The latest on leukodystrophies


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The latest on leukodystrophies

  1. 1. The latest on leukodystrophies Raphael Schiffmanna and Marjo S. van der Knaapb Purpose of review Abbreviations Important advances in our understanding of genetic disorders of ALDP adrenoleukodystrophy protein the white matter have been made and are discussed here. CACH childhood ataxia with central hypomyelination eIF eukaryotic initiation factor Recent findings H-ABC hypomyelination with atrophy of the basal ganglia and cerebellum It has recently been discovered that mutations in the genes LBSL leukoencephalopathy with brain-stem and spinal cord involvement and elevated white-matter lactate encoding the five subunits of eukaryocytic initiation factor 2B MRI magnetic resonance imaging (eIF2B) are the cause of vanishing white-matter disease/ MRS magnetic resonance spectroscopy PLP proteolipid protein childhood ataxia with central hypomyelination syndrome. The VWM vanishing white matter extension of the clinical features of the eIF2B-related disorders X-ALD X-linked adrenoleukodystrophy to encompass both infant- and adult-onset disorders is # 2004 Lippincott Williams & Wilkins discussed. New clinico-imaging syndromes such as 1350-7540 hypomyelination with atrophy of the basal ganglia and cerebellum and leukoencephalopathy with brain-stem and spinal cord involvement and elevated white-matter lactate are described. Recent findings include evidence that mitochondrial Introduction fat-oxidation abnormalities may be important in the pathogenesis In the past few years, a number of advances have of adrenoleukodystrophy, and that a mutant myelin protein can occurred in our understanding of the nosology and cause maldistribution of other myelin proteins, causing etiology of the leukodystrophies (genetic white-matter dysmyelination, axonal damage, or both. brain disorders). This review focuses on the more Summary recently described syndromes, including vanishing white This review focuses on advances in the understanding of the matter (VWM)/childhood ataxia with central hypomye- role of eIF2B as a cause of a common leukodystrophy lination (CACH), that are now known to be caused by syndrome. eIF2B-related disorders have a clinical spectrum defects in eukaryotic initiation factor (eIF) 2B. Other ranging from a severe, rapidly progressive congenital or early newly described leukodystrophy syndromes of unknown infantile encephalopathy to a slowly progressive cognitive and cause are also described here. In addition, recent motor deterioration often associated with premature ovarian developments in adrenoleukodystrophy and proteoli- failure. Two newly recognized leukodystrophy syndromes are pid-related disorders are briefly updated. described: hypomyelination with atrophy of the basal ganglia and cerebellum, and leukoencephalopathy with brain-stem and Vanishing white-matter disease/childhood spinal cord involvement and elevated white-matter lactate. An ataxia with central nervous system update is also given for adrenoleukodystrophy and myelin- hypomyelination protein-related disorders. This update demonstrates that an VWM disease and CACH are two names for the same increasing number of genetic defects are being identified that disease. After definition of the disease in the 1990s, the may cause primary white-matter disorders. initial focus was on the clinical phenotype, the magnetic resonance imaging (MRI) features and the histopatholo- Keywords gical findings [1]. It was clear from the beginning that adrenoleukodystrophy, eukaryocytic initiation factor, H-ABC, the disease had an autosomal recessive mode of LBSL, leukodystrophy, proteolipid protein inheritance, but linkage studies were hampered by evident genetic heterogeneity. An important break- Curr Opin Neurol 17:187–192. # 2004 Lippincott Williams & Wilkins. through came in 2001, when the first two genes for the disease were identified with the help of two Dutch a Developmental and Metabolic Neurology Branch, National Institute of Neurological founder effects, one in the eastern part of the country Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA and b Department of Child Neurology, Free University Medical Center, Amsterdam, The and another in the southern part [2,3 .]. The most Netherlands surprising finding was that the disease, clinically Correspondence to Dr Marjo S. van der Knaap, Department of Child Neurology, Free characterized by signs of a leukoencephalopathy only, University Medical Center, PO Box 7057, 1007 MB Amsterdam, The Netherlands was caused not by mutations in brain-specific genes, but E-mail: by mutations in the ubiquitously expressed house- Current Opinion in Neurology 2004, 17:187–192 keeping genes EIF2B5 and EIF2B2. Soon, mutations in three other genes were also found to cause VWM/ CACH: EIF2B1, EIF2B3 and EIF2B4 [3 .,4 .]. EIF2B1– 5, located on chromosomes 12q24.3, 14q24, 1p34.1, DOI: 10.1097/01.wco.0000124710.26506.23 187
  2. 2. 188 Metabolic disorders and neurotoxicology 2p23.3 and 3q27, respectively, encode the a, b, g, d and e eIF2B complex genes and, in fact, had VWM/CACH subunits of translation initiation factor eIF2B. [12 .]. Translation of mRNA into polypeptides is a tightly Further evidence for involvement of multiple organs regulated process [5]. Multiple so-called eIFs are outside the brain was provided in a study of eight involved in translation initiation and eIF2 is the central neonates and infants with a leukoencephalopathy and, factor [6]. If eIF2 is in complex with GTP, translation is additionally, a variable combination of oligohydramnios, on, and if it is in complex with GDP, translation is off. intrauterine growth retardation, cataracts, pancreatitis, Conversion of GTP to GDP produces the energy hepatosplenomegaly, hypoplasia and dysplasia of the necessary to deliver methionine to the start codon of an kidneys and, again, dysgenesis of the ovaries [13 .]. mRNA. Regeneration of active eIF2 by exchange of GDP for GTP is catalyzed by eIF2B. The exchange of GDP for Initially, no evidence was found for a genotype– GTP by eIF2B is required for each round of translation phenotype correlation [2,3 .], but the fact that some initiation, and regulation of this step can control global mutations are consistently associated with a more severe rates of protein synthesis under diverse conditions [6]. phenotype than other mutations is the first indication of Protein synthesis is markedly inhibited under a variety of a genotype–phenotype correlation [13 .]. stress conditions and in the recovery phase that follows. eIF2B is the most important factor to down-regulate The pathophysiology of the disease in VWM/CACH is translation under conditions of fever. still far from clear. A recent study using phosphorus magnetic resonance spectroscopy of the brain revealed The essential role of eIF2B in normal protein production evidence of an altered energy state of the residual cells and in its regulation under different conditions is [14]. Nucleoside triphosphate and inorganic phosphate reflected in the observation that survival of an organism were reduced, whereas phosphocreatine was elevated is not possible without eIF2B (yeast knockouts are not [14]. The relative preservation of gray matter over white viable), and in the type of mutations found. Most matter may have contributed to this observation, the mutations in patients with VWM/CACH are missense nucleoside triphosphate to inorganic phosphate normally mutations. Until now, major mutations, which prevent being lower in gray matter than in white matter. Of the the expression of full-length eIF2B subunits, have only metabolites involved in biosynthesis and catabolism of been observed in the compound-heterozygous state with membrane phospholipids, glycerophosphorylethanola- a missense mutation as the second mutation [2,3 .,4 .]. mine was reduced and phosphorylelthanolamine was increased, whereas choline-containing phosphorylated A recent observation is that the neuropathology in Cree metabolites were unchanged [14]. It is difficult to leukoencephalopathy shows similarities to that of VWM/ interpret these findings, largely because the composition CACH [7 .]. Most strikingly, abnormal, foamy oligoden- of the remaining brain tissue in VWM/CACH is drocytes are found in Cree leukoencephalopathy – a dramatically changed with serious rarefaction and altered feature observed in most patients with VWM/CACH [8]. ratios of constituent cell types. Why a defect in the One particular mutation in EIF2B5 was subsequently regulation of protein synthesis would selectively affect identified in all patients with Cree leukoenephalopathy ethanolamine phospholipid metabolism and leave cho- that were studied [7 .]. Cree leukoencephalopathy is line phospholipid metabolism unaffected is presently clinically more severe than classical VWM/CACH. Its unclear. onset is invariably within the first year of life, and death occurs before the age of 2 years. Furthermore, two New leukoencephalopathies of unknown Italian siblings with a particularly severe variant of cause VWM/CACH were described, and the responsible Several ‘new’ leukoencephalopathy syndromes have mutations in EIF2B5 were identified [9]. been defined in the nineties on the basis of distinct patterns of MRI abnormalities or magnetic resonance Thus far, it had been thought that VWM/CACH was a spectroscopy (MRS) findings. Nevertheless, a large disease affecting only the brain. In 1997, one patient number of patients with significant white-matter ab- with VWM and dysgenesis of the ovaries, which could normalities on MRI still remain without a specific be an incidental finding, was described [10]. The first diagnosis. Multi-institutional studies have led to the evidence for a more consistent association between identification of two additional novel disorders. leukoencephalopathies and dysgenesis of the ovaries was provided by Schiffmann et al. [11], who described several Hypomyelination with atrophy of the basal ganglia and female patients with these features under the heading of cerebellum ‘ovarioleukodystrophy’ in 1997. Recently, it was demon- A novel leukoencephalopathy with a distinct MRI strated that most of these patients had mutations in pattern, characterized by hypomyelination and atrophy
  3. 3. The latest on leukodystrophies Schiffmann and van der Knaap 189 of the basal ganglia and cerebellum (H-ABC), was of the cerebral white matter occurs, associated with described in 2002 [15]. Both males and females are variable dilatation of the lateral ventricles. The atrophy affected. The disease has its onset in infancy or early of cerebral white matter and the basal ganglia is more childhood and its severity is variable. Patients with serious in the severely affected patients. severe disease present soon after birth with poor eye contact and absence of any motor development. Proton magnetic resonance spectroscopy reveals that Ophthalomological examination reveals pale optic discs. within the white matter total N-acetylaspartate and Over the years there are signs of slowly progressive choline are normal; this argues against significant spasticity and extrapyramidal movement abnormalities neuronal/axonal loss and active demyelination. Myo- including rigidity, dystonia and choreoathetosis. The inositol and total creatine are elevated, suggesting patients seem to have a better mental function than significant white-matter gliosis. motor function and appear to have a social awareness. They may have incidental seizures. The severely The diagnosis in H-ABC is MRI-based. As soon as the affected patients tend to be small and have a head full-blown picture with absence of the putamen in the circumference below the third percentile. Patients with presence of hypomyelination is present, a definitive intermediate severity of disease have a delayed early diagnosis can be made [15]. The basic defect underlying development, but achieve grasping and unsupported the disorder is presently unknown. It is highly likely that sitting. The patients with the mildest form of the the disease is genetic. However, since until now all disorder may have a normal initial development and they patients have been isolated cases, it is unclear whether achieve unsupported walking. In these patients, slow the mode of inheritance is autosomal recessive or deterioration becomes evident in early childhood, with autosomal dominant, all patients being de-novo muta- increasing spasticity, ataxia and often prominent extra- tions. pyramidal movement abnormalities consisting of dysto- nia, choreoathetosis and rigidity. Some patients are Leukoencephalopathy with brain-stem and spinal cord predominantly and severely spastic. The patients involvement and elevated white-matter lactate typically have learning problems, but further cognitive Leukoencephalopathy with brain-stem and spinal cord decline is, at most, mild. Incidental epileptic seizures involvement and elevated white-matter lactate (LBSL) may occur. Vision is normal and ophthalmological is a white-matter disease that has been recently defined examination reveals no abnormalities. Height and head on the basis of distinct MRI findings [16,17]. Multiple circumference are normal. affected siblings have been identified within the same family, suggesting an autosomal recessive mode of Laboratory examinations, including extensive metabolic inheritance. Clinically, it is a slowly progressive disease, studies, have been uninformative. Cerebrospinal fluid which has its onset in childhood. In all known patients to neurotransmitters and neurotransmitter metabolites have date, initial development was normal. In some of the been studied in several patients and found to be within patients, independent walking was unstable from the the normal range. Visual evoked responses and somato- beginning. Motor deterioration starts at a variable age in sensory evoked responses are delayed. Brain-stem childhood or adolescence with signs of spasticity and auditory evoked responses show a normal latency for ataxia, involving the legs more than the arms. Patients waves I and II, whereas the later waves are not become wheelchair-dependent in their teens or twen- recordable or are delayed. Motor and sensory nerve- ties. In the later stages, manual dexterity is also conduction velocities are normal. compromised. Most patients have a distal decrease in position and vibration sense. Some patients develop Early MRI is characterized by the presence of very little epilepsy with infrequent seizures. Some of the patients myelin. In some patients, the putamen is already absent have learning problems from early on, but cognitive within the first year of life, and the caudate nucleus is decline is of late occurrence. There is some variation in small, making the diagnosis of H-ABC possible. How- the severity of the disease: some patients manifest ever, in other patients, MRI within the first year of life significant neurological problems in early childhood, shows myelin deficiency only, and the putamen and whereas others display only minor dysfunction in caudate nucleus are still normal. The severity of the adolescence. It is striking that some patients have been myelin deficit is variable. It is striking that the pyramidal reported as experiencing an episode of more rapid and tracts in the brain stem are also hypomyelinated. Over partially reversible neurological deterioration accompa- time, the putamen disappears. The caudate nucleus nied by fever following a minor head trauma [17]. becomes smaller, disappearing in some of the patients. The thalamus and globus pallidus remain normal in size. Somatosensory evoked potentials with stimulation of the The cerebellum, in particular the vermis, becomes tibial and median nerves are delayed or negative. progressively atrophic. Over the years, a variable atrophy Sensory and motor nerve-conduction velocities are
  4. 4. 190 Metabolic disorders and neurotoxicology normal. Extensive laboratory investigations have proved and gliosis, respectively. White-matter choline is in- uninformative. Only in some patients have mild eleva- creased too, but the increase is minor, suggesting mildly tions of serum lactate been found on several occasions. enhanced membrane turnover and possibly myelin loss. However, extensive mitochondrial work-up in fresh Cortex spectra do not show significant abnormalities. muscle tissue has not revealed abnormalities in any of the patients. No mitochondrial DNA mutations have The MRI pattern is distinct [16,17]. A similar MRI been found. pattern has not been described for any other condition. If present, the pattern is diagnostic. The basic defect of the LBSL has a distinct MRI pattern. The cerebral white disease remains unknown. matter is involved to a variable extent. In some patients, the abnormalities are extensive; in others, The classic leukodystrophies they are more limited. The white-matter abnormalities Definition of new leukoencephalopathy syndromes and are progressive over time and spread from the identification of their related gene defects are only a periventricular region outwards. In all patients, even beginning. Further research on the well known leuko- in the oldest, the U-fibers are spared. In some patients, dystrophies is indispensible to obtain a better under- the cerebral white-matter abnormalities are homoge- standing of the pathphysiology of degeneration of white neous, but in most patients the abnormal cerebral white matter and its components. matter has an inhomogeneous, spotty aspect. On images obtained using fluid-attentuated inversion recovery, the X-linked adrenoleukodystrophy white-matter abnormalities are also inhomogeneous X-linked adrenoleukodystrophy (X-ALD) is considered with spots of lower signal intensity suggesting focal to be the most common leukodystrophy, having a rarefaction. The corpus callosum is involved, almost hemizygous frequency in the USA of 1:42 000 and a always more seriously in the posterior part than the minimal frequency of heterozygotes of 1:16 800. X-ALD anterior part, but sometimes the corpus callosum is consists of an inflammatory demyelinating disease of the homogeneously affected throughout. The posterior limb central nervous system in 40% of male hemizygotes of the internal capsule is also affected. Within the brain between the ages of 5 and 12 (the cerebral form of X- stem and spinal cord, the disease involves certain tracts ALD), or a more chronic disease, adrenomyeloneuro- selectively. The pyramidal tracts are affected over their pathy with distal axonopathy leading to a spastic entire length extending downwards through the poster- paraparesis and an axonal peripheral neuropathy (40% ior limb of the internal capsule and the brain stem into of patients). Adrenal insufficiency frequently occurs, and the lateral corticospinal tracts of the spinal cord. In 20% of women carriers may develop a milder form of addition, sensory tracts are affected over their entire these syndromes. The disease is caused by accumulation length, involving the dorsal columns in the spinal cord, of very-long-chain fatty acids in neural tissue and the the medial lemniscus through the brain stem up to the adrenals due to mutations in the adrenoleukodystrophy level of the thalamus, and the corona radiata above the protein (ALDP), an ATP-binding cassette half transpor- level of the thalamus. The transverse pontine fibers ter of 75 kDa. However, the exact role of ALPD or the become involved in later stages of the disease. mechanism by which an excess of long-chain fatty acids Cerebellar connections are selectively involved: first induces disease are still not fully understood. Peroxiso- the superior and inferior cerebellar peduncles and, only mal b-oxidation activity occurs in the absence of ALPD, at a late stage, the middle cerebellar peduncles. Also, and in ALPD-deficient mice, the rate of b-oxidation of the anterior spinocerebellar tracts at the level of the very-long-chain fatty acids is normal. Recent evidence medulla become abnormal. A remarkable finding is the points toward a disturbance of fatty acid oxidation in the consistent involvement of the intraparenchymal trajec- mitochondria as a major consequence of ALPD defi- tories of the trigeminal nerve and the mesencephalic ciency. This finding suggests the possibility of novel trigeminal tracts. The cerebellar white matter may approaches in the development of therapy for X-ALD, develop signal abnormalities, first in the subcortical approaches that increase mitochondrial activity or mass regions and subsequently spreading inwards to involve [18]. Since inflammation is part of X-ALD, it is of all cerebellar white matter. The cerebellum becomes interest that adrenal hormone replacement therapy with atrophic over time. prednisone can lead to clinical and electrophysiological improvements [19]. Prediction of progression in X-ALD The most striking finding in proton MRS of the brain is is very important in order to determine the correct time a consistent elevation of lactate within the abnormal for risky interventions such as bone-marrow transplanta- white matter in almost all patients, albeit to a variable tion. Prediction of the clinical course can be better degree. MRS shows a significant decrease in N- accomplished by combining the cranial MRI severity acetylaspartate and an increase in myo-inositol in the score with the regional pattern of white-matter lesions abnormal white matter, suggesting axonal damage or loss [20].
  5. 5. The latest on leukodystrophies Schiffmann and van der Knaap 191 Myelin-protein-related disorders An additional finding was that the severity of the disease The syndromes related to proteolipid protein (PLP) 1 significantly correlated with the age of disease onset [29]. defects have recently been reviewed [1]. An increasing Another study provided evidence that the 338G4A number of publications describe a variety of peripheral mutation in EIF2B5 (R133H at protein level) was nerve abnormalities in affected patients [21,22]. The associated with a particular wild phenotype (adult onset, clinical presentation is of a multifocal motor and sensory slow disease course) [30]. demyelinating neuropathy, but sometimes there is an axonal disease and a lower motor neuron presentation. Conclusion The peripheral nervous system signs and electrodiag- The update described herein underlines the fact that nostic findings in the other reported clinical cases and defects in genes coding for proteins that are not typically kindreds are more consistent with a lower motor neuron associated with the myelin sheath can cause myelin disease rather than a dysmyelinating peripheral neuro- disorders. It remains to be discovered why, for example, pathy [21]. A variety of PLP1 mutations have been a generalized dysfunction in the cellular response to described in patients who have peripheral nerve stress leads to a rather selective involvement of brain involvement. However, they all have in common an glial cells, as in the case of eIF2B-related syndromes. On alteration of the PLP-specific transcript, although not the other hand, a deficiency of a myelin protein may necessarily DM20 [23 .]. This suggests that the PLP- affect axonal survival rather than myelin structure. With specific domain plays an important role in normal the discovery of a number of new causes of leukody- peripheral nerve function. We recently found a family strophies, we increase our understanding of the physiol- with a combined central and peripheral nerve involve- ogy of myelin and myelination. However, at present, ment that was caused by a novel splice-site mutation in therapy for genetic white-matter disorders lags far intron 4 of the PLP1 gene [24 . .]. This mutation altered behind our general knowledge of the pathogenesis of PLP1 RNA splicing, predicted to produce truncated PLP these diseases. and DM20 proteins. Using immunogold electron micro- scopy, we found that at least one form of the mutant protein was present in the myelin sheath of the sural References and recommended reading nerve, despite a predicted loss of at least the fourth Papers of particular interest, published within the annual period of review, have been highlighted as: transmembrane domain and the C-terminus of both PLP . of special interest .. of outstanding interest and DM20. The presence of mutant PLP1 led to an abnormal distribution in the myelin sheath of other 1 Schiffmann R, Boespflug-Tanguy O. An update on the leukodsytrophies. Curr major myelin proteins such as P0, myelin basic protein Opin Neurol 2001; 14:789–794. and myelin-associated glycoprotein [24 . .]. We assume 2 Leegwater PA, Vermeulen G, Konst AA, et al. Subunits of the translation that the misdistribution of myelin proteins contributes to initiation factor eIF2B are mutant in leukoencephalopathy with vanishing white matter. Nat Genet 2001; 29:383–388. the dysmyelination and axonal damage in this disease. It 3 van der Knaap MS, Leegwater PA, Konst AA, et al. Mutations in each of the remains to be seen how common this pathogenic . five subunits of translation initiation factor eIF2B can cause leukoencephalo- mechanism is in the PLP1-related disorders. PLP1 pathy with vanishing white matter. Ann Neurol 2002; 51:264–270. The authors discovered the full extent of this complex syndrome. mutations were found to induce the unfolded protein response and it was shown that abnormal activation of 4 Leegwater PA, Pronk JC, van der Knaap MS. Leukoencephalopathy with . vanishing white matter: from magnetic resonance imaging pattern to five this pathway dramatically increases disease severity [25]. genes. J Child Neurol 2003; 18:639–645. These and other mechanisms probably play a role in the This is a recent and comprehensive review on this topic. variable expression of the disease, depending on the 5 Proud CG. Regulation of mammalian translation factors by nutrients. Eur J Biochem 2002; 269:5338–5349. genetic background [26]. One clear consequence of 6 Proud CG. Regulation of eukaryotic initiation factor eIF2B. Prog Mol Subcell PLP1 mutations is axonal loss that is probably the main Biol 2001; 26:95–114. factor responsible for the neurological deterioration seen 7 Fogli A, Wong K, Eymard-Pierre E, et al. Cree leukoencephalopathy and in the patients. Axonal length-dependent loss occurs in . CACH/VWM disease are allelic at the EIF2B5 locus. Ann Neurol 2002; 52:506–510. all types of mutations but is especially evident in This first ‘non-classic’ phenotype of VWM/CACH was suspected initially on the patients and in mouse models with an absence of PLP basis of similar abnormalities of oligodendrocytes that are present in the classic form of this syndrome. [27]. Axonal loss with normal myelin caused by a null mutant of a myelin protein also occurs in a mouse model 8 Wong K, Armstrong RC, Gyure KA, et al. Foamy cells with oligodendroglial phenotype in childhood ataxia with diffuse central nervous system hypomye- for 2’,3’-cyclic nucleotide phosphodiesterase [28 .]. lination syndrome. Acta Neuropathol (Berl) 2000; 100:635–646. 9 Fogli A, Dionisi-Vici C, Deodato F, et al. A severe variant of childhood ataxia In a large cohort of 83 individuals with a leukodystrophy with central hypomyelination/vanishing white matter leukoencephalopathy related to EIF21B5 mutation. Neurology 2002; 59:1966–1968. and a specific MRI pattern, the predominance of 10 van der Knaap MS, Barth PG, Gabreels FJ, et al. A new leukoencephalo- EIF2B5 mutations was confirmed (62% of the families), pathy with vanishing white matter. Neurology 1997; 48:845–855. and specific mutations in the homozygous state were 11 Schiffmann R, Tedeschi G, Kinkel RP, et al. Leukodystrophy in patients with clearly associated with a mild or severe phenotype [29]. ovarian dysgenesis. Ann Neurol 1997; 41:654–661.
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