future neurol. (2012) 7(5), 595–612

59510.2217/FNL.12.52 2012 Future Medicine Ltd ISSN 1479-6708Future Neurol. (2012) 7(5), 595612

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Advances in the diagnosis of leukodystrophies

Bradley Osterman1, Roberta La Piana2 & Genevive Bernard*11Montreal Childrens Hospital, 2300 Tupper, Room A-506, Montreal, Quebec, H3H 1P3, Canada 2Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, H3A 2B4, Canada *Author for correspondence: Tel.: +1 514 412 4466 n Fax: +1 514 412 4373 n [email protected]

Leukodystrophies are a heterogeneous group of inherited disorders that preferentially affect the CNS white matter. They are classified as demyelinating (or classic) or hypomyelinating according to brain MRI characteristics. As these disorders often have a similar clinical presentation according to their age of onset, the initial diagnostic approach is often challenging. This review aims to help clinicians approach these disorders using information from the history (e.g., age of onset), the examination (e.g., presence of macrocrania) and MRI scans in order to reduce the number of possible diagnoses for a given patient and to hopefully lead to a precise (molecular) diagnosis.

Keywords

n demyelination n diagnostic approach n hypomyelination n leukodystrophies n leukoencephalopathies n MRI

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Learning objectives

Upon completion of this activity, participants should be able to:

nDescribe classification of leukodystrophies based on MRI characteristics, according to a review

nDescribe differential diagnosis of leukodystrophies based on clinical features, according to a review

nDescribe genetic features of leukodystrophies, according to a review

Financial & competing interests disclosureEditor: Elisa Manzotti, Publisher, Future Science Group. Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.CME author: Laurie Barclay, Freelance writer and reviewer, Medscape, LLC. Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.Authors & credentials: Bradley Osterman, MD, Montreal Childrens Hospital, 2300 Tupper, Room A-506, Montreal, Quebec, H3H 1P3, Canada. Disclosure: Bradley Osterman has disclosed no relevant financial relation-ships. Roberta La Piana, MD, Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, H3A 2B4, Canada. Disclosure: R La Piana has received a fellowship grant from the Montreal Neurological Institute. She has no other relevant financial relationships. Genevive Bernard, MD, Montreal Childrens Hospital, 2300 Tupper, Room A-506, Montreal, Quebec, H3H 1P3, Canada. Disclosure: Genevive Bernard has received funding from the Fondation sur les Leucodystrophies, the Fondation Go and the Montreal Childrens Hospital and McGill University Health Center Research Institutes. She has also received clinician-scientist salary awards from the Fonds de Recherche en Sant du Qubec. She has no other relevant financial relationships.

No writing assistance was utilized in the production of this manuscript.

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Future Neurol. (2012) 7(5)596 future science group

The realm of leukodystrophies can often be intimidating; this perception has probably never been truer, with the recent addition of many newly discovered leukodystrophies, confounded by the countless described phenotypes for previously recognized leukodystrophies. This review aims to provide readers with a simplified and clear-cut approach to these rare, yet fascinating, disorders and to summarize the recent d iscoveries in the field.

Leukodystrophies are a heterogeneous group of inherited neurodegenerative disorders affecting the CNS white matter [1,2]. Most leukodystrophies are inherited in an autosomal recessive fashion (e.g., Krabbe, metachromatic and so on) [3,4], while others are inherited in an X-linked (e.g., adreno-leukodystrophy, PelizaeusMerzbacher disease) [5,6] or autosomal dominant (e.g., adult-onset autosomal dominant leukodystrophy) [7] fash-ion. Leukodystrophies can be classified as either demyelinating (or classic) or hypomyelinating based on their MRI features [2]. The tables and figures presented in this article are meant to help clinicians to orient their diagnostic process when a leukodystrophy is suspected; the order of tables and figures follows that of the clinical approach and investigations as they are usually performed in daily clinical practice.

Clinical approachThe clinical presentation of the different types of leukodystrophies is often similar among the same age group. Figure 1 presents the main forms of leukodystrophies according to their age of onset, while Table 1 summarizes and compares their c linical presentation.

Age of onsetAmong the important clinical features to con-sider when formulating a differential diagnosis of a leukodystrophy is the age of onset. Indeed, all leukodystrophies have a typical age of onset (Figure 1). In general, hypomyelinating leuko-dystrophies present early in life, as early as the neonatal period. Certain forms of hypomyelinat-ing leukodystrophies can, however, present later. As for demyelinating leuko dystrophies, they have very variable ages of onset, ranging from child-hood to adulthood, with some forms having dif-ferent ages at presentation (e.g., meta chromatic leuko dystrophy) while others have a preferential or unique age of onset (e.g., adult-onset autosomal dominant leukodystrophy in adulthood).

Clinical featuresThe clinical presentation of the different leuko-dystrophies is often similar for a given age group.

Patients with a neonatal or infantile presentation will typically present with axial hypotonia, which will evolve over time into spastic quadrapare-sis. They can also present other features such as nystagmus or seizures, amongst others. Patients with onset during childhood typically present with motor delay and regression, with progressive upper motor neuron signs, with or without other manifestations, such as ataxia, dysarthria and so on. The adolescent or adult presentations are usually characterized by cognitive regression and psychiatric manifestations, including behavioral abnormalities, while the motor manifestations are typically more subtle.

Despite the fact that the clinical presentations are very similar for each age group, some clinical features may be more specific to one or more disor-ders and can help orient the investigations. Table 1 can help the clinician differentiate between dif-ferent leukodystrophies based on the presence of such clinical features, classified by specific organ/system involvement. For example, in a neonatal or infantile presentation, the presence of congenital cataracts in a hypomyelinating leuko dystrophy would strongly suggest the diagnosis of hypomy-elination with congenital cataracts (HCC) [8]. On the other hand, the absence of such a feature has been described in HCC and cannot be used to rule out the diagnosis. Another example would be the presence of macrocephaly, which is typi-cally seen in Alexander, Canavan and megalen-cephalic leukoencephalopathy with subcortical cysts (MLC) [9].

Neuroradiology: the importance of MRI pattern recognition

When a leukodystrophy is suspected, the brain MRI becomes a crucial tool to formulate a diag-nostic hypothesis. The first distinction to make when looking at the MRI is whether the white matter abnormalities correspond to a demy-elinating or hypomyelinating process (Figure 2). Demyelinating leukodystrophies are characterized by prominent hyperintensity of the white matter in T2-weighted and prominent hypointensity in T1-weighted images compared with gray matter structures, while in hypomyelinating leukodys-trophies, the white matter abnormalities appears mildly hyperintense in T2-weighted images and have a variable signal (hyper-, iso- or hypo-intense) in T1-weighted images [2,10].

van der Knaap introduced the concept of pattern recognition in the early 1990s and currently, it is well recognized that MRI features can greatly help to orient molecular testing, ultimately leading to a precise diagnosis [11]. Indeed, many entities have

Review Osterman, La Piana & Bernard CME

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0 3 m 6 m 1 year 6 years 10 years 20 years 30 years

Congenital neonatal

Early infantile

Late infantile

Age of onset of demyelinating and hypomyelinating leukodystrophies

Juvenile Adult

MLD

VWM

Canavan

Krabbe

MLC

AMN

SPG2PMD

HABC

Pol-III

18q del

FSASD

ODDD

Fucosidosis

PCWH

HEMS

CTX

HDLS

HCC

PMD-likeSPG44

ALD

ADLD

Alexander

Figure 1. Visual representation of the age of onset of the different demyelinating and hypomyelinating leukodystrophies. The top ten disorders are demyelinating leukodystrophies while the others are hypomyelinating. Shades of gray correspond to the different ages of onset with dark zones representing the incidence peaks. 18q del: 18q deletion syndrome; ADLD: Adult-onset autosomal dominant leukodystrophy; ALD: Adrenoleukodystrophy; AMN: Adrenomyeloneuropathy; CTX: Cerebrotendinous xanthomatosis; FSASD: Free sialic acid storage disease; HABC: Hypomyelination with atrophy of the basal ganglia and cerebellum; HCC: Hypomyelination and congenital cataract; HDSL: Hereditary diffuse leukoencephalopathy with spheroids; HEMS: Hypomyelination of early myelinating structures; MLC: Megalencephalic leukoencephalopathy with subcortical cysts; MLD: Metachromatic leukodystrophy; ODDD: Oculodentodigital dysplasia; PCWH: Peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome and Hirschsprung disease; PMD: PelizaeusMerzbacher disease; PMLD: PelizaeusMerzbacher-like disease; Pol III: Polymerase III-related leukodystrophies; SPG: Spastic paraplegia; VWM: Vanishing white matter disease. Data taken from [46,8,26,32,40,42,4452,54,58,6070].

been described using this approach (e.g., MLC [12], vanishing white matter disease [13], leuko-encephalopathy with brainstem and spinal cord

involvement and lactic acidosis [14], and leuko-encephalopathy with thalamus and brainstem involvement and high lactate [LTBL] [15]).

Advances in the diagnosis of leukodystrophies ReviewCME


Table 1. Relevant clinical features.

System involved

Clinical feature Demyelinating leukodystrophies

Hypomyelinating leukodystrophies

Ref.

Neurological Episodic deteriorations triggered by fevers, infections or minor head traumas

Vanishing white matter disease [38]

Irritability and excessive startle

Krabbe, AicardiGoutires [3,33]

Neuropsychiatric symptoms

Metachromatic, adrenoleukodystrophy, adult-onset autosomal dominant leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids and cerebrotendinous xanthomatosis

18q deletion [4,5,7,41,61,66]

Macrocrania Alexander, Canavan and megalencephalic leukoencephalopathy with subcortical cysts

[30,63,64]

Relative macrocrania Krabbe and metachromatic [3,4]

Microcephaly 18q deletion, AIMP1-related disorders, Hsp60

[17,71,72]

Peripheral neuropathy Metachromatic, Krabbe and adrenomyeloneuropathy

Cockayne, hypomyelination with congenital cataracts, PelizaeusMerzbacher (PLP1-null syndrome), peripheral neuropathy, central hypomyelination, Waardenburg, Hirschsprung syndrome, Pol III-related and 18q deletion

[36,51,58,66,73,74]

Spastic paraparesis, bladder dysfunction

Adrenomyeloneuropathy, adult-onset Krabbe and adult-onset metachromatic

PelizaeusMerzbacher (SPG2), PelizaeusMerzbacher-like disease (SPG44), Hsp60 (SPG13), adult-onset GM1 and GM2 gangliosidosis

[3,4,28,46,7577]

Facial features Coarsening Fucosidosis, Salla, AIMP1-related disorders

[70,72,78]

Dysmorphisms 18q deletion, AllanHerndonDudley [71,79]

Dentition Hypodontia, oligodontia, delayed tooth eruption

Pol III-related [54,80]

Tooth enamel hypoplasia Oculodentodigital dysplasia [67]

Ophthalmological Cataracts Cerebrotendinous xanthomathosis

Hypomyelination with congenital cataracts; 18q deletion; Cockayne; and Pol III-related (one case)

[8,61,73,81]

Microphthalmia Oculodentodigital dysplasia and Cockayne

[67,73]

Nystagmus PelizaeusMerzbacher (except PLP1 null syndrome), PelizaeusMerzbacher-like disease and Pol III-related (gaze-evoked)

[6,44,45,54,55]

Progressive external ophthalmoplegia, ptosis

KearnsSayre syndrome [82]

Primary neuronal disorders with associated hypomyelination.Myelination delay syndrome. Pol III: Polymerase III.



MRI pattern recognition is also useful for discriminating between the many hypomy-elinating disorders [16]. Beyond the common diffuse hypomyelination [16], each of these disorders have other specific characterizing features on MRI, which can help to differen-tiate one from the others [16]. It is important to note that whether the MRI pattern shows demyelination or hypomyelination, the differ-ential diagnosis should include, when appropri-ate, primary neuronal, hereditary and acquired disorders [2,17,18].

When faced with a first MRI showing hypo-myelination, especially in a child younger than 2 years, it is important to consider that this could represent a delay in myelination rather than a true hypomyelination [2,10,19]. A practi-cal way to distinguish the two conditions is by repeating a brain MRI 6 months after the first,

in order to identify whether there is a progres-sion in myelination. In myelination delay, the myelination progresses, while in hypomyelin-ation, it does not [2]. This distinction is crucial to make as the differential diagnosis for the two entities is quite different. Indeed, myelination delay is, in general, considered a nonspecific finding associated with global developmental delay [19]. Various etiologies have been described as causing myelination delay, such as chromo-somal abnormalities (e.g., trisomy 21), inborn errors of metabolism (e.g., methylmalonic acide-mia [20] and phenylketonuria [21]) and acquired causes (e.g., hypoxicischemic encephalopathy [22]).One exception to this is the X-linked dis-order, AllanHerndonDudley syndrome, for-merly called MCT8-specific thyroid hormone cell transporter deficiency, a disorder charac-terized by myelination delay, but that presents

Table 1. Relevant clinical features (cont.).

System involved

Clinical feature Demyelinating leukodystrophies

Hypomyelinating leukodystrophies

Ref.

Hearing Neurosensorial hearing loss

KearnsSayre syndrome 18q deletion; Peripheral neuropathy, central hypomyelination; Waardenburg, Hirschsprung sydrome; and Cockayne

[58,71,73,82]

Endocrine Adrenal insufficiency Adrenoleukodystrophy [5]

Ovarian dysfunction Vanishing white matter disease [36]

Hypogonadotropic hypogonadism (delayed puberty)

Pol III-related [54,55]

Growth hormone deficiency

Pol III-related; 18q deletion [54,55,66]

Thyroid functions abnormalities

18q deletion; Allan-Herndon-Dudley [71,79]

Heart Cardiac conduction block

KearnsSayre syndrome [82]

Cardiac malformations 18q deletion [71]

Cardiomegaly Fucosidosis [70]

Gastrointestinal Hepatosplenomegaly Free sialic acid storage disease, fucosidosis

[70,78]

Hirschsprung Peripheral neuropathy central hypomyelination, Waardenburg and Hirschsprung syndrome

[58]

Skin Chilblains AicardiGoutires [33]

Xanthomas (skin and tendons)

Cerebrotendinous xanthomatosis [61]

Musculoskeletal Deformities 18q deletion [71]

Syndactyly of toes and fingers

Oculodentodigital dysplasia [67]

Primary neuronal disorders with associated hypomyelination.Myelination delay syndrome. Pol III: Polymerase III.



clinically very similarly to a hypomyelinating leukodystrophy, with infantile hypotonia, pro-gressing to spastic quadraparesis with associated movement disorders and/or intellectual dis-abilities with or without seizures [23,24]. Serum thyroid function tests show normal/slightly elevated thyroid stimulating hormone, high serum T3, low serum reverse T3 and normal/low T4. Thus, the investigations of children with myelination delay should include what is recommended for global developmental delay, as well as thyroid s timulating hormone, T3, reverse T3 and T4 [25].

Once a leukodystrophy has been classified either as demyelinating or hypomyelinating, the distribution of the white matter signal abnormalities will help to orient the diagnosis (Figures 3 & 4) [2,16,26,27].

Moreover, sometimes peculiar MRI fea-tures can be useful in the diagnostic process. This is the case of contrast enhancement in adrenoleuko dystrophy [28] and in Alexander disease [29] or of the presence of cysts as found in MLC [30] and in RNASET2-deficient leuko-encephalopathy [31]. Rarefaction of the cerebral white matter is pathognomonic in vanishing white matter disease [32]. Besides MRI, brain CT

scans can provide important information, and in particular, can show cerebral calcifications that are a hallmark of some leuko dystrophies (i.e., AicardiGoutires syndrome [33] and RNASET2-deficient l eukodystrophy) [31].

GeneticsOnce the differential diagnosis has been nar-rowed to one or more diagnostic hypotheses based on salient clinical features and more importantly on MRI characteristics, molecular studies can confirm it, when available. Tables 2 & 3 present the inheritance, mutated genes, screening and molecular genetic tests and indicate whether the latter is clinically available or not, for the different demyelinating and h ypomyelinating leukodystrophies, respectively.

Recent advances in leukodystrophiesIn this section, the authors will review the recent discoveries in the field of leukodystrophies, with an emphasis on the recently described syndromes or recently discovered genes.

LTBLLTBL is a newly described mitochondrial dis-ease caused by recessive mutations in EARS2

Figure 2. Hypomyelinating versus demyelinating pattern on MRI. (A) Sagittal T1- and (B & C) axial T2-weighted images of a patient with a polymerase III-related hypomyelinating leukodystrophy showing diffuse mild T1 hypointense and mild T2 hyperintense signal of the cerebral white matter. The diffuse signal abnormalities presented in the second patient, affected by vanishing white matter disease, are more prominent both in the (D) sagittal T1 and in the (E & F) axial T2-weighted images.



leading to a mitochondrial translation deficit [27]. The clinical presentation is usually set in the first year of life and is characterized by neu-rological decline, including progressive spas-ticity. A subsequent clinical improvement and partial recovery is frequently noticed and has

been correlated to the degree of brain involve-ment. Brain MRI shows diffuse abnormal sig-nals in the cerebral white matter, with relative sparing of the periventricular region, associ-ated with a striking signal abnormality in the thalami and mesencephalon. An incomplete

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Cerebellar involvement Alexander disease Krabbe Cerebrotendinous xanthomatosis LBSL ADLD Megalencephalic leukoencephalopathy with subcortical cysts

Brainstem involvement LBSL Alexander disease Cerebrotendinous xanthomatosis ADLD

Frontal and/or temporal cysts Megalencephalic leukoencephalopathy with subcortical cysts

AicardiGoutieres syndrome (inconstant) RNAseT2-deficient leukoencephalopathy (temporal)

Diffuse involvement Vanishing white matter disease Canavan disease Megalencephalic leukoencephalopathy with subcortical cysts LBSL End stage of most leukodystrophies

Frontal predominance Adrenoleukodystrophy (frontal variant) Alexander disease Metachromatic leukodystrophy Hereditary diffuse leukoencephalopathy with spheroids

Periventricular predominance Metachromatic leukodystrophy Krabbe LBSL

Subcortical involvement Canavan disease L2-hydroxyglutaric aciduria

Thalamic involvement LTBL LBSL

Posterior predominance Adrenoleukodystrophy Krabbe

Figure 3. Regional distribution of white matter abnormalities in the different types of demyelinating leukodystrophies. Graphical representation of the different brain regions with the corresponding demyelinating leukodystrophies presenting a prominent involvement of each specific region. ADLD: Adult-onset autosomal dominant leukodystrophy; LBSL: Leukoencephalopathy with brainstem and spinal cord involvement and lactic acidosis; LTBL: Leukoencephalopathy with thalamus and brainstem involvement and high lactate.



development of the posterior part of the cor-pus callosum has been reported. Magnetic resonance spectroscopy reveals a peak of lac-tate. The abovementioned neuroradio logical findings can improve in subsequent follow-up examinations [27]. The description of LTBL

has shed new light into mitochondrial transla-tion deficits such as those due to mutations in DARS2 (leukoencephalopathy with brainstem and spinal cord involvement and high lactate) [34] and RARS2 (pontocerebellar hypoplasia type 6) [35].

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Thin corpus callosum Pol III-related leukodystrophies Hypomyelination with congenital cataracts Salla disease Fucosidosis

Basal ganglia T2-hypointensity Pol III-related leukodystrophies (anterolateral nuclei of the thalami, globi pallidi)

Fucosidosis (globi pallidi) ODDD

Thalamic involvement HEMS (T2 hyperintensity of the anterolateral nuclei)

Optic radiations T2-hypointensity Pol III-related leukodystrophies

Optic radiations involvement

HEMS (T2 hyperintensity)

Brainstem involvement HEMS PelizaeusMerzbacher-like disease

Cerebellar white matter

involvement PelizaeusMerzbacher disease PelizaeusMerzbacher-like disease Pol III-related leukodystrophies 18q deletion syndrome HEMS (peridentate and hilus)

Cerebellar atrophy Pol III-related leukodystrophies HABC ODDD Salla disease Cockayne syndrome

Dentate nuclei T2-hypointensity Pol III-related leukodystrophies

Basal ganglia atrophy HABC (especially putamen)

Figure 4. Structures specifically involved in hypomyelinating leukodystrophies. Graphical representation of different brain structures with the corresponding hypomyelinating leukodystrophies presenting with specific involvement or preservation of each structure. HABC: Hypomyelination with atrophy of the basal ganglia and cerebellum; HEMS: Hypomyelination of early myelinating structures; ODDD: Oculodentodigital dysplasia; Pol III: Polymerase III.



eIF2B-related disorders: extending the phenotype

The classic phenotype of vanishing white mat-ter disease [13] or childhood ataxia with central hypomyelination has expanded. Nowadays,

the term eIF2B-related disorders appears more appropriate as it includes all the different pheno-types. Besides the typical late infantile onset, characterized by neurologic deterioration fol-lowing even mild infections or head traumas,

Table 2. Genetics and diagnostic testing for demyelinating leukodystrophies.

Demyelinating leukodystrophies Inheritance Mutated gene Diagnostic test Ref.

Adult-onset autosomal dominant leukodystrophy AD LMNB1 Molecular(clinical)

[60]

Adrenoleukodystrophy XL ABCD1 VLCFA (plasma)Molecular (clinical)

[5]

Alexander AD de novoAD in familial adult-onset cases

GFAP Molecular (clinical) [63]

AicardiGoutires AR(except some TREX1 mutations are de novo AD)

RNASEH2ARNASEH2BRNASEH2CSAMHD1TREX1

CSF IFN-aMolecular (clinical)

[33,83,84]

Canavan AR ASPA (aspartoacylase)

Elevated NAA (urine, MRS)Molecular (clinical)

[64]

Cerebrotendinous xanthomatosis AR CYP27A1 Elevated cholestanol:cholesterol ratio (blood)Molecular (clinical)

[85]

Cystical leukoencephalopathy without megalencephaly

AR RNASET2 Molecular (research) [31]

Krabbe (globoid cell) AR GALC GALC enzymatic activity (leukocytes, fibroblasts)Molecular (clinical)

[3]

Krabbe due to saposin A deficiency AR PSAP Molecular (clinical) [86]

Hereditary diffuse leukoencephalopathy with spheroids

AD CSFR1 Molecular (research) [41]

Leukoencephalopathy with brainstem and spinal cord involvement and elevated lactate

AR DARS2 MRS: elevated lactate in the abnormal white matterMolecular (clinical)

[34]

MLC type 1 AR MLC1 Molecular (clinical) [30]

MLC2AMLC2B

ARAD

HEPACAM Molecular (clinical) [39]

Metachromatic AR ARSA ARSA enzymatic activity (leukocytes, fibroblasts) with urine sulfatides

Molecular (clinical)

[4]

Metachromatic-like(normal ARSA enzymatic activity) due to saposin B deficiency

AR PSAP Urine sulfatidesSaposin B levelsMolecular (clinical)

[87]

Austin variant of metachromatic leukodystrophy caused by multiple sulfatase deficiency

AR SUMF1 Urine sulfatides, urine MPS, ARSA enzymatic activityMolecular (clinical)

[88]

Vanishing white matter disease AR EIF2B15 Molecular (clinical) [36,38]Urine sulfatides are important to perform in conjunction with ARSA enzymatic assay in order to differentiate metachromatic leukodystrophy from ARSA pseudodeficiency [87]. AD: Autosomal dominant; AR: Autosomal recessive; ARSA: Arylsulfatase A; CSF: Cerebrospinal fluid; MLC: Megalencephalic leukoencephalopathy with subcortical cysts; MPS: Mucopolysaccharides; MRS: Magnetic resonance spectroscopy; NAA: N-acetyl aspartate; VLCFA: Very long chain fatty acids; XL: X-linked.



the age of onset of eIF2B disorders can vary from the neonatal period (such as what is seen in the allelic disorder Cree leuko encephalopathy) to slowly progressive adult forms [36,37], includ-ing the disorder formerly called ovarioleuko-dystrophy [37] characterized by the presence of premature menopause due to ovarian failure. Some adult cases have also been reported with a classic history of complicated migraines pre-ceding the neurological deterioration [36,38]. The brain MRI reveals a demyelinating leukodys-trophy with characteristic white matter rarefac-tion [13]. Recessive mutations in the five genes (EIF2B15) coding for the subunits of eIF2B are responsible for the disorder. Some genotypephenotype correlations have been observed, including some mutations in EIF2B5 associated to late-onset forms [38].

MLC focus on the new phenotypeMLC is an autosomal recessive disorder firstly described in 1995 by van der Knaap et al. in patients with macrocephaly, insidious neuro-logical deterioration and MRI evidence of white matter swelling and subcortical cysts, particularly of the temporal poles [12]. Subsequently, recessive mutations in the MLC1 gene were found to cause the disease in almost 75% of the affected sub-jects [30]. The recent discovery that mutations in the HEPACAM gene are responsible for MLC in patients negative to MLC1 ana lysis has provided new insight in the knowledge of the disease [39]. MLC has a typical onset in infancy, with macro-cephaly being the first clinical sign, followed by slow neurological deterioration in the classical phenotype. In the last few years, a new pheno-type has been reported, characterized by the lack of the clinical decline and improvement of the neuroradiological findings [40]. When inherited in an autosomal recessive fashion, mutations in HEPACAM have been correlated with the clas-sic phenotype of MLC, while the autosomal dominant transmission has been associated with MLC2, which is characterized by the absence of clinical deterioration and with transient MRI findings. Autosomal dominant mutations in HEPACAM have also been associated with other phenotypes: familiar macrocephaly, as well as macrocephaly and mental retardation with or without autistic features [39].

Hereditary diffuse leukoencephalopathy with spheroids

Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an adult-onset autosomal dominant white matter disease, associated with

progressive cognitive and motor dysfunction [41]. The typical age of onset is from 20 to 60 years of age [42]. Clinical features include initial per-sonality and behavioral changes, as well as cog-nitive dysfunction (e.g., memory problems), followed by limb spasticity, ataxia and seizures [42]. Considering its autosomal dominant inheri-tance, HDLS should certainly be included in the differential diagnosis of patients with a strong family history of early-onset, predomi-nantly frontal dementia. Notable MRI findings include bilateral, patchy and often asymmetri-cal T1-hypointense and T2-hyperintense signal of the white matter, with frontal predominance [43]. Frontal lobe atrophy can also be seen in advanced stages of the disease. The brainstem can also be affected with mainly corticospinal tract involvement [43]. Until recently, the diag-nosis of HDLS was solely made on pathology, with the presence of abundant axonal spheroids in the cerebral white matter. CSF1R has been identified as the causative gene responsible for HDLS [41]. It encodes for a colony stimulating factor 1 receptor that is thought to play a crucial role in the mediation of microglial proliferation and differentiation [41].

PelizaeusMerzbacher-like disease caused by mutations in GJC2PelizaeusMerzbacher-like disease is an autoso-mal recessive leukodystrophy presenting both clinical and radiological similarities to PelizaeusMerzbacher disease, the prototypical hypomy-elinating leukodystrophy. PelizaeusMerzbacher-like disease typically presents in early infancy with nystagmus [44]. The patients then develop axial hypotonia, progressive limb spasticity, cer-ebellar dysfunction and movement disorders [45]. As it is the case with PMD, a milder pheno-type of hereditary spastic paraparesis (SPG44) has been described [46]. Similarly to PMD, the MRI brain typically shows diffuse hypomyelin-ation [2] but with a typical involvement of the pons, which is usually not seen in PMD [16]. PelizaeusMerzbacher-like disease is caused by GJC2 mutations (formerly called GJA12) on chromosome 1 [4446]. GJC2 encodes for the gap junction protein g-2 (also known as connexin 46.6 or 47), which is thought to play a key role in central myelination and to some extent in peripheral myelination [45].

Polymerase III-related leukodystrophiesThis novel group of disorders includes five clinically distinct hypomyelinating leuko-dystrophies, which share some clinical and



radiological features, and are all caused by reces-sive mutations in POLR3A and POLR3B [4749]. The first of these disorders to be described was leuko dystrophy with oligodontia, by Atrouni et al. in 2003 [50]. Since then, four other disor-ders have been described, namely hypomyelin-ation, hypodontia and hypogonadotropic hypo-gonadism (4H syndrome) [51], ataxia, delayed dentition and hypomyelination [52], tremor-ataxia with central hypomyelination [53] and hypomyelination with cerebellar atrophy and hypoplasia of the corpus callosum [47]. These disorders are likely representing a spectrum of clinical presentations, and for this reason, are referred to as polymerase III (Pol III)-related leukodystrophies.

Pol III-related leukodystrophies have a variable age of onset, ranging from infancy to adoles-cence [54]. Their core clinical features include motor delay and/or regression, progressive spasticity, cerebellar ataxia, tremor, abnormal dentition (e.g., delayed dentition, hypodontia, oligodontia and so on) and hypogonadotropic hypogonadism [54,55]. The brain MRI demon-strates diffuse hypomyelination, typically associ-ated with T2-hypointensities of the anterolateral nuclei of the thalami, the optic radiations, the dentate nuclei, as well as the pyramidal tracts at the level of the post erior limb of the internal cap-sules. Other possible findings on MRI are cer-ebellar atrophy, white matter atrophy and thin-ning of the corpus callosum [16,53,54]. This group

of disorders was recently found to be caused by recessive mutations in POLR3A (chromosome 10) [47,48] and POLR3B (chromosome 12) [47,49], encoding for the two largest subunits of the Pol III, an essential macro molecule responsible for the transcription of DNA into RNA.

Peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, Hirschsprung disease or SOX10-related disorders

SOX10 is a gene coding for a transcription fac-tor important for neural crest and glia develop-ment. Mutations in SOX10 have been reported to cause certain cases of the neuro logical variant of Waardenburg syndrome type IV (WaardenburgShah syndrome), also known as peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease [56]. Recently, heterozygous mutations in SOX10 have been associated with an expanding clini-cal spectrum. In fact, they have been found in patients with Waardenburg syndrome type 2, type 4, and peripheral demyelinating neuropa-thy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung dis-ease [57]. Classically, the age of onset of SOX10-related disorders is in the first year of life; how-ever, cases have been reported with onset in late infancy. Other than the classic Waardenburg syndrome features (pigmentary abnormalities

Table 3. Genetics and diagnostic testing for hypomyelinating leukodystrophies.

Hypomyelinating leukodystrophy Inheritance Mutated gene

Diagnostic test Ref.

PelizaeusMerzbacher XL PLP1 Molecular (clinical) [75]

PelizaeusMerzbacher-like AR GJC2 (GJA12)

Molecular (clinical) [45]

Hypomyelination and congenital cataract AR FAM126A Molecular (clinical) [8]

Hypomyelination with atrophy of the basal ganglia Sporadic or AR Unknown MRI [69]

Pol III-related leukodystrophies AR POLR3A; POLR3B

Molecular (research and clinical)

[4749]

18q deletion Sporadic N/A aCGH [66]

Sialic acid storage disorders (including Salla disease) AR SLC17A5 Elevated free sialic acid (urine)Molecular (clinical)

[89]

Oculodentodigital dysplasia AD(rarely AR)

GJA1 Molecular (clinical) [90]

Fucosidosis AR FUCA1 a-L-fucosidase enzymatic activitymolecular (clinical)

[70]

Peripheral neuropathy, central hypomyelination, Waardenburg and Hirschsprung syndrome

AD SOX10 Molecular (clinical) [59]

aCGH: Array comparative genomic hybridization; AD: Autosomal dominant; AR: Autosomal recessive; N/A: Not applicable; XL: X-linked.



and sensorineural deafness), the clinical picture is characterized by developmental delay and hypotonia with or without peripheral neuropa-thy. Early-onset nystagmus, ataxia and spasticity

often complete the clinical picture [58]. Other possible phenotypes are Waardenburg syndrome type 2E and Waardenburg syndrome type 4C [57]. Interestingly, Waardenburg syndrome type 2E is

Executive summary

Backgroundn Leukodystrophies are a group of inherited disorders affecting the cerebral white matter.n Leukodystrophies are classified based on their MRI features.n Demyelinating leukodystrophies (classic): prominent hyperintense T2 signal and prominent hypointense T1 signal of the affected white

matter compared with gray matter structures.n Hypomyelinating leukodystrophies: mildly hyperintense T2 signal and hyper-, iso- or slightly hypo-intense T1 signal of the affected

white matter compared with gray matter structures.n Myelination delay: progression of the myelination on a second MRI of the brain performed at least 6 months after the first MRI.

Clinical approachn Age of onset

Demyelinating leukodystrophies have variable ages of onset from the neonatal period to adulthood.

Hypomyelinating leukodystrophies typically present early on, either in the neonatal period or during infancy.

n Clinical features Certain clinical features can orient toward one diagnosis or another, such as macrocrania (Alexander, Canavan and megalencephalic

leukoencephalopathy with subcortical cysts), oligodontia/hypodontia/delayed dental eruption (polymerase III-related leukodystrophies), Addisons disease (adrenoleukodystrophy) and so on.

n MRI: pattern recognition MRI is crucial in the diagnostic process in order to narrow the differential diagnosis. Once the category of white matter abnormality

has been determined (e.g., demyelinating and hypomyelinating), careful attention to other MRI characteristics can substantially reduce the possible diagnoses, allowing for more precise biochemical and molecular genetic testing to be performed.

n Genetics Most leukodystrophies are inherited in an autosomal recessive fashion (e.g., Krabbe, metachromatic, Pol III-related leukodystrophies

and so on), while some are inherited in an X-linked (e.g., adrenoleukodystrophy, PelizaeusMerzbacher disease) or autosomal dominant (e.g., adult-onset autosomal dominant leukodystrophy) fashion.

n Recent advances in leukodystrophies Leukoencephalopathy with thalamus and brainstem involvement and high lactate is a recently described mitochondrial disorder

caused by recessive mutations in EARS2. Leukoencephalopathy with thalamus and brainstem involvement and high lactate typically presents in the first year of life with neurological deterioration and spasticity followed by some improvement. The brain MRI features include diffuse white matter abnormalities with relative sparing of the periventricular region and striking abnormalities of the thalami and mesencephalon.

eIF2B-related disorders include the classic form of vanishing white matter disease, as well as the more recently described phenotypes associated with recessive mutations in eIF2B15.

A second causal gene was recently identified for megalencephalic leukoencephalopathy with subcortical cysts: HEPACAM. Recessive mutations in this gene are associated with the classic megalencephalic leukoencephalopathy with subcortical cysts phenotype, as well as a more benign form without clinical deterioration and with transient MRI features. Autosomal dominant mutations in this gene lead to the following phenotypes: familial macrocephaly and macrocephaly with mental retardation with or without autistic features.

Hereditary diffuse leukoencephalopathy with spheroids is an adult-onset autosomal dominant leukodystrophy characterized by personality and behavioral changes. Recently, this disorder was found to be caused by mutations in CSF1R gene encoding for the colony stimulating factor 1 receptor.

PelizaeusMerzbacher-like disease is an autosomal recessive disorder caused by mutations in GJC2. This hypomyelinating leukodystrophy is quite similar to PelizaeusMerzbacher disease.

Polymerase III-related leukodystrophies are a group of hypomyelinating leukodystrophies characterized by childhood onset motor delay/regression, cerebellar features, tremor, with or without teeth abnormalities (e.g., oligodontia, hypodontia, delayed eruption) and hypogonadotropic hypogonadism. This group of disorders was recently found to be caused by recessive mutations in POLR3A and POLR3B, encoding for the two largest subunits of the polymerase III.

SOX10-related disorders are a group of disorders characterized by peripheral neuropathy, central hypomyelination, Waardenburg syndrome and Hirschsprung disease.

Hypomyelinating leukoencephalopathy affecting early myelinating structures is a recently described hypomyelinating leukodystrophy where early myelinating structures are preferentially involved. This disorder is characterized by prominent cerebellar findings. It is presumed to be inherited in an X-linked fashion.



also characterized by pigmentary abnormalities and sensorineural deafness with or without neu-rological signs (mental retardation, ataxia and nystagmus) [56].

Diffuse central hypomyelination with fea-tures reminiscent of PelizaeusMerzbacher dis-ease characterizes the neuroradiological picture [59]. The presence of hypomyelination and/or demyelination on MRI brain imaging has been described in some Waardenburg syndrome type 2E cases [56].

Hypomyelinating leukoencephalopathy affecting early myelinating structures

A new distinct pattern of hypomyelination has been recently described in four boys [26]. Hypomyelinating leukoencephalopathy affect-ing early myelinating structures is presumed to be X-linked. All patients presented a spe-cific MRI involvement, with hypomyelination (mild T2-hyperintensity, T1-hyper-, iso- or mild hypo-intensity) of structures that are known to myelinate early in life. In particular, the optic radiations and the frontoparietal periventricu-lar white matter were involved in all cases; the brainstem and the cerebellar white matter were also hypomyelinated, as well as the thalamus. The posterior limb of the internal capsule showed a striped altered signal in T2-weighted images in the majority of cases. The clinical pre-sentation is characterized by onset around the age of 620 months with nystagmus. Cerebellar signs (ataxia and d ysarthria) were reported in all patients.

It is interesting to note that this entity differs from all other hypomyelinating disorders. In fact, hypomyelinating leukodystrophies usually

present with a pattern of hypomyelination in which the early myelinating structures are the most myelinated in comparison to regions of late myelination. In other words, the myelina-tion sequence is respected in hypomyelinating leukodystrophies, except in hypomyelinating leukoencephalopathy affecting early myelinat-ing structures where the structures involved are those of early myelination.

Future perspectiveLeukodystrophies are a group of disorders where research is advancing quickly. The challenges are huge, and range from clinical description of new disorders, identification of their causal genes, understanding their epidemiology, clinical fea-tures and natural evolution to the understand-ing of their pathophysiology and development of therapeutic strategies. Hopefully, the next few decades will be as rich in discoveries in this field as the last few have been.

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Advances in the diagnosis of leukodystrophies

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[email protected]. For technical assistance, contact [email protected]. American Medical Associations Physicians Recognition Award (AMA PRA) credits are accepted in the US as evidence of participation in CME activi-ties. For further information on this award, please refer to http://www.ama-assn.org/ama/pub/category/2922.html. The AMA has determined that physicians not licensed in the US who participate in this CME activity are eligible for AMA PRA Category 1 Credits. Through agreements that the AMA has made with agencies in some countries, AMA PRA credit may be acceptable as evidence of par-ticipation in CME activities. If you are not licensed in the US, please complete the ques-tions online, print the AMA PRA CME credit certif icate and present it to your national medical association for review.

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1. Your patient is an 8-month-old male in whom leukodystrophy is suspected. Based on the review by Dr. Osterman and colleagues, which of the following statements about classification of leukodystrophies based on MRI characteristics is most likely correct?

A MRI in demyelinating leukodystrophies shows prominent hypointense T2 signal and prominent hyperintense T1 signal of the affected white matter compared with gray matter structures

B MRI in hypomyelinating leukodystrophies shows a mildly hyperintense T1 signal and hyper-, iso-, or slightly hypointense T2 signal of the affected white matter compared with gray matter structures

C In myelination delay syndrome, a second MRI of the brain done at least 6 months after the first MRI shows progression of the myelination

D Subcortical cysts on MRI are highly associated with lactic acidosis



3. Based on the review by Dr. Osterman and colleagues, which of the following statements about genetic features of leukodystrophies would most likely be correct?

A Leukodystrophies have an X-linked pattern of inheritance

B No leukodystrophies have an autosomal dominant pattern of inheritance

C Krabbes has an autosomal recessive pattern of inheritance

D Pol III-related leukodystrophies have an X-linked pattern of inheritance

2. Based on the review by Dr. Osterman and colleagues, which of the following statements about differential diagnosis according to clinical features is most likely correct?

A Macrocephaly rules out Canavans disease

B Coarsening of facial features is associated with peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease (PCWH)

C Peripheral neuropathy is inconsistent with hypomyelination with congenital cataracts (HCC)

D Dental abnormalities are associated with Pol III-related leukodystrophies


future neurol. (2012) 7(5), 595–612

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