Effects of gene replacement therapy with resamirigene bilparvovec (AT132) on skeletal muscle pathology in X-linked myotubular myopathy: results from a substudy of the ASPIRO open-label clinical trial.

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital muscle disease caused by mutations in the MTM1 gene that result in profound muscle weakness, significant respiratory insufficiency, and high infant mortality. There is no approved disease-modifying therapy for XLMTM. Resamirigene bilparvovec (AT132; rAAV8-Des-hMTM1) is an investigational adeno-associated virus (AAV8)-mediated gene replacement therapy designed to deliver MTM1 to skeletal muscle cells and achieve long-term correction of XLMTM-related muscle pathology. The clinical trial ASPIRO (NCT03199469) investigating resamirigene bilparvovec in XLMTM is currently paused while the risk:benefit balance associated with this gene therapy is further investigated. METHODS: Muscle biopsies were taken before treatment and 24 and 48 weeks after treatment from ten boys with XLMTM in a clinical trial of resamirigene bilparvovec (ASPIRO; NCT03199469). Comprehensive histopathological analysis was performed. FINDINGS: Baseline biopsies uniformly showed findings characteristic of XLMTM, including small myofibres, increased internal or central nucleation, and central aggregates of organelles. Biopsies taken at 24 weeks post-treatment showed marked improvement of organelle localisation, without apparent increases in myofibre size in most participants. Biopsies taken at 48 weeks, however, did show statistically significant increases in myofibre size in all nine biopsies evaluated at this timepoint. Histopathological endpoints that did not demonstrate statistically significant changes with treatment included the degree of internal/central nucleation, numbers of triad structures, fibre type distributions, and numbers of satellite cells. Limited (predominantly mild) treatment-associated inflammatory changes were seen in biopsy specimens from five participants. INTERPRETATION: Muscle biopsies from individuals with XLMTM treated with resamirigene bilparvovec display statistically significant improvement in organelle localisation and myofibre size during a period of substantial improvements in muscle strength and respiratory function. This study identifies valuable histological endpoints for tracking treatment-related gains with resamirigene bilparvovec, as well as endpoints that did not show strong correlation with clinical improvement in this human study. FUNDING: Astellas Gene Therapies (formerly Audentes Therapeutics, Inc.).

Safety and efficacy of gene replacement therapy for X-linked myotubular myopathy (ASPIRO): a multinational, open-label, dose-escalation trial.

BACKGROUND: X-linked myotubular myopathy is a rare, life-threatening, congenital muscle disease observed mostly in males, which is caused by mutations in MTM1. No therapies are approved for this disease. We aimed to assess the safety and efficacy of resamirigene bilparvovec, which is an adeno-associated viral vector serotype 8 delivering human MTM1. METHODS: ASPIRO is an open-label, dose-escalation trial at seven academic medical centres in Canada, France, Germany, and the USA. We included boys younger than 5 years with X-linked myotubular myopathy who required mechanical ventilator support. The trial was initially in two parts. Part 1 was planned as a safety and dose-escalation phase in which participants were randomly allocated (2:1) to either the first dose level (1·3 × 1014 vector genomes [vg]/kg bodyweight) of resamirigene bilparvovec or delayed treatment, then, for later participants, to either a higher dose (3·5 × 1014 vg/kg bodyweight) of resamirigene bilparvovec or delayed treatment. Part 2 was intended to confirm the dose selected in part 1. Resamirigene bilparvovec was administered as a single intravenous infusion. An untreated control group comprised boys who participated in a run-in study (INCEPTUS; NCT02704273) or those in the delayed treatment cohort who did not receive any dose. The primary efficacy outcome was the change from baseline to week 24 in hours of daily ventilator support. After three unexpected deaths, dosing at the higher dose was stopped and the two-part feature of the study design was eliminated. Because of changes to the study design during its implementation, analyses were done on an as-treated basis and are deemed exploratory. All treated and control participants were included in the safety analysis. The trial is registered with ClinicalTrials.gov, NCT03199469. Outcomes are reported as of Feb 28, 2022. ASPIRO is currently paused while deaths in dosed participants are investigated. FINDINGS: Between Aug 3, 2017 and June 1, 2021, 30 participants were screened for eligibility, of whom 26 were enrolled; six were allocated to the lower dose, 13 to the higher dose, and seven to delayed treatment. Of the seven children whose treatment was delayed, four later received the higher dose (n=17 total in the higher dose cohort), one received the lower dose (n=7 total in the lower dose cohort), and two received no dose and joined the control group (n=14 total, including 12 children from INCEPTUS). Median age at dosing or enrolment was 12·1 months (IQR 10·0-30·9; range 9·5-49·7) in the lower dose cohort, 31·1 months (16·0-64·7; 6·8-72·7) in the higher dose cohort, and 18·7 months (10·1-31·5; 5·9-39·3) in the control cohort. Median follow-up was 46·1 months (IQR 41·0-49·5; range 2·1-54·7) for lower dose participants, 27·6 months (24·6-29·1; 3·4-41·0) for higher dose participants, and 28·3 months (9·7-46·9; 5·7-32·7) for control participants. At week 24, lower dose participants had an estimated 77·7 percentage point (95% CI 40·22 to 115·24) greater reduction in least squares mean hours per day of ventilator support from baseline versus controls (p=0·0002), and higher dose participants had a 22·8 percentage point (6·15 to 39·37) greater reduction from baseline versus controls (p=0·0077). One participant in the lower dose cohort and three in the higher dose cohort died; at the time of death, all children had cholestatic liver failure following gene therapy (immediate causes of death were sepsis; hepatopathy, severe immune dysfunction, and pseudomonal sepsis; gastrointestinal haemorrhage; and septic shock). Three individuals in the control group died (haemorrhage presumed related to hepatic peliosis; aspiration pneumonia; and cardiopulmonary failure). INTERPRETATION: Most children with X-linked myotubular myopathy who received MTM1 gene replacement therapy had important improvements in ventilator dependence and motor function, with more than half of dosed participants achieving ventilator independence and some attaining the ability to walk independently. Investigations into the risk for underlying hepatobiliary disease in X-linked myotubular myopathy, and the need for monitoring of liver function before gene replacement therapy, are ongoing. FUNDING: Astellas Gene Therapies.

Biodistribution of Adeno-Associated Virus Gene Therapy Following Cerebrospinal Fluid-Directed Administration.

Adeno-associated virus (AAV)-based gene therapies, exemplified by the approved therapy for spinal muscular atrophy, have the potential to deliver disease-course-altering treatments for central nervous system (CNS) indications. However, several clinical trials have reported severe adverse events, including patient deaths following high-dose systemic administration for muscle-directed gene transfer, highlighting the need to explore approaches utilizing lower doses when targeting the CNS. Animal models of disease provide insight into the response to new AAV therapies. However, translation from small to larger animals and eventually to humans is hampered by anatomical and biological differences across the species and their impact on AAV delivery. We performed a literature review of preclinical studies of AAV gene therapy biodistribution following cerebrospinal fluid (CSF) delivery (intracerebroventricular, intra-cisterna magna, and intrathecal lumbar). The reviewed literature varies greatly in the reported biodistribution of AAV following administration into the CSF. Differences between studies, including animal model, vector serotype used, method used to assess biodistribution, and route of administration, among other variables, contribute to differing outcomes and difficulties in translating these preclinical results. For example, only half of the published AAV-based gene therapy studies report vector copy number, the most direct readout following administration of a vector; none of these studies reported details such as the empty:full capsid ratio and quality of encapsidated genome. Analysis of the last decade's literature focusing on AAV-based gene therapies targeting the CNS underscores limitations of the body of knowledge and room for continued research. In particular, there is a need to understand the biodistribution achieved by different CSF-directed routes of administration and determining if specific cell types/structures of interest will be transduced. Our findings point to a clear need for a more systematic approach across the field to align the assessments and elements reported in preclinical research to enable more reliable translation across animal models and into human studies.

SLC13A5 Deficiency Disorder: From Genetics to Gene Therapy.

Epileptic encephalopathies may arise from single gene variants. In recent years, next-generation sequencing technologies have enabled an explosion of gene identification in monogenic epilepsies. One such example is the epileptic encephalopathy SLC13A5 deficiency disorder, which is caused by loss of function pathogenic variants to the gene SLC13A5 that results in deficiency of the sodium/citrate cotransporter. Patients typically experience seizure onset within the first week of life and have developmental delay and intellectual disability. Current antiseizure medications may reduce seizure frequency, yet more targeted treatments are needed to address the epileptic and non-epileptic features of SLC13A5 deficiency disorder. Gene therapy may offer hope to these patients and better clinical outcomes than current available treatments. Here, we discuss SLC13A5 genetics, natural history, available treatments, potential outcomes and assessments, and considerations for translational medical research for an AAV9-based gene replacement therapy.

Immune Responses and Immunosuppressive Strategies for Adeno-Associated Virus-Based Gene Therapy for Treatment of Central Nervous System Disorders: Current Knowledge and Approaches.

Adeno-associated viruses (AAVs) are being increasingly used as gene therapy vectors in clinical studies especially targeting central nervous system (CNS) disorders. Correspondingly, host immune responses to the AAV capsid or the transgene-encoded protein have been observed in various clinical and preclinical studies. Such immune responses may adversely impact patients' health, prevent viral transduction, prevent repeated dosing strategies, eliminate transduced cells, and pose a significant barrier to the potential effectiveness of AAV gene therapy. Consequently, multiple immunomodulatory strategies have been used in attempts to limit immune-mediated responses to the vector, enable readministration of AAV gene therapy, prevent end-organ toxicity, and increase the duration of transgene-encoded protein expression. Herein we review the innate and adaptive immune responses that may occur during CNS-targeted AAV gene therapy as well as host- and treatment-specific factors that could impact the immune response. We also summarize the available preclinical and clinical data on immune responses specifically to CNS-targeted AAV gene therapy and discuss potential strategies for incorporating prophylactic immunosuppression regimens to circumvent adverse immune responses.

Gene Therapy: Novel Approaches to Targeting Monogenic Epilepsies.

Genetic epilepsies are a spectrum of disorders characterized by spontaneous and recurrent seizures that can arise from an array of inherited or de novo genetic variants and disrupt normal brain development or neuronal connectivity and function. Genetically determined epilepsies, many of which are due to monogenic pathogenic variants, can result in early mortality and may present in isolation or be accompanied by neurodevelopmental disability. Despite the availability of more than 20 antiseizure medications, many patients with epilepsy fail to achieve seizure control with current therapies. Patients with refractory epilepsy-particularly of childhood onset-experience increased risk for severe disability and premature death. Further, available medications inadequately address the comorbid developmental disability. The advent of next-generation gene sequencing has uncovered genetic etiologies and revolutionized diagnostic practices for many epilepsies. Advances in the field of gene therapy also present the opportunity to address the underlying mechanism of monogenic epilepsies, many of which have only recently been described due to advances in precision medicine and biology. To bring precision medicine and genetic therapies closer to clinical applications, experimental animal models are needed that replicate human disease and reflect the complexities of these disorders. Additionally, identifying and characterizing clinical phenotypes, natural disease course, and meaningful outcome measures from epileptic and neurodevelopmental perspectives are necessary to evaluate therapies in clinical studies. Here, we discuss the range of genetically determined epilepsies, the existing challenges to effective clinical management, and the potential role gene therapy may play in transforming treatment options available for these conditions.

INCEPTUS Natural History, Run-in Study for Gene Replacement Clinical Trial in X-Linked Myotubular Myopathy.

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a life-threatening congenital myopathy that, in most cases, is characterized by profound muscle weakness, respiratory failure, need for mechanical ventilation and gastrostomy feeding, and early death. OBJECTIVE: We aimed to characterize the neuromuscular, respiratory, and extramuscular burden of XLMTM in a prospective, longitudinal study. METHODS: Thirty-four participants < 4 years old with XLMTM and receiving ventilator support enrolled in INCEPTUS, a prospective, multicenter, non-interventional study. Disease-related adverse events, respiratory and motor function, feeding, secretions, and quality of life were assessed. RESULTS: During median (range) follow-up of 13.0 (0.5, 32.9) months, there were 3 deaths (aspiration pneumonia; cardiopulmonary failure; hepatic hemorrhage with peliosis) and 61 serious disease-related events in 20 (59%) participants, mostly respiratory (52 events, 18 participants). Most participants (80%) required permanent invasive ventilation (>16 hours/day); 20% required non-invasive support (6-16 hours/day). Median age at tracheostomy was 3.5 months (95% CI: 2.5, 9.0). Thirty-three participants (97%) required gastrostomy. Thirty-one (91%) participants had histories of hepatic disease and/or prospectively experienced related adverse events or laboratory or imaging abnormalities. CHOP INTEND scores ranged from 19-52 (mean: 35.1). Seven participants (21%) could sit unsupported for≥30 seconds (one later lost this ability); none could pull to stand or walk with or without support. These parameters remained static over time across the INCEPTUS cohort. CONCLUSIONS: INCEPTUS confirmed high medical impact, static respiratory, motor and feeding difficulties, and early death in boys with XLMTM. Hepatobiliary disease was identified as an under-recognized comorbidity. There are currently no approved disease-modifying treatments.

Use of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) in X-Linked Myotubular Myopathy: Content Validity and Psychometric Performance.

X-linked myotubular myopathy (XLMTM) is a life-threatening, congenital myopathy characterized by extreme hypotonia, weakness, delayed motor milestones, and respiratory failure, often resulting in pediatric mortality. This study evaluated the content validity and psychometric performance of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders as a measure of neuromuscular functioning in children with X-linked myotubular myopathy. This study was conducted in two phases. Phase I assessed the content validity of the measure for use in an XLMTM pediatric population through: literature review, clinical expert interviews, caregiver interviews, and a modified-Delphi panel among clinicians. Phase II assessed psychometric performance based on the INCEPTUS observational clinical study and the ASPIRO interventional gene therapy study, including tests of reliability (internal consistency, test-retest, and interrater), validity (construct and criterion), and responsiveness based on observational and interventional clinical trial data analyses. Data established construct validity and reliability of the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders among XLMTM patients before administration of resamirigene bilparvovec, and sensitivity to study drug administration as evidenced by the significant post-administration response in ASPIRO. Findings support the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders as an appropriate neuromuscular functioning assessment in a pediatric X-linked myotubular myopathy patient population.

Disease burden of Crigler-Najjar syndrome: Systematic review and future perspectives.

BACKGROUND AND AIM: Crigler-Najjar syndrome (CNS) results from biallelic mutations of UGT1A1 causing partial or total loss of uridine 5'-diphosphate glucuronyltransferase activity leading to unconjugated hyperbilirubinemia and its attendant risk for irreversible neurological injury (kernicterus). CNS is exceedingly rare and has been only partially characterized through relatively small studies, each comprising between two and 57 patients. METHODS: A systematic literature review was conducted to consolidate data on the patient, caregiver, and societal burden of CNS. RESULTS: Twenty-eight articles on clinical aspects of CNS were identified, but no published data on its humanistic or economic burden were found. In patients with complete UGT1A1 deficiency (type 1 CNS [CNS-I]), unconjugated bilirubin levels increase 3-6 mg/dL/day during the newborn period and reach neurologically dangerous levels between 5 and 14 days of age. Phototherapy is the mainstay of treatment but poses significant challenges to patients and their families. Despite consistent phototherapy, patients with CNS-I have worsening hyperbilirubinemia with advancing age. Liver transplantation is the only definitive therapy for CNS-I and is increasingly associated with excellent long-term survival but also incurs high costs, medical and surgical morbidities, and risks of immunosuppression. CONCLUSIONS: Crigler-Najjar syndrome is associated with a substantial burden, even with existing standards of care. The development of novel disease-modifying therapies has the potential to reduce disease burden and improve the lives of CNS patients and their families.

Mortality and respiratory support in X-linked myotubular myopathy: a RECENSUS retrospective analysis.

PURPOSE: Individuals with X-linked myotubular myopathy (XLMTM) who survive infancy require extensive supportive care, including ventilator assistance, wheelchairs and feeding tubes. Half die before 18 months of age. We explored respiratory support and associated mortality risk in RECENSUS, particularly among patients ≤5 years old who received respiratory support at birth; this subgroup closely matches patients in the ASPIRO trial of gene therapy for XLMTM. DESIGN: RECENSUS is an international, retrospective study of patients with XLMTM. Descriptive and time-to-event analyses examined survival on the basis of age, respiratory support, tracheostomy use, predicted mutational effects and life-sustaining care. RESULTS: Outcomes for 145 patients were evaluated. Among 126 patients with respiratory support at birth, mortality was 47% overall and 59% among those ≤5 years old. Median survival time was shorter for patients ≤5 years old than for those >5 years old (2.2 years (IQR 0.7-5.6) vs 30.2 years (IQR 19.4-30.2)). The most common cause of death was respiratory failure (66.7%). Median survival time was longer for patients with a tracheostomy than for those without (22.8 years (IQR 8.7-30.2) vs 1.8 years (IQR 0.2-not estimable)). The proportion of patients living without a tracheostomy was 50% at age 6 months and 28% at age 2 years. Median survival time was longer with provision of life-sustaining care than without (19.4 years (IQR 3.1-not estimable) vs 0.2 years (IQR 0.1-2.1)). CONCLUSIONS: High mortality, principally due to respiratory failure, among patients with XLMTM ≤5 years old despite respiratory support underscores the need for early diagnosis, informed decision-making and disease-modifying therapies. TRIAL REGISTRATION NUMBER: NCT02231697.

A Systematic Review of the Health Economics of Pompe Disease.

BACKGROUND: Pompe disease is a rare, severe neuromuscular disease with high mortality and substantial clinical and humanistic burden. However, the economic burden of Pompe disease and the health economic value of its treatments are not well understood. The objectives of this systematic review were to characterize the health economic evidence on Pompe disease, including healthcare resource use and costs (direct and indirect), health utilities, and the cost-effectiveness of current treatments used to manage patients with Pompe disease. METHODS: A systematic search of MEDLINE® and Embase® was performed to retrieve publications on the health economics of Pompe disease. Publications were screened according to predefined criteria, extracted, and quality assessed using the Newcastle-Ottawa Scale. Data were narratively synthesized. RESULTS: Eight publications evaluated patients with infantile-onset Pompe disease (IOPD) (two studies), late-onset Pompe disease (LOPD) (four studies), or both (two studies). In IOPD, total cost of supportive therapy (excluding treatment) was €32,871 (equivalent to US$41,667 when adjusted for currency and inflation to 2017 US dollars) over a life expectancy of 0.4 years. In adult LOPD, the average annual cost per patient of supportive therapy was €22,475 (adjusted $28,489). Resource use in LOPD was high, with nursing home admissions accounting for 19% of annual direct medical costs. Health economic evaluations estimating incremental costs per quality-adjusted life year (QALY) gained with enzyme-replacement therapy (ERT) versus supportive therapy ranged from £109,991 (adjusted, $186,851) per QALY gained in Columbia to €1,043,868 (adjusted, $1,323,207) in the Netherlands. DISCUSSION: Despite a full systematic literature search, only eight relevant publications were identified, most of which were of relatively poor quality. However, a significant economic burden of Pompe disease on patients, families, healthcare systems, and society was found, with the majority of costs driven by the only currently approved treatment, ERT. Health economic evaluations of ERT versus supportive therapy vary significantly, with the majority well above willingness-to-pay thresholds. New therapies and approaches to care are needed to address the persistent and lifelong economic burden of Pompe disease and the large incremental cost-effectiveness ratios observed.

A multicenter, retrospective medical record review of X-linked myotubular myopathy: The recensus study.

INTRODUCTION: X-linked myotubular myopathy (XLMTM), characterized by severe hypotonia, weakness, respiratory distress, and early mortality, is rare and natural history studies are few. METHODS: RECENSUS is a multicenter chart review of male XLMTM patients characterizing disease burden and unmet medical needs. Data were collected between September 2014 and June 2016. RESULTS: Analysis included 112 patients at six clinical sites. Most recent patient age recorded was ≤18 months for 40 patients and >18 months for 72 patients. Mean (SD) age at diagnosis was 3.7 (3.7) months and 54.3 (77.1) months, respectively. Mortality was 44% (64% ≤18 months; 32% >18 months). Premature delivery occurred in 34/110 (31%) births. Nearly all patients (90%) required respiratory support at birth. In the first year of life, patients underwent an average of 3.7 surgeries and spent 35% of the year in the hospital. DISCUSSION: XLMTM is associated with high mortality, disease burden, and healthcare utilization. Muscle Nerve 57: 550-560, 2018.

The humanistic burden of Pompe disease: are there still unmet needs? A systematic review.

BACKGROUND: Humanistic burden considers the impact of an illness on a patient's health-related quality of life (HRQoL), activities of daily living (ADL), caregiver health, and caregiver QoL. Humanistic burden also considers treatment satisfaction and adherence to treatment regimens. Pompe disease is an autosomal recessive, progressive, multisystemic neuromuscular disease. Approval of enzyme-replacement therapy (ERT) markedly improved prognosis for patients, but considerable morbidity and a substantial humanistic burden remain. This article characterizes the humanistic burden of Pompe disease through a systematic literature review. METHODS: A systematic search of MEDLINE® and Embase® with back-referencing and supplementary literature searches was performed to retrieve data from interventional and non-interventional studies on the humanistic burden of Pompe disease. Publications were screened according to predefined criteria, extracted, and assessed for quality. Extracted data were narratively synthesized. RESULTS: No publications on the humanistic burden of infantile-onset Pompe disease (IOPD) were identified. As such, of 17 publications included here, all are in patients with late-onset Pompe disease (LOPD). Thirteen publications were initiated after approval of ERT, two were initiated before, and two overlapped the approval of ERT. The review shows that LOPD patients have a significantly lower HRQoL than the general population, even if treated with ERT. On transitioning to ERT, treatment was associated with improvement in the physical component score of the SF-36 and fatigue, although the SF-36 mental component score remained stable. Physical HRQoL remained below population norms after 4 years of ERT. Significantly more ERT-treated patients reported pain than controls, and bodily pain worsened in later years following ERT initiation. Treatment-naïve LOPD patients had significantly poorer ADL functioning compared with the general population, although ERT stabilized deteriorating functioning impairment. ERT studies showed caregivers provide 17.7 h/week informal care on average. Fifty percent, 40% and <20% of caregivers reported mental health, physical health, and financial/relational problems, respectively. In ERT-naïve patients, wheelchair use and home ventilatory support was associated with lower physical HRQoL and ADL functioning. In ERT-treated patients, key factors predicting worse HRQoL and ADL functioning were higher respiratory distress, poorer sleep quality, greater pain, and more fatigue. CONCLUSIONS: Pompe disease has a substantial humanistic burden, with strong inter-relationships among and between humanistic burden parameters and clinical progression.

Systematic Review and Meta-Analysis of Neuropsychiatric Symptoms and Executive Functioning in Adults With Phenylketonuria.

This systematic review and meta-analysis (MA) investigates the impact of elevated blood phenylalanine (Phe) on neuropsychiatric symptoms in adults with phenylketonuria (PKU). The meta-analysis of PKU is challenging because high-quality evidence is lacking due to the limited number of affected individuals and few placebo-controlled, double-blind studies of adults with high and low blood Phe. Neuropsychiatric symptoms associated with PKU exceed general population estimates for inattention, hyperactivity, depression, and anxiety. High Phe is associated with an increased prevalence of neuropsychiatric symptoms and executive functioning deficits whereas low Phe is associated with improved neurological performance. Findings support lifelong maintenance of low blood Phe.

Skeletal Muscle Pathology in X-Linked Myotubular Myopathy: Review With Cross-Species Comparisons.

X-linked myotubular myopathy (XLMTM) is a devastating, rare, congenital myopathy caused by mutations in the MTM1 gene, resulting in a lack of or dysfunction of the enzyme myotubularin. This leads to severe perinatal weakness and distinctive muscle pathology. It was originally thought that XLMTM was related to developmental arrest in myotube maturation; however, the generation and characterization of several animal models have significantly improved our understanding of clinical and pathological aspects of this disorder. Myotubularin is now known to participate in numerous cellular processes including endosomal trafficking, excitation-contraction coupling, cytoskeletal organization, neuromuscular junction structure, autophagy, and satellite cell proliferation and survival. The available vertebrate models of XLMTM, which vary in severity from complete absence to reduced functional levels of myotubularin, recapitulate features of the human disease to a variable extent. Understanding how pathological endpoints in animals with XLMTM translate to human patients will be essential to interpret preclinical treatment trials and translate therapies into human clinical studies. This review summarizes the published animal models of XLMTM, including those of zebrafish, mice, and dogs, with a focus on their pathological features as compared to those seen in human XLMTM patients.

Content Validity of the ADHD Rating Scale (ADHD RS-IV) and Adult ADHD Self-Report Scale (ASRS) in Phenylketonuria

Abstract The ADHD Rating Scale (ADHD RS-IV; parent report) and Adult ADHD Self-Rating Scale (ASRS; self-report) are validated instruments for measuring symptoms of attention-deficit/hyperactivity disorder (ADHD). The objectives of this study were to elicit descriptions of phenylketonuria (PKU) symptoms and assess content validity of these instruments in PKU. Parents (N = 15) of children with PKU (?8 years old) and adults with PKU (N=13) described PKU-related symptoms and commented on the scale's clarity, comprehensiveness, and relevance to their experience with PKU. Most of the adults (84.6%) and all of the children were on a phenylalanine-restricted diet, according to respondent report. The inattentiveness symptoms reported by participants mapped to the inattentive items of the questionnaires. Most participants felt the inattentive items were clear and relevant to their experience. Despite study design limitations, these results demonstrate the relevance of assessing inattentiveness in PKU, and both instruments achieved content validity for inattentive subscale items.

Evaluation of Neuropsychiatric Function in Phenylketonuria: Psychometric Properties of the ADHD Rating Scale-IV and Adult ADHD Self-Report Scale Inattention Subscale in Phenylketonuria.

BACKGROUND: Previous qualitative research among adults and parents of children with phenylketonuria (PKU) has identified inattention as an important psychiatric aspect of this condition. The parent-reported ADHD Rating Scale-IV (ADHD RS-IV) and the Adult ADHD Self-Report Scale (ASRS) have been validated for measuring inattention symptoms in persons with attention-deficit/hyperactivity disorder (ADHD); however, their psychometric attributes for measuring PKU-related inattention have not been established. OBJECTIVE: The primary objective of this investigation was to demonstrate the reliability, validity, and responsiveness of the ADHD RS-IV and ASRS inattention symptoms subscales in a randomized controlled trial of patients with PKU aged 8 years or older. METHODS: A post hoc analysis investigated the psychometric properties (Rasch model fit, reliability, construct validity, and responsiveness) of the ADHD RS-IV and ASRS inattention subscales using data from a phase 3b, double-blind, placebo-controlled clinical trial in those with PKU aged 8 years or older. RESULTS: The Rasch results revealed good model fit, and reliability analyses revealed strong internal consistency reliability (α ≥ 0.87) and reproducibility (intraclass correlation coefficient ≥ 0.87) for both measures. Both inattention measures demonstrated the ability to discriminate between known groups (P < 0.001) created by the Clinical Global Impression-Severity scale. Correlations between the ADHD RS-IV and the ASRS with the Clinical Global Impression-Severity scale and the age-appropriate Behavior Rating Inventory of Executive Function Working Memory subscale were consistently moderate to strong (r ≥ 0.56). Similarly, results of the change score correlations were of moderate magnitude (r ≥ 0.43) for both measures when compared with changes over time in Behavior Rating Inventory of Executive Function Working Memory subscales. CONCLUSIONS: These findings of reliability, validity, and responsiveness of both the ADHD RS-IV and the ASRS inattention scales, in addition to content validation results, support their use for the assessment of inattention symptoms among persons with PKU aged 8 years or older in both clinical and research settings.

Long-term developmental progression in infants and young children taking sapropterin for phenylketonuria: a two-year analysis of safety and efficacy.

PURPOSE: Sapropterin is an oral synthetic formulation of tetrahydrobiopterin prescribed as adjunctive therapy for phenylketonuria. The efficacy of sapropterin in reducing blood phenylalanine levels has been demonstrated in clinical studies of individuals with phenylketonuria older than 4 years of age. Its effect on neurocognitive functioning in younger children has not been examined. METHODS: A 2-year interim analysis of blood phenylalanine levels, prescribed dietary phenylalanine intake, and neurocognitive functioning was performed in children who started receiving sapropterin at 0-6 years of age and responded with a ≥30% mean blood phenylalanine reduction. Children were evaluated at baseline and 2-year follow-up. RESULTS: Sapropterin had a favorable safety profile and lowered blood phenylalanine levels with increased prescribed dietary phenylalanine intakes. Mean full-scale intelligence quotient was 103 ± 12 at baseline and 104 ± 10 at 2-year follow-up (P = 0.50, paired t-test, n = 25). For children younger than 30 months of age, the cognitive composite score from the Bayley Scales of Infant and Toddler Development, Third Edition, remained within the average range. CONCLUSION: Sapropterin had a favorable safety profile, was effective in lowering blood phenylalanine levels while clinically requiring dietary adjustment, resulting in increased phenylalanine intake, and preserved neurocognitive performance in children who started therapy between 0 and 6 years of age.

Phenylketonuria Scientific Review Conference: state of the science and future research needs.

New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360 µmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360 µmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.

Recommendations for the use of sapropterin in phenylketonuria.

Phenylketonuria (PKU) is an inherited disorder of phenylalanine (Phe) metabolism. Until recently, the only treatment for PKU was a Phe-restricted diet. Increasing evidence of suboptimal outcomes in diet-treated individuals, inconsistent PKU management practices, and the recent availability of tetrahydrobiopterin (BH(4)) therapy have fueled the need for new management and treatment recommendations for this metabolic disorder. BH(4), now available as sapropterin dihydrochloride (sapropterin), may offer the potential for improved metabolic control as well as enhanced dietary Phe tolerance in some PKU patients. A group of metabolic dietitians from North America convened in June 2011 to draft recommendations for the use of sapropterin therapy in PKU. Physicians with extensive experience in PKU management were invited at a later date to contribute to the development of these recommendations. Based on extensive clinical experience and current evidence, the present recommendations provide guidance from patient selection and determination of sapropterin response to the long-term management of patients on sapropterin therapy. Target Phe levels, nutritional adequacy, neurocognitive screening and adherence to treatment are addressed to optimize patient outcomes.