Bio

Bio


Child neurologist and medical geneticist focusing on the diagnosis and management of rare neurologic disorders. Specific interests are in genetic epilepsy syndromes, childhood neurodegenerative and neurometabolic diseases and undiagnosed suspected genetic conditions.

Clinical Focus


  • Neurology - Child Neurology
  • Neurogenetics
  • Medical Genetics

Academic Appointments


Professional Education


  • Fellowship: Stanford University School of Medicine (2017) CA
  • Board Certification: American Board of Medical Genetics and Genomics, Clinical Genetics (2019)
  • Board Certification, Clinical Genetics and Genomics, American Board of Genetics and Genomics (2019)
  • Board Certification: American Board of Psychiatry and Neurology, Neurology - Child Neurology (2016)
  • Fellowship: University of California - San Francisco (2015) CA
  • Residency: University of California - San Francisco (2012) CA
  • Medical Education: New York University School of Medicine (2010) NY

Research & Scholarship

Clinical Trials


  • NGLY1 Deficiency: A Prospective Natural History Study Not Recruiting

    NGLY1 deficiency is a rare genetic disorder that is characterized by: global developmental delay and/or intellectual disability, hypo- or alacrima, transient elevation of transaminases, and a hyperkinetic movement disorder. Significant phenotypic variability has been observed in the small number of affected individuals described in the medical literature. The purpose of this study is to describe the natural history of NGLY1 deficiency in a prospective, detailed, and highly uniform manner. Study participants will be closely monitored over the course of five years in order to: - understand the clinical spectrum and progression of NGLY1 deficiency using standardized clinical and neurodevelopmental assessments - identify clinical and biomarker endpoints for use in therapeutic trials, and - identify genotype-phenotype correlations Close clinical follow-up will allow for generation of a rich dataset and detailed understanding of the natural history of NGLY1 deficiency.

    Stanford is currently not accepting patients for this trial. For more information, please contact Study Team, 650-736-0885.

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Publications

All Publications


  • Variants in PRKAR1B cause a neurodevelopmental disorder with autism spectrum disorder, apraxia, and insensitivity to pain GENETICS IN MEDICINE Marbach, F., Stoyanov, G., Erger, F., Stratakis, C. A., Settas, N., London, E., Rosenfeld, J. A., Torti, E., Haldeman-Englert, C., Sklirou, E., Kessler, E., Ceulemans, S., Nelson, S. F., Martinez-Agosto, J. A., Palmer, C. S., Signer, R. H., Acosta, M. T., Adam, M., Adams, D. R., Agrawal, P. B., Alejandro, M. E., Alvey, J., Amendola, L., Andrews, A., Ashley, E. A., Azamian, M. S., Bacino, C. A., Bademci, G., Baker, E., Balasubramanyam, A., Baldridge, D., Bale, J., Bamshad, M., Barbouth, D., Bayrak-Toydemir, P., Beck, A., Beggs, A. H., Behrens, E., Bejerano, G., Bennett, J., Berg-Rood, B., Bernstein, J. A., Berry, G. T., Bican, A., Bivona, S., Blue, E., Bohnsack, J., Bonnenmann, C., Bonner, D., Botto, L., Boyd, B., Briere, L. C., Brokamp, E., Brown, G., Burke, E. A., Burrage, L. C., Butte, M. J., Byers, P., Byrd, W. E., Carey, J., Carrasquillo, O., Chang, T., Chanprasert, S., Chao, H., Clark, G. D., Coakley, T. R., Cobban, L. A., Cogan, J. D., Coggins, M., Cole, F., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., Crouse, A. B., Cunningham, M., D'Souza, P., Dai, H., Dasari, S., Davis, J., Daya, J. G., Deardorff, M., Dell'Angelica, E. C., Dhar, S. U., Dipple, K., Doherty, D., Dorrani, N., Doss, A. L., Douine, E. D., Draper, D. D., Duncan, L., Earl, D., Eckstein, D. J., Emrick, L. T., Eng, C. M., Esteves, C., Falk, M., Fernandez, L., Ferreira, C., Fieg, E. L., Findley, L. C., Fisher, P. G., Fogel, B. L., Forghani, I., Fresard, L., Gahl, W. A., Glass, I., Gochuico, B., Godfrey, R. A., Golden-Grant, K., Goldman, A. M., Goldrich, M. P., Goldstein, D. B., Grajewski, A., Groden, C. A., Gutierrez, I., Hahn, S., Hamid, R., Hanchard, N. A., Hassey, K., Hayes, N., High, F., Hing, A., Hisama, F. M., Holm, I. A., Hom, J., Horike-Pyne, M., Huang, A., Huang, Y., Huryn, L., Isasi, R., Jamal, F., Jarvik, G. P., Jarvik, J., Jayadev, S., Karaviti, L., Kennedy, J., Kiley, D., Kohane, I. S., Kohler, J. N., Korrick, S., Kozuira, M., Krakow, D., Krasnewich, D. M., Kravets, E., Krier, J. B., LaMoure, G. L., Lalani, S. R., Lam, B., Lam, C., Lanpher, B. C., Lanza, I. R., Latham, L., LeBlanc, K., Lee, B. H., Lee, H., Levitt, R., Lewis, R. A., Lincoln, S. A., Liu, P., Liu, X., Longo, N., Loo, S. K., Loscalzo, J., Maas, R. L., MacDowall, J., MacRae, C. A., Macnamara, E. F., Maduro, V. V., Majcherska, M. M., Mak, B. C., Malicdan, M. V., Mamounas, L. A., Manolio, T. A., Mao, R., Maravilla, K., Markello, T. C., Marom, R., Marth, G., Martin, B. A., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., McCauley, J., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., McGee, E., Mefford, H., Merritt, J., Might, M., Mirzaa, G., Morava, E., Moretti, P. M., Moretti, P., Mosbrook-Davis, D., Mulvihill, J. J., Murdock, D. R., Nagy, A., Nakano-Okuno, M., Nath, A., Nelson, S. F., Newman, J. H., Nicholas, S. K., Nickerson, D., Nieves-Rodriguez, S., Novacic, D., Oglesbee, D., Orengo, J. P., Pace, L., Pak, S., Pallais, J., Palmer, C. S., Papp, J. C., Parker, N. H., Phillips, J. A., Posey, J. E., Potocki, L., Power, B., Pusey, B. N., Quinlan, A., Raja, A. N., Rao, D. A., Raskind, W., Renteria, G., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Rosenwasser, N., Rossignol, F., Ruzhnikov, M., Sacco, R., Sampson, J. B., Samson, S. L., Saporta, M., Schaechter, J., Schedl, T., Schoch, K., Scott, C., Scott, D. A., Shashi, V., Shin, J., Signer, R. H., Silverman, E. K., Sinsheimer, J. S., Sisco, K., Smith, E. C., Smith, K. S., Solem, E., Solnica-Krezel, L., Ben Solomon, Spillmann, R. C., Stoler, J. M., Sullivan, J. A., Sullivan, K., Sun, A., Sutton, S., Sweetser, D. A., Sybert, V., Tabor, H. K., Tan, A. M., Tan, Q., Tekin, M., Telischi, F., Thorson, W., Thurm, A., Tifft, C. J., Toro, C., Tran, A. A., Tucker, B. M., Urv, T. K., Vanderver, A., Velinder, M., Viskochil, D., Vogel, T. P., Wahl, C. E., Walker, M., Wallace, S., Walley, N. M., Walsh, C. A., Wambach, J., Wan, J., Wang, L., Wangler, M. F., Ward, P. A., Wegner, D., Wener, M., Wenger, T., Perry, K., Westerfield, M., Wheeler, M. T., Whitlock, J., Wolfe, L. A., Woods, J. D., Yamamoto, S., Yang, J., Yousef, M., Zastrow, D. B., Zein, W., Zhao, C., Zuchner, S., Andrews, M. V., Grange, D. K., Willaert, R., Person, R., Telegrafi, A., Sievers, A., Laugsch, M., Theiss, S., Cheng, Y., Lichtarge, O., Katsonis, P., Stocco, A., Schaaf, C. P., Undiagnosed Diseases Network 2021

    Abstract

    We characterize the clinical and molecular phenotypes of six unrelated individuals with intellectual disability and autism spectrum disorder who carry heterozygous missense variants of the PRKAR1B gene, which encodes the R1? subunit of the cyclic AMP-dependent protein kinase A (PKA).Variants of PRKAR1B were identified by single- or trio-exome analysis. We contacted the families and physicians of the six individuals to collect phenotypic information, performed in vitro analyses of the identified PRKAR1B-variants, and investigated PRKAR1B expression during embryonic development.Recent studies of large patient cohorts with neurodevelopmental disorders found significant enrichment of de novo missense variants in PRKAR1B. In our cohort, de novo origin of the PRKAR1B variants could be confirmed in five of six individuals, and four carried the same heterozygous de novo variant c.1003C>T (p.Arg335Trp; NM_001164760). Global developmental delay, autism spectrum disorder, and apraxia/dyspraxia have been reported in all six, and reduced pain sensitivity was found in three individuals carrying the c.1003C>T variant. PRKAR1B expression in the brain was demonstrated during human embryonal development. Additionally, in vitro analyses revealed altered basal PKA activity in cells transfected with variant-harboring PRKAR1B expression constructs.Our study provides strong evidence for a PRKAR1B-related neurodevelopmental disorder.

    View details for DOI 10.1038/s41436-021-01152-7

    View details for Web of Science ID 000638059400001

    View details for PubMedID 33833410

  • Early Signs and Symptoms of Leukodystrophies: A Case-Based Guide. Pediatrics in review Ruzhnikov, M. R., Brimble, E., Hickey, R. E., Leukodystrophy Care Network 2021; 42 (3): 133?46

    View details for DOI 10.1542/pir.2019-0184

    View details for PubMedID 33648992

  • Commonalities across computational workflows for uncovering explanatory variants in undiagnosed cases. Genetics in medicine : official journal of the American College of Medical Genetics Kobren, S. N., Baldridge, D., Velinder, M., Krier, J. B., LeBlanc, K., Esteves, C., Pusey, B. N., Zuchner, S., Blue, E., Lee, H., Huang, A., Bastarache, L., Bican, A., Cogan, J., Marwaha, S., Alkelai, A., Murdock, D. R., Liu, P., Wegner, D. J., Paul, A. J., Undiagnosed Diseases Network, Sunyaev, S. R., Kohane, I. S., Acosta, M. T., Adam, M., Adams, D. R., Agrawal, P. B., Alejandro, M. E., Alvey, J., Amendola, L., Andrews, A., Ashley, E. A., Azamian, M. S., Bacino, C. A., Bademci, G., Baker, E., Balasubramanyam, A., Baldridge, D., Bale, J., Bamshad, M., Barbouth, D., Bayrak-Toydemir, P., Beck, A., Beggs, A. H., Behrens, E., Bejerano, G., Bennett, J., Berg-Rood, B., Bernstein, J. A., Berry, G. T., Bican, A., Bivona, S., Blue, E., Bohnsack, J., Bonnenmann, C., Bonner, D., Botto, L., Boyd, B., Briere, L. C., Brokamp, E., Brown, G., Burke, E. A., Burrage, L. C., Butte, M. J., Byers, P., Byrd, W. E., Carey, J., Carrasquillo, O., Chang, T. C., Chanprasert, S., Chao, H., Clark, G. D., Coakley, T. R., Cobban, L. A., Cogan, J. D., Coggins, M., Cole, F. S., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., Crouse, A. B., Cunningham, M., D'Souza, P., Dai, H., Dasari, S., Davis, J., Daya, J. G., Deardorff, M., Dell'Angelica, E. C., Dhar, S. U., Dipple, K., Doherty, D., Dorrani, N., Doss, A. L., Douine, E. D., Draper, D. D., Duncan, L., Earl, D., Eckstein, D. J., Emrick, L. T., Eng, C. M., Esteves, C., Falk, M., Fernandez, L., Ferreira, C., Fieg, E. L., Findley, L. C., Fisher, P. G., Fogel, B. L., Forghani, I., Fresard, L., Gahl, W. A., Glass, I., Gochuico, B., Godfrey, R. A., Golden-Grant, K., Goldman, A. M., Goldrich, M. P., Goldstein, D. B., Grajewski, A., Groden, C. A., Gutierrez, I., Hahn, S., Hamid, R., Hanchard, N. A., Hassey, K., Hayes, N., High, F., Hing, A., Hisama, F. M., Holm, I. A., Hom, J., Horike-Pyne, M., Huang, A., Huang, Y., Huryn, L., Isasi, R., Jamal, F., Jarvik, G. P., Jarvik, J., Jayadev, S., Karaviti, L., Kennedy, J., Kiley, D., Kohane, I. S., Kohler, J. N., Korrick, S., Kozuira, M., Krakow, D., Krasnewich, D. M., Kravets, E., Krier, J. B., LaMoure, G. L., Lalani, S. R., Lam, B., Lam, C., Lanpher, B. C., Lanza, I. R., Latham, L., LeBlanc, K., Lee, B. H., Lee, H., Levitt, R., Lewis, R. A., Lincoln, S. A., Liu, P., Liu, X. Z., Longo, N., Loo, S. K., Loscalzo, J., Maas, R. L., MacDowall, J., MacRae, C. A., Macnamara, E. F., Maduro, V. V., Majcherska, M. M., Mak, B. C., Malicdan, M. C., Mamounas, L. A., Manolio, T. A., Mao, R., Maravilla, K., Markello, T. C., Marom, R., Marth, G., Martin, B. A., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., McCauley, J., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., McGee, E., Mefford, H., Merritt, J. L., Might, M., Mirzaa, G., Morava, E., Moretti, P. M., Moretti, P., Mosbrook-Davis, D., Mulvihill, J. J., Murdock, D. R., Nagy, A., Nakano-Okuno, M., Nath, A., Nelson, S. F., Newman, J. H., Nicholas, S. K., Nickerson, D., Nieves-Rodriguez, S., Novacic, D., Oglesbee, D., Orengo, J. P., Pace, L., Pak, S., Pallais, J. C., Palmer, C. G., Papp, J. C., Parker, N. H., Phillips, J. A., Posey, J. E., Potocki, L., Power, B., Pusey, B. N., Quinlan, A., Raja, A. N., Rao, D. A., Raskind, W., Renteria, G., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Rosenwasser, N., Rossignol, F., Ruzhnikov, M., Sacco, R., Sampson, J. B., Samson, S. L., Saporta, M., Schaechter, J., Schedl, T., Schoch, K., Scott, C. R., Scott, D. A., Shashi, V., Shin, J., Signer, R. H., Silverman, E. K., Sinsheimer, J. S., Sisco, K., Smith, E. C., Smith, K. S., Solem, E., Solnica-Krezel, L., Ben Solomon, S., Spillmann, R. C., Stoler, J. M., Sullivan, J. A., Sullivan, K., Sun, A., Sutton, S., Sweetser, D. A., Sybert, V., Tabor, H. K., Tan, A. L., Tan, Q. K., Tekin, M., Telischi, F., Thorson, W., Thurm, A., Tifft, C. J., Toro, C., Tran, A. A., Tucker, B. M., Urv, T. K., Vanderver, A., Velinder, M., Viskochil, D., Vogel, T. P., Wahl, C. E., Walker, M., Wallace, S., Walley, N. M., Walsh, C. A., Wambach, J., Wan, J., Wang, L., Wangler, M. F., Ward, P. A., Wegner, D., Wener, M., Wenger, T., Perry, K. W., Westerfield, M., Wheeler, M. T., Whitlock, J., Wolfe, L. A., Woods, J. D., Yamamoto, S., Yang, J., Yousef, M., Zastrow, D. B., Zein, W., Zhao, C., Zuchner, S. 2021

    Abstract

    PURPOSE: Genomic sequencing has become an increasingly powerful and relevant tool to be leveraged for the discovery of genetic aberrations underlying rare, Mendelian conditions. Although the computational tools incorporated into diagnostic workflows for this task are continually evolving and improving, we nevertheless sought to investigate commonalities across sequencing processing workflows to reveal consensus and standard practice tools and highlight exploratory analyses where technical and theoretical method improvements would be most impactful.METHODS: We collected details regarding the computational approaches used by a genetic testing laboratory and 11 clinical research sites in the United States participating in the Undiagnosed Diseases Network via meetings with bioinformaticians, online survey forms, and analyses of internal protocols.RESULTS: We found that tools for processing genomic sequencing data can be grouped into four distinct categories. Whereas well-established practices exist for initial variant calling and quality control steps, there is substantial divergence across sites in later stages for variant prioritization and multimodal data integration, demonstrating a diversity of approaches for solving the most mysterious undiagnosed cases.CONCLUSION: The largest differences across diagnostic workflows suggest that advances in structural variant detection, noncoding variant interpretation, and integration of additional biomedical data may be especially promising for solving chronically undiagnosed cases.

    View details for DOI 10.1038/s41436-020-01084-8

    View details for PubMedID 33580225

  • Aicardi-Goutières syndrome may present with positive newborn screen for X-linked adrenoleukodystrophy. American journal of medical genetics. Part A Tise, C. G., Morales, J. A., Lee, A. S., Velez-Bartolomei, F. n., Floyd, B. J., Levy, R. J., Cusmano-Ozog, K. P., Feigenbaum, A. S., Ruzhnikov, M. R., Lee, C. U., Enns, G. M. 2021

    Abstract

    We report three unrelated probands, two male and one female, diagnosed with Aicardi-Goutières syndrome (AGS) after screening positive on California newborn screening (CA NBS) for X-linked adrenoleukodystrophy (X-ALD) due to elevated C26:0 lysophosphatidylcholine (C26:0-LPC). Follow-up evaluation was notable for elevated C26:0, C26:1, and C26:0/C22:0 ratio, and normal red blood cell plasmalogens levels in all three probands. Diagnoses were confirmed by molecular sequencing prior to 12?months of age after clinical evaluation was inconsistent with X-ALD or suggestive of AGS. For at least one proband, the early diagnosis of AGS enabled candidacy for enrollment into a therapeutic clinical trial. This report demonstrates the importance of including AGS on the differential diagnosis for individuals who screen positive for X-ALD, particularly infants with abnormal neurological features, as this age of onset would be highly unusual for X-ALD. While AGS is not included on the Recommended Universal Screening Panel, affected individuals can be identified early through state NBS programs so long as providers are aware of a broader differential that includes AGS. This report is timely, as state NBS algorithms for X-ALD are actively being established, implemented, and refined.

    View details for DOI 10.1002/ajmg.a.62160

    View details for PubMedID 33683010

  • Use of electronic medical record templates improves quality of care for patients with infantile spasms HEALTH INFORMATION MANAGEMENT JOURNAL Santoro, J. D., Sandoval Karamian, A. G., Ruzhnikov, M., Brimble, E., Chadwick, W., Wusthoff, C. J. 2021; 50 (1-2): 47?54
  • Identification of protein quality control regulators using a Drosophila model of TPI deficiency. Neurobiology of disease Hrizo, S. L., Eicher, S. L., Myers, T. D., McGrath, I. n., Wodrich, A. P., Venkatesh, H. n., Manjooran, D. n., Swoger, S. n., Gagnon, K. n., Bruskin, M. n., Lebedev, M. V., Zheng, S. n., Vitantonio, A. n., Kim, S. n., Lamb, Z. J., Vogt, A. n., Ruzhnikov, M. R., Palladino, M. J. 2021: 105299

    Abstract

    Triosephosphate isomerase (TPI) deficiency (Df) is a rare recessive metabolic disorder that manifests as hemolytic anemia, locomotor impairment, and progressive neurodegeneration. Research suggests that TPI Df mutations, including the "common" TPIE104Dmutation, results in reduced TPI protein stability that appears to underlie disease pathogenesis. Drosophila with the recessive TPIsugarkill allele (a.k.a. sgk or M80T) exhibit progressive locomotor impairment, neuromuscular impairment and reduced longevity, modeling the human disorder. TPIsugarkill produces a functional protein that is degraded by the proteasome. Molecular chaperones, such as Hsp70 and Hsp90, have been shown to contribute to the regulation of TPIsugarkill degradation. In addition, stabilizing the mutant protein through chaperone modulation results in improved TPI deficiency phenotypes. To identify additional regulators of TPIsugarkill degradation, we performed a genome-wide RNAi screen that targeted known and predicted quality control proteins in the cell to identify novel factors that modulate TPIsugarkill turnover. Of the 430 proteins screened, 25 regulators of TPIsugarkill were identified. Interestingly, 10 proteins identified were novel, previously undescribed Drosophila proteins. Proteins involved in co-translational protein quality control and ribosome function were also isolated in the screen, suggesting that TPIsugarkill may undergo co-translational selection for polyubiquitination and proteasomal degradation as a nascent polypeptide. The proteins identified in this study may reveal novel pathways for the degradation of a functional, cytosolic protein by the ubiquitin proteasome system and define therapeutic pathways for TPI Df and other biomedically important diseases.

    View details for DOI 10.1016/j.nbd.2021.105299

    View details for PubMedID 33600953

  • Metabolic Disorders Presenting with Seizures in the Neonatal Period. Seminars in neurology Brimble, E., Ruzhnikov, M. R. 2020

    Abstract

    Metabolic disorders represent rare but often treatable causes of seizures and epilepsy of neonatal onset. As seizures are relatively common in the neonatal period, systemic clues to a specific diagnosis may be lacking or shrouded by acute illness. An important role of the consulting pediatric neurologist is to identify neonates with a possible metabolic or otherwise genetic diagnosis. In this review, the authors describe presenting signs and symptoms, a diagnostic framework, and disorder-specific treatment options for inborn errors of metabolism that may present in the neonatal period. Specific attention is given to the neurologic aspects of each condition, including the electroclinical phenotype and findings on brain imaging. As expedited diagnosis and prompt initiation of available therapies have been demonstrated to result in improved epilepsy and developmental outcomes, this work acts as a framework to guide evaluation when an inherited metabolic disorder is suspected. In addition to informing treatment, a definitive diagnosis allows for appropriate counseling regarding prognosis, any associated screening or preventive measures, and family planning.

    View details for DOI 10.1055/s-0040-1705119

    View details for PubMedID 32185789

  • Expanding the Molecular and Clinical Phenotypes of FUT8-CDG. Journal of inherited metabolic disease Ng, B. G., Dastsooz, H., Silawi, M., Habibzadeh, P., Jahan, S. B., Fard, M. A., Halliday, B. J., Raymond, K., Ruzhnikov, M. R., Tabatabaei, Z., Taghipour-Sheshdeh, A., Brimble, E., Robertson, S. P., Faghihi, M. A., Freeze, H. H. 2020

    Abstract

    Pathogenic variants in the Golgi localized alpha 1,6 fucosyltransferase, FUT8, cause a rare inherited metabolic disorder known as FUT8-CDG. To date, only three affected individuals have been reported presenting with a constellation of symptoms including intrauterine growth restriction, severe delays in growth and development, other neurological impairments, significantly shortened limbs, respiratory complications and shortened lifespan. Here we report an additional four unrelated affected individuals homozygous for novel pathogenic variants in FUT8. Analysis of serum N-glycans revealed a complete lack of core fucosylation, an important diagnostic biomarker of FUT8-CDG. Our data expands both the molecular and clinical phenotypes of FUT8-CDG and highlights the importance of identifying a reliable biomarker for confirming potentially pathogenic variants. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/jimd.12221

    View details for PubMedID 32049367

  • De novo EIF2AK1 and EIF2AK2 Variants Are Associated with Developmental Delay, Leukoencephalopathy, and Neurologic Decompensation. American journal of human genetics Mao, D. n., Reuter, C. M., Ruzhnikov, M. R., Beck, A. E., Farrow, E. G., Emrick, L. T., Rosenfeld, J. A., Mackenzie, K. M., Robak, L. n., Wheeler, M. T., Burrage, L. C., Jain, M. n., Liu, P. n., Calame, D. n., Küry, S. n., Sillesen, M. n., Schmitz-Abe, K. n., Tonduti, D. n., Spaccini, L. n., Iascone, M. n., Genetti, C. A., Koenig, M. K., Graf, M. n., Tran, A. n., Alejandro, M. n., Lee, B. H., Thiffault, I. n., Agrawal, P. B., Bernstein, J. A., Bellen, H. J., Chao, H. T. 2020

    Abstract

    EIF2AK1 and EIF2AK2 encode members of the eukaryotic translation initiation factor 2 alpha kinase (EIF2AK) family that inhibits protein synthesis in response to physiologic stress conditions. EIF2AK2 is also involved in innate immune response and the regulation of signal transduction, apoptosis, cell proliferation, and differentiation. Despite these findings, human disorders associated with deleterious variants in EIF2AK1 and EIF2AK2 have not been reported. Here, we describe the identification of nine unrelated individuals with heterozygous de novo missense variants in EIF2AK1 (1/9) or EIF2AK2 (8/9). Features seen in these nine individuals include white matter alterations (9/9), developmental delay (9/9), impaired language (9/9), cognitive impairment (8/9), ataxia (6/9), dysarthria in probands with verbal ability (6/9), hypotonia (7/9), hypertonia (6/9), and involuntary movements (3/9). Individuals with EIF2AK2 variants also exhibit neurological regression in the setting of febrile illness or infection. We use mammalian cell lines and proband-derived fibroblasts to further confirm the pathogenicity of variants in these genes and found reduced kinase activity. EIF2AKs phosphorylate eukaryotic translation initiation factor 2 subunit 1 (EIF2S1, also known as EIF2?), which then inhibits EIF2B activity. Deleterious variants in genes encoding EIF2B proteins cause childhood ataxia with central nervous system hypomyelination/vanishing white matter (CACH/VWM), a leukodystrophy characterized by neurologic regression in the setting of febrile illness and other stressors. Our findings indicate that EIF2AK2 missense variants cause a neurodevelopmental syndrome that may share phenotypic and pathogenic mechanisms with CACH/VWM.

    View details for DOI 10.1016/j.ajhg.2020.02.016

    View details for PubMedID 32197074

  • Clinical sites of the Undiagnosed Diseases Network: unique contributions to genomic medicine and science. Genetics in medicine : official journal of the American College of Medical Genetics Schoch, K. n., Esteves, C. n., Bican, A. n., Spillmann, R. n., Cope, H. n., McConkie-Rosell, A. n., Walley, N. n., Fernandez, L. n., Kohler, J. N., Bonner, D. n., Reuter, C. n., Stong, N. n., Mulvihill, J. J., Novacic, D. n., Wolfe, L. n., Abdelbaki, A. n., Toro, C. n., Tifft, C. n., Malicdan, M. n., Gahl, W. n., Liu, P. n., Newman, J. n., Goldstein, D. B., Hom, J. n., Sampson, J. n., Wheeler, M. T., Cogan, J. n., Bernstein, J. A., Adams, D. R., McCray, A. T., Shashi, V. n. 2020

    Abstract

    The NIH Undiagnosed Diseases Network (UDN) evaluates participants with disorders that have defied diagnosis, applying personalized clinical and genomic evaluations and innovative research. The clinical sites of the UDN are essential to advancing the UDN mission; this study assesses their contributions relative to standard clinical practices.We analyzed retrospective data from four UDN clinical sites, from July 2015 to September 2019, for diagnoses, new disease gene discoveries and the underlying investigative methods.Of 791 evaluated individuals, 231 received 240 diagnoses and 17 new disease-gene associations were recognized. Straightforward diagnoses on UDN exome and genome sequencing occurred in 35% (84/240). We considered these tractable in standard clinical practice, although genome sequencing is not yet widely available clinically. The majority (156/240, 65%) required additional UDN-driven investigations, including 90 diagnoses that occurred after prior nondiagnostic exome sequencing and 45 diagnoses (19%) that were nongenetic. The UDN-driven investigations included complementary/supplementary phenotyping, innovative analyses of genomic variants, and collaborative science for functional assays and animal modeling.Investigations driven by the clinical sites identified diagnostic and research paradigms that surpass standard diagnostic processes. The new diagnoses, disease gene discoveries, and delineation of novel disorders represent a model for genomic medicine and science.

    View details for DOI 10.1038/s41436-020-00984-z

    View details for PubMedID 33093671

  • MRI Surveillance of Boys with X-linked Adrenoleukodystrophy Identified by Newborn Screening: Meta-analysis and Consensus Guidelines. Journal of inherited metabolic disease Mallack, E. J., Turk, B. R., Yan, H. n., Price, C. n., Mlis, M. D., Moser, A. B., Becker, C. n., Hollandsworth, K. n., Adang, L. n., Vanderver, A. n., Van Haren, K. n., Ruzhnikov, M. n., Kurtzberg, J. n., Maegawa, G. n., Orchard, P. J., Lund, T. C., Raymond, G. V., Regelmann, M. n., Orsini, J. J., Seeger, E. n., Kemp, S. n., Eichler, F. n., Fatemi, A. n. 2020

    Abstract

    Among boys with X-Linked adrenoleukodystrophy, a subset will develop childhood cerebral adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy.To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus.One hundred twenty-three studies met inclusion criteria yielding 1,285 patients. The overall mean age of CCALD diagnosis is 7.91?years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0?years old (IQR: 6.0 - 9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (1) Obtain an MRI between 12 and 18 months old. (2) Obtain a second MRI 1 year after baseline. (3) Between 3 and 12?years old, obtain a contrast-enhanced MRI every 6 months. (4) After 12?years, obtain an annual MRI.Boys with adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/jimd.12356

    View details for PubMedID 33373467

  • LOCALIZING NEUROLOGIC FEATURES AT PRESENTATION OF VLCAD DEFICIENCY Leahy, P., Matalon, D., Ruzhnikov, M., Cowan, T., Enns, G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2019: 282
  • Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review AMERICAN JOURNAL OF MEDICAL GENETICS PART A Kumar, A., Zastrow, D. B., Kravets, E. J., Beleford, D., Ruzhnikov, M. Z., Grove, M. E., Dries, A. M., Kohler, J. N., Waggott, D. M., Yang, Y., Huang, Y., Mackenzie, K. M., Eng, C. M., Fisher, P. G., Ashley, E. A., Teng, J. M., Stevenson, D. A., Shieh, J. T., Wheeler, M. T., Bernstein, J. A., Adams, D. R., Aday, A., Alejandro, M. E., Allard, P., Azamian, M. S., Bacino, C. A., Baker, E., Balasubramanyam, A., Barseghyan, H., Batzli, G. F., Beggs, A. H., Behnam, B., Bellen, H. J., Bican, A., Bick, D. P., Birch, C. L., Bonner, D., Boone, B. E., Bostwick, B. L., Briere, L. C., Brokamp, E., Brown, D. M., Brush, M., Burke, E. A., Burrage, L. C., Butte, M. J., Chen, S., Clark, G. D., Coakley, T. R., Cogan, J. D., Colley, H. A., Cooper, C. M., Cope, H., Craigen, W. J., D'Souza, P., Davids, M., Davidson, J. M., Dayal, J. G., Dell'Angelica, E. C., Dhar, S. U., Dipple, K. M., Donnell-Fink, L. A., Dorrani, N., Dorset, D. C., Douine, E. D., Draper, D. D., Eckstein, D. J., Emrick, L. T., Enns, G. M., Eskin, A., Esteves, C., Estwick, T., Fairbrother, L., Fernandez, L., Ferreira, C., Fieg, E. L., Fogel, B. L., Friedman, N. D., Gahl, W. A., Glanton, E., Godfrey, R. A., Goldman, A. M., Goldstein, D. B., Gould, S. E., Gourdine, J. F., Groden, C. A., Gropman, A. L., Haendel, M., Hamid, R., Hanchard, N. A., High, F., Holm, I. A., Hom, J., Howerton, E. M., Jamal, F., Jiang, Y., Johnston, J. M., Jones, A. L., Karaviti, L., Koeller, D. M., Kohane, I. S., Krasnewich, D. M., Korrick, S., Koziura, M., Krier, J. B., Kyle, J. E., Lalani, S. R., Lau, C., Lazar, J., LeBlanc, K., Lee, B. H., Lee, H., Levy, S. E., Lewis, R. A., Lincoln, S. A., Loo, S. K., Loscalzo, J., Maas, R. L., Macnamara, E. F., MacRae, C. A., Maduro, V. V., Majcherska, M. M., Malicdan, M., Mamounas, L. A., Manolio, T. A., Markello, T. C., Marom, R., Martin, M. G., Martinez-Agosto, J. A., Marwaha, S., May, T., McConkie-Rosell, A., McCormack, C. E., McCray, A. T., Merker, J. D., Metz, T. O., Might, M., Moretti, P. M., Morimoto, M., Mulvihill, J. J., Murdock, D. R., Murphy, J. L., Muzny, D. M., Nehrebecky, M. E., Nelson, S. F., Newberry, J., Newman, J. H., Nicholas, S. K., Novacic, D., Orange, J. S., Orengo, J. P., Pallais, J., Palmer, C. S., Papp, J. C., Parker, N. H., Pena, L. M., Phillips, J. A., Posey, J. E., Postlethwait, J. H., Potocki, L., Pusey, B. N., Reuter, C. M., Rives, L., Robertson, A. K., Rodan, L. H., Rosenfeld, J. A., Sampson, J. B., Samson, S. L., Schoch, K., Scott, D. A., Shakachite, L., Sharma, P., Shashi, V., Signer, R., Silverman, E. K., Sinsheimer, J. S., Smith, K. S., Spillmann, R. C., Staler, J. M., Stong, N., Sullivan, J. A., Sweetser, D. A., Tan, Q., Tifft, C. J., Toro, C., Tran, A. A., Urv, T. K., Vilain, E., Vogel, T. P., Wahl, C. E., Walley, N. M., Walsh, C. A., Walker, M., Wan, J., Wangler, M. F., Ward, P. A., Waters, K. M., Webb-Robertson, B. M., Westerfield, M., Wise, A. L., Wolfe, L. A., Worthey, E. A., Yamamoto, S., Yang, J., Yoon, A. J., Yu, G., Zhao, C., Zheng, A., Undiagnosed Dis Network 2019; 179 (6): 966?77
  • Consensus Guidelines: MRI surveillance of Children with Presymptomatic Adrenoleukodystrophy Turk, B., Mallack, E., Adang, L., Becker, C., Eichler, F., Van Haren, K., Hollandsworth, K., Kurtzberg, J., Kwon, J., Lund, T., Maegawa, G., Moser, A., Orchard, P., Orsini, J., Rauner, B., Raymond, G., Regelman, M., Ruzhnikov, M., Salzman, A., Vanderver, A., Seeger, E., Fatemi, S. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder AMERICAN JOURNAL OF HUMAN GENETICS Calpena, E., Hervieu, A., Kaserer, T., Swagemakers, S. A., Goos, J. C., Popoola, O., Ortiz-Ruiz, M., Barbaro-Dieber, T., Bownass, L., Brilstra, E. H., Brimble, E., Foulds, N., Grebe, T. A., Harder, A. E., Lees, M. M., Monaghan, K. G., Newbury-Ecob, R. A., Ong, K., Osio, D., Santos, F., Ruzhnikov, M. Z., Telegrafi, A., van Binsbergen, E., van Dooren, M. F., van der Spek, P. J., Blagg, J., Twigg, S. F., Mathijssen, I. J., Clarke, P. A., Wilkie, A. M., Deciphering Dev Disorders Study 2019; 104 (4): 709?20
  • Extracutaneous manifestations in phacomatosis cesioflammea and cesiomarmorata: Case series and literature review. American journal of medical genetics. Part A Kumar, A., Zastrow, D. B., Kravets, E. J., Beleford, D., Ruzhnikov, M. R., Grove, M. E., Dries, A. M., Kohler, J. N., Waggott, D. M., Yang, Y., Huang, Y., Undiagnosed Diseases Network, Mackenzie, K. M., Eng, C. M., Fisher, P. G., Ashley, E. A., Teng, J. M., Stevenson, D. A., Shieh, J. T., Wheeler, M. T., Bernstein, J. A. 2019

    Abstract

    Phacomatosis pigmentovascularis (PPV) comprises a family of rare conditions that feature vascular abnormalities and melanocytic lesions that can be solely cutaneous or multisystem in nature. Recently published work has demonstrated that both vascular and melanocytic abnormalities in PPV of the cesioflammea and cesiomarmorata subtypes can result from identical somatic mosaic activating mutations in the genes GNAQ and GNA11. Here, we present three new cases of PPV with features of the cesioflammea and/or cesiomarmorata subtypes and mosaic mutations in GNAQ or GNA11. To better understand the risk of potentially occult complications faced by such patients we additionally reviewed 176 cases published in the literature. We report the frequency of clinical findings, their patterns of co-occurrence as well as published recommendations for surveillance after diagnosis. Features assessed include: capillary malformation; dermal and ocular melanocytosis; glaucoma; limb asymmetry; venous malformations; and central nervous system (CNS) anomalies, such as ventriculomegaly and calcifications. We found that ocular findings are common in patients with phacomatosis cesioflammea and cesiomarmorata. Facial vascular involvement correlates with a higher risk of seizures (p=.0066). Our genetic results confirm the role of mosaic somatic mutations in GNAQ and GNA11 in phacomatosis cesioflammea and cesiomarmorata. Their clinical and molecular findings place these conditions on a clinical spectrum encompassing other GNAQ and GNA11 related disorders and inform recommendations for their management.

    View details for PubMedID 30920161

  • De Novo Missense Substitutions in the Gene Encoding CDK8, a Regulator of the Mediator Complex, Cause a Syndromic Developmental Disorder. American journal of human genetics Calpena, E., Hervieu, A., Kaserer, T., Swagemakers, S. M., Goos, J. A., Popoola, O., Ortiz-Ruiz, M. J., Barbaro-Dieber, T., Bownass, L., Brilstra, E. H., Brimble, E., Foulds, N., Grebe, T. A., Harder, A. V., Lees, M. M., Monaghan, K. G., Newbury-Ecob, R. A., Ong, K., Osio, D., Reynoso Santos, F. J., Ruzhnikov, M. R., Telegrafi, A., van Binsbergen, E., van Dooren, M. F., Deciphering Developmental Disorders Study, van der Spek, P. J., Blagg, J., Twigg, S. R., Mathijssen, I. M., Clarke, P. A., Wilkie, A. O. 2019

    Abstract

    The Mediator is an evolutionarily conserved, multi-subunit complex that regulates multiple steps of transcription. Mediator activity is regulated by the reversible association of a four-subunit module comprising CDK8 or CDK19 kinases, together with cyclin C, MED12 or MED12L, and MED13 or MED13L. Mutations in MED12, MED13, and MED13L were previously identified in syndromic developmental disorders with overlapping phenotypes. Here, we report CDK8 mutations (located at 13q12.13) that cause a phenotypically related disorder. Using whole-exome or whole-genome sequencing, and by international collaboration, we identified eight different heterozygous missense CDK8 substitutions, including 10 shown to have arisen de novo, in 12 unrelated subjects; a recurrent mutation, c.185C>T (p.Ser62Leu), was present in five individuals. All predicted substitutions localize to the ATP-binding pocket of the kinase domain. Affected individuals have overlapping phenotypes characterized by hypotonia, mild to moderate intellectual disability, behavioral disorders, and variable facial dysmorphism. Congenital heart disease occurred in six subjects; additional features present in multiple individuals included agenesis of the corpus callosum, ano-rectal malformations, seizures, and hearing or visual impairments. To evaluate the functional impact of the mutations, we measured phosphorylation at STAT1-Ser727, a known CDK8 substrate, in a CDK8 and CDK19 CRISPR double-knockout cell line transfected with wild-type (WT) or mutant CDK8 constructs. These experiments demonstrated a reduction in STAT1 phosphorylation by all mutants, in most cases to a similar extent as in a kinase-dead control. We conclude that missense mutations in CDK8 cause a developmental disorder that has phenotypic similarity to syndromes associated with mutations in other subunits of the Mediator kinase module, indicating probable overlap in pathogenic mechanisms.

    View details for PubMedID 30905399

  • LOCALIZING NEUROLOGIC FEATURES AT PRESENTATION OF VLCAD DEFICIENCY Leahy, P., Matalon, D., Ruzhnikov, M., Cowan, T., Enns, G. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2019: 311
  • De Novo Mutations Affecting the Catalytic C alpha Subunit of PP2A, PPP2CA, Cause Syndromic Intellectual Disability Resembling Other PP2A-Related Neurodevelopmental Disorders AMERICAN JOURNAL OF HUMAN GENETICS Reynhout, S., Jansen, S., Haesen, D., van Belle, S., de Munnik, S. A., Bongers, E. F., Schieving, J. H., Marcelis, C., Amiel, J., Rio, M., Mclaughlin, H., Ladda, R., Sell, S., Kriek, M., Peeters-Scholte, C. D., Terhal, P. A., van Gassen, K. L., Verbeek, N., Henry, S., Schwoerer, J., Malik, S., Revencu, N., Ferreira, C. R., Macnamara, E., Braakman, H. H., Brimble, E., Ruznikov, M. Z., Wagner, M., Harrer, P., Wieczorek, D., Kuechler, A., Tziperman, B., Barel, O., de Vries, B. A., Gordon, C. T., Janssens, V., Vissers, L. M. 2019; 104 (1): 139?56

    Abstract

    Type 2A protein phosphatases (PP2As) are highly expressed in the brain and regulate neuronal signaling by catalyzing phospho-Ser/Thr dephosphorylations in diverse substrates. PP2A holoenzymes comprise catalytic C-, scaffolding A-, and regulatory B-type subunits, which determine substrate specificity and physiological function. Interestingly, de novo mutations in genes encoding A- and B-type subunits have recently been implicated in intellectual disability (ID) and developmental delay (DD). We now report 16 individuals with mild to profound ID and DD and a de novo mutation in PPP2CA, encoding the catalytic C? subunit. Other frequently observed features were severe language delay (71%), hypotonia (69%), epilepsy (63%), and brain abnormalities such as ventriculomegaly and a small corpus callosum (67%). Behavioral problems, including autism spectrum disorders, were reported in 47% of individuals, and three individuals had a congenital heart defect. PPP2CA de novo mutations included a partial gene deletion, a frameshift, three nonsense mutations, a single amino acid duplication, a recurrent mutation, and eight non-recurrent missense mutations. Functional studies showed complete PP2A dysfunction in four individuals with seemingly milder ID, hinting at haploinsufficiency. Ten other individuals showed mutation-specific biochemical distortions, including poor expression, altered binding to the A subunit and specific B-type subunits, and impaired phosphatase activity and C-terminal methylation. Four were suspected to have a dominant-negative mechanism, which correlated with severe ID. Two missense variants affecting the same residue largely behaved as wild-type in our functional assays. Overall, we found that pathogenic PPP2CA variants impair PP2A-B56(?) functionality, suggesting that PP2A-related neurodevelopmental disorders constitute functionally converging ID syndromes.

    View details for PubMedID 30595372

  • Perinatal distress in 1p36 deletion syndrome can mimic hypoxic ischemic encephalopathy. American journal of medical genetics. Part A Carter, L. B., Battaglia, A. n., Cherry, A. n., Manning, M. A., Ruzhnikov, M. R., Bird, L. M., Dowsett, L. n., Graham, J. M., Alkuraya, F. S., Hashem, M. n., Dinulos, M. B., Vallee, S. n., Adam, M. P., Glass, I. n., Beck, A. E., Stevens, C. A., Zackai, E. n., McDougall, C. n., Keena, B. n., Peron, A. n., Vignoli, A. n., Seaver, L. H., Slavin, T. P., Hudgins, L. n. 2019

    Abstract

    1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress." Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of "hypoxic insult" was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder.

    View details for DOI 10.1002/ajmg.a.61266

    View details for PubMedID 31207089

  • Infantile Spasms of Unknown Cause: Predictors of Outcome and Genotype-Phenotype Correlation PEDIATRIC NEUROLOGY Yuskaitis, C. J., Ruzhnikov, M. Z., Howell, K. B., Allen, I., Kapur, K., Dlugos, D. J., Scheffer, I. E., Poduri, A., Sherr, E. H., EPGP Investigators 2018; 87: 48?56
  • A case report of a suspected dual diagnosis: 22q11.2 deletion syndrome and X-linked chondrodysplasia punctata CLINICAL DYSMORPHOLOGY Brimble, E., Pacione, M., Farrelly, E., Stevenson, D. A., Ruzhnikov, M. Z. 2018; 27 (4): 151?53

    View details for DOI 10.1097/MCD.0000000000000231

    View details for Web of Science ID 000445749500011

    View details for PubMedID 29912012

  • Use of electronic medical record templates improves quality of care for patients with infantile spasms. Health information management : journal of the Health Information Management Association of Australia Santoro, J. D., Sandoval, A., Ruzhnikov, M., Brimble, E., Chadwick, W., Wusthoff, C. J. 2018: 1833358318794501

    Abstract

    BACKGROUND: Infantile spasms (IS) is a neurologic disorder of childhood where time to treatment may affect long-term outcomes. Due to the clinical complexity of IS, care can be delayed.OBJECTIVE: To determine if the use of electronic medical record templates (EMRTs) improved care quality in patients treated for IS.METHOD: Records of patients newly diagnosed with IS were retrospectively reviewed both before and after creation of an EMRT for the workup and treatment of IS. Quality of care measures reviewed included delays in treatment plan, medication administration, obtaining neurodiagnostic studies and discharge. The need for repeat neurodiagnostic studies was also assessed. Resident physicians were surveyed regarding template ease of use and functionality.RESULTS: Of 17 patients with IS, 7 received template-based care and 10 did not. Patients in the non-template group had more delays in treatment ( p = 0.010), delay in medication administration ( p = 0.10), delay in diagnostic studies ( p = 0.01) and delay in discharge ( p = 0.39). Neurodiagnostic studies needed to be repeated in 5 out of 10 patients in the non-template group and none of the 7 patients in the template group ( p = 0.04). Surveyed resident physicians reported improved coordination in care, avoidance of delays in discharge and improved ability to predict side effects of treatment with template use.CONCLUSION: In a single centre, the use of protocolised EMRTs decreased treatment delays and the need for repeated invasive procedures in patients with newly diagnosed IS and was reported as easy to use by resident physicians.IMPLICATIONS: The use of protocolised EMRTs may improve the quality of patient care in IS and other rare diseases.

    View details for PubMedID 30124080

  • Infantile Spasms of Unknown Cause: Predictors of Outcome and Genotype-Phenotype Correlation. Pediatric neurology Yuskaitis, C. J., Ruzhnikov, M. R., Howell, K. B., Allen, I. E., Kapur, K., Dlugos, D. J., Scheffer, I. E., Poduri, A., Sherr, E. H. 2018

    Abstract

    BACKGROUND: No large-scale studies have specifically evaluated the outcomes of infantile spasms (IS) of unknown cause, previously known as cryptogenic or idiopathic. The Epilepsy Phenome/Genome Project aimed to characterize IS of unknown cause by phenotype and genotype analysis.METHODS: We undertook a retrospective multicenter observational cohort of 133 individuals within the Epilepsy Phenome/Genome Project database met criteria for IS of unknown cause with at least six months of follow-up data. Clinical medical records, imaging, and electroencephalography were examined.RESULTS: Normal development occurred in only 15% of IS of unknown cause. The majority (85%) had clinically documented developmental delay (15% mild, 20% moderate, and 50% severe) at last assessment (median 2.7 years; interquartile interval 1.71-6.25 years). Predictors of positive developmental outcomes included no delay prior to IS (P < 0.001), older age of IS onset (median six months old), and resolution of IS after initial treatment (P < 0.001). Additional seizures after IS occurred in 67%, with predictors being seizures prior to IS (P = 0.018), earlier age of IS onset (median five months old), and refractory IS (P = 0.008). On a research basis, whole exome sequencing identified 15% with de novo variants in known epilepsy genes. Individuals with a genetic finding were more likely to have poor developmental outcomes (P = 0.035).CONCLUSIONS: The current study highlights the predominately unfavorable developmental outcomes and that subsequent seizures are common in children with IS of unknown cause. Ongoing genetic evaluation of IS of seemingly unknown cause is likely to yield a diagnosis and provide valuable prognostic information.

    View details for PubMedID 30174244

  • Clinical Transcriptome Sequencing Confirms Activation of a Cryptic Splice Site in Suspected <it><bold>SYNGAP1</it></bold>-Related Disorder MOLECULAR SYNDROMOLOGY Brimble, E., Lee-Messer, C., Nagy, P. L., Propst, J., Ruzhnikov, M. Z. 2018; 9 (6): 295?99

    View details for DOI 10.1159/000492706

    View details for Web of Science ID 000456045700004

  • Variable clinical course of identical twin neonates with Alström syndrome presenting coincidentally with dilated cardiomyopathy. American journal of medical genetics. Part A Hollander, S. A., Alsaleh, N., Ruzhnikov, M., Jensen, K., Rosenthal, D. N., Stevenson, D. A., Manning, M. 2017; 173 (6): 1687-1689

    Abstract

    Alström Syndrome (AS) is a rare autosomal recessive disorder caused by mutations in the ALMS1 gene. We report monozygotic twin infants who presented concurrently with symptoms of congestive heart failure (CHF) due to dilated cardiomyopathy (DCM). Following their initial presentation, one twin improved both echocardiographically and functionally while the other twin showed a progressive decline in ventricular function and worsening CHF symptoms requiring multiple hospitalizations and augmentation of heart failure therapy. Concordant findings of nystagmus, vision loss, and developmental delay were noted in both twins. Additional discordant findings included obesity and signs of insulin resistance in one twin. Genetic testing on one sibling confirmed AS. These twins underscore the importance of considering AS in any child presenting with DCM, particularly in infancy, and highlights that, even in monozygotic twins, the clinical course of AS is variable with regard to both the cardiac and non-cardiac manifestations of the disease.

    View details for DOI 10.1002/ajmg.a.38200

    View details for PubMedID 28407410

  • DIAGNOSTIC OUTCOMES AND RELATIVE COST OF CLINICAL WHOLE EXOME SEQUENCING Ruzhnikov, M. R., Alsadah, A., Mendelsohn, B., Alhariri, A., Cilio, M. R., Wu, Y., Marco, E. J., Hsiao, E., Sullivan, J., Shieh, J., Slavotinek, A., Sherr, E. H. LIPPINCOTT WILLIAMS & WILKINS. 2016: 247
  • De novo mutations in KIF1A cause progressive encephalopathy and brain atrophy. Annals of clinical and translational neurology Esmaeeli Nieh, S. n., Madou, M. R., Sirajuddin, M. n., Fregeau, B. n., McKnight, D. n., Lexa, K. n., Strober, J. n., Spaeth, C. n., Hallinan, B. E., Smaoui, N. n., Pappas, J. G., Burrow, T. A., McDonald, M. T., Latibashvili, M. n., Leshinsky-Silver, E. n., Lev, D. n., Blumkin, L. n., Vale, R. D., Barkovich, A. J., Sherr, E. H. 2015; 2 (6): 623?35

    Abstract

    To determine the cause and course of a novel syndrome with progressive encephalopathy and brain atrophy in children.Clinical whole-exome sequencing was performed for global developmental delay and intellectual disability; some patients also had spastic paraparesis and evidence of clinical regression. Six patients were identified with de novo missense mutations in the kinesin gene KIF1A. The predicted functional disruption of these mutations was assessed in silico to compare the calculated conformational flexibility and estimated efficiency of ATP binding to kinesin motor domains of wild-type (WT) versus mutant alleles. Additionally, an in vitro microtubule gliding assay was performed to assess the effects of de novo dominant, inherited recessive, and polymorphic variants on KIF1A motor function.All six subjects had severe developmental delay, hypotonia, and varying degrees of hyperreflexia and spastic paraparesis. Microcephaly, cortical visual impairment, optic neuropathy, peripheral neuropathy, ataxia, epilepsy, and movement disorders were also observed. All six patients had a degenerative neurologic course with progressive cerebral and cerebellar atrophy seen on sequential magnetic resonance imaging scans. Computational modeling of mutant protein structures when compared to WT kinesin showed substantial differences in conformational flexibility and ATP-binding efficiency. The de novo KIF1A mutants were nonmotile in the microtubule gliding assay.De novo mutations in KIF1A cause a degenerative neurologic syndrome with brain atrophy. Computational and in vitro assays differentiate the severity of dominant de novo heterozygous versus inherited recessive KIF1A mutations. The profound effect de novo mutations have on axonal transport is likely related to the cause of progressive neurologic impairment in these patients.

    View details for DOI 10.1002/acn3.198

    View details for PubMedID 26125038

    View details for PubMedCentralID PMC4479523

  • De novo mutations in epileptic encephalopathies. Nature Allen, A. S., Berkovic, S. F., Cossette, P. n., Delanty, N. n., Dlugos, D. n., Eichler, E. E., Epstein, M. P., Glauser, T. n., Goldstein, D. B., Han, Y. n., Heinzen, E. L., Hitomi, Y. n., Howell, K. B., Johnson, M. R., Kuzniecky, R. n., Lowenstein, D. H., Lu, Y. F., Madou, M. R., Marson, A. G., Mefford, H. C., Esmaeeli Nieh, S. n., O'Brien, T. J., Ottman, R. n., Petrovski, S. n., Poduri, A. n., Ruzzo, E. K., Scheffer, I. E., Sherr, E. H., Yuskaitis, C. J., Abou-Khalil, B. n., Alldredge, B. K., Bautista, J. F., Berkovic, S. F., Boro, A. n., Cascino, G. D., Consalvo, D. n., Crumrine, P. n., Devinsky, O. n., Dlugos, D. n., Epstein, M. P., Fiol, M. n., Fountain, N. B., French, J. n., Friedman, D. n., Geller, E. B., Glauser, T. n., Glynn, S. n., Haut, S. R., Hayward, J. n., Helmers, S. L., Joshi, S. n., Kanner, A. n., Kirsch, H. E., Knowlton, R. C., Kossoff, E. H., Kuperman, R. n., Kuzniecky, R. n., Lowenstein, D. H., McGuire, S. M., Motika, P. V., Novotny, E. J., Ottman, R. n., Paolicchi, J. M., Parent, J. M., Park, K. n., Poduri, A. n., Scheffer, I. E., Shellhaas, R. A., Sherr, E. H., Shih, J. J., Singh, R. n., Sirven, J. n., Smith, M. C., Sullivan, J. n., Lin Thio, L. n., Venkat, A. n., Vining, E. P., Von Allmen, G. K., Weisenberg, J. L., Widdess-Walsh, P. n., Winawer, M. R. 2013; 501 (7466): 217?21

    Abstract

    Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here we report a screen for de novo mutations in patients with two classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ?4,000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9?×?10(-3)). Among these are GABRB3, with de novo mutations in four patients, and ALG13, with the same de novo mutation in two patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1?×?10(-10) and P = 7.8?×?10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P?

    View details for DOI 10.1038/nature12439

    View details for PubMedID 23934111

    View details for PubMedCentralID PMC3773011

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