Leukodystrophies: a proposed classification system based on pathological changes and pathogenetic mechanisms

Leukodystrophies are genetically determined disorders characterized by the selective involvement of the central nervous system white matter. Onset may be at any age, from prenatal life to senescence. Many leukodystrophies are degenerative in nature, but some only impair white matter function. The clinical course is mostly progressive, but may also be static or even improving with time. Progressive leukodystrophies are often fatal, and no curative treatment is known. The last decade has witnessed a tremendous increase in the number of defined leukodystrophies also owing to a diagnostic approach combining magnetic resonance imaging pattern recognition and next generation sequencing. Knowledge on white matter physiology and pathology has also dramatically built up. This led to the recognition that only few leukodystrophies are due to mutations in myelin- or oligodendrocyte-specific genes, and many are rather caused by defects in other white matter structural components, including astrocytes, microglia, axons and blood vessels. We here propose a novel classification of leukodystrophies that takes into account the primary involvement of any white matter component. Categories in this classification are the myelin disorders due to a primary defect in oligodendrocytes or myelin (hypomyelinating and demyelinating leukodystrophies, leukodystrophies with myelin vacuolization); astrocytopathies; leuko-axonopathies; microgliopathies; and leuko-vasculopathies. Following this classification, we illustrate the neuropathology and disease mechanisms of some leukodystrophies taken as example for each category. Some leukodystrophies fall into more than one category. Given the complex molecular and cellular interplay underlying white matter pathology, recognition of the cellular pathology behind a disease becomes crucial in addressing possible treatment strategies

Lysosomal storage diseases—the horizon expands

Since the discovery of the lysosome in 1955, advances have been made in understanding the key roles and functions of this organelle. The concept of lysosomal storage diseases (LSDs) - disorders characterized by aberrant, excessive storage of cellular material in lysosomes - developed following the discovery of α-glucosidase deficiency as the cause of Pompe disease in 1963. Great strides have since been made in understanding the pathobiology of LSDs and the neuronal ceroid lipofuscinoses (NCLs). The NCLs are neurodegenerative disorders that display symptoms of cognitive and motor decline, seizures, blindness, early death, and accumulation of lipofuscin in various cell types, and also show some similarities to 'classic' LSDs. Defective lysosomal storage can occur in many cell types, but the CNS and PNS are particularly vulnerable to LSDs and NCLs, being affected in two-thirds of these disorders. Most LSDs are inherited in an autosomal recessive manner, with the exception of X-linked Hunter disease, Fabry disease and Danon disease, and a variant type of adult NCL (Kuf disease). This Review provides a summary of known LSDs, and the pathways affected in these disorders. Existing therapies and barriers to development of novel and improved treatments for LSDs and NCLs are also discussed. © 2013 Macmillan Publishers Limited.Abbott MA, 2011, MOL GENET METAB, V104, P583, DOI 10.1016-j.ymgme.2011.08.003; Aerts JM, 2008, P NATL ACAD SCI USA, V105, P2812, DOI 10.1073-pnas.0712309105; Aliabadi H, 2010, NEUROSURGERY, V67, P1476, DOI 10.1227-NEU.0b013e3181f8c11d; Al Sawaf S, 2008, J INHERIT METAB DIS, V31, P473, DOI 10.1007-s10545-008-0878-x; Alvarez VE, 2012, BBA-PROTEINS PROTEOM, V1824, P195, DOI 10.1016-j.bbapap.2011.05.011; [Anonymous], 2009, SUMM GAUCH DIS PAT P; Arsov T, 2011, AM J HUM GENET, V88, P566, DOI 10.1016-j.ajhg.2011.04.004; ARVIO M, 1993, ACTA PAEDIATR, V82, P587, DOI 10.1111-j.1651-2227.1993.tb12761.x; Auffray C, 2011, GENOME MED, V3, DOI 10.1186-gm220; AULA P, 1979, ARCH NEUROL-CHICAGO, V36, P88; Bailey L., 2008, ONLINE J ISSUE UNPUB, V13, P3; Ballabio A, 2009, BBA-MOL CELL RES, V1793, P684, DOI 10.1016-j.bbamcr.2008.12.001; B'chir W., NUCL ACIDS RES; Batten FE., 1903, T OPHTHAL SOC UK, V23, P386; Benitez BA, 2011, PLOS ONE, V6, DOI 10.1371-journal.pone.0026741; Berkovic SE, 2008, AM J HUM GENET, V82, P673, DOI 10.1016-j.ajhg.2007.12.019; Biegstraaten M, 2012, MOL GENET METAB, V106, P135, DOI 10.1016-j.ymgme.2012.03.010; Bielschowsky M., 1913, DEUTSCHE Z NERVENHEI, V50, P7; Birch DG, 1999, MOL GENET METAB, V66, P356, DOI 10.1006-mgme.1999.2829; Bonten EJ, 2004, FASEB J, V18, P971, DOI 10.1096-fj.03-0941fje; Boustany R. M., 2013, EMERY RIMOINS PRINCI; Boustany R. M., 2007, EMERY RIMOINS PRINCI, P2449; Boustany R M, 1988, Am J Med Genet Suppl, V5, P47; Brady RO, 2006, ANNU REV MED, V57, P283, DOI 10.1146-annurev.med.57.110104.115650; BRAMA I, 1986, INT J PEDIATR OTORHI, V11, P229, DOI 10.1016-S0165-5876(86)80034-9; Braunlin EA, 2011, J INHERIT METAB DIS, V34, P1183, DOI 10.1007-s10545-011-9359-8; Brooks DA, 2006, TRENDS MOL MED, V12, P367, DOI 10.1016-j.molmed.2006.06.001; Chang JW, 2011, J NEUROCHEM, V116, P659, DOI 10.1111-j.1471-4159.2010.07158.x; Chattopadhyay S, 2000, J BACTERIOL, V182, P6418, DOI 10.1128-JB.182.22.6418-6423.2000; Chen CS, 1999, LANCET, V354, P901, DOI 10.1016-S0140-6736(98)10034-X; Choudhury A, 2002, J CLIN INVEST, V109, P1541, DOI 10.1172-JCI200215420; Ciechanover A, 2012, BBA-PROTEINS PROTEOM, V1824, P3, DOI 10.1016-j.bbapap.2011.03.007; COLLINS RC, 1989, ANN INTERN MED, V110, P992; Coutinho MF, 2012, MOL GENET METAB, V105, P542, DOI 10.1016-j.ymgme.2011.12.012; Crystal RG, 2004, HUM GENE THER, V15, P1131; Czeh M, 2011, DEV NEUROSCI-BASEL, V33, P199, DOI 10.1159-000328989; d'Azzo A., 2009, NATHAN OSKIS HEMATOL, P1301; Davidson CD, 2009, PLOS ONE, V4, DOI 10.1371-journal.pone.0006951; de Ru MH, 2011, ORPHANET J RARE DIS, V6, DOI 10.1186-1750-1172-6-55; Debs R., J INHERIT METAB DIS; DEDUVE C, 1964, FED PROC, V23, P1045; de Duve C, 2005, NAT CELL BIOL, V7, P847, DOI 10.1038-ncb0905-847; Desnick RJ, 2012, ANNU REV GENOM HUM G, V13, P307, DOI 10.1146-annurev-genom-090711-163739; Dhar S, 2002, ANN NEUROL, V51, P448, DOI 10.1002-ana.10143; DiRosario J, 2009, J NEUROSCI RES, V87, P978, DOI 10.1002-jnr.21912; Domon MM, 2011, BIOCHEM BIOPH RES CO, V405, P192, DOI 10.1016-j.bbrc.2010.12.138; Eliyahu E, 2011, PLOS ONE, V6, DOI 10.1371-journal.pone.0022447; Eng CM, 2007, J INHERIT METAB DIS, V30, P184, DOI 10.1007-s10545-007-0521-2; Escolar ML, 2006, PEDIATRICS, V118, pE879, DOI 10.1542-peds.2006-0747; Escolar ML, 2005, NEW ENGL J MED, V352, P2069, DOI 10.1056-NEJMoa042604; Frustaci A, 2001, NEW ENGL J MED, V345, P25, DOI 10.1056-NEJM200107053450104; Futerman AH, 2004, NAT REV MOL CELL BIO, V5, P554, DOI 10.1038-nrm1423; Garbutt S, 2000, BRIT J OPHTHALMOL, V84, P451, DOI 10.1136-bjo.84.5.451; Ghosh A, 2012, J BIOL CHEM, V287, P38922, DOI 10.1074-jbc.M112.365148; Ginzburg L, 2005, J NEUROCHEM, V95, P1619, DOI 10.1111-j.1471-4159.2005.03534.x; Ginzburg L, 2008, J NEUROCHEM, V104, P140, DOI 10.1111-j.1471-4159.2007.04983.x; Giri S, 2006, J LIPID RES, V47, P1478, DOI 10.1194-jlr.M600084-JLR200; Goebel HH, 1996, BRAIN PATHOL, V6, P225, DOI 10.1111-j.1750-3639.1996.tb00850.x; Guillemot N, 2007, PEDIATR PULM, V42, P1207, DOI 10.1002-ppul.20725; Guo WX, 1999, CELL MOL NEUROBIOL, V19, P671, DOI 10.1023-A:1006992704108; Gupta Nidhi, 2012, Saudi J Anaesth, V6, P178, DOI 10.4103-1658-354X.97036; Haddad Saria El, 2012, Electrophoresis, V33, P3798, DOI 10.1002-elps.201200472; Haltia M., BIOCH BIOPHYS ACTA; HANNUN YA, 1989, SCIENCE, V243, P500, DOI 10.1126-science.2643164; Harati H., 2012, 13 INT C NEUR CER LI, P54; HERS HG, 1965, GASTROENTEROLOGY, V48, P625; Hirabayashi Y., 2006, SPHINGOLIPID BIOL, P83; Hoffmann B, 2005, NEUROPEDIATRICS, V36, P285, DOI 10.1055-s-2005-872810; Huebner EA, 2009, RESULTS PROBL CELL D, V48, P339, DOI 10.1007-400_2009_19; Huizing M, 2008, ANNU REV GENOM HUM G, V9, P359, DOI 10.1146-annurev.genom.9.081307.164303; Husebye H, 2006, EMBO J, V25, P683, DOI 10.1038-sj.emboj.7600991; Jakobkiewicz-Banecka J, 2009, J BIOMED SCI, V16, DOI 10.1186-1423-0127-16-26; Jansky J., 1908, SB LEK, V13, P165; Jardim LB, 2010, J INHERIT METAB DIS, V33, P315, DOI 10.1007-s10545-010-9079-5; Jeyakumar Mylvaganam, 2005, Nat Rev Neurosci, V6, P713; Jmoudiak M, 2005, BRIT J HAEMATOL, V129, P178, DOI 10.1111-j.1365-2141.2004.05351.x; Johnson GB, 2002, J IMMUNOL, V168, P5233; Jurecka A, 2012, PEDIATR NEUROSURG, V48, P191, DOI 10.1159-000345635; Kamate M, 2011, PEDIATR NEUROL, V44, P155, DOI 10.1016-j.pediatrneurol.2010.09.015; Kanazawa T, 2000, J CELL BIOL, V149, P943, DOI 10.1083-jcb.149.4.943; Khoury M. J., 2013, PUBLIC HLTH GENOMICS; Kim SJ, 2006, HUM MOL GENET, V15, P1580, DOI 10.1093-hmg-ddi078; Kim SJ, 2006, HUM MOL GENET, V15, P1826, DOI 10.1093-hmg-ddl105; Kirkegaard T, 2010, NATURE, V463, P549, DOI 10.1038-nature08710; Klenk E., 1939, Z PHYSL CHEM, V262, P128; KOBAYASHI T, 1987, BIOCHEM BIOPH RES CO, V144, P41, DOI 10.1016-S0006-291X(87)80472-2; KOBAYASHI T, 1992, J NEUROCHEM, V59, P1452, DOI 10.1111-j.1471-4159.1992.tb08460.x; Koeberl DD, 2011, MOL GENET METAB, V103, P107, DOI 10.1016-j.ymgme.2011.02.006; Kohan R, 2011, CURR PHARM BIOTECHNO, V12, P867, DOI 1389-2010-11 $58.00+.00; Koike M, 2005, AM J PATHOL, V167, P1713, DOI 10.1016-S0002-9440(10)61253-9; Kolodny E., 1983, METABOLIC BASIS INHE, P881; Kolodny E. H., 1987, HEMATOLOGY INFANCY C, P1212; Korkotian E, 1999, J BIOL CHEM, V274, P21673, DOI 10.1074-jbc.274.31.21673; Kumperscak HG, 2005, J PSYCHIATR NEUROSCI, V30, P33; Kwon JY, 2011, AM J MED GENET A, V155A, P1329, DOI 10.1002-ajmg.a.34013; Lake BD, 1998, BRAIN PATHOL, V8, P133; Lane SC, 1996, J NEUROCHEM, V67, P677; Lang G. E., 1988, RETINAL DYSTROPHIES, P319; Li ST, 2013, FASEB J, V27, P34, DOI 10.1096-fj.12-207472; Lloyd-Evans E, 2003, J BIOL CHEM, V278, P23594, DOI 10.1074-jbc.M300212200; te Vruchte Danielle, 2004, J Biol Chem, V279, P26167; Lukina E, 2010, BLOOD, V116, P893, DOI [10.1182-blood-2010-03-273151, 10.1182-blood-2010-06-293902]; Ma XC, 2007, MOL THER, V15, P889, DOI 10.1038-mt.sj.6300112; Maegawa GHB, 2009, MOL GENET METAB, V98, P215, DOI 10.1016-j.ymgme.2009.06.005; Maga JA, 2013, J BIOL CHEM, V288, P1428, DOI 10.1074-jbc.M112.438663; Maiuri MC, 2007, NAT REV MOL CELL BIO, V8, P741, DOI 10.1038-nrm2239; Manara R, 2011, J INHERIT METAB DIS, V34, P763, DOI 10.1007-s10545-011-9317-5; Messinger YH, 2012, GENET MED, V14, P135, DOI 10.1038-gim.2011.4; Miller JN, 2013, HUM MOL GENET, V22, P2723, DOI 10.1093-hmg-ddt120; Mohrenschlager M, 2010, EUR J MED GENET, V53, P225, DOI 10.1016-j.ejmg.2010.02.001; Mole S., 2012, NEURONAL CEROID LIPO; Montano AM, 2008, MOL GENET METAB, V94, P178, DOI 10.1016-j.ymgme.2008.01.007; MOREHEAD JM, 1993, INT J PEDIATR OTORHI, V26, P255, DOI 10.1016-0165-5876(93)90096-L; Muenzer J, 2011, RHEUMATOLOGY, V50, pV4, DOI 10.1093-rheumatology-ker394; Muhlebach MS, 2011, PAEDIATR RESPIR REV, V12, P133, DOI 10.1016-j.prrv.2010.10.005; Muller S, 2012, BBA-PROTEINS PROTEOM, V1824, P34, DOI 10.1016-j.bbapap.2011.07.003; Neto ARD, 2013, J NEUROSURG-PEDIATR, V11, P327, DOI 10.3171-2012.11.PEDS11419; NILSSON O, 1982, BIOCHIM BIOPHYS ACTA, V712, P453, DOI 10.1016-0005-2760(82)90272-7; Pacheco CD, 2007, AUTOPHAGY, V3, P487; Palmucci S., INSIGHTS IMAGING; Pan CD, 2005, BLOOD, V106, P1956, DOI 10.1182-blood-2005-02-0657; Pastores GM, 2007, MOL GENET METAB, V91, P37, DOI 10.1016-j.ymgme.2007.01.011; Pelled D, 2005, NEUROBIOL DIS, V18, P83, DOI 10.1016-j.nbd.2004.09.004; Pelled D, 2003, J BIOL CHEM, V278, P29496, DOI 10.1074-jbc.M302964200; Persaud-Sawin DA, 2005, APOPTOSIS, V10, P973, DOI 10.1007-s10495-005-0733-6; Persaud-Sawin DA, 2007, PEDIATR RES, V61, P146, DOI 10.1203-pdr.0b013e31802d8a4a; Persaud-Sawin DANW, 2002, HUM MOL GENET, V11, P2129, DOI 10.1093-hmg-11.18.2129; Platt FM, 2008, ACTA PAEDIATR, V97, P88, DOI 10.1111-j.1651-2227.2008.00656.x; Platt FM, 2009, BBA-MOL CELL RES, V1793, P737, DOI 10.1016-j.bbamcr.2008.08.009; Puranam K, 1997, NEUROPEDIATRICS, V28, P37, DOI 10.1055-s-2007-973664; Puranam KL, 1999, MOL GENET METAB, V66, P294, DOI 10.1006-mgme.1999.2834; Raben N, 2007, Acta Myol, V26, P45; Repnik U, 2012, BBA-PROTEINS PROTEOM, V1824, P22, DOI 10.1016-j.bbapap.2011.08.016; Rountree JSS, 2009, CHEMMEDCHEM, V4, P378, DOI 10.1002-cmdc.200800350; Rusyn E, 2008, PEDIATR RES, V63, P625, DOI 10.1203-PDR.0b013e31816fdc17; Sachs B., 1896, NEW YORK M J, V63, P697; Saftig P, 2008, AUTOPHAGY, V4, P510; Saftig P, 2009, NAT REV MOL CELL BIO, V10, P623, DOI 10.1038-nrm2745; Sands MS, 2006, MOL THER, V13, P839, DOI 10.1016-j.ymthe.2006.01.006; Sarpong A, 2009, CLIN GENET, V76, P38, DOI 10.1111-j.1399-0004.2009.01179.x; Schultz ML, 2011, TRENDS NEUROSCI, V34, P401, DOI 10.1016-j.tins.2011.05.006; Seehafer SS, 2011, J NEUROIMMUNOL, V230, P169, DOI 10.1016-j.jneuroim.2010.08.024; Sehgal R, 2011, NEUROLOGY, V77, pE20, DOI 10.1212-WNL.0b013e318225aaf5; Settembre C, 2008, AUTOPHAGY, V4, P113; Shapiro BE, 2009, GENET MED, V11, P425, DOI 10.1097-GIM.0b013e3181a1b5c5; Shih SL, 2002, ACTA RADIOL, V43, P40, DOI 10.1034-j.1600-0455.2002.430108.x; Siddiqi ZA, 2006, NEUROLOGY, V67, P268, DOI 10.1212-01.wnl.0000230156.01228.33; Simonaro CM, 2010, P NATL ACAD SCI USA, V107, P222, DOI 10.1073-pnas.0912937107; Smith KR, 2012, AM J HUM GENET, V90, P1102, DOI 10.1016-j.ajhg.2012.04.021; Smith KR, 2013, HUM MOL GENET, V22, P1417, DOI 10.1093-hmg-dds558; Spranger J., 2007, EMERY RIMOINS PRINCI, P2403; Staropoli JF, 2012, AM J HUM GENET, V91, P202, DOI 10.1016-j.ajhg.2012.05.023; Staretz-Chacham O, 2009, PEDIATRICS, V123, P1191, DOI 10.1542-peds.2008-0635; Stengel O. C., 1826, EYR MED TIDSKRIFT, V1, P347; SHAPIRO J, 1985, ANN OTO RHINOL LARYN, V94, P458; Su M., 2013, J ONCOL, V2013, DOI [10.1155-2013-102735, DOI 10.1155-2013-102735]; Sunwoo MK, 2011, J CLIN NEUROL, V7, P99, DOI 10.3988-jcn.2011.7.2.99; Suvarna JC, 2008, J POSTGRAD MED, V54, P54; Suzuki M, 2007, J NEUROSCI, V27, P1879, DOI 10.1523-JNEUROSCI.5282-06.2007; SVENNERHOLM L, 1962, BIOCHEM BIOPH RES CO, V9, P436, DOI 10.1016-0006-291X(62)90030-X; Tessitore A, 2004, MOL CELL, V15, P753, DOI 10.1016-j.molcel.2004.08.029; Thappa DM, 1998, PEDIATR DERMATOL, V15, P370, DOI 10.1046-j.1525-1470.1998.1998015370.x; The International Batten Disease Consortium, 1995, CELL, V82, P949; Tokushige S, 2013, BRAIN DEV-JPN, V35, P579, DOI 10.1016-j.braindev.2012.08.004; Tropak MB, 2010, GLYCOBIOLOGY, V20, P356, DOI 10.1093-glycob-cwp183; Tuttolomondo A., CURR PHARM DES; Urbanelli Lorena, 2013, Recent Pat CNS Drug Discov, V8, P91; Vainio S, 2005, BIOCHEM J, V391, P465, DOI 10.1042-BJ20050460; Valayannopoulos V, 2011, RHEUMATOLOGY, V50, pV49, DOI 10.1093-rheumatology-ker396; Vitner EB, 2010, J BIOL CHEM, V285, P20423, DOI 10.1074-jbc.R110.134452; Vogt H., 1909, ARCH KINDERHEILKD, V51, P1; Vogt H., 1905, MSCHR PSYCHIAT NEURO, V19, P161; Walkley SU, 2009, J INHERIT METAB DIS, V32, P181, DOI 10.1007-s10545-008-1040-5; Weaver TE, 2002, SEMIN CELL DEV BIOL, V13, P263, DOI 10.1016-S1084-9521(02)00055-1; Worgall S, 2007, NEUROLOGY, V69, P521, DOI 10.1212-01.wnl.0000267885.47092.40; Xu M, 2012, J BIOL CHEM, V287, DOI 10.1074-jbc.M112.357707; Young-Gqamana B, 2013, PLOS ONE, V8, DOI 10.1371-journal.pone.0057631; Zaka M, 2004, NEUROSCI LETT, V358, P205, DOI 10.1016-j.neulet.2003.12.126; Zhang ZJ, 2001, NAT MED, V7, P478, DOI 10.1038-86554; Zheng Z., FEBS J; Zhou QH, 2012, DRUG METAB DISPOS, V40, P329, DOI 10.1124-dmd.111.0429038171