Future Neurol. (2012) 7 (5), 595-612

Advances in the diagnosis of leukodystrophies
Bradley Osterman1, Roberta La Piana2 & Genevive Bernard*1

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Future Neurology
Montreal Childrens Hospital, 2300 Tupper, Room A-506, Montreal, Quebec, H3H 1P3, Canada Montreal 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 genevieve.bernard@mcgill.ca
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. Medscape: Continuing Medical Education Online
This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Future Medicine Ltd. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at www.medscape.org/journal/fnl; (4) view/print certificate.
Release date: 10 September 2012; Expiration date: 10 September 2013 Learning objectives
Upon completion of this activity, participants should be able to:

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Describe classification of leukodystrophies based on MRI characteristics, according to a review Describe differential diagnosis of leukodystrophies based on clinical features, according to a review Describe genetic features of leukodystrophies, according to a review
Financial & competing interests disclosure
Editor: 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 relationships. 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.
10.2217/FNL.12.52 2012 Future Medicine Ltd
Keywords
demyelination n diagnostic approach n hypomyelination n leukodystrophies nleukoencephalopathies nMRI
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Future Neurol. (2012) 7(5), 595612
ISSN 1479-6708
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Osterman, La Piana & Bernard
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Patients with a neonatal or infantile presentation will typically present with axial hypotonia, which will evolve over time into spastic quadraparesis. 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 disorders and can help orient the investigations. Table1 can help the clinician differentiate between different 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 hypomyelination 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 typically seen in Alexander, Canavan and megalencephalic leukoencephalopathy with subcortical cysts (MLC)[9].
Neuroradiology: the importance of MRI pattern recognition
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.,adrenoleukodystrophy, PelizaeusMerzbacher disease) [5,6] or autosomal dominant (e.g., adult-onset autosomal dominant leukodystrophy) [7] fashion. 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 approach
The clinical presentation of the different types of leukodystrophies is often similar among the same age group. Figure1 presents the main forms of leukodystrophies according to their age of onset, while Table1 summarizes and compares their c linical presentation.
Age of onset
Among the important clinical features to consider 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 hypomyelinating leukodystrophies can, however, present later. As for demyelinating leuko dystrophies, they have very variable ages of onset, ranging from childhood to adulthood, with some forms having different 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 features
The clinical presentation of the different leukodystrophies is often similar for a given age group.
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When a leukodystrophy is suspected, the brain MRI becomes a crucial tool to formulate a diagnostic hypothesis. The first distinction to make when looking at the MRI is whether the white matter abnormalities correspond to a demyelinating 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 leukodystrophies, 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
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ADLD ALD Alexander Canavan CTX Krabbe HDLS MLC MLD VWM PMD PMD-like HCC HABC Pol-III 18q del FSASD ODDD Fucosidosis PCWH HEMS 0 3m 6m 1 year Early infantile 6 years Late infantile 10 years Juvenile 20 years Adult 30 years SPG2 SPG44 AMN
Congenital neonatal
Age of onset of demyelinating and hypomyelinating leukodystrophies
Figure1. 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; PolIII:PolymeraseIII-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], leukoencephalopathy with brainstem and spinal cord
involvement and lactic acidosis [14], and leuko encephalopathy with thalamus and b rainstem involvement and high lactate [LTBL] [15]).
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Table1. Relevant clinical features.

System involved
Neurological
Clinical feature
Demyelinating leukodystrophies
Hypomyelinating leukodystrophies
Ref.
[38]
Episodic deteriorations Vanishing white matter disease triggered by fevers, infections or minor head traumas Irritability and excessive startle Neuropsychiatric symptoms Krabbe, AicardiGoutires Metachromatic, adrenoleukodystrophy, adultonset autosomal dominant leukodystrophy, hereditary diffuse leukoencephalopathy with spheroids and cerebrotendinous xanthomatosis Alexander, Canavan and megalencephalic leukoencephalopathy with subcortical cysts Krabbe and metachromatic 18q deletion, AIMP1-related disorders, Hsp60 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 PelizaeusMerzbacher (SPG2), PelizaeusMerzbacher-like disease (SPG44), Hsp60 (SPG13), adult-onset GM1 and GM2 gangliosidosis Fucosidosis, Salla, AIMP1-related disorders 18q deletion, AllanHerndonDudley Pol III-related Oculodentodigital dysplasia Cerebrotendinous xanthomathosis Hypomyelination with congenital cataracts; 18q deletion; Cockayne; and PolIII-related (onecase) Oculodentodigital dysplasia and Cockayne PelizaeusMerzbacher (except PLP1 null syndrome), PelizaeusMerzbacher-like disease and PolIII-related (gaze-evoked) KearnsSayre syndrome 18q deletion
[3,33] [4,5,7,41,61,66]
Macrocrania
[30,63,64]
Relative macrocrania Microcephaly Peripheral neuropathy
[3,4] [17,71,72] [36,51,58,66,73,74]
Spastic paraparesis, bladder dysfunction
Adrenomyeloneuropathy, adult-onset Krabbe and adult-onset metachromatic
[3,4,28,46,7577]
Facial features
Coarsening Dysmorphisms
[70,72,78] [71,79] [54,80] [67] [8,61,73,81]
Dentition
Hypodontia, oligodontia, delayed tooth eruption Tooth enamel hypoplasia
Ophthalmological Cataracts
Microphthalmia Nystagmus
[67,73] [6,44,45,54,55]
Progressive external ophthalmoplegia, ptosis

[82]
Primary neuronal disorders with associated hypomyelination. Myelination delay syndrome. Pol III: Polymerase III.
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Table1. Relevant clinical features (cont.).

System involved
Hearing
Clinical feature
Neurosensorial hearingloss
KearnsSayre syndrome
Hypomyelinating leukodystrophies
18q deletion; Peripheral neuropathy, central hypomyelination; Waardenburg, Hirschsprung sydrome; and Cockayne
Ref.
[58,71,73,82]
Endocrine
Adrenal insufficiency Ovarian dysfunction Hypogonadotropic hypogonadism (delayed puberty) Growth hormone deficiency Thyroid functions abnormalities
Adrenoleukodystrophy Vanishing white matter disease Pol III-related
[5] [36] [54,55]
Pol III-related; 18q deletion 18q deletion; Allan-Herndon-Dudley KearnsSayre syndrome 18q deletion Fucosidosis Free sialic acid storage disease, fucosidosis Peripheral neuropathy central hypomyelination, Waardenburg and Hirschsprung syndrome AicardiGoutires Cerebrotendinous xanthomatosis 18q deletion Oculodentodigital dysplasia
[54,55,66] [71,79] [82] [71] [70] [70,78] [58]
Heart
Cardiac conductionblock Cardiac malformations Cardiomegaly
Gastrointestinal
Hepatosplenomegaly Hirschsprung
Skin
Chilblains Xanthomas (skin and tendons)
[33] [61] [71] [67]
Musculoskeletal
Deformities Syndactyly of toes and fingers
Primary neuronal disorders with associated hypomyelination. Myelination delay syndrome. Pol III: Polymerase III.

MRI pattern recognition is also useful for discriminating between the many hypomyelinating disorders [16]. Beyond the common diffuse hypomyelination [16], each of these disorders have other specific characterizing features on MRI, which can help to differentiate one from the others [16]. It is important to note that whether the MRI pattern shows demyelination or hypomyelination, the differential diagnosis should include, when appropriate, primary neuronal, hereditary and acquired disorders[2,17,18]. When faced with a first MRI showing hypomyelination, especially in a child younger than 2years, it is important to consider that this could represent a delay in myelination rather than a true hypomyelination [2,10,19]. A practical 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 progression in myelination. In myelination delay, the myelination progresses, while in hypomyelination, 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 chromosomal abnormalities (e.g., trisomy 21), inborn errors of metabolism (e.g., methylmalonic acidemia [20] and phenylketonuria [21]) and acquired causes (e.g., hypoxicischemic encephalopathy [22]).One exception to this is the X-linked disorder, AllanHerndonDudley syndrome, formerly called MCT8-specific thyroid hormone cell transporter deficiency, a disorder characterized by myelination delay, but that presents
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Figure2. 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 T1hypointense 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.
clinically very similarly to a hypomyelinating leukodystrophy, with infantile hypotonia, progressing to spastic quadraparesis with associated movement disorders and/or intellectual disabilities 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 stimulating 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 (Figures3&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 adrenoleukodystrophy [28] and in Alexander disease [29] or of the presence of cysts as found in MLC [30] and in RNASET2-deficient leukoencephalopathy [31]. Rarefaction of the cerebral white matter is pathognomonic in vanishing white matter disease [32]. Besides MRI, brain CT
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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].
Genetics
Once the differential diagnosis has been narrowed 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 y pomyelinating leukodystrophies, respectively.
Recent advances in leukodystrophies
In 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.
LTBL
LTBL is a newly described mitochondrial disease caused by recessive mutations in EARS2

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leading to a mitochondrial translation deficit [27]. The clinical presentation is usually set in the first year of life and is characterized by neurological decline, including progressive spasticity. A subsequent clinical improvement and partial recovery is frequently noticed and has
Frontal predominance Adrenoleukodystrophy (frontal variant) Alexander disease Metachromatic leukodystrophy Hereditary diffuse leukoencephalopathy with spheroids
Review
been correlated to the degree of brain involvement. Brain MRI shows diffuse abnormal signals in the cerebral white matter, with relative sparing of the periventricular region, associated with a striking signal abnormality in the thalami and mesencephalon. An incomplete
Periventricular predominance Metachromatic leukodystrophy Krabbe LBSL
Subcortical involvement Canavan disease L2-hydroxyglutaric aciduria
Posterior predominance Adrenoleukodystrophy Krabbe Thalamic involvement LTBL LBSL
Diffuse involvement Vanishing white matter disease Canavan disease Megalencephalic leukoencephalopathy with subcortical cysts LBSL End stage of most leukodystrophies
Frontal and/or temporal cysts Megalencephalic leukoencephalopathy with subcortical cysts AicardiGoutieres syndrome (inconstant) RNAseT2-deficient leukoencephalopathy (temporal)
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Brainstem involvement LBSL Alexander disease Cerebrotendinous xanthomatosis ADLD
Cerebellar involvement Alexander disease Krabbe Cerebrotendinous xanthomatosis LBSL ADLD Megalencephalic leukoencephalopathy with subcortical cysts
Figure3. 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.
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Basal ganglia atrophy Thin corpus callosum HABC (especially putamen) 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)
Dentate nuclei T2-hypointensity Pol III-related leukodystrophies Cerebellar white matter involvement PelizaeusMerzbacher disease PelizaeusMerzbacher-like disease Pol III-related leukodystrophies 18q deletion syndrome HEMS (peridentate and hilus)
Brainstem involvement HEMS PelizaeusMerzbacher-like disease
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Cerebellar atrophy Pol III-related leukodystrophies HABC ODDD Salla disease Cockayne syndrome
Figure4. 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; PolIII: Polymerase III.
development of the posterior part of the corpus callosum has been reported. Magnetic resonance spectroscopy reveals a peak of lactate. The abovementioned neuroradio logical findings can improve in subsequent follow-up examinations [27]. The description of LTBL
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has shed new light into mitochondrial translation deficits such as those due to mutations in DARS2 (leukoencephalopathy with brainstem and spinal cord involvement and high lactate) [34] and R ARS2 (pontocerebellar hypoplasia type 6) [35].
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eIF2B -related disorders: extending the phenotype
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The classic phenotype of vanishing white matter 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 following even mild infections or head traumas,
Table2. Genetics and diagnostic testing for demyelinating leukodystrophies.

Adult-onset autosomal dominant leukodystrophy Adrenoleukodystrophy Alexander
Inheritance
AD XL AD denovo AD in familial adult-onset cases AR (except some TREX1 mutations are denovo AD) AR AR
Mutated gene
LMNB1 ABCD1 GFAP
Diagnostic test
Molecular (clinical) VLCFA (plasma) Molecular (clinical) Molecular (clinical)
Ref.
[60] [5] [63]
AicardiGoutires
RNASEH2A RNASEH2B RNASEH2C SAMHD1 TREX1 ASPA (aspartoacylase) CYP27A1
CSF IFN- a Molecular (clinical)
[33,83,84]
Canavan Cerebrotendinous xanthomatosis
Elevated NAA (urine, MRS) Molecular (clinical) Elevated cholestanol:cholesterol ratio (blood) Molecular (clinical) Molecular (research) GALC enzymatic activity (leukocytes, fibroblasts) Molecular (clinical) Molecular (clinical) Molecular (research) MRS: elevated lactate in the abnormal white matter Molecular (clinical) Molecular (clinical) Molecular (clinical) ARSA enzymatic activity (leukocytes, fibroblasts) with urine sulfatides Molecular (clinical) Urine sulfatides Saposin B levels Molecular (clinical) Urine sulfatides, urine MPS, ARSA enzymatic activity Molecular (clinical) Molecular (clinical)
[64] [85]
Cystical leukoencephalopathy without megalencephaly Krabbe (globoid cell)
AR AR
RNASET2 GALC
[31] [3]
Krabbe due to saposin A deficiency Hereditary diffuse leukoencephalopathy with spheroids
AR AD
PSAP CSFR1 DARS2
[86] [41] [34]
Leukoencephalopathy with brainstem and spinal cord AR involvement and elevated lactate MLC type 1 MLC2A MLC2B Metachromatic AR AR AD AR
MLC1 HEPACAM ARSA
[30] [39] [4]
Metachromatic-like (normal ARSA enzymatic activity) due to saposin B deficiency Austin variant of metachromatic leukodystrophy caused by multiple sulfatase deficiency Vanishing white matter disease
AR
PSAP
[87]
AR
SUMF1
[88]
AR
EIF2B15
[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.
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progressive cognitive and motor dysfunction [41]. The typical age of onset is from 20 to 60years of age [42]. Clinical features include initial personality and behavioral changes, as well as cognitive dysfunction (e.g., memory problems), followed by limb spasticity, ataxia and seizures [42]. Considering its autosomal dominant inheritance, HDLS should certainly be included in the differential diagnosis of patients with a strong family history of early-onset, predominantly frontal dementia. Notable MRI findings include bilateral, patchy and often asymmetrical 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 diagnosis 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 GJC2
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], including 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 preceding the neurological deterioration [36,38]. The brain MRI reveals a demyelinating leukodystrophy with characteristic white matter rarefaction [13]. Recessive mutations in the five genes (EIF2B15 ) coding for the subunits of eIF2B are responsible for the disorder. Some genotype phenotype correlations have been observed, including some mutations in EIF2B5 associated to late-onset forms [38].
MLC focus on the new phenotype
MLC is an autosomal recessive disorder firstly described in 1995 by van der Knaap etal. 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 subjects [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 phenotype 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 classic 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
PelizaeusMerzbacher-like disease is an autosomal recessive leukodystrophy presenting both clinical and radiological similarities to Pelizaeus Merzbacher disease, the prototypical hypomyelinating leukodystrophy. PelizaeusMerzbacherlike disease typically presents in early infancy with nystagmus [44]. The patients then develop axial hypotonia, progressive limb spasticity, cerebellar dysfunction and movement disorders [45]. As it is the case with PMD, a milder phenotype of hereditary spastic paraparesis (SPG44) has been described [46]. Similarly to PMD, the MRI brain typically shows diffuse hypomyelination [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 leukodystrophies
Hereditary diffuse leukoencephalopathy with spheroids (HDLS) is an adult-onset autosomal dominant white matter disease, associated with
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This novel group of disorders includes five clinically distinct hypomyelinating leuko dystrophies, which share some clinical and
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Table3. Genetics and diagnostic testing for hypomyelinating leukodystrophies.

Hypomyelinating leukodystrophy
PelizaeusMerzbacher PelizaeusMerzbacher-like Hypomyelination and congenital cataract Hypomyelination with atrophy of the basal ganglia Pol III-related leukodystrophies 18q deletion Sialic acid storage disorders (including Salla disease) Oculodentodigital dysplasia Fucosidosis
Inheritance
XL AR AR Sporadic or AR AR Sporadic AR AD (rarely AR) AR
Mutated gene
PLP1 GJC2 (GJA12) FAM126A Unknown POLR3A ; POLR3B N/A SLC17A5 GJA1 FUCA1
Diagnostic test
Molecular (clinical) Molecular (clinical) Molecular (clinical) MRI Molecular (research and clinical) aCGH Elevated free sialic acid (urine) Molecular (clinical) Molecular (clinical) a-L-fucosidase enzymatic activity molecular (clinical) Molecular (clinical)
Ref.
[75] [45] [8] [69] [4749] [66] [89] [90] [70]
Peripheral neuropathy, central hypomyelination, Waardenburg and Hirschsprung syndrome
AD
SOX10
[59]
aCGH: Array comparative genomic hybridization; AD: Autosomal dominant; AR: Autosomal recessive; N/A: Not applicable; XL: X-linked.
radiological features, and are all caused by recessive mutations in POLR3A and POLR3B[4749]. The first of these disorders to be described was leuko dystrophy with oligodontia, by Atrouni etal. in 2003 [50]. Since then, four other disorders have been described, namely hypomyelination, hypodontia and hypogonadotropic hypogonadism (4Hsyndrome) [51], ataxia, delayed dentition and hypomyelination [52], tremorataxia 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 adolescence [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 demonstrates diffuse hypomyelination, typically associated 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 posterior limb of the internal capsules. Other possible findings on MRI are cerebellar atrophy, white matter atrophy and thinning 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 (chromosome12) [47,49], encoding for the two largest subunits of the PolIII, 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 factor important for neural crest and glia development. 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 clinical spectrum. In fact, they have been found in patients with Waardenburg syndrome type 2, type 4, and peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome and Hirschsprung disease [57]. Classically, the age of onset of SOX10 related disorders is in the first year of life; however, cases have been reported with onset in late infancy. Other than the classic Waardenburg syndrome features (pigmentary abnormalities
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often complete the clinical picture [58]. Other possible phenotypes are Waardenburg syndrome type 2E and Waardenburg syndrome type 4C [57]. Interestingly, Waardenburg syndrome type2E is
and sensorineural deafness), the clinical picture is characterized by developmental delay and hypotonia with or without peripheral neuropathy. Early-onset nystagmus, ataxia and spasticity
Executive summary
Background Leukodystrophies are a group of inherited disorders affecting the cerebral white matter. Leukodystrophies are classified based on their MRI features. Demyelinating leukodystrophies (classic): prominent hyperintense T2 signal and prominent hypointense T1 signal of the affected white matter compared with gray matter structures. 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. Myelination delay: progression of the myelination on a second MRI of the brain performed at least 6 months after the first MRI. Clinical approach 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.
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. 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. 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. 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.
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also characterized by pigmentary abnormalities and sensorineural deafness with or without neurological signs (mental retardation, ataxia and nystagmus) [56]. Diffuse central hypomyelination with features reminiscent of PelizaeusMerzbacher disease characterizes the neuroradiological picture [59]. The presence of hypomyelination and/or demyelination on MRI brain imaging has been described in some Waardenburg syndrome type2E cases [56].
Hypomyelinating leukoencephalopathy affecting early myelinating structures
Review
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 myelination sequence is respected in hypomyelinating leukodystrophies, except in hypomyelinating leukoencephalopathy affecting early myelinating structures where the structures involved are those of early myelination.
Future perspective
A new distinct pattern of hypomyelination has been recently described in four boys [26]. Hypomyelinating leukoencephalopathy affecting early myelinating structures is presumed to be X-linked. All patients presented a specific 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 periventricular 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 presentation is characterized by onset around the age of 620months 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
References
Papers of special note have been highlighted as: n of interest nn of considerable interest
1. 4.
Leukodystrophies 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 features and natural evolution to the understanding 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.
Acknowledgements
G Bernard wishes to thank the Fondation sur les Leucodystrophies, the Fondation Go, the European Leukodystrophy Association and the Montreal Childrens Hospital and McGill University Health Center Research Institutes for financing her research projects on leukodystrophies. She also wishes to thank the Montreal Childrens Hospital Foundation, the MSSA (Medical Staff Service Association), the Montreal Childrens Hospital Associates in Neurology and FRSQ (Fonds de Recherche en Sant du Qubec) for her clinician-scientist salary awards. B Osterman, R La Piana and G Bernard wish to acknowledge the courage of all the affected patients and their families; they are a source of inspiration.
Gieselmann V, Krageloh-Mann I. Metachromatic leukodystrophy an update. Neuropediatrics 41(1), 16 (2010). Moser HW, Mahmood A, Raymond GV. X-linked adrenoleukodystrophy. Nat. Clin. Pract. Neurol. 3(3), 140151 (2007). Inoue K. PLP1-related inherited dysmyelinating disorders: Pelizaeus Merzbacher disease and spastic paraplegia type 2. Neurogenetics 6(1), 116 (2005). Dos Santos MM, Grond-Ginsbach C, Aksay SS etal. Adult-onset autosomal dominant leukodystrophy due to LMNB1 gene duplication. J.Neurol. 259(3), 579581 (2012). Biancheri R, Zara F, Rossi A etal. Hypomyelination and congenital cataract: broadening the clinical phenotype. Arch. Neurol. 68(9), 11911194 (2011).
9.
5.
Kohlschutter A, Eichler F. Childhood leukodystrophies: a clinical perspective. Expert Rev. Neurother. 11(10), 14851496 (2011). myelination in neuroradiology. AJNR Am. J.Neuroradiol. 21(6), 10991109 (2000).
Schiffmann R, van der Knaap MS. The latest on leukodystrophies. Curr. Opin. Neurol. 17(2), 187192 (2004). Schiffmann R, van der Knaap MS. Invited article: an MRI-based approach to the diagnosis of white matter disorders. Neurology 72(8), 750759 (2009). Reference for clinicians and neuroradiologists to orient themselves through white matter diseases using MRI pattern recognition ana lysis. Suzuki K. Globoid cell leukodystrophy (Krabbes disease): update. J.Child Neurol. 18(9), 595603 (2003).
10. Barkovich AJ.Concepts of myelin and
6.
2.
7.
nn
Provides a complete and extended iconographic description of normal myelination throughout the first years of life. A comparison with myelination problems is also given. Pattern recognition in magnetic resonance imaging of white matter disorders in children and young adults. Neuroradiology 33(6), 478493 (1991).
11. van der Knaap MS, Valk J, de NN, Nauta JJ.
3.
8.
Highlights, for the first time, the importance of MRI pattern recognition as
607
Review
CME
presentation of MCT8 mutated male subjects. Ann. Neurol. 65(1), 114118 (2009).
35. Edvardson S, Shaag A, Kolesnikova O etal.
an important tool for diagnosis in white matter diseases.

12. van der Knaap MS, Barth PG, Stroink H
24. Dempsey MA, Dumitrescu AM, Refetoff S.
etal. Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann. Neurol. 37(3), 324334 (1995).
13. van der Knaap MS, Barth PG, Gabreels FJ
MCT8 ( SLC16A2)-Specific Thyroid Hormone Cell Transporter Deficiency. Pagon RA, Bird TD, Dolan CR etal. (Eds). GeneReviews, Seattle, WA, USA (1993).
25. Michelson DJ, Shevell MI, Sherr EH,
Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am. J.Hum. Genet. 81(4), 857862 (2007).
36. La Piana R, Vanderver A, van der Knaap M
etal. A new leukoencephalopathy with vanishing white matter. Neurology 48(4), 845855 (1997).
14. van der Knaap MS, Scheper GC.
Leukoencephalopathy with Brain Stem and Spinal Cord Involvement and Lactate Elevation. Pagon RA, Bird TD, Dolan CR etal. (Eds). GeneReviews, Seattle, WA, USA (1993).
15. Steenweg ME, Ghezzi D, Haack T etal.
Moeschler JB, Gropman AL, Ashwal S. Evidence report: genetic and metabolic testing on children with global developmental delay: report of the quality standards subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 77(17), 16291635 (2011).
n
etal. Adult-onset vanishing white matter disease due to a novel EIF2B3 mutation. Arch. Neurol. 69(6), 765768 (2012).
37. Fogli A, Rodriguez D, Eymard-Pierre E etal.
Ovarian failure related to eukaryotic initiation factor 2B mutations. Am. J.Hum. Genet. 72(6), 15441550 (2003).
38. Bugiani M, Boor I, Powers JM, Scheper GC,
Leukoencephalopathy with thalamus and brainstem involvement and high lactate LTBL caused by EARS2 mutations. Brain 135(Pt 5), 13871394 (2012).
16. Steenweg ME, Vanderver A, Blaser S etal.
Review of the evidence regarding genetic and metabolic investigations in children with developmental delay. Recommendations for future perspectives are also provided. Novel hypomyelinating leukoencephalopathy affecting early myelinating structures. Arch. Neurol. 69(1), 125128 (2012).
van der Knaap MS. Leukoencephalopathy with vanishing white matter: a review. J.Neuropathol. Exp. Neurol. 69(10), 987996 (2010).
39. Lopez-Hernandez T, Ridder MC, Montolio
26. Steenweg ME, Wolf NI, Schieving JH etal.
Magnetic resonance imaging pattern recognition in hypomyelinating disorders. Brain 133(10), 29712982 (2010).
nn
M etal. Mutant glial CAM causes megalencephalic leukoencephalopathy with subcortical cysts, benign familial macrocephaly, and macrocephaly with retardation and autism. Am. J.Hum. Genet. 88(4), 422432 (2011).
40. van der Knaap MS, Lai V, Kohler W etal.
27. Steenweg ME, Vanderver A, Ceulemans B
Comprehensive article on MRI pattern recognition applied to hypomyelinating leukodystrophies. It confirms the usefulness of this tool in undefined leukoencephalopathies. Mitochondrial hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy. Am. J.Hum. Genet. 83(1), 3042 (2008).
etal. Novel infantile-onset leukoencephalopathy with high lactate level and slow improvement. Arch. Neurol. 69(6), 718722 (2012).
28. Steinberg SJ, Moser AB, Raymond GV.
Megalencephalic leukoencephalopathy with cysts without MLC1 defect. Ann. Neurol. 67(6), 834837 (2010).
41. Rademakers R, Baker M, Nicholson AM etal.
17. Magen D, Georgopoulos C, Bross P etal.
X-Linked Adrenoleukodystrophy. Pagon RA, Bird TD, Dolan CR etal. (Eds). GeneReviews, Seattle, WA, USA (1993).
29. van der Knaap MS, Naidu S, Breiter SN etal.
Mutations in the colony stimulating factor 1 receptor (CSF1R ) gene cause hereditary diffuse leukoencephalopathy with spheroids. Nat. Genet. 44(2), 200205 (2012).
42. Van Gerpen JA, Wider C, Broderick DF,
18. Feinstein M, Markus B, Noyman I etal.
Alexander disease: diagnosis with MR imaging. AJNR Am. J.Neuroradiol. 22(3), 541552 (2001).
30. van der Knaap MS, Scheper GC.
PelizaeusMerzbacher-like disease caused by AIMP1/p43 homozygous mutation. Am.J.Hum. Genet. 87(6), 820828 (2010).
19. van der Knaap MS, Wolf NI.
Dickson DW, Brown LA, Wszolek ZK. Insights into the dynamics of hereditary diffuse leukoencephalopathy with axonal spheroids. Neurology 71(12), 925929 (2008).
43. van der Knaap MS, Naidu S, Kleinschmidt-
Hypomyelination versus delayed myelination. Ann. Neurol. 68(1), 115 (2010).

20. Radmanesh A, Zaman T, Ghanaati H,
Megalencephalic Leukoencephalopathy With Subcortical Cysts. Pagon RA, Bird TD, Dolan CR etal. (Eds). GeneReviews, Seattle, WA, USA (1993).
31. Henneke M, Diekmann S, Ohlenbusch A
Demasters BK, Kamphorst W, Weinstein HC. Autosomal dominant diffuse leukoencephalopathy with neuroaxonal spheroids. Neurology 54(2), 463468 (2000).
44. Bugiani M, Al SS, Lamantea E etal.
MolaeiS, Robertson RL, Zamani AA. Methylmalonic acidemia: brain imaging findings in 52 children and a review of the literature. Pediatr. Radiol. 38(10), 10541061 (2008).
21. Koch R, Verma S, Gilles FH. Neuropathology
etal. RNASET2-deficient cystic leukoencephalopathy resembles congenital cytomegalovirus brain infection. Nat. Genet. 41(7), 773775 (2009).
32. van der Knaap MS, Pronk JC, Scheper GC.
GJA12mutations in children with recessive hypomyelinating leukoencephalopathy. Neurology 67(2), 273279 (2006).
45. Uhlenberg B, Schuelke M, Ruschendorf F
Vanishing white matter disease. Lancet Neurol. 5(5), 413423 (2006).

33. Orcesi S, La Piana R, Fazzi E.
of a 4month-old infant born to a woman with phenylketonuria. Dev. Med. Child Neurol. 50(3), 230233 (2008).
22. Segovia KN, McClure M, Moravec M etal.
AicardiGoutieres syndrome. Br. Med. Bull. 89, 183201 (2009).

34. Scheper GC, van der Klok T, van Andel RJ
etal. Mutations in the gene encoding gap junction protein a 12 (connexin 46.6) cause PelizaeusMerzbacher-like disease. Am.J.Hum. Genet. 75(2), 251260 (2004).
46. Orthmann-Murphy JL, Salsano E, Abrams
Arrested oligodendrocyte lineage maturation in chronic perinatal white matter injury. Ann.Neurol. 63(4), 520530 (2008).
23. Vaurs-Barriere C, Deville M, Sarret C etal.
PelizaeusMerzbacher-like disease
etal. Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat. Genet. 39(4), 534539 (2007).
CK etal. Hereditary spastic paraplegia is a novel phenotype for GJA12/GJC2 mutations. Brain 132(Pt 2), 426438 (2009).
47. Saitsu H, Osaka H, Sasaki M etal. Mutations
in POLR3A and POLR3B encoding RNA polymerase III subunits cause an autosomal-
608
CME
recessive hypomyelinating leukoencephalopathy. Am. J.Hum. Genet. 89(5), 644651 (2011).
48. Bernard G, Chouery E, Putorti ML etal.
Review
60. Padiath QS, Saigoh K, Schiffmann R etal.
72. Biancheri R, Rossi A, Zara F, Filocamo M.
Lamin B1 duplications cause autosomal dominant leukodystrophy. Nat. Genet. 38(10), 11141123 (2006).
61. Dotti MT, Rufa A, Federico A.
AIMP1/p43 mutation and PMLD. Am. J.Hum. Genet. 88(3), 391395 (2011).
73. Laugel V. Cockayne Syndrome. Pagon RA,
Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. Am. J.Hum. Genet. 89(3), 415423 (2011).
49. Tetreault M, Choquet K, Orcesi S etal.
Recessive mutations in POLR3B, encoding the second largest subunit of Pol III, cause a rare hypomyelinating leukodystrophy. Am.J.Hum. Genet. 89(5), 652655 (2011).
50. Atrouni S, Daraze A, Tamraz J, Cassia A,
Cerebrotendinous xanthomatosis: heterogeneity of clinical phenotype with evidence of previously undescribed ophthalmological findings. J.Inherit. Metab. Dis. 24(7), 696706 (2001).
62. Duffner PK, Barczykowski A, Jalal K, Yan L,
Bird TD, Dolan CR etal. (Eds). Seattle, WA, USA (1993).

74. Biancheri R, Zara F, Bruno C etal.
Phenotypic characterization of hypomyelination and congenital cataract. Ann. Neurol. 62(2), 121127 (2007).
75. Garbern JY, Hobson GM. PLP1-Related
Caillaud C, Megarbane A. Leukodystrophy associated with oligodontia in a large inbred family: fortuitous association or new entity? Am. J.Med. Genet. A 118A(1), 7681 (2003).
51. Timmons M, Tsokos M, Asab MA etal.
Kay DM, Carter RL. Early infantile Krabbe disease: results of the World-Wide Krabbe Registry. Pediatr. Neurol. 45(3), 141148 (2011).
63. Gorospe JR, Maletkovic J.Alexander disease
Disorders. Pagon RA, Bird TD, Dolan CR etal. (Eds). GeneReviews, Seattle, WA, USA (1993).
76. Hansen JJ, Durr A, Cournu-Rebeix I etal.
Peripheral and central hypomyelination with hypogonadotropic hypogonadism and hypodontia. Neurology 67(11), 20662069 (2006).
52. Wolf NI, Harting I, Boltshauser E etal.
and megalencephalic leukoencephalopathy with subcortical cysts: leukodystrophies arising from astrocyte dysfunction. Ment. Retard. Dev. Disabil. Res. Rev. 12(2), 113122 (2006).
64. Matalon R, Bhatia G. Canavan Disease. Pagon
Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. Am. J.Hum. Genet. 70(5), 13281332 (2002).
77. Baumann N, Turpin JC. Adult-onset
RA, Bird TD, Dolan CR etal. (Eds). GeneReviews, Seattle, WA, USA (1993).
65. Froissart R, Cheillan D, Bouvier R etal.
leukodystrophies. J.Neurol. 247(10), 751759 (2000).

78. Varho TT, Alajoki LE, Posti KM etal.
Leukoencephalopathy with ataxia, hypodontia, and hypomyelination. Neurology 64(8), 14611464 (2005).
53. Bernard G, Thiffault I, Tetreault M etal.
Tremor-ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.310q23.31. Neurogenetics 11(4), 457464 (2010).
54. Bernard G, Vanderver A. Pol III-Related
Clinical, morphological, and molecular aspects of sialic acid storage disease manifesting in utero. J.Med. Genet. 42(11), 829836 (2005).
66. Linnankivi T, Tienari P, Somer M etal. 18q
Phenotypic spectrum of Salla disease, a free sialic acid storage disorder. Pediatr. Neurol. 26(4), 267273 (2002).
79. Schwartz CE, Stevenson RE. The MCT8
deletions: clinical, molecular, and brain MRI findings of 14individuals. Am. J.Med. Genet. A 140(4), 331339 (2006).
67. Loddenkemper T, Grote K, Evers S, Oelerich
thyroid hormone transporter and AllanHerndon-Dudley syndrome. Best Pract. Res. Clin. Endocrinol. Metab. 21(2), 307321 (2007).
80. Wolf NI, Harting I, Innes AM etal. Ataxia,
Leukodystrophies. Pagon RA, Bird TD, Dolan CR etal. (Eds). GeneReviews, Seattle, WA, USA (1993).
55. Orcesi S, Tonduti D, Uggetti C, Larizza D,
M, Stogbauer F. Neurological manifestations of the oculodentodigital dysplasia syndrome. J.Neurol. 249(5), 584595 (2002).
68. van der Knaap MS, Valk J.Magnetic
delayed dentition and hypomyelination: anovel leukoencephalopathy. Neuropediatrics 38(2), 6470 (2007).
81. Sato I, Onuma A, Goto N etal. A case with
Fazzi E, Balottin U. New case of 4H syndrome and a review of the literature. Pediatr. Neurol. 42(5), 359364 (2010).
56. Bondurand N, Dastot-Le MF, Stanchina L
etal. Deletions at the SOX10 gene locus cause Waardenburg syndrome types 2 and 4. Am.J.Hum. Genet. 81(6), 11691185 (2007).
57. Chaoui A, Watanabe Y, Touraine R etal.
Resonance of Myelination and Myelin Disorders (3rd Edition). Heilmann U, MenneckeBhler D (Eds). Springer, Berlin, Germany, 11084 (2005).
nn
central and peripheral hypomyelination with hypogonadotropic hypogonadism and hypodontia (4H syndrome) plus cataract. J.Neurol. Sci. 300(12), 179181 (2011).
82. Phadke M, Lokeshwar MR, Bhutada S etal.
Identification and functional ana lysis of SOX10 missense mutations in different subtypes of Waardenburg syndrome. Hum.Mutat. 32(12), 14361449 (2011).
58. Inoue K, Shilo K, Boerkoel CF etal.
Analyzes and presents the clinical, pathogenetic and neuroradiological aspects of the most important white matter diseases. An extensive introduction on myelin development and on myelin diseases definition is also provided. etal. Hypomyelination with atrophy of the basal ganglia and cerebellum: follow-up and pathology. Neurology 69(2), 166171 (2007).
Kearns sayre syndrome-case report with review of literature. Indian J.Pediatr. 79(5), 650654 (2012).
83. Crow YJ, Leitch A, Hayward BE etal.
69. van der Knaap MS, Linnankivi T, Paetau A
Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutieres syndrome and mimic congenital viral brain infection. Nat. Genet. 38(8), 910916 (2006).
84. Crow YJ, Hayward BE, Parmar R etal.
Congenital hypomyelinating neuropathy, central dysmyelination, and WaardenburgHirschsprung disease: phenotypes linked by SOX10 mutation. Ann. Neurol. 52(6), 836842 (2002).
59. Inoue K, Tanabe Y, Lupski JR. Myelin
70. Willems PJ, Seo HC, Coucke P, Tonlorenzi
deficiencies in both the central and the peripheral nervous systems associated with a SOX10 mutation. Ann. Neurol 46(3), 313318 (1999).
R, OBrien JS. Spectrum of mutations in fucosidosis. Eur. J.Hum. Genet. 7(1), 6067 (1999).
71. Wertelecki W, Gerald PS. Clinical and
Mutations in the gene encoding the 35 DNA exonuclease TREX1 cause Aicardi Goutieres syndrome at the AGS1 locus. Nat.Genet. 38(8), 917920 (2006).
85. Gallus GN, Dotti MT, Federico A. Clinical
chromosomal studies of the 18q- syndrome. J.Pediatr. 78(1), 4452 (1971).
and molecular diagnosis of cerebrotendinous xanthomatosis with a review of the mutations in the CYP27A1 gene. Neurol. Sci. 27(2), 143149 (2006).
609
Review
CME
detected by ana lysis of urinary sphingolipids and carrying novel PSAP gene mutations. Am.J.Med. Genet. A 149A(4), 613621 (2009).
89. Aula N, Salomaki P, Timonen R etal. The
86. Spiegel R, Bach G, Sury V etal. A mutation
in the saposin A coding region of the prosaposin gene in an infant presenting as Krabbe disease: first report of saposin A deficiency in humans. Mol. Genet. Metab. 84(2), 160166 (2005).
87. Kuchar L, Ledvinova J, Hrebicek M etal.
88. Annunziata I, Bouche V, Lombardi A,
spectrum of SLC17A5 -gene mutations resulting in free sialic acid-storage diseases indicates some genotypephenotype correlation. Am. J.Hum. Genet. 67(4), 832840 (2000).
90. Paznekas WA, Boyadjiev SA, Shapiro RE
Prosaposin deficiency and saposin B deficiency (activator-deficient metachromatic leukodystrophy): report on two patients
Settembre C, Ballabio A. Multiple sulfatase deficiency is due to hypomorphic mutations of the SUMF1 gene. Hum. Mutat. 28(9), 928 (2007).
etal. Connexin 43 (GJA1) mutations cause the pleiotropic phenotype of oculodentodigital dysplasia. Am. J.Hum. Genet. 72(2), 408418 (2003).
610
CME
Review

To obtain credit, you should first read the journal article. After reading the article, you should be able to answer the following, related, multiple-choice questions. To complete the questions (with a minimum 70% passing score) and earn continuing medical education (CME) credit, please go to www.medscape.org/journal/fnl. Credit cannot be obtained for tests completed on paper, although you may use the worksheet below to keep a record of your answers. You must be a registered user on Medscape.org. If you are not registered on Medscape.org, please click on the New Users: Free Registration link on the left hand side of the website to register. Only one answer is correct for each question. Once you successfully answer all post-test questions you will be able to view and/or print your certificate. For questions regarding the content of this activity, contact the accredited provider, CME@medscape.net. For technical assistance, contact CME@webmd.net. American Medical Associations Physicians Recognition Award (AMA PR A) credits are accepted in the US as evidence of participation in CME activities. 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 PR A credit may be acceptable as evidence of participation in CME activities. If you are not licensed in the US, please complete the questions online, print the AMA PRA CME credit certificate and present it to your national medical association for review.
Activity evaluation: where 1 is strongly disagree and 5 is strongly agree.

1
The activity supported the learning objectives. The material was organized clearly for learning to occur. The content learned from this activity will impact my practice. The activity was presented objectively and free of commercial bias.
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
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 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
611
Review
CME
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 C

Coarsening of facial features is associated with peripheral demyelinating neuropathy, central dysmyelination, Waardenburg syndrome, and Hirschsprung disease (PCWH) Peripheral neuropathy is inconsistent with hypomyelination with congenital cataracts (HCC)
D Dental abnormalities are associated with Pol III-related leukodystrophies
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 C

No leukodystrophies have an autosomal dominant pattern of inheritance Krabbes has an autosomal recessive pattern of inheritance
D Pol III-related leukodystrophies have an X-linked pattern of inheritance
612

Future Neurol. (2012) 7 (5), 595-612

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Future Neurol. (2012) 7 (5), 595-612

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Advances in the diagnosis of leukodystrophies

Bradley Osterman1, Roberta La Piana2 & Genevive Bernard*1

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

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