Presymptomatic Treatment Research Articles

Newborn screening and rapid genomic diagnosis of neuromuscular diseases

Background In recent years, treatments have been approved for certain neuromuscular diseases. In some cases, early pre-symptomatic treatment is necessary for optimal response, and thus newborn screening is critical. Objective To review the current status of newborn screening programs for neuromuscular diseases and early diagnosis through genetic testing. Methods Following the PRISMA guidelines, a literature search was performed on PubMed for screening of neuromuscular diseases; the search was conducted on literature available as of 1 May 2024. Results Included were 77 articles on newborn screening for seven diseases: spinal muscular atrophy (19 studies), Duchenne muscular dystrophy (15), Pompe disease (20), X-linked adrenoleukodystrophy (14), Krabbe disease (6), metachromatic leukodystrophy (2), and myotonic dystrophy 1 (1). Ten articles on rapid genomic diagnosis were identified. Conclusion Since 2021, newborn screening programs for neuromuscular diseases have been established, notably in X-linked adrenoleukodystrophy, spinal muscular atrophy, Pompe disease, and Duchenne Muscular Dystrophy. Even in diseases where treatment is currently not life-changing, such as Krabbe disease, new newborn screening programs continue to be implemented, especially in the USA. The use of genetic diagnostic tests does not yet appear to be widespread or at least not widely reported. As new treatments become available, genomic newborn screening programs will need to be rapidly and broadly implemented.

Cost-utility analysis of newborn screening for spinal muscular atrophy in Japan

ABSTRACT Aims Spinal muscular atrophy (SMA) is a rare genetic disorder characterized by progressive muscle weakness, atrophy, respiratory failure, and in severe cases, infantile death. Early detection and treatment before symptom onset may substantially improve outcomes, allowing patients to achieve age-appropriate motor milestones and longer survival. We assessed the cost-utility of newborn screening (NBS) for SMA in Japan. Materials and Methods A cost-utility model (decision tree and Markov model) compared lifetime health effects and costs between “NBS” for SMA (presymptomatic treatment) or “no NBS” (treatment initiated at symptom onset). Model inputs were sourced from literature, local data, and expert opinion. Sensitivity and scenario analyses were conducted to assess model robustness and data validity. Results Based on the 1:10,000 SMA incidence, it was estimated that 43 newborns/year would have SMA, and a total of 39 patients with SMA would initiate presymptomatic treatment after NBS. An estimated 736 quality-adjusted life-years were gained per annual birth cohort with NBS. NBS for SMA was dominant compared with no NBS (i.e., less costly and more effective), with ¥8,856,960,096 reduced total costs with NBS versus no NBS (base-case). Sensitivity and scenario analyses supported cost effectiveness of NBS for SMA versus no NBS. A greater percentage of patients was estimated to enjoy longer survival and be without permanent assisted ventilation with NBS versus no NBS. Limitations Real-world observations may differ from single-arm clinical trial outcomes. It was assumed that patients with SMA identified via NBS were asymptomatic and would receive treatment prior to symptoms. Best supportive care was not considered, and Japan-specific variations in gene replacement therapy protocol were not fully reflected. Conclusion NBS for SMA allows for early identification of patients with SMA and treatment initiation before symptom onset, improving health outcomes and reducing total costs than without NBS.

Phenotypic and Genetic Spectrum in 309 Consecutive Pediatric Patients with Inherited Retinal Disease.

Inherited retinal dystrophies (IRDs) are a common cause of blindness or severe visual impairment in children and may occur with or without systemic associations. The aim of the present study is to describe the phenotypic and genotypic spectrum of IRDs in a pediatric patient cohort in Retrospective single-center cross-sectional analysis. Presenting symptoms, clinical phenotype, and molecular genetic diagnosis were assessed in 309 pediatric patients with suspected IRD. Patients were grouped by age at genetic diagnosis (preschool: 0-6 years, n = 127; schoolchildren: 7-17 years, n = 182). Preschool children most frequently presented with nystagmus (34.5% isolated, 16.4% syndromic), no visual interest (20.9%; 14.5%), or nyctalopia (22.4%; 3.6%; p < 0.05); schoolchildren most frequently presented with declining visual acuity (31% isolated, 21.1% syndromic), nyctalopia (10.6%; 13.5%), or high myopia (5.3%; 13.2%). Pathogenic variants were identified in 96 different genes (n = 69 preschool, n = 73 schoolchildren). In the preschool group, 57.4% had isolated and 42.6% had syndromic IRDs, compared to 70.9% and 29.1% in schoolchildren. In the preschool group, 32.4% of the isolated IRDs were related to forms of Leber's congenital amaurosis (most frequent were RPE65 (11%) and CEP290 (8.2%)), 31.5% were related to stationary IRDs, 15.1% were related to macular dystrophies (ABCA4, BEST1, PRPH2, PROM1), and 8.2% to rod-cone dystrophies (RPGR, RPB3, RP2, PDE6A). All rod-cone dystrophies (RCDs) were subjectively asymptomatic at the time of genetic diagnosis. At schoolage, 41% were attributed to cone-dominated disease (34% ABCA4), 10.3% to BEST1, and 10.3% to RCDs (RP2, PRPF3, RPGR; IMPG2, PDE6B, CNGA1, MFRP, RP1). Ciliopathies were the most common syndromic IRDs (preschool 37%; schoolchildren 45.1%), with variants in USH2A, CEP290 (5.6% each), CDH23, BBS1, and BBS10 (3.7% each) being the most frequent in preschoolers, and USH2A (11.7%), BBS10 (7.8%), CEP290, CDHR23, CLRN1, and ICQB1 (3.9% each) being the most frequent in syndromic schoolkids. Vitreoretinal syndromic IRDs accounted for 29.6% (preschool: COL2A1, COL11A1, NDP (5.6% each)) and 23.5% (schoolage: COL2A1, KIF11 (9.8% each)), metabolic IRDs for 9.4% (OAT, HADHA, MMACHD, PMM2) and 3.9% (OAT, HADHA), mitochondriopathies for 3.7% and 7.8%, and syndromic albinism accounted for 5.6% and 3.9%, respectively. In conclusion we show here that the genotypic spectrum of IRDs and its quantitative distribution not only differs between children and adults but also between children of different age groups, with an almost equal proportion of syndromic and non-syndromic IRDs in early childhood. Ophthalmic screening visits at the preschool and school ages may aid even presymptomatic diagnosis and treatment of potential sight and life-threatening systemic sequelae.

Promises and challenges of genomic newborn screening (NBS) - lessons from public health NBS programs.

Newborn screening (NBS) in the United States began in the 1960s to detect inborn errors of metabolism that benefited from presymptomatic treatment compared with treatment after the development of symptoms and diagnosis. Over time, it expanded to include endocrinological disorders, hematological disorders, immunodeficiencies, and other treatable diseases such as lysosomal storage diseases (LSD), cystic fibrosis, X-linked adrenoleukodystrophy, and spinal muscular dystrophy. This expansion has been driven by new technologies (e.g., tandem mass spectrometry) and novel treatments (e.g., enzyme replacement therapy and stem cell transplant for LSDs). Advances in next-generation gene sequencing (NGS) enable rapid identification of many additional conditions that might benefit from early presymptomatic intervention. We review the NGS technologies that evolved as diagnostic testing and suggest issues to be resolved before their potential application to screening the asymptomatic population. We illustrate the importance of selecting diseases to be screened and propose recommendations to follow when variants of uncertain significance are found. We address ethical issues around achieving equity in the sensitivity of genomic NBS, access to follow-up and management, especially for people from diverse backgrounds, and other considerations. Finally, we discuss the potential benefits and harms of genomic NBS to the overall health of children with monogenic diseases. IMPACT: Genomic newborn screening programs are ongoing worldwide. Public discussion is needed as to whether genomic newborn screening should be offered as a public health program and, if so, what conditions should be screened for. Providers should understand that the sensitivity of genomic newborn screening is especially low for newborns from non-European populations. Methylation, large structural variants and repeat expansion variants are not amenable to next-generation sequencing-based genomic newborn screening. The article serves as a comprehensive guide to understanding issues that need to be solved before genomic newborn screening is implemented as a public health program.

Early Intervention services in the era of genomic medicine: setting a research agenda.

Newborn genomic sequencing (NBSeq) has the potential to substantially improve early detection of rare genetic conditions, allowing for pre-symptomatic treatment to optimize outcomes. Expanding conceptions of the clinical utility of NBSeq include earlier access to behavioral early intervention to support the acquisition of core motor, cognitive, communication, and adaptive skills during critical windows in early development. However, important questions remain about equitable access to early intervention programs for the growing number of infants identified with a genetic condition via NBSeq. We review the current NBSeq public health, clinical, and research landscape, and highlight ongoing international research efforts to collect population-level data on the utility of NBSeq for healthy newborns. We then explore the challenges facing a specific Early Intervention (EI) system-the US federally supported "Part C" system-for meeting the developmental needs of young children with genetic diagnoses, including structural limitations related to funding, variable eligibility criteria, and lack of collaboration with newborn screening programs. We conclude with a set of questions to guide future research at the intersection of NBSeq, newborn screening, and EI, which once answered, can steer future policy to ensure that EI service systems can optimally support the developmental needs of infants impacted by broader implementation of NBSeq. IMPACT: Existing literature on the clinical benefits of genome sequencing in newborns tends to focus on earlier provision of medical interventions, with less attention to the ongoing developmental needs of very young children with genetic conditions. This review outlines the developmental needs of a growing number of children diagnosed with genetic conditions in infancy and describes the strengths and limitations of the United States Early Intervention system (IDEA Part C) for meeting those needs.

Cost-Effectiveness Analysis of Newborn Screening for Spinal Muscular Atrophy in Italy.

A decision-analytic model assessed the cost effectiveness of newborn screening from the National Health Service perspective in 400,000 newborns. Newborn screening enabling early identification and presymptomatic treatment of SMA was compared with no newborn screening, symptomatic diagnosis, and treatment. Transition probabilities between health states were estimated from clinical trial data. Higher-functioning health states were associated with increased survival, higher utility values, and lower costs. Long-term survival and utilities were extrapolated from scientific literature. Health care costs were collected from official Italian sources. A lifetime time horizon was applied, and costs and outcomes were discounted at an annual rate of 3%. Deterministic and probabilistic sensitivity analyses were conducted. Newborn screening followed by presymptomatic treatment yielded 324 incremental life-years, 390 incremental quality-adjusted life-years, and reduced costs by €1,513,375 over a lifetime time horizon compared with no newborn screening. Thus, newborn screening was less costly and more effective than no newborn screening. Newborn screening has a 100% probability of being cost effective, assuming a willingness-to-pay threshold of >€40,000. Newborn screening followed by presymptomatic SMA treatment is cost effective from the Italian National Health Service perspective.

Systematic Review of Presymptomatic Treatment for Spinal Muscular Atrophy.

Spinal muscular atrophy (SMA) causes the degeneration of motor neurons in the spinal cord. Treatments including nusinersen, risdiplam, and onasemnogene abeparvovec have been shown to be effective in reducing symptoms, with recent studies suggesting greater effectiveness when treatment is initiated in the presymptomatic stage. This systematic review synthesises findings from prospective studies of presymptomatic treatment for 5q SMA published up to December 2023. The review identified three single-arm interventional studies of presymptomatic treatment (NURTURE, RAINBOWFISH, and SPR1NT), six observational studies comparing presymptomatic or screened cohorts versus symptomatic cohorts, and twelve follow-up studies of screened cohorts only (i.e., babies identified via newborn screening for SMA). Babies with three SMN2 copies met most motor milestones in the NURTURE study of nusinersen and in the SPR1NT study of onasemnogene abeparvovec. Babies with two SMN2 copies in these two studies met most motor milestones but with some delays, and some required ventilatory or feeding support. The RAINBOWFISH study of risdiplam is ongoing. Naïve comparisons of presymptomatic treatment in SPR1NT, versus untreated or symptomatic treatment cohorts, suggested improved outcomes in patients treated presymptomatically. Comparative observational studies supported the finding that presymptomatic treatment, and early treatment following screening, may improve outcomes compared with treatment at the symptomatic stage. Further research should assess the long-term clinical outcomes and cost-effectiveness of presymptomatic treatment for SMA.

Hematopoietic stem cell transplantation leads to biochemical and functional correction in two mouse models of acid ceramidase deficiency

Farber disease (FD) and spinal muscular atrophy with progressive myoclonic epilepsy (SMA-PME) are ultra-rare lysosomal storage disorders caused by deficient acid ceramidase (ACDase) activity. Although both conditions are caused by mutations in the ASAH1 gene, clinical presentations differ considerably. FD patients usually die in childhood while SMA-PME patients can live until adulthood. There is no treatment for FD or SMA-PME. Hematopoietic stem cell transplantation (HSCT) and gene therapy strategies for the treatment of ACDase deficiency are being investigated. We have previously generated and characterized mouse models of both FD and SMA-PME that recapitulate the symptoms described in patients. Here, we show that HSCT improves lifespan, behavior, hematopoietic system anomalies, plasma cytokine levels, and significantly reduces histiocytic infiltration and ceramide accumulation throughout the tissues investigated, including the CNS, in both models of ACDase deficient mice. HSCT was also successful in preventing lesion development and significant demyelination of the spinal cord seen in SMA-PME mice. Importantly, we note that only early and generally pre-symptomatic treatment was effective and kidney impairment was not improved in either model.

A Five-Year Review of Newborn Screening for Spinal Muscular Atrophy in the State of Utah: Lessons Learned.

Spinal muscular atrophy (SMA) is an autosomal recessive condition characterized by alpha motor neuron degeneration in the spinal cord anterior horn. Clinical symptoms manifest in the first weeks to months of life in the most severe cases, resulting in progressive symmetrical weakness and atrophy of the proximal voluntary muscles. Approximately 95% of SMA patients present with homozygous deletion of the SMN1 gene. With multiple available therapies preventing symptom development and slowing disease progression, newborn screening for SMA is essential to identify at-risk individuals. From 2018 to 2023, a total of 239,844 infants were screened. 13 positive screens were confirmed to have SMA. An additional case was determined to be a false positive. We are not aware of any false-negative cases. All patients were seen promptly, with diagnosis confirmed within 1 week of the initial clinical visit. Patients were treated with nusinersen or onasemnogene abeparvovec. Treated patients with two copies of SMN2 are meeting important developmental milestones inconsistent with the natural history of type 1 SMA. Patients with 3-4 copies of SMN2 follow normal developmental timelines. Newborn screening is an effective tool for the early identification and treatment of patients with SMA. Presymptomatic treatment dramatically shifts the natural history of SMA, with most patients meeting appropriate developmental milestones. Patients with two copies of SMN2 identified through newborn screening constitute a neurogenetic emergency. Due to the complexities of follow-up, a multidisciplinary team, including close communication with the newborn screening program, is required to facilitate timely diagnosis and treatment.

Time to change our approach to presymptomatic treatment of Sturge-Weber syndrome.

This commentary is on the original article by Mankel et al. on pages 111–118 of this issue.

A consensus survey of neurologists and clinical geneticists on spinal muscular atrophy treatment in Singapore

Just a decade ago, spinal muscular atrophy (SMA) was considered a debilitating, progressive neuromuscular disease that inevitably led to chronic disability and a shortened lifespan. Now, it is treatable with nusinersen, onasemnogene abeparvovec (OAV) and risdiplam—the 3 disease-modifying drugs approved by the US Food and Drug Administration, the European Medicines Agency and most recently, the Health Science Authority in Singapore.1 Clinical trials and real-world data have consistently shown improvement in motor milestones for all 3 drugs, especially if introduced early in the disease course.2-4 More significantly, presymptomatic treatment has enabled age-appropriate development of motor milestones, leading to improved respiratory, orthopaedic and nutritional outcomes.

Improved therapeutic approach for spinal muscular atrophy via ubiquitination-resistant survival motor neuron variant.

Zolgensma is a gene-replacement therapy that has led to a promising treatment for spinal muscular atrophy (SMA). However, clinical trials of Zolgensma have raised two major concerns: insufficient therapeutic effects and adverse events. In a recent clinical trial, 30% of patients failed to achieve motor milestones despite pre-symptomatic treatment. In addition, more than 20% of patients showed hepatotoxicity due to excessive virus dosage, even after the administration of an immunosuppressant. Here, we aimed to test whether a ubiquitination-resistant variant of survival motor neuron (SMN), SMNK186R, has improved therapeutic effects for SMA compared with wild-type SMN (SMNWT). A severe SMA mouse model, SMA type 1.5 (Smn-/-; SMN2+/+; SMN∆7+/-) mice, was used to compare the differences in therapeutic efficacy between AAV9-SMNWT and AAV9-SMNK186R. All animals were injected within Postnatal Day (P) 1 through a facial vein or cerebral ventricle. AAV9-SMNK186R-treated mice showed increased lifespan, body weight, motor neuron number, muscle weight and functional improvement in motor functions as compared with AAV9-SMNWT-treated mice. Lifespan increased by more than 10-fold in AAV9-SMNK186R-treated mice (144.8±26.11days) as compared with AAV9-SMNWT-treated mice (26.8±1.41days). AAV9-SMNK186R-treated mice showed an ascending weight pattern, unlike AAV9-SMNWT-treated mice, which only gained weight until P20 up to 5g on average. Several motor function tests showed the improved therapeutic efficacy of SMNK186R. In the negative geotaxis test, AAV9-SMNK186R-treated mice turned their bodies in an upward direction successfully, unlike AAV9-SMNWT-treated mice, which failed to turn upwards from around P23. Hind limb clasping phenotype was rarely observed in AAV9-SMNK186R-treated mice, unlike AAV9-SMNWT-treated mice that showed clasping phenotype for more than 20 out of 30s. At this point, the number of motor neurons (1.5-fold) and the size of myofibers (2.1-fold) were significantly increased in AAV9-SMNK186R-treated mice compared with AAV9-SMNWT-treated mice without prominent neurotoxicity. AAV9-SMNK186R had fewer liver defects compared with AAV9-SMNWT, as judged by increased proliferation of hepatocytes (P<0.0001) and insulin-like growth factor-1 production (P<0.0001). Especially, low-dose AAV9-SMNK186R (nine-fold) also reduced clasping time compared with SMNWT. SMNK186R will provide improved therapeutic efficacy in patients with severe SMA with insufficient therapeutic efficacy. Low-dose treatment of SMA patients with AAV9-SMNK186R can reduce the adverse events of Zolgensma. Collectively, SMNK186R has value as a new treatment for SMA that improves treatment effectiveness and reduces adverse events simultaneously.

Long-Term Follow-Up Cares and Check Initiative: A Program to Advance Long-Term Follow-Up in Newborns Identified with a Disease through Newborn Screening.

In the United States and around the world, newborns are screened on a population basis for conditions benefiting from pre-symptomatic diagnosis and treatment. The number of screened conditions continues to expand as novel technologies for screening, diagnosing, treating, and managing disease are discovered. While screening all newborns facilitates early diagnosis and treatment, most screened conditions are treatable but not curable. Patients identified by newborn screening often require lifelong medical management and community support to achieve the best possible outcome. To advance the long-term follow-up of infants identified through newborn screening (NBS), the Long-Term Follow-up Cares and Check Initiative (LTFU-Cares and Check) designed, implemented, and evaluated a system of longitudinal data collection and annual reporting engaging parents, clinical providers, and state NBS programs. The LTFU-Cares and Check focused on newborns identified with spinal muscular atrophy (SMA) through NBS and the longitudinal health information prioritized by parents and families. Pediatric neurologists who care for newborns with SMA entered annual data, and data tracking and visualization tools were delivered to state NBS programs with a participating clinical center. In this publication, we report on the development, use of, and preliminary results from the LTFU-Cares and Check Initiative, which was designed as a comprehensive model of LTFU. We also propose next steps for achieving the goal of a national system of LTFU for individuals with identified conditions by meaningfully engaging public health agencies, clinicians, parents, families, and communities.

Analysis of 9 patients with adolescence-onset methylenetetrahydrofolate reductase deficiency

Objective: To explore the diagnosis and treatment of adolescence-onset methylenetetrahydrofolate reductase (MTHFR) deficiency. Methods: This was a retrospective case study. Nine patients with adolescence-onset MTHFR deficiency were diagnosed at Peking University First Hospital from January 2016 to December 2022, and followed up for more than 1 year. Their general information, clinical manifestations, laboratory tests, cranial images, MTHFR gene variants, diagnosis, treatment, and outcome were analyzed retrospectively. Results: The 9 patients came from 8 families. They had symptoms at age of 8.0 years to 17.0 years and diagnosed at 9.0 years to 17.5 years. Eight were male and 1 was female. Two patients were brothers, the elder brother developed abnormal gait at 17.0 years; and the younger brother was then diagnosed at 15.0 years of age and treated at the asymptomatic stage, who was 18.0 years old with normal condition during this study. The main manifestations of the 8 symptomatic patients included progressive dyskinesia and spastic paralysis of the lower limbs, with or without intellectual decline, cognitive impairment and behavioral abnormalities. Totally, 15 variants of MTHFR gene were identified in the 9 patients, including 8 novel variants. Five patients had brain image abnormalities. Increased plasma total homocysteine level (65-221 μmol/L) was found in all patients, and decreased to 20-70 μmol/L after treatment with betaine and calcium folinate. Besides, the 8 symptomatic patients had their behavior and cognitive problems significantly improved, with a legacy of lower limb motor disorders. Conclusions: Late-onset MTHFR deficiency can occur in adolescence. The diagnosis is usually delayed because of non-specific clinical symptoms. The test of blood total homocysteine could be used as a selective screening test. Eight novel varients of MTHFR gene were identified. Timely treatment can improve clinical condition significantly, and pre-symptomatic treatment may prevent brain damage.

Long-term monitoring of fatty acid oxidation defects: results from a MetabERN survey.

Implementation of long-chain fatty acid oxidation defects (LCFAOD) in newborn screening (NBS) programs allows for pre-symptomatic diagnosis and treatment. The long-term natural history of NBS LCFAOD patients is largely unknown and may differ from clinically diagnosed pre-NBS patients. This complicates long-term monitoring of LCFAOD and may cause high monitoring variability. To gain insight in current clinical practice, we performed a web-based questionnaire among all metabolic members of the European Reference Network for Hereditary Metabolic Disorders (MetabERN). Thirty-seven colleagues representing at least 35 European metabolic centres shared their experience and results were discussed at the European Metabolic Group (EMG) meeting 2022. The centres concurred in many aspects of long-term monitoring of LCFAOD including the frequency of clinical visits, determination of laboratory parameters, cardiac monitoring and retinopathy screening. Main discrepancies comprised hepatic imaging, glucose monitoring and electrophysiological investigations. Discrepancies may reflect differences in local availability of monitoring tools, the inclusion of LCFAOD in NBS programs as well as differences in local genotypes and phenotypes. Because monitoring strategies are largely based on the natural disease course of clinically identified patients, there might be over-monitoring of some NBS patients. Nevertheless, we advocate long-term monitoring because resulting information is essential to further characterize the natural disease course, develop evidence-based guidelines and provide a basis for evaluation of future therapies.

Retrospective Analysis of Presymptomatic Treatment In Sturge-Weber Syndrome.

Ninety percent of infants with Sturge-Weber syndrome (SWS) brain involvement have seizure onset before 2 years of age; this is associated with worse neurologic outcome. Presymptomatic treatment before seizure onset may delay seizure onset and improve outcome, as has been shown in other conditions with a high-risk of developing epilepsy such as tuberous sclerosis complex. Electroencephalogram (EEG) may be a biomarker to predict seizure onset. This retrospective clinical data analysis aims to assess impact of presymptomatic treatment in SWS. This two-centered, IRB-approved, retrospective study analyzed records from patients with SWS brain involvement. Clinical data recorded included demographics, age of seizure onset (if present), brain involvement extent (unilateral versus bilateral), port-wine birthmark (PWB) extent, family history of seizure, presymptomatic treatment if received, neuroscore, and anti-seizure medication. EEG reports prior to seizure onset were analyzed. Ninety-two patients were included (48 females), and 32 received presymptomatic treatment outside of a formal protocol (5 aspirin, 16 aspirin and levetiracetam; 9 aspirin and oxcarbazepine, 2 valproic acid). Presymptomatically-treated patients were more likely to be seizure-free at 2 years (15 of 32; 47% versus 7 of 60; 12%; p<.001). A greater percentage of presymptomatically-treated patients had bilateral brain involvement (38% treated versus 17% untreated; p=.026). Median hemiparesis neuroscore at 2 years was better in presymptomatically-treated patients. In EEG reports prior to seizure onset, the presence of slowing, epileptiform discharges, or EEG-identified seizures was associated with seizure onset by 2 (p=.001). Presymptomatic treatment is a promising approach to children diagnosed with SWS prior to seizure onset. Further study is needed, including prospective drug trials, long-term neuropsychological outcome, and prospective EEG analysis to assess this approach and determine biomarkers for presymptomatic treatment.

Molecular EPISTOP, a comprehensive multi-omic analysis of blood from Tuberous Sclerosis Complex infants age birth to two years

We present a comprehensive multi-omic analysis of the EPISTOP prospective clinical trial of early intervention with vigabatrin for pre-symptomatic epilepsy treatment in Tuberous Sclerosis Complex (TSC), in which 93 infants with TSC were followed from birth to age 2 years, seeking biomarkers of epilepsy development. Vigabatrin had profound effects on many metabolites, increasing serum deoxycytidine monophosphate (dCMP) levels 52-fold. Most serum proteins and metabolites, and blood RNA species showed significant change with age. Thirty-nine proteins, metabolites, and genes showed significant differences between age-matched control and TSC infants. Six also showed a progressive difference in expression between control, TSC without epilepsy, and TSC with epilepsy groups. A multivariate approach using enrollment samples identified multiple 3-variable predictors of epilepsy, with the best having a positive predictive value of 0.987. This rich dataset will enable further discovery and analysis of developmental effects, and associations with seizure development in TSC.

Overview of Newborn Screening of Lysosomal Storage Diseases for Pediatric Care Providers

Lysosomal storage disorders (LSD) are caused by enzymatic failure to degrade specific cellular byproducts of metabolism within the lysosome. They have a wide range of presentations involving multiple body systems and can manifest from infancy through adulthood. As treatments have become available for many of these disorders, newborn screening has been adapted for early identification and pre-symptomatic treatment. This article will review some of the LSD that are now being added to newborn screening panels, including globoid cell leukodystrophy (Krabbe), Gaucher disease, Fabry disease, Mucopolysaccharidosis Type I (Hurler; MPSI), Mucopolysaccharidosis Type II (Hunter; MPSII), Acid Sphingomyelinase deficiency (ASMD), and Pompe disease.

Oral treatment with the all-d-peptide RD2 enhances cognition in aged beagle dogs – A model of sporadic Alzheimer’s disease

Disease-modifying therapies to treat Alzheimer's disease (AD) are of fundamental interest for aging humans, societies, and health care systems. Predictable disease progression in transgenic AD models favors preclinical studies employing a preventive study design with an early pre-symptomatic treatment start, instead of assessing a truly curative approach with treatment starting after diagnosed disease onset. The aim of this study was to investigate the pharmacokinetic profile and efficacy of RD2 to enhance short-term memory and cognition in cognitively impaired aged Beagle dogs - a non-transgenic model of truly sporadic AD. RD2 has previously demonstrated pharmacodynamic efficacy in three different transgenic AD mouse models in three different laboratories. Here, we demonstrate that oral treatment with RD2 significantly reduced cognitive deficits in cognitively impaired aged Beagle dogs even beyond the treatment end, which suggests in combination with the treatment dependent CSF tau oligomer decrease a disease-modifying effect of RD2 treatment.

Alberta Spinal Muscular Atrophy Newborn Screening-Results from Year 1 Pilot Project.

Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by biallelic pathogenic/likely pathogenic variants of the survival motor neuron 1 (SMN1) gene. Early diagnosis via newborn screening (NBS) and pre-symptomatic treatment are essential to optimize health outcomes for affected individuals. We developed a multiplex quantitative polymerase chain reaction (qPCR) assay using dried blood spot (DBS) samples for the detection of homozygous absence of exon 7 of the SMN1 gene. Newborns who screened positive were seen urgently for clinical evaluation. Confirmatory testing by multiplex ligation-dependent probe amplification (MLPA) revealed SMN1 and SMN2 gene copy numbers. Six newborns had abnormal screen results among 47,005 newborns screened during the first year and five were subsequently confirmed to have SMA. Four of the infants received SMN1 gene replacement therapy under 30 days of age. One infant received an SMN2 splicing modulator due to high maternally transferred AAV9 neutralizing antibodies (NAb), followed by gene therapy at 3 months of age when the NAb returned negative in the infant. Early data show that all five infants made excellent developmental progress. Based on one year of data, the incidence of SMA in Alberta was estimated to be 1 per 9401 live births.