diffuse cerebral sclerosis of schilder

Summary

Summary: A rare central nervous system demyelinating condition affecting children and young adults. Pathologic findings include a large, sharply defined, asymmetric focus of myelin destruction that may involve an entire lobe or cerebral hemisphere. The clinical course tends to be progressive and includes dementia, cortical blindness, cortical deafness, spastic hemiplegia, and pseudobulbar palsy. Concentric sclerosis of Balo is differentiated from diffuse cerebral sclerosis of Schilder by the pathologic finding of alternating bands of destruction and preservation of myelin in concentric rings. Alpers' Syndrome refers to a heterogeneous group of diseases that feature progressive cerebral deterioration and liver disease. (From Adams et al., Principles of Neurology, 6th ed, p914; Dev Neurosci 1991;13(4-5):267-73)

Top Publications

  1. Davidzon G, Mancuso M, Ferraris S, Quinzii C, Hirano M, Peters H, et al. POLG mutations and Alpers syndrome. Ann Neurol. 2005;57:921-3 pubmed
    ..We conclude that AHS should be included in the clinical spectrum of mtDNA depletion and is often associated with POLG mutations, which can cause either multiple mtDNA deletions or mtDNA depletion...
  2. Chen C. Serial proton magnetic resonance spectroscopy in lesions of Balò concentric sclerosis. J Comput Assist Tomogr. 2001;25:713-8 pubmed
    ..Balò concentric sclerosis is a rare demyelinating disorder. Serial proton magnetic resonance spectroscopic (1H-MRS) studies were carried out to better understand the biochemical changes within concentric lesions...
  3. Naviaux R, Nguyen K. POLG mutations associated with Alpers syndrome and mitochondrial DNA depletion. Ann Neurol. 2005;58:491 pubmed
  4. Tzoulis C, Engelsen B, Telstad W, Aasly J, Zeviani M, Winterthun S, et al. The spectrum of clinical disease caused by the A467T and W748S POLG mutations: a study of 26 cases. Brain. 2006;129:1685-92 pubmed
    ..Compound heterozygotes have a significantly more severe phenotype raising the possibility of a dominant negative effect...
  5. Naviaux R, Nguyen K. POLG mutations associated with Alpers' syndrome and mitochondrial DNA depletion. Ann Neurol. 2004;55:706-12 pubmed
    ..In addition, each affected child was heterozygous for the G1681A mutation in exon 7 that led to an Ala467Thr substitution in POLG, within the linker region of the protein...
  6. Kavanagh E, Heran M, Fenton D, Lapointe J, Nugent R, Graeb D. Diffusion-weighted imaging findings in Balo concentric sclerosis. Br J Radiol. 2006;79:e28-31 pubmed
    ..We describe the diffusion-weighted imaging findings in a 45-year-old lady with Balo concentric sclerosis. Diffusion-weighted imaging offers insight into the possible pathophysiology of this rare disease...
  7. Hakonen A, Davidzon G, Salemi R, Bindoff L, Van Goethem G, DiMauro S, et al. Abundance of the POLG disease mutations in Europe, Australia, New Zealand, and the United States explained by single ancient European founders. Eur J Hum Genet. 2007;15:779-83 pubmed
    ..They have effectively spread to populations of European descent with carrier frequencies up to 1% in several populations. Our data predict that these mutations are common causes of ataxia and Alpers disease in the Western world...
  8. Mowry E, Woo J, Ances B. Baló's concentric sclerosis presenting as a stroke-like syndrome. Nat Clin Pract Neurol. 2007;3:349-54 pubmed
    ..Examination revealed left-sided hemiparesis (in the arm greater than in the leg) and hypoesthesia...
  9. Isohanni P, Hakonen A, Euro L, Paetau I, Linnankivi T, Liukkonen E, et al. POLG1 manifestations in childhood. Neurology. 2011;76:811-5 pubmed publisher
    ..Because some patients with MIRAS have presented with ataxia or epilepsy already in childhood, we searched for POLG1 mutations in neurologic manifestations in childhood...

More Information

Publications62

  1. Wong L, Naviaux R, Brunetti Pierri N, Zhang Q, Schmitt E, Truong C, et al. Molecular and clinical genetics of mitochondrial diseases due to POLG mutations. Hum Mutat. 2008;29:E150-72 pubmed publisher
  2. Hunter M, Peters H, Salemi R, Thorburn D, Mackay M. Alpers syndrome with mutations in POLG: clinical and investigative features. Pediatr Neurol. 2011;45:311-8 pubmed publisher
    ..Three common polymerase-? mutations, in patients of European descent, can assist with rapid diagnosis, circumventing the need for liver biopsy...
  3. Joshi C, Greenberg C, Mhanni A, Salman M. Ketogenic diet in Alpers-Huttenlocher syndrome. Pediatr Neurol. 2009;40:314-6 pubmed publisher
    ..We present a literature review of the utility of a ketogenic diet in mitochondrial disorders, and speculations as to why the diet may be helpful in Alpers-Huttenlocher syndrome...
  4. Lindquist S, Bodammer N, Kaufmann J, Konig F, Heinze H, Bruck W, et al. Histopathology and serial, multimodal magnetic resonance imaging in a multiple sclerosis variant. Mult Scler. 2007;13:471-82 pubmed
    ..This is the first report comparing 1H-magnetic resonance spectroscopy, magnetization transfer and diffusion tensor imaging with histopathology in a patient with Balo's concentric sclerosis...
  5. Nguyen K, Østergaard E, Ravn S, Balslev T, Danielsen E, Vardag A, et al. POLG mutations in Alpers syndrome. Neurology. 2005;65:1493-5 pubmed
    ..Mitochondrial respiratory chain studies in skeletal muscle were normal in each case. Nine combinations of mutant POLG alleles that cause Alpers syndrome are summarized...
  6. Uusimaa J, Hinttala R, Rantala H, Päivärinta M, Herva R, Roytta M, et al. Homozygous W748S mutation in the POLG1 gene in patients with juvenile-onset Alpers syndrome and status epilepticus. Epilepsia. 2008;49:1038-45 pubmed publisher
    ..Here we studied the molecular etiology of juvenile-onset AHS manifesting with status epilepticus and liver disease in three teenagers...
  7. Ball T, Malik O, Roncaroli F, Quest R, Aviv R. Apparent diffusion coefficient changes and lesion evolution in Balo's type demyelination-correlation with histopathology. Clin Radiol. 2007;62:498-503 pubmed
  8. Chan S, Copeland W. DNA polymerase gamma and mitochondrial disease: understanding the consequence of POLG mutations. Biochim Biophys Acta. 2009;1787:312-9 pubmed publisher
    ..We review the results of these studies, which provide clues to the mechanisms leading to the disease state. ..
  9. Anschel D. Reply to the paper by Wiendl et al.: diffusion abnormality in Baló's concentric sclerosis: clues for the pathogenesis. Eur Neurol. 2006;55:111-2 pubmed
  10. Chan S, Naviaux R, Basinger A, Casas K, Copeland W. De novo mutation in POLG leads to haplotype insufficiency and Alpers syndrome. Mitochondrion. 2009;9:340-5 pubmed publisher
    ..2157+5_+6 gc-->ag allele, which is likely responsible for the Alpers syndrome phenotype. ..
  11. Pohl D, Rostasy K, Krone B, Hanefeld F. Baló's concentric sclerosis associated with primary human herpesvirus 6 infection. J Neurol Neurosurg Psychiatry. 2005;76:1723-5 pubmed
    ..Primary infection with HHV-6 usually occurs in early childhood manifesting as exanthema subitum. The clinical spectrum of primary infection in adolescents or adults has not yet been evaluated...
  12. Boes M, Bauer J, Urbach H, Elger C, Frank S, Baron M, et al. Proof of progression over time: finally fulminant brain, muscle, and liver affection in Alpers syndrome associated with the A467T POLG1 mutation. Seizure. 2009;18:232-4 pubmed publisher
    ..Consecutive diagnostic examinations clearly reflected the devastating clinical course and cerebral deterioration evolving over time in Alpers syndrome...
  13. Schneider A, Montague P, Griffiths I, Fanarraga M, Kennedy P, Brophy P, et al. Uncoupling of hypomyelination and glial cell death by a mutation in the proteolipid protein gene. Nature. 1992;358:758-61 pubmed
    ..We suggest that PLP has a vital function in glial cell development, distinct from its later role in myelin assembly, and that this dichotomy of action may explain the clinical spectrum of Pelizaeus-Merzbacher disease...
  14. Moore G, Berry K, Oger J, Prout A, Graeb D, Nugent R. Baló's concentric sclerosis: surviving normal myelin in a patient with a relapsing-remitting dinical course. Mult Scler. 2001;7:375-82 pubmed
    ..The pathogenesis of this concentric lesion may be explained by periodic suppression of demyelination in the rapidly expanding border, allowing remyelination or only transient incomplete demyelination to occur...
  15. Gow A, Lazzarini R. A cellular mechanism governing the severity of Pelizaeus-Merzbacher disease. Nat Genet. 1996;13:422-8 pubmed
    ..Moreover, we show that transport-competent mutant DM20s facilitate trafficking of cognate PLPs and hence may influence disease severity...
  16. Khiat A, Lesage J, Boulanger Y. Quantitative MRS study of Baló's concentric sclerosis lesions. Magn Reson Imaging. 2007;25:1112-5 pubmed
    ..In addition, previously unreported decreases of mI (-19% to -29%) and increases of Glx (+55% to +198%) were measured; these could be useful in characterizing BCS lesions...
  17. Cohen B, Naviaux R. The clinical diagnosis of POLG disease and other mitochondrial DNA depletion disorders. Methods. 2010;51:364-73 pubmed publisher
    ..However, this remains a rapidly evolving field, with additional proteins and genes are being discovered as DNA testing becomes part of the standard of care in everyday medical practice...
  18. Kasiviswanathan R, Longley M, Chan S, Copeland W. Disease mutations in the human mitochondrial DNA polymerase thumb subdomain impart severe defects in mitochondrial DNA replication. J Biol Chem. 2009;284:19501-10 pubmed publisher
    ..To our knowledge this study represents the first structure-function analysis of the thumb subdomain in pol gamma and examines the consequences of mitochondrial disease mutations in this region...
  19. Kastrup O, Stude P, Limmroth V. Balo's concentric sclerosis. Evolution of active demyelination demonstrated by serial contrast-enhanced MRI. J Neurol. 2002;249:811-4 pubmed
    ..There were no oligoclonal bands or intrathecal Ig-G synthesis. The hypothesis concerning the pathophysiology of the lesions' typical and peculiar morphological appearance and its relationship to multiple sclerosis are briefly discussed...
  20. Wiendl H, Weissert R, Herrlinger U, Krapf H, Kuker W. Diffusion abnormality in Balo's concentric sclerosis: clues for the pathogenesis. Eur Neurol. 2005;53:42-4 pubmed
  21. Stadelmann C, Ludwin S, Tabira T, Guseo A, Lucchinetti C, Leel Ossy L, et al. Tissue preconditioning may explain concentric lesions in Baló's type of multiple sclerosis. Brain. 2005;128:979-87 pubmed
    ..Due to their neuroprotective effects, the rim of periplaque tissue, where these proteins are expressed, may be resistant to further damage in an expanding lesion and may therefore remain as a layer of preserved myelinated tissue...
  22. Ferrari G, Lamantea E, Donati A, Filosto M, Briem E, Carrara F, et al. Infantile hepatocerebral syndromes associated with mutations in the mitochondrial DNA polymerase-gammaA. Brain. 2005;128:723-31 pubmed
  23. Nguyen K, Sharief F, Chan S, Copeland W, Naviaux R. Molecular diagnosis of Alpers syndrome. J Hepatol. 2006;45:108-16 pubmed
    ..Mutations in the gene for the mitochondrial DNA polymerase (POLG) have recently been shown to cause this disorder...
  24. Stewart J, Tennant S, Powell H, Pyle A, Blakely E, He L, et al. Novel POLG1 mutations associated with neuromuscular and liver phenotypes in adults and children. J Med Genet. 2009;46:209-14 pubmed publisher
    ..1814_1815TT>GC)-to the growing list of defects further confirms the importance of POLG1 mutations as the underlying abnormality in a range of neurological presentations. ..
  25. Kobayashi H, Hoffman E, Marks H. The rumpshaker mutation in spastic paraplegia. Nat Genet. 1994;7:351-2 pubmed
  26. Euro L, Farnum G, Palin E, Suomalainen A, Kaguni L. Clustering of Alpers disease mutations and catalytic defects in biochemical variants reveal new features of molecular mechanism of the human mitochondrial replicase, Pol ?. Nucleic Acids Res. 2011;39:9072-84 pubmed publisher
    ..Our results suggest that cluster prediction can be used as a diagnosis-supporting tool to evaluate the pathogenic role of new Pol ? variants...
  27. Chan S, Longley M, Naviaux R, Copeland W. Mono-allelic POLG expression resulting from nonsense-mediated decay and alternative splicing in a patient with Alpers syndrome. DNA Repair (Amst). 2005;4:1381-9 pubmed
    ..Therefore, the Alpers phenotype in this patient was a consequence of a single-copy gene dose of the A467T allele, and selective elimination of transcripts bearing the E873stop mutation...
  28. Kurt B, Jaeken J, Van Hove J, Lagae L, Löfgren A, Everman D, et al. A novel POLG gene mutation in 4 children with Alpers-like hepatocerebral syndromes. Arch Neurol. 2010;67:239-44 pubmed publisher
    ..In the Belgian patients, the familial occurrence without consanguinity is related to the high frequency of the recessive p.A467T and p.W748S mutations in northwestern Europe and reveals a pitfall for diagnosis and genetic counseling. ..
  29. de Vries M, Rodenburg R, Morava E, van Kaauwen E, Ter Laak H, Mullaart R, et al. Multiple oxidative phosphorylation deficiencies in severe childhood multi-system disorders due to polymerase gamma (POLG1) mutations. Eur J Pediatr. 2007;166:229-34 pubmed
    ..Conclusion We suggest performing POLG1 mutation analysis in children with combined oxidative phosphorylation deficiencies in muscle, even if the clinical picture is not Alpers syndrome...
  30. Karaarslan E, Altintas A, Senol U, Yeni N, Dincer A, Bayindir C, et al. Baló's concentric sclerosis: clinical and radiologic features of five cases. AJNR Am J Neuroradiol. 2001;22:1362-7 pubmed
    ..Our case report supports the concept that BCS may be a self-limited disease that is not always fatal. Characteristic MR imaging findings may allow antemortem diagnosis of BCS when performed at the onset of the disease...
  31. Horvath R, Hudson G, Ferrari G, Fütterer N, Ahola S, Lamantea E, et al. Phenotypic spectrum associated with mutations of the mitochondrial polymerase gamma gene. Brain. 2006;129:1674-84 pubmed
    ..1399G-->A (A467T) is common in children, but complete POLG1 sequencing is required to identify multiple mutations that can have complex implications for genetic counselling...
  32. Ergun T, Lakadamyali H. Multiple extradural spinal arachnoid cysts causing diffuse myelomalacia of the spinal cord. Neurologist. 2009;15:347-50 pubmed publisher
    ..We present a case of multiple spinal arachnoid cysts causing diffuse myelomalacia secondary to a significant compression of the spinal cord with no symptom relief after surgical decompression...
  33. Garbern J, Spence A, Alvord E. Balo's concentric demyelination diagnosed premortem. Neurology. 1986;36:1610-4 pubmed
    ..The patient improved with prednisone therapy, but relapsed temporarily 15 months later. CT and MRI showed additional lesions, but no features unique to this process. He remains alive and employed 3 years after diagnosis...
  34. Visser N, Braun K, Leijten F, van Nieuwenhuizen O, Wokke J, van den Bergh W. Magnesium treatment for patients with refractory status epilepticus due to POLG1-mutations. J Neurol. 2011;258:218-22 pubmed publisher
    ..Given the difficulties encountered while treating epilepsy in patients with this syndrome, magnesium therapy might be considered...
  35. de Vries M, Rodenburg R, Morava E, Lammens M, van den Heuvel L, Korenke G, et al. Normal biochemical analysis of the oxidative phosphorylation (OXPHOS) system in a child with POLG mutations: a cautionary note. J Inherit Metab Dis. 2008;31 Suppl 2:S299-302 pubmed publisher
  36. Schochet S, Lampert P, Earle K. Alexander's disease. A case report with electron microscopic observations. Neurology. 1968;18:543-9 pubmed
  37. Tselis A, Lisak R. Other demyelinating diseases. Adv Neurol. 2006;98:335-49 pubmed
  38. Nagi S, Megdiche H, Mrabet H, Sebai R, Chaabane S, Belghith L, et al. [Balò's concentric sclerosis in a North-African patient]. Rev Neurol (Paris). 2005;161:78-80 pubmed
    ..Balo's concentric sclerosis is a rare variant of multiple sclerosis described by Balo in 1928. It is characterized by alternating rings of demyelination and spared myelin...
  39. Inoue K, Osaka H, Kawanishi C, Sugiyama N, Ishii M, Sugita K, et al. Mutations in the proteolipid protein gene in Japanese families with Pelizaeus-Merzbacher disease. Neurology. 1997;48:283-5 pubmed
    ..Since linkage analysis has shown homogeneity at the PLP locus in patients with PMD, our findings suggest that there may be genetic abnormalities other than exonic mutations that cause milder forms of PMD...
  40. Saugier Veber P, Munnich A, Bonneau D, Rozet J, Le Merrer M, Gil R, et al. X-linked spastic paraplegia and Pelizaeus-Merzbacher disease are allelic disorders at the proteolipid protein locus. Nat Genet. 1994;6:257-62 pubmed
    ..63, theta = 0.00). It appears, therefore, that SPG2 and PMD are allelic disorders...
  41. Mohamed K, Fathallah W, Ahmed E. Gender variability in presentation with Alpers' syndrome: a report of eight patients from the UAE. J Inherit Metab Dis. 2011;34:439-41 pubmed publisher
    ..Alpers' syndrome is a progressive and often fatal cerebral and hepatic degeneration caused by a mutation in the polymerase gamma (POLG) gene involved in mitochondrial DNA replication...
  42. Mowry E, Woo J, Ances B. Technology insight: can neuroimaging provide insights into the role of ischemia in Baló's concentric sclerosis?. Nat Clin Pract Neurol. 2007;3:341-8 pubmed
    ..In this Review, we discuss evidence from longitudinal neuroimaging studies that supports the role of ischemic preconditioning in BCS...
  43. Bao X, Wu Y, Wong L, Zhang Y, Xiong H, Chou P, et al. Alpers syndrome with prominent white matter changes. Brain Dev. 2008;30:295-300 pubmed
    ..In addition, there were prominent white matter changes in a series of brain magnetic resonance imaging (MRI) and increased immunological factors in CSF...
  44. Ishii M, Takanashi J, Sugita K, Suzuki A, Goto M, Tanabe Y, et al. [Serial MR imaging of possible Pelizaeus-Merzbacher disease]. No To Hattatsu. 1993;25:9-15 pubmed
    ..It was speculated that MRI in case 1 and case 2-4 might correspond to neuropathologic findings of classical and connatal form as reported in the literature...
  45. Meier C, Herschkowitz N, Bischoff A. Morphological and biochemical observations in the Jimpy spinal cord. Acta Neuropathol. 1974;27:349-62 pubmed
  46. Xiong H, Liu C, Zhang Y, Bao X, Jiang Y, Zhao H, et al. [Valproic acid-induced idiosyncratic liver injury in 4 cases]. Zhonghua Er Ke Za Zhi. 2012;50:890-4 pubmed
    ..The clinical manifestations and therapeutic approaches were investigated in order to improve its diagnosis and management...
  47. Tzoulis C, Neckelmann G, Mørk S, Engelsen B, Viscomi C, Moen G, et al. Localized cerebral energy failure in DNA polymerase gamma-associated encephalopathy syndromes. Brain. 2010;133:1428-37 pubmed publisher
    ..We suggest therefore that both infantile and later onset polymerase gamma related encephalopathies are part of a continuum...
  48. Pelzers E, Van Goethem J, van den Hauwe L, Degryse H, Geens K, Parizel P. Baló's concentric sclerosis. JBR-BTR. 2008;91:108-9 pubmed
  49. Khan A, Trevenen C, Wei X, Sarnat H, Payne E, Kirton A. Alpers syndrome: the natural history of a case highlighting neuroimaging, neuropathology, and fat metabolism. J Child Neurol. 2012;27:636-40 pubmed publisher
  50. Kartvelishvili E, Tworowski D, Vernon H, Moor N, Wang J, Wong L, et al. Kinetic and structural changes in HsmtPheRS, induced by pathogenic mutations in human FARS2. Protein Sci. 2017;26:1505-1516 pubmed publisher
    ..Using steady-state kinetic measurements of phenylalanine activation and tRNAPhe aminoacylation, we gained insight into the structural and kinetic effects of mitochondrial disease-related mutations in FARS2 gene. ..
  51. Obara S, Takeshima H, Awa R, Yonezawa H, Oyoshi T, Nagayama T, et al. Tumefactive myelinoclastic diffuse sclerosis--case report. Neurol Med Chir (Tokyo). 2003;43:563-6 pubmed
    ..MDS must be included in the differential diagnosis in young patients with a brain tumor with atypical radiological appearance...
  52. Wiltshire E, Davidzon G, DiMauro S, Akman H, Sadleir L, Haas L, et al. Juvenile Alpers disease. Arch Neurol. 2008;65:121-4 pubmed publisher
    ..Alpers disease is commonly associated with polymerase gamma deficiency and usually affects infants or young children...
  53. Scalais E, Francois B, Schlesser P, Stevens R, Nuttin C, Martin J, et al. Polymerase gamma deficiency (POLG): clinical course in a child with a two stage evolution from infantile myocerebrohepatopathy spectrum to an Alpers syndrome and neuropathological findings of Leigh's encephalopathy. Eur J Paediatr Neurol. 2012;16:542-8 pubmed publisher
    ..Description of the clinical course in a child compound heterozygous for POLG1 mutations, neuropathology findings and results of dietary treatment based on fasting avoidance and long chain triglycerides (LCT) restriction...