0-0017 PDF

Review Article
Genetic
Address correspondence to
Dr Adeline Vanderver, Children’s
National Health System, 111
Michigan Ave NW,
Washington, DC 20010,
avanderv@childrensnational.org.
Relationship Disclosure:
Leukoencephalopathies
Dr Vanderver serves on the
scientific advisory board of
the European Leukodystrophy
in Adults
Association and receives
research support from Eli Lilly Adeline Vanderver, MD
and Company; Gilead
Sciences, Inc; Illumina, Inc;
the National Institutes of
Health; and the
ABSTRACT
PMD Foundation. Purpose of Review: More than 100 heritable disorders can present with abnormal
Unlabeled Use of white matter on neuroimaging. While acquired disorders remain a more common
Products/Investigational
Use Disclosure:
cause of leukoencephalopathy in the adult than genetic causes, the clinician must
Dr Vanderver reports remain aware of features that suggest a possible genetic etiology.
no disclosure. Recent Findings: The differential diagnosis of heritable white matter disorders in
* 2016 American Academy adults has been revolutionized by next-generation sequencing approaches and the
of Neurology.
recent identification of the molecular cause of a series of adult-onset disorders.
Summary: The identification of a heritable etiology of white matter disease will
often have important prognostic and family counseling implications. It is thus im-
portant to be aware of the most common hereditary disorders of the white matter
and to know how to distinguish them from acquired disorders and how to ap-
proach their diagnosis.
Continuum (Minneap Minn) 2016;22(3):916–942.
INTRODUCTION to revisions as the field advances in

While acquired demyelinating condi- the coming years.
tions are more common than genetic Broadly characterized, genetic
etiologies in the adult population, a mimickers of white matter disease in
growing number of heritable leukoen- adults may be divided into two
cephalopathies have been identified. groups. The first includes genetic
The clinician caring for patients with disorders that present with primarily
multiple sclerosis (MS) and other multifocal white matter abnormalities
conditions of the white matter should and can closely mimic acquired demy-
be aware of these conditions and elinating disorders such as MS or is-
adept at identifying potential genetic chemic vascular disease (Table 12-11).
mimickers of white matter disease in These disorders can present at various
the adult population. Next-generation ages and may ultimately evolve toward
sequencing technologies and their confluency, but at initial presentation
ability to provide rapid and broad- they are often nondiffuse with isolated
based genetic information have revo- multifocal white matter lesions.
lutionized this field and provide a The second group of disorders,
broad differential diagnosis in herita- with some overlap with the first
ble leukoencephalopathies. Thus, this group, includes adult presentations
review should be considered a current of leukodystrophies (Table 12-2). Of-
view of genetic leukoencephalopa- ten, even disorders that present in the
thies that are potential mimickers of pediatric population with diffuse or
MS and other adult disorders, subject confluent white matter lesions may
916 www.ContinuumJournal.com June 2016
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

KEY POINTS
a h Clinicians caring for
TABLE 12-1 Leukoencephalopathies With Multifocal Onset
patients with multiple
b Progressive (May Evolve to Confluency) sclerosis and other
conditions of the white
Hereditary diffuse leukoencephalopathy with spheroids matter should be aware
Adult-onset polyglucosan body disease of, and adept at
identifying, potential
L2-Hydroxyglutaric aciduria
genetic mimickers
Leukoencephalopathy with brainstem and spinal cord involvement and of white matter
elevated white matter lactate disease (heritable
Urea cycle disorders leukoencephalopathies)
in the adult population.
Hydroxymethylglutaryl coenzyme A lyase deficiency
h Broadly characterized,
Histiocytosis genetic mimickers of
Incontinentia pigmenti white matter disease in
adults may be divided
Vasculopathies (eg, CADASIL, CARASIL, Fabry disease)
into two groups. The
Multiple sclerosis, neuromyelitis optica (NMO), acute disseminated first includes genetic
encephalomyelitis (ADEM), progressive multifocal leukoencephalopathy disorders that present
Mitochondrial diseases with primarily multifocal
white matter
Subacute sclerosing panencephalitis abnormalities and can
b Static closely mimic acquired
demyelinating disorders
18q deletion syndrome
such as multiple sclerosis
Sjögren-Larsson syndrome or ischemic vascular
disease. The second
RNASET2-deficient leukoencephalopathy
group of disorders, with
Congenital Cytomegalovirus some overlap with the
b Prominent Perivascular Spaces first group, includes adult
presentations of
Mucopolysaccharidoses leukodystrophies.
Chromosomal abnormalities or genetic mosaicism h Adult-onset
Lowe syndrome presentations of typically
pediatric leukodystrophies
PTEN-associated disorders
usually do not follow the
Histiocytosis standard clinical and
neuroimaging features
Disorders of branched chain amino acids
usually seen in children
CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and and may be
leukoencephalopathy; CARASIL = cerebral autosomal recessive arteriopathy with subcortical
infarcts and leukoencephalopathy.
paucisymptomatic with
a
Data from Vanderver A, et al, GeneReviews.1 www.ncbi.nlm.nih.gov/books/NBK184570/ limited radiologic
?report=reader. abnormalities.
present in older patients with more clinician to a degenerative condition.

restricted areas of signal abnormality. Together, these two groups should be
In these cases, the likelihood of a considered as a nonexhaustive list of
heritable disorder may not be consid- heritable white matter disease affect-
ered until disease evolution alerts the ing the adult population.
Continuum (Minneap Minn) 2016;22(3):916–942 www.ContinuumJournal.com 917

Genetic Leukoencephalopathies
KEY POINT
h Inherited disorders of TABLE 12-2 A Nonexhaustive List of Adult-Onset Leukodystrophies
the white matter can and Leukoencephalopathies
present as asymmetric
multifocal conditions of b With Typical Adult Onset
the white matter in
Hereditary diffuse leukoencephalopathy with spheroids
certain specific conditions.
Adult-onset polyglucosan body disease
Dentatorubral-pallidoluysian atrophy
Autosomal dominant leukodystrophy
Cerebrotendinous xanthomatosis
Cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL)
Fabry disease
SPG11-related hereditary spastic paraplegia
b With Special Presentations in the Adult Population
Metachromatic leukodystrophy
Globoid cell leukodystrophy (Krabbe disease)
GM1/GM2 gangliosidosis
Alexander disease
X-linked adrenoleukodystrophy/adrenomyeloneuropathy
L2-Hydroxyglutaric aciduria
Leukoencephalopathy with brainstem and spinal cord involvement and
elevated white matter lactate and other tRNA synthase disorders
Hypomyelinating conditions, including Pelizaeus-Merzbacher disease;
hypomyelination, hypogonadotropic hypogonadism, and hypodontia
syndrome; and hypomyelination with atrophy of the basal ganglia
and cerebellum
Peroxisomal biogenesis disorders
Kearns-Sayre syndrome and other mitochondrial disorders
Vanishing white matter disease
tRNA = transfer ribonucleic acid.
HERITABLE DISORDERS WITH abnormalities have milder systemic pre-

MULTIFOCAL PRESENTATIONS sentations more likely to be mistaken
A number of heritable disorders that for acquired disorders. In most of these
can have multifocal white matter abnor- conditions, white matter changes will
malities have such distinct clinical pre- ultimately evolve to become confluent,
sentations, typically affecting the very but early in the disease course they may
young, that it makes them unlikely to be strikingly multifocal in appearance.
be mistaken for more common disor-
ders such as MS or ischemic vascular L2-Hydroxyglutaric Aciduria
disease. Other heritable disorders that Clinical. L2-Hydroxyglutaric aciduria
include multifocal white matter signal is an inborn error of small molecule

KEY POINTS
metabolism. Patients may initially through their entire length including h L2-Hydroxyglutaric
appear normal or may have a static the spinal cord, sensory tracts through aciduria is an inborn
encephalopathy. Over time, cerebellar their entire trajectory including the error of small molecule
ataxia and progressive intellectual de- medial lemniscus, the superior and metabolism. Patients
cline become apparent. Patients may inferior cerebellar peduncles, and the may initially appear
also have hearing loss. In some cases, intraparenchymal trajectory of the tri- normal or may have a
these features only become apparent geminal nerve, among others, may be static encephalopathy.
in young adulthood. seen (Figure 12-1). Cerebellar white Over time, cerebellar
Neuroimaging. MRI in L2- matter is often involved. Magnetic res- ataxia and progressive
hydroxyglutaric aciduria demonstrates onance spectroscopy (MRS) demon- intellectual decline
become apparent.
predominant subcortical white matter strates elevated lactate in the affected
involvement, initially focal and evolv- white matter.3 h Certain features, such
ing to be confluent. Periventricular Diagnosis. The diagnosis of leu- as basal ganglia or
tissue remains spared. Increased sig- koencephalopathy with brainstem dentate nucleus
involvement in patients
nal is seen in the globus pallidus and and spinal cord involvement and ele-
with otherwise
less significantly in the caudate and vated white matter lactate is made
multifocal
putamen. Signal change may also be based on the typical MRI features and leukoencephalopathies,
seen in the dentate nucleus.2 sequencing of the causative gene. should alert the clinician
Diagnosis. Urine organic acids Mechanism/genetics. Leukoen- to the possibility of an
demonstrating increased L2- cephalopathy with brainstem and spinal underlying genetic
hydroxyglutaric acid are diagnostic. cord involvement and elevated white diagnosis.
L2-Hydroxyglutaric acid is increased matter lactate is caused by mutations h Leukoencephalopathy
in urine, plasma, and CSF. Plasma in DARS2, encoding mitochondrial with brainstem and
amino acids may demonstrate in- aspartyl tRNA synthase.4 It is inherited spinal cord involvement
creased lysine. in an autosomal recessive manner. and elevated white
Mechanism/genetics. L2- matter lactate presents
Hydroxyglutaric aciduria is caused by Hypomyelinating Leukodystrophy in childhood or
a deficiency of L2-hydroxyglutarate With Brainstem and Spinal Cord adolescence with motor
dehydrogenase, encoded by L2HGDH. Involvement and Leg Spasticity deterioration and a
It is inherited in an autosomal reces- Clinical. Hypomyelinating leukodys- progressive spastic
ataxia, cognitive decline,
sive manner. trophy with brainstem and spinal cord
and sensory neuropathy.
involvement and leg spasticity is clin-
Leukoencephalopathy With ically and radiologically similar to
Brainstem and Spinal Cord leukoencephalopathy with brainstem
Involvement and Elevated and spinal cord involvement and ele-
White Matter Lactate vated white matter lactate. Patients
Clinical. Leukoencephalopathy with can present in infancy with a disorder
brainstem and spinal cord involve- with neurologic regression, often dis-
ment and elevated white matter proportionately affecting the lower
lactate presents in childhood or ado- extremities with spasticity and ataxia.
lescence with motor deterioration and Cognition may be spared, or children
a progressive spastic ataxia, cognitive may be encephalopathic. Over time, a
decline, and sensory neuropathy. Mild loss of reflexes without nerve conduc-
elevations of serum or CSF lactate are tion abnormalities may develop. Pa-
known to occur on occasion. tients may also present in adolescence
Neuroimaging. On MRI, cerebral with a picture more reminiscent of
white matter is involved in a patchy spastic paraplegia, but often with epi-
inhomogeneous fashion. Selective in- sodic decline. These episodes of func-
volvement of the pyramidal tracts tional decline have led to confusion

KEY POINTS
h Hypomyelinating
leukodystrophy with
brainstem and spinal
cord involvement and
leg spasticity is clinically
and radiologically similar
to leukoencephalopathy
with brainstem and
spinal cord involvement
and elevated white
matter lactate. Patients
can present in infancy
with a disorder with
neurologic regression,
often disproportionately
affecting the lower
extremities with
spasticity and ataxia.
h Certain leukodystrophies,
in particular
hypomyelinating
leukodystrophy with
brainstem and spinal
cord involvement and leg
spasticity, can appear to
respond to treatment
with IV steroids similar to
acquired inflammatory Leukoencephalopathy with brainstem and spinal cord involvement and elevated
brain disorders. An FIGURE 12-1
white matter lactate. T2-weighted images show longitudinally extensive whole
atypical MRI feature, cord involvement on sagittal views of the spine (A, C, thin arrows) as well as
anterior and posterior tract involvement in the brainstem and cervical cord (B, D, thick arrows)
such as whole cord T2 on axial views.
signal changes or tract
involvement along the
entire length in the brain with MS, and patients have been brainstem and spinal cord involve-
and brainstem, should treated with IV steroids, often with ment and leg spasticity is made based
alert the clinician to the partial recovery.5 on the typical MRI features and se-
possibility of an underlying
Neuroimaging. In the adolescent- quencing of the causative gene.
genetic condition.
onset variant, MRI shows cerebral Mechanism/genetics. Hypomyeli-
white matter involvement in a patchy nating leukodystrophy with brainstem
inhomogeneous fashion. Selective in- and spinal cord involvement and leg
volvement of the pyramidal, sensory, spasticity is caused by mutations in
and brainstem tracts is seen, much as DARS, encoding a cytoplasmic aspartyl
in leukoencephalopathy with brain- tRNA synthase.6 Similarities with leuko-
stem and spinal cord involvement encephalopathy with brainstem and
and elevated white matter lactate. In spinal cord involvement and elevated
the early-onset variant, patients may white matter lactate, caused by muta-
have a diffuse leukoencephalopathy tions in the same tRNA synthetase but
involving the entirety of the supraten- for the mitochondrial compartment
torial white matter. DARS2, offer intriguing insight into
Diagnosis. The diagnosis of possible pathogenesis. It is inherited
hypomyelinating leukodystrophy with in an autosomal recessive manner.

KEY POINTS
AARS2-Related responsible for loading its cogent h Patients with
Leukoencephalopathy amino acid. Given the rapid accumu- AARS2-related
Clinical. Patients with AARS2-related lation of these disorders in the leukoencephalopathy
leukoencephalopathy present with a leukoencephalopathy family, it is rea- present with a progressive
progressive spastic diplegia, dystonia, sonable to expect that more disorders spastic diplegia, dystonia,
and ataxia. Significant dysarthria and in this family are likely to be included. and ataxia.
bulbar dysfunction often restrict com- The reason for the large number of h Persistent areas of
munication and make feeding more neurologic disorders, and specifically restricted diffusion in
difficult over time. Over time, patients leukoencephalopathy disorders, an individual in
develop a progressive encephalopathy. caused by mutations in these genes whom a genetic
Neuroimaging. On MRI, cerebral remains unknown. It should also be leukoencephalopathy is
white matter is involved in a patchy noted that improvement with steroids suspected should
inhomogeneous fashion predomi- has been noted in hypomyelinating raise concern for a
leukodystrophy with brainstem and toxic-metabolic defect,
nating in the frontal and parietal re-
including mitochondrial
gions. Selective involvement of the spinal cord involvement and leg spas-
cytopathies and tRNase
corpus callosum and longitudinal in- ticity and is being explored in other
synthetase defects.
volvement of the frontopontine, pyra- tRNA synthase defects.
midal, or parieto-occipitopontine tracts h Hereditary diffuse
Hereditary Diffuse leukoencephalopathy
may be seen. Diffusion-weighted im-
Leukoencephalopathy with spheroids can
ages often show multiple small areas of present as a
restricted diffusion in the cerebral With Spheroids
frontotemporal
white matter and corpus callosum. Var- Pathologic and now genetic data sug- dementia syndrome,
iable cerebellar atrophy can be seen.7 gest that hereditary diffuse leukoen- and patients with this
Diagnosis. The diagnosis of AARS2- cephalopathy with spheroids is the type of neuropsychiatric
related leukoencephalopathy is made same as a disorder with another name, presentation in the
based on the typical MRI features and orthochromatic leukodystrophy.8 context of compelling
sequencing of the causative gene. Clinical. Initial manifestations of white matter changes
Mechanism/genetics. AARS2-related this disorder are neurobehavioral and should be tested for
leukoencephalopathy is caused by evolve to include spasticity and extra- this condition.
mutations in AARS2, encoding a mi- pyramidal features, although progres-
tochondrial alanyl-tRNA synthase.7 It sive dementia often overshadows
is inherited in an autosomal reces- other neurologic features, as demon-
sive manner. strated in Case 12-1.9
Neuroimaging. White matter signal
Trends: Leukoencephalopathies abnormalities on MRI are most prom-
Caused by tRNA Synthase inent at the precentral and postcentral
Defects gyri or in the frontal white matter. Ab-
It is important to note that leukoen- normalities may be patchy and asym-
cephalopathy with brainstem and spi- metric. Atrophy of the frontal lobe
nal cord involvement and elevated may be seen. Abnormalities may ex-
white matter lactate, hypomyelinating tend into the posterior limb of the in-
leukodystrophy with brainstem and ternal capsule and the pyramidal tracts
spinal cord involvement and leg spas- of the brainstem (Figure 12-2).9,10
ticity, and AARS2-related leukoen- Diagnosis. In the past, the diagno-
cephalopathy are part of a growing sis of hereditary diffuse leukoen-
group of disorders caused by defects cephalopathy with spheroids was
in tRNase synthases. These currently often made in familial cases in which
include the genes MARS, AARS, and an affected patient had undergone
EARS2 in addition to DARS2. Each is brain biopsy documenting excessive

Case 12-1
A 44-year-old woman presented with a several-year history of cognitive
changes. Approximately 5 years before presentation, the patient and
family began noting social withdrawal and disengagement even from the
parenting of her then-teenaged daughters. This was initially attributed to
depression and resulted in the patient losing her position as a nurse. In
the subsequent years, she developed a progressive gait apraxia as well as
spasticity and had progressive cognitive difficulties, with reported changes
in short-term memory and sequencing of tasks, disorientation in time, and
significant abulia. More recently, she had progressive motor difficulties,
with a slow shuffling gait evolving to complete inability to initiate
movement, despite apparently normal strength.
Her general examination was unremarkable. On mental status, she had
slow responses and no spontaneous initiation of conversation. She was
unable to perform simple calculations and serial 7’s. She had abnormal
glabellar response and a snouting response. She had slow saccades to
pursuit, but cranial nerves were otherwise normal to examination. She had
motor impersistence for all tasks. She was unable to correctly perform
rapid alternating movements and simple motor sequences. When she was
helped to a standing position, she was unable to initiate walking, although
when supine, full movements were demonstrated. Sensory and cerebellar
testing were normal.
Extensive biochemical testing was normal. MRI demonstrated multifocal
but fairly symmetric white matter signal abnormalities with increased
signal on T2 and decreased signal on T1 involving the periventricular and
deep white matter fibers with sparing of the subcortical fibers. White
matter abnormalities had a clear frontal predominance, particularly in the
involvement of the corpus callosum with significant atrophy of the frontal
lobes. Nonspecific abnormalities were reported on an outside brain biopsy,
but when results were reviewed again, clear axonal spheroids were seen.
Comment. Based on the clinical features with a predominance of frontal
lobe symptoms (psychiatric manifestations, severe motor apraxia, frontal
release signs on neurologic examination), biopsy findings, and MRI
evidence of a multifocal leukodystrophy with involvement of the pyramidal
tracts, testing of the CSF1R gene was recommended. A pathogenic
heterozygous change was identified, confirming a diagnosis of hereditary
diffuse leukoencephalopathy with spheroids.
axonal spheroids in appropriate clini- Mechanism/genetics. Hereditary

cal conditions, although these are not diffuse leukoencephalopathy with
a unique feature of this disorder. spheroids is caused by mutations in
Recently, hereditary diffuse leukoen- CSF1R.11 The mechanism of this dis-
cephalopathy with spheroids families order is unknown, although mutations
have been shown to harbor mutations in a myeloid lineage gene suggest the
affecting the tyrosine kinase domain possibility that central nervous system
of the colony stimulating factor 1 re- microglia are important in this condi-
ceptor (encoded by CSF1R).11 The tion. The disorder is inherited in an
diagnosis is now made based on iden- autosomal dominant fashion. Because
tification of mutations in CSF1R in the no treatment for this condition exists
appropriate clinical circumstances. at this time, descendants of patients

KEY POINT
h A patient presenting
with a strong
neuropsychiatric
prodrome prior to the
development of obvious
motor impairment
should lead the
clinician to suspect
hereditary diffuse
leukoencephalopathy
with spheroids
or lysosomal
leukoencephalopathies,
such as GM1
gangliosidosis, GM2
gangliosidosis, globoid
cell leukodystrophy, or
metachromatic
leukodystrophy.
FIGURE 12-2 Hereditary diffuse leukoencephalopathy with spheroids. Fluid-attenuated

inversion recovery (FLAIR) (A, B) and T2-weighted images (C, D) show
asymmetric white matter abnormalities and frontal predominance as well as
frontal atrophy. The right frontal regions show evidence of the surgical biopsy (D, arrow) that
helped establish the diagnosis in this patient.
with hereditary diffuse leukoenceph- presenting in the fifth to seventh

alopathy with spheroids need to be decades of life. Patients present with
carefully counseled regarding the im- gait difficulties with both lower and
pact of a diagnosis prior to testing. upper motor neuron involvement and
peripheral neuropathy, with sensory
Adult-Onset Polyglucosan deficits predominantly in the lower
Body Disease extremities, neurogenic bladder, and
Clinical. Adult-onset polyglucosan dementia. The combination of upper
body disease is a disorder typically and lower motor neuron signs can

KEY POINT
h Adult-onset polyglucosan sometimes be mistaken for amyo- ease tend to be most evident in the
body disease is a disorder trophic lateral sclerosis. CSF protein periventricular white matter. They are
typically presenting in the may be elevated, and electrophysio- often multifocal and poorly defined
fifth to seventh decades logic studies are abnormal. A skin or initially and progress to confluency.
of life. Patients present nerve biopsy can help identify poly- Significant abnormalities are often
with gait difficulties with glucosan bodies, although genetic test- seen in the brainstem and cerebellar
both lower and upper ing is now the mainstay of diagnosis. white matter (Figure 12-3).12
motor neuron involvement Neuroimaging. White matter ab- Diagnosis. Diagnosis is typically
and peripheral normalities in polyglucosan body dis- made by molecular screening of
neuropathy, with sensory
deficits predominantly in
the lower extremities,
neurogenic bladder, and
dementia. The
combination of upper
and lower motor neuron
signs with
leukoencephalopathy
should lead the
clinician to suspect
adult-onset polyglucosan
body disease.
FIGURE 12-3 Adult-onset polyglucosan body disease. A, The relatively hypointense normal
body of the pons within the affected brainstem on sagittal fluid-attenuated
inversion recovery (FLAIR) images is a classic feature of the disease. B, C, D,
Confluent white matter disease is seen in this advanced case with significant brainstem and
cerebellar signal abnormalities on axial T2-weighted images.

KEY POINTS
GBE1, the gene encoding the glucan encephalopathy caused by a trinucle- h Adult-onset polyglucosan
branching enzyme.13,14 Abnormalities otide repeat disorder. body disease is allelic
of glucan branching enzyme activity Mechanism/genetics. DRPLA is an with a childhood-onset
are not constant, so this measurement autosomal dominant disorder caused condition, glycogen
is not an ideal test for the condition. by expansion of a CAG repeat in the storage disease type IV,
Mechanism/genetics. Deficiency of ATN1 (DRPLA) gene.16 The CAG repeat with very different
glucan branching enzyme also causes ranges from 48 to 93 in affected per- symptom manifestations,
glycogen storage disease type IV. These sons. Some cases are sporadic, but in demonstrating the
patients have no glucan branching en- familial cases, anticipation may occur. phenotypic spectrum of
zyme activity. Patients with adult-onset Transmission is autosomal dominant. disorders affecting the
polyglucosan body disease may have white matter of the brain.
normal or decreased glucan branch- Autosomal Dominant h Patients may present
ing enzyme activity, and it is unclear Leukodystrophy with dentatorubral-
what leads to the formation of the Clinical. Autosomal dominant leuko- pallidoluysian atrophy
typical abnormality, accumulation of dystrophy is an adult-onset leuko- from the first to the
dystrophy with early autonomic sixth decades, but most
polyglucosan bodies. Adult-onset
patients present in
polyglucosan body disease is inherited involvement, such as urgency in uri-
adulthood. In adult-onset
in an autosomal recessive manner. nation, impotence, constipation, an-
cases, ataxia,
hidrosis, and postural hypotension, choreoathetosis, and
Dentatorubral-Pallidoluysian and progressive gait disturbance as- dementia are the most
Atrophy sociated with spasticity and ataxia.17 prominent features.
Clinical. Patients may present with Case 12-2 provides an example of a
h Exome testing, which
dentatorubral-pallidoluysian atrophy typical clinical course.
does not detect
(DRPLA) from the first to the sixth de- Neuroimaging. Notable radiologic trinucleotide repeat
cades, but most patients present in features include confluent white mat- disorders, will not
adulthood. Patients present with het- ter changes in supratentorial regions, detect dentatorubral-
erogeneous features, including myo- predominantly affecting the deep pallidoluysian atrophy.
clonic epilepsy, choreoathetosis, white matter, with relative sparing of Dentatorubral-
cerebellar ataxia, and cognitive/ the periventricular white matter and pallidoluysian atrophy is
behavioral decline. In adult-onset cases, the subcortical fibers. In some cases, the only genetic
ataxia, choreoathetosis, and dementia predominance in the perirolandic re- leukoencephalopathy
caused by a trinucleotide
are the most prominent features.15 gions and pyramidal tracts is seen at
repeat disorder.
Neuroimaging. MRI features in- onset, evolving over time into diffuse
clude atrophy of the tegmentum of white matter abnormalities. The cor- h Autosomal dominant
the midbrain, pons, dentate nucleus, pus callosum is relatively spared but leukodystrophy is an
adult-onset
superior cerebellar peduncles, and can show posterior abnormalities. The
leukodystrophy with
cerebellum. T2 signal increase of posterior limb of the internal capsule
early autonomic
the globus pallidus and thalamus is is often involved. Abnormal signal is involvement, such as
present. White matter changes may seen in brainstem tracts, and the up- urgency in urination,
be initially patchy and periventricular per and middle cerebellar peduncles impotence, constipation,
and evolve to confluency. are often involved (Figure 12-4).18,19 anhidrosis, and postural
Diagnosis. Diagnosis is suggested Diagnosis. The diagnosis of auto- hypotension, and
by typical MRI manifestations and somal dominant leukodystrophy is sug- progressive gait
clinical history and confirmed by ge- gested by typical MRI features, family disturbance associated
netic testing that can detect trinu- history, and clinical characteristics and with spasticity and ataxia.
cleotide expansions. Exome testing, is confirmed by mutation testing.
which does not detect trinucleotide Mechanism/genetics. Autosomal
repeat disorders, will not detect DRPLA. dominant leukodystrophy is caused
DRPLA is the only genetic leuko- by duplications in the gene encoding

Case 12-2
A 50-year-old man presented with a 10-year history of progressive neurologic deterioration. His first
symptoms were nocturnal enuresis followed by erectile dysfunction. Progression of symptoms included
gradual worsening of urinary symptoms, with diurnal incontinence and recurrent urinary tract infections,
constipation, impotence, and, later, a progressive spastic diplegia. These symptoms and the lack of a
spinal cord lesion on neuroimaging led to imaging of the brain, which documented a leukoencephalopathy.
The patient was initially clinically suspected to have multiple sclerosis, but he was later reevaluated and
established to have a leukodystrophy of unknown cause. He became wheelchair dependent approximately
1 year before presentation and in recent months became unable to transition himself from bed to
wheelchair. Autonomic symptoms, including cold and burning extremities, orthostatic symptoms, urinary
and bowel dysfunction and impotence, continued to evolve. He had no relevant family history, but his
parents both died in their fifties of non-neurologic causes.
On examination, he was orthostatic (blood pressure sitting 110/70, standing 90/40). His affect was
mildly labile, but mental status examination was otherwise normal. He had mildly reduced muscle bulk
distally in both lower extremities, but his general examination was otherwise unremarkable. His cranial
nerve examination was notable for mild dysarthria. Tone was remarkable for increased tone and
decreased strength in the lower greater than upper extremities. Deep tendon reflexes were brisk
FIGURE 12-4 Autosomal dominant adult-onset leukodystrophy. T2-weighted MRI images demonstrate classic brainstem
and middle cerebellar peduncle signal abnormalities accompanying diffuse central white matter signal
abnormalities at a late stage. Images from three unrelated individuals demonstrate the stereotypical
brainstem (A) and supratentorial (B) signal abnormalities, such as seen in the patient in Case 12-2.
Continued on page 927


Continued from page 926
throughout. He had decreased recognition on sensory testing of sharp versus dull sensation, decreased
temperature sensation, and subjective burning of his feet in a stocking distribution and an area over
the left thigh. He had ataxia while sitting and was unable to stand. He also had mild dysmetria on
finger-to-nose testing and was unable to perform heel to shin.
Extensive biochemical testing was unrevealing. MRI of the brain demonstrated confluent white
matter changes in the supratentorial regions. Individual brainstem tracts had abnormal signal. The
middle cerebellar peduncles were also involved (Figure 12-4).
Comment. Based on the clinical features of an individual with initial symptoms of autonomic
dysfunction and progressive spastic tetraparesis with neuroimaging remarkable for a
leukoencephalopathy with confluent white matter abnormalities and prominent brainstem and
middle cerebellar peduncle involvement, LMNB1 duplication testing was performed and confirmed
a diagnosis of autosomal dominant leukodystrophy.
lamin B1 (LMNB1).20 The mechanism but these may come to medical atten- KEY POINTS
of disease remains poorly understood. tion only in adulthood. Patients de- h Significant symmetric
Lamin B1 is overexpressed in autoso- velop cataracts and xanthomas of the involvement of the
mal dominant leukodystrophy. This tendons, as well as neurologic dys- middle cerebellar
protein is an intermediate filament peduncles in an
function, most often including spastic
adult-onset
expressed in the nuclear lamina within paresis, cerebellar ataxia, posterior leukodystrophy should
the nuclear envelope. Believed to be column dysfunction, peripheral neu- raise concern for
involved in either altered nuclear ropathy, seizures, and progressive autosomal dominant
envelope stability or in transcriptional dementia. Premature atherosclerosis leukodystrophy.
regulating, lamin B1 duplications have and coronary artery disease have
a yet unknown mechanism that dis- h Cerebrotendinous
been reported. xanthomatosis is an inborn
rupts myelin homeostasis. Available Neuroimaging. The hallmark and error of metabolism. In
histopathologic reports suggest loss earliest MRI features of cerebro- late childhood or early
of myelin in the cerebrum and cere- adolescence, patients
tendinous xanthomatosis are involve-
bellum, preserved oligodendrocytes, may begin to manifest
ment of the cerebellar white matter.
and mild astrogliosis. No evidence of more specific features of
T2 hyperintensity of the dentate nu-
inflammation is seen. Inheritance is the disease, but these
cleus and cerebellar white matter are
autosomal dominant. Apparent de may come to medical
seen, along with cerebellar atrophy.
novo cases are reported in addition attention only in
to cases of autosomal inheritance. Occasionally, T2 hypointensity can be adulthood.
Because no treatment for this condi- seen in the dentate. If this is present
tion exists at this time, descendants of along with cerebellar white matter
individuals with autosomal dominant hyperintensity, it is highly suggestive
leukodystrophy should be carefully of cerebrotendinous xanthomatosis.
counseled regarding the impact of a Brainstem lesions may involve the
diagnosis prior to testing. corticospinal tracts and the medial
lemniscus. Ill-defined symmetric but
Cerebrotendinous Xanthomatosis sometime patchy periventricular T2
Clinical. Cerebrotendinous xanthoma- hyperintensity may be seen in the
tosis is an inborn error of metabolism. supratentorial white matter.21
Patients often have a history of pro- Diagnosis. Measurement of serum
longed cholestatic jaundice in infancy cholestanol, the 5 alpha-dihydro deriv-
as well as unexplained chronic diar- ative of cholesterol, can be performed,
rhea. In late childhood or early ado- and elevations are diagnostic of the
lescence, patients may begin to manifest disorder in addition to normal to low
more specific features of the disease, plasma cholesterol concentrations,

KEY POINTS
h Patients with decreased chenodeoxycholic acid, and Neuroimaging. MRI in CADASIL
cerebrotendinous increased concentration of bile acids. may show extensive abnormalities in
xanthomatosis develop Mechanism/genetics. Cerebro- the white matter without large cor-
cataracts and xanthomas tendinous xanthomatosis is character- tical infarcts. Subcortical lacunar le-
of the tendons, as well as ized as a lipid storage disease caused sions, characteristically aligned at
neurologic dysfunction, by deficiency of the mitochondrial en- the junction of the gray and white
most often including zyme 27-hydroxylase, which catalyzes matter, are typically seen. Cerebral
spastic paresis, cerebellar one of the first steps in the metabo- microbleeds are most commonly seen
ataxia, posterior column lism of sterols. The sterol 27-hydroxy- in the thalamus. Symmetric involve-
dysfunction, peripheral lase gene (CYP27A1) can be sequenced ment of the centrum semiovale, exter-
neuropathy, seizures,
for mutations or deletions for con- nal capsules, temporal lobes, and basal
and progressive dementia.
firmation of the diagnosis. Recogni- ganglia are seen.22
Carefully soliciting the
history of cataracts in
tion of this disorder is important Diagnosis. The diagnosis of
patients, which may have because long- term treatment with CADASIL previously required a skin
been diagnosed and chenodeoxycholic acid improves neu- biopsy documenting electron-dense
treated decades earlier, rologic outcome. granules. Currently, molecular testing
may be a clue to the Trends. Because evidence exists is the mainstay of diagnosis.
diagnosis of that early long-term treatment with Mechanism/genetics. More than
cerebrotendinous chenodeoxycholic acid improves out- 90% of individuals have mutations in
xanthomatosis. come, this disorder should be ac- NOTCH3,23 and molecular genetic test-
h Cerebral autosomal tively sought so that a potentially ing is available. CADASIL is inherited in
dominant arteriopathy treatable condition is not missed. In an autosomal dominant manner. Be-
with subcortical particular, history of previous cata- cause no treatment exists at this time
infarcts and ract removal should be sought. for this condition, descendants of in-
leukoencephalopathy is Cerebrotendinous xanthomatosis dividuals with CADASIL need to be
characterized by a history should not be discounted because of carefully counseled regarding the im-
of migraines, middle
absence of the typical xanthomas of pact of a diagnosis prior to testing.
adultYonset
the tendons and ocular manifesta-
cerebrovascular disease,
tions. Some experts maintain that Fabry Disease
progressive dementia,
diffuse white matter cholestanol should be measured in Clinical. Although Fabry disease has
lesions, and all patients with unexplained cataracts systemic symptoms, often with onset
subcortical infarcts. and neurologic decline with white in childhood, the white matter ab-
h Involvement of the matter changes. normalities are typically seen in later
extreme capsule and decades. This X-linked disorder typi-
multifocal white matter
Cerebral Autosomal cally presents in affected males with
changes perpendicular Dominant Arteriopathy With symptoms including angiokeratomas,
to the gray-white matter Subcortical Infarcts and chronic acral paresthesia, recurrent gas-
junction should raise Leukoencephalopathy trointestinal symptoms, hypohidrosis,
concern for cerebral Clinical. Cerebral autosomal domi- cardiovascular disease, and renal fail-
autosomal dominant nant arteriopathy with subcortical in- ure. Heterozygous females may have
arteriopathy with farcts and leukoencephalopathy some of the above features.
subcortical infarcts and (CADASIL) is characterized by a his- Neuroimaging. CT and MRI may
leukoencephalopathy.
tory of migraines, middle adultYonset suggest calcification of the pulvi-
cerebrovascular disease, progressive nar, globus pallidus, cerebellar-
dementia, diffuse white matter le- corticomedullary junction, and cere-
sions, and subcortical infarcts. Skin bral subcortical-cortical junction. MRI
biopsies demonstrate electron-dense demonstrates progressive lacunar in-
granules in the media of arterioles on farctions that, with time, can progress
electron microscopy. to confluency.12

KEY POINTS
Diagnosis. Diagnosis is made based presence of enlarged perivascular h Fabry disease is one of
on deficient activity of "-galactosidase spaces, with surrounding white matter only three X-linked
A and molecular analysis of GLA. signal changes. This group of disor- leukoencephalopathies
Mechanism/genetics. Deficient ac- ders has very similar imaging features presenting in adulthood,
tivity of "-galactosidase results in pro- overall, with numerous different etiol- in addition to X-linked
gressive lysosomal deposition of ogies. The mucopolysaccharidoses are adrenoleukodystrophy
globotriaosylceramide. The disorder the most striking example of this and Pelizaeus-Merzbacher
is transmitted in an X-linked fashion. abnormality, and other systemic man- disease. It typically
ifestations often result in an appropri- presents in affected
3-Hydroxy-3-Methylglutaryl ate diagnosis. However, other disorders males with symptoms
Coenzyme A Lyase Deficiency including angiokeratomas,
may be more subtle in presentation.
chronic acral paresthesia,
Clinical. Patients with 3-hydroxy-3- Patients with almost any chromosomal
recurrent gastrointestinal
methylglutaryl coenzyme A (HMG- abnormality, including fairly common symptoms, hypohidrosis,
CoA) lyase deficiency have metabolic sex chromosome aneuploidy (eg, XXY) cardiovascular disease,
acidosis without ketonuria, hypoglyce- may have enlarged perivascular spaces and renal failure.
mia, and a characteristic pattern of and multifocal white matter abnormali-
h Patients with 3-hydroxy-
elevated urinary organic acid metabo- ties. Additionally, disorders with cogni- 3-methylglutaryl
lites. Features of presentation can also tive impairment and developmental coenzyme A lyase
include hepatomegaly, seizures, or abnormalities, such as Lowe syndrome, deficiency have metabolic
acute encephalopathy/coma. There Coffin-Lowry syndrome, and PTEN- acidosis without
have been reported cases in which associated hamartoma syndrome, can ketonuria, hypoglycemia,
this diagnosis has been unrecog- all be associated with enlarged peri- and a characteristic
nized into adulthood, 24 although vascular spaces (Figure 12-5). pattern of elevated
the advent of universal newborn urinary organic acid
screening for organic acidemias HERITABLE metabolites. Features of
should greatly decrease this possibility LEUKOENCEPHALOPATHIES presentation can also
in coming years. WITH SPECIAL PRESENTATIONS include hepatomegaly,
IN THE ADULT POPULATION seizures, or acute
Neuroimaging. Axial T2-weighted
encephalopathy/coma.
MRI shows multifocal increased signal A number of leukodystrophies typi-
intensity in periventricular and sub- cally associated with onset in the pe- h Adults and adolescents
cortical areas of the white matter. In with 3-hydroxy-3-
diatric age group can present in older
methylglutaryl coenzyme
certain cases, treatment with a leucine- adolescents or throughout the adult
A deficiency may not
restricted diet has normalized the ab- decades. They may have typical phe- have benefited from the
normalities on neuroimaging.25 notypic presentations or may present expanded newborn
Diagnosis. Diagnosis can be made with symptom complexes very differ- screening protocols now
by the detection of 3-hydroxy-3- ent from their pediatric counterparts. in place, and urine
methylglutaric acid, 3-methylglutaconate, In many cases, they present at disease organic acids should be
3-hydroxyisovalerate, and 3-methylglutarate onset with less confluent white matter ordered if this diagnosis
in urine organic acid analysis. changes than in pediatric cases and is considered.
Mechanism/genetics.. Hydroxy- should be considered, in select cases,
methylglutaryl-CoA lyase is deficient, as part of the differential diagnosis of
and molecular analysis of HMGCL can MS and other presentations of abnor-
confirm the diagnosis. mal white matter in adults.
HERITABLE DISORDERS Metachromatic Leukodystrophy

WITH ENLARGED Clinical. Metachromatic leukodystro-
PERIVASCULAR SPACES phy can be seen in any age group,
An important cause of multifocal although it classically presents in the
white matter abnormalities is the infantile period. Late juvenile- and

KEY POINTS
h A number of
leukodystrophies
typically associated with
onset in the pediatric
age group can present
in older adolescents or
throughout the adult
decades. They may have
typical phenotypic
presentations or may
present with symptom
complexes very different
from their pediatric
counterparts. In many
cases, they present at
disease onset with
less confluent white
FIGURE 12-5 Enlarged perivascular spaces in a patient with Lowe syndrome. The areas with
matter changes than in decreased T1 signal (A) and increased T2 signal (B) have small nonenhancing
pediatric cases and cystic regions that are isointense with the CSF, corresponding to increased
should be considered, in perivascular spaces.
select cases, as part of
the differential diagnosis
of multiple sclerosis and adult-onset cases exist. In contrast to are notable for frontal predominance
other presentations of early-onset cases, in which motor of white matter abnormalities, an
abnormal white matter
features predominate early on, later- absence of characteristic radiating
in adults.
onset cases demonstrate significant stripes, and the presence of pyramidal
h In contrast to behavioral and cognitive deficits at tract involvement. This is similar to
early-onset cases of symptom onset. Over time, spasticity, that seen in globoid cell leukodystro-
metachromatic
seizures, movement disorders, cere- phy (Figure 12-6). Significant atrophy
leukodystrophy, in
bellar ataxia, and peripheral neuro- may be present.
which motor features
predominate early on,
pathy may develop. Absence of Diagnosis. The diagnosis of meta-
later-onset cases peripheral reflexes is a suggestive chromatic leukodystrophy is based
demonstrate significant finding. Increased CSF protein, com- on demonstration of decreased aryl-
behavioral and cognitive monly seen in early-onset cases, is an sulfatase A levels in blood leukocytes28
deficits at symptom inconsistent finding in later-onset meta- and increased urinary sulfatides. Care
onset. Over time, chromatic leukodystrophy. should be taken to include urinary
spasticity, seizures, Neuroimaging. MRI of the brain in sulfatides in diagnosis as arylsulfatase
movement disorders, infantile metachromatic leukodystro- A level activity that is 5% to 20% of
cerebellar ataxia, and phy is characterized by diffuse white controls can be seen in normal indi-
peripheral neuropathy matter abnormalities with an appear- viduals and is classified as pseudo-
may develop.
ance of radiating stripes (tigroid pat- deficiency. Molecular genetic testing
tern), sparing of subcortical white of the ARSA gene may be performed.
matter, and involvement of the corpus Mechanism/genetics. Mutations in
callosum and pyramidal tracts in the the ARSA gene cause loss of arylsul-
brainstem.26 Isolated involvement of fatase A activity. This, in turn, results in
cranial nerves, radicular nerves, and accumulation of sulfatated lipids that
cauda equina is increasingly recog- are a constitutive part of the myelin
nized as an initial presentation in sheath and is presumed to result in the
some patients.27 Juvenile- and adult- degradation of myelin in patients with
onset metachromatic leukodystrophy metachromatic leukodystrophy. The

FIGURE 12-6 Globoid cell leukodystrophy (Krabbe disease). A, Axial T2-weighted MRI of infantile-onset globoid cell
leukodystrophy with diffuse white matter involvement sparing the subcortical fibers, atrophy, and dentate
signal abnormality. B, Axial T2-weighted MRI of adult-onset globoid cell leukodystrophy demonstrating
selective parietal involvement.
disorder is inherited in an autosomal deterioration may be variable but is KEY POINT

recessive pattern. relentlessly progressive. Increased CSF h Pseudodeficiency of
protein, a hallmark of early-infantile arylsulfatase is not
Globoid Cell Leukodystrophy causative of disease and
cases, is an inconsistent finding in
should not be confused
Clinical. Globoid cell leukodystrophy, later-onset cases.
with a diagnosis
or Krabbe disease, can be seen in any Neuroimaging. Later-onset globoid of metachromatic
age group, but the early-infantile pre- cell leukodystrophy may manifest as leukodystrophy.
sentation is most common. In later- hyperdensity of the basal ganglia and
onset cases, the presentation may be thalamus on CT as seen in early-onset
very variable. Initial signs may include cases. Juvenile- and adult-onset glo-
spastic paraparesis, visual impairment, boid cell leukodystrophy may be char-
cerebellar ataxia, seizures, behavioral acterized by predominant involvement
or cognitive decline, and peripheral on MRI of the parietooccipital regions
neuropathy. In contrast to metachro- or even selective involvement of
matic leukodystrophy, motor or visual corticospinal tracts (Figure 12-6).29
dysfunction is more often the initial Pyramidal tract involvement may ex-
manifestation.12 The rate of disease tend from the motor cortex through

KEY POINTS
h Globoid cell the posterior limb of the internal GM1 Gangliosidosis/GM2
leukodystrophy, or capsule and into the brainstem. In- Gangliosidosis
Krabbe disease, can be volvement of the splenium of the Clinical. GM1 and GM2 gangliosidoses
seen in any age group. In corpus callosum may be seen. typically present in the pediatric pop-
later-onset cases, the Diagnosis. The diagnosis of glo- ulation, but adult-onset variants do
presentation may be very boid cell leukodystrophy is made by occur. In GM1 adult-onset cases, gait
variable. Initial signs may demonstrating decreased activity of disturbance and speech impairment
include spastic galactocerebroside "-galactosidase are often the first clinical signs. On
paraparesis, visual (galactocerebrosidase or GALC) in physical examination, extrapyramidal
impairment, cerebellar leukocyte lysosomal assays. Molecular features predominate. Typical bony
ataxia, seizures,
genetic testing can also be performed abnormalities, visceromegaly, cherry
behavioral or cognitive
of the GALC gene. red spots, and facial dysmorphisms
decline, and peripheral
neuropathy.
Mechanism/Genetics. Globoid cell are not usually seen. In GM2 adult-
leukodystrophy is caused by muta- onset cases, symptoms may be highly
h In adult-onset cases of tions in GALC. In late-onset globoid variable and include ataxia, spasticity,
GM1 gangliosidosis, gait
cell leukodystrophy, a mutation weakness, muscle atrophy, fascicula-
disturbance and speech
impairment are often
c.809G9A is often seen.30,31 Psychosine, tions, dystonia, and psychosis. Abnor-
the first clinical signs. In which accumulates as a result of de- mal urinary oligosaccharides are seen
adult-onset cases of ficiency of galactocerebrosidase, is but may be less abundant than in
GM2 gangliosidosis, hypothesized to be toxic to oligoden- early-onset cases.
symptoms may be highly drocytes, but the exact mechanism of Neuroimaging. Characteristics of
variable and include toxicity to the oligodendrocytes, and MRI in GM1 and GM2 adult-onset cases
ataxia, spasticity, in particular the role played by the are nearly identical. Slight white mat-
weakness, muscle multinucleated cells typical of this ter T2 signal increase and diffuse
atrophy, fasciculations, disorder (globoid), remains unclear. atrophy are seen. T2 signal hyperin-
dystonia, and psychosis. The disorder is inherited in an autoso- tensity may be seen in the caudate
h Alexander disease can mal recessive fashion. nucleus and the putamen, while
be seen in any age hypointensity may be seen in the
group, and a growing Lysosomal Disorders With globus pallidus.12
number of publications White Matter Abnormalities Diagnosis. The diagnosis of GM1
have documented and GM2 gangliosidoses is made by
Trends. Because of their slow onset of
adult-onset cases.
disease manifestations, juvenile- or analysis of "-galactosidase or hexosa-
Adult-onset Alexander
adult- onset cases of these disorders minidase A enzyme activity, respec-
disease tends to
manifest with may be partially responsive to disease tively. Rarely, GM2 can be caused by
predominantly bulbar management approaches such as deficiency of an activator protein
and autonomic bone marrow transplantation. Thus, (GM2 AB variant). An alternative is mo-
disturbances, as well these disorders should be actively lecular sequencing of the GLB1 and
as more typical sought so that a potentially treatable HEXA genes.
long-tract signs. or modifiable disease condition is not Mechanism/genetics. "-Galactosidase
missed. Additionally, the advent of and hexosaminidase A enzyme deficiency
newborn screening for metachromatic result in excessive neuronal glycolipid
leukodystrophy and globoid cell leu- storage. Both disorders are inherited
kodystrophy in many states will iden- in an autosomal recessive fashion.
tify some patients with uncertain
outcomes who will need to be fol- Alexander Disease
lowed into adulthood to establish the Clinical. Alexander disease can be
absence of disease. Thus the adult seen in any age group, and a growing
neurologist should become familiar number of publications have docu-
with this group of disorders. mented adult-onset cases. Adult-onset

KEY POINTS
Alexander disease tends to manifest minant inheritance patterns can be h Adult patients with
with predominantly bulbar and auto- seen; familial cases should be sought Alexander disease may
nomic disturbances, as well as more once a proband is identified. lack supratentorial
typical long-tract signs. Patients pres- white matter changes
ent with palatal myoclonus, swallow- X-linked Adrenoleukodystrophy/ and instead present
ing difficulties, dysphonia, obstructive Adrenomyeloneuropathy with symptoms mainly
sleep apnea, unexplained syncope, Clinical. X-linked adrenoleukodystro- attributable to brainstem
and gait disturbance. Biochemical phy often presents in a rapidly pro- involvement. Palatal
and standard laboratory evaluations gressive childhood cerebral-onset myoclonus, dysphonia,
will be unrevealing. form; however, up to 40% to 45% of swallowing difficulties,
and sleep apnea are
Neuroimaging. MRI of the brain affected male subjects will manifest
strongly suggestive of
may demonstrate typical Alexander a slower later-onset form called
this condition.
disease findings. These include frontal adrenomyeloneuropathy. Less fre-
predominance of white matter ab- quently, adult males may present h Adult-onset Alexander
disease may not show
normalities, contrasting T2 signal with a rapidly progressive cerebral
typical MRI manifestations
hypointensity/T1 signal hyperintensity form much like the childhood-
but may show
around the periatrial white matter, onset presentation. Female hetero- brainstem-predominant
basal ganglia and brainstem signal zygotes may also present with an lesions.
abnormalities, and contrast enhance- adrenomyeloneuropathy-like pheno-
h Many adult-onset
ment of specific intracranial structures type. At any age, cerebral X-linked
leukodystrophies and
(Figure 12-7A).32 More often than in adrenoleukodystrophy typically first leukoencephalopathies,
early-onset Alexander disease, MRIs in presents with significant behavioral including cerebral
adult-onset Alexander disease will changes that may be misdiagnosed as autosomal dominant
show space-occupying lesions of the attention deficit hyperactivity disorder, arteriopathy with
brainstem, brainstem atrophy, or cer- psychiatric illness, or, in older patients, subcortical infarcts and
ebellar white matter abnormalities. In primary dementia. Deteriorating cogni- leukoencephalopathy,
adults, supratentorial white matter tive function, gait changes, or visual hereditary diffuse
changes may be absent on typical loss may be the first indication of an leukoencephalopathy
MRI sequences (Figure 12-7B).33,34 If organic neurologic disorder. Rapid de- with spheroids,
sought, signal abnormalities of the terioration ensues and typically results adult-onset polyglucosan
body disease, autosomal
basal ganglia and contrast enhance- in severe dementia and spastic quadri-
dominant leukodystrophy,
ment of Alexander diseaseYsuggestive plegia over a period of months. In
adult-onset Alexander
structures may often help in the contrast, adrenomyeloneuropathy pre- disease, and others, are
diagnosis. In rare instances, posterior sents with symptoms and signs of autosomal dominant
fossa involvement may be so signifi- myelopathy and neuropathy. In all inherited conditions.
cant as to cause confusion with presentations, adrenal insufficiency These may occur
brainstem gliomas. may accompany neurologic features. sporadically or a
Diagnosis. The diagnosis of Alexander Isolated Addison disease may also be consistent family history
disease can be confirmed by sequenc- seen in this disorder. Because of the may exist, but regardless,
ing of the GFAP gene, encoding glial clinical implications, adrenal function these disorders have a
fibrillary acidic protein (GFAP).35 should be investigated in any subject 50% recurrence risk in
Mechanism/genetics. Heterozy- affected by or suspected to be affected the proband’s
descendants.
gous mutations cause gain of function by X-linked adrenoleukodystrophy.
in GFAP, and accumulation of mutant Neuroimaging. Classic MRI fea-
GFAP along with other proteins in tures in cerebral X-linked adrenoleu-
Rosenthal fibers is thought to be path- kodystrophy are predominantly
ogenic to astrocytes. In early-onset parietooccipital white matter abnor-
cases, mutations are often sporadic, malities involving the splenium of the
but in adult-onset cases, autosomal do- corpus callosum and often sparing the

FIGURE 12-7 Adult-onset Alexander disease. A, In some cases, MRI features resemble early-onset Alexander disease with
classic characteristics including frontal preponderance, contrasting T2 signal hypointensity relative to the
remainder of the abnormal white matter signal around the periatrial white matter, and basal ganglia signal
abnormalities. B, In other cases, MRI abnormalities are predominantly in the posterior fossa, with few supratentorial white
matter signal abnormalities.
KEY POINT arcuate fibers (Figure 12-8). Less com- ropathy, the principal abnormality is
h Cerebral X-linked mon (15%) is frontal predominance spinal cord atrophy, but patients with
adrenoleukodystrophy with a similar pattern, mostly in adrenomyeloneuropathy may also
typically first presents with adolescents and young adults pre- have brain involvement, including in-
significant behavioral
senting with cerebral X-linked adre- volvement of corticopontine and
changes that may be
noleukodystrophy. Careful attention corticospinal fibers and tracts as well
misdiagnosed as
attention deficit
to abnormal white matter permits as parietooccipital white matter and
hyperactivity disorder, identification of two zones, a central the splenium of the corpus callosum.
psychiatric illness, or, in zone with more severe demyelination MRI features are crucial in the moni-
older patients, primary and a relatively preserved peripheral toring of patients with X-linked adre-
dementia. zone. The hallmark of cerebral X-linked noleukodystrophy, and the presence
adrenoleukodystrophy is contrast of specific criteria may determine
enhancement of the border between eligibility for therapeutics such as
these two zones. In adrenomyeloneu- bone marrow transplant.

KEY POINTS
h Isolated Addison disease
should prompt testing
for X-linked
adrenoleukodystrophy.
h Classic MRI features in
cerebral X-linked
adrenoleukodystrophy
are predominantly
parietooccipital white
matter abnormalities
involving the splenium
of the corpus callosum
and often sparing the
arcuate fibers.
FIGURE 12-8 X-linked adrenoleukodystrophy. Axial MRIs show features seen in adult-onset
presentations of cerebral adrenoleukodystrophy with frontal rather than
parietal signal abnormalities on T2-weighted imaging (A, C), while still having
the typical features of callosal involvement on fluid-attenuated inversion recovery (FLAIR)
imaging (genu rather than splenium, B) and contrast enhancement of affected white matter
on T1 imaging with contrast (D).
Diagnosis. The diagnosis of X-linked transporter protein. Mutation testing

adrenoleukodystrophy and adreno- for this gene is clinically available.
myeloneuropathy is typically made When a proband is identified, careful
by testing very-long-chain fatty acids attention to family history and evalua-
in plasma, with characteristic elevation of other potentially affected males
tions in the concentration of C26:0 should be performed.
and the ratios of C24:0 to C22:0 and Trends. With the advent of success-
C26:0 to C22:0.36 ful bone marrow transplantation in the
Mechanism/genetics. X-linked management of X-linked adrenoleuko-
adrenoleukodystrophy and adreno- dystrophy when caught early in the
myeloneuropathy are caused by muta- disease course and the need for urgent
tions in the gene ABCD1, a peroxisomal medical management of potential

KEY POINTS
h Patients with Kearns- mineralocorticoid deficiency, the is often involved. Brainstem tracts and
Sayre syndrome present identification of X-linked adrenoleu- the cerebellum may also be involved
with ptosis and kodystrophy has become a medical (Figure 12-9).12
progressive external emergency. If an individual potentially Diagnosis. Kearns-Sayre syndrome
ophthalmoplegia, affected by X-linked adrenoleukodys- is one of three overlapping phenotypes,
pigmentary degeneration trophy has been identified, measures including also Pearson syndrome and
of the retina, cardiac to test for and manage endocrine progressive external ophthalmoplegia,
conduction block, disturbances should immediately be caused by mitochondrial DNA dele-
developmental delay, tions. Characteristic clinical features
put into place. Additionally, the pa-
growth failure, may be helpful in establishing a diag-
tient should be urgently transferred to
sensorineural hearing
the care of a center with experience in nosis, along with supportive evidence
loss, endocrine
bone marrow transplantation in pa- such as ragged red fibers on muscle
dysfunction, and
nonspecific neurologic tients with metabolic disease where biopsy and decreased activity of respi-
abnormalities. decisions regarding the appropriate- ratory chain complexes.
ness of transplantation based on dis- Mechanism/genetics. Approxi-
h Vanishing white matter
ease state can be made. Finally, the mately 90% of individuals with Kearns-
disease, also known as
childhood ataxia with clinician should be diligent in Sayre syndrome have a large deletion
cerebral hypomyelination, searching for and testing other poten- of mitochondrial DNA.37 Often, lym-
is a disorder in which tially affected individuals within the phocytes used for blood testing of the
presentation classically family of the proband, such that even mutant DNA do not carry a deletion,
occurs in early childhood, if the index case cannot be fully and other tissue must be biopsied for
manifesting by acute treated because of disease advance- diagnosis. Kearns-Sayre syndrome is
decompensations after usually sporadic but when inherited is
ment, other members of the family
falls or febrile illnesses. transmitted by maternal inheritance.
might be better managed.
Kearns-Sayre Syndrome Other Mitochondrial Syndromes

Clinical. Patients with Kearns-Sayre Other mitochondrial syndromes that
syndrome present with ptosis and can present with leukoencephalopa-
progressive external ophthalmoplegia, thy in the adult age group include
pigmentary degeneration of the ret- mitochondrial encephalomyopathy,
ina, cardiac conduction block, de- lactic acidosis, and strokelike episodes
velopmental delay, growth failure, (MELAS), mitochondrial neuro-
sensorineural hearing loss, endocrine gastrointestinal encephalomyopathy
dysfunction, and nonspecific neuro- (MNGIE), and other mutations in
logic abnormalities. Blood and CSF nuclear mitochondrial genes. A com-
lactic acid are usually elevated. CSF plete discussion of these phenotypes
protein is elevated. EMG may demon- is beyond the scope of this article.
strate myopathy, and nerve conduction
studies may demonstrate peripheral Vanishing White Matter Disease
neuropathy. ECG may show various Clinical. Vanishing white matter dis-
types of conduction abnormalities. ease, also known as childhood ataxia
Neuroimaging. CT may demon- with cerebral hypomyelination38 is a
strate calcifications of the globus disorder in which presentation classi-
pallidus and caudate nucleus. MRI cally occurs in early childhood, man-
often shows a characteristic pattern ifesting by acute decompensations
of symmetric lesions of the globus after falls or febrile illnesses.39 Pa-
pallidus and thalamus along with sub- tients can present with altered mental
cortical white matter abnormalities. status, acute paresis, or hypotonia or
The splenium of the corpus callosum may even develop coma in the initial

FIGURE 12-9 Kearns-Sayre syndrome. T2-weighted MRIs show cerebellar and globus pallidus
involvement. Cerebral white matter is selectively involved in the subcortical
regions, with preservation of the periventricular white matter and deep white
matter to a lesser degree.
period of illness. Death may ensue, or sive rarefaction and cystic degenera-
the patient may experience partial tion until white matter is replaced with
neurologic recovery, followed by re- signal isointense to the CSF spaces
peated episodes and a progressive (Figure 12-10). Cerebellar white mat-
neurologic decline. Paucisymptomatic ter is relatively spared. Signal abnor-
adult forms exist, which may present mality in the midbrain and the pons
with a progressive spastic paraparesis, may be seen. More rarely, signal
cognitive changes, or even isolated abnormality may be seen in the thala-
ovarian failure. mus and the globus pallidus. These
Neuroimaging. MRI demonstrates MRI features are seen across all age
diffuse white matter T2 signal increase. groups, except early-onset vanishing
Over time, fluid-attenuated inversion white matter disease, which may have
recovery (FLAIR) images show progres- a distinct MRI picture.12

FIGURE 12-10 Vanishing white matter disease. T2-weighted images of the pediatric
presentation of the disorder show white matter signal that is isointense with
CSF spaces, giving the impression that it has “vanished” (A). Fluid-attenuated
inversion recovery (FLAIR) imaging documents rarefaction of affected white matter (B).
Adult-onset cases show T2 hyperintensity (C), with abnormal signal and loss of white matter
volume on FLAIR (D) but without the characteristic rarefaction.
Diagnosis. Diagnosis in vanishing Mechanism/genetics. eIF2B is a

white matter disease is based on clas- critical rate-limiting factor for protein
sic MRI features and sequencing of the translation that is modulated by the
related genes (EIF2B1 to EIF2B5),40,41 endoplasmic reticulum stress re-
encoding a eukaryotic translation sponse.42 The mechanism by which
initiation factor eIF2B with five com- mutations in a ubiquitous housekeep-
ponents: alpha, beta, gamma, delta, ing gene result in fairly selective glial
and epsilon. cell dysfunction remains unknown.

KEY POINTS
The disorder is inherited in an autoso- conditions, recent studies suggest a h Although not considered
mal recessive manner. lysosomal trafficking or storage defect leukodystrophies,
may be present.44 hereditary spastic
Spastic Paraplegia SPG11 paraplegias, including
Although not considered leukodystro- Hypomyelinating SPG11, are occasionally
phies, hereditary spastic paraplegias, Leukodystrophies misdiagnosed as such
including SPG11, are occasionally mis- Special consideration should be given because of the prominent
diagnosed as such because of the prom- to the hypomyelinating leukodystro- periventricular white
inent periventricular white matter phies, including Pelizaeus-Merzbacher matter abnormalities
abnormalities seen in these conditions. disease; hypomyelination, hypogonad- seen in these conditions.
Clinical. SPG11 is characterized by otropic hypogonadism, and hypodontia h Certain symptom
childhood onset of progressive spastic (4H syndrome); and hypomyelination complexes, such as
paraparesis, cognitive deterioration, with atrophy of the basal ganglia and hereditary spastic
cerebellar signs, peripheral neuropathy/ cerebellum, seen commonly in the pe- paraplegia, may be
more amendable to
neuronopathy, and central retinal de- diatric population, as in adults they may
testing groups of genes
generation. Several patients with an present without the characteristic clin-
rather than single genes
early-onset primarily extrapyramidal ical features seen in their childhood- because of overlapping
phenotype have also been described, onset counterparts. disorders.
on occasion associated with abnormal- Clinical. Features are often pre-
h In adults, the
ities on neurochemistry of CSF.43 dominantly motor, with significant
hypomyelinating
Neuroimaging. Patients with spastic paraplegia and extrapyramidal leukodystrophies may
SPG11 have signal changes of peri- features. In some cases, these motor present without the
ventricular white matter in the frontal features are superimposed on a chronic characteristic clinical
region centered in the area of the encephalopathy with learning dis- features seen in their
forceps minor of the corpus callosum. ability or autistic features that went childhood-onset
They also have a characteristic thin undiagnosed in childhood. In other counterparts.
corpus callosum, more pronounced in cases, cognitive status is normal until
the mid and anterior portions with adulthood. Specific clinical features,
relative sparing of the splenium, giv- such as the hypogonadotropic hy-
ing a beaked appearance to the ante- pogonadism and myopia commonly
rior portion of the corpus callosum. seen in 4H syndrome, should alert the
White matter atrophy is seen. neurologist to a specific clinical con-
Diagnosis. The diagnosis of SPG11 dition. Adult teeth may be normal in
is based on classic MRI features and 4H syndrome, so an antecedent his-
sequencing of the related gene. It tory of abnormalities of eruption in
should be noted that overlapping phe- the primary teeth should be sought.
notypic features with other hereditary Pelizaeus-Merzbacher disease is an
spastic paraplegias exist, in particular X-linked disorder and should be con-
SPG15, and that sequencing of more sidered in affected males. Hypomyeli-
than one gene may be indicated in a nation with atrophy of the basal ganglia
tiered fashion or using a panel of genes. and cerebellum has no extraneurologic
Mechanism/genetics. SPG11 is manifestations and may be more diffi-
caused by mutations in SPG11 encod- cult to suspect clinically.
ing spatacsin. SPG15 is caused by Neuroimaging. Neuroimaging in
mutations in ZFYVE26 encoding adult-onset cases of hypomyelination
spastizin. Both are inherited in an may be less striking, without the ac-
autosomal recessive fashion. While companying cerebellar and basal
limited information exists on the path- ganglia changes seen in pediatric
ogenic mechanism in both of these disease, or may even have relatively

normal appearing myelination with neurologist as mimickers of MS or

abnormalities restricted to the corti- other acquired leukoencephalop-
cospinal tracts. athies. The etiologic diagnosis of
Diagnosis. A broad approach leukodystrophies or leukoenceph-
should be taken in these conditions, alopathies remains challenging in any
with either panel or tiered testing for age group. A diagnosis remains im-
PLP1 (in males), TUBB4A, POLR3A, portant for family counseling and
and POLR3B at least.45Y48 Other etiol- treatment of these devastating disor-
ogies of hypomyelination, such as ders. With careful attention to clinical
Salla disease, GJC2-related disease, features and MRI pattern recognition
and SOX10-related disease, are less for described disorders, diagnosis can
likely to present in the adult. No be achieved in a large proportion of
biochemical testing is available for cases. Additionally, when MRI and
these conditions. clinical features do not suggest a
Mechanism/genetics. Pelizaeus- specific disorder or targeted testing
Merzbacher disease is caused by does not result in an etiologic diagnosis,
X-linked mutations in PLP1. PLP1 agnostic testing using next-generation
encodes one of the major protein con- sequencing approaches such as whole
stituents of mature myelin, proteolipid exome sequencing is warranted. Al-
protein, and misfolding and mis- though currently not all are curable,
targeting of this protein is thought an increasing number of these disor-
to result in oligodendrocyte-related ders have etiologic treatment, and all
disease. 4H syndrome is caused by the disorders respond to symptom
autosomal recessive mutations in management. Thus, early and rapid
POLR3A, POLR3B, and the more re- diagnosis is the mainstay of these con-
cently identified POLR1C, although this ditions, and the treating neurologist
has only been seen in early-onset cases. should seek expert help in reaching a
These genes encode components of diagnosis, if necessary.
the polymerase III (Pol III), thought to
result in disease through its role in ACKNOWLEDGMENTS
protein synthesis. Hypomyelination This work was supported by an Inter-
with atrophy of the basal ganglia and governmental Personnel Act assignment
cerebellum is caused by de novo spo- from the National Institutes of Health.
radic mutations in TUBB4A, encoding
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Review Article

Continuum (Minneap Minn) 2016;22(3):916–942.

INTRODUCTION to revisions as the field advances in

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present in older patients with more clinician to a degenerative condition.

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HERITABLE DISORDERS WITH abnormalities have milder systemic pre-

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axonal spheroids in appropriate clini- Mechanism/genetics. Hereditary

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FIGURE 12-2 Hereditary diffuse leukoencephalopathy with spheroids. Fluid-attenuated

with hereditary diffuse leukoenceph- presenting in the fifth to seventh

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Continued on page 927

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HERITABLE DISORDERS Metachromatic Leukodystrophy

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disorder is inherited in an autosomal deterioration may be variable but is KEY POINT

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Diagnosis. The diagnosis of X-linked transporter protein. Mutation testing

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Kearns-Sayre Syndrome Other Mitochondrial Syndromes

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Diagnosis. Diagnosis in vanishing Mechanism/genetics. eIF2B is a

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normal appearing myelination with neurologist as mimickers of MS or

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