Genetic Myelopathies.8

Genetic Myelopathies REVIEW ARTICLE

By Kara Stavros, MD, FAAN 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
Downloaded from http://journals.lww.com/continuum by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCyw
ABSTRACT
OBJECTIVE: This article provides an overview of genetic myelopathies, a
CX1AWnYQp/IlQrHD3i3D0OdRyi7TvSFl4Cf3VC4/OAVpDDa8K2+Ya6H515kE= on 02/16/2024
diverse group of inherited, degenerative conditions that may be broadly

categorized as motor neuron disorders, disorders of spinocerebellar
degeneration, leukodystrophies, and hereditary spastic paraplegia.
Clinical examples from each category are provided to illustrate the
spectrum of genetic myelopathies and their distinguishing features that aid
in differentiating genetic myelopathies from potentially treatable acquired
causes of myelopathy.
LATEST DEVELOPMENTS: Advances in genetic testing have vastly enhanced

current knowledge of genetic myelopathies and the ability to diagnose and
provide appropriate counseling to patients and their families. However,
potential health care disparities in access to genetic testing is a topic that
must be further explored. Although treatment for most of these conditions
is typically supportive, there have been recent therapeutic breakthroughs
in treatments for amyotrophic lateral sclerosis, spinal muscular atrophy,
and Friedreich ataxia.
Genetic myelopathies may present with chronic and

ESSENTIAL POINTS:
progressive symptoms, a family history of similar symptoms, and
involvement of other structures outside of the spinal cord. Imaging often
shows spinal cord atrophy, but cord signal change is rare. Exclusion of
reversible causes of myelopathy is a key step in the diagnosis. There are
many different causes of genetic myelopathies, and in some cases,
symptoms may overlap, which underscores the utility of genetic testing in
CITE AS:
confirming the precise underlying neurologic condition. CONTINUUM (MINNEAP MINN)
2024;30(1, SPINAL CORD
DISORDERS):119–132.
Address correspondence to
Dr Kara Stavros, 593 Eddy St,
APC 5, Providence, RI 02903,
INTRODUCTION Kara_stavros1@brown.edu.
G
enetic myelopathies encompass a wide range of inherited, RELATIONSHIP DISCLOSURE:
degenerative neurologic disorders. Advances in genetics have Dr Stavros reports no
identified a growing array of genes associated with genetic disclosure.
myelopathies, providing a greater understanding of the breadth UNLABELED USE OF

and pathophysiology of these conditions, facilitating greater PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
diagnostic closure for patients, and identifying potential targets for future
Dr Stavros reports no
therapeutics. In this article, the range of genetic causes of myelopathy is disclosure.
considered in four broad categories, with specific examples provided in each
category: (1) hereditary spastic paraplegia (HSP), (2) motor neuron disorders, © 2024 American Academy
(3) leukodystrophies, and (4) spinocerebellar degeneration. of Neurology.
CONTINUUMJOURNAL.COM 119
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

GENETIC MYELOPATHIES
GENERAL APPROACH TO PATIENTS WITH SUSPECTED GENETIC

MYELOPATHY
It is important to consider an inherited cause of myelopathy in the differential
diagnosis for patients presenting with myelopathic symptoms and, conversely, to
consider spinal cord involvement in patients known to have certain
neurodegenerative conditions. Clinical symptoms of myelopathy due to a genetic
cause are similar to those in patients with chronic myelopathy from other causes.
Presentations typically include a variable combination of motor and sensory
deficits, spasticity, hyperreflexia, and bladder symptoms. The age of onset of
symptoms may be variable because genetic myelopathies can present across the
lifespan from infancy to adulthood, but the time course is typically chronic and
slowly progressive. In genetic myelopathies, other manifestations of the
underlying disorder outside of the spinal cord may be detected by history or
clinical examination (TABLE 5-1). However, there are some exceptions; for
example, patients with HSP may present with predominantly myelopathic
symptoms without significant systemic features.1,2
Assessment of a patient with a suspected genetic cause of myelopathy requires
obtaining a detailed family history to probe for relatives with similar symptoms.
However, it should be noted that a negative family history does not exclude the
possibility of a genetic cause. Family history may be unrevealing for a variety of
reasons, such as cases of de novo genetic variations, variable penetrance and
phenotypes within the same family, autosomal recessive inheritance, or a
patient’s lack of knowledge of family members’ medical histories.3
Evaluation of a suspected genetic myelopathy should always include testing to
exclude acquired and potentially treatable causes of myelopathy, such as
structural, nutritional, vascular, or demyelinating etiologies. This may include
neuroimaging of the brain and spinal cord, as well as laboratory studies or nerve
conduction studies and EMG. In patients with genetic myelopathies, MRI of the
spinal cord may be normal or may show spinal cord atrophy without signal
TABLE 5-1 Extraspinal Symptoms in Selected Genetic Myelopathies
Genetic myelopathy Extraspinal symptoms
Familial amyotrophic Pseudobulbar affect, cognitive impairment, dementia

lateral sclerosis
Spinobulbar muscular Gynecomastia, infertility, testicular atrophy, diabetes,

atrophy sensory neuropathy
Hereditary spastic Numerous phenotypes; may include cognitive changes,

paraparesis extrapyramidal symptoms, seizures, hearing loss, optic
atrophy, ataxia, dysarthria
Hexosaminidase A Cerebellar atrophy, ataxia, dysarthria, dysphagia,

deficiency psychiatric symptoms
Adrenomyeloneuropathy Adrenal insufficiency, cognitive changes, peripheral

neuropathy
Friedreich ataxia Optic atrophy, hearing loss, hypertrophic cardiomyopathy,

ataxia, dysphagia, nystagmus, scoliosis, dysarthria,
peripheral neuropathy
120 F E B R U A R Y 2 0 24

change. It is rare for MRI to show signal change in the spinal cord in these cases; KEY POINTS
there are some exceptions, including several of the genetic leukodystrophies, but
● Genetic myelopathies
in these patients, there is usually concomitant cerebral involvement.4 Diagnostic often manifest with other
testing not only excludes acquired causes of myelopathy but may offer clues as to systemic signs or symptoms
the underlying inherited condition. associated with the
myelopathy, and these may
be clues to the diagnosis.

GENETIC TESTING
Genetic testing can help confirm the diagnosis once the initial diagnostic workup ● On neurologic history,
is performed to exclude acquired causes and narrow the differential diagnosis.
suspicion for genetic

Genetic testing plays an important role in making a final diagnosis, particularly myelopathy may be raised if
because many of the clinical symptoms may overlap in different genetic there is a slow progression
of symptoms and a family
conditions. There are no clinical guidelines providing recommendations for history of similar symptoms.
when and how to pursue genetic testing in genetic myelopathies, but testing However, a negative family
should always be carefully considered and the potential disadvantages and history does not exclude a
benefits explored. Options may include testing a panel of genes targeted to the genetic cause.
suspected condition or whole-exome sequencing. Whole-exome sequencing ● Evaluation for a genetic
diagnostic yield is highly variable but may identify a specific diagnosis in myelopathy should always
neurogenetic conditions at a rate of approximately 30%.5,6 Whole-exome include testing to rule out
sequencing may be less sensitive in detecting gene deletions or duplications. potentially reversible
causes of myelopathy.
Current understanding of the genes implicated in genetic myelopathies has
steadily advanced, but it is still an evolving landscape. Results of testing can at ● In genetic myelopathies,
times be inconclusive or falsely negative because many of the genetic variations MRI of the spine most
that underlie these disorders have yet to be identified; therefore, a negative test commonly shows spinal
result does not definitively exclude a potential genetic etiology. Interpretation of cord atrophy without signal
change.
variants of uncertain significance is a persistent challenge. Another limitation of
genetic testing may be the cost, although free sponsored testing may be available ● Barriers to access to
in some cases from nonprofit organizations or pharmaceutical companies. genetic testing exist,
Additionally, health care disparities exist regarding ensuring equitable access to including cost, location, lack
of awareness, and distrust.
genetic testing; some patients may have limited access because of location,
socioeconomic factors, a lack of awareness, or distrust of how their medical ● Genetic testing should be
information will be used.7-9 performed by a physician
Genetic testing should be ordered and reviewed always by a physician who has with expertise in counseling
patients and their families,
the expertise and resources to counsel patients and their families on the results
and coordination of care
regardless of whether they are positive, negative, or inconclusive. Coordination with a medical geneticist
of care with a medical geneticist and genetic counselor is extremely beneficial. may be beneficial.
HEREDITARY SPASTIC PARAPLEGIA

HSP comprises a large group of disorders characterized by degeneration of the
corticospinal tracts and dorsal column tracts and classically presents with
progressive spasticity, weakness in the lower extremities, and hyperreflexia,
typically with sensory deficits and bladder involvement. This clinical
presentation is further illustrated in CASE 5-1. In the realm of genetic
myelopathies, HSP may be variably characterized as a motor neuron disorder or a
distal motor-sensory axonopathy. Onset may occur during childhood or
adulthood, and many associated symptoms have been described in different
genotypes and phenotypes of HSP, including neuropathy, cognitive changes,
extrapyramidal symptoms, hearing loss, seizures, optic atrophy, ataxia, and
dysarthria among others.2 HSP may be classified as complicated when associated
with these additional neurologic or systemic findings, as opposed to what may
variably be referred to as the pure, simple, or uncomplicated form presenting

predominantly with weakness and spasticity. These classifications do not reflect

the wide variability in genotypic-phenotypic correlation that may be seen; for
example, patients with genetic variations typically associated with
uncomplicated HSP may present with other systemic manifestations, and
conversely, patients with genetic variations typically associated with complicated
HSP may have relatively few systemic manifestations.10,11
The inheritance pattern of HSP can be autosomal recessive, autosomal

dominant, or X-linked. To date, more than 79 genes have been implicated in
HSP,11 and this heterogeneity in genotype as well as phenotype contributes to the
challenges in both diagnosis and development of therapeutic advances for this

disorder. The most frequent type of autosomal dominant HSP is caused by a
variation in the SPG4 gene, which encodes the spastin protein. Several different
SPG4 variations have been observed, including missense, frameshift, deletions,
and nonsense variants, all resulting in a reduction in the spastin protein, which
plays a role in microtubule function.11 The specific type of genetic variation may
be associated with the age of onset of symptoms because age of onset is highly
variable, ranging from infancy through late adulthood. This type of HSP typically
presents with a phenotype characterized by weakness and spasticity, although
there have been reports of patients with cognitive impairment, ataxia, and
thinning of the corpus callosum.10
Variants in SPG11 are the most common autosomal recessive form of HSP,
impacting the spatacsin protein, which is involved in lysosome recycling and
clearance of gangliosides.11 This form of HSP typically presents early in childhood
or adolescence, and it may be associated with other neurologic and systemic
symptoms, including cognitive impairment, ataxia, neuropathy, and retinal
CASE 5-1 A 33-year-old man presented to the neurology clinic with symptoms of
gradually progressive lower extremity spasticity over the past several
years. He reported a family history of similar symptoms in his father who
had leg stiffness and trouble walking, and more recently a younger sibling
started to notice similar symptoms. He has no symptoms in his arms. On
neurologic examination, he has spasticity in both lower extremities
without any other neurologic abnormalities. MRI of his brain and entire
spine was unremarkable. Serum laboratory values for vitamin B12 and
copper were normal, human immunodeficiency virus (HIV) and human
T-cell lymphotropic virus type 1 (HTLV-1) tests were negative, and a
lumbar puncture showed no evidence of infection or inflammation.
COMMENT This patient’s clinical presentation raised concern for hereditary spastic
paraplegia, with hallmark features of bilateral lower extremity spasticity in
the setting of a family history of similar symptoms and exclusion of other
causes of myelopathy through imaging, serum, and CSF studies. The next
step is consultation with a geneticist and genetic counselor to discuss the
advantages and disadvantages of seeking genetic testing to confirm this
diagnosis for the patient and possibly his family members.
122 F E B R U A R Y 2 0 24

degeneration.11 Both SPG11 and KEY POINT
SPG15 variations have been
● The hereditary spastic
associated with thinning of the paraplegia inheritance
corpus callosum and a pattern may be autosomal
characteristic finding on MRI of dominant, autosomal
the brain wherein the forceps recessive, or X-linked, with
significant genotypic and

minor of the corpus callosum
phenotypic heterogeneity.
appears bright on FLAIR images
and dark on T1-weighted
images.12 This is known as the

ears of the lynx sign, reminiscent
of the tufts of hair seen on the
pointed ears of the lynx wild cat
(FIGURE 5-1). Other notable gene
variations in HSP include SPG7,
which is autosomal recessive and
has been associated with
cerebellar ataxia, and SACS,
which is also autosomal recessive
and associated with FIGURE 5-1
11 Ears of the lynx on MRI. A, Axial MRIs from a
neuropathy.
patient with hereditary spastic paraplegia (HSP)
Although genotype-
due to SPG11 genetic variation show an
phenotype correlations are not abnormality in the corpus callosum (red arrows)
always straightforward in HSP,13 appearing dark on a T1-weighted image and bright
the pursuit of genetic diagnosis is on fluid-attenuated inversion recovery (FLAIR)
still important in guiding patient imaging. This is known as the ears of the lynx sign
and may be seen in SPG11 and SPG15 forms of HSP.
management, counseling, and Comparison to healthy control patients without
anticipation of any associated HSP is illustrated in the first and third images.
symptoms outside of the spinal B, Corresponding images of a lynx wild cat.
Reprinted with permission from Pascual B, et al, AJNR Am J
cord. Treatment is supportive,
Neuroradiol.12 © 2019 American Society of Neuroradiology.
consisting of pharmacologic
therapy for spasticity to increase
mobility and reduce discomfort as well as bracing and assistive devices as
indicated. Systemic symptoms such as fatigue, sphincter dysfunction, and others
should also be addressed and often require multidisciplinary care.
MOTOR NEURON DISORDERS

Motor neuron disorders may be caused by dysfunction of the lower motor
neurons, corticospinal tracts, or both and may be either inherited or acquired.
Patients can present with lower motor neuron signs such as fasciculations,
hyporeflexia, or atrophy and upper motor neuron signs such as increased tone,
hyperreflexia, or positive plantar reflexes (the Babinski sign). This section
focuses on two examples of inherited motor neuron disorders: amyotrophic
lateral sclerosis (ALS) and spinal muscular atrophy (SMA).
Inherited Amyotrophic Lateral Sclerosis

While ALS is not conventionally considered a myelopathy, the spinal cord is one
site of the pathophysiology of this disease, and patients with ALS may present
with clinical features similar to myelopathy (especially with lower limb–onset
disease). ALS often presents with bulbar or limb onset of symptoms and a

combination of both upper and lower motor neuron signs. Associated symptoms
may also include cognitive impairment that varies in severity but may meet the
criteria for frontotemporal dementia in some cases.14 Patients may also
experience pseudobulbar affect, a dysregulation of motor output of emotion that
is difficult to localize anatomically but may involve more widely dispersed
networks.15,16 ALS is most commonly sporadic; however, approximately 10% to
15% of cases of ALS are familial,17,18 with speculation that this range could
underestimate the true prevalence of inherited ALS because of factors such as
incomplete knowledge of family history or low-penetrance genetic variations.17
So far, more than 50 genes have been implicated in familial ALS, with the most
common being C9orf72, which has a notable association with frontotemporal
dementia.14 The mechanism by which variations in C9orf72 cause disease is still
being elucidated.19 Other notable genes implicated in familial ALS include SOD1,
TDP-43, and FUS.17,18,20
The diagnosis of familial ALS, like acquired ALS, is based on history and
neurologic examination coupled with nerve conduction studies and EMG
suggestive of a motor neuron disorder and exclusion of other possible diagnoses
through additional testing as indicated by each patient’s presentation. There may
be a family history of ALS that prompts the patient’s evaluation. The clinical
symptoms of familial ALS may be clinically indistinguishable from sporadic ALS,
although the average age of onset of ALS symptoms in patients with familial ALS
is approximately 5 years younger than for nongenetic, sporadic ALS.21
Studies show that patients are generally favorable to genetic testing in ALS and
view it as beneficial, although access to testing and awareness may be limited,
and among presymptomatic individuals, 60% of patients would choose to get
tested.22-24 The ethical implications of performing genetic testing on
presymptomatic family members should be carefully considered. Any discussion
should be undertaken with the goal of better informing the patient and include
consideration of the disadvantages versus benefits of pursuing this testing.25
Recommendations for the principles and practice of presymptomatic genetic
testing for ALS are available for guidance.26
Currently, the treatment for ALS, whether familial or sporadic, is centered on
symptomatic care and four US Food and Drug Administration (FDA)–approved
medications that may modestly delay progression of the disease. These include
riluzole, edaravone,27 combination sodium phenylbutyrate and taurursodiol,28
and tofersen.29 Toferson is indicated only for patients with ALS caused by
variations in SOD1.
Spinal Muscular Atrophy

SMA is an autosomal recessive, lower motor neuron disorder that encompasses a
spectrum of clinical phenotypes that are separated by age of onset and degree of
weakness.30 It is caused by variations in the SMN1 gene, resulting in reduced
expression of the survival motor neuron protein and leading to loss of anterior
horn cells.31 Infantile-onset forms are severe, with patients demonstrating
profound hypotonia and progressive respiratory and swallowing difficulties. Left
untreated, the infantile-onset forms of SMA are usually fatal before the age of
2 years.32 Symptoms are relatively milder in later-onset forms but still include a
slow progression of weakness impacting mobility and gait with more severe
phenotypes and poorer prognosis associated with an earlier age of onset. Genetic
testing typically confirms the diagnosis. In patients presenting later in life, nerve
124 F E B R U A R Y 2 0 24

conduction studies and EMG may also provide important clues in narrowing the KEY POINTS
differential diagnosis.
● The most common
The mainstays of treatment were previously supportive in nature and genetic variation implicated
comprised physical therapy, orthopedic management, and respiratory care. in inherited forms of
However, in recent years treatments with novel mechanisms of action have amyotrophic lateral
been developed that increase the expression of the survival motor neuron sclerosis is in the C9orf72
gene.
protein. These treatments include an antisense oligonucleotide, nusinersen;
a small molecule splicing modifier, risdiplam; and gene therapy with ● Presymptomatic genetic
onasemnogene abeparvovec-xioi.33-35 These treatments are quickly becoming
testing for amyotrophic

routine components of care for early-onset SMA. The advent of these new lateral sclerosis in a patient
therapies has led to the consideration of new SMA phenotypes and redefinition with a known family history
should be undertaken with
of the natural history of this condition.31 These treatment options underscore caution and with reference
the need to diagnose and treat patients as soon as possible to prevent more to available practice
severe disease manifestations and has led to a call for increased newborn principles.
screening for SMA.36 Issues of cost and insurance coverage for these new
● Several disease-
medications and access for patients with later-onset forms of SMA may create modifying medications with
socioeconomic health care disparities.37 novel mechanisms of action
for the treatment of spinal
Other Hereditary Motor Neuron Disorders muscular atrophy have
become integrated into
Numerous other disorders affecting the motor neurons fall on the spectrum of
routine practice and are
genetic myelopathy. Inherited forms of primary lateral sclerosis, a demonstrating improved
predominantly upper motor neuron syndrome, are very rare but have been patient outcomes.
described.38 Primary lateral sclerosis presents at a mean age of 50 years old with
upper motor neuron–predominant symptoms including stiffness, corticobulbar ● Hallmark clinical features
of spinal bulbar muscular
dysfunction, and reduced mobility.39 atrophy (Kennedy disease)
Hexosaminidase A deficiency is a rare cause of lower motor neuron include limb and bulbar
dysfunction, presenting with symptoms of limb muscle weakness and atrophy, weakness, atrophy, facial
and may be associated with dysphagia and dysarthria.40 The disorder is fasciculations, and
gynecomastia.
caused by a variation in the HEXA gene. The infantile form results in a more
severe presentation of Tay-Sachs disease, whereas the adult-onset form presents ● Workup for
with a more variable phenotype and better prognosis. Adult onset of adrenomyeloneuropathy
hexosaminidase A deficiency has also been associated with syndromes of may include testing of
adrenal function, evaluation
cerebellar ataxia and cerebellar atrophy on neuroimaging, as well as
for elevation in very long
psychiatric symptoms.40 chain fatty acids in the
Spinal bulbar muscular atrophy, or Kennedy disease, is inherited in an serum, and genetic testing
X-linked recessive pattern associated with a CAG repeat expansion in the for pathogenic variants in
the ABCD1 gene on the X
androgen receptor gene AR. Patients with spinal bulbar muscular atrophy
chromosome.
typically present in the third to seventh decades of life and may report symptoms
of muscle atrophy, weakness in the bulbar and limb muscles, sensory ● Friedreich ataxia presents
neuropathy, and perioral facial fasciculations.41 Non-neurologic hallmarks of this with symptoms of ataxia,
syndrome are gynecomastia and reduced fertility. The diagnosis is confirmed by neuropathy, and upper
motor neuron signs. Patients
genetic testing. CASE 5-2 illustrates a patient presenting to a neurology clinic with are at risk for
spinal bulbar muscular atrophy. cardiomyopathy and must
undergo cardiac evaluation.
LEUKODYSTROPHIES
Many of the leukodystrophies present predominantly with cerebral symptoms;
however, several leukodystrophies may be associated with myelopathic
features in addition to cerebral involvement. This section highlights
adrenomyeloneuropathy and adult polyglucosan body disease as two examples
of leukodystrophies with myelopathic involvement.

X-linked Adrenoleukodystrophy and Adrenomyeloneuropathy

Adrenoleukodystrophy and adrenomyeloneuropathy are X-linked conditions
caused by a variation on the ABCD1 gene that encodes a peroxisomal
transmembrane protein, leading to accumulation of very long chain fatty acids.
In adrenoleukodystrophy, symptoms manifest in boys during childhood, with
symptoms of cognitive changes, optic atrophy, hearing loss, seizures, and
spasticity, as well as adrenal insufficiency.42 As demonstrated in CASE 5-3, the

adrenomyeloneuropathy phenotype typically presents in the third to fifth
decades of life with progressive spastic paraparesis and peripheral neuropathy.
Adrenal insufficiency is evident in most patients with

adrenomyeloneuropathy, and cognitive changes may develop in some patients
later in the disease course. Recognition of cerebral complications in patients with
adrenomyeloneuropathy is increasing, with 60% of patients with
adrenomyeloneuropathy found to develop cerebral demyelination, which is
associated with rapid progression and poor survival.43 Female carriers can rarely
develop symptoms, such as progressive myelopathy later in life.44,45 The
diagnosis may be made by genetic testing; however, a finding of elevated very
long chain fatty acid levels on laboratory evaluation is also key. Patients may also
have laboratory evidence of adrenal insufficiency, providing additional clues to
the diagnosis.
Adrenal insufficiency may be treated with replacement therapy, and other
adrenomyeloneuropathy symptoms may be addressed with supportive therapies
for pain and spasticity to enhance functional ability and quality of life, often
CASE 5-2 A 44-year-old man presented to the clinic for evaluation of proximal
muscle weakness, including difficulty raising his arms and trouble
climbing stairs. He also reported that he had noticed muscle twitches in
his body and face over the past few years, which he mostly ignored, but it
could sometimes cause him to feel self-conscious. He described a family
history of symptoms of weakness and trouble walking on his mother’s
side. Neurologic examination demonstrated proximal muscle weakness
with 4/5 strength in shoulder abduction and hip flexion, associated
muscle atrophy in his shoulder girdle and hip girdle muscles, diffuse
hyporeflexia, rare fasciculations in the perioral area, and evidence of
gynecomastia. His electrodiagnostic evaluation demonstrated a
widespread, chronic disorder of motor neurons with a mild superimposed
sensory neuropathy.
COMMENT This patient presented with a clinical picture suggestive of spinal bulbar
muscular atrophy, or Kennedy disease. If the patient consents, genetic
testing would help confirm this diagnosis. There currently are no
disease-modifying treatments for this disorder, but he could benefit from
physical therapy and consideration of an assistive device for greater safety
during ambulation. He should be screened for any bulbar weakness
affecting his speech, chewing, or swallowing that might require further
assessment.
126 F E B R U A R Y 2 0 24

benefitting from a multidisciplinary approach.46 There are currently no proven
disease-modifying therapies for the neurologic manifestations in patients with
adult-onset disease.42,45 Leriglitazone is a selective peroxisome proliferator-
activated receptor gamma agonist implicated in neuroinflammation and
degeneration, and although a recent trial of leriglitazone did not demonstrate
efficacy, other potential targeted therapies may follow.47
Other Leukodystrophies
Other leukodystrophies that may involve the spinal cord include Alexander
disease (GFAP), leukoencephalopathy with brainstem and spinal cord

involvement and lactate elevation (DARS2), and adult polyglucosan body disease
(GBE1).4,42,48 Adult polyglucosan body disease is an autosomal recessive
condition resulting from a variation in the GBE1 gene, which causes a deficiency
in glycogen-debranching enzyme and storage of polyglucosan bodies.49 This
disorder may be underrecognized and can manifest with a variety of clinical
phenotypes, typically presenting in adults in the fourth to seventh decades with
slowly progressive weakness, spasticity, bulbar symptoms, neurogenic bladder,
and neuropathy.49 Cognitive symptoms such as impairment in memory and
executive function have also been described,50 and brain imaging may reveal
cerebral and cerebellar atrophy and diffuse leukoencephalopathy.49 Spinal
imaging may show medullary and spinal cord atrophy without signal change
A 40-year-old man presented to the clinic with progressive neurologic CASE 5-3
symptoms spanning many years. He could not recall any symptoms in his
childhood or adolescence but said that in his early twenties, he started to
notice numbness and tingling in his feet and poor balance. This gradually
worsened over the past few years, and he started using a cane to walk.
He also reported some progressive issues emptying his bladder, and he
had to start doing self-catheterization. His past medical history was
notable for multiple hospital admissions for hypotension and
hypoglycemia, requiring steroids. He did not have a close relationship
with his mother but could recall that she had trouble walking. On
examination, he had normal strength and tone in both legs but
hyperreflexia and an abnormal plantar reflex. Sensation to vibration was
reduced distally in his lower extremities on both sides. MRI of his brain
and entire spinal cord was normal.
This patient’s symptoms raise concern for adrenomyeloneuropathy. He COMMENT

can be further evaluated for this by serum testing for elevation in very long
chain fatty acids and through genetic testing. His history of hypotension
and hypoglycemia may be indicative of adrenal dysfunction, and
consultation with an endocrinology specialist may be warranted. Although
there are no effective disease-modifying treatments for adult-onset
disease at this time, he may benefit from physical therapy, counseling on
fall risk, and optimization of home safety and assistive devices.

(FIGURE 5-2).4,49 There are no

disease-modifying treatments
available for adult polyglucosan
body disease at present, and the
mainstay of treatment
is supportive.
SPINOCEREBELLAR
DEGENERATION
The hereditary ataxias are a

widely diverse group of inherited
disorders that can involve
progressive ataxia, dorsal column
impairment, and corticospinal
FIGURE 5-2 tract degeneration to varying
Sagittal T2-weighted MRI of the cervical spine in a degrees.
patient with adult polyglucosan body disease
demonstrates severe spinal cord atrophy without
signal change.
Figure courtesy of Shamik Bhattacharyya, MD, FAAN.
CASE 5-4 A 54-year-old woman was referred to the clinic for evaluation of ataxia.
She said that her symptoms started about 8 years ago and had been slowly
worsening over time. She reported weakness in both legs, intermittent
dizziness, and trouble with balance. She had been using a walker for the
past year, and she had several falls. She recalled that she was diagnosed
with a degenerative neurologic condition in the past but didn’t recall if a
specific diagnosis was made. She reported that past nerve conduction
studies and EMG, lumbar puncture, and MRI of her brain and spine were
normal. Of note, she reported that she was currently undergoing a cardiac
workup because of symptoms of leg swelling and fatigue. On neurologic
examination, she had intact strength in all limbs, reduced vibration and
joint position sensation in her toes, hyperreflexia, and marked dysmetria
on finger-to-nose testing on both sides. Her rapid alternating movements
were slow and clumsy. Her gait was slow, wide-based, and cautious.
Her laboratory workup was unremarkable. An echocardiogram
showed evidence of cardiomyopathy. Repeated nerve conduction
studies and EMG and MRI of her brain and spine were unrevealing. She
was referred to a genetics clinic for further evaluation for a suspected
inherited cause of ataxia. Genetic testing demonstrated a pathogenic
GAA repeat expansion in the FXN gene (repeat number 144 in both
alleles), consistent with Friedreich ataxia.
COMMENT This patient presented with a late onset of Friedreich ataxia, which was
confirmed by genetic testing. Although Friedreich ataxia typically presents
during childhood or adolescence, later-onset forms may be seen and are
important to consider. Hypertrophic cardiomyopathy is an important
associated feature of the disorder.
128 F E B R U A R Y 2 0 24

Friedreich Ataxia
Friedreich ataxia is autosomal recessive, caused by an expanded GAA
trinucleotide repeat in the FXN gene. Friedreich ataxia typically presents in
childhood or adolescence with symptoms of ataxia, neuropathy, and upper
motor neuron findings. Other symptoms may include dysarthria, optic atrophy,
hearing loss, and cardiomyopathy. Late-onset forms in adulthood, as shown in
CASE 5-4, have also been described. In the case of late-onset Friedreich ataxia,
symptoms may be atypical and can be characterized by retained reflexes, lack of
dysarthria, lack of systemic signs, or slower overall progression.51
Patients with Friedreich ataxia benefit from a multidisciplinary care team,

including a cardiologist to monitor cardiac complications, to address the
numerous associated symptoms. Until recently, there were no specific
disease-modifying treatments available for Friedreich ataxia.52 The first
treatment for Friedreich ataxia was approved by the FDA in 2023 after
omaveloxolone, which acts to restore mitochondrial function, demonstrated a
benefit in the disease course and progression in randomized trials.53
Other Hereditary Ataxias

There are more than 40 different types of spinocerebellar ataxias, not all of which
have predominant spinal cord involvement. Spinocerebellar ataxia type 1 and
spinocerebellar ataxia type 3 (Machado-Joseph disease) may include symptoms
of spasticity and involve a CAG repeat in the ATXN1 and ATXN3 genes,
respectively.54,55 Ataxia and spinal cord involvement have also been reported in
abetalipoproteinemia and ataxia with isolated vitamin E deficiency.48
CONCLUSION
Genetic myelopathies comprise a large and diverse group of neurologic disorders.
Key features that may help distinguish a potential genetic myelopathy from an
acquired cause include a family history of similar neurologic symptoms, chronic
or slow progression over time, and the presence of additional symptoms not
strictly isolated to the spinal cord. In general, imaging typically shows spinal cord
atrophy without signal change. Genetic testing capabilities have expanded to
identify more genes implicated in these disorders than ever before but is still an
area in which knowledge is continuing to evolve. Few treatments are available for
any of the genetic myelopathies; however, in recent years new disease-modifying
treatments have become available for SMA, ALS, and Friedreich ataxia.
USEFUL WEBSITES
Brain & Life National Ataxia Foundation
The Brain & Life website offers patient education Patients with ataxia, including spinocerebellar ataxia
materials on several inherited myelopathies, and Friedreich ataxia, may find helpful resources on
including ALS, SMA, HSP, and Friedreich ataxia. the National Ataxia Foundation website.
brainandlife.org ataxia.org
Spastic Paraplegia Foundation

Further information and resources for patients with
HSP and primary lateral sclerosis can be found on
the website of the Spastic Paraplegia Foundation.
sp-foundation.org

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Genetic Myelopathies REVIEW ARTICLE

diverse group of inherited, degenerative conditions that may be broadly

LATEST DEVELOPMENTS: Advances in genetic testing have vastly enhanced

Genetic myelopathies may present with chronic and

myelopathies, providing a greater understanding of the breadth UNLABELED USE OF

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

GENERAL APPROACH TO PATIENTS WITH SUSPECTED GENETIC

TABLE 5-1 Extraspinal Symptoms in Selected Genetic Myelopathies

Genetic myelopathy Extraspinal symptoms

Familial amyotrophic Pseudobulbar affect, cognitive impairment, dementia

Spinobulbar muscular Gynecomastia, infertility, testicular atrophy, diabetes,

Hereditary spastic Numerous phenotypes; may include cognitive changes,

Hexosaminidase A Cerebellar atrophy, ataxia, dysarthria, dysphagia,

Adrenomyeloneuropathy Adrenal insufficiency, cognitive changes, peripheral

Friedreich ataxia Optic atrophy, hearing loss, hypertrophic cardiomyopathy,

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

be clues to the diagnosis.

suspicion for genetic

HEREDITARY SPASTIC PARAPLEGIA

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

predominantly with weakness and spasticity. These classifications do not reflect

The inheritance pattern of HSP can be autosomal recessive, autosomal

challenges in both diagnosis and development of therapeutic advances for this

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

significant genotypic and

images.12 This is known as the

MOTOR NEURON DISORDERS

Inherited Amyotrophic Lateral Sclerosis

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

Spinal Muscular Atrophy

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

testing for amyotrophic

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

X-linked Adrenoleukodystrophy and Adrenomyeloneuropathy

spasticity, as well as adrenal insufficiency.42 As demonstrated in CASE 5-3, the

Adrenal insufficiency is evident in most patients with

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

disease (GFAP), leukoencephalopathy with brainstem and spinal cord

This patient’s symptoms raise concern for adrenomyeloneuropathy. He COMMENT

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(FIGURE 5-2).4,49 There are no

The hereditary ataxias are a

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Patients with Friedreich ataxia benefit from a multidisciplinary care team,

Other Hereditary Ataxias

Spastic Paraplegia Foundation

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

2 McDermott C, White K, Bushby K, Shaw P. 14 Balendra R, Isaacs AM. C9orf72-mediated

2000;69(2):150-160. doi:10.1136/jnnp.69.2.150 s41582-018-0047-2

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

patients with amyotrophic lateral sclerosis.

28 Paganoni S, Hendrix S, Dickson SP, et al. doi:10.1002/ana.25689

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

52 Alper G, Narayanan V. Friedreich’s ataxia. 54 Sullivan R, Yau WY, O’Connor E, Houlden H.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

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