Olaf A Bodamer

University of Miami Miller School of Medicine, Miami, Florida, United States

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Publications (137)496.22 Total impact

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    ABSTRACT: Gaucher disease, an autosomal recessive condition due to deficiency of lysosomal glucocerebrosidase, is a multisystemic disease, with variable age of onset, severity and progression. It is classified into subtypes delineated by the absence (type 1) or presence (type 2 and 3) of primary nervous system involvement.The ethnically diverse, largely immigrant population in South Florida has a spectrum of Gaucher disease phenotypes, creating a challenge for optimization of disease management and an opportunity to explore treatment patterns. Ninety-three records from patients with Gaucher type I in South Florida were retrieved from the International Collaborative Gaucher Group (ICGG) Registry. Individual genotypes were correlated with severity scores and success at achieving published therapeutic goals for haemoglobin concentration, platelet count, spleen volume, liver volume and amelioration of bone pain and bone crises. The majority of patients were diagnosed during the fifth decade of life. Almost two-thirds were homozygous for the N370S mutation, reflecting the large Ashkenazi Jewish population in South Florida. The majority received imiglucerase (62.8%) at various intervals. 24.5% of patients underwent splenectomy before starting enzyme replacement therapy. After a median 12 treatment years, South Florida patients matched or exceeded the ICCG 4 year therapeutic goal achievement for platelet count (85.4% vs. 79.6% success), spleen volume (93.3% vs. 78.0% success), liver volume (93.4% vs. 90.6% success), and bone crises (100% vs. 99% success). Nevertheless, fewer patients with intact spleens had sustained achievement of all 6 therapeutic goals (30.4% versus 41.4%) and only 40% of the splenectomy patients sustained achievement of 5/5 possible goals. 54.7% of the intact spleen patients continued to have bone pain vs. 29.8% in ICCG. Significantly, only 37% of the ICGG patient cohort had bone pain prior to initiation of treatment compared to 73.4% of the South Florida patients (moderate or severe pain in 59.6%). Demographic characteristics are a significant determinant of the differences in response to treatment observed in South Florida Gaucher patients compared to those described in the international population enrolled in the ICGG Gaucher Registry. Individual genotypes and ethnic background are important considerations for optimizing patient care for Gaucher disease.
    Orphanet Journal of Rare Diseases 03/2014; 9(1):45. · 4.32 Impact Factor
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    ABSTRACT: New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.
    Molecular Genetics and Metabolism 03/2014; · 2.83 Impact Factor
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    ABSTRACT: The first GalT gene knockout (KO) mouse model for Classic Galactosemia (OMIM 230400) accumulated some galactose and its metabolites upon galactose challenge, but was seemingly fertile and symptom free. Here we constructed a new GalT gene-trapped mouse model by injecting GalT gene-trapped mouse embryonic stem cells into blastocysts, which were later implanted into pseudo-pregnant females. High percentage GalT gene-trapped chimera obtained were used to generate heterozygous and subsequently, homozygous GalT gene-trapped mice. Biochemical assays confirmed total absence of galactose-1 phosphate uridylyltransferase (GALT) activity in the homozygotes. Although the homozygous GalT gene-trapped females could conceive and give birth when fed with normal chow, they had smaller litter size (P=0.02) and longer time-to-pregnancy (P=0.013) than their wild-type littermates. Follicle-stimulating hormone levels of the mutant female mice were not significantly different from the age-matched, wild-type females, but histological examination of the ovaries revealed fewer follicles in the homozygous mutants (P=0.007). Administration of a high-galactose (40% w/w) diet to lactating homozygous GalT gene-trapped females led to lethality in over 70% of the homozygous GalT gene-trapped pups before weaning. Cerebral edema, abnormal changes in the Purkinje and the outer granular cell layers of the cerebellum, as well as lower blood GSH/GSSG ratio were identified in the galactose-intoxicated pups. Finally, reduced growth was observed in GalT gene-trapped pups fed with normal chow and all pups fed with high-galactose (20% w/w) diet. This new mouse model presents several of the complications of Classic Galactosemia and will be useful to investigate pathogenesis and new therapies.European Journal of Human Genetics advance online publication, 19 February 2014; doi:10.1038/ejhg.2014.12.
    European journal of human genetics: EJHG 02/2014; · 3.56 Impact Factor
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    ABSTRACT: Gaucher Disease (GD) is a progressive lysosomal storage disorder caused by deficiency of glucocerebrosidase (GBA). The clinical phenotype follows a spectrum ranging from severe early-onset to milder late-onset disease. The absence of neurological involvement defines GD type I, whereas neuronopathic features define GD type II and III. Early diagnosis may be important for timely initiation of enzyme replacement therapy to prevent disease complications, although the enzyme does not cross the blood brain barrier. Diagnosis of GD can be readily achieved by analysis of GBA in leukocytes, fibroblasts, and/or dried blood spots using fluorometric, microfluidic or mass spectrometry-based assays. Low GBA activities are typically confirmed through molecular analysis of the GBA gene. GBA analysis in dried blood spots may be attractive for high-throughput screening of at-risk individuals and/or newborn infants. The method detailed in this unit is based on GBA analysis by tandem mass spectrometry following incubation of dried blood spots with the GBA-specific substrate D-glucosyl-β1-1'-N-dodecanoyl-D-erythro-sphingosine [C12-glucocerebroside (C36 H69 NO8 )] and internal standard N-myristoyl-D-erythro-sphingosine [C14-ceramide (C32 H63 NO3 )]. GBA activities in more than 2,000 newborn infants showed a mean of 22.0 ± 13.8 μmol/hr/liter (median: 19.9 μmol/hr/liter; 95% CI: 21.41-22.59 μmol/hr/liter). GBA activities in an adult population (n >1,200) showed generally lower enzyme activities than newborns, with a mean of 9.87 ± 9.35 μmol/hr/liter (median: 8.06 μmol/hr/liter). GBA activities in ten adult patients with confirmed GD were less than 4.2 μmol/hr/liter and in seven infants and children with GD less than 1.24 μmol/hr/liter. This method is robust, sensitive, and suitable for high-throughput analysis of hundreds of samples. Curr. Protoc. Hum. Genet. 82:17.15.1-17.15.6. © 2014 by John Wiley & Sons, Inc.
    Current protocols in human genetics / editorial board, Jonathan L. Haines ... [et al.] 01/2014; 82:17.15.1-6.
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    ABSTRACT: The lysosomal storage disorders (LSDs) are a group of genetic disorders resulting from defective lysosomal metabolism and subsequent accumulation of substrates. Patients present with a large phenotypic spectrum of disease manifestations that are generally not specific for LSDs, leading to considerable diagnostic delay and missed cases. Introduction of new disease modifying therapies for LSDs has made early diagnosis a priority. Increased awareness, but particularly the introduction of screening programs allow for early diagnosis and timely initiation of treatment. This review will provide insight into the epidemiology and diagnostic process for LSDs. In addition, challenges for carrier screening, high-risk screening and newborn population screening for LSDs are discussed.
    Best Practice & Research: Clinical Endocrinology & Metabolism 01/2014; · 4.91 Impact Factor
  • Olaf A. Bodamer, Roberto Giugliani, Tim Wood
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    ABSTRACT: Mucopolysaccharidosis type III (MPS III) is characterized by progressive neurological deterioration, behavioral abnormalities, a relatively mild somatic phenotype, and early mortality. Because of the paucity of somatic manifestations and the rarity of the disease, early diagnosis is often difficult. Therapy targeting the underlying disease pathophysiology may offer the greatest clinical benefit when started prior to the onset of significant neurologic sequale. Here we review current practices in the laboratory diagnosis of MPS III in order to facilitate earlier patient identification and diagnosis. When clinical suspicion of MPS III arises, the first step is to order a quantitative assay that screens urine for the presence of glycosaminoglycan biomarkers using a spectrophotometric compound (e.g., dimethylmethylene blue). We recommend testing all patients with developmental delay and/or behavioral abnormalities as part of the diagnostic work-up because quantitative urine screening is inexpensive and non-invasive. Semi-quantitative urine screening assays using cationic dyes on filter paper (e.g., spot tests) have relatively high rates of false-positives and false-negatives and are obsolete. Of note, a negative urinary glycosaminoglycan assay does not necessarily rule out MPS because, in some patients, an overlap in excretion levels with healthy controls may occur. All urine samples that test positive for glycosaminoglycans with a quantitative assay should be confirmed by electrophoresis, thin layer chromatography, or tandem mass spectrometry, which further improves the sensitivity and specificity. The gold standard for diagnosis remains the enzyme activity assay in cultured skin fibroblasts, leukocytes, plasma, or serum, which can be used as a first-line diagnostic test in some regions. Molecular genetic analysis should be offered to all families of patients to allow genetic counseling for informed family planning. For a small number of variants, genotype-phenotype correlations are available and can offer prognostic value. Prenatal testing via enzyme activity assay in chorionic villi or amniotic fluid cells is available at a limited number of centers worldwide, but whenever possible, a molecular genetic analysis is preferred for prenatal diagnosis. To conclude, we discuss the development of newborn screening assays in dried blood spots and high-throughput methods for sequencing the protein-coding regions of the genome (whole exome sequencing) and their relevance to future changes in the MPS III diagnostic landscape.
    Molecular Genetics and Metabolism 01/2014; · 2.83 Impact Factor
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    ABSTRACT: Transcobalamin (TC) transports cobalamin from blood into cells. TC deficiency is a rare autosomal recessive disorder usually presenting in early infancy with failure to thrive, weakness, diarrhoea, pallor, anemia, and pancytopenia or agammaglobulinemia. It can sometimes resemble neonatal leukemia or severe combined immunodeficiency disease. Diagnosis of TC deficiency is suspected based on megaloblastic anemia, elevation of total plasma homocysteine, and blood or urine methylmalonic acid. It is confirmed by studying the synthesis of TC in cultured fibroblasts, or by molecular analysis of the TCN2 gene. TC deficiency is treatable with supplemental cobalamin, but the optimal type, route and frequency of cobalamin administration and long term patient outcomes are unknown. Here we present a series of 30 patients with TC deficiency, including an update on multiple previously published patients, in order to evaluate the different treatment strategies and provide information about long term outcome. Based on the data presented, current practice appears to favour treatment of individuals with TC deficiency by intramuscular injections of hydroxy- or cyanocobalamin. In most cases presented, at least weekly injections (1 mg IM) were necessary to ensure optimal treatment. Most centres adjusted the treatment regimen based on monitoring CBC, total plasma homocysteine, plasma and urine methylmalonic acid, as well as, clinical status. Finally, continuing IM treatment into adulthood appears to be beneficial.
    Journal of Inherited Metabolic Disease 12/2013; · 4.07 Impact Factor
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    ABSTRACT: Genomic microarrays have been used as the first-tier cytogenetic diagnostic test for patients with developmental delay/intellectual disability, autism spectrum disorders and/or multiple congenital anomalies. The use of SNP arrays has revealed regions of homozygosity in the genome which can lead to identification of uniparental disomy and parental consanguinity in addition to copy number variations. Consanguinity is associated with an increased risk ofbirth defects and autosomal recessive disorders. However, the frequency of parental consanguinity in children with developmental disabilities is unknown, and consanguineouscouples may not be identified during doctor's visit or genetic counseling without microarray. We studied 607 proband pediatric patients referred for developmental disorders using a 4 x 180 K array containing both CGH and SNP probes. Using 720, 360, 180, and 90 Mb as the expected sizes of homozygosity for an estimated coefficient of inbreeding (F) 1/4, 1/8, 1/16, 1/32, parental consanguinity was detected in 21cases (3.46%). Parental consanguinity is not uncommon in children with developmental problems in our study population, and can be identified by use of a combined CGH and SNP chromosome microarray. Identification of parental consanguinity in such cases can be important for further diagnostic testing.
    Molecular Cytogenetics 09/2013; 6(1):38. · 2.36 Impact Factor
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    ABSTRACT: Recently, lyso-globotriaosylsphingosine (lyso-Gb3) was found to be elevated in plasma of treatment naive male patients and some female patients with Fabry Disease (FD). This study tested whether lyso-Gb3 could be analyzed in dried blood spots (DBS) from filter cards and whether concentrations are elevated in newborn infants with FD. Lyso-Gb3 concentrations were analyzed in DBS following extraction using a novel HPLC-mass spectrometry (MS)/MS method. Lyso-Gb3 levels in DBS were above the lower limit of quantitation (0.28 ng/mL) in 5/17 newborn FD infants (16 males; range: 1.02-8.81 ng/mL), but in none of the newborn controls, in all 13 patients (4 males) with classic FD (range: 2.06-54.1 ng/mL), in 125/159 Taiwanese individuals with symptomatic or asymptomatic FD who carry the late onset α-galactosidase A (GLA) mutation c.936+919G>A (IVS4+919G>A) (3.75±0.69 ng/mL; range: 0.418-3.97 ng/mL) and in 20/29 healthy controls (0.77±0.24 ng/mL; range: 0.507-1.4 ng/mL). The HPLC-MS/MS method for analysis of lyso-Gb3 is robust and yields reproducible results in DBS in patients with FD. However, concentrations of lyso-Gb3 were below the limit of quantitation in most newborn infants with FD rendering this approach not suitable for newborn screening. In addition, most females with the late onset mutation have undetectable lyso-Gb3 concentrations.
    Annals of Laboratory Medicine 07/2013; 33(4):274-8. · 1.48 Impact Factor
  • Olaf A Bodamer, Britt Johnson, Angela Dajnoki
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    ABSTRACT: Fabry disease (FD) is an X-linked lysosomal storage disorder due to deficiency of alpha galactosidase A (GLA). Progressive, intralysosomal accumulation of neutral glycosphingolipids in endothelial cells and podocytes leads to multi-organ involvement in affected males and to a lesser extent in affected females. Diagnosis of FD is based on GLA analysis in leukocytes or dried blood spots (DBS) in FD males while GLA activities may be within the normal range in FD females. The advent of fluorometric and mass spectrometry methods for enzyme analysis in DBS has simplified the diagnostic approach for FD males, facilitating high-throughput screening of at risk populations and newborn infants. However, the diagnostic mainstay for FD females remains molecular analysis of the GLA gene. The following unit will provide the detailed analytical protocol for measurement of GLA activity in DBS using tandem mass spectrometry. Curr. Protoc. Hum. Genet. 77:17.13.1-17.13.7. © 2013 by John Wiley & Sons, Inc.
    Current protocols in human genetics / editorial board, Jonathan L. Haines ... [et al.] 04/2013; Chapter 17:Unit17.13.
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    ABSTRACT: BACKGROUND: Propionic acidemia is an inherited disorder caused by deficiency of propionyl-CoA carboxylase. Although it is one of the most frequent organic acidurias, information on the outcome of affected individuals is still limited.Study design/methods: Clinical and outcome data of 55 patients with propionic acidemia from 16 European metabolic centers were evaluated retrospectively. 35 patients were diagnosed by selective metabolic screening while 20 patients were identified by newborn screening. Endocrine parameters and bone age were assessed. In addition, IQ testing was performed and the patients' and their families' quality of life was assessed. RESULTS: The vast majority of patients (>85%) presented with metabolic decompensation in the neonatal period. Asymptomatic individuals were the exception. About three quarters of the study population was mentally retarded, median IQ was 55. Apart from neurologic symptoms, complications comprised hematologic abnormalities, cardiac diseases, feeding problems and impaired growth. Most patients considered their quality of life high. However, according to the parents' point of view psychic problems were four times more common in propionic acidemia patients than in healthy controls. CONCLUSION: Our data show that the outcome of propionic acidemia is still unfavourable, in spite of improved clinical management. Many patients develop long-term complications affecting different organ systems. Impairment of neurocognitive development is of special concern. Nevertheless, self-assessment of quality of life of the patients and their parents yielded rather positive results.
    Orphanet Journal of Rare Diseases 01/2013; 8(1):6. · 4.32 Impact Factor
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    ABSTRACT: Mucopolysaccharidosis type II (MPS II) is an X-linked lysosomal storage disorder caused by a deficiency of iduronate 2-sulfatase (IDS). Progressive, intralysosomal accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate in almost all tissues leads to multi-organ involvement in affected males but to virtual absence of symptoms in heterozygote female carriers due to preferential inactivation of the mutant allele. Diagnosis of MPS II in males is based on IDS analysis in leukocytes, fibroblasts, plasma, or dried blood spots (DBS), whereas IDS activities may be within the normal range in heterozygote females. The advent of fluorometric and mass spectrometry methods for enzyme analysis in DBS has simplified the diagnostic approach for MPS II males. Molecular analysis of the IDS gene confirms the diagnosis of MPS II in males and is the only diagnostic test to confirm carrier status in females. This unit provides detailed analytical protocols for measurement of IDS activity in DBS and plasma using a fluorometric assay. Curr. Protoc. Hum. Genet. 79:17.14.1-17.14.9. © 2013 by John Wiley & Sons, Inc.
    Current protocols in human genetics / editorial board, Jonathan L. Haines ... [et al.] 01/2013; 79:17.14.1-9.
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    ABSTRACT: Lyso-globotriaosylsphingosine (lyso-Gb(3)) is a useful biomarker in the diagnosis and monitoring of treatment for Fabry disease. However, it is unclear whether lyso-Gb(3) is elevated in patients with later-onset Fabry disease. Thus, we measured lyso-Gb(3) levels from dried blood spots (DBS) from male newborns with the Fabry disease later-onset phenotype, IVS4+919G>A mutation, and their family members. The lyso-Gb(3) levels were below the detection limit in normal control newborns and were slightly higher in adults. In males of all ages with the IVS4+919G>A mutation, lyso-Gb(3) levels were elevated and were higher than in age-matched controls. The elevation of lyso-Gb(3) levels in males with the IVS4+919G>A mutation was only slightly elevated compared with patients with the classical Fabry phenotype. The measurement of lyso-Gb(3) levels is useful in the diagnosis of Fabry disease, including the later-onset phenotype. The DBS lyso-Gb(3) level was not elevated in IVS4+919G>A heterozygotes, and is not useful for their diagnosis. Since lyso-Gb(3) levels are elevated from birth in Fabry disease males, "an elevated lyso-Gb(3) level" may be of little values for deciding when to begin enzyme replacement therapy.
    Journal of Inherited Metabolic Disease 10/2012; · 4.07 Impact Factor
  • Olaf A Bodamer, Angela Dajnoki
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    ABSTRACT: Pompe disease is a lysosomal storage disorder caused by a deficiency of acid alpha glucosidase (GAA). Diagnosis of Pompe disease is typically based on an enzyme analysis of blood or tissues, such as fibroblasts, followed by confirmation through molecular testing. The advent of fluorometric and mass spectrometry methods for enzyme analysis in dried blood spots (DBS) has simplified the diagnostic approach for Pompe disease, facilitating high-throughput screening of at-risk populations and newborn infants. The following unit will provide the detailed analytical protocol for measurement of GAA activity in DBS using tandem mass spectrometry. Curr. Protoc. Hum. Genet. 75:17.11.1-17.11.6. © 2012 by John Wiley & Sons, Inc.
    Current protocols in human genetics / editorial board, Jonathan L. Haines ... [et al.] 10/2012; Chapter 17:Unit17.11.
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    ABSTRACT: Deficiency of β-1,4 mannosyltransferase (MT-1) congenital disorder of glycosylation (CDG), due to ALG1 gene mutations. Features in 9 patients reported previously consisted of prenatal growth retardation, pregnancy-induced maternal hypertension and fetal hydrops. Four patients died before 5 years of age, and survivors showed a severe psychomotor retardation. We report on 7 patients with psychomotor delay, microcephaly, strabismus and coagulation abnormalities, seizures and abnormal fat distribution. Four children had a stable clinical course, two had visual impairment, and 1 had hearing loss. Thrombotic and vascular events led to deterioration of the clinical outcome in 2 patients. Four novel ALG1 mutations were identified. Pathogenicity was determined in alg1 yeast mutants transformed with hALG1. Functional analyses showed all novel mutations representing hypomorphs associated with residual enzyme activity. We extend the phenotypic spectrum including the first description of deafness in MT1 deficiency, and report on mildly affected patients, surviving to adulthood. The dysmorphic features, including abnormal fat distribution and strabismus highly resemble CDG due to phosphomannomutase-2 deficiency (PMM2-CDG), the most common type of CDG. We suggest testing for ALG1 mutations in unsolved CDG patients with a type 1 transferrin isoelectric focusing pattern, especially with epilepsy, severe visual loss and hemorrhagic/thrombotic events.
    PEDIATRICS 09/2012; 130(4):e1034-9. · 4.47 Impact Factor
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    ABSTRACT: Niemann Pick disease (NP) is a rare, lysosomal storage disorder due to deficiency of the intra-lysosomal enzyme acid sphingomyelinase (ASM) resulting in intracellular accumulation of sphingomyelin. We evaluated a tandem mass spectrometry (MS/MS) method to analyze ASM activity in dried blood spots (DBS) that may be suitable for laboratory diagnosis of NP including high throughput screening of at-risk populations and potentially for newborn screening. ASM activity was measured in 3.2 mm punches from DBS. The eluate was incubated with the ASM substrate (N-Hexanoyl-D-erythro-sphingosylphosphorylcholine [C6-sphingomyelin (C(29)H(59)N(2)O(6)P)]) and an internal standard (N-butyroyl-D-erythro-sphingosine [C4-ceramide (C(22)H(43)NO(3))]). ASM product and IS were analyzed using MS/MS in multiple reaction monitoring mode for transitions m/z 370.6>264.3 (ASM internal standard) and m/z 398.6>264.3 (ASM product). ASM activities were stable for up to 2 months at or below 4℃. Position of the punch in the DBS and/or hematocrit of the DBS had a limited effect on ASM activities. Both intra- and inter-assay variability were below 10%. There was no carry-over. The median ASM activity in 2,085 newborn infants was 9.5 µmol/h/L (mean 10.6) with a SD of 5.06 µmol/h/L. Six of 2,085 (0.3%) infants were found to have ASM activities below the cut-off of 2.5 µmol/h/L. ASM activities were below the cut-off level in all 10 previously diagnosed cases with NP (range: 0.16 to 2.08 µmol/h/L). This MS/MS method for the measurement of ASM activity in DBS is robust and suitable for laboratory diagnosis of NP.
    Annals of Laboratory Medicine 09/2012; 32(5):319-23. · 1.48 Impact Factor
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    ABSTRACT: Purpose:To improve quality of newborn screening by tandem mass spectrometry with a novel approach made possible by the collaboration of 154 laboratories in 49 countries.Methods:A database of 767,464 results from 12,721 cases affected with 60 conditions was used to build multivariate pattern recognition software that generates tools integrating multiple clinically significant results into a single score. This score is determined by the overlap between normal and disease ranges, penetration within the disease range, differences between conditions, and weighted correction factors.Results:Ninety tools target either a single condition or the differential diagnosis between multiple conditions. Scores are expressed as the percentile rank among all cases with the same condition and are compared to interpretation guidelines. Retrospective evaluation of past cases suggests that these tools could have avoided at least half of 279 false-positive outcomes caused by carrier status for fatty-acid oxidation disorders and could have prevented 88% of known false-negative events.Conclusion:Application of this computational approach to raw data is independent from single analyte cutoff values. In Minnesota, the tools have been a major contributing factor to the sustained achievement of a false-positive rate below 0.1% and a positive predictive value above 60%.Genet Med advance online publication 16 February 2012.
    Genetics in medicine: official journal of the American College of Medical Genetics 07/2012; 14(7):648-55. · 3.92 Impact Factor
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    ABSTRACT: Mucopolysaccharidosis type I (MPS I) is traditionally divided into three phenotypes: the severe Hurler (MPS I-H) phenotype, the intermediate Hurler-Scheie (MPS I-H/S) phenotype and the attenuated Scheie (MPS I-S) phenotype. However, there are no clear criteria for delineating the different phenotypes. Because decisions about optimal treatment (enzyme replacement therapy or hematopoietic stem cell transplantation) need to be made quickly and depend on the presumed phenotype, an assessment of phenotypic severity should be performed soon after diagnosis. Therefore, a numerical severity scale for classifying different MPS I phenotypes at diagnosis based on clinical signs and symptoms was developed. A consensus procedure based on a combined modified Delphi method and a nominal group technique was undertaken. It consisted of two written rounds and a face-to-face meeting. Sixteen MPS I experts participated in the process. The main goal was to identify the most important indicators of phenotypic severity and include these in a numerical severity scale. The correlation between the median subjective expert MPS I rating and the scores derived from this severity scale was used as an indicator of validity. Full consensus was reached on six key clinical items for assessing severity: age of onset of signs and symptoms, developmental delay, joint stiffness/arthropathy/contractures, kyphosis, cardiomyopathy and large head/frontal bossing. Due to the remarkably large variability in the expert MPS I assessments, however, a reliable numerical scale could not be constructed. Because of this variability, such a scale would always result in patients whose calculated severity score differed unacceptably from the median expert severity score, which was considered to be the 'gold standard'. Although consensus was reached on the six key items for assessing phenotypic severity in MPS I, expert opinion on phenotypic severity at diagnosis proved to be highly variable. This subjectivity emphasizes the need for validated biomarkers and improved genotype-phenotype correlations that can be incorporated into phenotypic severity assessments at diagnosis.
    Orphanet Journal of Rare Diseases 04/2012; 7:22. · 4.32 Impact Factor
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    ABSTRACT: We sought to modify a previously published tandem mass spectrometry method of screening for 5 lysosomal storage disorders (LSDs) in order to make it better suited for high-throughput newborn screening. Two 3-mm dried blood spot (DBS) punches were incubated, each with a different assay solution. The quadruplex solution was used for screening for Gaucher, Pompe, Krabbe and Fabry diseases, while a separate solution was used for Niemann-Pick A/B disease. The mean activities of acid-β-glucocerebrosidase (ABG), acid sphingomyelinase (ASM), acid glucosidase (GAA), galactocerebroside-β-galactosidase (GALC) and acid-galactosidase A (GLA) were measured on 5055 unidentified newborns. The mean activities (compared with their disease controls) were, 15.1 (0.35), 22.2 (1.34), 16.8 (0.51), 3.61 (0.23), and 20.7 (1.43) (μmol/L/h), respectively. The number of specimens that fell below our retest level cutoff of <20% daily mean activity (DMA) for each analyte is: ABG (6), ASM (0), GAA (5), GALC (17), and GLA (2). This method provides a simplified and reliable assay for screening for five LSDs with clear distinction between activities from normal and disease samples. Advantages of this new method include significant decreases in processing time and the number of required assay solutions and overall decreased complexity.
    Clinica chimica acta; international journal of clinical chemistry 04/2012; 413(15-16):1270-3. · 2.54 Impact Factor
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    ABSTRACT: CLTA4 is relevant for FOXP3(+)Treg cells, and the link between skewed X chromosome inactivation (XCI) and autoimmunity is recognized. The observation of immune dysregulation polyendocrinopathy enteropathy X-linked syndrome and multiorgan endocrine autoimmune phenomena in various members of one family, associated with a CTLA4 polymorphism and skewed XCI, provides an in vivo model of how mechanisms of immune dysregulation may cooperate.
    European Journal of Endocrinology 03/2012; 167(1):131-4. · 3.14 Impact Factor

Publication Stats

1k Citations
496.22 Total Impact Points


  • 2011–2014
    • University of Miami Miller School of Medicine
      • • Division of Clinical and Translational Genetics
      • • Department of Human Genetics (Dr. John T. Macdonald Foundation)
      Miami, Florida, United States
    • University of Miami
      • • Miller School of Medicine
      • • Dr. John T. Macdonald Foundation Department of Human Genetics
      كورال غيبلز، فلوريدا, Florida, United States
    • Bahauddin Zakariya University
      • Institute of Pure and Applied Biology
      Multān, Punjab, Pakistan
  • 2010–2012
    • University of Padova
      • • Department of Women’s and Children’s Health SDB
      • • Department of Pediatrics
      Padova, Veneto, Italy
    • University of Salzburg
      Salzburg, Salzburg, Austria
  • 2009–2012
    • Paracelsus Medical University Salzburg
      Salzburg, Salzburg, Austria
    • Allgemeines Krankenhaus Linz
      Linz, Upper Austria, Austria
  • 2003–2012
    • Medical University of Vienna
      • Department of Paediatrics and Adolescent Medicine
      Wien, Vienna, Austria
  • 2004–2010
    • University of Iowa Children's Hospital
      Iowa City, Iowa, United States
  • 2005–2009
    • Universität Heidelberg
      • • Division of General Pediatrics
      • • Neurological Clinic
      Heidelberg, Baden-Wuerttemberg, Germany
  • 2008
    • St Anna's Kinderspital
      Wien, Vienna, Austria
  • 2007
    • Charles University in Prague
      • 3. lékařská fakulta
      Praha, Hlavni mesto Praha, Czech Republic
  • 2003–2006
    • University of Vienna
      Wien, Vienna, Austria
  • 1999–2004
    • Baylor College of Medicine
      • Department of Molecular & Human Genetics
      Houston, Texas, United States
  • 2002
    • Great Ormond Street Hospital for Children NHS Foundation Trust
      Londinium, England, United Kingdom
  • 2000
    • University of California, San Diego
      • Department of Psychiatry
      San Diego, CA, United States