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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.

Long‐chain fatty acid oxidation disorders (LC‐FAOD) are autosomal recessive conditions that impair conversion of long‐chain fatty acids into energy, leading to significant clinical symptoms. Triheptanoin is a highly purified, 7‐carbon chain triglyceride approved in the United States as a source of calories and fatty acids for treatment of pediatric and adult patients with molecularly confirmed LC‐FAOD. CL202 is an open‐label, long‐term extension study evaluating triheptanoin (Dojolvi) safety and efficacy in patients with LC‐FAOD. Patients rolled over from the CL201 triheptanoin clinical trial (rollover); were triheptanoin‐naïve (naïve); or had participated in investigator‐sponsored trials/expanded access programs (IST/other). Results focus on rollover and naïve groups, as pretreatment data allow comparison. Primary outcomes were annual rate and duration of major clinical events (MCEs; rhabdomyolysis, hypoglycemia, and cardiomyopathy events). Seventy‐five patients were enrolled (24 rollover, 20 naïve, 31 IST/other). Mean study duration was 23.0 months for rollover, 15.7 months for naïve, and 34.7 months for IST/other. In the rollover group, mean annualized MCE rate decreased from 1.76 events/year pre‐triheptanoin to 0.96 events/year with triheptanoin (P = .0319). Median MCE duration was reduced by 66%. In the naïve group, median annualized MCE rate decreased from 2.33 events/year pre‐triheptanoin to 0.71 events/year with triheptanoin (P = .1072). Median MCE duration was reduced by 80%. The most common related adverse events (AEs) were diarrhea, abdominal pain/discomfort, and vomiting, most mild to moderate. Three patients had serious AEs (diverticulitis, ileus, rhabdomyolysis) possibly related to drug; all resolved. Two patients had AEs leading to death; neither drug related. Triheptanoin reduced rate and duration of MCEs. Safety was consistent with previous observations.

Phenylketonuria (PKU), caused by variants in the phenylalanine hydroxylase (PAH) gene, is the most common autosomal-recessive Mendelian phenotype of amino acid metabolism. We estimated that globally 0.45 million individuals have PKU, with global prevalence 1:23,930 live births (range 1:4,500 [Italy]–1:125,000 [Japan]). Comparing genotypes and metabolic phenotypes from 16,092 affected subjects revealed differences in disease severity in 51 countries from 17 world regions, with the global phenotype distribution of 62% classic PKU, 22% mild PKU, and 16% mild hyperphenylalaninemia. A gradient in genotype and phenotype distribution exists across Europe, from classic PKU in the east to mild PKU in the southwest and mild hyperphenylalaninemia in the south. The c.1241A>G (p.Tyr414Cys)-associated genotype can be traced from Northern to Western Europe, from Sweden via Norway, to Denmark, to the Netherlands. The frequency of classic PKU increases from Europe (56%) via Middle East (71%) to Australia (80%). Of 758 PAH variants, c.1222C>T (p.Arg408Trp) (22.2%), c.1066−11G>A (IVS10−11G>A) (6.4%), and c.782G>A (p.Arg261Gln) (5.5%) were most common and responsible for two prevalent genotypes: p.[Arg408Trp];[Arg408Trp] (11.4%) and c.[1066−11G>A];[1066−11G>A] (2.6%). Most genotypes (73%) were compound heterozygous, 27% were homozygous, and 55% of 3,659 different genotypes occurred in only a single individual. PAH variants were scored using an allelic phenotype value and correlated with pre-treatment blood phenylalanine concentrations (n = 6,115) and tetrahydrobiopterin loading test results (n = 4,381), enabling prediction of both a genotype-based phenotype (88%) and tetrahydrobiopterin responsiveness (83%). This study shows that large genotype databases enable accurate phenotype prediction, allowing appropriate targeting of therapies to optimize clinical outcome. Fil: Hillert, Alicia. No especifíca; Fil: Anikster, Yair. No especifíca; Fil: Belanger Quintana, Amaya. No especifíca; Fil: Burlina, Alberto. No especifíca; Fil: Burton, Barbara K.. No especifíca; Fil: Carducci, Carla. No especifíca; Fil: Chiesa, Ana Elena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina Fil: Christodoulou, John. No especifíca; Fil: Dordevic, Maja. No especifíca; Fil: Desviat, Lourdes R.. No especifíca; Fil: Eliyahu, Aviva. No especifíca; Fil: Evers, Roeland A.F.. No especifíca; Fil: Fajkusova, Lena. No especifíca; Fil: Feillet, Francois. No especifíca; Fil: Bonfim Freitas, Pedro E.. No especifíca; Fil: Gizewska, María. No especifíca; Fil: Gundorova, Polina. No especifíca; Fil: Karall, Daniela. No especifíca; Fil: Kneller, Katya. No especifíca; Fil: Kutsev, Sergey I.. No especifíca; Fil: Leuzzi, Vincenzo. No especifíca; Fil: Levy, Harvey L.. No especifíca; Fil: Lichter Koneck, Uta. No especifíca; Fil: Muntau, Ania C.. No especifíca; Fil: Namour, Fares. No especifíca; Fil: Oltarzewsk, Mariusz. No especifíca; Fil: Paras, Andrea. No especifíca; Fil: Perez, Belén. No especifíca; Fil: Polak, Emil. No especifíca; Fil: Polyakov, Alexander V.. No especifíca; Fil: Porta, Francesco. No especifíca; Fil: Rohrbach, Marianne. No especifíca; Fil: Scholl Bürgi, Sabine. No especifíca; Fil: Spécola, Norma. No especifíca; Fil: Stojiljkovic, Maja. No especifíca; Fil: Shen, Nan. No especifíca; Fil: Santana da Silva, Luiz C.. No especifíca; Fil: Skouma, Anastasia. No especifíca; Fil: van Spronsen, Francjan. No especifíca; Fil: Stoppioni, Vera. No especifíca; Fil: Thöny, Beat. No especifíca; Fil: Trefz, Friedrich K.. No especifíca; Fil: Vockley, Jerry. No especifíca; Fil: Yu, Youngguo. No especifíca; Fil: Zschocke, Johannes. No especifíca; Fil: Hoffmann, Georg F.. No especifíca; Fil: Garbade, Sven F.. No especifíca; Fil: Blau, Nenad. No especifíca

Background Phenylketonuria (PKU) is characterized by a deficiency in phenylalanine hydroxylase (PAH) that may lead to elevated blood phenylalanine (Phe) and significant neurocognitive and neuropsychological comorbidities. Pegvaliase (PALYNZIQ®, BioMarin Pharmaceutical Inc.) is a PEGylated recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL), which converts Phe to trans-cinnamic acid and ammonia, and was approved in May 2018 in the United States and in May 2019 in the European Union for decreasing blood Phe levels in adults with PKU with blood Phe levels >600 μmol/L. The efficacy and safety of pegvaliase was assessed in two phase 2 dose-finding studies in adults with PKU (PAL-002, NCT00925054 , and PAL-004, NCT01212744 ). Participants completing these studies could enroll in a long-term extension study (PAL-003, NCT00924703 ). Methods Participants in PAL-002 received pegvaliase 0.001, 0.003, 0.01, 0.03, or 0.1 mg/kg weekly for 8 weeks, then continued treatment for a further 8 weeks with dose and/or frequency adjusted to achieve blood Phe concentrations of 60 to 600 μmol/L. Participants in PAL-004 received pegvaliase 0.001 to 0.4 mg/kg 5 days/week for 13 weeks, with modifications made to the starting dose in response to safety and/or efficacy, followed by 3 additional weeks of follow-up assessments. The maximum allowable daily dose in both studies was 1.0 mg/kg/day (5.0 mg/kg/week). Participants who completed any of the phase 2 studies (PAL-002; PAL-004; or a third phase 2 study, 165-205) were eligible to enroll in an open-label, multicenter, long-term extension study (PAL-003, NCT00924703 ). Results Thirty-seven of the 40 enrolled participants completed PAL-002 and 15 of the 16 enrolled participants completed PAL-004. Mean blood Phe at baseline was 1311.0 (standard deviation [SD] 354) μmol/L in PAL-002 and 1482.1 (SD 363.5) μmol/L in PAL-004. Mean blood Phe did not substantially decrease with pegvaliase treatment in PAL-002 (−206.3 [SD 287.1] μmol/L at Week 16) or PAL-004 (−410.8 [SD 653.7] μmol/L at Week 13). In PAL-004, mean blood Phe dropped from baseline by 929.1 μmol/L (SD 691.1) by Week 2; subsequent to dose modifications and interruptions, this early decrease in mean Phe level was not sustained. With increased pegvaliase dose and duration in PAL-003, mean blood Phe levels steadily decreased from baseline, with mean reductions by Week 120 of 68.8% (SD 44.2%) in PAL-002 participants and 75.9% (SD 32.4%) in PAL-004 participants. All participants in PAL-002 and PAL-004 reported ≥1 adverse event (AE), with higher exposure-adjusted event rates in PAL-004. The majority of AEs were mild (87.2% in PAL-002, 86.7% in PAL-004) or moderate (12.4% in PAL-002, 13.3% in PAL-004). The most commonly reported AEs in PAL-002 were injection site reaction (50.0% of participants), headache (42.1%), injection site erythema (36.8%), nausea (34.2%), and arthralgia (29.0%), and in PAL-004 were arthralgia (75.0%), headache (62.5%), dizziness (56.3%), injection site erythema (56.3%), and injection site reaction (50.0%). Conclusions In two phase 2 dose-finding studies, pegvaliase did not lead to substantial blood Phe reductions. Higher and more frequent pegvaliase dosing in PAL-004 led to a substantial initial drop in blood Phe, but an increase in the number of hypersensitivity AEs and dose reductions or interruptions. With increased dose and duration of treatment in PAL-003, mean blood Phe reduction was substantial and sustained, and the frequency of hypersensitivity AEs decreased and stabilized. Together, these studies led to the development of an induction-titration-maintenance regimen that has been approved for pegvaliase, with patients starting at a low weekly dose that gradually increases in dose and frequency until they achieve a standard non-weight-based daily maintenance dose. This regimen has been tested in a third phase 2 study, as well as in two successful phase 3 studies of pegvaliase.

Objective Previous research has documented executive function (EF) impairments in individuals with early treated phenylketonuria (ETPKU). It remains unclear, however, whether some aspects of EF may be more affected than others. A number of factors, including small sample sizes and variability in EF tasks, have likely contributed to past mixed findings. The present objective was to elucidate further the EF profile associated with ETPKU, particularly as it relates to report-based assessment of EF. Method Data from 286 individuals (5-48 years of age) with ETPKU on the child and adult versions of the Behavior Rating Inventory of Executive Function (BRIEF), a well-established report-based assessment tool, were analyzed. Results The Working Memory scale showed the largest effect size in both young and older ETPKU samples, with 19% of children and 29% of adults scoring in the "abnormally elevated" range. In addition, EF impairment appeared more general (i.e., affecting more domains) in the adult sample as compared to the child sample. Exploratory analyses also suggested that the presence/absence of overall impairment on the BRIEF among our ETPKU participants could be predicted based on a small subset of items. A 10-item subset showed total classification accuracy values of 90% and above for both groups. Conclusions Working memory represents an aspect of EF that appears to be particularly affected in individuals with ETPKU. Findings also provide preliminary support of the viability for the development and/or adoption of an abbreviated screening measure for EF difficulties in children and adults with ETPKU. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Morquio syndrome type A, also known as MPS IVA, is a rare autosomal recessive disorder caused by deficiency of N-acetylgalactosamine-6-sulfatase, a lysosomal hydrolase critical in the degradation of keratan sulfate (KS) and chondroitin sulfate (CS). The CS that accumulates in MPS IVA patients has a disease-specific nonreducing end (NRE) terminating with N-acetyl-D-galactosamine 6-sulfate, which can be specifically quantified after enzymatic depolymerization of CS polysaccharide chains. The abundance of N-acetyl-D-galactosamine 6-sulfate over other possible NRE structures is diagnostic for MPS IVA. Here, we describe an assay for the liberation and measurement of N-acetyl-D-galactosamine 6-sulfate and explore its application to MPS IVA patient samples in pilot studies examining disease detection, effects of age and treatment with enzyme-replacement therapy. This assay complements the existing urinary KS assay by quantifying CS-derived substrates, which represent a distinct biochemical aspect of MPS IVA. A more complete understanding of the disease could help to more definitively detect disease across age ranges and more completely measure the pharmacodynamic efficacy of therapies. Larger studies will be needed to clarify the potential value of this CS-derived substrate to manage disease in MPS IVA patients.

Long-chain fatty-acid oxidation disorders (LC-FAODs) are autosomal recessive inherited metabolic conditions that occur due to a disruption in the body's ability to perform mitochondrial beta oxidation. Expanded newborn screening is widening phenotypic understanding of these disorders, as well improving our knowledge of disease incidence. Management of these disorders is focused on avoidance of fasting, dietary changes and supplementation with energy sources that bypass the metabolic block. Recent US Food and Drug Administration approval of triheptanoin has improved the outcome for affected individuals. New research into dietary modifications and novel pharmacologic therapies continues for these disorders. In this article, we review the major LC-FAODs and their clinical presentation.

Purpose Norrie disease is a rare X-linked recessive vitreoretinopathy. Variants of the NDP gene are associated with this condition. This case reports aims to demonstrate the variations of clinical presentations and exam findings of this disease. Observations A retrospective chart review of the patient's ocular and systemic findings and imaging results was performed. The patient had received genetic testing, including mutational analysis of targeted genes associated with retrolental masses. The patient had a comprehensive eye exam for bilateral leukocoria, demonstrating large retrolental masses, anterior polar cataracts, stretched ciliary processes, and roving eye movements. B-scan ultrasonography and magnetic resonance imaging indicated total, funnel-shaped retinal detachments, which is a unique retinal configuration in Norrie disease. Genetic testing confirmed deletion of the coding region of all three exons in the NDP gene, which confirmed Norrie disease. He has not shown any extraocular involvement to date. Conclusions and Importance This is a case demonstrating the association between deletion of the coding region NDP gene and Norrie disease. The phenotypical variation of this disease warrants further studies of genotype-phenotype correlations and mutations of the NDP gene.

Phenylketonuria (PKU) is caused by phenylalanine hydroxylase (PAH) deficiency, resulting in high blood and brain Phenylalanine (Phe) concentrations that can lead to impaired brain development and function. Standard treatment involves a Phe-restricted diet alone or in conjunction with sapropterin dihydrochloride in responsive patients. The Food and Drug Administration approved pegvaliase enzyme substitution therapy for adults with blood Phe >600 μmol/L in the US. Recently, the European Commission also approved pegvaliase for treatment of PKU patients aged 16 years or older with blood Phe >600 μmol/L. The analyses presented below were conducted to provide comparative evidence on long-term treatment effectiveness of pegvaliase versus standard of care in adults with PKU. Adult patients (≥18 years) with baseline blood Phe >600 μmol/L who had enrolled in the pegvaliase phase 2 and phase 3 clinical trials were propensity score-matched to historical cohorts of patients treated with “sapropterin + diet” or with “diet alone”. These cohorts were derived from the PKU Demographics, Outcome and Safety (PKUDOS) registry and compared for clinical outcomes including blood Phe concentration and natural intact protein intake after 1 and 2 years. Propensity scores were estimated using logistic regression with probability of treatment as outcome (i.e. pegvaliase, “sapropterin + diet”, or “diet alone”) and patient demographic and disease severity covariates as predictors. An additional analysis in adult PKU patients with baseline blood Phe ≤600 μmol/L comparing non-matched patient groups “sapropterin + diet” to “diet alone” using PKUDOS registry data only was also conducted. The analyses in patients with baseline blood Phe >600 μmol comparing pegvaliase with “sapropterin + diet” (N = 64 matched pairs) showed lower mean blood Phe concentrations after 1 and 2 years with pegvaliase (505 and 427 μmol/L) versus “sapropterin + diet” (807 and 891 μmol/L); mean natural intact protein intake after 1 and 2 years was 49 and 57 g/day respectively with pegvaliase versus 23 and 28 g/day with “sapropterin + diet”. The analysis comparing pegvaliase with “diet alone” (N = 120 matched pairs) showed lower mean blood Phe at 1 and 2 years with pegvaliase (473 and 302 μmol/L) versus “diet alone” (1022 and 965 μmol/L); mean natural intact protein intake after 1 and 2 years was 47 and 57 g/day with pegvaliase and 27 and 22 g/day with “diet alone”. Considerably more patients achieved blood Phe ≤600, ≤360, and ≤120 μmol/L and reductions from baseline of ≥20%, ≥30%, and ≥50% in blood Phe after 1 and 2 years of pegvaliase versus standard treatments. The analysis in patients with baseline blood Phe ≤600 μmol/L showed lower blood Phe after 1 and 2 years with “sapropterin + diet” (240 and 324 μmol/L) versus “diet alone” (580 and 549 μmol/L) and greater percentages of patients achieving blood Phe targets ≤600, ≤360, and ≤120 μmol/L and reductions from baseline of ≥20%, ≥30%, and ≥50% in blood Phe. These results support pegvaliase as the more effective treatment option to lower Phe levels in adults with PKU who have difficulty keeping blood Phe ≤600 μmol/L with “diet alone”. For patients with blood Phe ≤600 μmol/L, adding sapropterin to dietary management is an appropriate treatment option, for those responsive to the treatment.

Phenylketonuria (PKU) is a rare metabolic disorder that requires life-long management to reduce phenylalanine (Phe) concentrations within the recommended range. The availability of pegvaliase (PALYNZIQ™, an enzyme that can metabolize Phe) as a new therapy necessitates the provision of guidance for its use. A Steering Committee comprising 17 health-care professionals with experience in using pegvaliase through the clinical development program drafted guidance statements during a series of face-to-face meetings. A modified Delphi methodology was used to demonstrate consensus among a wider group of health-care professionals with experience in using pegvaliase. Guidance statements were developed for four categories: (1) treatment goals and considerations prior to initiating therapy, (2) dosing considerations, (3) considerations for dietary management, and (4) best approaches to optimize medical management. A total of 34 guidance statements were included in the modified Delphi voting and consensus was reached on all after two rounds of voting. Here we describe evidence- and consensus-based recommendations for the use of pegvaliase in adults with PKU. The manuscript was evaluated against the Appraisal of Guidelines for Research and Evaluation (AGREE II) instrument and is intended for use by health-care professionals who will prescribe pegvaliase and those who will treat patients receiving pegvaliase.

Long-chain fatty acid oxidation disorders (LC-FAOD) are rare disorders characterized by acute crises of energy metabolism and severe energy deficiency that may present with cardiomyopathy, hypoglycemia, and/or rhabdomyolysis, which can lead to frequent hospitalizations and early death. An open-label Phase 2 study evaluated the efficacy of UX007, an investigational odd-carbon medium-chain triglyceride, in 29 subjects with severe LC-FAOD. UX007 was administered over 78 weeks at a target dose of 25-35% total daily caloric intake (mean 27.5%). The frequency and duration of major clinical events (hospitalizations, emergency room visits, and emergency home interventions due to rhabdomyolysis, hypoglycemia, and cardiomyopathy) occurring during 78 weeks of UX007 treatment was compared with the frequency and duration of events captured retrospectively from medical records for 78 weeks before UX007 initiation. The mean annualized event rates decreased from 1.69 to 0.88 events/year following UX007 initiation (p = 0.021; 48.1% reduction). The mean annualized duration rate decreased from 5.96 to 2.96 days/year (p = 0.028; 50.3% reduction). Hospitalizations due to rhabdomyolysis, the most common event, decreased from 1.03 to 0.63 events/year (p = 0.104; 38.7% reduction). Initiation of UX007 eliminated hypoglycemia events leading to hospitalization (from 11 pre-UX007 hospitalizations, 0.30 events/year vs. 0; p = 0.067) and intensive care unit (ICU) care (from 2 pre-UX007 ICU admissions, 0.05 events/year vs. 0; p = 0.161) and reduced cardiomyopathy events (3 events vs. 1 event; 0.07 to 0.02 events/year; 69.7% decrease). The majority of treatment-related adverse events (AEs) were mild to moderate gastrointestinal symptoms, including diarrhea, vomiting, and abdominal or gastrointestinal pain, which can be managed with smaller, frequent doses mixed with food.

Phenylketonuria (PKU), a deficiency in the activity of the enzyme phenylalanine hydroxylase, leads to toxic levels of phenylalanine (Phe) in the blood and brain. Pegvaliase (recombinant Anabaena variabilis phenylalanine ammonia lyase conjugated with polyethylene glycol) is approved to manage PKU in patients aged greater than or equal to 18 years in the United States and in patients aged greater than or equal to 16 years in the European Union. Pharmacokinetic, pharmacodynamic, and immunogenicity results from five open‐label pegvaliase trials were assessed. Studies with induction/titration/maintenance (I/T/M) dosing regimens demonstrated pharmacokinetic stabilization and sustained efficacy associated with maintenance doses (20, 40, or 60 mg/day). Immune‐mediated pegvaliase clearance was high during induction/titration phases when the early immune response was peaking. The combination of low drug dosage and high drug clearance led to low drug exposure and minimal decreases in blood Phe levels during induction/titration. Higher drug exposure and substantial reductions in blood Phe levels were observed later in treatment as drug clearance was reduced due to the maturation of the immune response, which allowed for increased dosing to target levels. The incidence of hypersensitivity reactions was temporally associated with the peaking of the early antidrug immune response and decreased with time as immune response matured after the first 6 months of treatment. These results support an I/T/M dosing regimen and suggest a strategy for administration of other nonhuman biologics to achieve efficacy and improve tolerability.

Background Niemann-Pick Disease Type C (NPC) is an ultra-rare progressive neurodegenerative disease caused by autosomal recessive mutations in the NPC1 or NPC2 genes that lead to premature death, with most individuals dying between 10 and 25 years of age. NPC can present at any age and many individuals with NPC may be misdiagnosed or undiagnosed. A key challenge with recognizing NPC is the heterogeneous and nonspecific clinical presentation. Currently, there are no approved treatments for NPC in the United States; miglustat, an FDA-approved treatment for Gaucher disease, is used off-label for NPC and GM1 gangliosidosis. Objectives To estimate the number of people in the United States that 1) have an NPC diagnosis 2) have an NPC diagnosis and/or are treated off-label with miglustat for NPC and 3) are likely to have NPC. Methods For the first two objectives, patients were identified using the Symphony Integrated DataVerse database (Oct 2015-Jan 2020). To identify the number of people with NPC for Objective 1, cases of NPC were defined as any patients with an ICD-10 code of E75.242 (NPC) during the study period. Objective 2 expands upon Objective 1, including (a) patients from Objective 1 and (b) patients with documented miglustat use (NDC 43975–0310 or 10,148–0201) who did not have any claim with Gaucher disease (ICD-10 E75.22) or GM1 gangliosidosis (ICD-10 E75.1) during the study period. For the third objective, published NPC incidence (1 per 89,000 live births) and expected mortality estimates were applied to the 2018 United States birth rate (11.6 per 1000) and population size (326.7 million). Results A total of 308 million unique individuals were represented in the database. Of these, 294 individuals had an NPC diagnosis, yielding an identified NPC prevalence of 0.95 per million people in the United States. 305 individuals were diagnosed with NPC and/or were treated with miglustat without having a diagnosis for either Gaucher or GM1 gangliosidosis, yielding an NPC diagnosed or treated prevalence of 0.99 per million people in the United States. Based on the published literature, there are an estimated 42 new NPC cases per year. Applying this number to the distribution of NPC type (based on age of neurologic symptom onset) and corresponding mortality estimates generates an estimated 943 prevalent cases of NPC, or 2.9 cases of NPC per million people in the United States. Conclusions NPC is an ultra-rare, progressive neurodegenerative disease with approximately 1 per million people in the United States diagnosed with or treated off-label for NPC. Given that NPC is often misdiagnosed or undiagnosed, the estimated prevalence from the epidemiology calculations (2.9 per million) approximates the number of NPC cases if disease awareness, screening and diagnosis efforts were enhanced.

Background & Aims Children and adults with lysosomal acid lipase deficiency (LAL-D) experience cirrhosis and dyslipidemia from lysosomal accumulation of cholesteryl esters and triglycerides. Sebelipase alfa enzyme replacement therapy is indicated for individuals with LAL-D. We report final results of the phase 3 randomized ARISE study of sebelipase alfa in children aged ≥4 years and adults with LAL-D. Methods The study included a 20-week, double-blind, placebo-controlled phase, a 130-week, open-label extension period, and a 104-week, open-label expanded treatment period. In the open-label periods, all patients received intravenous sebelipase alfa every other week. The primary outcome was alanine aminotransferase (ALT) level normalization; aspartate aminotransferase (AST) levels, lipid parameters, liver histology, liver and spleen volume and fat content, and safety were also assessed. Results Of 66 patients enrolled, 59 completed the study. Median (range) age at randomization was 13 (4.7–59) years. At the last open-label visit, ALT and AST levels had normalized in 47% and 66% of patients, respectively. Patients who switched from placebo to sebelipase alfa experienced sustained improvements in ALT and AST during the open-label periods that mirrored those observed in the sebelipase alfa group during the double-blind period. Median (interquartile range) percent changes in lipid levels included a 25% (39%, 6.5%) reduction in low-density lipoprotein cholesterol and a 27% (19%, 44%) increase in high-density lipoprotein cholesterol. Most adverse events during the open-label periods were mild to moderate in severity; 13 patients had infusion-associated reactions (serious in 1 patient). Six patients (9%) developed anti-drug antibodies. Conclusions Early and rapid improvements in markers of liver injury and lipid abnormalities with sebelipase alfa were sustained, with no progression of liver disease, for up to 5 years. Lay Summary Sebelipase alfa is used to treat lysosomal acid lipase deficiency (LAL-D), a rare, inherited disease of lipid metabolism. We report the final results of the phase 3 ARISE clinical study, which show that replacement of the defective LAL enzyme with sebelipase alfa for up to 5 years allows adults and children 4 years of age and older to maintain their initial improvements in liver and cholesterol parameters over the long term, without worsening of liver disease. Clinical Trial Number NCT01757184; EudraCT Number: 2011-002750-31

Sapropterin dihydrochloride has been approved for the treatment of hyperphenylalaninemia in infants and young children with phenylketonuria (PKU). Sapropterin can reduce phenylalanine (Phe) levels in tetrahydrobiopterin (BH4)-responsive patients, potentially preventing the intellectual impairment caused by elevated Phe levels. The long-term effect of sapropterin on intellectual functioning was assessed using the Full-Scale Intelligence Quotient (FSIQ) in 62 children who began treatment before the age of 6 years. Over each 2-year interval, the estimate of mean change in FSIQ was −0.5768 with a lower limit of the 95% confidence interval (CI) of −1.60. At the end of the follow-up period (Year 7), the least squares mean estimate of the change in FSIQ from baseline was 1.14 with a lower limit of the 95% CI of −3.53. These lower limits were both within the clinically expected variation of 5 points. During the whole study period, mean blood Phe levels remained within the American College of Medical Genetics (ACMG) target range of 120–360 μmol/L. In addition, height, weight, and head circumference were maintained within normal ranges throughout follow-up, as defined by growth charts from the World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) for children below and above the age of 24 months, respectively. All patients (n = 65) enrolled in this study experienced at least one adverse event, as expected from previous studies. In conclusion, long-term use of sapropterin in individuals with PKU helps to control blood Phe, preserve intellectual functioning, and maintain normal growth in BH4-responsive children who initiated treatment between the ages of 0 to 6 years.

Mucopolysaccharidosis type II (MPS II, Hunter syndrome) is a rare, progressive multisystemic lysosomal storage disorder with significant morbidity and premature mortality. Infants with MPS II develop signs and symptoms of the disorder in the early years of life, yet diagnostic delays are very common. Enzyme replacement therapy is an effective treatment option. It has been shown to prolong survival and improve or stabilize many somatic manifestations of the disorder. Our initial experience with newborn screening in 162,000 infants was previously reported. Here, we update that experience with the findings in 339,269 infants. Measurement of iduronate-2-sulfatase (I2S) activity was performed on dried blood spot samples submitted for other newborn screening disorders. A positive screen was defined as I2S activity less than or equal to 10% of the daily median. In this series, 28 infants had a positive screening test result, and four other infants had a borderline result. Three positive diagnoses of MPS II were established, and 25 were diagnosed as having I2S pseudodeficiency. The natural history and the clinical features of MPS II make it an ideal target for newborn screening. Newborn screening was effective in identifying affected infants in our population with an acceptable rate of false positive results.

Statewide newborn screening for Pompe disease began in Illinois in 2015. As of 30 September 2019, a total of 684,290 infants had been screened and 395 infants (0.06%) were screen positive. A total of 29 cases of Pompe disease were identified (3 infantile, 26 late-onset). While many of the remainder were found to have normal alpha-glucosidase activity on the follow-up testing (234 of 395), other findings included 62 carriers, 39 infants with pseudodeficiency, and eight infants who could not be given a definitive diagnosis due to inconclusive follow-up testing.

Purpose TANGO2-related disorders were first described in 2016 and prior to this publication, only 15 individuals with TANGO2-related disorder were described in the literature. Primary features include metabolic crisis with rhabdomyolysis, encephalopathy, intellectual disability, seizures, and cardiac arrhythmias. We assess whether genotype and phenotype of TANGO2-related disorder has expanded since the initial discovery and determine the efficacy of exome sequencing (ES) as a diagnostic tool for detecting variants. Methods We present a series of 14 individuals from 11 unrelated families with complex medical and developmental histories, in whom ES or microarray identified compound heterozygous or homozygous variants in TANGO2. Results The initial presentation of patients with TANGO2-related disorders can be variable, including primarily neurological presentations. We expand the phenotype and genotype for TANGO2, highlighting the variability of the disorder. Conclusion TANGO2-related disorders can have a more diverse clinical presentation than previously anticipated. We illustrate the utility of routine ES data reanalysis whereby discovery of novel disease genes can lead to a diagnosis in previously unsolved cases and the need for additional copy-number variation analysis when ES is performed.

Objectives To assess the outcomes of newborn screening for 5 lysosomal storage disorders (LSDs) in the first cohort of infants tested in the state of Illinois. Study design Tandem mass spectrometry was used to assay for the 5 LSD-associated enzymes in dried blood spot specimens obtained from 219 973 newborn samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago. Results The total number of cases with a positive diagnosis and the incidence for each disorder were as follows: Fabry disease, n = 26 (1 in 8454, including the p.A143T variant); Pompe disease, n = 10 (1 in 21 979); Gaucher disease, n = 5 (1 in 43 959); mucopolysaccharidosis (MPS) type 1, n = 1 (1 in 219 793); and Niemann-Pick disease type A/B, n = 2 (1 in 109 897). Twenty-two infants had a positive screen for 1 of the 5 disorders but could not be classified as either affected or unaffected after follow-up testing, including genotyping. Pseudodeficiencies for alpha-L-iduronidase and alpha-glucosidase were detected more often than true deficiencies. Conclusions The incidences of Fabry disease and Pompe disease were significantly higher than published estimates, although most cases detected were predicted to be late onset. The incidences of Gaucher disease, MPS I, and Niemann-Pick disease were comparable with previously published estimates. A total of 16 infants could not be positively identified as either affected or unaffected. To validate the true risks and benefits of newborn screening for LSD, long term follow-up in these infants and those detected with later-onset disorders will be essential.

Mucopolysaccharidosis type II (MPS II; Hunter syndrome; OMIM 309900) is a rare lysosomal storage disease with progressive multisystem manifestations caused by deficient activity of the enzyme iduronate-2-sulfatase. Disease-specific treatment is available in the form of enzyme replacement therapy with intravenous idursulfase (Elaprase®, Shire). Since 2005, the Hunter Outcome Survey (HOS) has collected real-world, long-term data on the safety and effectiveness of this therapy, as well as the natural history of MPS II. Individuals with a confirmed diagnosis of MPS II who are untreated or who are receiving/have received treatment with idursulfase or bone marrow transplant can be enrolled in HOS. A broad range of disease- and treatment-related information is captured in the registry and, over the past decade, data from more than 1000 patients from 124 clinics in 29 countries have been collected. Evidence generated from HOS has helped to improve our understanding of disease progression in both treated and untreated patients and has extended findings from the formal clinical trials of idursulfase. As a long-term, global, observational registry, various challenges relating to data collection, entry, and analysis have been encountered. These have resulted in changes to the HOS database platform, and novel approaches to maximize the value of the information collected will also be needed in the future. The continued evolution of the registry should help to ensure that HOS provides further insights into the burden of the disease and patient care and management in the coming years.

Hunter syndrome (mucopolysaccharidosis II [MPS II]) is characterized by lysosomal glycosaminoglycan (GAG) accumulation. Although a majority of patients with MPS II experience neurocognitive involvement, few data are available on cerebrospinal fluid (CSF) GAG levels in these patients. This study measured GAG levels in CSF collected from 9 patients with MPS II, including 4 adults (aged ≥18 years) with normal cognition, and 5 children, 3 of them with cognitive impairment. The CSF total GAG levels were generally higher in the 3 patients with cognitive impairment (range 842.9-2360.9 ng/mL) versus those with normal cognitive status (range 356.8-1181.1 ng/mL). Heparan sulfate levels, as measured by mass spectrometry, generally followed a similar pattern, with patients with the severe phenotype having the highest values. These data, limited by small sample size, suggest CSF GAG levels and heparan sulfate levels may be higher in patients with cognitive impairment versus patients with cognitively intact MPS II.

Objectives To assess the outcome of population-based newborn screening for mucopolysaccharidosis type II (MPS II) during the first year of screening in Illinois. Study design Tandem mass spectrometry was used to measure iduronate-2-sulfatase (I2S) activity in dried blood spot specimens obtained from 162 000 infant samples sent to the Newborn Screening Laboratory of the Illinois Department of Public Health in Chicago. Results One case of MPS II and 14 infants with pseudodeficiency for I2S were identified. Conclusions Newborn screening for MPS II by measurement of I2S enzyme activity was successfully integrated into the statewide newborn screening program in Illinois.

Introduction There is limited understanding of relationships between genotype, phenotype and other conditions contributing to health in neonates with medium-chain acyl-coenzyme A dehydrogenase deficiency (MCADD) identified through newborn screening. Methods Retrospective analysis of comprehensive data from a cohort of 221 newborn-screened subjects identified as affected with MCADD in the Inborn Errors of Metabolism – Information System (IBEM-IS), a long term follow-up database of the Inborn Errors of Metabolism Collaborative, was performed. Results The average age at notification of first newborn screen results to primary care or metabolic providers was 7.45 days. The average octanoylcarnitine (C8) value on first newborn screen was 11.2 μmol/L (median 8.6, range 0.36–43.91). A higher C8 level correlated with an earlier first subspecialty visit. Subjects with low birth weight had significantly lower C8 values. Significantly higher C8 values were found in symptomatic newborns, in newborns with abnormal lab testing in addition to newborn screening and/or diagnostic tests, and in subjects homozygous for the c.985A > G ACADM gene mutation or compound heterozygous for the c.985A > G mutation and deletions or other known highly deleterious mutations. Subjects with neonatal symptoms, or neonatal abnormal labs, or neonatal triggers were more likely to have at least one copy of the severe c.985A > G ACADM gene mutation. C8 and genotype category were significant predictors of the likelihood of having neonatal symptoms. Neonates with select triggers were more likely to have symptoms and laboratory abnormalities. Conclusions This collaborative study is the first in the United States to describe health associations of a large cohort of newborn-screened neonates identified as affected with MCADD. The IBEM-IS has utility as a platform to better understand the characteristics of individuals with newborn-screened conditions and their follow-up interactions with the health system.

The US Food and Drug Administration (FDA) and National Organization for Rare Disease (NORD) convened a public workshop titled "Immune Responses to Enzyme Replacement Therapies: Role of Immune Tolerance Induction" to discuss the impact of anti-drug antibodies (ADAs) on efficacy and safety of enzyme replacement therapies (ERTs) intended to treat patients with lysosomal storage diseases (LSDs). Participants in the workshop included FDA staff, clinicians, scientists, patients, industry, and advocacy group representatives. The risks and benefits of implementing prophylactic immune tolerance induction (ITI) to reduce the potential clinical impact of antibody development were considered. Complications due to immune responses to ERT are being recognized with increasing experience and lengths of exposure to ERTs to treat several LSDs. Strategies to mitigate immune responses and to optimize therapies are needed. Discussions during the workshop resulted in the identification of knowledge gaps and future areas of research, as well as the following proposals from the participants: (1) systematic collection of longitudinal data on immunogenicity to better understand the impact of ADAs on long-term clinical outcomes; (2) development of disease-specific biomarkers and outcome measures to assess the effect of ADAs and ITI on efficacy and safety; (3) development of consistent approaches to ADA assays to allow comparisons of immunogenicity data across different products and disease groups, and to expedite reporting of results; (4) establishment of a system to widely share data on antibody titers following treatment with ERTs; (5) identification of components of the protein that are immunogenic so that triggers and components of the immune responses can be targeted in ITI; and (6) consideration of early ITI in patients who are at risk of developing clinically relevant ADA that have been demonstrated to worsen treatment outcomes.

Background The hepatic urea cycle is the main metabolic pathway for detoxification of ammonia. Inborn errors of urea cycle function present with severe hyperammonemia and a high case fatality rate. Long-term prognosis depends on the residual activity of the defective enzyme. A reliable method to estimate urea cycle activity in-vivo does not exist yet. The aim of this study was to evaluate a practical method to quantify 13 C-urea production as a marker for urea cycle function in healthy subjects, patients with confirmed urea cycle defect (UCD) and asymptomatic carriers of UCD mutations. Methods 13 C-labeled sodium acetate was applied orally in a single dose to 47 subjects (10 healthy subjects, 28 symptomatic patients, 9 asymptomatic carriers). Results The oral 13 C-ureagenesis assay is a safe method. While healthy subjects and asymptomatic carriers did not differ with regards to kinetic variables for urea cycle flux, symptomatic patients had lower 13 C-plasma urea levels. Although the 13 C-ureagenesis assay revealed no significant differences between individual urea cycle enzyme defects, it reflected the heterogeneity between different clinical subgroups, including male neonatal onset ornithine carbamoyltransferase deficiency. Applying the 13 C-urea area under the curve can differentiate between severe from more mildly affected neonates. Late onset patients differ significantly from neonates, carriers and healthy subjects. Conclusion This study evaluated the oral 13 C-ureagenesis assay as a sensitive in-vivo measure for ureagenesis capacity. The assay has the potential to become a reliable tool to differentiate UCD patient subgroups, follow changes in ureagenesis capacity and could be helpful in monitoring novel therapies of UCD.

In mucopolysaccharidoses (MPS), glycosaminoglycans (GAG) accumulate in tissues. In MPS II, approximately two-thirds of patients are cognitively impaired. We investigated levels of GAG in cerebrospinal fluid (CSF) in different populations from four clinical studies (including NCT00920647 and NCT01449240). Data indicate that MPS II patients with cognitive impairment have elevated levels of CSF GAG, whereas those with the attenuated phenotype typically have levels falling between those of the cognitively affected patients and healthy controls.

Graphical abstract key: ADHD, attention deficit hyperactivity disorder; ASD, atrial septal defect; DD, developmental delay; EEG, electroencephalogram; Ht, height; ID, intellectual disability; OCD, obsessive-compulsive disorder; OFC, open fontanelle; PDA, patent ductus arteriosis; PFO, patent foramen ovale; VSD, ventricular septal defect; Wt, weight.

Phenylalanine hydroxylase (PAH) deficiency, otherwise known as phenylketonuria (PKU), is an inborn error of metabolism that requires treatment to be initiated in the newborn period and continued throughout life. Due to the challenges of treatment adherence and the resulting cumulative effects of high and labile blood phenylalanine, PKU exerts a significant burden of disease. Retrospective studies using large databases allow for unique perspectives on comorbidities associated with rare diseases. An evaluation of comorbidities across various organ systems is warranted to understand the disease burden in adult patients.The aim of this insurance claim-based observational study was to assess the prevalence of comorbid conditions across various organ systems (e.g. dermatological, renal, respiratory, gastrointestinal, hematological, and others) among adult PKU patients compared with matched controls from the general population.This retrospective, case-controlled study selected patients from United States insurance claims databases from 1998 to 2014 using International Classification of Diseases, Ninth Revision (ICD-9) codes for diagnosis of PKU. The date of first diagnosis during the study period was index date and this was not necessarily the first time the patient was diagnosed with PKU. Cases were matched with a 1:5 ratio with general population (non-PKU controls) on age, sex, race, geographic location, duration of time in the database and insurance type. Prevalence and prevalence ratio (PR) calculations for comorbidities across various organ systems among adults (≥20 years old) with PKU were compared with the general population (non-PKU controls). The conditions were selected based on complications associated with PKU and feedback from clinicians treating PKU patients.A total of 3691 PKU patients and 18,455 matched, non-PKU controls were selected, with an average age of 35 years. The mean healthcare costs incurred by the PKU patients during baseline, were approximately 4 times that of the controls ($4141 vs $1283; p .0001). The prevalence rates of comorbidities across various organ systems during the follow-up period were significantly higher for those with PKU than in the control group. After adjusting for baseline characteristics, the adjusted prevalence ratios (PR) of 15 conditions studied (asthma, alopecia, urticaria, gallbladder disease, rhinitis, esophageal disorders, anemia, overweight, GERD, eczema, renal insufficiency, osteoporosis, gastritis/esophagitis and kidney calculus) were all above PR = 1.24 and significantly higher for the PKU cohort (p ≤ .001). The highest adjusted PR were for renal insufficiency with hypertension (PR [95% CI]: 2.20 [1.60-3.00]; p .0001) and overweight (PR [95%CI]: 2.06 [1.85-2.30]; p .0001).The prevalence of selected comorbidities across several organ systems is significantly higher among PKU patients than for general population controls. Regular screening for common co-morbidities may be warranted as part of PKU management.

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.

Pegvaliase is a recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL) enzyme under investigation for treatment of adult phenylketonuria (PKU). This manuscript describes results of a randomized discontinuation trial (RDT) designed to evaluate the effects of pegvaliase treatment on blood phenylalanine (Phe) and neuropsychiatric outcomes in adults with PKU.PRISM-2 is a 4-part, Phase 3 study that enrolled adults with PKU receiving pegvaliase treatment (initiated in a prior Phase 2 or Phase 3 study). The RDT, Part 2 of PRISM-2, was an 8-week trial that evaluated change in blood Phe concentrations, neuropsychiatric and neurocognitive measures, and safety outcomes in PRISM-2 participants who had achieved at least a 20% blood Phe reduction from pre-treatment baseline with pegvaliase treatment. Participants were randomized 2:1 to either continue pegvaliase (20 mg/day or 40 mg/day) or switch to matching placebo.The pooled pegvaliase group enrolled 66 participants and each placebo group enrolled 14 participants. The primary endpoint of change in blood Phe concentration from RDT entry to RDT Week 8 was met with clinically meaningful and statistically significant differences between the pegvaliase and placebo groups. Mean (SD) blood Phe at the beginning of the RDT when all participants were receiving pegvaliase was 563.9 μM (504.6) in the group assigned to the 20 mg/day placebo group (n = 14), 508.2 μM (363.7) in those assigned to the 40 mg/day placebo group (n = 14), and 503.9 μM (520.3) in those assigned to continue pegvaliase treatment (n = 58). At Week 8 of the RDT, the least squares mean change (95% confidence interval) in blood Phe was 949.8 μM (760.4 to 1139.1) for the 20 mg/day placebo group and 664.8 μM (465.5 to 864.1) for the 40 mg/day placebo group in comparison to 26.5 μM (-68.3 to 121.3) for the pooled (20 mg/day and 40 mg/day) pegvaliase group (P 0.0001 for pooled pegvaliase group vs each placebo group). Adverse events (AEs) were usually lower in the pooled placebo group when compared to the pooled pegvaliase group. The most common AEs for the pooled pegvaliase and pooled placebo groups were arthralgia (13.6% and 10.3%, respectively), headache (12.1% and 24.1%), anxiety (10.6% and 6.9%), fatigue (10.6% and 10.3%), and upper respiratory tract infection (1.5% and 17.2%).Mean blood Phe reduction was sustained in the pegvaliase group, while placebo groups had mean blood Phe concentration increase toward pre-treatment baseline levels. Results from this study confirmed the efficacy of pegvaliase in maintaining reduced blood Phe concentrations with a manageable safety profile for most participants.