The latest on leukodystrophies
Raphael Schiffmanna and Marjo S. van der Knaapb
Purpose of review Abbreviations
Important advances in our understanding of genetic disorders of ALDP adrenoleukodystrophy protein
the white matter have been made and are discussed here. CACH childhood ataxia with central hypomyelination
eIF eukaryotic initiation factor
Recent findings H-ABC hypomyelination with atrophy of the basal ganglia and cerebellum
It has recently been discovered that mutations in the genes LBSL leukoencephalopathy with brain-stem and spinal cord involvement and
elevated white-matter lactate
encoding the five subunits of eukaryocytic initiation factor 2B MRI magnetic resonance imaging
(eIF2B) are the cause of vanishing white-matter disease/ MRS magnetic resonance spectroscopy
PLP proteolipid protein
childhood ataxia with central hypomyelination syndrome. The VWM vanishing white matter
extension of the clinical features of the eIF2B-related disorders X-ALD X-linked adrenoleukodystrophy
to encompass both infant- and adult-onset disorders is
# 2004 Lippincott Williams & Wilkins
discussed. New clinico-imaging syndromes such as
hypomyelination with atrophy of the basal ganglia and
cerebellum and leukoencephalopathy with brain-stem and spinal
cord involvement and elevated white-matter lactate are
described. Recent findings include evidence that mitochondrial Introduction
fat-oxidation abnormalities may be important in the pathogenesis In the past few years, a number of advances have
of adrenoleukodystrophy, and that a mutant myelin protein can occurred in our understanding of the nosology and
cause maldistribution of other myelin proteins, causing etiology of the leukodystrophies (genetic white-matter
dysmyelination, axonal damage, or both. brain disorders). This review focuses on the more
Summary recently described syndromes, including vanishing white
This review focuses on advances in the understanding of the matter (VWM)/childhood ataxia with central hypomye-
role of eIF2B as a cause of a common leukodystrophy lination (CACH), that are now known to be caused by
syndrome. eIF2B-related disorders have a clinical spectrum defects in eukaryotic initiation factor (eIF) 2B. Other
ranging from a severe, rapidly progressive congenital or early newly described leukodystrophy syndromes of unknown
infantile encephalopathy to a slowly progressive cognitive and cause are also described here. In addition, recent
motor deterioration often associated with premature ovarian developments in adrenoleukodystrophy and proteoli-
failure. Two newly recognized leukodystrophy syndromes are pid-related disorders are brieﬂy updated.
described: hypomyelination with atrophy of the basal ganglia
and cerebellum, and leukoencephalopathy with brain-stem and Vanishing white-matter disease/childhood
spinal cord involvement and elevated white-matter lactate. An ataxia with central nervous system
update is also given for adrenoleukodystrophy and myelin- hypomyelination
protein-related disorders. This update demonstrates that an VWM disease and CACH are two names for the same
increasing number of genetic defects are being identified that disease. After deﬁnition of the disease in the 1990s, the
may cause primary white-matter disorders. initial focus was on the clinical phenotype, the magnetic
resonance imaging (MRI) features and the histopatholo-
Keywords gical ﬁndings . It was clear from the beginning that
adrenoleukodystrophy, eukaryocytic initiation factor, H-ABC, the disease had an autosomal recessive mode of
LBSL, leukodystrophy, proteolipid protein inheritance, but linkage studies were hampered by
evident genetic heterogeneity. An important break-
Curr Opin Neurol 17:187–192. # 2004 Lippincott Williams & Wilkins. through came in 2001, when the ﬁrst two genes for the
disease were identiﬁed with the help of two Dutch
Developmental and Metabolic Neurology Branch, National Institute of Neurological founder effects, one in the eastern part of the country
Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA and
Department of Child Neurology, Free University Medical Center, Amsterdam, The and another in the southern part [2,3 .]. The most
Netherlands surprising ﬁnding was that the disease, clinically
Correspondence to Dr Marjo S. van der Knaap, Department of Child Neurology, Free
characterized by signs of a leukoencephalopathy only,
University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands was caused not by mutations in brain-speciﬁc genes, but
E-mail: email@example.com by mutations in the ubiquitously expressed house-
Current Opinion in Neurology 2004, 17:187–192 keeping genes EIF2B5 and EIF2B2. Soon, mutations
in three other genes were also found to cause VWM/
CACH: EIF2B1, EIF2B3 and EIF2B4 [3 .,4 .]. EIF2B1–
5, located on chromosomes 12q24.3, 14q24, 1p34.1,
DOI: 10.1097/01.wco.0000124710.26506.23 187
188 Metabolic disorders and neurotoxicology
2p23.3 and 3q27, respectively, encode the a, b, g, d and e eIF2B complex genes and, in fact, had VWM/CACH
subunits of translation initiation factor eIF2B. [12 .].
Translation of mRNA into polypeptides is a tightly Further evidence for involvement of multiple organs
regulated process . Multiple so-called eIFs are outside the brain was provided in a study of eight
involved in translation initiation and eIF2 is the central neonates and infants with a leukoencephalopathy and,
factor . If eIF2 is in complex with GTP, translation is additionally, a variable combination of oligohydramnios,
on, and if it is in complex with GDP, translation is off. intrauterine growth retardation, cataracts, pancreatitis,
Conversion of GTP to GDP produces the energy hepatosplenomegaly, hypoplasia and dysplasia of the
necessary to deliver methionine to the start codon of an kidneys and, again, dysgenesis of the ovaries [13 .].
mRNA. Regeneration of active eIF2 by exchange of GDP
for GTP is catalyzed by eIF2B. The exchange of GDP for Initially, no evidence was found for a genotype–
GTP by eIF2B is required for each round of translation phenotype correlation [2,3 .], but the fact that some
initiation, and regulation of this step can control global mutations are consistently associated with a more severe
rates of protein synthesis under diverse conditions . phenotype than other mutations is the ﬁrst indication of
Protein synthesis is markedly inhibited under a variety of a genotype–phenotype correlation [13 .].
stress conditions and in the recovery phase that follows.
eIF2B is the most important factor to down-regulate The pathophysiology of the disease in VWM/CACH is
translation under conditions of fever. still far from clear. A recent study using phosphorus
magnetic resonance spectroscopy of the brain revealed
The essential role of eIF2B in normal protein production evidence of an altered energy state of the residual cells
and in its regulation under different conditions is . Nucleoside triphosphate and inorganic phosphate
reﬂected in the observation that survival of an organism were reduced, whereas phosphocreatine was elevated
is not possible without eIF2B (yeast knockouts are not . The relative preservation of gray matter over white
viable), and in the type of mutations found. Most matter may have contributed to this observation, the
mutations in patients with VWM/CACH are missense nucleoside triphosphate to inorganic phosphate normally
mutations. Until now, major mutations, which prevent being lower in gray matter than in white matter. Of the
the expression of full-length eIF2B subunits, have only metabolites involved in biosynthesis and catabolism of
been observed in the compound-heterozygous state with membrane phospholipids, glycerophosphorylethanola-
a missense mutation as the second mutation [2,3 .,4 .]. mine was reduced and phosphorylelthanolamine was
increased, whereas choline-containing phosphorylated
A recent observation is that the neuropathology in Cree metabolites were unchanged . It is difﬁcult to
leukoencephalopathy shows similarities to that of VWM/ interpret these ﬁndings, largely because the composition
CACH [7 .]. Most strikingly, abnormal, foamy oligoden- of the remaining brain tissue in VWM/CACH is
drocytes are found in Cree leukoencephalopathy – a dramatically changed with serious rarefaction and altered
feature observed in most patients with VWM/CACH . ratios of constituent cell types. Why a defect in the
One particular mutation in EIF2B5 was subsequently regulation of protein synthesis would selectively affect
identiﬁed in all patients with Cree leukoenephalopathy ethanolamine phospholipid metabolism and leave cho-
that were studied [7 .]. Cree leukoencephalopathy is line phospholipid metabolism unaffected is presently
clinically more severe than classical VWM/CACH. Its unclear.
onset is invariably within the ﬁrst year of life, and death
occurs before the age of 2 years. Furthermore, two New leukoencephalopathies of unknown
Italian siblings with a particularly severe variant of cause
VWM/CACH were described, and the responsible Several ‘new’ leukoencephalopathy syndromes have
mutations in EIF2B5 were identiﬁed . been deﬁned in the nineties on the basis of distinct
patterns of MRI abnormalities or magnetic resonance
Thus far, it had been thought that VWM/CACH was a spectroscopy (MRS) ﬁndings. Nevertheless, a large
disease affecting only the brain. In 1997, one patient number of patients with signiﬁcant white-matter ab-
with VWM and dysgenesis of the ovaries, which could normalities on MRI still remain without a speciﬁc
be an incidental ﬁnding, was described . The ﬁrst diagnosis. Multi-institutional studies have led to the
evidence for a more consistent association between identiﬁcation of two additional novel disorders.
leukoencephalopathies and dysgenesis of the ovaries was
provided by Schiffmann et al. , who described several Hypomyelination with atrophy of the basal ganglia and
female patients with these features under the heading of cerebellum
‘ovarioleukodystrophy’ in 1997. Recently, it was demon- A novel leukoencephalopathy with a distinct MRI
strated that most of these patients had mutations in pattern, characterized by hypomyelination and atrophy
The latest on leukodystrophies Schiffmann and van der Knaap 189
of the basal ganglia and cerebellum (H-ABC), was of the cerebral white matter occurs, associated with
described in 2002 . Both males and females are variable dilatation of the lateral ventricles. The atrophy
affected. The disease has its onset in infancy or early of cerebral white matter and the basal ganglia is more
childhood and its severity is variable. Patients with serious in the severely affected patients.
severe disease present soon after birth with poor eye
contact and absence of any motor development. Proton magnetic resonance spectroscopy reveals that
Ophthalomological examination reveals pale optic discs. within the white matter total N-acetylaspartate and
Over the years there are signs of slowly progressive choline are normal; this argues against signiﬁcant
spasticity and extrapyramidal movement abnormalities neuronal/axonal loss and active demyelination. Myo-
including rigidity, dystonia and choreoathetosis. The inositol and total creatine are elevated, suggesting
patients seem to have a better mental function than signiﬁcant white-matter gliosis.
motor function and appear to have a social awareness.
They may have incidental seizures. The severely The diagnosis in H-ABC is MRI-based. As soon as the
affected patients tend to be small and have a head full-blown picture with absence of the putamen in the
circumference below the third percentile. Patients with presence of hypomyelination is present, a deﬁnitive
intermediate severity of disease have a delayed early diagnosis can be made . The basic defect underlying
development, but achieve grasping and unsupported the disorder is presently unknown. It is highly likely that
sitting. The patients with the mildest form of the the disease is genetic. However, since until now all
disorder may have a normal initial development and they patients have been isolated cases, it is unclear whether
achieve unsupported walking. In these patients, slow the mode of inheritance is autosomal recessive or
deterioration becomes evident in early childhood, with autosomal dominant, all patients being de-novo muta-
increasing spasticity, ataxia and often prominent extra- tions.
pyramidal movement abnormalities consisting of dysto-
nia, choreoathetosis and rigidity. Some patients are Leukoencephalopathy with brain-stem and spinal cord
predominantly and severely spastic. The patients involvement and elevated white-matter lactate
typically have learning problems, but further cognitive Leukoencephalopathy with brain-stem and spinal cord
decline is, at most, mild. Incidental epileptic seizures involvement and elevated white-matter lactate (LBSL)
may occur. Vision is normal and ophthalmological is a white-matter disease that has been recently deﬁned
examination reveals no abnormalities. Height and head on the basis of distinct MRI ﬁndings [16,17]. Multiple
circumference are normal. affected siblings have been identiﬁed within the same
family, suggesting an autosomal recessive mode of
Laboratory examinations, including extensive metabolic inheritance. Clinically, it is a slowly progressive disease,
studies, have been uninformative. Cerebrospinal ﬂuid which has its onset in childhood. In all known patients to
neurotransmitters and neurotransmitter metabolites have date, initial development was normal. In some of the
been studied in several patients and found to be within patients, independent walking was unstable from the
the normal range. Visual evoked responses and somato- beginning. Motor deterioration starts at a variable age in
sensory evoked responses are delayed. Brain-stem childhood or adolescence with signs of spasticity and
auditory evoked responses show a normal latency for ataxia, involving the legs more than the arms. Patients
waves I and II, whereas the later waves are not become wheelchair-dependent in their teens or twen-
recordable or are delayed. Motor and sensory nerve- ties. In the later stages, manual dexterity is also
conduction velocities are normal. compromised. Most patients have a distal decrease in
position and vibration sense. Some patients develop
Early MRI is characterized by the presence of very little epilepsy with infrequent seizures. Some of the patients
myelin. In some patients, the putamen is already absent have learning problems from early on, but cognitive
within the ﬁrst year of life, and the caudate nucleus is decline is of late occurrence. There is some variation in
small, making the diagnosis of H-ABC possible. How- the severity of the disease: some patients manifest
ever, in other patients, MRI within the ﬁrst year of life signiﬁcant neurological problems in early childhood,
shows myelin deﬁciency only, and the putamen and whereas others display only minor dysfunction in
caudate nucleus are still normal. The severity of the adolescence. It is striking that some patients have been
myelin deﬁcit is variable. It is striking that the pyramidal reported as experiencing an episode of more rapid and
tracts in the brain stem are also hypomyelinated. Over partially reversible neurological deterioration accompa-
time, the putamen disappears. The caudate nucleus nied by fever following a minor head trauma .
becomes smaller, disappearing in some of the patients.
The thalamus and globus pallidus remain normal in size. Somatosensory evoked potentials with stimulation of the
The cerebellum, in particular the vermis, becomes tibial and median nerves are delayed or negative.
progressively atrophic. Over the years, a variable atrophy Sensory and motor nerve-conduction velocities are
190 Metabolic disorders and neurotoxicology
normal. Extensive laboratory investigations have proved and gliosis, respectively. White-matter choline is in-
uninformative. Only in some patients have mild eleva- creased too, but the increase is minor, suggesting mildly
tions of serum lactate been found on several occasions. enhanced membrane turnover and possibly myelin loss.
However, extensive mitochondrial work-up in fresh Cortex spectra do not show signiﬁcant abnormalities.
muscle tissue has not revealed abnormalities in any of
the patients. No mitochondrial DNA mutations have The MRI pattern is distinct [16,17]. A similar MRI
been found. pattern has not been described for any other condition. If
present, the pattern is diagnostic. The basic defect of the
LBSL has a distinct MRI pattern. The cerebral white disease remains unknown.
matter is involved to a variable extent. In some
patients, the abnormalities are extensive; in others, The classic leukodystrophies
they are more limited. The white-matter abnormalities Deﬁnition of new leukoencephalopathy syndromes and
are progressive over time and spread from the identiﬁcation of their related gene defects are only a
periventricular region outwards. In all patients, even beginning. Further research on the well known leuko-
in the oldest, the U-ﬁbers are spared. In some patients, dystrophies is indispensible to obtain a better under-
the cerebral white-matter abnormalities are homoge- standing of the pathphysiology of degeneration of white
neous, but in most patients the abnormal cerebral white matter and its components.
matter has an inhomogeneous, spotty aspect. On images
obtained using ﬂuid-attentuated inversion recovery, the X-linked adrenoleukodystrophy
white-matter abnormalities are also inhomogeneous X-linked adrenoleukodystrophy (X-ALD) is considered
with spots of lower signal intensity suggesting focal to be the most common leukodystrophy, having a
rarefaction. The corpus callosum is involved, almost hemizygous frequency in the USA of 1:42 000 and a
always more seriously in the posterior part than the minimal frequency of heterozygotes of 1:16 800. X-ALD
anterior part, but sometimes the corpus callosum is consists of an inﬂammatory demyelinating disease of the
homogeneously affected throughout. The posterior limb central nervous system in 40% of male hemizygotes
of the internal capsule is also affected. Within the brain between the ages of 5 and 12 (the cerebral form of X-
stem and spinal cord, the disease involves certain tracts ALD), or a more chronic disease, adrenomyeloneuro-
selectively. The pyramidal tracts are affected over their pathy with distal axonopathy leading to a spastic
entire length extending downwards through the poster- paraparesis and an axonal peripheral neuropathy (40%
ior limb of the internal capsule and the brain stem into of patients). Adrenal insufﬁciency frequently occurs, and
the lateral corticospinal tracts of the spinal cord. In 20% of women carriers may develop a milder form of
addition, sensory tracts are affected over their entire these syndromes. The disease is caused by accumulation
length, involving the dorsal columns in the spinal cord, of very-long-chain fatty acids in neural tissue and the
the medial lemniscus through the brain stem up to the adrenals due to mutations in the adrenoleukodystrophy
level of the thalamus, and the corona radiata above the protein (ALDP), an ATP-binding cassette half transpor-
level of the thalamus. The transverse pontine ﬁbers ter of 75 kDa. However, the exact role of ALPD or the
become involved in later stages of the disease. mechanism by which an excess of long-chain fatty acids
Cerebellar connections are selectively involved: ﬁrst induces disease are still not fully understood. Peroxiso-
the superior and inferior cerebellar peduncles and, only mal b-oxidation activity occurs in the absence of ALPD,
at a late stage, the middle cerebellar peduncles. Also, and in ALPD-deﬁcient mice, the rate of b-oxidation of
the anterior spinocerebellar tracts at the level of the very-long-chain fatty acids is normal. Recent evidence
medulla become abnormal. A remarkable ﬁnding is the points toward a disturbance of fatty acid oxidation in the
consistent involvement of the intraparenchymal trajec- mitochondria as a major consequence of ALPD deﬁ-
tories of the trigeminal nerve and the mesencephalic ciency. This ﬁnding suggests the possibility of novel
trigeminal tracts. The cerebellar white matter may approaches in the development of therapy for X-ALD,
develop signal abnormalities, ﬁrst in the subcortical approaches that increase mitochondrial activity or mass
regions and subsequently spreading inwards to involve . Since inﬂammation is part of X-ALD, it is of
all cerebellar white matter. The cerebellum becomes interest that adrenal hormone replacement therapy with
atrophic over time. prednisone can lead to clinical and electrophysiological
improvements . Prediction of progression in X-ALD
The most striking ﬁnding in proton MRS of the brain is is very important in order to determine the correct time
a consistent elevation of lactate within the abnormal for risky interventions such as bone-marrow transplanta-
white matter in almost all patients, albeit to a variable tion. Prediction of the clinical course can be better
degree. MRS shows a signiﬁcant decrease in N- accomplished by combining the cranial MRI severity
acetylaspartate and an increase in myo-inositol in the score with the regional pattern of white-matter lesions
abnormal white matter, suggesting axonal damage or loss .
The latest on leukodystrophies Schiffmann and van der Knaap 191
Myelin-protein-related disorders An additional ﬁnding was that the severity of the disease
The syndromes related to proteolipid protein (PLP) 1 signiﬁcantly correlated with the age of disease onset .
defects have recently been reviewed . An increasing Another study provided evidence that the 338G4A
number of publications describe a variety of peripheral mutation in EIF2B5 (R133H at protein level) was
nerve abnormalities in affected patients [21,22]. The associated with a particular wild phenotype (adult onset,
clinical presentation is of a multifocal motor and sensory slow disease course) .
demyelinating neuropathy, but sometimes there is an
axonal disease and a lower motor neuron presentation. Conclusion
The peripheral nervous system signs and electrodiag- The update described herein underlines the fact that
nostic ﬁndings in the other reported clinical cases and defects in genes coding for proteins that are not typically
kindreds are more consistent with a lower motor neuron associated with the myelin sheath can cause myelin
disease rather than a dysmyelinating peripheral neuro- disorders. It remains to be discovered why, for example,
pathy . A variety of PLP1 mutations have been a generalized dysfunction in the cellular response to
described in patients who have peripheral nerve stress leads to a rather selective involvement of brain
involvement. However, they all have in common an glial cells, as in the case of eIF2B-related syndromes. On
alteration of the PLP-speciﬁc transcript, although not the other hand, a deﬁciency of a myelin protein may
necessarily DM20 [23 .]. This suggests that the PLP- affect axonal survival rather than myelin structure. With
speciﬁc domain plays an important role in normal the discovery of a number of new causes of leukody-
peripheral nerve function. We recently found a family strophies, we increase our understanding of the physiol-
with a combined central and peripheral nerve involve- ogy of myelin and myelination. However, at present,
ment that was caused by a novel splice-site mutation in therapy for genetic white-matter disorders lags far
intron 4 of the PLP1 gene [24 . .]. This mutation altered behind our general knowledge of the pathogenesis of
PLP1 RNA splicing, predicted to produce truncated PLP these diseases.
and DM20 proteins. Using immunogold electron micro-
scopy, we found that at least one form of the mutant
protein was present in the myelin sheath of the sural References and recommended reading
nerve, despite a predicted loss of at least the fourth Papers of particular interest, published within the annual period of review, have
been highlighted as:
transmembrane domain and the C-terminus of both PLP . of special interest
.. of outstanding interest
and DM20. The presence of mutant PLP1 led to an
abnormal distribution in the myelin sheath of other
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