Clinical Focus

  • Neonatology
  • Clinical Genetics

Academic Appointments

Honors & Awards

  • Recipient of the United Mitochondrial Diseases Foundation (UMDF) Clinical Fellowship Award., United Mitochondrial Diseases Foundation (UMDF) (8/16/2013 - 8/15/2014)
  • Recipient of the 2011-2012 Genzyme/ACMGF Clinical Genetics Fellowship in Biochemical Genetics Award., Genzyme/ACMGF (American College of Medical Genetics Foundation) (Award period 7/1/2011 ? 6/30/2012.)

Professional Education

  • Fellowship:Stanford University (2012) CA
  • Residency:Stanford University (2011) CA
  • Residency:Stanford University (2009) CA
  • Medical Education:University of Oulu Medical School (2003) Finland
  • Board Certification: Clinical Genetics, American Board of Medical Genetics (2011)
  • Board Certification: Pediatrics, American Board of Pediatrics (2009)
  • Biochemical Genetics Fellowship, Stanford University Medical Center, Medical Biochemical Genetics (2012)
  • Medical Genetics Residency, Stanford University Medical Center, Clinical Genetics (2011)
  • Pediatric Residency, Lucile Packard Children's Hospital, Stanford University Medical Center, Pediatrics (2009)
  • Ph.D., University of Oulu, Mitochondrial Genetics (2005)
  • M.D., University of Oulu, Finland (2003)

Research & Scholarship

Current Research and Scholarly Interests

Neonatology. Clinical Genetics. Biochemical Genetics. Integrative Medicine.


Journal Articles

  • Perinatal Features of the RASopathies: Noonan Syndrome, Cardiofaciocutaneous Syndrome and Costello Syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Myers, A., Bernstein, J. A., Brennan, M., Curry, C., Esplin, E. D., Fisher, J., Homeyer, M., Manning, M. A., Muller, E. A., Niemi, A., Seaver, L. H., Hintz, S. R., Hudgins, L. 2014; 164A (11): 2814-2821
  • Abnormal Hepatocellular Mitochondria in Methylmalonic Acidemia ULTRASTRUCTURAL PATHOLOGY Wilnai, Y., Enns, G. M., Niemi, A., Higgins, J., Vogel, H. 2014; 38 (5): 309-314
  • Degree of Glutathione Deficiency and Redox Imbalance Depend on Subtype of Mitochondrial Disease and Clinical Status PLOS ONE Enns, G. M., Moore, T., Le, A., Atkuri, K., Shah, M. K., Cusmano-Ozog, K., Niemi, A., Cowan, T. M. 2014; 9 (6)
  • Degree of glutathione deficiency and redox imbalance depend on subtype of mitochondrial disease and clinical status. PloS one Enns, G. M., Moore, T., Le, A., Atkuri, K., Shah, M. K., Cusmano-Ozog, K., Niemi, A., Cowan, T. M. 2014; 9 (6)


    Mitochondrial disorders are associated with decreased energy production and redox imbalance. Glutathione plays a central role in redox signaling and protecting cells from oxidative damage. In order to understand the consequences of mitochondrial dysfunction on in vivo redox status, and to determine how this varies by mitochondrial disease subtype and clinical severity, we used a sensitive tandem mass spectrometry assay to precisely quantify whole blood reduced (GSH) and oxidized (GSSG) glutathione levels in a large cohort of mitochondrial disorder patients. Glutathione redox potential was calculated using the Nernst equation. Compared to healthy controls (n = 59), mitochondrial disease patients (n = 58) as a group showed significant redox imbalance (redox potential -251 mV ± 9.7, p<0.0001) with an increased level of oxidation by ? 9 mV compared to controls (-260 mV ± 6.4). Underlying this abnormality were significantly lower whole blood GSH levels (p = 0.0008) and GSH/GSSG ratio (p = 0.0002), and significantly higher GSSG levels (p<0.0001) in mitochondrial disease patients compared to controls. Redox potential was significantly more oxidized in all mitochondrial disease subgroups including Leigh syndrome (n = 15), electron transport chain abnormalities (n = 10), mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (n = 8), mtDNA deletion syndrome (n = 7), mtDNA depletion syndrome (n = 7), and miscellaneous other mitochondrial disorders (n = 11). Patients hospitalized in metabolic crisis (n = 7) showed the greatest degree of redox imbalance at -242 mV ± 7. Peripheral whole blood GSH and GSSG levels are promising biomarkers of mitochondrial dysfunction, and may give insights into the contribution of oxidative stress to the pathophysiology of the various mitochondrial disorders. In particular, evaluation of redox potential may be useful in monitoring of clinical status or response to redox-modulating therapies in clinical trials.

    View details for DOI 10.1371/journal.pone.0100001

    View details for PubMedID 24941115

  • A new LC-MS/MS method for the clinical determination of reduced and oxidized glutathione from whole blood JOURNAL OF CHROMATOGRAPHY B-ANALYTICAL TECHNOLOGIES IN THE BIOMEDICAL AND LIFE SCIENCES Moore, T., Le, A., Niemi, A., Kwan, T., Cusmano-Ozog, K., Enns, G. M., Cowan, T. M. 2013; 929: 51-55


    Reduced levels of glutathione (?-glutamylcysteinylglycine, GSH) and the ratio of GSH to glutathione disulfide (GSSG) can serve as important indicators of oxidative stress and disease risk. Measured concentrations of GSH and GSSG vary widely between laboratories, largely due to the instability of GSH during sample handling and variables arising from different analytical methods. We have developed a simple and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for measuring whole blood GSH and GSSG that minimizes preanalytic and analytic variability, reliably eliminates interference from ion suppression, and can easily be implemented in clinical laboratories. Samples were deproteinized with sulfosalicylic acid (SSA) and derivatized with N-ethylmaleimide (NEM) in a single preparative step, and the resulting supernatants combined with stable-isotope internal standards (GSH-(13)C, (15)N-NEM and GSSG-(13)C,(15)N), subjected to chromatographic separation using a Hypercarb column, and analyzed by MS/MS in the positive-ion mode. Results showed excellent linearity for both GSH and GSSG over the ranges of physiologic normal, with inter- and intra-assay CV's of 3.1-4.3% and accuracy between 95% and 101%. The lower limits of detection (LLOD) were 0.4?M for GSH and 0.1?M for GSSG and the lower limits of quantitation (LLOQ) were 1.5?M for GSH and 0.1?M for GSSG. Derivatized samples are stable for at least 3 years when stored at -80°C, and underivatized samples for at least 24h at either 4°C or room temperature. Reference intervals were determined for 59 control samples, and were (mean±SD): GSH 900±140?M; GSSG 1.17±0.43?M; GSH/GSSG 880±370.

    View details for DOI 10.1016/j.jchromb.2013.04.004

    View details for Web of Science ID 000320085300009

  • Liver transplantation for urea cycle disorders in pediatric patients: A single-center experience PEDIATRIC TRANSPLANTATION Kim, I. K., Niemi, A., Krueger, C., Bonham, C. A., Concepcion, W., Cowan, T. M., Enns, G. M., Esquivel, C. O. 2013; 17 (2): 158-167


    LT has emerged as a surgical treatment for UCDs. We hypothesize that LT can be safely and broadly utilized in the pediatric population to effectively prevent hyperammonemic crises and potentially improve neurocognitive outcomes. To determine the long-term outcomes of LT for UCDs, charts of children with UCD who underwent LT were retrospectively reviewed at an academic institution between July 2001 and May 2012. A total of 23 patients with UCD underwent LT at a mean age of 3.4 yr. Fifteen (65%) patients received a whole-liver graft, seven patients (30%) received a reduced-size graft, and one patient received a living donor graft. Mean five-yr patient survival was 100%, and allograft survival was 96%. Mean peak blood ammonia (NH(3) ) at presentation was 772 ?mol/L (median 500, range 178-2969, normal <30-50). After transplantation, there were no episodes of hyperammonemia. Eleven patients were diagnosed with some degree of developmental delay before transplantation, which remained stable or improved after transplantation. Patients without developmental delay before transplantation maintained their cognitive abilities at long-term follow-up. LT was associated with the eradication of hyperammonemia, removal of dietary restrictions, and potentially improved neurocognitive development. Long-term follow-up is underway to evaluate whether LT at an early age (<1 yr) will attain improved neurodevelopmental outcomes.

    View details for DOI 10.1111/petr.12041

    View details for Web of Science ID 000315467000017

    View details for PubMedID 23347504

  • Report of Two Patients and Further Characterization of Interstitial 9p13 Deletion-A Rare But Recurrent Microdeletion Syndrome? AMERICAN JOURNAL OF MEDICAL GENETICS PART A Niemi, A., Kwan, A., Hudgins, L., Cherry, A. M., Manning, M. A. 2012; 158A (9): 2328-2335


    To date, an interstitial deletion of 9p13 has been described only two times in the medical literature. These reports were based on routine chromosomal analysis. We report on two additional patients with an interstitial deletion of 9p13 further defined on array CGH who share clinical features with the other two patients previously described. Our first patient is a 16-year-old girl with a 5.9?Mb deletion at 9p13.3-9p13.1, initially detected on routine karyotype analysis and further characterized on array CGH. Our second patient is a 7½-year-old boy with a 4.8?Mb deletion also at 9p13.3-9p13.1. Patients with 9p13 deletion appear to have mild to moderate developmental delay, social and interactive personality, behavior issues such as attention deficit-hyperactivity disorder, short stature, prominent antihelices, hypoplastic nails, and precocious/early puberty. Our 16-year-old patient is the oldest patient described thus far. This report further characterizes this condition and helps to delineate the long-term prognosis in these patients.

    View details for DOI 10.1002/ajmg.a.35536

    View details for Web of Science ID 000310068700037

    View details for PubMedID 22887577

  • Ectopia Lentis as the Presenting and Primary Feature in Marfan Syndrome AMERICAN JOURNAL OF MEDICAL GENETICS PART A Zadeh, N., Bernstein, J. A., Niemi, A. K., Dugan, S., Kwan, A., Liang, D., Hyland, J. C., Hoyme, H. E., Hudgins, L., Manning, M. A. 2011; 155A (11): 2661-2668


    Marfan syndrome (MFS) is a multisystem connective tissue disorder with primary involvement of the ocular, cardiovascular, and skeletal systems. We report on eight patients, all presenting initially with bilateral ectopia lentis (EL) during early childhood. These individuals did not have systemic manifestations of MFS, and did not fulfill the revised Ghent diagnostic criteria. However, all patients had demonstratable, disease-causing missense mutations in the FBN1 gene. Based on molecular results, cardiovascular imaging was recommended and led to the identification of mild aortic root changes in seven of the eight patients. The remaining patient had mitral valve prolapse with a normal appearing thoracic aorta. The findings presented in this paper validate the necessity of FBN1 gene testing in all individuals presenting with isolated EL. As we observed, these individuals are at increased risk of cardiovascular complications. Furthermore, we also noted that the majority of our patient cohort's mutations occurred in the 5' portion of the FBN1 gene, and were found to affect highly conserved cysteine residues, which may indicate a possible genotype-phenotype correlation. We conclude that in patients with isolated features of EL, FBN1 mutation analysis is necessary to aid in providing prompt diagnosis, and to identify patients at risk for potentially life-threatening complications. Additionally, knowledge of the type and location of an FBN1 mutation may be useful in providing further clinical correlation regarding phenotypic progression and appropriate medical management.

    View details for DOI 10.1002/ajmg.a.34245

    View details for Web of Science ID 000297199700009

    View details for PubMedID 21932315

  • Horseshoe Kidney and a Rare TSC2 Variant in Two Unrelated Individuals With Tuberous Sclerosis Complex AMERICAN JOURNAL OF MEDICAL GENETICS PART A Niemi, A., Northrup, H., Hudgins, L., Bernstein, J. A. 2011; 155A (10): 2534-2537


    Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by abnormalities involving the skin, brain, kidney (angiomyolipomas, cysts), and heart. Horseshoe kidney has not been considered to be a common renal manifestation of TSC but it has been previously reported in two patients with TSC. We report on two unrelated females with typical manifestations of TSC, horseshoe kidney, and an identical variant c.5138G>A in exon 39 (p.Arg1713His) of TSC2 gene. These cases provide evidence that horseshoe kidney is associated with TSC and add to the evidence for the pathogenicity of this variant. Furthermore, one of the patients also had a diaphragmatic hernia which has been reported twice in the medical literature in individuals with TSC. It is possible that a diaphragmatic hernia is another rare manifestation of TSC and that TSC should be included in the differential diagnosis of infants with a diaphragmatic hernia. Given that both a horseshoe kidney and a diaphragmatic hernia are findings that can be detected prenatally on an ultrasound examination, our findings may have implications for prenatal genetic counseling.

    View details for DOI 10.1002/ajmg.a.34197

    View details for Web of Science ID 000295326300032

    View details for PubMedID 21910228

  • Importance of culturing primary lymphocytes at physiological oxygen levels PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Atkuri, K. R., Herzenberg, L. A., Niemi, A., Cowan, T., Herzenberg, L. A. 2007; 104 (11): 4547-4552


    Although studies with primary lymphocytes are almost always conducted in CO(2) incubators maintained at atmospheric oxygen levels (atmosO(2); 20%), the physiological oxygen levels (physO(2); 5%) that cells encounter in vivo are 2-4 times lower. We show here that culturing primary T cells at atmosO(2) significantly alters the intracellular redox state (decreases intracellular glutathione, increases oxidized intracellular glutathione), whereas culturing at physO(2) maintains the intracellular redox environment (intracellular glutathione/oxidized intracellular glutathione) close to its in vivo status. Furthermore, we show that CD3/CD28-induced T cell proliferation (based on proliferation index and cell yield) is higher at atmosO(2) than at physO(2). This apparently paradoxical finding, we suggest, may be explained by two additional findings with CD3/CD28-stimulated T cells: (i) the intracellular NO (iNO) levels are higher at physO(2) than at atmosO(2); and (ii) the peak expression of CD69 is significantly delayed and more sustained at physO(2) that at atmosO(2). Because high levels of intracellular NO and sustained CD69 tend to down-regulate T cell responses in vivo, the lower proliferative T cell responses at physO(2) likely reflect the in vitro operation of the natural in vivo regulatory mechanisms. Thus, we suggest caution in culturing primary lymphocytes at atmosO(2) because the requisite adaptation to nonphysiological oxygen levels may seriously skew T cell responses, particularly after several days in culture.

    View details for DOI 10.1073/pnas.0611732104

    View details for Web of Science ID 000244972700055

    View details for PubMedID 17360561

  • Mitochondrial DNA and ACTN3 genotypes in Finnish elite endurance and sprint athletes EUROPEAN JOURNAL OF HUMAN GENETICS Niemi, A. K., Majamaa, K. 2005; 13 (8): 965-969


    Differences in ACTN3 (alpha-actinin 3) genotypes have been reported among endurance and power athletes. Elite athletic performance in endurance sports should also depend on mitochondrial oxidative phosphorylation (OXPHOS) that produces ATP for muscle metabolism. We determined mitochondrial DNA (mtDNA) and ACTN3 genotypes in Finnish elite endurance (n = 52) and sprint (n = 89) athletes, and found that the frequencies of mtDNA haplogroups differed significantly between the two groups. Most notably, none of the endurance athletes belonged to haplogroup K or subhaplogroup J2, both of which have previously been associated with longevity. The frequency of ACTN3 XX genotype was higher and that of RR was lower among Finnish endurance athletes, and, in addition, none of the top Finnish sprinters had the XX genotype. Lack of mtDNA haplogroup K and subhaplogroup J2 among elite endurance athletes suggests that these haplogroups are 'uncoupling genomes'. Such genomes should not be beneficial to endurance-type athletic performance but should be beneficial to longevity, since uncoupling of OXPHOS reduces the production of ATP, reduces the release of reactive oxygen species and generates heat.

    View details for Web of Science ID 000230760400012

    View details for PubMedID 15886711

  • A combination of three common inherited mitochondrial DNA polymorphisms promotes longevity in Finnish and Japanese subjects EUROPEAN JOURNAL OF HUMAN GENETICS Niemi, A. K., Moilanen, J. S., Tanaka, M., HERVONEN, A., Hurme, M., Lehtimaki, T., Arai, Y., Hirose, N., Majamaa, K. 2005; 13 (2): 166-170


    Mitochondrial DNA (mtDNA) coding region polymorphisms, as well as the 150T polymorphism in the noncoding region, have been associated with longevity. We have studied here the association of 150T with longevity further and assessed differences in this association between various mtDNA haplogroups. We analysed a sample of 321 very old subjects and 489 middle-aged controls from Finland and Japan. 150T was more frequent among the very old than among the controls in both the Finnish and Japanese subjects. Interestingly, the association was not similar in all haplogroups, and a stratified analysis revealed that two additional common polymorphisms, 489C and 10398G, modified the association between 150T and longevity. These findings suggest that longevity is partly determined by epistatic interactions involving these three mtDNA loci.

    View details for DOI 10.1038/sj.ejhg.5201308

    View details for Web of Science ID 000226413600009

    View details for PubMedID 15483642

  • Mitochondrial DNA polymorphisms associated with longevity in a Finnish population HUMAN GENETICS Niemi, A. K., HERVONEN, A., Hurme, M., Kurhunen, P. J., Jylha, M., MAJAMAA, K. 2003; 112 (1): 29-33


    Sequence variation in mitochondrial DNA (mtDNA) may cause slight differences both in the functioning of the respiratory chain and in free radical production, and an association between certain mtDNA haplogroups and longevity has been suggested. In order to determine further the role of mtDNA in longevity, we studied the frequencies of mtDNA haplogroups and haplogroup clusters among elderly subjects and controls in a Finnish population. Samples were obtained from 225 persons aged 90-91 years (Vitality 90+) and from 400 middle-aged controls and 257 infants. MtDNA haplogroups were determined by restriction fragment length polymorphism. The haplogroup frequencies of the Vitality 90+ group differed from both those of the middle-aged controls ( P=0.01) and the infants ( P=0.00005), haplogroup H being less frequent than among the middle-aged subjects ( P=0.001) and infants ( P=0.00001), whereas haplogroups U and J were more frequent. Haplogroup clusters also differed between Vitality 90+ and both the middle-aged subjects ( P=0.002) and infants ( P=0.00001), the frequency of haplogroup cluster HV being lower in the former and that of UK and WIX being higher. These data suggest an association between certain mtDNA haplogroups or haplogroup clusters and longevity. Furthermore, our data appear to favour the presence of advantageous polymorphisms and support a role for mitochondria and mtDNA in the degenerative processes involved in ageing.

    View details for DOI 10.1001/s00439-002-0843-y

    View details for Web of Science ID 000180552400005

    View details for PubMedID 12483296

  • [What happens to the organs in space?]. Duodecim; lääketieteellinen aikakauskirja Niemi, A. K., Vuolteenaho, O. 1999; 115 (13): 1379-1385

    View details for PubMedID 11912623

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