Bio

Clinical Focus


  • Clinical Genetics

Academic Appointments


Professional Education


  • Board Certification: Clinical Biochemical Genetics, American Board of Medical Genetics and Genomics (2015)
  • Fellowship:Stanford University - Fellowship (2014) CA
  • Board Certification: Clinical Genetics, American Board of Medical Genetics and Genomics (2013)
  • Fellowship:Stanford University School of Medicine (2012) CA
  • Residency:Tel Aviv Sourasky Medical Center (2008) Israel
  • Internship:Wolfson Medical Center (2004) Israel
  • Medical Education:Sackler School of Medicine (2003) Israel

Publications

All Publications


  • Prenatal treatment of ornithine transcarbamylase deficiency. Molecular genetics and metabolism Wilnai, Y., Blumenfeld, Y. J., Cusmano, K., Hintz, S. R., Alcorn, D., Benitz, W. E., Berquist, W. E., Bernstein, J. A., Castillo, R. O., Concepcion, W., Cowan, T. M., Cox, K. L., Lyell, D. J., Esquivel, C. O., Homeyer, M., Hudgins, L., Hurwitz, M., Palma, J. P., Schelley, S., Akula, V. P., Summar, M. L., Enns, G. M. 2018

    Abstract

    Patients with neonatal urea cycle defects (UCDs) typically experience severe hyperammonemia during the first days of life, which results in serious neurological injury or death. Long-term prognosis despite optimal pharmacological and dietary therapy is still poor. The combination of intravenous sodium phenylacetate and sodium benzoate (Ammonul®) can eliminate nitrogen waste independent of the urea cycle. We report attempts to improve outcomes for males with severe ornithine transcarbamylase deficiency (OTCD), a severe X-linked condition, via prenatal intravenous administration of Ammonul and arginine to heterozygous carrier females of OTCD during labor.Two heterozygote OTCD mothers carrying male fetuses with a prenatal diagnosis of OTCD received intravenous Ammonul, arginine and dextrose-containing fluids shortly before birth. Maintenance Ammonul and arginine infusions and high-caloric enteral nutrition were started immediately after birth. Ammonul metabolites were measured in umbilical cord blood and the blood of the newborn immediately after delivery. Serial ammonia and biochemical analyses were performed following delivery.Therapeutic concentrations of Ammonul metabolites were detected in umbilical cord and neonatal blood samples. Plasma ammonia and glutamine levels in the postnatal period were within the normal range. Peak ammonia levels in the first 24-48h were 53mcmol/l and 62mcmol/l respectively. The boys did not experience neurological sequelae secondary to hyperammonemia and received liver transplantation at ages 3months and 5months. The patients show normal development at ages 7 and 3years.Prenatal treatment of mothers who harbor severe OTCD mutations and carry affected male fetuses with intravenous Ammonul and arginine, followed by immediate institution of maintenance infusions after delivery, results in therapeutic levels of benzoate and phenylacetate in the newborn at delivery and, in conjunction with high-caloric enteral nutrition, prevents acute hyperammonemia and neurological decompensation. Following initial medical management, early liver transplantation may improve developmental outcome.

    View details for PubMedID 29396029

  • Recurrent Muscle Weakness with Rhabdomyolysis, Metabolic Crises, and Cardiac Arrhythmia Due to Bi-allelic TANGO2 Mutations. American journal of human genetics Lalani, S. R., Liu, P., Rosenfeld, J. A., Watkin, L. B., Chiang, T., Leduc, M. S., Zhu, W., Ding, Y., Pan, S., Vetrini, F., Miyake, C. Y., Shinawi, M., Gambin, T., Eldomery, M. K., Akdemir, Z. H., Emrick, L., Wilnai, Y., Schelley, S., Koenig, M. K., Memon, N., Farach, L. S., Coe, B. P., Azamian, M., Hernandez, P., Zapata, G., Jhangiani, S. N., Muzny, D. M., Lotze, T., Clark, G., Wilfong, A., Northrup, H., Adesina, A., Bacino, C. A., Scaglia, F., Bonnen, P. E., Crosson, J., Duis, J., Maegawa, G. H., Coman, D., Inwood, A., McGill, J., Boerwinkle, E., Graham, B., Beaudet, A., Eng, C. M., Hanchard, N. A., Xia, F., Orange, J. S., Gibbs, R. A., Lupski, J. R., Yang, Y. 2016; 98 (2): 347-357

    Abstract

    The underlying genetic etiology of rhabdomyolysis remains elusive in a significant fraction of individuals presenting with recurrent metabolic crises and muscle weakness. Using exome sequencing, we identified bi-allelic mutations in TANGO2 encoding transport and Golgi organization 2 homolog (Drosophila) in 12 subjects with episodic rhabdomyolysis, hypoglycemia, hyperammonemia, and susceptibility to life-threatening cardiac tachyarrhythmias. A recurrent homozygous c.460G>A (p.Gly154Arg) mutation was found in four unrelated individuals of Hispanic/Latino origin, and a homozygous ∼34 kb deletion affecting exons 3-9 was observed in two families of European ancestry. One individual of mixed Hispanic/European descent was found to be compound heterozygous for c.460G>A (p.Gly154Arg) and the deletion of exons 3-9. Additionally, a homozygous exons 4-6 deletion was identified in a consanguineous Middle Eastern Arab family. No homozygotes have been reported for these changes in control databases. Fibroblasts derived from a subject with the recurrent c.460G>A (p.Gly154Arg) mutation showed evidence of increased endoplasmic reticulum stress and a reduction in Golgi volume density in comparison to control. Our results show that the c.460G>A (p.Gly154Arg) mutation and the exons 3-9 heterozygous deletion in TANGO2 are recurrent pathogenic alleles present in the Latino/Hispanic and European populations, respectively, causing considerable morbidity in the homozygotes in these populations.

    View details for DOI 10.1016/j.ajhg.2015.12.008

    View details for PubMedID 26805781

  • The Phenotype of the Musculocontractural Type of Ehlers-Danlos Syndrome due to CHST14 Mutations AMERICAN JOURNAL OF MEDICAL GENETICS PART A Janecke, A. R., Li, B., Boehm, M., Krabichler, B., Rohrbach, M., Mueller, T., Fuchs, I., Golas, G., Katagiri, Y., Ziegler, S. G., Gahl, W. A., Wilnai, Y., Zoppi, N., Geller, H. M., Giunta, C., Slavotinek, A., Steinmann, B. 2016; 170 (1): 103-115

    Abstract

    The musculocontractural type of Ehlers-Danlos syndrome (MC-EDS) has been recently recognized as a clinical entity. MC-EDS represents a differential diagnosis within the congenital neuromuscular and connective tissue disorders spectrum. Thirty-one and three patients have been reported with MC-EDS so far with bi-allelic mutations identified in CHST14 and DSE, respectively, encoding two enzymes necessary for dermatan sulfate (DS) biosynthesis. We report seven additional patients with MC-EDS from four unrelated families, including the follow-up of a sib-pair originally reported with the kyphoscoliotic type of EDS in 1975. Brachycephaly, a characteristic facial appearance, an asthenic build, hyperextensible and bruisable skin, tapering fingers, instability of large joints, and recurrent formation of large subcutaneous hematomas are always present. Three of seven patients had mildly elevated serum creatine kinase. The oldest patient was blind due to retinal detachment at 45 years and died at 59 years from intracranial bleeding; her affected brother died at 28 years from fulminant endocarditis. All patients in this series harbored homozygous, predicted loss-of-function CHST14 mutations. Indeed, DS was not detectable in fibroblasts from two unrelated patients with homozygous mutations. Patient fibroblasts produced higher amounts of chondroitin sulfate, showed intracellular retention of collagen types I and III, and lacked decorin and thrombospondin fibrils compared with control. A great proportion of collagen fibrils were not integrated into fibers, and fiber bundles were dispersed into the ground substance in one patient, all of which is likely to contribute to the clinical phenotype. This report should increase awareness for MC-EDS.

    View details for DOI 10.1002/ajmg.a.37383

    View details for Web of Science ID 000367933600014

  • Abnormal Hepatocellular Mitochondria in Methylmalonic Acidemia ULTRASTRUCTURAL PATHOLOGY Wilnai, Y., Enns, G. M., Niemi, A., Higgins, J., Vogel, H. 2014; 38 (5): 309-314

    Abstract

    Methylmalonic acidemia (MMA) is one of the most frequently encountered forms of branched-chain organic acidemias. Biochemical abnormalities seen in some MMA patients, such as lactic acidemia and increased tricarboxylic acid cycle intermediate excretion, suggest mitochondrial dysfunction. In order to investigate the possibility of mitochondrial involvement in MMA, we examined liver tissue for evidence of mitochondrial ultrastructural abnormalities. Five explanted livers obtained from MMA mut(0) patients undergoing liver transplantation were biopsied. All patients had previous episodes of metabolic acidosis, lactic acidemia, ketonuria, and hyperammonemia. All biopsies revealed a striking mitochondriopathy by electron microscopy. Mitochondria were markedly variable in size, shape, and conformation of cristae. The inner matrix appeared to be greatly expanded and the cristae were diminutive and disconnected. No crystalloid inclusions were noted. This series clearly documents extensive mitochondrial ultrastructure abnormalities in liver samples from MMA patients undergoing transplantation, providing pathological evidence for mitochondrial dysfunction in the pathophysiology of MMA mut(0). Considering the trend to abnormally large mitochondria, the metabolic effects of MMA may restrict mitochondrial fission or promote fusion. The correlation between mitochondrial dysfunction and morphological abnormalities in MMA may provide insights for better understanding and monitoring of optimized or novel therapeutic strategies.

    View details for DOI 10.3109/01913123.2014.921657

    View details for Web of Science ID 000345348700003

  • Abnormal hepatocellular mitochondria in methylmalonic acidemia. Ultrastructural pathology Wilnai, Y., Enns, G. M., Niemi, A., Higgins, J., Vogel, H. 2014; 38 (5): 309-314

    Abstract

    Methylmalonic acidemia (MMA) is one of the most frequently encountered forms of branched-chain organic acidemias. Biochemical abnormalities seen in some MMA patients, such as lactic acidemia and increased tricarboxylic acid cycle intermediate excretion, suggest mitochondrial dysfunction. In order to investigate the possibility of mitochondrial involvement in MMA, we examined liver tissue for evidence of mitochondrial ultrastructural abnormalities. Five explanted livers obtained from MMA mut(0) patients undergoing liver transplantation were biopsied. All patients had previous episodes of metabolic acidosis, lactic acidemia, ketonuria, and hyperammonemia. All biopsies revealed a striking mitochondriopathy by electron microscopy. Mitochondria were markedly variable in size, shape, and conformation of cristae. The inner matrix appeared to be greatly expanded and the cristae were diminutive and disconnected. No crystalloid inclusions were noted. This series clearly documents extensive mitochondrial ultrastructure abnormalities in liver samples from MMA patients undergoing transplantation, providing pathological evidence for mitochondrial dysfunction in the pathophysiology of MMA mut(0). Considering the trend to abnormally large mitochondria, the metabolic effects of MMA may restrict mitochondrial fission or promote fusion. The correlation between mitochondrial dysfunction and morphological abnormalities in MMA may provide insights for better understanding and monitoring of optimized or novel therapeutic strategies.

    View details for DOI 10.3109/01913123.2014.921657

    View details for PubMedID 24933007

  • Clinical whole-exome sequencing: are we there yet? GENETICS IN MEDICINE Atwal, P. S., Brennan, M., Cox, R., Niaki, M., Platt, J., Homeyer, M., Kwan, A., Parkin, S., Schelley, S., Slattery, L., Wilnai, Y., Bernstein, J. A., Enns, G. M., Hudgins, L. 2014; 16 (9): 717-719

    Abstract

    Background:Clinical laboratories began offering whole-exome sequencing in 2011 at a cost between $4,500 and $9,000. Reported detection rates for deleterious mutations range from 25 to 50%. Based on the experience of our clinical genetics service, actual success rates may be lower than estimated rates. We report results from our own experience along with a survey of clinical geneticists to ascertain (i) current success rates for causal gene detection in a clinical setting; (ii) if there are insurance authorization issues; and (iii) if turnaround times quoted by the clinical laboratories are accurate; we also gauge provider opinions toward clinical whole-exome sequencing.Methods:We reviewed our results and the results of a survey that was electronically distributed to 47 clinical genetics centers.Results:A total of 35 exome reports were available. If all positive results are collated, we observe a success rate of 22.8%. One result incorrectly identified a known benign variant as pathogenic. Some insurers covered all testing, whereas others denied any insurance coverage. Only three (23.1%) of our reports were available within the laboratory's quoted turnaround times. More than 50% of clinicians queried in our survey had not ordered whole-exome sequencing at the current time, many stating concerns regarding interpretation, insurance coverage, and cost.Conclusion:Clinical whole-exome sequencing has proven diagnostic utility; however, currently many clinicians have concerns regarding interpretation of results, insurance coverage, and cost.Genet Med advance online publication 13 February 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.10.

    View details for DOI 10.1038/gim.2014.10

    View details for Web of Science ID 000341830800010

  • Clinical whole-exome sequencing: are we there yet? Genetics in medicine Atwal, P. S., Brennan, M., Cox, R., Niaki, M., Platt, J., Homeyer, M., Kwan, A., Parkin, S., Schelley, S., Slattery, L., Wilnai, Y., Bernstein, J. A., Enns, G. M., Hudgins, L. 2014; 16 (9): 717-719

    Abstract

    Background:Clinical laboratories began offering whole-exome sequencing in 2011 at a cost between $4,500 and $9,000. Reported detection rates for deleterious mutations range from 25 to 50%. Based on the experience of our clinical genetics service, actual success rates may be lower than estimated rates. We report results from our own experience along with a survey of clinical geneticists to ascertain (i) current success rates for causal gene detection in a clinical setting; (ii) if there are insurance authorization issues; and (iii) if turnaround times quoted by the clinical laboratories are accurate; we also gauge provider opinions toward clinical whole-exome sequencing.Methods:We reviewed our results and the results of a survey that was electronically distributed to 47 clinical genetics centers.Results:A total of 35 exome reports were available. If all positive results are collated, we observe a success rate of 22.8%. One result incorrectly identified a known benign variant as pathogenic. Some insurers covered all testing, whereas others denied any insurance coverage. Only three (23.1%) of our reports were available within the laboratory's quoted turnaround times. More than 50% of clinicians queried in our survey had not ordered whole-exome sequencing at the current time, many stating concerns regarding interpretation, insurance coverage, and cost.Conclusion:Clinical whole-exome sequencing has proven diagnostic utility; however, currently many clinicians have concerns regarding interpretation of results, insurance coverage, and cost.Genet Med advance online publication 13 February 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.10.

    View details for DOI 10.1038/gim.2014.10

    View details for PubMedID 24525916

  • PRENATAL TREATMENT OF ORNITHINE TRANSCARBAMYLASE DEFICIENCY Wilnai, Y., Alcorn, D., Benitz, W., Berquist, W., Bernstein, J., Blumenfeld, Y. J., Castillo, R., Concepcion, W., Cowan, T., Cox, K. L., Cusmano, K., Deirdre, L., Esquival, C., Hintz, S. R., Homeyer, M., Hudgins, L., Palma, J., Summar, M. L., Schelley, S., Vishnu, P., Enns, G. M. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2014: 248
  • Severe multi-systemic presentation of COX10 deficiency Wilnai, Y., Cox, R., Bai, R., Enns, G. M. ELSEVIER SCI LTD. 2013: 926
  • Axial spondylometaphyseal dysplasia with retinitis pigmentosa-a clinical report and diagnostic clues. Journal of applied genetics Reinstein, E., Okenfuss, E. B., Wadhawan, I., Wilnai, Y., Manning, M., Rimoin, D. L., Lachman, R. S. 2013; 54 (2): 231-234

    View details for DOI 10.1007/s13353-013-0136-2

    View details for PubMedID 23371363

  • Atypical Amyoplasia Congenita in an Infant With Leigh Syndrome: A Mitochondrial Cause of Severe Contractures? AMERICAN JOURNAL OF MEDICAL GENETICS PART A Wilnai, Y., Seaver, L. H., Enns, G. M. 2012; 158A (9): 2353-2357

    Abstract

    Amyoplasia congenita is a distinct form of arthrogryposis with characteristic features including internally rotated and adducted shoulders, extended elbows, flexion, and ulnar deviation of the wrists, and adducted thumbs. Fetal hypokinesia, secondary to a variety of genetic conditions, neuromuscular disorders, and environmental agents, is associated with contractures. In order to increase our understanding of the phenotypic spectrum associated with SURF 1 deficiency, a common cause of mitochondrial respiratory chain complex IV deficiency and Leigh syndrome, we describe a now 6-year-old boy who presented in the neonatal period with amyoplasia congenita. His development was normal until age 10.5 months, at which time he developed severe hypotonia and choreoathetosis following an episode of viral gastroenteritis. Following the onset of neurological symptoms, he gradually developed severe kyphosis and lower limb contractures. Blood and cerebrospinal fluid lactate levels were elevated and head imaging showed characteristic features of Leigh syndrome. He was found to harbor two pathogenic heterozygous mutations in the SURF 1 gene. In this case, mitochondrial dysfunction and the resultant energy deficiency may have played a role in causing abnormal neuronal development during embryogenesis, causing arthrogryposis. A variety of mitochondrial respiratory chain complex deficiencies have been associated with contractures of varying severity. Therefore, mitochondrial disorders should be considered in the differential diagnosis of neonatal arthrogryposis, especially if other characteristic findings such as lactic acidemia or basal ganglia abnormalities are present.

    View details for DOI 10.1002/ajmg.a.35533

    View details for PubMedID 22887355