A diagnosis of Birt-Hogg-Dubé syndrome in individuals with Smith-Magenis syndrome: Recommendation for cancer screening.

We report a series of four unrelated adults with Smith-Magenis syndrome (SMS) and concomitant features of Birt-Hogg-Dubé (BHD) syndrome based upon haploinsufficiency for FLCN and characteristic renal cell carcinomas and/or evidence of cutaneous fibrofolliculomas. Three of the cases constitute the first known association of histopathologically verified characteristic BHD-associated renal tumors in adults with SMS; the fourth was identified to have histologically confirmed skin fibrofolliculomas. Molecular analysis documented second-hit FLCN mutations in two of the three cases with confirmed BHD renal pathology. These cases suggest the need to expand management recommendations for SMS to include kidney cancer surveillance starting at 20 years of age, as per the screening recommendations for BHD syndrome.

The critical role of psychosine in screening, diagnosis, and monitoring of Krabbe disease.

PURPOSE: Newborn screening (NBS) for Krabbe disease (KD) is performed by measurement of galactocerebrosidase (GALC) activity as the primary test. This revealed that GALC activity has poor specificity for KD. Psychosine (PSY) was proposed as a disease marker useful to reduce the false positive rate for NBS and for disease monitoring. We report a highly sensitive PSY assay that allows identification of KD patients with minimal PSY elevations. METHODS: PSY was extracted from dried blood spots or erythrocytes with methanol containing d5-PSY as internal standard, and measured by liquid chromatography-tandem mass spectrometry. RESULTS: Analysis of PSY in samples from controls (N = 209), GALC pseudodeficiency carriers (N = 55), GALC pathogenic variant carriers (N = 27), patients with infantile KD (N = 26), and patients with late-onset KD (N = 11) allowed for the development of an effective laboratory screening and diagnostic algorithm. Additional longitudinal measurements were used to track therapeutic efficacy of hematopoietic stem cell transplantion (HSCT). CONCLUSION: This study supports PSY quantitation as a critical component of NBS for KD. It helps to differentiate infantile from later onset KD variants, as well as from GALC variant and pseudodeficiency carriers. Additionally, this study provides further data that PSY measurement can be useful to monitor KD progression before and after treatment.

Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State.

BACKGROUND: Early infantile Krabbe disease is rapidly fatal, but hematopoietic stem cell transplantation (HSCT) may improve outcomes if performed soon after birth. New York State began screening all newborns for Krabbe disease in 2006. METHODS: Infants with abnormal newborn screen results for Krabbe disease were referred to specialty-care centers. Newborns found to be at high risk for Krabbe disease underwent a neurodiagnostic battery to determine the need for emergent HSCT. RESULTS: Almost 2 million infants were screened. Five infants were diagnosed with early infantile Krabbe disease. Three died, two from HSCT-related complications and one from untreated disease. Two children who received HSCT have moderate to severe developmental delays. Forty-six currently asymptomatic children are considered to be at moderate or high risk for development of later-onset Krabbe disease. CONCLUSIONS: These results show significant HSCT-associated morbidity and mortality in early infantile Krabbe disease and raise questions about its efficacy when performed in newborns diagnosed through newborn screening. The unanticipated identification of "at risk" children introduces unique ethical and medicolegal issues. New York's experience raises questions about the risks, benefits, and practicality of screening newborns for Krabbe disease. It is imperative that objective assessments be made on an ongoing basis as additional states begin screening for this disorder.Genet Med 18 12, 1235-1243.

Newborn screening for Krabbe disease in New York State: the first eight years' experience.

PURPOSE: Krabbe disease (KD) results from galactocerebrosidase (GALC) deficiency. Infantile KD symptoms include irritability, progressive stiffness, developmental delay, and death. The only potential treatment is hematopoietic stem cell transplantation. New York State (NYS) implemented newborn screening for KD in 2006. METHODS: Dried blood spots from newborns were assayed for GALC enzyme activity using mass spectrometry, followed by molecular analysis for those with low activity (≤12% of the daily mean). Infants with low enzyme activity and one or more mutations were referred for follow-up diagnostic testing and neurological examination. RESULTS: Of >1.9 million screened, 620 infants were subjected to molecular analysis and 348 were referred for diagnostic testing. Five had enzyme activities and mutations consistent with infantile KD and manifested clinical/neurodiagnostic abnormalities. Four underwent transplantation, two are surviving with moderate to severe handicaps, and two died from transplant-related complications. The significance of many sequence variants identified is unknown. Forty-six asymptomatic infants were found to be at moderate to high risk for disease. CONCLUSIONS: The positive predictive value of KD screening in NYS is 1.4% (5/346) considering confirmed infantile cases. The incidence of infantile KD in NYS is approximately 1 in 394,000, but it may be higher for later-onset forms.

Low Psychosine in Krabbe Disease with Onset in Late Infancy: A Case Report.

Krabbe disease (KD) is a rare inherited neurodegenerative disorder caused by a deficiency in galactocerebrosidase enzyme activity, which can present in early infancy, requiring an urgent referral for hematopoietic stem cell transplantation, or later in life. Newborn screening (NBS) for KD requires identification and risk-stratification of patients based on laboratory values to predict disease onset in early infancy or later in life. The biomarker psychosine plays a key role in NBS algorithms to ascertain probability of early-onset disease. This report describes a patient who was screened positive for KD in New York State, had a likely pathogenic genotype, and showed markedly reduced enzyme activity but surprisingly low psychosine levels. The patient ultimately developed KD in late infancy, an outcome not clearly predicted by existing NBS algorithms. It remains critical that psychosine levels be evaluated alongside genotype, enzyme activity levels, and the patient's evolving clinical presentation, ideally in consultation with experts in KD, in order to guide diagnosis and plans for monitoring.

Lack of genotype-phenotype correlations and outcome in MCAD deficiency diagnosed by newborn screening in New York State.

INTRODUCTION: Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is one of the most common inborn errors of metabolism. Affected patients have impaired ability to break down medium chain fatty acids during fasting, and typically present in the early years of life with hypoketotic hypoglycemia, Reye syndrome-like symptoms, brain damage or death. The development of newborn screening (NBS) for MCAD deficiency has greatly improved outcome, but some patients still appear at risk for severe complications. We reviewed the outcome of patients identified with MCAD deficiency by the New York State NBS process to identify biochemical or genotypic markers which might predict outcome. METHOD: All eight NBS follow-up centers in New York State contributed the cases of MCAD deficiency diagnosed by newborn screen, who received diagnostic and follow-up care in their clinic. Data reviewed included gender, age, birthweight, initial NBS octanoylcarnitine level (C8) and C8/C2 ratio, follow-up C8 and hexanoylglycine, race/ethnicity, and presence of neonatal or later symptoms. RESULTS: We identified 53 cases of MCAD deficiency. More than one quarter of patients had a post-neonatal symptomatic admission (predominantly lethargy associated with an intercurrent illness). No genotype or C8 level was protective for neonatal or later symptoms. There was a relationship between initial C8 level or C8/C2 ratio and occurrence of later symptoms (7.3 micromol/L in the asymptomatic vs. 19.1 micromol/L in the symptomatic, p<0.0002 for C8, and 0.26 vs. 0.6, respectively, for C8/C2 ratio, p<0.012). Four infants had initial C8 level >30 micromol/L; these infants had a high rate of symptomatic or multiple symptomatic episodes or a history of sibling death from "SIDS", and typically had deletion, nonsense or splice sites mutations. Infants having a history of a symptomatic episode were more likely to have higher initial C8 on NBS and a genotype predicted to strongly affect protein function. In our ethnically diverse group of patients, the c.985A>G mutation was rarely found in non-Caucasians. DISCUSSION: No genotype or metabolite profile is protective from symptoms. The strong relationship between initial C8 level and outcome suggests that in at least some cases neonates having high initial C8 levels may be demonstrating an increased susceptibility to catabolic stress, and may merit additional precautions. Our data also suggest that these infants are more likely to carry severe mutations including homozygosity for the common mutation, deletions, nonsense or splice site mutations. The reports of significant lethargy or hypoglycemia during intercurrent illness in over one quarter of cases even when early medical intervention is recommended (and even when initial C8 is not profoundly elevated) underscores the importance of continued vigilance to prevent stressful fasting in this disorder.

Newborn screening for Krabbe disease: the New York State model.

Krabbe disease is a rare inherited neurologic disorder affecting the central and peripheral nervous systems. The disease has four phenotypes: early infantile, later onset, adolescent, and adult. The only known treatment is hematopoietic stem cell transplantation, which is, in the early infantile form of the disease, most beneficial if performed before onset of clinical symptoms. In August 2006, New York State began screening all newborns for Krabbe disease. A rapid and accurate technique for assessing galactocerebrosidase activity and performing DNA mutation analysis had been developed. Interpreting these results was limited, however, because neither enzyme activity nor genetic mutation reliably predicts phenotype. A series of initiatives were therefore developed by a multidisciplinary group of neurologists, geneticists, metabolic pediatricians, neurodevelopmental pediatricians, and transplant physicians (the Krabbe Consortium of New York State) to enhance the effectiveness of the newborn screening program. A standardized clinical evaluation protocol was designed based on the available literature, criteria for transplantation for the early infantile phenotype were formulated, a clinical database and registry was developed, and a study of developmental and functional outcomes was instituted. This multidisciplinary standardized approach to evaluating infants who have positive results on newborn screening may serve as a model for other states as they begin the process of screening for Krabbe disease and other lysosomal storage disorders.

A Method for Assigning Priorities to United States Measurement System (USMS) Needs: Nano-Electrotechnologies.

In 2006, the National Institute of Standards and Technology conducted an assessment of the U.S. measurement system (USMS), which encompasses all private and public organizations that develop, supply, use, or ensure the validity of measurement results. As part of that assessment, NIST collaborated with Energetics Incorporated to identify and authenticate 723 measurement needs that are barriers to technological innovations. A number of these measurement needs (64) are relevant to accelerating innovation and commercialization of nano-electrotechnologies. In this paper, we apply the taxonomy from a 2008 international survey that established a global consensus of priorities for standards and measurements in nano-electrotechnologies to rank in priority order the relevant 64 USMS-identified measurement needs. This paper presents a method for assigning priorities that is statistically based and represents a global consensus of stakeholders. Such a method is needed because limited resources exist to address the large number of measurement needs in nano-electrotechnologies, and the most critical measurement needs should be addressed first.

Priorities for Standards and Measurements to Accelerate Innovations in Nano-Electrotechnologies: Analysis of the NIST-Energetics-IEC TC 113 Survey.

In 2008, the National Institute of Standards and Technology and Energetics Incorporated collaborated with the International Electrotechnical Commission Technical Committee 113 (IEC TC 113) on nano-electrotechnologies to survey members of the international nanotechnologies community about priorities for standards and measurements to accelerate innovations in nano-electrotechnologies. In this paper, we analyze the 459 survey responses from 45 countries as one means to begin building a consensus on a framework leading to nano-electrotechnologies standards development by standards organizations and national measurement institutes. The distributions of priority rankings from all 459 respondents are such that there are perceived distinctions with statistical confidence between the relative international priorities for the several items ranked in each of the following five Survey category types: 1) Nano-electrotechnology Properties, 2) Nano-electrotechnology Taxonomy: Products, 3) Nano-electrotechnology Taxonomy: Cross-Cutting Technologies, 4) IEC General Discipline Areas, and 5) Stages of the Linear Economic Model. The global consensus prioritizations for ranked items in the above five category types suggest that the IEC TC 113 should focus initially on standards and measurements for electronic and electrical properties of sensors and fabrication tools that support performance assessments of nano-technology enabled sub-assemblies used in energy, medical, and computer products.

Postpartum "psychosis" in mild argininosuccinate synthetase deficiency.

BACKGROUND: Urea cycle disorders are relatively rare but well-established causes of postpartum coma and death. Such clinical presentations have been reported previously in ornithine transcarbamylase and carbamyl phosphate synthetase deficiencies. CASE: We describe a woman, without prior symptoms of metabolic disease, who presented with hyperammonemia and psychiatric symptoms in the postpartum period. Initial diagnoses included acute fatty liver of pregnancy and postpartum psychosis. She was later found to have argininosuccinate synthetase deficiency after further metabolic investigations. Rare heterozygous mutations in the argininosuccinate synthetase gene were identified. CONCLUSION: Urea cycle disorders may present initially with postpartum psychiatric symptoms and may represent an underrecognized cause of "postpartum psychosis." We recommend obtaining metabolic studies in women with neurologic or severe psychiatric symptoms in the postpartum period.

Measurement Science for Prognostics and Health Management for Smart Manufacturing Systems: Key Findings from a Roadmapping Workshop.

The National Institute of Standards and Technology (NIST) hosted the Roadmapping Workshop - Measurement Science for Prognostics and Health Management for Smart Manufacturing Systems (PHM4SMS) in Fall 2014 to discuss the needs and priorities of stakeholders in the PHM4SMS technology area. The workshop brought together over 70 members of the PHM community. The attendees included representatives from small, medium, and large manufacturers; technology developers and integrators; academic researchers; government organizations; trade associations; and standards bodies. The attendees discussed the current and anticipated measurement science challenges to advance PHM methods and techniques for smart manufacturing systems; the associated research and development needed to implement condition monitoring, diagnostic, and prognostic technologies within manufacturing environments; and the priorities to meet the needs of PHM in manufacturing. This paper will summarize the key findings of this workshop, and present some of the critical measurement science challenges and corresponding roadmaps, i.e., suggested courses of action, to advance PHM for manufacturing. Milestones and targeted capabilities will be presented for each roadmap across three areas: PHM Manufacturing Process Techniques; PHM Performance Assessment; and PHM Infrastructure - Hardware, Software, and Integration. An analysis of these roadmaps and crosscutting themes seen across the breakout sessions is also discussed.

Diagnostic Exome Sequencing and Tailored Bioinformatics of the Parents of a Deceased Child with Cobalamin Deficiency Suggests Digenic Inheritance of the MTR and LMBRD1 Genes.

Disorders of cobalamin deficiency are a heterogeneous group of disorders with at least 19 autosomal recessive-associated genes. Familial samples of an infant who died due to presumed cobalamin deficiency were referred for clinical exome sequencing. The patient died before obtaining a blood sample or skin biopsy, autopsy was declined, and DNA yielded from the newborn screening blood spot was insufficient for diagnostic testing. Whole-exome sequencing of the mother, father, and unaffected sister and tailored bioinformatics analysis was applied to search for mutations in underlying disorders with recessive inheritance. This approach identified alterations within two genes, each of which was carried by one parent. The mother carried a missense alteration in the MTR gene (c.3518C>T; p.P1173L) which was absent in the father and the sister. The father carried a translational frameshift alteration in the LMBRD1 gene (c.1056delG; p.L352Lfs*18) which was absent in the mother and present in the heterozygous state in the sister. These mutations in the MTR (MIM# 156570) and LMBRD1 (MIM# 612625) genes have been described in patients with disorders of cobalamin metabolism complementation groups cblG and cblF, respectively. The child's clinical presentation and biochemical results demonstrated overlap with both cblG and cblF. Sanger sequencing using DNA from the infant's blood spot confirmed the inheritance of the two alterations in compound heterozygous form. We present the first example of exome sequencing leading to a diagnosis in the absence of the affected patient. Furthermore, the data support the possibility for potential digenic inheritance associated with cobalamin deficiency.

Opportunities in the industrial biobased products industry.

Approximately 89 million metric t of organic chemicals and lubricants, the majority of which are fossil based, are produced annually in the United States. The development of new industrial bioproducts, for production in stand-alone facilities or biorefineries, has the potential to reduce our dependence on imported oil and improve energy security. Advances in biotechnology are enabling the optimization of feedstock composition and agronomic characteristics and the development of new and improved fermentation organisms for conversion of biomass to new end products or intermediates. This article reviews recent biotechnology efforts to develop new industrial bioproducts and improve renewable feedstocks and key market opportunities.