Molecular Genetics and Metabolism 114 (2015) 491–493
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Commentary
Leukodystrophy or genetic leukoencephalopathy? Nature does not make leaps Ettore Salsano ⁎ Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico “Carlo Besta,” via Celoria 11, Milano 20133, Italy
The importance of classification was first recognized by Aristotle of Stagira, the great Greek philosopher who proposed rigorous classifications in literally every area of human knowledge. Classifications are indispensable for language and convenient for our ordinary mental operations [1], but—as Aristotle also suggested—every classification presents pitfalls and limitations. Nature does not make leaps (natura non facit saltus), and it does not conform to rigorous divisions. Pragmatically speaking, however, one classification may be, if not more correct, at least more useful than another one. In this issue of Molecular Genetics and Metabolism, Vanderver et al. [2] first address an important and controversial topic in neurology, i.e., the definition of the term “leukodystrophy,” and make a conceptual distinction between “leukodystrophies” and “genetic leukoencephalopathies.” Subsequently, they propose a classification of all the inherited white matter (WM) diseases under one of these two groups. This esoteric work—as defined by the authors—was largely performed for epidemiological purposes, including the assessment of the frequency and burden of these diseases as a group, but it also led to a very comprehensive list of inherited disorders characterized by brain WM involvement. What is a “leukodystrophy”? It is true that this question has been rarely discussed in a scholarly way and an approved definition did not exist [2], but this is probably because the answer was assumed to be self-evident. The term “leukodystrophy,” introduced by Bielschowski and Henneberg in 1928 [3], is in its essence a neuropathological term, which reflects the presence of abnormalities in central nervous system (CNS) glial cell types as the primary or fundamental pathological abnormality. Therefore, we should use the term “leukodystrophy” only when the pathology of the disease is (well-)known, and we could admit that subjects with late onset Alexander Disease (AxD), SPG2, or adrenomyeloneuropathy (AMN) meet the criterion for being classified as having a “leukodystrophy.” The pathology of late onset AxD shows the abundant presence of Rosenthal fibers, i.e., the astrocytic inclusions containing a mixture of glial fibrillary acidic protein, ubiquitin and heat shock proteins, which are the key diagnostic feature of the neuropathology in AxD [4]. The pathology of SPG2, which is caused by mutations in the PLP1 gene encoding for the predominant CNS myelin protein, shows diffuse hypomyelination/dysmyelination with some WM tracts preferentially affected [5]. The pathology in AMN, which is ⁎ Tel.: +39 2 2394 2388; fax: +39 2 2394 2293. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.ymgme.2015.02.005 1096-7192/© 2015 Elsevier Inc. All rights reserved.
caused by mutations in the ABCD1 gene that is variably expressed in glial cells, but not in neurons [6], shows microscopic dysmyelinative lesions of the cerebral WM [7]. In contrast, as also discussed by Vanderver et al. [2], it is questionable to consider the disease hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) as “leukodystrophy,” given that no autopsy study is available, lesions in the basal ganglia and cerebellum are a characteristic imaging finding, and the disease-causing gene TUBB4A is expressed in neurons. Nature, however, does make leaps, and the individual contributions by neurons and glial cells to the pathology over time can be hard to be determined, thus complicating the matter of nomenclature. In particular, given the intimate connection between glial cells and neurons/axons, it can be difficult to distinguish between a process that primarily afflicts the myelin (leukodystrophy sensu stricto) and a process that primarily afflicts the neurons/axons, especially when the physiopathology of the disorder is unclear, and the pathological examination is performed at the advanced, “end-life” stage of the disease [7,8]. In the 1980s, with the advent of neuroimaging techniques, and in particular brain MRI, it became rapidly evident that the WM abnormalities described in “leukodystrophies” could be detected in vivo, and the diagnosis of these diseases was dramatically improved. It became also evident, however, that these techniques were unable to distinguish inherited diseases with WM abnormalities caused by primary myelin dysfunction from those caused by primary dysfunction in non-glial cells. Additionally, the distinction between hereditary and acquired forms of WM abnormalities may remain difficult, at least in sporadic adult cases. As a result, the generic term “leukoencephalopathy” probably became more and more popular, unlike the term “leukodystrophy” (Fig. 1). However, when should we use the term “leukoencephalopathy”? To classify a disease as “leukoencephalopathy,” I believe that it should have WM abnormalities on neuroimaging so prominent or characteristic to be considered as a fundamental hint for the diagnosis. For instance, Vanderver et al. [2] have classified diseases like NOTCH3-related cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) or COL4A1-related brain small vessel disease as “genetic leukoencephalopathies,” and not as “leukodystrophies.” This is an excellent point, as in these inherited diseases the primary dysfunction is not in glial cells, but in the brain vessels, and extensive WM abnormalities are by far the most prominent feature on neuroimaging. In contrast, it is questionable whether diseases like mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), mitochondrial DNA depletion syndromes, SPG11, SPG15, Wilson's
492
E. Salsano / Molecular Genetics and Metabolism 114 (2015) 491–493
Fig. 1. Number of publications in PubMed per year by using the term “leukodystrophy” [All Fields] (dark gray bars) or “leukoencephalopathy AND (genetic OR hereditary OR inherited)” [All Fields] (light gray bars). The search was limited to articles regarding humans and published between 1967 and 2014. The graph shows that the term “leukodystrophy” has been used in a relatively constant fashion over time, whereas the term “leukoencephalopathy” has been used in a more and more frequent fashion from the 1980s onwards to designate inherited white matter diseases of the brain. This is probably because the term “leukodystrophy” is mainly a pathological term, whereas the term “leukoencephalopathy” relies on neuroimaging techniques which developed since the mid-1980s.
disease and Niemann–Pick type C may be considered as “genetic leukoencephalopathies.” A variety of inherited diseases present WM abnormalities on neuroimaging, but the relevance of these abnormalities to their diagnosis can be negligible, or at most they can be regarded as a feature among others or even a confounding diagnostic factor [9–11]. Does a “leukocentric” classification of the inherited diseases make sense from a practical and clinical perspective in the cases in which WM abnormalities on neuroimaging does not give the most or at least an important diagnostic hint? Analogously, the classification of some inherited white matter diseases as “leukodystrophy” or “genetic leukoencephalopathy” seems to be arbitrary. Unlike other cerebral hereditary microangiopathies with demyelination like CADASIL, the Aicardi–Goutières syndrome (AGS) has been classified as “leukodystrophy,” despite the vascular pathology, the presence of wedge-shaped micro-infarctions in the cerebral and cerebellar cortices, and the widespread but inhomogeneous aspect of the demyelinative process suggest hypoxia/ischemia from vascular insufficiency as pathological mechanism [12]. Moreover, AGS can be caused by mutations in TREX1 gene, which is associated with a form of hereditary endotheliopathy (retinal vasculopathy with cerebral leukodystrophy [RVCL]), and it is clinically characterized by microcephaly, psychomotor retardation and seizures, which are clinical features that suggest a neuronal disorder, as stated by Vanderver et al. [2] for 3-phosphoglycerate dehydrogenase deficiency. According to Vanderver et al. [2], CNS diseases in which neuropathology shows primary involvement of grey matter structures and inborn errors of metabolism in which non-neurological manifestations predominate should not be characterized as “leukodystrophies.” However, cerebrotendineous xanthomatosis (CTX), which is a cholesterolrelated disorder, has been classified as “leukodystrophy,” despite the involvement of several grey matter nuclei, including the globus pallidum and dentate nucleus, is remarkable, and it has been suggested even that the disease process initially involves particularly grey matter areas within the CNS [8]. Moreover, the disease-causing gene CYP27A1 is widely expressed in human tissues, and there are key non-neurological manifestations, including bilateral cataracts, diarrhea, and xanthomas. Unlike CTX, SPG35, also known as dysmyelinating leukodystrophy and spastic paraparesis with or without dystonia or fatty acid hydroxylaseassociated neurodegeneration (FAHN), has been classified as “genetic leukoencephalopathy,” despite it is a glycosphyngolipid-related disorder,
the disease-causing gene FA2H (Fatty Acid 2-Hydroxylase) is primarily expressed in myelin-forming oligodendrocytes and Schwann cells, WM defects are prominent alterations, and the disease has no extraneurological manifestation [13,14]. Of note, FA2H mutations have been associated with a form of neurodegeneration with brain iron accumulation (NBIA) because brain MRI can show bilateral T2 hypointensities in the globi pallidi consistent with iron deposition [14]. However, no autopsy study is available, there is no evidence of iron deposition in the basal ganglia of a mouse model of FA2H deficiency [15], and T2-weighted hypointensities might be from secondary hemosiderin deposition, like in the dentate nuclei of the subjects with CTX, which is not considered as a form of NBIA [8]. This is to stress that caution is needed before using pathological labels when the pathology is unknown. L-2-hydroxyglutaric aciduria (L2HGA) has been classified as “genetic leukoencephalopathy” because it is caused by a toxic substance—the L-2-hydroxyglutarate—which is generated in a systemic fashion [2]. However, L2HGA affects exclusively the CNS, post-mortem neuropathological findings show predominant, constant subcortical white matter involvement with intramyelinic vacuolation [16], and the toxic substance is generated in a systemic way just like the very long chain fatty acids in adrenoleukodystrophy. The Nasu–Hakola disease (NHD), which is caused by TREM2 or TYROBP mutations, has been classified as “genetic leukoencephalopathy,” but the non-neurological manifestations, such as pathological fractures and bone cysts, can be absent or under recognized [17], and its neuropathological findings resemble those of hereditary diffuse leukoencephalopathy with spheroids (HDLS), which is caused by CSF1R mutations and has been classified as “leukodystrophy.” The proteins encoded by TREM2 and CSF1R work with the transmembrane adaptor protein encoded by TYROBP and, in the brain, they all are expressed exclusively in microglia. As a result, the pathogenesis of both NHD and HDLS is a microglial dysfunction, and NHD and HDLS are considered as microgliopathies, i.e., primary microglial disorders of the CNS [18]. Finally, in the last years, with the diffusion of next-generation sequencing (NGS), there is more and more room to find novel disease-causing genes and novel phenotypes associated with known disease-causing genes, even in single sporadic cases. Many disorders caused by mutations in novel disease-causing genes, however, are so rare that no pathological and functional study is carried out to define their pathological and physiopathological bases. As
E. Salsano / Molecular Genetics and Metabolism 114 (2015) 491–493
a consequence, if these new entities have WM abnormalities, their classification as “leukodystrophy” remains arbitrary and can be erroneous. Despite the limits and dangers of differentiating inherited diseases of the WM of the brain in “leukodystrophy” and “genetic leukoencephalopathy,” the presence of WM abnormalities on neuroimaging remains an acceptable criterion for classifying inherited disorders when these abnormalities give important diagnostic hints. As stated by Vanderver et al. [2], the inherited disorders of the WM of the brain have “highly variable clinical manifestations,” and their diagnosis cannot be based on clinical assessment. Therefore, in the nosology of neurological diseases, the imaging-centric term “leukoencephalopathy” might be systematically used for a re-classification of the inherited diseases of the WM of the brain, such as the clinical-centric terms SPastic Gait (SPG), SpinoCerebellar Ataxia (SCA), hereditary motor sensory neuropathy (HMSN), dystonia (DYT), and so on, have been used for the (re-)classification of a variety of inherited neurological disorders. Alternatively, the further improvement of NGS may encourage a gene-centric nomenclature, which probably copes better with the fact that mutations in the same genes can be associated with a broad range of clinical and neuroimaging phenotypes. Moreover, it may cope better with the fact that in the next future clinicians dealing with inherited neurological disorders may be required to establish which of the (many) mutant genes uncritically identified by NGS is responsible for the phenotype of the patients, rather than to critically choose which gene to analyze on the basis of their clinical manifestations. Of note, a gene-centric nomenclature is similar to the biochemical-centric nomenclature used for naming the many inborn errors of metabolism, including those classified as “genetic leukoencephalopathies” by Vanderver et al. [2]. For example, it is conceptually similar to designate a disease as phosphoglycerate dehydrogenase (PHGDH) deficiency or as PHGDH-related disorder. The problem of nomenclature seems to be open, with clinical, neuroimaging and genetic categories which may diverge one from the other. For our ordinary mental operations, what is more convenient, if not more correct, of the following: to talk about the Pelizaeus–Merzbacher disease and SPG2, hypomyelinating leukodystrophy 1 (HLD1), or PLP1-related disorders [19]; to talk about Pelizaeus–Merzbacher-like disease 1 and SPG44, hypomyelinating leukodystrophy 2 (HLD2), or GJC2-related disorders [20]; to talk about hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), hypomyelinating leukodystrophy 6 (HLD6), autosomal dominant torsion dystonia-4 (DYT4), or TUBB4A-related disorders [21,22]; to talk about leukoencephalopathy with vanishing white matter or EIF2B- related disorders [23]; or to talk about adrenoleukodystrophy, adrenomyeloneuropathy, and adrenal insufficiency-only phenotype or ABCD1-related disorders? Are SPG11 and SPG15 to be considered as “genetic leukoencephalopathies” or are adreno(leuko)myeloneuropathy and adult-onset Krabbe disease to be considered as SPG? Are the inborn errors of metabolism (with or without white matter abnormalities) to be named on the basis of their metabolic defect, or is time to re-classify these disorders in a clinicalfriendly manner?
Dedication This commentary is dedicated to the memory of Mario Savoiardo. He was a great neuroradiologist, a great mentor and a dear friend.
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Iwaki, An autopsy case of adult-onset hereditary spastic paraplegia type 2 with a novel mutation in exon 7 of the proteolipid protein 1 gene, Acta Neuropathol. 122 (2011) 775–781. [6] F. Fouquet, J.M. Zhou, E. Ralston, K. Murray, F. Troalen, E. Magal, O. Robain, M. Dubois-Dalcq, P. Aubourg, Expression of the adrenoleukodystrophy protein in the human and mouse central nervous system, Neurobiol. Dis. 3 (1997) 271–285. [7] J.M. Powers, D.P. De Ciero, M. Ito, A.B. Moser, H.W. Moser, Adrenomyeloneuropathy: a neuropathologic review featuring its non inflammatory myelopathy, J. Neuropathol. Exp. Neurol. 59 (2000) 89–102. [8] F. Barkhof, A. Verrips, P. Wesseling, M.S. van Der Knaap, B.G. van Engelen, F.J. Gabreëls, A. Keyser, R.A. Wevers, J. Valk, Cerebrotendinous xanthomatosis: the spectrum of imaging findings and the correlation with neuropathologic findings, Radiology 217 (2000) 869–876. [9] A. Charil, T.A. Yousry, M. Rovaris, F. Barkhof, N. De Stefano, F. Fazekas, D.H. Miller, X. Montalban, J.H. Simon, C. Polman, M. Filippi, MRI and the diagnosis of multiple sclerosis: expanding the concept of “no better explanation”, Lancet Neurol. 5 (2006) 841–852. [10] S. O'Riordan, P. McMonagle, J.C. Janssen, N.C. Fox, M. Farrell, J. Collinge, M.N. Rossor, M. Hutchinson, Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-matter abnormalities, Neurology 59 (2002) 1108–1110. [11] Y. Karmon, A. Kurzweil, E. Lindzen, T. Holmlund, B. Weinstock-Guttman, Gerstmann– Sträussler–Scheinker syndrome masquerading as multiple sclerosis, J. Neurol. Sci. 309 (2011) 55–57. [12] P.G. Barth, A. Walter, I. van Gelderen, Aicardi–Goutières syndrome: a genetic microangiopathy? Acta Neuropathol. 98 (1999) 212–216. [13] R. Chrast, G. Saher, K.A. Nave, M.H. Verheijen, Lipid metabolism in myelinating glial cells: lessons from human inherited disorders and mouse models, J. Lipid Res. 52 (2011) 419–434. [14] C. Colombelli, M. Aoun, V. Tiranti, Defective lipid metabolism in neurodegeneration with brain iron accumulation (NBIA) syndromes: not only a matter of iron, J. Inherit. Metab. Dis. 38 (2015) 123–136. [15] K.A. Potter, M.J. Kern, G. Fullbright, J. Bielawski, S.S. Scherer, S.W. Yum, J.J. Li, H. Cheng, X. Han, J.K. Venkata, P.A. Khan, B. Rohrer, H. Hama, Central nervous system dysfunction in a mouse model of FA2H deficiency, Glia 59 (2011) 1009–1021. [16] M. Seijo-Martínez, C. Navarro, M. Castro del Río, O. Vila, M. Puig, A. Ribes, M. Butron, L-2- hydroxyglutaric aciduria: clinical, neuroimaging, and neuropathological findings, Arch. Neurol. 62 (2005) 666–670. [17] R.J. Guerreiro, E. Lohmann, J.M. Brás, J.R. Gibbs, J.D. Rohrer, N. Gurunlian, B. Dursun, B. Bilgic, H. Hanagasi, H. Gurvit, M. Emre, A. Singleton, J. Hardy, Using exome sequencing to reveal mutations in TREM2 presenting as a frontotemporal dementialike syndrome without bone involvement, JAMA Neurol. 70 (2011) 78–84. [18] M.M. Bianchin, K.C. Martin, A.C. de Souza, M.A. de Oliveira, C.R. Rieder, Nasu–Hakola disease and primary microglial dysfunction, Nat. Rev. Neurol. 6 (2010) 523 (2 p following). [19] K. Inoue, PLP1-related inherited dysmyelinating disorders: Pelizaeus–Merzbacher disease and spastic paraplegia type 2, Neurogenetics 6 (2005) 1–16. [20] C.K. Abrams, S.S. Scherer, R. Flores-Obando, M.M. Freidin, S. Wong, E. Lamantea, L. Farina, V. Scaioli, D. Pareyson, E. Salsano, A new mutation in GJC2 associated with subclinical leukodystrophy, J. Neurol. 261 (2014) 1929–1938. [21] K. Lohmann, C. Klein, The many faces of TUBB4A mutations, Neurogenetics 15 (2014) 81–82. [22] S. Miyatake, H. Osaka, M. Shiina, M. Sasaki, J. Takanashi, K. Haginoya, T. Wada, M. Morimoto, N. Ando, Y. Ikuta, M. Nakashima, Y. Tsurusaki, N. Miyake, K. Ogata, N. Matsumoto, H. Saitsu, Expanding the phenotypic spectrum of TUBB4A-associated hypomyelinating leukoencephalopathies, Neurology 82 (2014) 2230–2237. [23] P. Labauge, L. Horzinski, X. Ayrignac, P. Blanc, S. Vukusic, D. Rodriguez, F. Mauguiere, L. Peter, C. Goizet, F. Bouhour, C. Denier, C. Confavreux, M. Obadia, F. Blanc, J. de Sèze, A. Fogli, O. Boespflug-Tanguy, Natural history of adult-onset eIF2B-related disorders: a multi-centric survey of 16 cases, Brain 132 (2009) 2161–2169.
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism journal homepage: www.elsevier.com/locate/ymgme
Commentary
Leukodystrophy or genetic leukoencephalopathy? Nature does not make leaps Ettore Salsano ⁎ Department of Clinical Neurosciences, Fondazione IRCCS Istituto Neurologico “Carlo Besta,” via Celoria 11, Milano 20133, Italy
The importance of classification was first recognized by Aristotle of Stagira, the great Greek philosopher who proposed rigorous classifications in literally every area of human knowledge. Classifications are indispensable for language and convenient for our ordinary mental operations [1], but—as Aristotle also suggested—every classification presents pitfalls and limitations. Nature does not make leaps (natura non facit saltus), and it does not conform to rigorous divisions. Pragmatically speaking, however, one classification may be, if not more correct, at least more useful than another one. In this issue of Molecular Genetics and Metabolism, Vanderver et al. [2] first address an important and controversial topic in neurology, i.e., the definition of the term “leukodystrophy,” and make a conceptual distinction between “leukodystrophies” and “genetic leukoencephalopathies.” Subsequently, they propose a classification of all the inherited white matter (WM) diseases under one of these two groups. This esoteric work—as defined by the authors—was largely performed for epidemiological purposes, including the assessment of the frequency and burden of these diseases as a group, but it also led to a very comprehensive list of inherited disorders characterized by brain WM involvement. What is a “leukodystrophy”? It is true that this question has been rarely discussed in a scholarly way and an approved definition did not exist [2], but this is probably because the answer was assumed to be self-evident. The term “leukodystrophy,” introduced by Bielschowski and Henneberg in 1928 [3], is in its essence a neuropathological term, which reflects the presence of abnormalities in central nervous system (CNS) glial cell types as the primary or fundamental pathological abnormality. Therefore, we should use the term “leukodystrophy” only when the pathology of the disease is (well-)known, and we could admit that subjects with late onset Alexander Disease (AxD), SPG2, or adrenomyeloneuropathy (AMN) meet the criterion for being classified as having a “leukodystrophy.” The pathology of late onset AxD shows the abundant presence of Rosenthal fibers, i.e., the astrocytic inclusions containing a mixture of glial fibrillary acidic protein, ubiquitin and heat shock proteins, which are the key diagnostic feature of the neuropathology in AxD [4]. The pathology of SPG2, which is caused by mutations in the PLP1 gene encoding for the predominant CNS myelin protein, shows diffuse hypomyelination/dysmyelination with some WM tracts preferentially affected [5]. The pathology in AMN, which is ⁎ Tel.: +39 2 2394 2388; fax: +39 2 2394 2293. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.ymgme.2015.02.005 1096-7192/© 2015 Elsevier Inc. All rights reserved.
caused by mutations in the ABCD1 gene that is variably expressed in glial cells, but not in neurons [6], shows microscopic dysmyelinative lesions of the cerebral WM [7]. In contrast, as also discussed by Vanderver et al. [2], it is questionable to consider the disease hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) as “leukodystrophy,” given that no autopsy study is available, lesions in the basal ganglia and cerebellum are a characteristic imaging finding, and the disease-causing gene TUBB4A is expressed in neurons. Nature, however, does make leaps, and the individual contributions by neurons and glial cells to the pathology over time can be hard to be determined, thus complicating the matter of nomenclature. In particular, given the intimate connection between glial cells and neurons/axons, it can be difficult to distinguish between a process that primarily afflicts the myelin (leukodystrophy sensu stricto) and a process that primarily afflicts the neurons/axons, especially when the physiopathology of the disorder is unclear, and the pathological examination is performed at the advanced, “end-life” stage of the disease [7,8]. In the 1980s, with the advent of neuroimaging techniques, and in particular brain MRI, it became rapidly evident that the WM abnormalities described in “leukodystrophies” could be detected in vivo, and the diagnosis of these diseases was dramatically improved. It became also evident, however, that these techniques were unable to distinguish inherited diseases with WM abnormalities caused by primary myelin dysfunction from those caused by primary dysfunction in non-glial cells. Additionally, the distinction between hereditary and acquired forms of WM abnormalities may remain difficult, at least in sporadic adult cases. As a result, the generic term “leukoencephalopathy” probably became more and more popular, unlike the term “leukodystrophy” (Fig. 1). However, when should we use the term “leukoencephalopathy”? To classify a disease as “leukoencephalopathy,” I believe that it should have WM abnormalities on neuroimaging so prominent or characteristic to be considered as a fundamental hint for the diagnosis. For instance, Vanderver et al. [2] have classified diseases like NOTCH3-related cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) or COL4A1-related brain small vessel disease as “genetic leukoencephalopathies,” and not as “leukodystrophies.” This is an excellent point, as in these inherited diseases the primary dysfunction is not in glial cells, but in the brain vessels, and extensive WM abnormalities are by far the most prominent feature on neuroimaging. In contrast, it is questionable whether diseases like mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), mitochondrial DNA depletion syndromes, SPG11, SPG15, Wilson's
492
E. Salsano / Molecular Genetics and Metabolism 114 (2015) 491–493
Fig. 1. Number of publications in PubMed per year by using the term “leukodystrophy” [All Fields] (dark gray bars) or “leukoencephalopathy AND (genetic OR hereditary OR inherited)” [All Fields] (light gray bars). The search was limited to articles regarding humans and published between 1967 and 2014. The graph shows that the term “leukodystrophy” has been used in a relatively constant fashion over time, whereas the term “leukoencephalopathy” has been used in a more and more frequent fashion from the 1980s onwards to designate inherited white matter diseases of the brain. This is probably because the term “leukodystrophy” is mainly a pathological term, whereas the term “leukoencephalopathy” relies on neuroimaging techniques which developed since the mid-1980s.
disease and Niemann–Pick type C may be considered as “genetic leukoencephalopathies.” A variety of inherited diseases present WM abnormalities on neuroimaging, but the relevance of these abnormalities to their diagnosis can be negligible, or at most they can be regarded as a feature among others or even a confounding diagnostic factor [9–11]. Does a “leukocentric” classification of the inherited diseases make sense from a practical and clinical perspective in the cases in which WM abnormalities on neuroimaging does not give the most or at least an important diagnostic hint? Analogously, the classification of some inherited white matter diseases as “leukodystrophy” or “genetic leukoencephalopathy” seems to be arbitrary. Unlike other cerebral hereditary microangiopathies with demyelination like CADASIL, the Aicardi–Goutières syndrome (AGS) has been classified as “leukodystrophy,” despite the vascular pathology, the presence of wedge-shaped micro-infarctions in the cerebral and cerebellar cortices, and the widespread but inhomogeneous aspect of the demyelinative process suggest hypoxia/ischemia from vascular insufficiency as pathological mechanism [12]. Moreover, AGS can be caused by mutations in TREX1 gene, which is associated with a form of hereditary endotheliopathy (retinal vasculopathy with cerebral leukodystrophy [RVCL]), and it is clinically characterized by microcephaly, psychomotor retardation and seizures, which are clinical features that suggest a neuronal disorder, as stated by Vanderver et al. [2] for 3-phosphoglycerate dehydrogenase deficiency. According to Vanderver et al. [2], CNS diseases in which neuropathology shows primary involvement of grey matter structures and inborn errors of metabolism in which non-neurological manifestations predominate should not be characterized as “leukodystrophies.” However, cerebrotendineous xanthomatosis (CTX), which is a cholesterolrelated disorder, has been classified as “leukodystrophy,” despite the involvement of several grey matter nuclei, including the globus pallidum and dentate nucleus, is remarkable, and it has been suggested even that the disease process initially involves particularly grey matter areas within the CNS [8]. Moreover, the disease-causing gene CYP27A1 is widely expressed in human tissues, and there are key non-neurological manifestations, including bilateral cataracts, diarrhea, and xanthomas. Unlike CTX, SPG35, also known as dysmyelinating leukodystrophy and spastic paraparesis with or without dystonia or fatty acid hydroxylaseassociated neurodegeneration (FAHN), has been classified as “genetic leukoencephalopathy,” despite it is a glycosphyngolipid-related disorder,
the disease-causing gene FA2H (Fatty Acid 2-Hydroxylase) is primarily expressed in myelin-forming oligodendrocytes and Schwann cells, WM defects are prominent alterations, and the disease has no extraneurological manifestation [13,14]. Of note, FA2H mutations have been associated with a form of neurodegeneration with brain iron accumulation (NBIA) because brain MRI can show bilateral T2 hypointensities in the globi pallidi consistent with iron deposition [14]. However, no autopsy study is available, there is no evidence of iron deposition in the basal ganglia of a mouse model of FA2H deficiency [15], and T2-weighted hypointensities might be from secondary hemosiderin deposition, like in the dentate nuclei of the subjects with CTX, which is not considered as a form of NBIA [8]. This is to stress that caution is needed before using pathological labels when the pathology is unknown. L-2-hydroxyglutaric aciduria (L2HGA) has been classified as “genetic leukoencephalopathy” because it is caused by a toxic substance—the L-2-hydroxyglutarate—which is generated in a systemic fashion [2]. However, L2HGA affects exclusively the CNS, post-mortem neuropathological findings show predominant, constant subcortical white matter involvement with intramyelinic vacuolation [16], and the toxic substance is generated in a systemic way just like the very long chain fatty acids in adrenoleukodystrophy. The Nasu–Hakola disease (NHD), which is caused by TREM2 or TYROBP mutations, has been classified as “genetic leukoencephalopathy,” but the non-neurological manifestations, such as pathological fractures and bone cysts, can be absent or under recognized [17], and its neuropathological findings resemble those of hereditary diffuse leukoencephalopathy with spheroids (HDLS), which is caused by CSF1R mutations and has been classified as “leukodystrophy.” The proteins encoded by TREM2 and CSF1R work with the transmembrane adaptor protein encoded by TYROBP and, in the brain, they all are expressed exclusively in microglia. As a result, the pathogenesis of both NHD and HDLS is a microglial dysfunction, and NHD and HDLS are considered as microgliopathies, i.e., primary microglial disorders of the CNS [18]. Finally, in the last years, with the diffusion of next-generation sequencing (NGS), there is more and more room to find novel disease-causing genes and novel phenotypes associated with known disease-causing genes, even in single sporadic cases. Many disorders caused by mutations in novel disease-causing genes, however, are so rare that no pathological and functional study is carried out to define their pathological and physiopathological bases. As
E. Salsano / Molecular Genetics and Metabolism 114 (2015) 491–493
a consequence, if these new entities have WM abnormalities, their classification as “leukodystrophy” remains arbitrary and can be erroneous. Despite the limits and dangers of differentiating inherited diseases of the WM of the brain in “leukodystrophy” and “genetic leukoencephalopathy,” the presence of WM abnormalities on neuroimaging remains an acceptable criterion for classifying inherited disorders when these abnormalities give important diagnostic hints. As stated by Vanderver et al. [2], the inherited disorders of the WM of the brain have “highly variable clinical manifestations,” and their diagnosis cannot be based on clinical assessment. Therefore, in the nosology of neurological diseases, the imaging-centric term “leukoencephalopathy” might be systematically used for a re-classification of the inherited diseases of the WM of the brain, such as the clinical-centric terms SPastic Gait (SPG), SpinoCerebellar Ataxia (SCA), hereditary motor sensory neuropathy (HMSN), dystonia (DYT), and so on, have been used for the (re-)classification of a variety of inherited neurological disorders. Alternatively, the further improvement of NGS may encourage a gene-centric nomenclature, which probably copes better with the fact that mutations in the same genes can be associated with a broad range of clinical and neuroimaging phenotypes. Moreover, it may cope better with the fact that in the next future clinicians dealing with inherited neurological disorders may be required to establish which of the (many) mutant genes uncritically identified by NGS is responsible for the phenotype of the patients, rather than to critically choose which gene to analyze on the basis of their clinical manifestations. Of note, a gene-centric nomenclature is similar to the biochemical-centric nomenclature used for naming the many inborn errors of metabolism, including those classified as “genetic leukoencephalopathies” by Vanderver et al. [2]. For example, it is conceptually similar to designate a disease as phosphoglycerate dehydrogenase (PHGDH) deficiency or as PHGDH-related disorder. The problem of nomenclature seems to be open, with clinical, neuroimaging and genetic categories which may diverge one from the other. For our ordinary mental operations, what is more convenient, if not more correct, of the following: to talk about the Pelizaeus–Merzbacher disease and SPG2, hypomyelinating leukodystrophy 1 (HLD1), or PLP1-related disorders [19]; to talk about Pelizaeus–Merzbacher-like disease 1 and SPG44, hypomyelinating leukodystrophy 2 (HLD2), or GJC2-related disorders [20]; to talk about hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC), hypomyelinating leukodystrophy 6 (HLD6), autosomal dominant torsion dystonia-4 (DYT4), or TUBB4A-related disorders [21,22]; to talk about leukoencephalopathy with vanishing white matter or EIF2B- related disorders [23]; or to talk about adrenoleukodystrophy, adrenomyeloneuropathy, and adrenal insufficiency-only phenotype or ABCD1-related disorders? Are SPG11 and SPG15 to be considered as “genetic leukoencephalopathies” or are adreno(leuko)myeloneuropathy and adult-onset Krabbe disease to be considered as SPG? Are the inborn errors of metabolism (with or without white matter abnormalities) to be named on the basis of their metabolic defect, or is time to re-classify these disorders in a clinicalfriendly manner?
Dedication This commentary is dedicated to the memory of Mario Savoiardo. He was a great neuroradiologist, a great mentor and a dear friend.
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