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


  • Board Certification, Clinical Genetics and Genomics, American Board of Genetics and Genomics (2019)
  • Fellowship:Stanford University School of Medicine Registrar (2017) CA
  • Board Certification: Neurology - Child Neurology, American Board of Psychiatry and 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 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.

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Publications

All Publications


  • 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 Cα 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(δ) 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., Cherry, A., Manning, M. A., Ruzhnikov, M. R., Bird, L. M., Dowsett, L., Graham, J. M., Alkuraya, F. S., Hashem, M., Dinulos, M. B., Vallee, S., Adam, M. P., Glass, I., Beck, A. E., Stevens, C. A., Zackai, E., McDougall, C., Keena, B., Peron, A., Vignoli, A., Seaver, L. H., Slavin, T. P., Hudgins, L. 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

  • 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

  • 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
  • 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., Madou, M. R., Sirajuddin, M., Fregeau, B., McKnight, D., Lexa, K., Strober, J., Spaeth, C., Hallinan, B. E., Smaoui, N., Pappas, J. G., Burrow, T. A., McDonald, M. T., Latibashvili, M., Leshinsky-Silver, E., Lev, D., Blumkin, L., 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., Delanty, N., Dlugos, D., Eichler, E. E., Epstein, M. P., Glauser, T., Goldstein, D. B., Han, Y., Heinzen, E. L., Hitomi, Y., Howell, K. B., Johnson, M. R., Kuzniecky, R., Lowenstein, D. H., Lu, Y. F., Madou, M. R., Marson, A. G., Mefford, H. C., Esmaeeli Nieh, S., O'Brien, T. J., Ottman, R., Petrovski, S., Poduri, A., Ruzzo, E. K., Scheffer, I. E., Sherr, E. H., Yuskaitis, C. J., Abou-Khalil, B., Alldredge, B. K., Bautista, J. F., Berkovic, S. F., Boro, A., Cascino, G. D., Consalvo, D., Crumrine, P., Devinsky, O., Dlugos, D., Epstein, M. P., Fiol, M., Fountain, N. B., French, J., Friedman, D., Geller, E. B., Glauser, T., Glynn, S., Haut, S. R., Hayward, J., Helmers, S. L., Joshi, S., Kanner, A., Kirsch, H. E., Knowlton, R. C., Kossoff, E. H., Kuperman, R., Kuzniecky, R., Lowenstein, D. H., McGuire, S. M., Motika, P. V., Novotny, E. J., Ottman, R., Paolicchi, J. M., Parent, J. M., Park, K., Poduri, A., Scheffer, I. E., Shellhaas, R. A., Sherr, E. H., Shih, J. J., Singh, R., Sirven, J., Smith, M. C., Sullivan, J., Lin Thio, L., Venkat, A., Vining, E. P., Von Allmen, G. K., Weisenberg, J. L., Widdess-Walsh, P., 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 < 10(-8)), as has been reported previously for autism spectrum disorders.

    View details for DOI 10.1038/nature12439

    View details for PubMedID 23934111

    View details for PubMedCentralID PMC3773011