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Objective To provide updated evidence and consensus-based recommendations for the classification of individuals who screen positive for Krabbe Disease (KD) and recommendations for long-term follow-up for those who are at risk for late onset Krabbe Disease (LOKD). Methods KD experts (KD NBS Council) met between July 2017 and June 2020 to develop consensus-based classification and follow-up recommendations. The resulting newly proposed recommendations were assessed in a historical cohort of 47 newborns from New York State who were originally classified at moderate or high risk for LOKD. Results Infants identified by newborn screening with possible KD should enter one of three clinical follow-up pathways (Early infantile KD, at-risk for LOKD, or unaffected), based on galactocerebrosidase (GALC) activity, psychosine concentration, and GALC genotype. Patients considered at-risk for LOKD based on low GALC activity and an intermediate psychosine concentration are further split into a high-risk or low-risk follow-up pathway based on genotype. Review of the historical New York State cohort found that the updated follow-up recommendations would reduce follow up testing by 88%. Conclusion The KD NBS Council has presented updated consensus recommendations for efficient and effective classification and follow-up of NBS positive patients with a focus on long-term follow-up of those at-risk for LOKD.

We conducted a consented pilot newborn screening (NBS) for Pompe, Gaucher, Niemann–Pick A/B, Fabry, and MPS 1 to assess the suitability of these lysosomal storage disorders (LSDs) for public health mandated screening. At five participating high–birth rate, ethnically diverse New York City hospitals, recruiters discussed the study with postpartum parents and documented verbal consent. Screening on consented samples was performed using multiplexed tandem mass spectrometry. Screen-positive infants underwent confirmatory enzymology, DNA testing, and biomarker quantitation when available. Affected infants are being followed for clinical management and long-term outcome. Over 4 years, 65,605 infants participated, representing an overall consent rate of 73%. Sixty-nine infants were screen-positive. Twenty-three were confirmed true positives, all of whom were predicted to have late-onset phenotypes. Six of the 69 currently have undetermined disease status. Our results suggest that NBS for LSDs is much more likely to detect individuals at risk for late-onset disease, similar to results from other NBS programs. This work has demonstrated the feasibility of using a novel consented pilot NBS study design that can be modified to include other disorders under consideration for public health implementation as a means to gather critical evidence for evidence-based NBS practices.

BACKGROUND: Niemann-Pick disease type C1 (NPC1) is a rare, neurodegenerative cholesterol storage disorder. Diagnostic delay of more than 5 years is common due to the rarity of the disease and non-specific early symptoms. To improve diagnosis and facilitate early intervention, we previously developed a newborn screening assay based on newly identified plasma bile acid biomarkers. Because the newborn screen had been validated using dried blood spots (DBS) from already diagnosed NPC1 patients, an unanswered question was whether the screen would be able to detect individuals with NPC1 at birth. METHODS: To address this critical question, we obtained the newborn DBS for already diagnosed NPC1 subjects (n=15) and carriers (n=3) residing in California, New York, and Michigan, states that archive residual DBS in biorepositories. For each of the DBS, we obtained two neighbor controls – DBS from patients born on the same day and in the same hospital as the NPC1 patients and carriers. 3β,5α,6β-trihydroxycholanic acid (bile acid A) and trihydroxycholanic acid glycine conjugate (bile acid B) were measured in the DBS using a liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay. RESULTS: Bile acid B, the more specific biomarker for which the fully validated DBS assay was developed, was detected in 8/15 NPC1 patients, and elevated above the cut-off in 2/15 patients (the two samples with the shortest storage time). Bile acid B was detected in 2/2, 6/10, and 0/7 NPC1 samples that have been stored for < 10.5 years, 13–20 years, and >20 years, respectively, indicating that the glycine conjugate is detectable in DBS but may have reduced long term stability compared with bile acid A, the precursor trihydroxycholanic acid, which was elevated in 15/15 NPC1 subjects, but not in carriers and controls. CONCLUSIONS: These results demonstrate that newborn screening for NPC1 disease is feasible using bile acid biomarkers.

The goal of newborn screening is to enhance the outcome of individuals with serious, treatable disorders through early, pre-symptomatic detection. The lysosomal storage disorders (LSDs) comprise a group of more than 50 diseases with a combined frequency of approximately 1:7000. With the availability of existing and new enzyme replacement therapies, small molecule treatments and gene therapies, there is increasing interest in screening newborns for LSDs with the goal of reducing disease-related morbidity and mortality through early detection. Novel screening methods are being developed, including efforts to enhance accuracy of screening using an array of multi-tiered, genomic, statistical, and bioinformatic approaches. While NBS data for Gaucher disease, Fabry disease, Krabbe disease, MPS I, and Pompe disease has demonstrated the feasibility of widespread screening, it has also highlighted some of the complexities of screening for LSDs. These include the identification of infants with later-onset, untreatable, and uncertain phenotypes, raising interesting ethical concerns that should be addressed as part of the NBS implementation process. Taken together, these efforts will provide critical, detailed data to help guide objective, ethically sensitive decision-making about NBS for LSDs.

Background Among boys with X-Linked adrenoleukodystrophy, a subset will develop childhood cerebral adrenoleukodystrophy (CCALD). CCALD is typically lethal without hematopoietic stem cell transplant before or soon after symptom onset. We sought to establish evidence-based guidelines detailing the neuroimaging surveillance of boys with neurologically asymptomatic adrenoleukodystrophy. Methods To establish the most frequent age and diagnostic neuroimaging modality for CCALD, we completed a meta-analysis of relevant studies published between January 1, 1970 and September 10, 2019. We used the consensus development conference method to incorporate the resulting data into guidelines to inform the timing and techniques for neuroimaging surveillance. Final guideline agreement was defined as >80% consensus. Results One hundred twenty-three studies met inclusion criteria yielding 1285 patients. The overall mean age of CCALD diagnosis is 7.91 years old. The median age of CCALD diagnosis calculated from individual patient data is 7.0 years old (IQR: 6.0-9.5, n = 349). Ninety percent of patients were diagnosed between 3 and 12. Conventional MRI was most frequently reported, comprised most often of T2-weighted and contrast-enhanced T1-weighted MRI. The expert panel achieved 95.7% consensus on the following surveillance parameters: (a) Obtain an MRI between 12 and 18 months old. (b) Obtain a second MRI 1 year after baseline. (c) Between 3 and 12 years old, obtain a contrast-enhanced MRI every 6 months. (d) After 12 years, obtain an annual MRI. Conclusion Boys with adrenoleukodystrophy identified early in life should be monitored with serial brain MRIs during the period of highest risk for conversion to CCALD.

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. 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. 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. 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.

Live newborn screening for Krabbe's disease (KD) was initiated in New York on August 7, 2006, and started in Missouri in August, 2012. As of August 7, 2015, nearly 2.5 million infants had been screened, and 443 (0.018%) infants had been referred for followup clinical evaluation; only five infants had been determined to have KD. As of August, 2015, the combined incidence of infantile KD in New York and Missouri is ∼1 per 500,000; however, patients who develop later-onset forms of KD may still emerge. This Review provides an overview of the processes used to develop the screening and followup algorithms. It also includes updated results from screening and discussion of observations, lessons learned, and suggested areas for improvement that will reduce referral rates and the number of infants defined as at risk for later-onset forms of KD. Although current treatment options for infants with early-infantile Krabbe's disease are not curative, over time treatment options should improve; in the meantime, it is essential to evaluate the lessons learned and to ensure that screening is completed in the best possible manner until these improvements can be realized. © 2016 Wiley Periodicals, Inc.

Krabbe's disease (KD) is a fatal neurodegenerative disorder, with the early-infantile form (EIKD) defined by onset of symptoms before age 6 months. Early and highly accurate identification of EIKD is required to maximize benefits of hematopoietic stem cell transplantation treatment. This study investigates the potential for accurate prediction of EIKD based on a novel newborn screening (NBS) tool developed from two biomarkers, galactocerebrosidase (GALC) enzyme activity and galactosylsphingosine concentration (psychosine [PSY]). Normative information about PSY and GALC, derived from distinct samples of normal newborns, was used to develop the novel diagnostic tool. Bivariate normal limits (BVNL) were constructed, assuming a multivariate normal distribution of natural logarithms of GALC and PSY of normal newborns. The (lnGALC, lnPSY) points for newborns in various "abnormal groups," including one group of infants who subsequently suffered EIKD, were plotted on a graph of BVNL. The points for all EIKD patients fell outside of BVNL (100% sensitivity). In a simulation study to compare the false-positive rate of existing univariate methods of diagnosis with our new BVNL-based method, we generated 100 million normal newborn data points. All fell within BVNL (i.e., zero false positives), whereas 5,682 false positives were observed when applying a two-tiered univariate method of the type suggested in the literature. These results suggest that (lnGALC, lnPSY) BVNLs will allow highly accurate prediction of EIKD, whereas two-tiered univariate approaches will not. Redevelopment of the BVNL based on GALCs and PSYs measured on a common large sample of normal newborns is required for NBS use. © 2016 Wiley Periodicals, Inc.

Measurement of the absolute concentration of the biomarker psychosine in dried blood spots (DBS) is useful for diagnosis and prognosis of Krabbe disease and to support newborn screening of this leukodystrophy. As for assays for more common diseases, it is important to achieve congruence when multiple clinical laboratories provide testing. Four clinical laboratories, one research laboratory, and a commercial vendor collaborated with the goal to achieve congruence in quantitative psychosine measurement in DBS. A set of DBS calibrators was prepared by a single vendor and used in each reference laboratory to make a standard curve of measured psychosine in DBS versus the stated calibrator psychosine level. Congruence between the participating five laboratories was achieved using the psychosine DBS calibrators. This allowed application of disease-specific reference ranges obtained by the reference laboratory with the most extensive data by the other reference laboratories. Congruence between multiple reference laboratories in the measurement of the absolute concentration of biomarkers in DBS (and by extension other samples) is possible by the use of a common set of DBS calibrators.

Purpose Newborn screening for Krabbe disease (KD) originated in New York State in 2006 but has proven to have a high false positive rate and low positive predictive value. To improve accuracy of presymptomatic prediction, we propose a screening tool based on two biomarkers, psychosine and galactocerebrosidase enzyme activity (GalC). Methods We developed the tool using measures from dried blood spots of 166 normal newborns and tested it on dried blood spot measures from 15 newborns who later developed KD, 8 newborns identified as "high risk" by the New York screening protocol but were disease-free at follow-up, and 3 symptomatic children with onset before 4 years of age. The tool was developed from the (1–10−6)100% prediction region of the natural logarithms of psychosine and GalC measures, assuming bivariate normality, and their univariate normal limits. Results Krabbe disease was predicted correctly for every patient who developed symptoms in infancy or early childhood. None of the high-risk patients were incorrectly identified as having early KD. Conclusion Bivariate analysis of psychosine and GalC in newborn blood spots can accurately predict early Krabbe symptoms, control false positive rates, and permit presymptomatic treatment.

Background Krabbe disease is a rare neurodegenerative genetic disorder caused by deficiency of galactocerebrosidase. Patients with the infantile form of Krabbe disease can be treated at a presymptomatic stage with human stem cell transplantation which improves survival and clinical outcomes. However, without a family history, most cases of infantile Krabbe disease present after onset of symptoms and are ineligible for transplantation. In 2006, New York began screening newborns for Krabbe disease to identify presymptomatic cases. To ensure that those identified with infantile disease received timely treatment, New York public health and medical systems took steps to accurately diagnose and rapidly refer infants for human stem cell transplantation within the first few weeks of life. After 11 years of active screening in New York and the introduction of Krabbe disease newborn screening in other states, new information has been gained which can inform the design of newborn screening programs to improve infantile Krabbe disease outcomes. Findings Recent information relevant to Krabbe disease screening, diagnosis, and treatment were assessed by a diverse group of public health, medical, and advocacy professionals. Outcomes after newborn screening may improve if treatment for infantile disease is initiated before 30 days of life. Newer laboratory screening and diagnostic tools can improve the speed and specificity of diagnosis and help facilitate this early referral. Given the rarity of Krabbe disease, most recommendations were based on case series or expert opinion. Conclusion This report updates recommendations for Krabbe disease newborn screening to improve the timeliness of diagnosis and treatment of infantile Krabbe disease. In the United States, several states have begun or are considering Krabbe disease newborn screening. These recommendations can guide public health laboratories on methodologies for screening and inform clinicians about the need to promptly diagnose and treat infantile Krabbe disease. The timing of the initial referral after newborn screening, the speed of diagnostic confirmation of infantile disease, and the transplantation center’s experience and ability to rapidly respond to a suspected patient with newly diagnosed infantile Krabbe disease are critical for optimal outcomes.

Purpose To describe a diagnostic protocol, surveillance and treatment guidelines, genetic counseling considerations and long-term follow-up data elements developed in preparation for X-linked adrenoleukodystrophy (X-ALD) newborn screening in New York State. Methods A group including the director from each regional NYS inherited metabolic disorder center, personnel from the NYS Newborn Screening Program, and others prepared a follow-up plan for X-ALD NBS. Over the months preceding the start of screening, a series of conference calls took place to develop and refine a complete newborn screening system from initial positive screen results to long-term follow-up. Results A diagnostic protocol was developed to determine for each newborn with a positive screen whether the final diagnosis is X-ALD, carrier of X-ALD, Zellweger spectrum disorder, acyl CoA oxidase deficiency or D-bifunctional protein deficiency. For asymptomatic males with X-ALD, surveillance protocols were developed for use at the time of diagnosis, during childhood and during adulthood. Considerations for timing of treatment of adrenal and cerebral disease were developed. Conclusion Because New York was the first newborn screening laboratory to include X-ALD on its panel, and symptoms may not develop for years, long-term follow-up is needed to evaluate the presented guidelines.

Newborn screening (NBS) for Krabbe disease (KD) in New York and Missouri is conducted by measuring galactocerebrosidase (GALC) activity using tandem mass spectrometry (MS/MS). These NBS efforts have shown that the incidence of KD is unexpectedly low (1:400,000) while many individuals (ca. 1:6000) with reduced GALC activity and genotypes of uncertain significance are detected and subjected to follow up testing. Psychosine (PSY) is a putative marker of KD progression and can be measured in dried blood spots (DBS). We sought to determine the role that PSY levels play in NBS for KD, follow up, and treatment monitoring. PSY was eluted from DBS with methanol containing N,N-dimethyl-D-erythro-sphingosine as internal standard (IS). Liquid chromatography-MS/MS was conducted over 17 minutes in the multiple reaction monitoring positive mode to follow the precursor to product species transitions for PSY and IS. Separation of the structural isomers PSY and glucosylsphingosine was accomplished by hydrophilic interaction liquid chromatography. Pre-analytical and analytical factors were studied and revealed satisfactory results. PSY was also measured in DBS collected from controls (range

To describe a novel biochemical marker in dried blood spots suitable to improve the specificity of newborn screening for Pompe disease. The new marker is a ratio calculated between the creatine/creatinine (Cre/Crn) ratio as the numerator and the activity of acid α-glucosidase (GAA) as the denominator. Using Collaborative Laboratory Integrated Reports (CLIR), the new marker was incorporated in a dual scatter plot that can achieve almost complete segregation between Pompe disease and false-positive cases. The (Cre/Crn)/GAA ratio was measured in residual dried blood spots of five Pompe cases and was found to be elevated (range 4.41–13.26; 99%ile of neonatal controls: 1.10). Verification was by analysis of 39 blinded specimens that included 10 controls, 24 samples with a definitive classification (16 Pompe, 8 false positives), and 5 with genotypes of uncertain significance. The CLIR tool showed 100% concordance of classification for the 24 known cases. Of the remaining five cases, three p.V222M homozygotes, a benign variant, were classified by CLIR as false positives; two with genotypes of unknown significance, one likely informative, were categorized as Pompe disease. The CLIR tool inclusive of the new ratio could have prevented at least 12 of 13 (92%) false-positive outcomes.

X-linked adrenoleukodystrophy (ALD) is the most common leukodystrophy with a birth incidence of 1:14,700 live births. The disease is caused by mutations in ABCD1 and characterized by very long-chain fatty acids (VLCFA) accumulation. In childhood, male patients are at high-risk to develop adrenal insufficiency and/or cerebral demyelination. Timely diagnosis is essential. Untreated adrenal insufficiency can be life-threatening and hematopoietic stem cell transplantation is curative for cerebral ALD provided the procedure is performed in an early stage of the disease. For this reason, ALD is being added to an increasing number of newborn screening programs. ALD newborn screening involves the quantification of C26:0-lysoPC in dried blood spots which requires a dedicated method. C26:0-carnitine, that was recently identified as a potential new biomarker for ALD, has the advantage that it can be added as one more analyte to the routine analysis of amino acids and acylcarnitines already in use. The first objective of this study was a comparison of the sensitivity of C26:0-carnitine and C26:0-lysoPC in dried blood spots from control and ALD newborns both in a case-control study and in newborns included in the New York State screening program. While C26:0-lysoPC was elevated in all ALD newborns, C26:0-carnitine was elevated only in 83%. Therefore, C26:0-carnitine is not a suitable biomarker to use in ALD newborn screen. In women with ALD, plasma VLCFA analysis results in a false negative result in approximately 15-20% of cases. The second objective of this study was to compare plasma VLCFA analysis with C26:0-carnitine and C26:0-lysoPC in dried blood spots of women with ALD. Our results show that C26:0-lysoPC was elevated in dried blood spots from all women with ALD, including from those with normal plasma C26:0 levels. This shows that C26:0-lysoPC is a better and more accurate biomarker for ALD than plasma VLCFA levels. We recommend that C26:0-lysoPC be added to the routine biochemical array of diagnostic tests for peroxisomal disorders.

Early diagnosis of males with X-linked adrenoleukodystrophy (X-ALD) is essential for preventing loss of life due to adrenal insufficiency and for timely therapy of the childhood cerebral form of X-ALD with hematopoietic cell transplantation. This article describes X-ALD, the current therapies, the history of the development of the newborn screening test, the approval by the Secretary of Health and Human Services for the addition of X-ALD newborn screening to the recommended uniform panel of disorders screened as newborns (RUSP) and the successful implementation of X-ALD newborn screening in the state of New York beginning on 30 December 2013. Follow-up guidelines that have been established in New York are outlined. Based on the success of newborn screening in New York, and early results in Connecticut, where X-ALD newborn screening started in December 2015, and in California, where X-ALD newborn screening began in September 2016, we are confident and hopeful that X-ALD newborn screening will expand to include all US states and to countries that have established neonatal screening programs. The Minster of Health in the Netherlands has approved the addition of X-ALD to the newborn screening program with a start date expected in 2017. The states, such as Massachusetts, Illinois, Minnesota, New Jersey, Florida and Washington, that have legislative approval will commence screening as soon as budgetary resources, testing and follow-up procedures are in place.

Background Fabry disease (FD) is an X-linked lysosomal storage disorder caused by the deficiency of α-galactosidase A (GLA). We evaluated a tandem mass spectrometry method to measure GLA activity. Methods One 3.2 mm punch from a dried blood spot sample (DBS) was incubated with substrate and internal standard in the reaction buffer for 22 h. The resulting product was quantified against internal standard using MS/MS. Results The median GLA activity of male newborn DBS (N = 5025) was 9.85 ± 6.4 µmol/h/l (CI 95% is 9.67–10.02 µmol/h/l); The median GLA activity of female newborns (N = 4677) was 10.2 ± 6.3 µmol/h/l (CI 95% is 10.02–10.38 µmol/h/l). The difference between the two subgroups is within assay analytical variation. The GLA activities in the DBS samples from 9 juvenile and adult males with previously identified FD were below 1.64 µmol/h/l. The GLA activities from 32 juvenile and adult females with confirmed FD were below 4.73 µmol/h/l. In 5 (16%) females GLA activities were above the 0.5th percentile of lower limit of CI 95% at 3.18 µmol/h/l. Conclusions The MS/MS method for Fabry disease newborn screening is robust and can be readily multiplexed with other lysosomal disorders such as Pompe, Gaucher, Niemann–Pick, and Krabbe diseases.

Objective The aim of this study was to develop a newborn screening algorithm for Krabbe disease. Design and methods We measured the galactocerebrosidase activity of 139,074 anonymous newborns, 56 known carriers, and 16 Krabbe patients using a tandem mass spectrometry method. The activities were converted to percentages of daily mean activity (%DMA), and the results from diseased and normal populations were used to establish cutoffs. Results The absolute activities for the newborns ranged from 0.17 to 355 μmol/L h ( N = 139,074) and activities for Krabbe-positive controls ranged from 0.08 to 0.48 μmol/L h ( N = 16, n = 91 measurements) while activities for carriers ranged from 0.28 to 2.71 μmol/L h ( N = 56, n = 72 measurements). Cutoffs were set based on results from Krabbe-positive and carrier controls and the newborn population distribution. Conclusions The algorithm and cutoffs we propose provided 100% detection of all positive controls with 60/100,000 screen positive results predicted. In the course of this study, one anonymous newborn was predicted to have Krabbe disease based on enzyme activity and subsequent DNA analysis.

Background: Lysosomal storage disorders (LSDs) comprise more than 40 genetic diseases that result in the accumulation of products that would normally be degraded by lysosomal enzymes. A tandem mass spectrometry (MS/MS)-based method is available for newborn screening for 5 LSDs, and many laboratories are initiating pilot studies to evaluate the incorporation of this method into their screening panels. We developed and evaluated dried blood spot (DBS) QC materials for LSDs and used the MS/MS method to investigate their suitability for LSD QC monitoring. Methods: We incubated 3.2-mm punches from DBS controls for 20–24 h with assay cocktails containing substrate and internal standard. Using MS/MS, we quantified the resulting product and internal standard. Samples were run in triplicate for 3 consecutive days, and results were reported as product-to-internal standard ratios and enzyme activity units (μmol/L/h). Results: Enzyme activity interday imprecision (CV) for the high, medium, and low series were 3.4%–14.3% for galactocerebroside α-galactosidase, 6.8%–24.6% for acid α-galactosidase A, 7.36%–22.1% for acid sphingomyelinase, 6.2%–26.2% for acid α-glucocerebrosidase, and 7.0%–24.8% for lysosomal acid α-glucosidase (n = 9). In addition, DBS stored at −20° and 4 °C showed minimal enzyme activity loss over a 187-d period. DBS stored at 37° and 45 °C had lower activity values over the 187-day evaluation time. Conclusions: Suitable QC materials for newborn screening of LSDs were developed for laboratories performing DBS LSD screening. Good material linearity was observed, with goodness-of-fit values of 0.953 and higher. The QC materials may be used by screening laboratories that perform LSD analysis by MS and/or more conventional fluorescence-based screening methods.

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. 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. 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. 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. Genet Med 18 3, 239–248.

Newborn screening (NBS) for Krabbe disease (KD) began in New York (NY) in August 2006. In summary, after eight years of screening there were five infants identified with early-onset Krabbe disease. Four underwent transplant, two are surviving with moderate to severe handicaps, and two died from transplant-related complications. An additional forty-six asymptomatic infants were found to be at moderate or high risk for disease. Screening for KD is both analytically and medically challenging; since screening for KD possesses both of these challenges, and many more, the lessons learned thus far could be used to predict the challenges that may be faced when screening for other lysosomal storage disorders (LSDs). This paper briefly reviews reports of NBS for LSDs from varied world programs. The challenges encountered in screening for KD in NY will be highlighted, and this experience, combined with hindsight, will inform what may be expected in the future as screening for LSDs expands.

Background New York State has screened over 1.2 million newborns for Krabbe disease, and we identified 4 newborns with infantile Krabbe disease. In addition, 6 other newborns were identified with very low galactosylcerebrosidase (GALC) activity. Because these patients remain asymptomatic, we investigated whether psychosine levels could be a useful marker for disease. Methods HPLC–MS/MS methodology was used to determine the psychosine concentrations in dried blood spots (DBS) collected from the following cohorts: known Krabbe patients, screened babies that were determined to have infantile Krabbe disease, asymptomatic infants with low GALC activity, and normal controls. Results The psychosine concentrations from the known Krabbe patients ranged from 7 to 50 ng/ml. Newborns identified by screening who were confirmed with infantile Krabbe disease ranged from 23 to 73 ng/ml. Asymptomatic individuals with low GALC activity had concentrations ranging from 1.7 to 5.7 ng/ml. Concentrations in newborns with normal GALC activity were all Conclusions The psychosine concentrations in DBS from confirmed infantile patients are at least four times higher than the asymptomatic newborns and nearly an order of magnitude greater than normal newborns. Further studies are needed to determine if psychosine can be used as a predictor of disease status/progression in screen positive newborns.

Purpose To present clinical, biochemical and molecular information on six new clinically diagnosed Krabbe disease patients and assess the sensitivity of retrospective galactocerebrosidase measurement in their newborn screening samples. Methods Medical records were reviewed. Galactocerebrosidase activity was measured in leukocytes and, retrospectively, in the patients' newborn screening cards (stored for 1.4 to 13.5 years). GALC gene mutation analysis was performed. Results Five patients with Krabbe disease, one of whom also had hydrocephalus, became symptomatic during infancy. A sixth patient presented with seizures and developmental regression at age two and had a protracted disease course. Galactocerebrosidase activity in leukocytes ranged from 0.00 to 0.20 nmol/h/mg protein. Low galactocerebrosidase activity (range: 3.2% to 11.1% of the daily mean), consistent with Krabbe disease, was detected in each of the newborn screening samples. GALC molecular analysis identified six previously unreported mutations and two novel sequence variants. Conclusion Our cases highlight the clinical variability of Krabbe disease. Galactocerebrosidase activity in newborn dried blood spots is a highly sensitive test, even when samples have been stored for many years. The high frequency of private mutations in the GALC gene may limit the use of genetic information for making treatment decisions in the newborn period.

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.

at age 9 years 9 months. The average number of months on treatment was 2 years 3 months, ranging from 9 months to 4 years 3 months. Regarding AE/IAR: 3 patients presented IAR considered mild and resolved with standard management; 3 patients presented AE during betagalsidase shortage and these were pain in hands and feet and proteinuria in a female patient, which was considered severe. Although betagalsidase is currently approved in Brazil for patients at age 16 years or older, the patients herein presented were started on treatment at a younger age due to important clinical symptoms.Mild IARwere reported in a few patients and managed with standard procedures. Current data shows that ERT with betagalsidase at 1,0 mg/kg EoW in a Brazilian younger than 16 years of age population appears to be as safe as in adults.