade of life.8 The
rate of progression is slow, and wheel-
chair dependency or need for an assis-
tive walking device is relatively rare.
This is in stark contrast to SPG6 and
SPG8, which can also rarely present
as early-onset pure AD HSP, but tend
to have more aggressive courses, with
most patients eventually becoming
wheelchair dependent. The very slow
progression of SPG3A led to the sug-
gestion that it is a neurodevelopmental
rather than a neurodegenerative disor-
der. Very few patients with mutations
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KEY POINT
in ATL1, however, manifest an adult h Early-onset hereditary
onset of the disease, an observation spastic paraplegia is
that argues against the neurodevelop- caused by mutations in
mental classification. Most patients with the atlastin GTPase
SPG3A have an uncomplicated motor 1 gene, ATL1, in more
phenotype and, in comparison to other than 50% of patients
types of HSP, impaired vibration sensa- who developed the
tion and urinary bladder hyperactivity disease before the age
are less frequent. Additionally, these pa- of 10 years.
tients commonly develop scoliosis and
pes cavus deformities and should be
monitored for orthopedic complications.
If genetic testing is performed, these
patients may be initially tested for SPG3A
only, and a comprehensive HSP panel
can be added in those with a normal
sequence of ATL1.
Autosomal dominant hereditary spas-
tic paraplegia with early age of onset and
complicated phenotype. Even though
SPG3A is mostly a pure HSP, it can also
be associated with motor axonal neu-
ropathy, resulting in a distal weakness
and amyotrophy. SPG10, caused by mu-
tations in the kinesin family member
5A gene, KIF5A, is probably the second
most common cause of this HSP sub-
group. SPG10 was originally described as
an infantile-onset HSP associated with
axonal motor neuropathy and clinically
virtually indistinguishable from SPG3A.
SPG10 can also cause an adult onset of
the disease and, in addition to axonal
motor neuropathy, can be complicated
by deafness, retinitis pigmentosa, mental
retardation, and parkinsonism. Severe
amyotrophy of the hands and feet is
designated as Silver syndrome. Because
most of Silver syndrome HSP has an
adult onset, it is discussed in the section
on adult-onset complicated AD HSP.
Autosomal dominant hereditary
spastic paraplegia with adult age of
onset and uncomplicated phenotype.
The degree of genetic heterogeneity
(the number of causative genes) is very
high in this subgroup of HSP. Because of
the considerable clinical overlap among
the different types of AD HSP and the
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 Hereditary Myelopathies
KEY POINTS
h Mutations in the spastin
gene, SPAST, cause the
most common type of
hereditary spastic
paraplegia, accounting
for approximately 40%
of all patients.
h Silver syndrome is
hereditary spastic
paraplegia with
amyotrophy of distal
hand and foot muscles.
It can be also classified
as distal hereditary motor
neuropathy type V.
FIGURE 5-1
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significant interfamilial and intrafamilial
variability within the same genetic types,
reliable clinical differentiation is not
possible.1,3 Genetic epidemiology iden-
tified SPG4 caused by SPAST mutations
as the most common type, accounting
for approximately 40% of all AD HSP.
Other AD HSPs with predominant adult
onset are relatively rare.6,9 The current
HSP panel for diagnostic genetic testing
includes SPG6 (non-imprinted in Prader-
Willi/Angelman syndrome 1 gene, NIPA1,
mutations), SPG8 (KIAA0196, encoding
WASH complex subunit strumpellin pro-
tein), and SPG31 (receptor accessory pro-
tein 1 gene, REEP1), together with ATL1
and Berardinelli-Seip congenital lipodys-
trophy 2 (seipin) gene, BSCL2, mutations.
No distinctive features exist for SPG6,
SPG8, and SPG31, although SPG6 tends
to have a more aggressive course. Most
patients with SPG4 have a pure HSP
phenotype. Dementia is age-related and
usually mild. The prevalence of dementia
in other types of AD HSP remains un-
known, but these patients should be
routinely screened for cognitive decline.
Laboratory genetic testing can be ini-
tially limited to SPAST, but both sequenc-
ing and gene dosing methods detecting
frequent deletions within this gene
need to be included. Negative testing
of AD HSP genes does not rule out this
diagnosis because several known genes
are not routinely included in clinical test-
Atrophy of small hand muscles in Silver
syndrome. Significant atrophy of thenar and
hypothenar muscles is present.
ing and other genes have not yet been
identified. The identification of a family-
specific mutation can be used for pre-
symptomatic or prenatal testing, and a
recommended testing approach should
be followed.10
Autosomal dominant hereditary
spastic paraplegia with adult age of
onset and complicated phenotype.
Even though no definitive epidemio-
logic studies are available, it appears
that the majority of genetic types of AD
HSP can occasionally manifest a com-
plex phenotype, further blurring the
boundaries of this clinical classification.
The presence of overt ataxia may cause
significant difficulties in syndromic di-
agnosis of HSP versus spinocerebellar
ataxia. If possible, examination of other
affected individuals from the same
lineal descent may help because HSP
kindreds are likely to contain other
individuals with more typical HSP.
The combination of lower extremity
spasticity and prominent amyotrophy
of the distal hand and foot muscles is
commonly designated as Silver syn-
drome (Figure 5-1).11 It may be easily
confused with motor neuron disorders,
but denervation of paraspinal and prox-
imal muscles is not a feature of Silver
syndrome. The BSCL2 gene, encoding
seipin protein, was identified as a cause
of Silver syndrome (also designated
SPG17). 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 the signs of pyra-
midal tract lesions are very subtle and
occur later in the course of the disease)
or Charcot-Marie-Tooth disease type 2
(spinal Charcot-Marie-Tooth disease)
phenotype with a mild involvement of
sensory nerves and absent upper motor
neuron signs. Silver syndrome itself is
genetically heterogeneous, and rare
mutations in the SPAST and ALT1 genes
have been reported in these patients.12
August 2011

Autosomal recessive hereditary
spastic paraplegia. In general, AR HSPs
tend to have an early age of onset and
a complicated phenotype. However, a
substantial overlap within the same ge-
netic types of AR HSP makes a sepa-
rate discussion of pure and complicated
HSP less practical. Most of the genes
causing AR HSP have not been cloned
yet, and the genetic epidemiology of AR
HSP is only emerging. This discussion
includes only more common types of
AR HSP.
Mutations in the spastic paraplegia
7 (pure and complicated autosomal re-
cessive) gene, SPG7, encoding para-
plegin protein, have been reported in
approximately 5% of all AR HSP cases
and in the same proportion of patients
with apparently sporadic HSP with a
pure or complex motor phenotype.
Muscle biopsy can reveal signs of oxida-
tive phosphorylation defects, including
ragged red fibers, but these patients do
not have other characteristics of mito-
chondrial disorders, and additional
therapies for mitochondrial defects are
not helpful. Both uncomplicated and
complicated phenotypes of SPG7 have
been described.
Mutations in the spastic paraplegia 11
(autosomal recessive) gene, SPG11, en-
coding spatacsin protein, cause AR HSP
with thin CC (Figure 5-2). Mental retar-
dation, polyneuropathy, pseudobulbar
signs, ataxia, and amyotrophy are addi-
tional signs commonly found in this com-
plicated HSP. A few patients with normal
CC appearance and mutations in the
SPG11 gene have been described; how-
ever, they had additional neurologic ab-
normalities. The yield of SPG11 genetic
testing in patients with a pure AR HSP or
apparently sporadic HSP is very low. Thin
CC is not entirely specific for SPG11;
other forms of AR HSP with the same
CC abnormalities are known, including
SPG15, which is caused by mutations in
the zinc finger, FYVE domain containing
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KEY POINT
26 gene, ZFYVE26, encoding zinc finger h Autosomal recessive
FYVE domain-containing protein 26. A va- hereditary spastic
riant of SPG15 with central retinal degen- paraplegias are
eration is known as Kjellin syndrome.13 commonly associated
Mutations in the cytochrome P450, with an early age of
family 7, subfamily B, polypeptide 1 onset and a complicated
gene, CYP7B1, cause another common motor phenotype.
type of AR HSP, called SPG5A, which Additional abnormalities
often has an uncomplicated phenotype may include optic nerve
and onset in the fourth or fifth decade. atrophy, ataxia,
dystonia, deafness,
Neuroimaging of SPG5A patients with
retinitis pigmentosa,
a complex phenotype typically demon-
amyotrophy, peripheral
strates a widespread leukodystrophy. neuropathy, absent or
White matter changes with hypomye- hypoplastic corpus
lination are also common in SPG35 callosum, and mental
caused by mutations in the fatty acid retardation.
2-hydroxylase gene, FA2H. These pa-
tients have a high incidence of seizures,
parkinsonism, and dystonia. Radiologi-
cally and clinically this condition can be
also classified as a leukodystrophy.
Mast syndrome (SPG21), character-
ized by spastic paraplegia and severe
presenile dementia, and Troyer syn-
drome (SPG20), characterized by spastic
paraplegia with a short stature, kypho-
scoliosis, and distal amyotrophy, have
been identified only in the Amish en-
clave. It is still unknown whether these
types of HSP, caused by mutations in the
Thin corpus callosum with its partial agenesis
FIGURE 5-2
in a patient with SPG11 (autosomal recessive
hereditary spastic paraplegia) with mutations
in the spastic paraplegia 11 (autosomal
recessive) gene, SPG11.
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 Hereditary Myelopathies
KEY POINTS
h SPG2 and
Pelizaeus-Merzbacher
disease are caused by
mutations in the same
gene, the proteolipid
protein 1 gene, PLP1.
MRI commonly shows
leukodystrophy in
patients with hereditary
spastic paraplegia.
h Autosomal recessive
ALS2 is characterized
by progressive leg
spasticity followed by
spastic quadriparesis
and amyotrophy of
distal muscles. The
progression is slower
than with other types
of ALS, with survival
for many decades.
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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
spastic paraplegia 21 (autosomal reces-
sive, Mast syndrome) gene, SPG21, and
the spastic paraplegia 20 (Troyer syn-
drome) gene, SPG20 (encoding maspar-
din and spartin proteins), respectively,
affect patients with different ethnic
backgrounds.
X-linked hereditary spastic paraple-
gia. Even though the molecular basis
for X-linked HSP was identified first,
X-linked is the rarest form of HSP. It pre-
dominantly affects males because it has
a recessive X-linked inheritance. Female
carriers rarely manifest a mild disease
because of unfavorable X-chromosome
inactivation.
SPG1 is also known as MASA syn-
drome (Mental retardation, Aphasia,
Shuffling gait, and Adducted thumbs).
The adducted thumbs are thought to be
caused by hypoplastic or absent exten-
sor 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 L1 cell
adhesion molecule gene, L1CAM. The
spastic paraplegia component is almost
always complicated by other features,
and the acronym CRASH (CC hypopla-
sia, retardation, adducted thumbs, spas-
tic paraplegia, and hydrocephalus) was
also proposed. Obstructive hydrocepha-
lus is not the cause of spasticity because
patients with a 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 gene, PLP1,
differs between these two disorders.
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 even though there is no
correlation between the degree of
white matter changes and uncompli-
cated or complicated phenotypes.14
MOTOR NEURON DISEASE
Motor neuron diseases (MNDs) are char-
acterized by a combination of upper and
lower motor neuron degeneration with-
out involvement of the sensory system.
Even though spinal cord pathology with
a neuronal loss in the anterior horns is
significant, MNDs are diffuse processes
with a high degree of cerebral cortex and
brainstem involvement as well. ALS is a
prototypical MND with an asymmetric
onset of limb or bulbar weakness com-
bined with spasticity.15 However, subtle
clinical abnormalities of the dorsal col-
umns may be found in a familial form of
AD ALS caused by mutations in the super-
oxide dismutase 1, soluble gene, SOD1
(ALS1), further blurring the distinction
from HSPs. This article focuses on only
those subtypes of ALS and MND that
may commonly resemble isolated mye-
lopathies because of a relative paucity of
bulbar signs and lower motor neuron
signs. This article also briefly reviews the
most common disorders with pathology
isolated to the lower motor neurons
(spinal muscular atrophy [SMA]).
ALS Subtypes
ALS2 is an AR disease caused by muta-
tions in the amyotrophic lateral sclerosis
2 (juvenile) gene, ALS2.16 Patients carry-
ing mutations in this gene have been
described as having juvenile-onset ALS,
infantile-onset HSP, or juvenile primary
lateral sclerosis (PLS). Progressive spas-
ticity of the lower extremities, otherwise
indistinguishable from HSP, is a typical
presenting symptom, and the upper
limbs are usually affected after the first
decade of disease duration. Amyotro-
phy is a later sign in the stage of spastic
quadriparesis and, similar to Silver syn-
drome (see section on HSP), affects mostly
distal muscles. The disease progression is
August 2011

slower than in other types of ALS and
some patients may still be ambulatory
after several decades of the disease. How-
ever, most patients develop anarthria
and severe dysphagia with ascending
progression of the motor degenera-
tion. Paresis of horizontal gaze may be
seen in patients with long-term sur-
vival. Dementia is not a phenotypic
feature of this type of MND. Neuro-
imaging in patients with an advanced
disease demonstrated T2-signal abnor-
malities along the pyramidal tracts.
The designation of PLS is still some-
what controversial. Some authorities con-
sider PLS an ALS variant without the
involvement of lower motor neurons,
while others consider it a discrete entity.17
The most commonly used criterion for
differentiating PLS from ALS requires the
absence of denervation 5 years after the
onset of spasticity. Most PLS is consid-
ered sporadic. Onset is asymmetric, in-
cluding a spastic monoparesis, and on
average occurs after age 40. Possible AD
PLS has been linked to chromosome 4,
but the molecular basis is still unknown.
ALS2 mutations are not the cause of
typical adult-onset PLS.
ALS4 is another type of ALS that can
have an isolated spasticity with absent or
minimal lower motor neuron signs. The
senataxin gene, SETX, which encodes
the probable helicase senataxin protein,
causes the disease, and the main phe-
notype associated with this gene is ataxia
with oculomotor apraxia type II (AOA2),
which is characterized by severe gait
ataxia, dystonia, oculomotor apraxia in
one-half of patients, and a mixed motor
and sensory neuropathy with distal
weakness.18 "-Fetoprotein and serum
creatine phosphokinase levels are ele-
vated. AOA2 is mostly found in Quebec
among French-Canadians. It is inherited
as an AR ataxia, and known mutations are
truncating. SETX mutations in ALS4 are
different from those seen in AOA2 and
are inherited as an AD ALS. ALS4 has an
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KEY POINTS
average age of onset in the second de- h Mutations in the
cade and much slower progression than senataxin gene, SETX,
other types of AD ALS, with patients cause ALS4 and ataxia
becoming wheelchair dependent in the with oculomotor apraxia
fifth and sixth decades. Amyotrophy is type II. Gait ataxia,
distal, and, in contrast to AOA2, sensory dystonia, oculomotor
findings are absent. Some patients with apraxia, neuropathy,
SETX mutations were originally reported and spasticity are the
as having distal hereditary motor neuro- main clinical problems.
pathy with upper motor neuron signs. ALS4 has a slower
progression than other
Previously described SPG11 with
types of ALS.
SPG11 mutations is also classified as
ALS5 if the patients show prominent h Spinal muscular atrophy
distal amyotrophy. is characterized by
progressive flaccid
Spinal Muscular Atrophy weakness, muscle
atrophy, and bulbar
SMAs comprise a group of disorders symptoms. Mortality
characterized by progressive flaccid and morbidity rates of
weakness and muscle atrophy due to spinal muscular atrophy
selective degeneration of the spinal cord are highest in patients
lower motor neurons (bulbar lower mo- with early onset of
tor neurons can be also affected). AR the disease.
SMA caused by mutations in the survival
of motor neuron 1, telomeric gene,
SMN1, accounts for about 95% of all
SMA cases. SMN1-related SMA is one of
the most common human AR diseases,
and type I (the infantile form) affects
approximately 1:10,000 births, with a
carrier frequency of approximately 2%
in the general population.19,20 The clini-
cal features of SMA are strongly related
to its severity and age of onset. Four
types of SMA have been recognized.
SMA type I is the most common and
accounts for one-half of all cases. SMA
types II and III each account for about
one-fourth of cases, and type IV is rare.
Types II and III are also known as
Kugelberg-Welander disease. The mor-
tality and morbidity rates of SMA are in-
versely correlated with the age of onset,
with the highest rates seen in patients
with early onset of the disease. Fur-
thermore, there is a strong genotype-
phenotype correlation with types of
SMA1 mutations and other modifying
genes in the 5q13 region, including the
survival of motor neuron 2, centromeric
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 Hereditary Myelopathies

KEY POINT
h Kennedy syndrome
(bulbospinal muscular
atrophy) is an X-linked
disorder caused by
polyglutamin expansion
in the androgen receptor
gene, AR. Proximal arm
weakness with bulbar
and lower facial
weakness are typical
clinical features.
Perioral and tongue
fasciculations with
tongue atrophy
are also common.
Gynecomastia,
oligospermia, testicular
atrophy, and erectile
dysfunction are typical
non-neurologic
problems.
gene, SMN2, and the NLR family, apo-
ptosis inhibitory protein gene, NAIP,
deletion of which is associated with
more severe phenotype in females.
Spinal muscular atrophy type I. SMA
type I is an acute infantile form also
designated as Werdnig-Hoffman disease.
The age of onset varies from birth to
6 months, with many infants showing
decreased in utero movements. Affected
children have diffuse weakness that is
more pronounced proximally and se-
vere hypotonia with poor feeding. Res-
piratory failure is the cause of death,
with almost 50% mortality by 7 months
and 95% by 18 months; a more chronic
course is quite rare. Molecular tests have
made the need for a diagnostic muscle
biopsy obsolete, but grouped muscle
fiber atrophy with most fibers of type I is
a typical finding. SMA type I is associated
mostly with SMN1 deletions; point muta-
tions are very rare. SMN2 copy number
is typically two; deletion of both SMN1
and SMN2 or the presence of only one
copy of SMN2 is lethal prenatally or
shortly after birth.18,19
Spinal muscular atrophy type II.
SMA type II is a chronic infantile form
with an age of onset between 6 and 18
months. Delayed acquisition of major
motor milestones, such as sitting or
standing independently, is typically the
presenting problem. Survival in SMA type
II varies from 2 years to the third decade,
and respiratory infections are usually the
cause of death. SMN1 is not deleted, and
point mutations in the SMN1 gene, in-
cluding those converting SNM1 to SMN2,
are common; the number of SMN2
copies is greater than or equal to 3.
Spinal muscular atrophy type III.
SMA type III is a chronic juvenile form
with symptoms occurring after the age
of 18 months. Slowly progressive prox-
imal weakness is the hallmark of this
type of SMA, and these patients can
walk but have difficulty standing up
from a chair or using stairs. In some
cases, however, muscle cramps may be
the heralding symptom. Because pseu-
dohypertrophy of calves can be seen,
these patients need to be differentiated
from patients with limb-girdle myopa-
thies, and EMG will show typical signs of
denervation. Advanced stages of the
disease may be associated with bulbar
signs, but they are not a constant feature.
The disease progression is slower, and
some patients experience normal life ex-
pectancy. Point mutations in the SMN1
gene are seen, and the number of SMN2
copies is greater than or equal to 3.
Spinal muscular atrophy type IV.
SMA type IV is an adult-onset form with
a benign course and normal life expec-
tancy. Overall, it resembles SMA type III
with a later onset and a milder course.
Bulbospinal muscular atrophy. Bul-
bospinal muscular atrophy or Kennedy
syndrome is an X-linked form of SMA
and is the most frequent type of adult-
onset SMA, with an estimated preva-
lence of 1:50,000 males.21 The average
age of onset is in the third decade but
can vary from 18 to 60 years. The first
symptoms may be nonspecific; cramps
and difficulty chewing, caused by mass-
eter muscle weakness, are common.
Weakness of the extremities is mostly
proximal and is associated with bulbar
muscle involvement, including chewing
difficulties and lower facial weakness.
Perioral and tongue fasciculations with
tongue atrophy are also common, and
more pronounced bulbar symptoms
with dysphagia and dysarthria may ap-
pear later.
The molecular basis of Kennedy syn-
drome is a CAG expansion in the
androgen receptor gene, AR. Neuro-
logic symptoms are induced by CAG
expansionYrelated neurodegeneration,
but another important aspect of this con-
dition is androgen insensitivity. Gy-
necomastia (present in 50% to 70% of
patients), oligospermia, testicular atro-
phy, and erectile dysfunction are typical

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non-neurologic problems seen in pa-
tients with Kennedy syndrome. Female
carriers may manifest muscle cramps and
muscle fasciculations, but the symptoms
are typically mild and appear late in the
sixth or seventh decades.
NEURODEGENERATIVE ATAXIAS
Neurodegenerative ataxias can be di-
vided into ‘‘pure’’ cerebellar ataxias, with
symptoms limited to cerebellar dys-
function, and ataxias associated with
additional ophthalmic (retinal degen-
eration) or neurologic problems, in-
cluding spasticity. In general, the
typical heralding symptoms of the dis-
ease (dysmetria, dysdiadochokinesis,
cerebellar dysarthria, and oculomotor
abnormalities) combined with spasticity
point to the diagnosis of spinocerebellar
ataxia (SCA) rather than to an isolated
myelopathy.
Considerable corticospinal tract dys-
function is especially common in SCA
types 1, 2 and 3, accounting for approxi-
mately 40% of all AD SCA.22 All three
types of SCA are caused by the expan-
sion of CAG repeats, but their motor
phenotypes vary considerably. SCA1 is
frequently associated with bulbar and
extrapyramidal signs. Hypokinetic-rigid
syndrome, occasionally resembling idi-
opathic Parkinson disease, may be seen
in SCA2, and slow horizontal saccades
are very typical for this type of SCA.
SCA3, also known as Machado-Joseph
disease, is arguably the most variable in
clinical presentation and can mimic
other neurodegenerative conditions.
Several patients manifesting only a
spastic gait without any obvious cere-
bellar signs have been diagnosed with
HSP rather than SCA3. In these pa-
tients, the appearance of gaze-evoked
nystagmus led to the diagnosis of com-
plicated HSP, and SCAs were not ini-
tially considered because of the relative
paucity of other cerebellar signs. The
emergence of oculomotor abnormali-
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KEY POINTS
ties should prompt the diagnosis of h Significant spasticity
SCA rather than HSP because cerebellar is common in
signs are extremely rare in AD HSP and spinocerebellar ataxia
only a few patients with SPAST muta- type 1 (SCA1), SCA2,
tions have been reported in the medical and SCA3. Spasticity is
literature. Spasticity can be a feature of also a feature of SCA8
other types of SCA, such as SCA8 and or SCA17, and precise
SCA17, and molecular diagnosis is nec- diagnosis may be reached
essary for the definitive differentiation only by genetic tests.
of HSP and SCA in these patients. h Ataxia of
Early spasticity is also a feature of Charlevoix-Saguenay
spastic ataxias, which are a heterogene- was identified in
ous group of hereditary ataxias with French-Canadian
both AD and AR inheritance.23 Ataxia of patients but can be
seen in diverse ethnic
Charlevoix-Saguenay (SACS) was iden-
groups. Progressive
tified among French-Canadians as an
spasticity, nystagmus,
AR ataxia, but after the discovery of gait ataxia, and severe
the mutations in the spastic ataxia of dysarthria are the main
Charlevoix-Saguenay (sacsin) gene, clinical features of this
SACS, patients from various ethnic back- autosomal recessive
grounds were confirmed to have SACS.24 spastic ataxia.
Progressive spasticity with acquired nys-
tagmus is the most common initial find-
ing, and most patients never acquire a
normal gait. SACS is progressive, and
the emergence of profound ataxia and
dysarthria is typical. SACS may easily
be confused with several AR HSPs, but
the presence of nystagmus and abnor-
mal smooth pursuit should suggest spas-
tic ataxia rather than HSP.
Friedreich ataxia (FRDA) is the most
common AR ataxia, with a prevalence of
1:50,000, although it is much more
common in some ethnic isolates.25 The
spinocerebellar tracts, dorsal columns,
and pyramidal tracts are mostly affected,
whereas the cerebellum and lower brain-
stem are involved to a lesser degree.
The disorder usually manifests before
adolescence, and most patients report
impaired coordination with staggering
gait and dysarthria. The combination of
bilateral Babinski sign and lower extrem-
ity areflexia with impaired vibration sen-
sation is a characteristic finding in FDRA.
The additional presence of cerebellar signs
with dysmetria, nystagmus, and scanning
dysarthria in patients with a juvenile onset
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 Hereditary Myelopathies

KEY POINT
h Friedreich ataxia may
resemble isolated
spastic paraplegia.
Characteristic clinical
features include gait
ataxia, dysmetria,
nystagmus, dysarthria,
bilateral Babinski sign
combined with
areflexia, and impaired
vibration sensation.
Patients need to be
screened for diabetes
mellitus and hypertrophic
cardiomyopathy.
of the disease is essentially diagnostic
for FRDA if vitamin E levels are normal.
Molecular diagnosis is now common,
and the expansion of GAA trinucleotide
in the first introns of the frataxin gene,
FXN, is diagnostic. 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 diabetes mellitus and hyper-
trophic cardiomyopathy (Case 5-2). A
small fraction of FRDA is caused by
point mutations in the coding sequence
of the gene. These patients are typically
compound heterozygotes with one
allele containing GAA expansion and a
point mutation on the other allele. Test-
ing for point mutations is not routinely
available, and the clinical course of these
patients is less progressive.
FRDA may have several atypical fea-
tures, which may delay the diagnosis.
For example, some patients may retain
their lower extremity reflexes. Addition-
ally, patients with FRDA that resembles a
typical HSP phenotype have been
reported, as illustrated in Case 5-2. The
case also discusses the need for medical
screening of these patients.
LEUKODYSTROPHIES AND
NEUROMETABOLIC DISORDERS
Leukodystrophies are caused by heredi-
tary metabolic defects, most commonly
causing lipid storage or peroxisomal
disorders. Disruption of normal myelin
maintenance leads to a progressive
demyelinization and subsequent axonal
degeneration.26 Many leukodystrophies
also affect the myelin of peripheral
nerves. Based on residual enzymatic ac-
tivity, these disorders may present from
infancy to adulthood; however, the
most typical phenotypes appear in
the first decade and result in a rapidly

Case 5-2
A 21-year-old woman reported having difficulties with balance and feeling drunk for the last
3 years. She had not noticed any changes in her speech or dexterity. Previous history was noticeable
for a mild scoliosis that had not required any surgical intervention. She also reported occasional
chest palpitations. Family history was negative. Her examination showed normal speech, no
abnormalities on cranial nerve examination, and full strength in every segment. Deep tendon reflexes
were 1+ in the upper extremities and absent in the lower extremities; both toes were upgoing.
Dysmetria was only present in the lower extremities. Sensory examination demonstrated reduced
vibration sensation from her ankles. High foot arches were also noticed bilaterally. Her gait was
spastic and ataxic with a wide base and an inability to perform a tandem gait.
Vitamin E and B12 levels and human T-cell lymphotropic virus type I titers were normal.
Genetic testing for Friedreich ataxia (FRDA) was ordered and showed an expanded number of
GAA of 256 and 412 in the first exon of the frataxin gene, FXN. After this test, a 2D cardiac
echo was ordered, and it showed a mild hypertrophic cardiomyopathy. Random fasting glucose
was normal.
Comment. This clinical scenario demonstrates that FRDA should be considered in a patient
whose examination shows areflexia with Babinski signs, even if other signs of cerebellar dysfunction,
such as nystagmus and cerebellar dysarthria, are absent. Vitamin E deficiency may mimic FRDA
and should be excluded before genetic testing. Early determination of the presence of FRDA is
important for additional screening because of other clinical problems associated with FRDA, most
notably hypertrophic cardiomyopathy, diabetes mellitus, and scoliosis; annual cardiologic evaluation
and laboratory screening for diabetes mellitus is recommended. Exclusion of FRDA eliminates the
need for this regular clinical monitoring.

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progressive neurologic deterioration
with cognitive, behavioral, visual, and
motor problems. MRI evaluation can
confirm the presence of demyeliniza-
tion, but the specific diagnosis is typi-
cally made by biochemical tests. Adult
onset of these disorders is atypical and
diagnosis requires a high index of
suspicion.
Krabbe disease is also known as
globoid cell leukodystrophy. This AR dis-
order is caused by deficiency in galacto-
sylceramide $-galactosidase. Nonclassic
or late-onset Krabbe disease has been
recognized since the advent of enzymo-
logic diagnosis. Adult onset is quite
variable and may resemble HSP with
peripheral polyneuropathy, with demen-
tia commonly appearing relatively early.
MRI changes of the white matter may
have a nonspecific appearance. Assaying
enzyme activity is diagnostic.
Metachromatic leukodystrophy is
an AR disorder caused by a deficiency
of arylsulfatase A enzyme. Early onset is
also typical for this leukodystrophy, and
patients with adult onset commonly de-
velop psychiatric problems combined
with spastic paraparesis; peripheral poly-
neuropathy is also common.
Adrenoleukodystrophy is a peroxiso-
mal X-linked disorder resulting in severe
white matter disease due to accumu-
lation of very long-chain fatty acids
(VLCFAs). It typically affects boys in the
first decade, and behavioral problems
are commonly the first presentation. Pro-
gressive spasticity, visual disturbances,
and severe cognitive decline are consis-
tent with a widespread leukoencephalo-
pathy rather than myelopathy. However,
an adrenomyeloneuropathy variant with
a progressive spastic paraparesis and
peripheral polyneuropathy, causing a
characteristic combination of upgoing
toes and areflexia, may be confused with
a complicated HSP. VLCFA assay is
diagnostic, and mutation analysis is not
routinely performed. Adrenal failure
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KEY POINTS
may occur when adrenal insufficiency h Adult onset of
is untreated; patients with adrenal in- leukodystrophies is
sufficiency must be evaluated by an atypical, and diagnosis
endocrinologist. Spastic paraparesis is requires a high
progressive, and some patients also index of suspicion.
develop dementia and visual problems MRI evaluation can
because of leukodystrophy, which are confirm the presence
less pronounced than in a typical cere- of demyelinization, but
bral form of adrenoleukodystrophy. the specific diagnosis
is typically made by
Female carriers can also develop clinical
biochemical tests.
problems (Case 5-3).
Argininemia is an AR urea cycle dis- h Vitamin E deficiency,
order, but hyperammonemia is rare caused by mutations
and typically only transient. Progressive in "-tocopherol
transfer protein, and
spasticity with a rapid progression into
Bassen-Kornzweig
quadriparesis and opisthotonus is a hall-
syndrome can mimic
mark of this entity. Arginine plasma Friedreich ataxia.
levels are significantly elevated, but en- The main cause of
zymatic activity of arginase should be ataxia is sensory
performed for the diagnosis. impairment from
Sjögren-Larsson syndrome consists of dorsal column
spastic paraparesis, congenital skin ich- dysfunction and
thyosis, retinal degeneration, and mental peripheral
retardation. Leukodystrophy is commonly polyneuropathy.
detected by neuroimaging. An aldehyde
dehydrogenase defect leads to the accu-
mulation of long-chain fatty alcohols.
Bassen-Kornzweig syndrome (abeta-
lipoproteinemia) and familial isolated
vitamin E deficiency lead to spinal cord
neurodegeneration because of vitamin
E deficiency.27,28 Dorsal column impair-
ment combined with peripheral poly-
neuropathy causes sensory ataxia, even
though cerebellar and brainstem ab-
normalities are also present. Bassen-
Kornzweig syndrome is associated
with the absence of very low and low-
density lipoproteins and subsequent mal-
absorption syndrome; vitamin A and K
levels may also be low. Retinitis pigmen-
tosa and acanthocytes are also features
of this disease. Vitamin E deficiency is
caused by mutations in "-tocopherol
transfer protein, and vitamin E defi-
ciency is the only biochemical abnor-
mality. Both disorders may resemble
FRDA. Vitamin E supplementation may
partially reverse the clinical phenotype.
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 Hereditary Myelopathies

Case 5-3
A 65-year-old woman reported a history of gait difficulties with frequent tripping and feeling out
of balance for the last 3 to 4 years. This was gradually progressive and she also developed urinary
bladder urgency. Her past medical history was noticeable for well-controlled hypertension and
hypothyroidism. Her brother died in his twenties after a prolonged neurologic disorder that
caused him to be blind and unable to leave his bed; no further details were available. She did not
have any children.
Examination showed normal cognition and no abnormalities on cranial nerve examination.
Examination of the motor system showed full-strength, abnormally brisk knee deep tendon reflexes
and trace ankle jerks with upgoing toes bilaterally and no dysmetria. Her sensory examination showed
reduced pinprick sensation distally up to her ankles. Her gait was spastic, but she was able to walk
unaided.
Neuroimaging did not show any spinal cord compressive lesions, and brain MRI showed very mild
and nonspecific white matter signal changes subcortically; these were patchy and no enhancement
was present. CSF analysis was normal, and vitamin E, vitamin B12, Venereal Disease Research
Laboratory, and human T-cell lymphotropic virus type I studies were all normal. Very long-chain
fatty acid (VLCFA) assay showed pathologically elevated levels with an abnormal ratio of C26:C22
VLCFA. A subsequently ordered adrenal function panel was normal.
Comment. This clinical scenario demonstrates that female carriers of X-linked
adrenoleukodystrophy may manifest a mild disease phenotype with a considerably later age of
onset. Assay of VLCFA is diagnostic, and her family history of a devastating neurologic disorder
resulting in blindness suggested this possibility. Adrenal insufficiency is typically absent in female
carriers. The clinical phenotype is again indistinguishable from a typical hereditary spastic paraplegia.
Genetic counseling would be warranted for relatives.

CONCLUSIONS broader availability of genotyping will

Hereditary myelopathies are a very di-
verse group of disorders, and the main
diagnostic task is to differentiate them
from acquired and potentially treatable
myelopathies. Because of the significant
phenotypic overlap among various neu-
rodegenerative conditions, definitive
diagnosis should be supported by iden-
tification of specific genetic mutations.
However, this identification is not always
possible because of the high cost of
these tests at present and the many as-
yet-unidentified genes. Furthermore, the
lack of any specific therapies is also an
important consideration in determining
whether to forgo expensive molecular
testing. The expected emergence of
novel therapies, which will likely be
specific to either genetic or biochemical
pathways, will undoubtedly increase the
need for comprehensive, high through-
put, and low-cost genetic testing. The
likely also expand the motor and non-
motor phenotypes of inherited myelo-
pathies and the understanding of their
position among other neurodegenera-
tive disorders.
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