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3. List of contributors

Author

Ah Mew, Nicholas, primary, Akamatsu, Wado, additional, Akman, Hasan Orhan, additional, AlHakeem, Afnan, additional, Aoyama, Koji, additional, Artuch, Rafael, additional, Beck, Michael, additional, Bennett, C. Frank, additional, Berry, Gerard T., additional, Bissell, D. Montgomery, additional, Canine, Brenda, additional, Caskey, C. Thomas, additional, Casy, Widler, additional, Chinnery, Patrick F., additional, Chuang, David T., additional, Cook, Emily K., additional, Cox, Rody P., additional, De Jager, Philip L., additional, Demirbas, Didem, additional, Desnick, Robert J., additional, DiMauro, Salvatore, additional, Eichler, Florian S., additional, Elger, Bernice, additional, Emmanuele, Valentina, additional, Evans, Patricia, additional, Fogel, Brent L., additional, García-Cazorla, Àngels, additional, Gellera, Cinzia, additional, Golla, Sailaja, additional, Goodspeed, Kimberly, additional, Gospe, Sidney M., additional, Gray, Steven J., additional, Gropman, Andrea L., additional, Gu, Yian, additional, Guerrini, Renzo, additional, Gunn, Teresa M., additional, Hadziahmetovic, Una, additional, Haffner, Darrah, additional, Hagerman, R.J., additional, Harel, Tamar, additional, Head, Elizabeth, additional, Horvath, Rita, additional, Hosoi, Yasushi, additional, Hou, Ying-Chen Claire, additional, Hsiao, Jane, additional, Ishiura, Hiroyuki, additional, Jack, Clifford R., additional, Jakkamsetti, Vikram, additional, Johnson†, William G., additional, Jotterand, Fabrice, additional, Kane, John P., additional, Khorkova, Olga, additional, Kinoshita, Chisato, additional, Klompe, Sanne E., additional, Koehl, Lisa M., additional, Kruer, Michael C., additional, Kukull, Walter A., additional, Lane, Roger M., additional, Lee, Joseph H., additional, Leigh, M.J., additional, Ling, Qinglan, additional, Lupski, James R., additional, Luzi, Paola, additional, Ma, Qian, additional, Maegawa, Gustavo H.B., additional, Malloy, Mary J., additional, Margolis, Seth S., additional, Marin-Valencia, Isaac, additional, Mastrianni, James A., additional, Matalon, Dena, additional, Matalon, Reuben, additional, Matalon Rd, Kimberlee Michals, additional, Mathews, Jennifer M., additional, Mayeux, Richard, additional, McCurdy, Jennifer, additional, Meltzer, Meira R., additional, Menkes†, John H., additional, Miron, Justin, additional, Mitsui, Jun, additional, Miyajima, Hiroaki, additional, Monteggia, Lisa M., additional, Morris, Mary Ann, additional, Moser†, Hugo W., additional, Murray, Melissa E., additional, Nakaki, Toshio, additional, Nilsson, Nathalie, additional, Nishino, Ichizo, additional, Nordlie, Sandra M.H., additional, Nussbaum, Robert L., additional, Nyhan, William L., additional, Okano, Hideyuki, additional, Padilla-Lopez, Sergio, additional, Parrini, Elena, additional, Pascual, Juan M., additional, Pastores, Gregory M., additional, Patel, Shailendra B., additional, Patterson, Marc C., additional, Pena, Izabella A., additional, Picard, Cynthia, additional, Poirier, Judes, additional, Posey, Jennifer E., additional, Raymond, Gerald V., additional, Renthal, William, additional, Rosenblatt, David S., additional, Rossignol, Francis, additional, Salen, Gerald, additional, Sandhoff, Konrad, additional, Schiffmann, Raphael, additional, Schindler, Detlev, additional, Schmitt, Frederick A., additional, Schneider, Susanne A., additional, Schon, Eric A., additional, Schuchman, Edward H., additional, Seashore, Margretta Reed, additional, Shaffo, Frances C., additional, Shevell, Michael, additional, Sinnett, Sarah E., additional, Srour, Myriam, additional, Sternberg, Samuel H., additional, Sugie, Kazuma, additional, Szabla, Kristen L., additional, Taroni, Franco, additional, Tedeschi Dauar, Marina, additional, Tsuji, Shoji, additional, Uhlmann, Wendy R., additional, van Karnebeek, Clara, additional, Van Pelt, Kathryn L., additional, Vemuri, Prashanthi, additional, Venditti, Charles P., additional, Wahlestedt, Claes, additional, Wang, Bruce, additional, Watkins, David, additional, Wenger, David A., additional, Williams, Charles A., additional, Wilson, Golder N., additional, Wolf, Barry, additional, Wynn, R. Max, additional, and Yu, Hung-Chun, additional

Published
2020
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5. List of Contributors

Author

Abbott, M.A., Akamatsu, Wado, Akman, Hasan Orhan, AlHakeem, Afnan, Ali, Sheliza, AlMutiri, Rowim, Aoyama, Koji, Artuch, Rafael, Aumont-Rodrigue, Gabriel, Baril, Andrée-Ann, Barshop, Bruce A., Beck, Michael, Bennett, C. Frank, Berry, Gerard T., Boitnott, Andrea, Calame, Daniel G., Canine, Brenda, Casy, Widler, Chinnery, Patrick F., Chuang, David T., De Jager, Philip L., Demirbas, Didem, Desnick, Robert J., DiMauro, Salvatore, d’Azzo, A., Eichler, Florian S., Elmquist, Joel K., Emmanuele, Valentina, Engelen, Marc, Esteves, S., Evans, Patricia, Fogel, Brent L., Fremuth, L.E., Gallagher, J., García-Cazorla, Àngels, Garza, Irvin T., Glueck, Amanda C., Golla, Sailaja, Goodarzi, Mohammad, Goodspeed, Kimberly, Gray, Steven J., Gray-Edwards, H., Gropman, Andrea L., Guerrini, Renzo, Guldner, Ian H., Gunn, Teresa M., Haffner, Darrah, Hagerman, R.J., Harel, Tamar, Harp, Jordan P., Head, Elizabeth, Horvath, Rita, Ishii, Makoto, Ishiura, Hiroyuki, Jakkamsetti, Vikram, Jalazo, Elizabeth R., Khorkova, Olga, Kinoshita, Chisato, Kukull, Walter A., Lane, Roger, Latham, Stephen R., Leigh, M.J., Ling, Qinglan, Lupski, James R., Luzi, Paola, Ma, Qian, Maegawa, Gustavo H.B., Marin-Valencia, Isaac, Mastrianni, James A., Matalon, Dena R., Matalon, Kimberlee Michals, Matalon, Reuben, Mathews, Jennifer M., Megagiannis, Platon, Mehta, Nikita, Meltzer, Meira R., Mengel, Eugen, Mew, Nicholas Ah, Millar Vernetti, Patricio, Mitsui, Jun, Monteggia, Lisa M., Morris, Mary Ann, Moser, Hugo W., Murray, Melissa E., Nakaki, Toshio, Nishino, Ichizo, Noble, Denis, Nussbaum, Robert L., Nyhan, William L., Okano, Hideyuki, Parrini, Elena, Pascual, Juan M., Pastores, Gregory M., Patterson, Marc C., Piazza, Michelle K., Picard, Cynthia, Poirier, Judes, Pomerantz, Daniel J., Posey, Jennifer E., Raymond, Gerald V., Renthal, William, Rossignol, Francis, Rouleau, Guy A., Saez-Calveras, Nil, Sandhoff, Konrad, Schiffmann, Raphael, Schindler, Detlev, Schmitt, Frederick A., Schon, Eric A., Schuchman, Edward H., Seashore, Margretta Reed, Sena-Esteves, M., Shaffo, Frances C., Shevell, Michael, Shishodia, Gauri, Sinnett, Sarah E., Srour, Myriam, Stevens, Hannah A., Sugie, Kazuma, Taylor, Alexa, Tedeschi Dauar, Marina, Thinwa, Josephine, Tifft, C., Tsuji, Shoji, Uhlmann, Wendy R., Van Pelt, Kathryn L., Vemuri, Prashanthi, Vernino, Steven, Wahlestedt, Claes, Wang, Bruce, Weesner, J.A., Wenger, David A., Williams, Kevin W., Wolf, Nicole I., Wolfe, John H., Wynn, R. Max, Wyss-Coray, Tony, Yingling, N., and Zhou, Yang

Published
2025
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12. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author

O’Donnell-Luria, Anne H., primary, Pais, Lynn S., additional, Faundes, Víctor, additional, Wood, Jordan C., additional, Sveden, Abigail, additional, Luria, Victor, additional, Abou Jamra, Rami, additional, Accogli, Andrea, additional, Amburgey, Kimberly, additional, Anderlid, Britt Marie, additional, Azzarello-Burri, Silvia, additional, Basinger, Alice A., additional, Bianchini, Claudia, additional, Bird, Lynne M., additional, Buchert, Rebecca, additional, Carre, Wilfrid, additional, Ceulemans, Sophia, additional, Charles, Perrine, additional, Cox, Helen, additional, Culliton, Lisa, additional, Currò, Aurora, additional, Demurger, Florence, additional, Dowling, James J., additional, Duban-Bedu, Benedicte, additional, Dubourg, Christèle, additional, Eiset, Saga Elise, additional, Escobar, Luis F., additional, Ferrarini, Alessandra, additional, Haack, Tobias B., additional, Hashim, Mona, additional, Heide, Solveig, additional, Helbig, Katherine L., additional, Helbig, Ingo, additional, Heredia, Raul, additional, Héron, Delphine, additional, Isidor, Bertrand, additional, Jonasson, Amy R., additional, Joset, Pascal, additional, Keren, Boris, additional, Kok, Fernando, additional, Kroes, Hester Y., additional, Lavillaureix, Alinoë, additional, Lu, Xin, additional, Maas, Saskia M., additional, Maegawa, Gustavo H.B., additional, Marcelis, Carlo L.M., additional, Mark, Paul R., additional, Masruha, Marcelo R., additional, McLaughlin, Heather M., additional, McWalter, Kirsty, additional, Melchinger, Esther U., additional, Mercimek-Andrews, Saadet, additional, Nava, Caroline, additional, Pendziwiat, Manuela, additional, Person, Richard, additional, Ramelli, Gian Paolo, additional, Ramos, Luiza L.P., additional, Rauch, Anita, additional, Reavey, Caitlin, additional, Renieri, Alessandra, additional, Rieß, Angelika, additional, Sanchez-Valle, Amarilis, additional, Sattar, Shifteh, additional, Saunders, Carol, additional, Schwarz, Niklas, additional, Smol, Thomas, additional, Srour, Myriam, additional, Steindl, Katharina, additional, Syrbe, Steffen, additional, Taylor, Jenny C., additional, Telegrafi, Aida, additional, Thiffault, Isabelle, additional, Trauner, Doris A., additional, van der Linden, Helio, additional, van Koningsbruggen, Silvana, additional, Villard, Laurent, additional, Vogel, Ida, additional, Vogt, Julie, additional, Weber, Yvonne G., additional, Wentzensen, Ingrid M., additional, Widjaja, Elysa, additional, Zak, Jaroslav, additional, Baxter, Samantha, additional, Banka, Siddharth, additional, Rodan, Lance H., additional, McRae, Jeremy F., additional, Clayton, Stephen, additional, Fitzgerald, Tomas W., additional, Kaplanis, Joanna, additional, Prigmore, Elena, additional, Rajan, Diana, additional, Sifrim, Alejandro, additional, Aitken, Stuart, additional, Akawi, Nadia, additional, Alvi, Mohsan, additional, Ambridge, Kirsty, additional, Barrett, Daniel M., additional, Bayzetinova, Tanya, additional, Jones, Philip, additional, Jones, Wendy D., additional, King, Daniel, additional, Krishnappa, Netravathi, additional, Mason, Laura E., additional, Singh, Tarjinder, additional, Tivey, Adrian R., additional, Ahmed, Munaza, additional, Anjum, Uruj, additional, Archer, Hayley, additional, Armstrong, Ruth, additional, Awada, Jana, additional, Balasubramanian, Meena, additional, Baralle, Diana, additional, Barnicoat, Angela, additional, Batstone, Paul, additional, Baty, David, additional, Bennett, Chris, additional, Berg, Jonathan, additional, Bernhard, Birgitta, additional, Bevan, A. Paul, additional, Bitner-Glindzicz, Maria, additional, Blair, Edward, additional, Blyth, Moira, additional, Bohanna, David, additional, Bourdon, Louise, additional, Bourn, David, additional, Bradley, Lisa, additional, Brady, Angela, additional, Brent, Simon, additional, Brewer, Carole, additional, Brunstrom, Kate, additional, Bunyan, David J., additional, Burn, John, additional, Canham, Natalie, additional, Castle, Bruce, additional, Chandler, Kate, additional, Chatzimichali, Elena, additional, Cilliers, Deirdre, additional, Clarke, Angus, additional, Clasper, Susan, additional, Clayton-Smith, Jill, additional, Clowes, Virginia, additional, Coates, Andrea, additional, Cole, Trevor, additional, Colgiu, Irina, additional, Collins, Amanda, additional, Collinson, Morag N., additional, Connell, Fiona, additional, Cooper, Nicola, additional, Cresswell, Lara, additional, Cross, Gareth, additional, Crow, Yanick, additional, D’Alessandro, Mariella, additional, Dabir, Tabib, additional, Davidson, Rosemarie, additional, Davies, Sally, additional, de Vries, Dylan, additional, Dean, John, additional, Deshpande, Charu, additional, Devlin, Gemma, additional, Dixit, Abhijit, additional, Dobbie, Angus, additional, Donaldson, Alan, additional, Donnai, Dian, additional, Donnelly, Deirdre, additional, Donnelly, Carina, additional, Douglas, Angela, additional, Douzgou, Sofia, additional, Duncan, Alexis, additional, Eason, Jacqueline, additional, Ellard, Sian, additional, Ellis, Ian, additional, Elmslie, Frances, additional, Evans, Karenza, additional, Everest, Sarah, additional, Fendick, Tina, additional, Fisher, Richard, additional, Flinter, Frances, additional, Foulds, Nicola, additional, Fry, Andrew, additional, Fryer, Alan, additional, Gardiner, Carol, additional, Gaunt, Lorraine, additional, Ghali, Neeti, additional, Gibbons, Richard, additional, Gill, Harinder, additional, Goodship, Judith, additional, Goudie, David, additional, Gray, Emma, additional, Green, Andrew, additional, Greene, Philip, additional, Greenhalgh, Lynn, additional, Gribble, Susan, additional, Harrison, Rachel, additional, Harrison, Lucy, additional, Harrison, Victoria, additional, Hawkins, Rose, additional, He, Liu, additional, Hellens, Stephen, additional, Henderson, Alex, additional, Hewitt, Sarah, additional, Hildyard, Lucy, additional, Hobson, Emma, additional, Holden, Simon, additional, Holder, Muriel, additional, Holder, Susan, additional, Hollingsworth, Georgina, additional, Homfray, Tessa, additional, Humphreys, Mervyn, additional, Hurst, Jane, additional, Hutton, Ben, additional, Ingram, Stuart, additional, Irving, Melita, additional, Islam, Lily, additional, Jackson, Andrew, additional, Jarvis, Joanna, additional, Jenkins, Lucy, additional, Johnson, Diana, additional, Jones, Elizabeth, additional, Josifova, Dragana, additional, Joss, Shelagh, additional, Kaemba, Beckie, additional, Kazembe, Sandra, additional, Kelsell, Rosemary, additional, Kerr, Bronwyn, additional, Kingston, Helen, additional, Kini, Usha, additional, Kinning, Esther, additional, Kirby, Gail, additional, Kirk, Claire, additional, Kivuva, Emma, additional, Kraus, Alison, additional, Kumar, Dhavendra, additional, Kumar, V. K. Ajith, additional, Lachlan, Katherine, additional, Lam, Wayne, additional, Lampe, Anne, additional, Langman, Caroline, additional, Lees, Melissa, additional, Lim, Derek, additional, Longman, Cheryl, additional, Lowther, Gordon, additional, Lynch, Sally A., additional, Magee, Alex, additional, Maher, Eddy, additional, Male, Alison, additional, Mansour, Sahar, additional, Marks, Karen, additional, Martin, Katherine, additional, Maye, Una, additional, McCann, Emma, additional, McConnell, Vivienne, additional, McEntagart, Meriel, additional, McGowan, Ruth, additional, McKay, Kirsten, additional, McKee, Shane, additional, McMullan, Dominic J., additional, McNerlan, Susan, additional, McWilliam, Catherine, additional, Mehta, Sarju, additional, Metcalfe, Kay, additional, Middleton, Anna, additional, Miedzybrodzka, Zosia, additional, Miles, Emma, additional, Mohammed, Shehla, additional, Montgomery, Tara, additional, Moore, David, additional, Morgan, Sian, additional, Morton, Jenny, additional, Mugalaasi, Hood, additional, Murday, Victoria, additional, Murphy, Helen, additional, Naik, Swati, additional, Nemeth, Andrea, additional, Nevitt, Louise, additional, Newbury-Ecob, Ruth, additional, Norman, Andrew, additional, O’Shea, Rosie, additional, Ogilvie, Caroline, additional, Ong, Kai-Ren, additional, Park, Soo-Mi, additional, Parker, Michael J., additional, Patel, Chirag, additional, Paterson, Joan, additional, Payne, Stewart, additional, Perrett, Daniel, additional, Phipps, Julie, additional, Pilz, Daniela T., additional, Pollard, Martin, additional, Pottinger, Caroline, additional, Poulton, Joanna, additional, Pratt, Norman, additional, Prescott, Katrina, additional, Price, Sue, additional, Pridham, Abigail, additional, Procter, Annie, additional, Purnell, Hellen, additional, Quarrell, Oliver, additional, Ragge, Nicola, additional, Rahbari, Raheleh, additional, Randall, Josh, additional, Rankin, Julia, additional, Raymond, Lucy, additional, Rice, Debbie, additional, Robert, Leema, additional, Roberts, Eileen, additional, Roberts, Jonathan, additional, Roberts, Paul, additional, Roberts, Gillian, additional, Ross, Alison, additional, Rosser, Elisabeth, additional, Saggar, Anand, additional, Samant, Shalaka, additional, Sampson, Julian, additional, Sandford, Richard, additional, Sarkar, Ajoy, additional, Schweiger, Susann, additional, Scott, Richard, additional, Scurr, Ingrid, additional, Selby, Ann, additional, Seller, Anneke, additional, Sequeira, Cheryl, additional, Shannon, Nora, additional, Sharif, Saba, additional, Shaw-Smith, Charles, additional, Shearing, Emma, additional, Shears, Debbie, additional, Sheridan, Eamonn, additional, Simonic, Ingrid, additional, Singzon, Roldan, additional, Skitt, Zara, additional, Smith, Audrey, additional, Smith, Kath, additional, Smithson, Sarah, additional, Sneddon, Linda, additional, Splitt, Miranda, additional, Squires, Miranda, additional, Stewart, Fiona, additional, Stewart, Helen, additional, Straub, Volker, additional, Suri, Mohnish, additional, Sutton, Vivienne, additional, Swaminathan, Ganesh Jawahar, additional, Sweeney, Elizabeth, additional, Tatton-Brown, Kate, additional, Taylor, Cat, additional, Taylor, Rohan, additional, Tein, Mark, additional, Temple, I. Karen, additional, Thomson, Jenny, additional, Tischkowitz, Marc, additional, Tomkins, Susan, additional, Torokwa, Audrey, additional, Treacy, Becky, additional, Turner, Claire, additional, Turnpenny, Peter, additional, Tysoe, Carolyn, additional, Vandersteen, Anthony, additional, Varghese, Vinod, additional, Vasudevan, Pradeep, additional, Vijayarangakannan, Parthiban, additional, Wakeling, Emma, additional, Wallwark, Sarah, additional, Waters, Jonathon, additional, Weber, Astrid, additional, Wellesley, Diana, additional, Whiteford, Margo, additional, Widaa, Sara, additional, Wilcox, Sarah, additional, Wilkinson, Emily, additional, Williams, Denise, additional, Williams, Nicola, additional, Wilson, Louise, additional, Woods, Geoff, additional, Wragg, Christopher, additional, Wright, Michael, additional, Yates, Laura, additional, Yau, Michael, additional, Nellåker, Chris, additional, Parker, Michael, additional, Firth, Helen V., additional, Wright, Caroline F., additional, FitzPatrick, David R., additional, Barrett, Jeffrey C., additional, and Hurles, Matthew E., additional

Published
2019
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16. Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations

Author

Lalani, Seema R., primary, Liu, Pengfei, additional, Rosenfeld, Jill A., additional, Watkin, Levi B., additional, Chiang, Theodore, additional, Leduc, Magalie S., additional, Zhu, Wenmiao, additional, Ding, Yan, additional, Pan, Shujuan, additional, Vetrini, Francesco, additional, Miyake, Christina Y., additional, Shinawi, Marwan, additional, Gambin, Tomasz, additional, Eldomery, Mohammad K., additional, Akdemir, Zeynep Hande Coban, additional, Emrick, Lisa, additional, Wilnai, Yael, additional, Schelley, Susan, additional, Koenig, Mary Kay, additional, Memon, Nada, additional, Farach, Laura S., additional, Coe, Bradley P., additional, Azamian, Mahshid, additional, Hernandez, Patricia, additional, Zapata, Gladys, additional, Jhangiani, Shalini N., additional, Muzny, Donna M., additional, Lotze, Timothy, additional, Clark, Gary, additional, Wilfong, Angus, additional, Northrup, Hope, additional, Adesina, Adekunle, additional, Bacino, Carlos A., additional, Scaglia, Fernando, additional, Bonnen, Penelope E., additional, Crosson, Jane, additional, Duis, Jessica, additional, Maegawa, Gustavo H.B., additional, Coman, David, additional, Inwood, Anita, additional, McGill, Jim, additional, Boerwinkle, Eric, additional, Graham, Brett, additional, Beaudet, Art, additional, Eng, Christine M., additional, Hanchard, Neil A., additional, Xia, Fan, additional, Orange, Jordan S., additional, Gibbs, Richard A., additional, Lupski, James R., additional, and Yang, Yaping, additional

Published
2016
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17. Neuropathic Lysosomal Storage Disorders

Author

Pastores, Gregory M. and Maegawa, Gustavo H.B.

Subjects
Lysosomal Storage Diseases, Humans, Article
Abstract

The lysosomal storage disorders (LSDs) are a clinically heterogeneous group of inborn errors of metabolism, associated with the accumulation of incompletely degraded macromolecules within several cellular sites. Affected individuals present with a broad range of clinical problems, including hepatosplenomegaly and skeletal dysplasia. Onset of symptoms may range from birth to adulthood. The majority are associated with neurological features, including developmental delay, behavioral/psychiatric disturbances, seizures, acroparesthesia, motor weakness, cerebrovascular ischemic events and extra-pyramidal signs. It should be noted that later-onset forms are often misdiagnosed as symptoms, which might include psychiatric manifestations, are slowly progressive and may precede other neurologic or systemic features. Inheritance is primarily autosomal recessive. For all subtypes, diagnosis can be confirmed using a combination of biochemical and/or molecular assays. In a few LSDs, treatment with either hematopoietic stem cell transplantation, enzyme replacement or substrate reduction therapy is available. Genetic counseling is important, so patients and their families can be informed of reproductive risks, disease prognosis and therapeutic options. Investigations of disease mechanisms are providing insights into potential therapeutic approaches. Symptomatic care, which remains the mainstay for most subtypes, can lead to significant improvement in quality of life.

Published
2013

23. Novel proton MR spectroscopy findings in adenylosuccinate lyase deficiency

Author

Zulfiqar, Maria, primary, Lin, Doris D.M., additional, Van der Graaf, Marinette, additional, Barker, Peter B., additional, Fahrner, Jill A., additional, Marie, Sandrine, additional, Morava, Eva, additional, De Boer, Lonneke, additional, Willemsen, Michel A.A.P., additional, Vining, Eileen, additional, Horská, Alena, additional, Engelke, Udo, additional, Wevers, Ron A., additional, and Maegawa, Gustavo H.B., additional

Published
2012
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26. The natural history of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported

Author

Maegawa, Gustavo H.B., Stockley, Tracy, Tropak, Michael, Banwell, Brenda, Blaser, Susan, Kok, Fernando, Giugliani, Roberto, Mahuran, Don, and Clarke, Joe T.R.

Subjects
Metabolism, Inborn errors of -- Risk factors, Tay-Sachs disease -- Causes of, Tay-Sachs disease -- Development and progression, Tay-Sachs disease -- Genetic aspects, Tay-Sachs disease -- History
Abstract

OBJECTIVE. Juvenile GM2 gangliosidosis is a group of inherited neurodegenerative diseases caused by deficiency of lysosomal [beta]-hexosaminidase resulting in GM2 ganglioside accumulation in brain. The purpose of this study was to delineate the natural history of the condition and identify genotype-phenotype correlations that might be helpful in predicting the course of the disease in individual patients. METHODS. A cohort of 21 patients with juvenile GM2 gangliosidosis, 15 with the Tay-Sachs variant and 6 with the Sandhoff variant, was studied prospectively in 2 centers. Our experience was compared with previously published reports on 134 patients. Information about clinical features, [beta]-hexosaminidase enzyme activity, and mutation analysis was collected. RESULTS. In our cohort of patients, the mean ([+ or -] SD) age of onset of symptoms was 5.3 [+ or -] 4.1 years, with a mean follow-up time of 8.4 years. The most common symptoms at onset were gait disturbances (66.7%), incoordination (52.4%), speech problems (28.6%), and developmental delay (28.6%). The age of onset of gait disturbances was 7.1 [+ or -] 5.6 years. The mean time for progression to becoming wheelchair-bound was 6.2 [+ or -] 5.5 years. The mean age of onset of speech problems was 7.0 [+ or -] 5.6 years, with a mean time of progression to anarthria of 5.6 [+ or -] 5.3 years. Muscle wasting (10.6 [+ or -] 7.4 years), proximal weakness (11.1 [+ or -] 7.7 years), and incontinence of sphincters (14.6 [+ or -] 9.7 years) appeared later in the course of the disease. Psychiatric disturbances and neuropathy were more prevalent in patients with the Sandhoff variant than in those with the TaySachs variant. However, dysphagia, sphincter incontinence, and sleep problems occurred earlier in those with the Tay-Sachs variant. Cerebellar atrophy was the most common finding on brain MRI (52.9%). The median survival time among the studied and reviewed patients was 14.5 years. The genotype-phenotype correlation revealed that in patients with the Tay-Sachs variant, the presence of R 178H and R499H mutations was predictive of an early onset and rapidly progressive course. The presence of either G269S or W474C mutations was associated with a later onset of symptoms along with a more slowly progressive disease course. CONCLUSIONS. Juvenile GM2 gangliosidosis is clinically heterogeneous, not only in terms of age of onset and clinical features but also with regard to the course of the disease. In general, the earlier the onset of symptoms, the more rapidly the disease progresses. The Tay-Sachs and Sandhuff variants differed somewhat in the frequency of specific clinical characteristics. Speech deterioration progressed more rapidly than gait abnormalities in both the Tay-Sachs variant and Sandhoff variant groups. Among patients with the Tay-Sachs variant, the HEXA genotype showed a significant correlation with the clinical course. KEY WORDS. juvenile GM2 gangliosidosis, [beta]-hexosaminidase deficiency, Tay-Sachs disease, Sandhoff disease, lysosomal storage disease., URL: www.pediatrics.org/cgi/doi/10.1542/peds.2006-0588 Gustavo H. B. Maegawa, MD, Tracy Stockley, PhD, Michael Tropak, PhD, Brenda Banwell, MD, Susan Blaser, MD, Fernando Kok, MD, PhD, Roberto Giugliani, MD, PhD, Don Mahuran, PhD, [...]

Published
2006

29. Substrate reduction therapy in juvenile GM2 gangliosidosis

Author

Maegawa, Gustavo H.B., Banwell, Brenda L., Blaser, Susan, Sorge, Geoffrey, Toplak, Maggie, Ackerley, Cameron, Hawkins, Cynthia, Hayes, Jason, and Clarke, Joe T.R.

Subjects
*GANGLIOSIDOSES, *INTELLECTUAL disabilities, *PEDIATRIC therapy, *TREATMENT effectiveness, *NEUROPSYCHOLOGY, *MAGNETIC resonance imaging of the brain, *HEALTH outcome assessment, *TRANSMISSION electron microscopy, *THERAPEUTICS
Abstract

Abstract: Substrate reduction therapy (SRT) is considered to be a potential therapeutic option for juvenile GM2 gangliosidosis (jGM2g). We evaluated the efficacy of SRT in jGM2g, assessing neurological, neuropsychological and brain magnetic resonance imaging (MRI) outcomes over a 24-month period of treatment. In an open-label and single-center study, five jGM2g patients (mean age 14.6±4.5years) received oral miglustat at doses of 100–200mg t.i.d. adjusted to body surface area. Patients underwent general and neurological examinations, neuropsychological, electrophysiological, and brain MRI studies. All patients showed neurological deterioration over the period of the study, with particularly notable worsening of gait, speech and coordination. One patient experienced acute psychosis, and another showed worsening of pre-existing epilepsy. Some neuropsychological tests showed no evidence of deterioration in the three patients with high enough cognitive functioning for reliable assessment. Profound cognitive impairment in two children precluded neuropsychological evaluation. In four patients, evaluation of brain MRI showed no changes in white matter signal abnormalities and cerebellar atrophy noted at baseline, while one patient showed progression of cerebellar and supratentorial brain atrophy. Transmission electron microscopy analysis of peripheral mononuclear cells showed reduction of intracytoplasmatic inclusions with treatment. SRT with miglustat of patients with jGM2g failed to ameliorate progressive neurological deterioration, but apparently no worsening of some areas of cognitive function tested and brain MRI lesions was noted over 24months of treatment. The results must be interpreted with care owing to the small sample of patients and the lack of a control-arm. [Copyright &y& Elsevier]

Published
2009
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