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1. Clinico-radiological features, molecular spectrum, and identification of prognostic factors in developmental and epileptic encephalopathy due to inosine triphosphate pyrophosphatase (ITPase) deficiency

Author

Scala, Marcello, Wortmann, Saskia B., Kaya, Namik, Stellingwerff, Menno D., Pistorio, Angela, Glamuzina, Emma, van Karnebeek, Clara D., Skrypnyk, Cristina, Iwanicka-Pronicka, Katarzyna, Piekutowska-Abramczuk, Dorota, Ciara, Elżbieta, Tort, Frederic, Sheidley, Beth, Poduri, Annapurna, Jayakar, Parul, Jayakar, Anuj, Upadia, Jariya, Walano, Nicolette, Haack, Tobias B., Prokisch, Holger, Aldhalaan, Hesham, Karimiani, Ehsan G., Yildiz, Yilmaz, Ceylan, Ahmet C., Santiago-Sim, Teresa, Dameron, Amy, Yang, Hui, Toosi, Mehran B., Ashrafzadeh, Farah, Akhondian, Javad, Imannezhad, Shima, Mirzadeh, Hanieh S., Maqbool, Shazia, Farid, Aisha, Al-Muhaizea, Mohamed A., Alshwameen, Meznah O., Aldowsari, Lama, Alsagob, Maysoon, Alyousef, Ashwaq, AlMass, Rawan, AlHargan, Aljouhra, Alwadei, Ali H., AlRasheed, Maha M., Colak, Dilek, Alqudairy, Hanan, Khan, Sameena, Lines, Matthew A., García Cazorla, M. Ángeles, Ribes, Antonia, Morava, Eva, Bibi, Farah, Haider, Shahzad, Ferla, Matteo P., Taylor, Jenny C., Alsaif, Hessa S., Firdous, Abdulwahab, Hashem, Mais, Shashkin, Chingiz, Koneev, Kairgali, Kaiyrzhanov, Rauan, Efthymiou, Stephanie, Genomics, Queen Square, Schmitt-Mechelke, Thomas, Ziegler, Andreas, Issa, Mahmoud Y., Elbendary, Hasnaa M., Striano, Pasquale, Alkuraya, Fowzan S., Zaki, Maha S., Gleeson, Joseph G., Barakat, Tahsin Stefan, Bierau, Jorgen, van der Knaap, Marjo S., Maroofian, Reza, Houlden, Henry, Scala, Marcello, Wortmann, Saskia B., Kaya, Namik, Stellingwerff, Menno D., Pistorio, Angela, Glamuzina, Emma, van Karnebeek, Clara D., Skrypnyk, Cristina, Iwanicka-Pronicka, Katarzyna, Piekutowska-Abramczuk, Dorota, Ciara, Elżbieta, Tort, Frederic, Sheidley, Beth, Poduri, Annapurna, Jayakar, Parul, Jayakar, Anuj, Upadia, Jariya, Walano, Nicolette, Haack, Tobias B., Prokisch, Holger, Aldhalaan, Hesham, Karimiani, Ehsan G., Yildiz, Yilmaz, Ceylan, Ahmet C., Santiago-Sim, Teresa, Dameron, Amy, Yang, Hui, Toosi, Mehran B., Ashrafzadeh, Farah, Akhondian, Javad, Imannezhad, Shima, Mirzadeh, Hanieh S., Maqbool, Shazia, Farid, Aisha, Al-Muhaizea, Mohamed A., Alshwameen, Meznah O., Aldowsari, Lama, Alsagob, Maysoon, Alyousef, Ashwaq, AlMass, Rawan, AlHargan, Aljouhra, Alwadei, Ali H., AlRasheed, Maha M., Colak, Dilek, Alqudairy, Hanan, Khan, Sameena, Lines, Matthew A., García Cazorla, M. Ángeles, Ribes, Antonia, Morava, Eva, Bibi, Farah, Haider, Shahzad, Ferla, Matteo P., Taylor, Jenny C., Alsaif, Hessa S., Firdous, Abdulwahab, Hashem, Mais, Shashkin, Chingiz, Koneev, Kairgali, Kaiyrzhanov, Rauan, Efthymiou, Stephanie, Genomics, Queen Square, Schmitt-Mechelke, Thomas, Ziegler, Andreas, Issa, Mahmoud Y., Elbendary, Hasnaa M., Striano, Pasquale, Alkuraya, Fowzan S., Zaki, Maha S., Gleeson, Joseph G., Barakat, Tahsin Stefan, Bierau, Jorgen, van der Knaap, Marjo S., Maroofian, Reza, and Houlden, Henry

Abstract

Developmental and epileptic encephalopathy 35 (DEE 35) is a severe neurological condition caused by biallelic variants in ITPA, encoding inosine triphosphate pyrophosphatase, an essential enzyme in purine metabolism. We delineate the genotypic and phenotypic spectrum of DEE 35, analyzing possible predictors for adverse clinical outcomes. We investigated a cohort of 28 new patients and reviewed previously described cases, providing a comprehensive characterization of 40 subjects. Exome sequencing was performed to identify underlying ITPA pathogenic variants. Brain MRI (magnetic resonance imaging) scans were systematically analyzed to delineate the neuroradiological spectrum. Survival curves according to the Kaplan–Meier method and log-rank test were used to investigate outcome predictors in different subgroups of patients. We identified 18 distinct ITPA pathogenic variants, including 14 novel variants, and two deletions. All subjects showed profound developmental delay, microcephaly, and refractory epilepsy followed by neurodevelopmental regression. Brain MRI revision revealed a recurrent pattern of delayed myelination and restricted diffusion of early myelinating structures. Congenital microcephaly and cardiac involvement were statistically significant novel clinical predictors of adverse outcomes. We refined the molecular, clinical, and neuroradiological characterization of ITPase deficiency, and identified new clinical predictors which may have a potentially important impact on diagnosis, counseling, and follow-up of affected individuals.

Published
2022

2. De novo substitutions of TRPM3 cause intellectual disability and epilepsy

Author

Dyment, David A., Terhal, Paulien A., Rustad, Cecilie F., Tveten, Kristian, Griffith, Christopher, Jayakar, Parul, Shinawi, Marwan, Ellingwood, Sara, Smith, Rosemarie, van Gassen, Koen, McWalter, Kirsty, Innes, A. Micheil, Lines, Matthew A., Dyment, David A., Terhal, Paulien A., Rustad, Cecilie F., Tveten, Kristian, Griffith, Christopher, Jayakar, Parul, Shinawi, Marwan, Ellingwood, Sara, Smith, Rosemarie, van Gassen, Koen, McWalter, Kirsty, Innes, A. Micheil, and Lines, Matthew A.

Published
2019

3. De novo substitutions of TRPM3 cause intellectual disability and epilepsy

Author

Dyment, David A., Terhal, Paulien A., Rustad, Cecilie F., Tveten, Kristian, Griffith, Christopher, Jayakar, Parul, Shinawi, Marwan, Ellingwood, Sara, Smith, Rosemarie, van Gassen, Koen, McWalter, Kirsty, Innes, A. Micheil, Lines, Matthew A., Dyment, David A., Terhal, Paulien A., Rustad, Cecilie F., Tveten, Kristian, Griffith, Christopher, Jayakar, Parul, Shinawi, Marwan, Ellingwood, Sara, Smith, Rosemarie, van Gassen, Koen, McWalter, Kirsty, Innes, A. Micheil, and Lines, Matthew A.

Published
2019

4. De novo substitutions of TRPM3 cause intellectual disability and epilepsy

Author

Dyment, David A., Terhal, Paulien A., Rustad, Cecilie F., Tveten, Kristian, Griffith, Christopher, Jayakar, Parul, Shinawi, Marwan, Ellingwood, Sara, Smith, Rosemarie, van Gassen, Koen, McWalter, Kirsty, Innes, A. Micheil, Lines, Matthew A., Dyment, David A., Terhal, Paulien A., Rustad, Cecilie F., Tveten, Kristian, Griffith, Christopher, Jayakar, Parul, Shinawi, Marwan, Ellingwood, Sara, Smith, Rosemarie, van Gassen, Koen, McWalter, Kirsty, Innes, A. Micheil, and Lines, Matthew A.

Published
2019

5. PLPHP deficiency: clinical, genetic, biochemical, and mechanistic insights.

Author

Johnstone, Devon L, Johnstone, Devon L, Al-Shekaili, Hilal H, Tarailo-Graovac, Maja, Wolf, Nicole I, Ivy, Autumn S, Demarest, Scott, Roussel, Yann, Ciapaite, Jolita, van Roermund, Carlo WT, Kernohan, Kristin D, Kosuta, Ceres, Ban, Kevin, Ito, Yoko, McBride, Skye, Al-Thihli, Khalid, Abdelrahim, Rana A, Koul, Roshan, Al Futaisi, Amna, Haaxma, Charlotte A, Olson, Heather, Sigurdardottir, Laufey Yr, Arnold, Georgianne L, Gerkes, Erica H, Boon, M, Heiner-Fokkema, M Rebecca, Noble, Sandra, Bosma, Marjolein, Jans, Judith, Koolen, David A, Kamsteeg, Erik-Jan, Drögemöller, Britt, Ross, Colin J, Majewski, Jacek, Cho, Megan T, Begtrup, Amber, Wasserman, Wyeth W, Bui, Tuan, Brimble, Elise, Violante, Sara, Houten, Sander M, Wevers, Ron A, van Faassen, Martijn, Kema, Ido P, Lepage, Nathalie, Care4Rare Canada Consortium, Lines, Matthew A, Dyment, David A, Wanders, Ronald JA, Verhoeven-Duif, Nanda, Ekker, Marc, Boycott, Kym M, Friedman, Jan M, Pena, Izabella A, van Karnebeek, Clara DM, Johnstone, Devon L, Johnstone, Devon L, Al-Shekaili, Hilal H, Tarailo-Graovac, Maja, Wolf, Nicole I, Ivy, Autumn S, Demarest, Scott, Roussel, Yann, Ciapaite, Jolita, van Roermund, Carlo WT, Kernohan, Kristin D, Kosuta, Ceres, Ban, Kevin, Ito, Yoko, McBride, Skye, Al-Thihli, Khalid, Abdelrahim, Rana A, Koul, Roshan, Al Futaisi, Amna, Haaxma, Charlotte A, Olson, Heather, Sigurdardottir, Laufey Yr, Arnold, Georgianne L, Gerkes, Erica H, Boon, M, Heiner-Fokkema, M Rebecca, Noble, Sandra, Bosma, Marjolein, Jans, Judith, Koolen, David A, Kamsteeg, Erik-Jan, Drögemöller, Britt, Ross, Colin J, Majewski, Jacek, Cho, Megan T, Begtrup, Amber, Wasserman, Wyeth W, Bui, Tuan, Brimble, Elise, Violante, Sara, Houten, Sander M, Wevers, Ron A, van Faassen, Martijn, Kema, Ido P, Lepage, Nathalie, Care4Rare Canada Consortium, Lines, Matthew A, Dyment, David A, Wanders, Ronald JA, Verhoeven-Duif, Nanda, Ekker, Marc, Boycott, Kym M, Friedman, Jan M, Pena, Izabella A, and van Karnebeek, Clara DM

Abstract

Biallelic pathogenic variants in PLPBP (formerly called PROSC) have recently been shown to cause a novel form of vitamin B6-dependent epilepsy, the pathophysiological basis of which is poorly understood. When left untreated, the disease can progress to status epilepticus and death in infancy. Here we present 12 previously undescribed patients and six novel pathogenic variants in PLPBP. Suspected clinical diagnoses prior to identification of PLPBP variants included mitochondrial encephalopathy (two patients), folinic acid-responsive epilepsy (one patient) and a movement disorder compatible with AADC deficiency (one patient). The encoded protein, PLPHP is believed to be crucial for B6 homeostasis. We modelled the pathogenicity of the variants and developed a clinical severity scoring system. The most severe phenotypes were associated with variants leading to loss of function of PLPBP or significantly affecting protein stability/PLP-binding. To explore the pathophysiology of this disease further, we developed the first zebrafish model of PLPHP deficiency using CRISPR/Cas9. Our model recapitulates the disease, with plpbp-/- larvae showing behavioural, biochemical, and electrophysiological signs of seizure activity by 10 days post-fertilization and early death by 16 days post-fertilization. Treatment with pyridoxine significantly improved the epileptic phenotype and extended lifespan in plpbp-/- animals. Larvae had disruptions in amino acid metabolism as well as GABA and catecholamine biosynthesis, indicating impairment of PLP-dependent enzymatic activities. Using mass spectrometry, we observed significant B6 vitamer level changes in plpbp-/- zebrafish, patient fibroblasts and PLPHP-deficient HEK293 cells. Additional studies in human cells and yeast provide the first empirical evidence that PLPHP is localized in mitochondria and may play a role in mitochondrial metabolism. These models provide new insights into disease mechanisms and can serve as a platform for drug disc

Published
2019

6. De novo substitutions of TRPM3 cause intellectual disability and epilepsy

Author

Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Dyment, David A., Terhal, Paulien A., Rustad, Cecilie F., Tveten, Kristian, Griffith, Christopher, Jayakar, Parul, Shinawi, Marwan, Ellingwood, Sara, Smith, Rosemarie, van Gassen, Koen, McWalter, Kirsty, Innes, A. Micheil, Lines, Matthew A., Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, Dyment, David A., Terhal, Paulien A., Rustad, Cecilie F., Tveten, Kristian, Griffith, Christopher, Jayakar, Parul, Shinawi, Marwan, Ellingwood, Sara, Smith, Rosemarie, van Gassen, Koen, McWalter, Kirsty, Innes, A. Micheil, and Lines, Matthew A.

Published
2019

7. Mandibulofacial Dysostosis with Microcephaly: Mutation and Database Update.

Author

Huang, Lijia, Huang, Lijia, Vanstone, Megan R, Hartley, Taila, Osmond, Matthew, Barrowman, Nick, Allanson, Judith, Baker, Laura, Dabir, Tabib A, Dipple, Katrina M, Dobyns, William B, Estrella, Jane, Faghfoury, Hanna, Favaro, Francine P, Goel, Himanshu, Gregersen, Pernille A, Gripp, Karen W, Grix, Art, Guion-Almeida, Maria-Leine, Harr, Margaret H, Hudson, Cindy, Hunter, Alasdair GW, Johnson, John, Joss, Shelagh K, Kimball, Amy, Kini, Usha, Kline, Antonie D, Lauzon, Julie, Lildballe, Dorte L, López-González, Vanesa, Martinezmoles, Johanna, Meldrum, Cliff, Mirzaa, Ghayda M, Morel, Chantal F, Morton, Jenny EV, Pyle, Louise C, Quintero-Rivera, Fabiola, Richer, Julie, Scheuerle, Angela E, Schönewolf-Greulich, Bitten, Shears, Deborah J, Silver, Josh, Smith, Amanda C, Temple, I Karen, UCLA Clinical Genomics Center, van de Kamp, Jiddeke M, van Dijk, Fleur S, Vandersteen, Anthony M, White, Sue M, Zackai, Elaine H, Zou, Ruobing, Care4Rare Canada Consortium, Bulman, Dennis E, Boycott, Kym M, Lines, Matthew A, Huang, Lijia, Huang, Lijia, Vanstone, Megan R, Hartley, Taila, Osmond, Matthew, Barrowman, Nick, Allanson, Judith, Baker, Laura, Dabir, Tabib A, Dipple, Katrina M, Dobyns, William B, Estrella, Jane, Faghfoury, Hanna, Favaro, Francine P, Goel, Himanshu, Gregersen, Pernille A, Gripp, Karen W, Grix, Art, Guion-Almeida, Maria-Leine, Harr, Margaret H, Hudson, Cindy, Hunter, Alasdair GW, Johnson, John, Joss, Shelagh K, Kimball, Amy, Kini, Usha, Kline, Antonie D, Lauzon, Julie, Lildballe, Dorte L, López-González, Vanesa, Martinezmoles, Johanna, Meldrum, Cliff, Mirzaa, Ghayda M, Morel, Chantal F, Morton, Jenny EV, Pyle, Louise C, Quintero-Rivera, Fabiola, Richer, Julie, Scheuerle, Angela E, Schönewolf-Greulich, Bitten, Shears, Deborah J, Silver, Josh, Smith, Amanda C, Temple, I Karen, UCLA Clinical Genomics Center, van de Kamp, Jiddeke M, van Dijk, Fleur S, Vandersteen, Anthony M, White, Sue M, Zackai, Elaine H, Zou, Ruobing, Care4Rare Canada Consortium, Bulman, Dennis E, Boycott, Kym M, and Lines, Matthew A

Abstract

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).

Published
2016

8. Infantile Sialic Acid Storage Disease : Two Unrelated Inuit Cases Homozygous for a Common Novel SLC17A5 Mutation

Author

Lines, Matthew A, Rupar, C Anthony, Rip, Jack W, Baskin, Berivan, Ray, Peter N, Hegele, Robert A, Grynspan, David, Michaud, Jean, Geraghty, Michael T, Lines, Matthew A, Rupar, C Anthony, Rip, Jack W, Baskin, Berivan, Ray, Peter N, Hegele, Robert A, Grynspan, David, Michaud, Jean, and Geraghty, Michael T

Abstract

Infantile sialic acid storage disease (ISSD) is a lysosomal storage disease characterized by accumulation of covalently unlinked (free) sialic acid in multiple tissues. ISSD and Salla disease (a predominantly neurological disorder) are allelic disorders caused by recessive mutations of a lysosomal anionic monosaccharide transporter, SLC17A5. While Salla disease is common in Finland due to a founder-effect mutation (p.Arg39Cys), ISSD is comparatively rare in all populations studied.Here, we describe the clinical and molecular features of two unrelated Canadian Inuit neonates with a virtually identical presentation of ISSD. Both individuals presented antenatally with fetal hydrops, dying shortly following delivery. Urinary free sialic acid excretion was markedly increased in the one case in which urine could be obtained for testing; postmortem examination showed a picture of widespread lysosomal storage in both. Both children were homozygous for a novel splice site mutation (NM_012434:c.526-2A>G) resulting in skipping of exon 4 and an ensuing frameshift. Analysis of a further 129 pan-Arctic Inuit controls demonstrated a heterozygous carrier rate of 1/129 (~0.4 %) in our sample. Interestingly, lysosomal enzyme studies showed an unexplained ninefold increase in neuraminidase activity, with lesser elevations in the activities of several other lysosomal enzymes. Our results raise the possibility of a common founder mutation presenting as hydrops in this population. Furthermore, if confirmed in subsequent cases, the marked induction of neuraminidase activity seen here may prove useful in the clinical diagnosis of ISSD.

Published
2014
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