Review

Diagnosis, prognosis, and treatment of leukodystrophies

Marjo S van der Knaap, Raphael Schiffmann, Fanny Mochel, Nicole I Wolf

Leukodystrophies comprise a large group of rare genetic disorders primarily affecting CNS white matter. Historically, Lancet Neurol 2019
the diagnostic process was slow and patient prognosis regarded as poor because curative treatment was only available Published Online
for very few leukodystrophies in early stages of the disease. Whole-exome sequencing has both greatly increased the July 12, 2019
http://dx.doi.org/10.1016/
number of known leukodystrophies and improved diagnosis. Whether MRI keeps its central place in diagnosis and S1474-4422(19)30143-7
what the role is of whole-exome sequencing are relevant questions for neurologists. Improved diagnosis has revealed
Department of Pediatric
the phenotypic variability of leukodystrophies, requiring adaptation of prognostication. Technological advance in Neurology, Emma Children’s
molecular techniques and improved insight into the pathophysiology of individual leukodystrophies have led to Hospital, Amsterdam
therapeutic developments, including drug design and gene therapy. Despite this progress, therapies are only beneficial University Medical Centre,
Amsterdam, Netherlands
early in the disease course, emphasising the need for a speedy diagnosis and for research on regenerative approaches
(M S van der Knaap MD,
to repair the damage already present. N I Wolf MD); Amsterdam
Neuroscience, Amsterdam,
Introduction recognition that all structural white-matter components Netherlands (M S van der Knaap,
N I Wolf); Department of
Leukodystrophies constitute a large, highly heterogeneous (including myelin, oligodendro­ cytes, astrocytes, micro­ Functional Genomics, Center
group of rare genetic disorders, characterised by selective glia, axons, and blood vessels) can be primary disease for Neurogenomics and
and primary involvement of the CNS white matter.1,2 Such targets.2,8 This new view affects the under­standing of dis­ Cognitive Research, Vrije
disorders can manifest in people of all ages. Various ease mechanisms and directs therapy development. This Universitiet Amstardam,
Amsterdam, Netherlands
underlying gene defects are known, each defin­ ing a Review provides an update on these advances in diagnosis, (M S van der Knaap); Institute of
specific leukodystrophy.1,2 Advances in molecular tech­ prognosis, and treatment of leukodystrophies. Metabolic Disease, Baylor Scott
niques have had a fundamental effect on the diagnosis, and White Research Institute,
understanding, and treatment of leukodystro­ ph­ies.3–6 Definition and categorisation Dallas, TX, USA
(R Schiffmann MD); Institut du
Diagnosis of leukodystrophy used to be time-consuming The definition of leuko­dystrophy has evolved over time, Cerveau et de la Moelle Épinière
and cumbersome, but whole-exome sequencing (WES; first focused only on myelin and oligodendrocytes, and (Sorbonne Université,
mostly used in clinical settings) and whole-genome subsequently including astrocytes.1 The latest defini­tion Université Pierre et Marie Curie,
sequencing (WGS; currently mostly used for research) includes all genetically determined disorders with Institut National de la Santé et
de la Recherche Médicale, and
now allow rapid identification of the underlying gene selective and primary involve­ment of CNS white matter, Centre National de la Recherche
defect. WES and WGS have led to the identification of the irrespective of the struc­ tural white-matter component Scientifique), Paris, France
molec­ular basis of many leukodystrophies, solving the involved and molecular process affected.2,8 By contrast, (F Mochel MD); and
persistent problem of a high proportion of leukodystrophy leukoencephalopathies comprise all primary CNS white- Department of Genetics and
Reference Center for Adult
cases without molecular diagnosis, increas­ing the number matter disorders, both genetic and acquired.2 This Review Neurometabolic diseases,
of diagnosable disorders,3,4 and adding knoweldge about specifically addresses the leukodystrophies. Some leuko­ Pitié-Salpêtrière University
clinical variability and prognosis.5 Therapy for leuko­ dystrophies are traditionally called leuko­encephalopathies; Hospital, Assistance Publique
des Hôpitaux de Paris, Paris,
dystrophies has lagged, but prospects are improving.6 although for clarity, we will refer to them as leuko­
France (F Mochel)
Gene-editing tech­niques are rapidly advancing, facilitating dystrophies. However, the outdated myelin-focused con­
Correspondence to:
in-vivo and in-vitro gene correct­ion, necessary for gene cept of leukodystrophies persists, and the new defini­tion Prof Marjo S van der Knaap,
therapy. Other treatment options include drugs that requires further imple­ mentation in clinical practice. Department of Pediatric
modu­ late disease pathways, antisense oligonucleotide For example, a review published in 2018 only recog­nised Neurology, University Medical
therapy, and therapy based on stem cells.6 demyelinat­ing and hypomyelinating cate­gories,9 hamper­ Centre, 1081 HV, Amsterdam,
Netherlands
The almost overwhelming increase in the number of ing under­stand­ing of, for instance, leuko­dystro­phies with [email protected]
known leukodystrophies necessitates an updated cate­ a primary astrocytic or microglial defect.10 Importantly, the
gorisation system to facilitate diagnosis. WES availability myelin-focused concept of leukodystro­ phies directs all
requires reconsideration of the traditional step-by-step therapy developments towards remyelina­tion, which is
approaches to achieve definitive diagnoses. The role of not a useful approach for leukodystrophies in which the
MRI as a primary diagnostic tool needs be also recon­ primary problem does not concern myelin.
sidered, and perhaps redefined. For the leukodystrophies For the diagnostic work-up, a leuko­ dystrophy cate­
with improving therapeutic prospects, a speedy diagnosis gorising system is helpful, providing a framework, inside
is particularly important, as such therapies are only which the numerous individual dis­orders can be recog­
relevant in early disease stages, when the brain is not yet nised, differentiated between, and understood. The most
irreparably damaged. New knowledge on wide clinical appropriate categor­ising principle might differ depending
variation and benign disease variants requires modi­ on purpose or target group. A proposed system for
fication of the traditional view on leukodystrophies as pathologists was based on a cellular pathology approach,
disorders with an invariably poor prognosis.7 New insights taking into account the contribution of various white-
into the molecular and cellular bases of the dis­orders have matter cell types and structures driving white-matter
changed the concept of leukodystrophies and have led to disease.2 Although this system is helpful for pathologists,

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 Review

A Leukodystrophy versus other disease

Gliomatosis diffusa Acute demyelinating encephalomyelitis Cerebral adrenoleukodystrophy

B Hypomyelination versus neuronal degenaration

Neuronal ceroid Pelizaeus-Merzbacher

PIGA mutation GM1 gangliosidosis lipofuscinosis disease H-ABC (UFM1) 4H leukodystrophy

C Multifocal white-matter abnormalities

ALSP Multiple sclerosis L-2-hydroxyglutaric aciduria

D Distribution of white-matter abnormalities

AARS2-related L-2-hydroxyglutaric
MLC LBSL leukodystrophy Krabbe disease MLD aciduria

E Special features

MLC VWM Mitochondrial Aicardi-Goutières syndrome Peroxisomal

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 Review

this perspective is less suitable for neurologists, for will be adapted whenever new insights are gained.
whom understanding the types of metabolic and molecular Importantly, since all disease categorisations represent
causes of leukodystrophies, and distinguishing cate­ simplifications of com­plex biology and pathophysiology,2
gories that facilitate the diagnostic process is more helpful. the categorisation of some defects is difficult, as they
In a framework for neurologists, we have subdivided would fit multiple categories (eg, mitochondrial trans­
leukodystrophies into categories, which are typically diag­ lation versus mito­chondrial defect). Similarly, mutations
nosed in the same special­ised laboratory (appendix pp 1–3): in the same gene can differentially affect white and See Online for appendix
lysosomal disorders, peroxisomal disorders, mito­chondrial also grey matter structures, depending on the specific
respiratory chain disorders, defects in amino acid and mutation.14
organic acid metabolism, and DNA repair disorders.
Genetic vasculo­pathies,11,12 translation defects,3 and defects Diagnosis
in ion and water homoeostasis13 are newly defined cate­ Whole-exome sequencing
gories. Newly detected disorders can be easily placed The introduction of WES has had a major effect on the
within this framework. diagnosis of rare diseases, including leukodystrophies.
This proposed categorisation should enhance insight Many previously undetermined cases have been given a
into pathophysiology by revealing the types of defects specific diagnosis and numerous new leukodystrophy
that CNS white matter is vulnerable to. This framework genetic defects have been identified. The percentage of
leukodystrophy cases without specific diagnosis has
decreased from about 50% in 2010 to 20–30% in 2016,3,4
Figure 1: MRI patterns of leukodystrophies
and this percentage is still decreasing. WES is cheaper15
(A) Non-selective involvement of grey and white matter in a patient who does not and delivers a much faster diagnosis (which takes a
have a leukodystrophy or leukoencephalopathy, but was diagnosed with few months) than the traditional step-by-step diag­nostic
gliomatosis diffusa, confirmed at autopsy. Multifocal white matter abnormalities approach (which can take years).16,17 With the major
with an asymmetrical distribution are more common in acquired diseases,
illustrated here by inflammatory demyelination in acute demyelinating
diagnostic success, high cost effectiveness, and easy
encephalomyelitis, while confluent and symmetrical abnormalities are more applicability of WES, the traditional diagnostic approach
common in leukodystrophies, illustrated here by cerebral adrenoleukodystrophy. used in clinical practice needs to be recon­ sidered.
(B) Primary hypomyelination versus secondary hypomyelination in neuronal Additionally, available and emerging therapies—only
degenerative disorders. Neuronal degenerative disorders commonly have earlier
onset and more severe atrophy than leukodystrophies, as illustrated by a patient
applicable in early disease stages—put pressure on the
with PIGA mutations versus a patient with Pelizaeus-Merzbacher disease. diagnostic process, requiring speed.
Infantile-onset neuronal degenerative disorders are characterised by abnormal For these reasons, it might be suggested that the use of
myelination, as shown by a patient with infantile GM1 gangliosidosis and a patient MRI in guiding the diagnostic process should be replaced
with PIGA mutations; later-onset neuronal degenerative disorders are often
characterised by a wide, ill-defined periventricular zone of mild signal abnormality,
by WES. However, WES has its own limitations. WES is a
as illustrated by the case of juvenile neuronal ceroid lipofuscinosis. In infantile labour-intensive and, in itself, a costly technique, and its
GM1 gangliosidosis, abnormalities are also present in the basal ganglia and turnaround time varies from a few weeks to several
thalami. Special features facilitate a diagnosis in hypomyelinating disorders, months depending on local facilities. Some genetic
like low T2 signal in the lateral thalamus in 4H leukodystrophy and absence of the
putamen in H-ABC. The abnormal signal in the lateral part of the head of the
variants, such as copy number variations, variants in
caudate nucleus is pathognomonic for H-ABC caused by recessive non-coding parts of the gene, and variants in non-coding
UFM1 mutations. (C) Multifocal cerebral white matter abnormalities are more RNAs, are not detected by WES.18 For instance, leuko­
common in acquired disorders, but can also occur in specific leukodystrophies, dystrophy with calcifica­tions and cysts, which is caused
hampering the differential diagnosis. Here these abnormalities are shown in ALSP,
multiple sclerosis, and L-2-hydroxyglutaric aciduria. The latter case also displays by mutations in SNORD118, a non-coding RNA, is not
signal abnormalities in the basal nuclei, facilitating the diagnosis. (D) Diagnostic detected by WES, but it is easily diagnosed by MRI.19 The
value of the analysis of the distribution of white matter abnormalities, with diffuse recessive variant of hypo­myelina­tion with atrophy of the
involvement in MLC versus involvement of periventricular and deep cerebral white
basal ganglia and cerebellum (H-ABC) that is caused
matter in LBSL, anterior predominance in AARS2-related leukodystrophy versus
posterior predominance in juvenile Krabbe disease, and periventricular and deep by a deletion in the promoter region of UFM1 is not
predominance in MLD versus subcortical predominance in L-2-hydroxyglutaric detected by WES, while the MRI abnormalities are patho­
aciduria. (E) Diagnostic value of special features. Swelling of the abnormal white gnomonic.20 Sometimes WES reveals variants of unclear
matter is a feature of MLC. Diffuse white matter rarefaction, as evident on FLAIR, is
significance and diag­nosis thus requires confirmatory
a feature of VWM. The presence of well delineated cysts in the abnormal white
matter is a feature of mitochondrial leukodystrophies. Anterior temporal cysts and evidence from other sources.21 Sometimes WES findings
calcium deposits, as observed on susceptibility-weighted images, are features of are negative, because the patient does not have a genetic
Aicardi-Goutières syndrome. Perisylvian polymicrogyria is often a feature of severe disease. Sometimes WES findings are negative and
variant of peroxisome biogenesis defects. White matter structures are marked in
clinical and MRI recog­nition of the disease and targeted
blue, grey matter structures in orange, and calcium deposits in purple.
4H leukodystrophy=hypomyelination, hypodontia, and hypogonadotropic genetic testing are still necessary. WES-based gene-panel
hypogonadism. ALSP=adult-onset leukodystrophy with axonal spheroids and analysis is faster than open WES, but it does share its
pigmented glia. FLAIR=fluid-attenuated inversion recovery. drawbacks. How the limitations of WES should be
H-ABC=hypomyelination with atrophy of the basal ganglia and cerebellum.
LBSL=leukodystrophy with brain stem and spinal cord involvement and lactate
weighed against the obvious advantages and which place
elevation. MLC=megalencephalic leukodystrophy with subcortical cysts. WES should have in the diagnostic process to maximise
MLD=metachromatic leukodystrophy. VWM=vanishing white matter. contribution and avoid pitfalls are important questions.

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 Review

dilemmas. For example, an MRI of cerebral adrenoleuko­

White-matter No Consider other diagnoses dystrophy (also known as ALD) with asymmetrical abnor­
abnormalities on MRI; (acquired white-matter disorders
are they suggestive of a and primary neuronal degenerative disorders) malities might suggest acquired disease.29 Additionally,
leukodystrophy? MRI pattern recognition is an evolving tool, and new
Yes information on disease variation should be continuously
incorporated into this tool as it becomes available.
MRI pattern or special Expert opinion
clinical features or With the use of new pulse sequences and higher
indicative of one or a Non-targeted genetic testing field strengths, the potential of MRI regarding the diag­
few specific • NGS gene panel for leukodystrophies
leukodystrophies • Open WES or WGS nosis of leuko­dystrophies is further increasing.30–32 New
If NGS-based genetic testing not available, MRI techniques specifically assess white-matter micro­
No not accessible, or slow metabolic screening
Yes structural integrity. The measurement of the intra­myelin
• Plasma amino acids, homocysteine,
lactate, pyruvate, very long-chain fatty water fraction is a promising technique to produce
Targeted testing with acids, cholestanol markers for mye­lin content and intactness,31 while neurite
metabolic or genetic • Urine organic acids, sulfatides, sialic acid
confirmation • Activity of lysosomal enzymes, activity of orientation dispersion and density imaging allows an
mitochondrial and cytoplasmic tRNA estimation of microstructural complexity of dendrites and
No synthases
axons within the white matter.32 The capacity of these new
Diagnosis MRI techniques to distinguish between different leuko­
Diagnosis
dystrophies or to provide better insight into leukodystrophy
Yes pathology has not been assessed yet.
Yes No
Proposed diagnostic algorithm
• Counselling Refer to Weighing up the available information, we propose a
• Family testing leukodystrophy
• Management expert centre diagnostic algorithm (figure 2), in which we combine the
options excellent diagnostic capabilities of MRI and the con­
• Therapy
options
tribution of clinical diagnostic features (if present) with
the powerful diagnostic options of WES or WGS to
Figure 2: Proposed diagnostic algorithm achieve a molecular diagnosis in the highest percentage of
The authors’ view on the up-to-date testing framework for leukodystrophies. patients of all ages as fast as possible. MRI is central in
Next-generation sequencing has an important role and should be considered answering the initial crucial question as to whether the
early, as its diagnostic yield is high, speeding up the diagnostic process. patient has a leukodystrophy (figure 1; appendix pp 10–11).
NGS=next-generation sequencing. WES=whole-exome sequencing.
WGS=whole-genome sequencing. If so, analysis of clinical details might also be valuable for
the diagnosis, especially if systems other than the CNS are
MRI involved (appendix p 12).7,9,11,22–25 If the combination of MRI
The clinical presentation and neurological findings in and clinical features suggests one or a few specific dis­
patients with leukodystrophy are often non-specific. With orders, targeted metabolic and genetic analyses are the
its extreme sensitivity for brain white-matter abnor­ fastest way to a confirmed diagnosis. If negative, the
malities, MRI is still typically the first technique used to diagnosis of leukodystrophy and the differential diagnoses
diagnose a CNS white-matter disease, and all diagnostic should be reconsidered. Import­ antly, in some cases,
algorithms proposed in the past few years are still MRI- MRI is pathognomonic for a specific disorder and this
centred.9,11,12,22–25 Considering that an MRI of the patient is diagnosis should not be discarded after initial negative
available and considering the limitations of WES as a test results.19,20 If the MRI pattern and clinical picture are
stand-alone test, we agree that the diag­ nostic process less specific or the differentiation from acquired leuko­
should start with in-depth MRI pattern recognition,26 encephalopathies is challenging, a leuko­dystrophy expert
which aids in the cru­cial distinction between genetic and should be consulted. The expert might recognise the
acquired disease and might allow a specific diagnosis or disease and go for targeted testing. If the expert does not
short differential diagnosis containing only a few items recognise the disease, non-selective screen­ing should be
(figure 1; appendix pp 10–17). started. Screening using next-generation sequencing with
However, MRI also has limitations and can be incon­ analysis of a white-matter gene panel or open WES or
clusive, especially in adults. For example, in adults WGS analysis is, if available, the most fruitful approach
with multifocal and asymmetrical white-matter lesions, with the highest diagnostic yield, fastest result, and lowest
adult-onset leukodystrophy with axonal spheroids and cost compared with all other testing approaches.4,15,17
pigmented glia (ALSP) constitutes an important dif­ However, if next-generation sequencing techniques are
ferential diagnosis to multiple sclerosis (figure 1C).27,28 not available, not accessible, or have a long turnaround
The distinc­tion by MRI between genetic vascular leuko­ time, one screening round of metabolic biomarker assess­
dystrophies and acquired white-matter abnormalities ment (figure 2) can be applied, with relatively fast results
related to vascular risk factors like hypertension might be compared with WES or WGS (which is the fastest) and the
im­possible.11 Unusual MRI presentations pose diagnostic traditional step-wise approach (which is the slowest).9

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 Review

Importantly, sequential metabolite and gene analysis while early-infantile onset disease can be rapidly pro­
should be avoided, because the approach is expensive and gressive and fatal.41 Leuko­dystrophy with thalamus and
takes many months or years.17 If all tests are unrevealing, brain stem involvement and lactate elevation (also called
the patient should be referred to a leukodystrophy expert LTBL), caused by mutations in EARS2, is associated with
centre for diagnosis;33 if no diagnosis is made, participa­ a single period of neurological decline in the antenatal
tion in studies to identify new genes associated with or infantile period, followed by improvement and then
leukodystrophies should be considered. stabilisation; a second episode of clinical deterioration has
Analysis of WES and WGS data will improve as more not been reported.42 MRI shows improvement of most
information on disease-causing and benign variants early brain abnormalities, and only structures that were
becomes available. WGS, in part, addresses the problems permanently damaged remain visibly abnormal.42 Timing
of WES discussed here.34 When WES, and particularly and severity of the episode determine the clinical out­
WGS become less expensive and more widely available come, varying from death to complete recovery.42,43 Disease
worldwide, the algorithm will need to be adapted again. phenotype can be extremely discordant between affected
We envision a time when assessment of metabolites in siblings, and some people have EARS2 mutations with
body fluids will be abandoned as a first-line screening no or minimal disease.42 Consequently, biallelic EARS2
technique, but will remain important in the evaluation of mutations might be picked up by WES in patients
pathogenicity of variants and in monitoring therapy. with another disease, causing diagnostic confus­ion.44 In
In contrast to the diagnostic algorithm outlined here, AARS2-related ovario­ leukodystrophy, onset is relatively
newborn screening aims at identification of patients before late, in adolescence or adulthood, but deteriora­tion is often
disease onset to install treatment before or at the beginning rapid, causing death within a few years after onset.45,46
of disease manifestations. The technique is available for a So, for unclear reasons, defects in three neighbouring
growing number of genetic disorders, including leuko­ enzymes involved in the translation of 13 genes of the
dystrophies, but the number of disorders screened for mitochondrial genome into respiratory chain proteins
differs per country or even region within a country due to cause leukodystrophies, but with major differences in
local decisions based on ethical considera­tions and fin­ MRI presentation and disease course.
ancial means.35,36 With this approach, means to confirm The group of hypomyelinating disorders comprises
presence of the disease and predict onset and severity are disorders of myelin development, suggesting an early
essential for making decisions regarding therapy.18 onset and subsequent deterioration. However, scarcity
of myelin might occur without clinical manifestations
Prognosis for years up to decades.47 An example is oligosympto­ ­
Leukodystrophies can present at any age. Age of onset matic hypomyelination, hypodontia, and hypogonado­
typically correlates inversely with disease severity and tropic hypo­­ gonadism (4H leukodystrophy) in adults.48
rate of progression.37,38 Leukodystrophies have a reputa­ Another example is TMEM106B-associated hypomyelina­
tion of being relentlessly progressive and fatal.7 Although tion, which presents in infancy, but only mild clinical
this concept is true for many leukodystrophies, more features are present in teenagers and adults, contrasting
variable and more benign disease phenotypes with with the severe disability observed, for instance, in
long episodes of stability, permanent improvement, or individuals with Pelizaeus-Merzbacher disease, which
complete recovery are now apparent.9,12 For example, manifests at the same early age with the same clinical
megalencephalic leuko­dystrophy with subcortical cysts signs and MRI changes.49
(MLC) invariably has its onset with macro­cephaly in the The prognoses of diseases with episodic deterioration
first year of life, but the subsequent disease course is of are difficult to predict and are not always poor. Mito­
variable severity: some patients die in adolescence, but chondrial leukodystrophies often have an onset in infancy,
others display hardly any disease signs as adults.39 but can present at any age.50 The disease course is typically
Interestingly, an MLC variant with dominant inheritance characterised by episodes of neurological decline, provoked
and transient white-matter disease is also part of the by febrile infections or other stressors, followed by partial
phenotypic range.39 recovery. Patients might die or survive for decades with
Counterintuitively, leukodystrophies with similar genetic highly variable disease signs or even no disability.50 The
defects are not necessarily associated with a similar course of vanishing white matter (VWM), also called
prognosis. Even though defects in mitochondrial tRNA childhood ataxia with CNS hypomyelination, is similar
synthetases all affect the same process of translation of and similarly vari­able.37 The episodic deterioration is often
13 genes of the mitochondrial genome into respiratory related to sensitivity of some leukodystrophies to external
chain proteins,40 only some defects are associated with factors, which co-determine disease course. In VWM,
leukodystrophies, and these have different disease courses. deteriorations are provoked by activators of the integrated
Leukodystrophy with brain stem and spinal cord involve­ stress response;51 in microglia-related leukodystrophies,
ment and lactate elevation (LBSL), caused by DARS2 such as adrenoleukodystrophy, by activators of immune
mutations, most often has a childhood or adolescent onset cascades;52 and in mitochon­drial disorders by high energy
and slow disease course without a life-limiting effect, demand during febrile infect­ ions.50 In such disorders,

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 Review

impair quality of life. Spasticity is a central problem in

Panel 1: Prognostic factors leukodystrophies, which is usually successfully managed
Specific disease by oral drugs, intramuscular botulinum toxins, intrathecal
Some disorders are predictable in their course (eg, metachromatic leukodystrophy [MLD], baclofen,53 or selective dorsal rhizotomy.62 Infections con­
leukodystrophy with brain stem and spinal cord involvement and lactate elevation stitute a major contribution to the disease burden and
[LBSL], and megalencephalic leukodystrophy with subcortical cysts [MLC]),39,41,53 whereas clinical outcome. They are a potentially modifiable factor,
others are highly unpredictable (eg, vanishing white matter [VWM]).37 for instance by vaccina­tions and prophylactic antibiotic
treatment to prevent respiratory tract infections.58,63 Given
Age at presentation the rarity of the disorders and heterogeneity of patient
In general, early onset is associated with more rapid decline;37 however, exceptions exist groups, evidence-based data on these approaches do not
(eg, MLC).39 exist, and is unlikely to be available in the future.
Disease severity at presentation Curative therapy development for leukodystrophies has
A severe and chronically progressive disease predicts a poor prognosis (eg, VWM).37 been lagging more than management. Considering the
A subacute severe encephalopathy is more unpredictable (eg, mitochondrial complexity of these diseases and the fact that patho­
leukodystrophies).50 mechanisms might not only differ for individual leuko­
dystrophies, but also for different mutations in the same
Specific mutations gene,14,21 this delay is not surprising. Fortunately, with
A clear genotype–phenotype correlation is present in some disorders (eg, VWM or technological developments, this prospect is reversing.6,60,64
Pelizaeus-Merzbacher disease),37,54 but not in others (eg, MLC).39 For designing clinical trials, in-depth knowledge on
MRI natural history in large patient cohorts65 (often hampered
In general, more extensive damage is associated with more severe disease course.47,48 by the ultra rarity of the disease) and identification of
For the episodic disorders, what damage is irreparable might not be immediately clear.50,55 suitable biomarkers (often MRI-derived)30–32 are essential.
For some disorders, the white-matter abnormalities are extensive or diffuse, yet disease Established treatments with proven efficacy are
severity is variable (eg, MLC or hypomyelination).39,49 haematopoietic stem-cell transplantation (HSCT) and ex-
vivo gene therapy. The feasibility and efficacy of other
treatment modalities remain to be proven.
environmental factors and genetic make-up, which for
instance determines suscepti­bility to infections and febrile Haematopoietic stem-cell transplantation
response, have a strong effect on the disease course and, For decades, a low-phenylalanine diet for phenyl­
more so with increasing disease duration.37 ketonuria, cheno­ deoxycholic acid for cerebrotendinous
Thus, a general statement on the prognosis of leuko­ xanthomatosis, and HSCT for early stages (presympto­
dystrophies cannot be made; statements regarding prog­ matic or early symptomatic) of cerebral adreno­ leuko­
nosis have to be ascertained for each leukodystrophy dystrophy, juvenile and adult MLD, and juvenile or adult
separately. Several factors can be considered when Krabbe disease were the only efficacious therapies
address­ing the wish of the patient and family for a available.6,64–66 HSCT in later disease stages and in patients
clear prognosis (panel 1). Large and long-term natural with early symptomatic late-infantile MLD or Krabbe
history studies combining genetic, clinical, imaging, and disease are associated with poor outcome.67–69 Unfortu­
environ­mental, information (such as infections, trauma, nately, the outcome of timely HSCT is not uniformly
or food habits) will help identify the contribution of each favourable either. In patients with Krabbe disease, diag­
and to improve prediction. These studies will also clarify nosed by prenatal testing or newborn screening, early
the true variation in disease phenotype and prognosis. HSCT does not cure the disease, but only modifies its
In analogy to adrenoleukodystrophy,56 we foresee that course.70 ALSP is caused by mutations in CSF1R, which
milder and later-onset leukodystrophy variants than are encodes the macrophage colony-stimulat­ ing factor 1
now known will be identified more frequently, since receptor (CSF-1-R). CSF-1 is a cyto­kine that controls the
these variants are currently underdiagnosed. production, differentiation, and function of macrophages
and microglia. As HSCT provides microglia derived from
Management and treatment bone marrow, ALSP is an excellent candidate for this
Currently, many interventions are available to manage therapy. Stabilisation of the disease after HSCT has been
disease manifestations, improve the quality of life of reported,71 but overall experience is scarce and criteria
patients,57 reduce the use of medical resources, and reduce for timing of the intervention in the disorder are still
expenses.58 Some clinical manifestations are disease- inadequate. As most leukodystrophies are currently
specific, while others are general (panel 2). Anticipation without therapeutic options, HSCT is sometimes done
and monitoring of manifestations allow initiation of out of desperation, without rationale, and outside of a
treatment (eg, hydro­ cortisone replacement for adrenal formal trial setting.72 Patients and families are confronted
failure in adreno­ leukodystrophy59 and chol­ ecystectomy with high costs, and considerable morbidity and mort­
for gallbladder involvement in metachromatic leuko­ ality, without any bene­fit;70 thus, use outside of current
dystrophy [MLD])61 before manifestations substantially indications is strongly discouraged.

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 Review

Gene therapy
Ex-vivo gene therapy allows transplantation of genetically Panel 2: Management of patients with leukodystrophies
engineered autologous haematopoietic cells in patients Disease specific
with cerebral adrenoleukodystrophy or MLD.73,74 This new • HydroCortisone supplementation for Addison syndrome in adrenoleukodystrophy or
strategy is a solution for patients without matched donors adrenomyeloneuropathy57,59,60
and allows further genetic modification. For example, in • Cholecystectomy for gallbladder dysfunction, polyps, and to prevent cancer in
patients with MLD, enhanced arylsulfatase A activity is metachromatic leukodystrophy (MLD)61
achieved by gene modification strategies and, for the first • Avoid head trauma and ensure prompt treatment of fever and infections to avoid
time, good functional outcomes are reported for patients triggering deterioration in vanishing white matter (VWM)37
with the late-infantile disease.73 The pro­cedure eliminates • Growth hormone substitution if deficient; hormone supplementation to induce
risks related to incompatibility between graft and host, puberty and prevent osteoporosis in hypomyelination, hypodontia, and
and even stabilises peripheral neuropathy, which does not hypogonadotropic hypogonadism (4H leukodystrophy)57
respond well to HSCT.73 The therapeutic window, however, • Treatment of ovarian failure in VWM or AARS2-related leukodystrophy60
does not differ from that of donor-derived HSCT—for a • Monitoring and treatment of immune-mediated disease features in Aicardi-Goutières
good outcome, treatment has to be performed early.73 syndrome60
Careful monitoring is required to indicate whether the • Avoid head trauma and ensure prompt treatment of status epilepticus in
overexpression of arylsulfatase A becomes problematic megalencephalic leukodystrophy with subcortical cysts (MLC)39
over time.
Gene therapy directly targeting the brain is becoming a General
realistic option. Treatment with a viral vector carrying the • Treatment of spasticity with spasmolytic drugs, botulinum toxin, intrathecal baclofen,
ASPA gene in 13 patients with Canavan disease proved to or selective dorsal rhizotomy53,57,62
be safe and resulted in some clinical and MRI improve­ • Maintenance of sufficient nutritional state (eg, percutaneous gastrostomy)57
ment.75 However, a small trial evaluating intra­cere­ bral • Prevention (eg, with prophylactic antibiotics) and treatment of infections37,57,58,63
gene therapy in patients with MLD was termin­ ated • Treatment of bladder and bowel dysfunction57
because of continuing patient deterioration.76 Why this • Monitoring and treatment of orthopaedic problems such as hip dislocation and
approach was unsuccessful is unclear; gene delivery alone scoliosis57
might not be sufficient and might have to be combined • Ensuring adequate calcium and vitamin D supplementation57
with imm­ unomodulation or silencing of the mutant • Treatment of neuropathic pain (eg, with amitriptyline or gabapentin)57
gene.76,77 • Treatment of irritability and disturbed sleep (eg, with melatonin or alimemazine)57
The CRISPR (clustered regularly interspaced palin­ • Treatment of sialorrhea (eg, with anticholinergic drugs or botulinum toxin
dromic repeats)-Cas (CRISPR-associated protein) ap­ injections)57
proach is a promising method for precise gene editing,78 • Treatment of epilepsy57
able to remove pathogenic variants, but also to silence • Ensuring adequate communication57
genes. This tool has not yet been tested in animal models
for leukodystrophies. Off-target effects are still a matter
of serious concern.78 Safety issues need to be addressed effects of thousands of compounds on cell or zebrafish
before application in the clinic. disease models.81,82 Also, advancing insights into disease
mechanisms facilitate identification of drug targets. For
Antisense nucleotides example, Janus kinase inhibition was used to block type I
Antisense nucleotides aim to target mutations with a interferon signalling in a case of Aicardi-Goutières synd­
dominant negative effect, silencing the mutant gene. A rome, showing clinical improve­ment with regain of previ­
single intrathecal injection of this treatment in a mouse ously lost skills and improvement of elevated inflammatory
model of Alexander disease led to long-lasting improve­ markers.83 Also in Aicardi-Goutières synd­ rome, reverse
ment (until the mice were sacrificed at 4 months).79 Other transcriptase inhibitors are being investig­ated to decrease
leukodystrophies with dominant inheritance, such as nucleotide load (NCT03304717/RTIAGS).84 Guanabenz is
H-ABC caused by TUBB4 mutations14 are also candidates being investigated for integrated stress response inhibition
for this approach. Antisense nucleo­tides can also be used in VWM. The drug has been shown to be effective in
to correct aberrant splicing. This has been shown for a ameliorating white-matter pathology in an animal model
PLP-related disorder, hypomyelina­tion of early myelinating of VWM and a trial in a small group of patients with VWM
structures (HEMS) in an animal model.80 Dose, timing, is currently in preparation (NTR7482).85 Finally, a PPAR-γ
and intervals of antisense nucleo­tide administration still agonist, MIN-102 is being used to target multiple intra­
have to be tested in clinical trials. The long-term conse­ cellular pathways (ADVANCE trial [NCT03231878] ongoing
quences of gene silencing also need to be closely monitored. in adrenomyeloneuropathy). Substrate reduction therapy
is an attractive approach to decrease the accumula­tion of
Targeted drug treatment storage material in MLD and Krabbe disease. Although
Drugs for individual leukodystrophies are being identified effect­ive in animal models, it has not yet been applied
in diverse ways. Drug screening can rapidly assess the to patients.86

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 Review

Enzyme-replacement therapy Future treatments will most likely be multimodal. The

For leukodystrophies, enzyme-replacement therapy has so Twitcher mouse model for Krabbe disease reacts much
far not proven effective, as intravenous formulations are better to a combination of substrate reduction therapy,
not able to cross the blood–brain barrier.87 Intraventricular intraventricular enzyme-replacement therapy, and HSCT
enzyme administration might solve this problem and a than to any of the three treatments alone.86 Microglia
phase 1/2 trial (NCT01510028) for patients with MLD has abnormality might have an important role in several
been done with possible disease-stabilising effects for the leukodystrophies, as shown in patients with Pelizaeus-
highest dose used.88 Given the availability of proven Merzbacher disease, adrenoleukodystrophy, Krabbe dis­
therapies for patients with presymptomatic MLD and the ease, MLD, and ALSP,97–99 and might become an addi­tional
disadvantages of frequent intrathecal enzyme admin­ therapeutic target, as already explored with success in the
istration, candidates for enzyme-replacement therapy Twitcher mouse.97
trials will be patients who are already symptomatic,
which might cause underestimation of efficacy. Still, Pathophysiological mechanisms
as intra­thecal enzyme-replacement therapy was also Increasing insights into the variety of gene defects
shown to be effective in an animal model of MLD,89 a underlying leukodystrophies has also greatly improved
phase 2 trial (NCT03771898) with frequent intrathecal the understanding of the pathological mechanisms.
enzyme administration is just starting.90 Leukodystrophies are not only caused by myelin defects
(either scarcity of myelin deposition [eg, in Pelizaeus-
Stem-cell-based therapies Merzbacher disease] or myelin loss [eg, in MLD]), but
Based on successful outcomes in leukodystrophy mouse also by defects affecting astrocytes (eg, in Alexander
models,91,92 stem-cell-based therapy holds promise for disease and MLC), microglia (eg, ALSP), and small blood
patients with leukodystrophies. To our know­ ledge, the vessels.2,8,10,11 At the molecular level, as opposed to the
only published trial on patients with Pelizaeus-Merzbacher structural level, a substantial number of leukodystrophies
disease confirmed safety, but the procedure did not find are caused by respiratory chain defects.3,50 Similarly,
a clinically significant effect in those patients.93 The many leukodystrophies are caused by defects that dir­
approach has been shown to be effective in an animal ectly or indirectly affect mRNA translation, together
model of VWM.92 constituting a large leukodystrophy category comprising
The most suitable type of stem cell (eg, pluripotent VWM, 4H leuko­dystrophy, and tRNA synthase defects.3,100
glial precursors, mesenchymal stem cells, or more dif­ Evi­dently, the brain white matter is vulnerable to defects
ferentiated cell types) and administration route (eg, affecting the translation and protein synthesis process.
intracerebral injections at multiple sites, or intrathecal or With the current state of knowledge, understanding
intranasal administration) remain to be identified and why defects affecting translation so often lead to a
might differ between leukodystrophies.93–95 leukodystrophy, why these leukodystrophies are dis­
similar and have individual distinct features, and why
General considerations on therapy other translation defects spare the brain white matter,
For patients with cerebral adrenoleukodystrophy, Krabbe is challenging.101 Importantly, a defect in one mol­ecular
disease, MLD, or ALSP, HSCT is only effective when process could trigger a cascade in another, seemingly
done before or soon after clinical disease onset.66–69,71–74 unrelated, pathway. An example of this mechanism
This timing will also be true for other therapies currently occurs in an animal model of Pelizaeus-Merzbacher
under development. Thus, patients need to be identified disease, where variants in the gene PLP1, encod­ing
early. Newborn screening allows treat­ment before clini­ a major myelin protein, also result in enhanced
cal onset. In-depth knowledge of patho­genicity of gene inflammation.99
variants is essential to predict presence, onset, and
severity of the disease to make therapy decisions.18 Conclusions and future directions
So far, leukodystrophy therapy strategies have been Substantial progress has occurred in many aspects
aimed at white-matter pathology. When successful, pa­ of leukodystrophies, in particular regarding diagnosis,
tients live longer and other disease manifestations might number of diseases known, insight into variability of
become apparent, sometimes unexpectedly. An example is clinical disease and prognosis, and options for therapy
that HSCT in patients with cerebral adreno­leukodystrophy and management. The cumulative change is immense,
does not prevent later spinal cord disease caused by a demanding review and discussion of the implications for
long-tract axonopathy.96 Another example is gallbladder the clinical approach of leukodystrophies. The number of
carcinoma, occurring after an otherwise successful HSCT disorders and gene defects known has steeply increased,
in patients with MLD.61 Although VWM mainly causes and with the introduction of next-generation sequenc­
neurological signs, the disorder is fun­damentally a multi- ing, the tools for diagnosis have drastically improved.
organ disease.37 One concern is that cure of white- Nowadays, most patients with leukodystrophy can be
matter pathology could be followed by disease of other accurately and timely diagnosed with molecular con­
organs. firma­­tion.3,4 The increased knowledge of phenotypic

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 Review

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 Review

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