Publications by authors named "Kristina Cusmano-Ozog"

29 Publications

  • Page 1 of 1

Aicardi-Goutières syndrome may present with positive newborn screen for X-linked adrenoleukodystrophy.

Am J Med Genet A 2021 Mar 8. Epub 2021 Mar 8.

Division of Medical Genetics, Department of Pediatrics, Lucile Packard Children's Hospital and Stanford University, Stanford, California, USA.

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.
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http://dx.doi.org/10.1002/ajmg.a.62160DOI Listing
March 2021

Growth, development, and phenotypic spectrum of individuals with deletions of 2q33.1 involving SATB2.

Clin Genet 2021 Apr 13;99(4):547-557. Epub 2021 Jan 13.

Department of Cardiology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

SATB2-Associated syndrome (SAS) is an autosomal dominant, multisystemic, neurodevelopmental disorder due to alterations in SATB2 at 2q33.1. A limited number of individuals with 2q33.1 contiguous deletions encompassing SATB2 (ΔSAS) have been described in the literature. We describe 17 additional individuals with ΔSAS, review the phenotype of 33 previously published individuals with 2q33.1 deletions (n = 50, mean age = 8.5 ± 7.8 years), and provide a comprehensive comparison to individuals with other molecular mechanisms that result in SAS (non-ΔSAS). Individuals in the ΔSAS group were often underweight for age (20/41 = 49%) with a progressive decline in weight (95% CI = -2.3 to -1.1, p < 0.0001) and height (95% CI = -2.3 to -1.0, p < 0.0001) Z-score means from birth to last available measurement. ΔSAS individuals were often noted to have a broad spectrum of facial dysmorphism. A composite image of ΔSAS individuals generated by automated image analysis was distinct as compared to matched controls and non-ΔSAS individuals. We also present additional genotype-phenotype correlations for individuals in the ΔSAS group such as an increased risk for aortic root/ascending aorta dilation and primary pulmonary hypertension for those individuals with contiguous gene deletions that include COL3A1/COL5A2 and BMPR2, respectively. Based on these findings, we provide additional care recommendations for individuals with ΔSAS variants.
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http://dx.doi.org/10.1111/cge.13912DOI Listing
April 2021

Laboratory analysis of acylcarnitines, 2020 update: a technical standard of the American College of Medical Genetics and Genomics (ACMG).

Genet Med 2021 Feb 19;23(2):249-258. Epub 2020 Oct 19.

Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA.

Acylcarnitine analysis is a useful test for identifying patients with inborn errors of mitochondrial fatty acid β-oxidation and certain organic acidemias. Plasma is routinely used in the diagnostic workup of symptomatic patients. Urine analysis of targeted acylcarnitine species may be helpful in the diagnosis of glutaric acidemia type I and other disorders in which polar acylcarnitine species accumulate. For newborn screening applications, dried blood spot acylcarnitine analysis can be performed as a multiplex assay with other analytes, including amino acids, succinylacetone, guanidinoacetate, creatine, and lysophosphatidylcholines. Tandem mass spectrometric methodology, established more than 30 years ago, remains a valid approach for acylcarnitine analysis. The method involves flow-injection analysis of esterified or underivatized acylcarnitines species and detection using a precursor-ion scan. Alternative methods utilize liquid chromatographic separation of isomeric and isobaric species and/or detection by selected reaction monitoring. These technical standards were developed as a resource for diagnostic laboratory practices in acylcarnitine analysis, interpretation, and reporting.
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http://dx.doi.org/10.1038/s41436-020-00990-1DOI Listing
February 2021

Biallelic variants in KYNU cause a multisystemic syndrome with hand hyperphalangism.

Bone 2020 04 7;133:115219. Epub 2020 Jan 7.

Department of Pediatric Genetics, Akdeniz University Medical School, 07059 Antalya, Turkey; Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address:

Catel-Manzke syndrome is characterized by the combination of Pierre Robin sequence and radial deviation, shortening as well as clinodactyly of the index fingers, due to an accessory ossification center. Mutations in TGDS have been identified as one cause of Catel-Manzke syndrome, but cannot be found as causative in every patient with the clinical diagnosis. We performed a chromosome microarray and/or exome sequencing in three patients with hand hyperphalangism, heart defect, short stature, and mild to severe developmental delay, all of whom were initially given a clinical diagnosis of Catel-Manzke syndrome. In one patient, we detected a large deletion of exons 1-8 and the missense variant c.1282C > T (p.Arg428Trp) in KYNU (NM_003937.2), whereas homozygous missense variants in KYNU were found in the other two patients (c.989G > A (p.Arg330Gln) and c.326G > C (p.Trp109Ser)). Plasma and urine metabolomic analysis of two patients indicated a block along the tryptophan catabolic pathway and urine organic acid analysis showed excretion of xanthurenic acid. Biallelic loss-of-function mutations in KYNU were recently described as a cause of NAD deficiency with vertebral, cardiac, renal and limb defects; however, no hand hyperphalangism was described in those patients, and Catel-Manzke syndrome was not discussed as a differential diagnosis. In conclusion, we present unrelated patients identified with biallelic variants in KYNU leading to kynureninase deficiency and xanthurenic aciduria as a very likely cause of their hyperphalangism, heart defect, short stature, and developmental delay. We suggest performance of urine organic acid analysis in patients with suspected Catel-Manzke syndrome, particularly in those with cardiac or vertebral defects or without mutations in TGDS.
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http://dx.doi.org/10.1016/j.bone.2019.115219DOI Listing
April 2020

Laboratory diagnosis of disorders of peroxisomal biogenesis and function: a technical standard of the American College of Medical Genetics and Genomics (ACMG).

Genet Med 2020 04 11;22(4):686-697. Epub 2019 Dec 11.

Department of Human Genetics and Pediatrics, McGill University, Montreal, QC, Canada.

Peroxisomal disorders are a clinically and genetically heterogeneous group of diseases caused by defects in peroxisomal biogenesis or function, usually impairing several metabolic pathways. Peroxisomal disorders are rare; however, the incidence may be underestimated due to the broad spectrum of clinical presentations. The inclusion of X-linked adrenoleukodystrophy to the Recommended Uniform Screening Panel for newborn screening programs in the United States may increase detection of this and other peroxisomal disorders. The current diagnostic approach relies heavily on biochemical genetic tests measuring peroxisomal metabolites, including very long-chain and branched-chain fatty acids in plasma and plasmalogens in red blood cells. Molecular testing can confirm biochemical findings and identify the specific genetic defect, usually utilizing a multiple-gene panel or exome/genome approach. When next-generation sequencing is used as a first-tier test, evaluation of peroxisome metabolism is often necessary to assess the significance of unknown variants and establish the extent of peroxisome dysfunction. This document provides a resource for laboratories developing and implementing clinical biochemical genetic testing for peroxisomal disorders, emphasizing technical considerations for sample collection, test performance, and result interpretation. Additionally, considerations on confirmatory molecular testing are discussed.
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http://dx.doi.org/10.1038/s41436-019-0713-9DOI Listing
April 2020

Clinical and molecular spectrum of CHOPS syndrome.

Am J Med Genet A 2019 07 6;179(7):1126-1138. Epub 2019 May 6.

Division of Human Genetics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania.

CHOPS syndrome is a multisystem disorder caused by missense mutations in AFF4. Previously, we reported three individuals whose primary phenotype included cognitive impairment and coarse facies, heart defects, obesity, pulmonary involvement, and short stature. This syndrome overlaps phenotypically with Cornelia de Lange syndrome, but presents distinct differences including facial features, pulmonary involvement, and obesity. Here, we provide clinical descriptions of an additional eight individuals with CHOPS syndrome, as well as neurocognitive analysis of three individuals. All 11 individuals presented with features reminiscent of Cornelia de Lange syndrome such as synophrys, upturned nasal tip, arched eyebrows, and long eyelashes. All 11 individuals had short stature and obesity. Congenital heart disease and pulmonary involvement were common, and those were seen in about 70% of individuals with CHOPS syndrome. Skeletal abnormalities are also common, and those include abnormal shape of vertebral bodies, hypoplastic long bones, and low bone mineral density. Our observation indicates that obesity, pulmonary involvement, skeletal findings are the most notable features distinguishing CHOPS syndrome from Cornelia de Lange syndrome. In fact, two out of eight of our newly identified patients were found to have AFF4 mutations by targeted AFF4 mutational analysis rather than exome sequencing. These phenotypic findings establish CHOPS syndrome as a distinct, clinically recognizable disorder. Additionally, we report three novel missense mutations causative for CHOPS syndrome that lie within the highly conserved, 14 amino acid sequence of the ALF homology domain of the AFF4 gene, emphasizing the critical functional role of this region in human development.
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http://dx.doi.org/10.1002/ajmg.a.61174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473581PMC
July 2019

FGF21 underlies a hormetic response to metabolic stress in methylmalonic acidemia.

JCI Insight 2018 12 6;3(23). Epub 2018 Dec 6.

Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, NIH, Bethesda, Maryland, USA.

Methylmalonic acidemia (MMA), an organic acidemia characterized by metabolic instability and multiorgan complications, is most frequently caused by mutations in methylmalonyl-CoA mutase (MUT). To define the metabolic adaptations in MMA in acute and chronic settings, we studied a mouse model generated by transgenic expression of Mut in the muscle. Mut-/-;TgINS-MCK-Mut mice accurately replicate the hepatorenal mitochondriopathy and growth failure seen in severely affected patients and were used to characterize the response to fasting. The hepatic transcriptome in MMA mice was characterized by the chronic activation of stress-related pathways and an aberrant fasting response when compared with controls. A key metabolic regulator, Fgf21, emerged as a significantly dysregulated transcript in mice and was subsequently studied in a large patient cohort. The concentration of plasma FGF21 in MMA patients correlated with disease subtype, growth indices, and markers of mitochondrial dysfunction but was not affected by renal disease. Restoration of liver Mut activity, by transgenesis and liver-directed gene therapy in mice or liver transplantation in patients, drastically reduced plasma FGF21 and was associated with improved outcomes. Our studies identify mitocellular hormesis as a hepatic adaptation to metabolic stress in MMA and define FGF21 as a highly predictive disease biomarker.
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http://dx.doi.org/10.1172/jci.insight.124351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6328030PMC
December 2018

Tissue acylcarnitine status in a mouse model of mitochondrial β-oxidation deficiency during metabolic decompensation due to influenza virus infection.

Mol Genet Metab 2018 09 23;125(1-2):144-152. Epub 2018 Jun 23.

Metabolism, Infection and Immunity Section, National Human Genome Research Institute, National Institutes of Health, United States. Electronic address:

Despite judicious monitoring and care, patients with fatty acid oxidation disorders may experience metabolic decompensation due to infection which may result in rhabdomyolysis, cardiomyopathy, hypoglycemia and liver dysfunction and failure. Since clinical studies on metabolic decompensation are dangerous, we employed a preclinical model of metabolic decompensation due to infection. By infecting mice with mouse adapted influenza and using a pair-feeding strategy in a mouse model of long-chain fatty acid oxidation (Acadvl), our goals were to isolate the effects of infection on tissue acylcarnitines and determine how they relate to their plasma counterparts. Applying statistical data reduction techniques (Partial Least Squares-Discriminant Analysis), we were able to identify critical acylcarnitines that were driving differentiation of our experimental groups for all the tissues studied. While plasma displayed increases in metabolites directly related to mouse VLCAD deficiency (e.g. C16 and C18), organs like the heart, muscle and liver also showed involvement of alternative pathways (e.g. medium-chain FAO and ketogenesis), suggesting adaptive measures. Matched correlation analyses showed strong correlations (r > 0.7) between plasma and tissue levels for a small number of metabolites. Overall, our results demonstrate that infection as a stress produces perturbations in metabolism in Acadvl that differ greatly from WT infected and Acadvl pair-fed controls. This model system will be useful for studying the effects of infection on tissue metabolism as well as evaluating interventions aimed at modulating the effects of metabolic decompensation.
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http://dx.doi.org/10.1016/j.ymgme.2018.06.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6626496PMC
September 2018

Extending the phenotypic spectrum of Sengers syndrome: Congenital lactic acidosis with synthetic liver dysfunction.

Transl Sci Rare Dis 2018 Apr 13;3(1):45-48. Epub 2018 Apr 13.

Children's National Health System, Rare Disease Institute, Genetics and Metabolism, Washington, DC, USA.

Sengers syndrome is a rare autosomal recessive mitochondrial disease characterized by lactic acidosis, hypertrophic cardiomyopathy and bilateral cataracts. We present here a case of neonatal demise, within the first day of life, who initially presented with severe lactic acidosis, with evidence of both chorioamnionitis and cardiogenic shock. Initial metabolic labs demonstrated a severe lactic acidosis prompting genetic testing which revealed a homozygous pathogenic variant for Sengers syndrome in c.979A >  T; p.K327. In addition to the canonical features of Sengers syndrome, our patient is the first reported case with liver dysfunction extending the phenotypic spectrum both in terms of severity and complications. This case also highlights the importance of maintaining a broad differential for congenital lactic acidosis.
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http://dx.doi.org/10.3233/TRD-180020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5904566PMC
April 2018

Correction of hyperleucinemia in MSUD patients on leucine-free dietary therapy.

Mol Genet Metab 2017 12 5;122(4):156-159. Epub 2017 Oct 5.

Department of Pathology, Stanford University School of Medicine, Stanford, CA, United States. Electronic address:

Purpose: Maple Syrup Urine Disease (MSUD) is a rare disorder of branched-chain amino acid catabolism associated with encephalopathy from accumulation of leucine. Leucine is closely monitored during normal growth and particularly during acute illness. As most hospitals do not have access to rapid plasma amino acid quantification, the initial management is often empirical. A model describing the reduction of plasma leucine in hyperleucinemic patients on leucine-free formula would help to guide management and optimize testing frequency.

Methods: We retrospectively reviewed charts from 15 MSUD patients comprising 29 episodes of hyperleucinemia that were managed with leucine-free formula. Episodes were categorized by clinical presentation.

Results: Upon leucine restriction, plasma leucine concentrations fell exponentially at a rate proportional to approximately 50% of the starting value over each 24-hour period. Recovery appears to be sensitive to clinical status and triggering event of the hyperleucinemic episode. Patients with upper respiratory infections generally recovered slowly, while cases of dietary non-adherence resolved more quickly.

Conclusion: This general model may help anticipate leucine levels during clinical management of MSUD patients when using nutritional support and leucine-free formula. The response of individual patients may vary depending on clinical status and triggering factors.
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http://dx.doi.org/10.1016/j.ymgme.2017.09.012DOI Listing
December 2017

Confirmation that p.Ala259Val mutation causes autosomal dominant hypermethioninemia.

Mol Genet Metab Rep 2017 Dec 15;13:9-12. Epub 2017 Jul 15.

Division of Genetics and Metabolism, Children's National Health System, Washington, DC, USA.

Methionine adenosyltransferase (MAT) I/III deficiency is an inborn error of metabolism caused by mutations in , encoding the catalytic subunit of MAT responsible for the synthesis of S-adenosylmethionine, and is characterized by persistent hypermethioninemia. While historically considered a recessive disorder, a milder autosomal dominant form of MAT I/III deficiency occurs, though only the most common mutation p.Arg264His has ample evidence to prove dominant inheritance. We report a case of hypermethioninemia caused by the p.Ala259Val substitution and provide evidence of autosomal dominant inheritance by showing both maternal inheritance of the mutation and concomitant hypermethioninemia. The p.Ala259Val mutation falls in the dimer interface, and thus likely leads to dominant inheritance by a similar mechanism to that described in the previously reported dominant negative mutation, that is, by means of interference with subunits encoded by the wild-type allele.
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http://dx.doi.org/10.1016/j.ymgmr.2017.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5512230PMC
December 2017

Time-dependent negative bias in plasma ammonia samples in a clinical setting.

Clin Chim Acta 2017 Aug 10;471:126-127. Epub 2017 May 10.

Children's National Medical Center, Washington, DC, United States.

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http://dx.doi.org/10.1016/j.cca.2017.05.011DOI Listing
August 2017

Diagnosis of LCHAD/TFP deficiency in an at risk newborn using umbilical cord blood acylcarnitine analysis.

Mol Genet Metab Rep 2017 Mar 9;10:8-10. Epub 2016 Dec 9.

Genetics and Metabolism, Children's National Health System, Washington, DC,USA.

Trifunctional protein deficiency/Long-chain hydroxyacyl-CoA dehydrogenase deficiency (LCHAD/TFP) deficiency is a disorder of fatty acid oxidation and ketogenesis. Severe neonatal lactic acidosis, cardiomyopathy, and hepatic dysfunction are caused by the accumulation of toxic long-chain acylcarnitines. The feasibility of umbilical cord blood use in screening for acylcarnitine analysis and free carnitine has been hypothesized but not reported in LCHAD/TFP neonates. We present a 4 week old female who was at risk of inheriting LCHAD/TFP deficiency and was diagnosed at the time of delivery using umbilical cord blood. Umbilical cord blood was collected at delivery and sent for acylcarnitine analysis. Treatment was started immediately. Acylcarnitine analysis demonstrated findings that are consistent with a biochemical diagnosis of LCHAD/TFP deficiency. Patients with LCHAD/TFP deficiency should have treatment initiated as early as possible to avoid acute decompensation and minimize the long-term complications of the disorder including cardiomyopathy. In pregnancies at risk of having a child with LCHAD/TFP deficiency, umbilical cord blood sample is an efficient method to diagnose an inborn error of metabolism such as LCHAD/TFP deficiency.
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http://dx.doi.org/10.1016/j.ymgmr.2016.11.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5155040PMC
March 2017

Hereditary fructose intolerance mimicking a biochemical phenotype of mucolipidosis: A review of the literature of secondary causes of lysosomal enzyme activity elevation in serum.

Am J Med Genet A 2017 Feb 31;173(2):501-509. Epub 2016 Oct 31.

Division of Genetics and Metabolism, Children's National Health System, Washington, District Of Columbia.

We describe a patient with failure to thrive, hepatomegaly, liver dysfunction, and elevation of multiple plasma lysosomal enzyme activities mimicking mucolipidosis II or III, in whom a diagnosis of hereditary fructose intolerance (HFI) was ultimately obtained. She presented before introduction of solid foods, given her consumption of a fructose-containing infant formula. We present the most extensive panel of lysosomal enzyme activities reported to date in a patient with HFI, and propose that multiple enzyme elevations in plasma, especially when in conjunction with a normal plasma α-mannosidase activity, should elicit a differential diagnosis of HFI. We also performed a review of the literature on the different etiologies of elevated lysosomal enzyme activities in serum or plasma. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.38023DOI Listing
February 2017

Spurious Elevation of Multiple Urine Amino Acids by Ion-Exchange Chromatography in Patients with Prolidase Deficiency.

JIMD Rep 2017 12;31:45-49. Epub 2016 Apr 12.

Children's National Health System, Washington, DC, USA.

The enzyme prolidase cleaves dipeptides where the C-terminal amino acid corresponds to proline or hydroxyproline. As a consequence, a deficiency of this enzyme leads to accumulation of these dipeptides, which correspondingly are found to be elevated in urine. In fact, the absence of dipeptiduria is sufficient to rule out a diagnosis of prolidase deficiency. However, given the fact that these dipeptides elute at the same position as more common amino acids, the analyzer's software will instead call an elevation of these corresponding amino acids. Thus, an elevation of glycylproline, aspartylproline, glutamylproline, threonylproline and serylproline, valylproline, leucylproline, isoleucylproline, alanylproline, phenylalanylproline, and lysylproline will instead be interpreted as an elevation of leucine, citrulline, methionine, isoleucine, beta-aminoisobutyric acid, gamma-aminobutyric acid, ethanolamine, tyrosine, histidine, and anserine/carnosine, respectively. This particular profile of elevated amino acids, however, can easily be overlooked. We hope that the recognition of this characteristic pattern of falsely elevated urinary amino acids will aid in the recognition of prolidase deficiency.
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http://dx.doi.org/10.1007/8904_2016_552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388643PMC
April 2016

The proteome of methylmalonic acidemia (MMA): the elucidation of altered pathways in patient livers.

Mol Biosyst 2016 Feb;12(2):566-74

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli, "Federico II", Naples, Italy and CEINGE Biotecnologie Avanzate, Naples, Italy.

Methylmalonic acidemia (MMA) is a heterogeneous and severe autosomal recessive inborn error of metabolism most commonly caused by the deficient activity of the vitamin B12 dependent enzyme, methylmalonyl-CoA mutase (MUT). The main treatment for MMA patients is the dietary restriction of propiogenic amino acids and carnitine supplementation. Despite treatment, the prognosis for vitamin B12 non-responsive patients remains poor and is associated with neonatal lethality, persistent morbidity and decreased life expectancy. While multi-organ pathology is a feature of MMA, the liver is severely impacted by mitochondrial dysfunction which likely underlies the metabolic instability experienced by the patients. Liver and/or combined liver/kidney transplantation is therefore sometimes performed in severely affected patients. Using liver specimens from donors and MMA patients undergoing elective liver transplantation collected under a dedicated natural history protocol (clinicaltrials.gov: NCT00078078), we employed proteomics to characterize the liver pathology and impaired hepatic metabolism observed in the patients. Pathway analysis revealed perturbations of enzymes involved in energy metabolism, gluconeogenesis and Krebs cycle anaplerosis. Our findings identify new pathophysiologic and therapeutic targets that could be valuable for designing alternative therapies to alleviate clinical manifestations seen in this disorder.
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http://dx.doi.org/10.1039/c5mb00736dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4858437PMC
February 2016

Kupffer cells modulate hepatic fatty acid oxidation during infection with PR8 influenza.

Biochim Biophys Acta 2015 Nov 28;1852(11):2391-401. Epub 2015 Aug 28.

Metabolism, Infection and Immunity Unit, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA. Electronic address:

In response to infection, patients with inborn errors of metabolism may develop a functional deterioration termed metabolic decompensation. The biochemical hallmarks of this disruption of metabolic homeostasis are disease specific and may include acidosis, hyperammonemia or hypoglycemia. In a model system previously published by our group, we noted that during influenza infection, mice displayed a depression in hepatic mitochondrial enzymes involved in nitrogen metabolism. Based on these findings, we hypothesized that this normal adaptation may extend to other metabolic pathways, and as such, may impact various inborn errors of metabolism. Since the liver is a critical organ in inborn errors of metabolism, we carried out untargeted metabolomic profiling of livers using mass spectrometry in C57Bl/6 mice infected with influenza to characterize metabolic adaptation. Pathway analysis of metabolomic data revealed reductions in CoA synthesis, and long chain fatty acyl CoA and carnitine species. These metabolic adaptations coincided with a depression in hepatic long chain β-oxidation mRNA and protein. To our surprise, the metabolic changes observed occurred in conjunction with a hepatic innate immune response, as demonstrated by transcriptional profiling and flow cytometry. By employing an immunomodulation strategy to deplete Kupffer cells, we were able to improve the expression of multiple genes involved in β-oxidation. Based on these findings, we are the first to suggest that the role of the liver as an immunologic organ is central in the pathophysiology of hepatic metabolic decompensation in inborn errors of metabolism due to respiratory viral infection.
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http://dx.doi.org/10.1016/j.bbadis.2015.08.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6662236PMC
November 2015

What is in the can? The dilemma with dietary supplements.

Mol Genet Metab 2014 Dec 22;113(4):239-40. Epub 2014 Oct 22.

Dept. of Pediatrics, Columbia University, College of Physicians and Surgeons, USA.

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http://dx.doi.org/10.1016/j.ymgme.2014.10.009DOI Listing
December 2014

Degree of glutathione deficiency and redox imbalance depend on subtype of mitochondrial disease and clinical status.

PLoS One 2014 18;9(6):e100001. Epub 2014 Jun 18.

Department of Pathology, Stanford University, Stanford, California, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0100001PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4062483PMC
October 2015

Concurrent non-ketotic hyperglycinemia and propionic acidemia in an eight year old boy.

Mol Genet Metab Rep 2014 22;1:237-240. Epub 2014 May 22.

Department of Genetics and Metabolism, Children's National Health Center, Washington, DC, USA.

This is the first reported case of a patient with both non-ketotic hyperglycinemia and propionic acidemia. At 2 years of age, the patient was diagnosed with non-ketotic hyperglycinemia by elevated glycine levels and mutations in the gene (paternal allele: c.1576_1577insC delT and c.1580delGinsCAA; p.S527Tfs*13, and maternal allele: c.1819G>A; p.G607S). At 8 years of age after having been placed on ketogenic diet, he became lethargic and had severe metabolic acidosis with ketonuria. Urine organic acid analysis and plasma acylcarnitine profile were consistent with propionic acidemia. He was found to have an apparently homozygous mutation in the gene: c.49C>A; p.Leu17Met. The patient was also treated with natural protein restriction, carnitine, biotin, and thiamine and had subjective and biochemical improvement.
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http://dx.doi.org/10.1016/j.ymgmr.2014.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121296PMC
May 2014

Thiamine pyrophosphokinase deficiency causes a Leigh Disease like phenotype in a sibling pair: identification through whole exome sequencing and management strategies.

Mol Genet Metab Rep 2014 11;1:66-70. Epub 2014 Feb 11.

Division of Genetics and Metabolism, Children's National Medical Center, Washington, DC, USA.

We present a sibling pair with Leigh-like disease, progressive hypotonia, regression, and chronic encephalopathy. Whole exome sequencing in the younger sibling demonstrated a homozygous thiamine pyrophosphokinase (TPK) mutation. Initiation of high dose thiamine, niacin, biotin, α-lipoic acid and ketogenic diet in this child demonstrated improvement in neurologic function and re-attainment of previously lost milestones. The diagnosis of TPK deficiency was difficult due to inconsistent biochemical and diagnostic parameters, rapidity of clinical demise and would not have been made in a timely manner without the use of whole exome sequencing. Molecular diagnosis allowed for attempt at dietary modification with cofactor supplementation which resulted in an improved clinical course.
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http://dx.doi.org/10.1016/j.ymgmr.2013.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5121315PMC
February 2014

A rapid, sensitive method for quantitative analysis of underivatized amino acids by liquid chromatography-tandem mass spectrometry (LC-MS/MS).

J Chromatogr B Analyt Technol Biomed Life Sci 2014 Jan 18;944:166-74. Epub 2013 Nov 18.

Department of Pathology, Stanford University, Palo Alto, CA, United States. Electronic address:

The quantitation of free amino acids from physiologic samples is essential for diagnosing and monitoring patients with inherited metabolic disorders. Current methods are hindered by long preparative and/or analysis times, expensive reagents, and often suboptimal performance characteristics. To overcome these challenges, a improved method for amino acid analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) has been developed and validated. Samples were deproteinized with sulfosalicylic acid and supernatants diluted with tridecafluoroheptanoic acid. Chromatographic separation of amino acids occurred using two columns, with conditions favoring resolution of isobaric compounds and minimizing ion suppression. Eluted compounds were detected by selective reaction monitoring, and quantitated by relating peak areas of amino acids to externally run standards. Validation studies evaluated linearity, within- and between-run imprecision, lower limits of detection and quantification for 33 amino acids, and correlation with the Biochrom 30 Amino Acid Analyzer. Total run time including re-equilibration was 15min per sample. Within-run precision averaged 2.8% for all compounds, with an average linear correlation coefficient of 0.995. The majority of compounds were reliably quantitated at ≤0.1μM. Between-run precision averaged 4.0%. Results showed excellent correlation with the Biochrom 30 amino acid analyzer with an average overall correlation of 0.908. We conclude that our method is extremely sensitive, specific and reproducible and represents an improvement over other currently available technologies.
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http://dx.doi.org/10.1016/j.jchromb.2013.11.017DOI Listing
January 2014

Expansion of the TARP syndrome phenotype associated with de novo mutations and mosaicism.

Am J Med Genet A 2014 Jan 20;164A(1):120-8. Epub 2013 Nov 20.

Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.

The TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistent left superior vena cava) is an X-linked disorder that was determined to be caused by mutations in RBM10 in two families, and confirmed in a subsequent case report. The first two original families were quite similar in phenotype, with uniform early lethality although a confirmatory case report showed survival into childhood. Here we report on five affecteds from three newly recognized families, including patients with atypical manifestations. None of the five patients had talipes and others also lacked cardinal TARP features of Robin sequence and atrial septal defect. All three families demonstrated de novo mutations, and one of the families had two recurrences, with demonstrable maternal mosaicism.
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http://dx.doi.org/10.1002/ajmg.a.36212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4443488PMC
January 2014

Targeting proximal tubule mitochondrial dysfunction attenuates the renal disease of methylmalonic acidemia.

Proc Natl Acad Sci U S A 2013 Aug 29;110(33):13552-7. Epub 2013 Jul 29.

Genetics and Molecular Biology Branch, National Human Genome Research Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.

Isolated methylmalonic acidemia (MMA), caused by deficiency of the mitochondrial enzyme methylmalonyl-CoA mutase (MUT), is often complicated by end stage renal disease that is resistant to conventional therapies, including liver transplantation. To establish a viable model of MMA renal disease, Mut was expressed in the liver of Mut(-/-) mice as a stable transgene under the control of an albumin (INS-Alb-Mut) promoter. Mut(-/-);Tg(INS-Alb-Mut) mice, although completely rescued from neonatal lethality that was displayed by Mut(-/-) mice, manifested a decreased glomerular filtration rate (GFR), chronic tubulointerstitial nephritis and ultrastructural changes in the proximal tubule mitochondria associated with aberrant tubular function, as demonstrated by single-nephron GFR studies. Microarray analysis of Mut(-/-);Tg(INS-Alb-Mut) kidneys identified numerous biomarkers, including lipocalin-2, which was then used to monitor the response of the GFR to antioxidant therapy in the mouse model. Renal biopsies and biomarker analysis from a large and diverse patient cohort (ClinicalTrials.gov identifier: NCT00078078) precisely replicated the findings in the animals, establishing Mut(-/-);Tg(INS-Alb-Mut) mice as a unique model of MMA renal disease. Our studies suggest proximal tubular mitochondrial dysfunction is a key pathogenic mechanism of MMA-associated kidney disease, identify lipocalin-2 as a biomarker of increased oxidative stress in the renal tubule, and demonstrate that antioxidants can attenuate the renal disease of MMA.
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http://dx.doi.org/10.1073/pnas.1302764110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3746875PMC
August 2013

Outcome of infants diagnosed with 3-methyl-crotonyl-CoA-carboxylase deficiency by newborn screening.

Mol Genet Metab 2012 Aug 20;106(4):439-41. Epub 2012 Apr 20.

Department of Pediatrics, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.

Introduction: 3-Methyl CoA carboxylase (3-MCC) deficiency is an inborn error of metabolism in the catabolism of the amino acid leucine. Original reports suggested this disorder was associated with significant neurological and biochemical effects. However newborn screening has identified a higher than expected incidence of this disorder with apparent normal outcome in most cases.

Method: A retrospective analysis of thirty-five cases of 3-MCC deficiency identified by newborn screening and diagnosed by enzyme or molecular analysis.

Results: There was a strong inverse correlation between initial C5OH level and residual enzyme activity. A few reports of hypoglycemia, ketosis, poor feeding/failure to thrive or fasting intolerance were reported, but there was no clear relationship between symptoms and residual enzyme activity. Developmental outcome included several children with mental retardation (including one with Down syndrome and one with schizencephaly) and two with Autism Spectrum disorders but there was no apparent relationship to residual enzyme activity. Free carnitine deficiency was relatively common.

Discussion: Although residual enzyme activity was clearly related to metabolite elevation, there was no apparent relationship with other measures of outcome. The number of reports of neurologic abnormalities or metabolic symptoms (poor feeding, hypoglycemia, fasting intolerance, etc.) is concerning, but the significance is unclear in this retrospective sample.
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http://dx.doi.org/10.1016/j.ymgme.2012.04.006DOI Listing
August 2012

The role of vanin-1 and oxidative stress-related pathways in distinguishing acute and chronic pediatric ITP.

Blood 2011 Apr 16;117(17):4569-79. Epub 2011 Feb 16.

Departments of Pathology, School of Medicine, Stanford University, Stanford, CA, USA.

Pediatric immune thrombocytopenia (ITP) is usually self-limited. However, approximately 20% of children develop chronic ITP, which can be associated with significant morbidity because of long-term immunosuppression and splenectomy in refractory cases. To explore the molecular mechanism of chronic ITP compared with acute ITP, we studied 63 pediatric patients with ITP. Gene expression analysis of whole blood revealed distinct signatures for acute and chronic ITP. Oxidative stress-related pathways were among the most significant chronic ITP-associated pathways. Overexpression of VNN1, an oxidative stress sensor in epithelial cells, was most strongly associated with progression to chronic ITP. Studies of normal persons demonstrated VNN1 expression in a variety of blood cells. Exposure of blood mononuclear cells to oxidative stress inducers elicited dramatic up-regulation of VNN1 and down-regulation of PPARγ, indicating a role for VNN1 as a peripheral blood oxidative stress sensor. Assessment of redox state by tandem mass spectrometry demonstrated statistically significant lower glutathione ratios in patients with ITP versus healthy controls; lower glutathione ratios were also seen in untreated patients with ITP compared with recently treated patients. Our work demonstrates distinct patterns of gene expression in acute and chronic ITP and implicates oxidative stress pathways in the pathogenesis of chronic pediatric ITP.
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http://dx.doi.org/10.1182/blood-2010-09-304931DOI Listing
April 2011

Dopa-responsive dystonia presenting as delayed and awkward gait.

Pediatr Neurol 2008 Apr;38(4):273-5

Department of Psychiatry, Center for Neurobiology and Psychiatry, University of California at San Francisco, San Francisco, California 94158-2324, USA.

Dopa-responsive dystonia is a hereditary disease characterized by inadequate dopamine production. Autosomal-dominant cases result from mutations in the GCH1 gene, encoding guanosine triphosphate (GTP)-cyclohydrolase 1. The most common presenting manifestation is dystonia of a lower extremity, often worsening late in the day. The onset and clinical severity are variable, sometimes even within a single family. Gender effects on allele penetrance have been reported. We present a male toddler with dopa-responsive dystonia caused by an autosomal-dominant GCH1 mutation. Three other family members were also found to carry the mutation, with widely different functional consequences.
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http://dx.doi.org/10.1016/j.pediatrneurol.2007.12.005DOI Listing
April 2008

Progressive and symmetric supraorbital hyperostosis with bony and soft tissue overgrowth in an Ethiopian female: a newly recognized overgrowth syndrome?

Am J Med Genet A 2008 Mar;146A(5):543-7

Department of Human Genetics, Division of Medical Genetics, Emory University School of Medicine, Atlanta, Georgia 30030, USA.

We report on an Ethiopian female with generalized overgrowth of postnatal onset accompanied by progressive and symmetric overgrowth of skeletal and soft tissues. Her phenotype consisted of progressive and symmetric overgrowth of the supraorbital ridges, glabella, occiput, cervical spine, and distal phalanges of all extremities, but particularly the 3rd and 4th digits. She also has overgrowth of soft tissues of the posterior neck (thought to be fatty in origin), alveolar hyperplasia, and overgrowth of the skin comprising the areola and umbilicus. Other clinical findings included obstructive sleep apnea and normal intelligence. A genetic workup of extended banding chromosome analysis and chromosomal microarray were normal, as were PTEN and FNLA mutation analyses. Histologic examination of the excised supraorbital ridges demonstrated normal bone. However, the bone began to regrow in a symmetric fashion within 3 months of removal. This patient's phenotype is at variance with any known overgrowth syndrome.
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http://dx.doi.org/10.1002/ajmg.a.32166DOI Listing
March 2008

22q13.3 deletion syndrome: a recognizable malformation syndrome associated with marked speech and language delay.

Am J Med Genet C Semin Med Genet 2007 Nov;145C(4):393-8

Division of Medical Genetics, H-315, Department of Pediatrics, Stanford University School of Medicine, Stanford, CA 94305-5208, USA.

The 22q13.3 deletion syndrome is a recognizable malformation syndrome associated with developmental delay, hypotonia, delayed or absent speech, autistic-like behavior, normal to accelerated growth and dysmorphic facies. The prevalence of this disorder is unknown, but it is likely under-diagnosed. Age at diagnosis has varied widely, from cases diagnosed prenatally to 46 years. Males and females are equally affected. The distal 22q deletion can be detected occasionally by routine or high resolution chromosome analysis; however, the majority of cases are detected by FISH analysis, associated with deletion of the ARSA (control) probe when performing a FISH analysis for the velocardiofacial syndrome (del 22q11.2). The 22q13.3 deletion syndrome can accompany a simple chromosome deletion, an unbalanced translocation, or a ring chromosome. Primary care physicians, in addition to numerous specialists, play an important role in caring for patients with this disorder. Although the dysmorphic features observed in this condition are nonspecific, it is an important consideration in the differential diagnosis of children with developmental delay, hypotonia, marked speech and language disability, autistic-like features, multiple minor anomalies, and normal growth and head circumference.
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http://dx.doi.org/10.1002/ajmg.c.30155DOI Listing
November 2007