Death In Early Childhood Research Articles

Osteopetrosis and related osteoclast disorders in adults: A review and knowledge gaps On behalf of the European calcified tissue society and ERN BOND

Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood. Subsequently, the AD form was shown to be a result of mutations in the gene CLCN7 encoding for the ClC-7 chloride channel). Traditionally, the diagnosis of osteopetrosis was made on radiograph appearance alone, but recent molecular and genetic advances have enabled a greater fidelity in classification of osteopetrosis subtypes. In the more severe ARO forms (e.g., malignant infantile osteopetrosis MIOP) typical clinical features have severe consequences and often result in death in early childhood. Major complications of ADO are atypical fractures with delay or failure of repair and challenge in orthopedic management. Bone marrow failure, dental abscess, deafness and visual loss are often underestimated and neglected in relation with lack of awareness and expertise. Accordingly, the care of adult patients with osteopetrosis requires a multidisciplinary approach ideally in specialized centers. Apart from hematopoietic stem cell transplantation in certain infantile forms, the treatment of patients with osteopetrosis, has not been standardized and remains supportive. Further clinical studies are needed to improve our knowledge of the natural history, optimum management and impact of osteopetrosis on the lives of patients living with the disorder.

DNA repair-related heritable photosensitivity syndromes: Mutation landscape in a multiethnic cohort of 17 multigenerational families with high degree of consanguinity

Inherited photosensitivity syndromes are a heterogeneous group of genetic skin disorders with tremendous phenotypic variability, characterized by photosensitivity and defective DNA repair, especially nucleotide excision repair. A cohort of 17 Iranian families with heritable photosensitivity syndromes was evaluated to identify their genetic defect. The patients' DNA was analyzed with either whole-exome sequencing or RNA sequencing (RNA-Seq). The interpretations of the genomic results were guided by genome-wide homozygosity mapping. Haplotype analysis was performed for cases with recurrent mutations. RNA-Seq, in addition to mutation detection, was also utilized to confirm the pathogenicity. Thirteen sequence variants, including six previously unreported pathogenic variants, were disclosed in 17 Iranian families, with XPC as the most common mutated gene in 10 families (59%). In one patient, RNA-Seq, as a first-tier diagnostic approach, revealed a non-canonical homozygous germline variant: XPC:c.413–9 T > A. The Sashimi plot showed skipping of exon 4 with dramatic XPC down-expression. Haplotype analysis of XPC:c.2251–1 G>C and XPC:1243 C>T in four families showed common haplotypes of 1.7 Mb and 2.6 Mb, respectively, denoting a founder effect. Lastly, two extremely rare cases were presented in this report: a homozygous UVSSA:c .1990 C>T was disclosed, and ERCC2-related cerebro-oculo-facio-skeletal (COFS) syndrome with an early childhood death. A direct comparison of our data with the results of previously reported cohorts demonstrates the international mutation landscape of DNA repair-related photosensitivity disorders, although population-specific differences were observed.

The effects of reproductive variables on child mortality in Ethiopia: evidence from demographic and health surveys from 2000 to 2016

BackgroundChild mortality is a crucial indicator reflecting a country's health and socioeconomic status. Despite significant global improvements in reducing early childhood deaths, Southern Asia and sub-Saharan Africa still bear the highest burden of newborn mortality. Ethiopia is one of five countries that account for half of new-born deaths worldwide.MethodsThis study examined the relationship between specific reproductive factors and under-five mortality in Ethiopia. A discrete-time survival model was applied to analyze data collected from four Ethiopian Demographic and Health Surveys (EDHS) conducted between 2000 and 2016. The study focused on investigating the individual and combined effects of three factors: preceding birth interval, maternal age at childbirth, and birth order, on child mortality.ResultsThe study found that lengthening the preceding birth interval to 18–23, 24–35, 36–47, or 48+ months reduced the risk of under-five deaths by 30%, 46%, 56%, and 60% respectively, compared to very short birth intervals (less than 18 months). Giving birth between the ages 20–34 and 35+ reduced the risk by 34% and 8% respectively, compared to giving birth below the age of 20. The risk of under-five death was higher for a 7th-born child by 17% compared to a 2nd or 3rd-born child. The combined effect analysis showed that higher birth order at a young maternal age increased the risk. In comparison, lower birth order in older maternal age groups was associated with higher risk. Lastly, very short birth intervals posed a greater risk for children with higher birth orders.ConclusionNot only does one reproductive health variable negatively affect child survival, but their combination has the strongest effect. It is therefore recommended that policies in Ethiopia should address short birth intervals, young age of childbearing, and order of birth through an integrated strategy.

Hypertrophic cardiomyopathy and lactic acidosis in a child with acyl-CoA dehydrogenase 9 deficiency. Review of the literature and clinical observation

Introduction. Acyl-CoA dehydrogenase 9 deficiency (mitochondrial complex I deficiency) is an autosomal recessive disease from the heterogeneous group of disorders of mitochondrial β-oxidation of fatty acids caused by mutations in the ACAD9 gene. The disease is characterized by a wide range of clinical manifestations, the most common of which are metabolic acidosis, hypertrophic cardiomyopathy, muscle hypotonicity, and impaired motor skills. The article presents the first Russian clinical observation of a rare variant of hypertrophic cardiomyopathy with early debut in a patient with mitochondrial complex I deficiency caused by homozygous mutation c.659C>T (p.A220V) in the ACAD9 gene and emphasizes the importance of early diagnosis of the disease and complex drug therapy to prevent the development of severe complications.
 Objective: to describe the clinical course and management of a patient with the pathogenic c.659C>T (p.A220V) variant of the ACAD9 gene.
 Detailed analysis of anamnesis data, results of clinical, laboratory, instrumental diagnostic methods, and molecular genetic research performed using high-throughput sequencing and direct Sanger sequencing technology. 
 The article presents a literature review and detailed data on clinical observation of a child with homozygous c.659C>T (p.A220V) mutation in the ACAD9 gene diagnosed on the basis of the cardiology department of the National Medical Research Center for Children’s Health. Early disease markers and possibilities of complex drug therapy to prevent the development of severe complications are described.
 Conclusion. Disruption of mitochondrial beta-oxidation of fatty acids is a heterogeneous group of inherited diseases due to abnormal mitochondrial beta-oxidation and transport of carnitine and fatty acids in mitochondria. A feature of these diseases is the multisystem nature of the lesion and its progressive course. In some cases, the initial clinical manifestations may be various disorders of the cardiovascular system (cardiomyopathy, heart rhythm disturbances), which may cause death in neonatal period and early childhood. Early molecular genetic research provides accurate diagnosis and, accordingly, timely prescription of complex therapy.

Cardiac Genetic Investigation of Sudden Infant and Early Childhood Death: A Study From Victims to Families.

Background Sudden infant death syndrome (SIDS) is the leading cause of death up to age 1. Sudden unexplained death in childhood (SUDC) is similar but affects mostly toddlers aged 1 to 4. SUDC is rarer than SIDS, and although cardiogenetic testing (molecular autopsy) identifies an underlying cause in a fraction of SIDS, less is known about SUDC. Methods and Results Seventy-seven SIDS and 16 SUDC cases underwent molecular autopsy with 25 definitive-evidence arrhythmia-associated genes. In 18 cases, another 76 genes with varying degrees of evidence were analyzed. Parents were offered cascade screening. Double-blind review of clinical-genetic data established genotype-phenotype correlations. The yield of likely pathogenic variants in the 25 genes was higher in SUDC than in SIDS (18.8% [3/16] versus 2.6% [2/77], respectively; P=0.03), whereas novel/ultra-rare variants of uncertain significance were comparably represented. Rare variants of uncertain significance and likely benign variants were found only in SIDS. In cases with expanded analyses, likely pathogenic/likely benign variants stemmed only from definitive-evidence genes, whereas all other genes contributed only variants of uncertain significance. Among 24 parents screened, variant status and phenotype largely agreed, and 3 cases positively correlated for cardiac channelopathies. Genotype-phenotype correlations significantly aided variant adjudication. Conclusions Genetic yield is higher in SUDC than in SIDS although, in both, it is contributed only by definitive-evidence genes. SIDS/SUDC cascade family screening facilitates establishment or dismissal of a diagnosis through definitive variant adjudication indicating that anonymity is no longer justifiable. Channelopathies may underlie a relevant fraction of SUDC. Binary classifications of genetic causality (pathogenic versus benign) could not always be adequate.

Renewal of oligodendrocyte lineage reverses dysmyelination and CNS neurodegeneration through corrected N-acetylaspartate metabolism.

Myelinating oligodendrocytes are essential for neuronal communication and homeostasis of the central nervous system (CNS). One of the most abundant molecules in the mammalian CNS is N-acetylaspartate (NAA), which is catabolized into L-aspartate and acetate by the enzyme aspartoacylase (ASPA) in oligodendrocytes. The resulting acetate moiety is thought to contribute to myelin lipid synthesis. In addition, affected NAA metabolism has been implicated in several neurological disorders, including leukodystrophies and demyelinating diseases such as multiple sclerosis. Genetic disruption of ASPA function causes Canavan disease, which is hallmarked by increased NAA levels, myelin and neuronal loss, large vacuole formation in the CNS, and early death in childhood. Although NAA's direct role in the CNS is inconclusive, in peripheral adipose tissue, NAA-derived acetate has been found to modify histones, a mechanism known to be involved in epigenetic regulation of cell differentiation. We hypothesize that a lack of cellular differentiation in the brain contributes to the disruption of myelination and neurodegeneration in diseases with altered NAA metabolism, such as Canavan disease. Our study demonstrates that loss of functional Aspa in mice disrupts myelination and shifts the transcriptional expression of neuronal and oligodendrocyte markers towards less differentiated stages in a spatiotemporal manner. Upon re-expression of ASPA, these oligodendrocyte and neuronal lineage markers are either improved or normalized, suggesting that NAA breakdown by Aspa plays an essential role in the maturation of neurons and oligodendrocytes. Also, this effect of ASPA re-expression is blunted in old mice, potentially due to limited ability of neuronal, rather than oligodendrocyte, recovery.

Antenatal steroids: benefits, risks, and new insights.

Being born before 37 weeks' gestation, or preterm birth, is a leading cause of early childhood death and life-long disability. Antenatal steroids (ANS) are recommended for women judged at risk of imminent preterm delivery. The primary intent of ANS treatment is to rapidly mature the fetal lungs to reduce the risk of mortality and lasting morbidity. Despite being used clinically for some 50 years, a large number of uncertainties remain surrounding the use of ANS. In particular, the choice of agent, dose / regimen, and appropriate gestational age range for ANS therapy all remain unclear. Unresolved concerns regarding potential risk of harms from ANS treatment, especially in light of the modest benefits seen with expanding late-preterm administration, make it increasingly important to optimize the dosing and application of this important and widely used treatment. This review will serve to summarize past data, provide an update on recent developments, and chart a way forward to maximize the overall benefit of this important therapy.

Triose phosphate isomerase deficiency: a rare erythrocyte enzymopathy with a poor prognosis

Triose phosphate isomerase (TPI) is a crucial enzyme for glycolysis. TPI deficiency is an autosomal recessive metabolic disease described in 1965, which remains exceptional by its rarity (less than 100 cases described worldwide), but by its extreme severity. Indeed, it is characterized by a chronic hemolytic anemia, an increased susceptibility to infections and especially, a progressive neurological degeneration which leads to death in early childhood for the majority of cases. We report in our observation the history of diagnosis and clinical course of monozygotic twins born at 32 WA with triose phosphate isomerase deficiency.

Development of multi-level standards of care recommendations for sickle cell disease: Experience from SickleInAfrica.

Introduction: Sickle Cell Disease (SCD) causes significant morbidity and mortality particularly in sub-Saharan Africa (SSA) where it contributes to early childhood deaths. There is need to standardize treatment guidelines to help improve overall SCD patient health outcomes. We set out to review existing guidelines on SCD and to set minimum standards for management of SCD for the different referral levels of healthcare. Methods: A standards of care working group (SoC-WG) was established to develop the SoC recommendations. About 15 available SCD management guidelines and protocols were reviewed and themes extracted from them. The first draft was on chosen themes with 64 major headings and subtopics. Using a summarised WHO levels of referral document, we were able to get six different referral levels of healthcare. The highest referral level was the tertiary facilities whilst the lowest level was the home setting. Recommendations for SCD management for the regional, district, sub-districts, health posts and CHPs compounds were also drafted. Results: The results from this review yielded a guidelines document which had recommendations for management of SCD on 64 topics and subtopic for all the six (6) different referral levels. Discussions: Every child with SCD need to receive comprehensive care that is coordinated at each level. This recommendation is unique in terms of the availability of recommendations for different levels of care as compared to the traditional guidelines which is more focused at the tertiary levels. Patients can access care at any of the other lower referral hospitals and be managed with recommendations that are in keeping with institutional resources at that level. When such patients need care that requires expertise that is not available at that level, the recommendations will be to refer to the appropriate referral level where those expertise are available. This encourages patients to have good clinical care nearer their homes but also having access to specialist screening modalities and expertise at the tertiary hospitals if need be. With this, patient are not limited to a specific referral level when interventions cannot be instituted for them. Conclusion: This SoC recommendations document is a useful material that can be used for consistent standards of treatment in SSA.

The landscape of acid sphingomyelinase deficiency in a new therapeutic era: insights from experts in the Gulf region

Acid sphingomyelinase deficiency (ASMD) is an autosomal-recessive progressive multiorgan metabolic disorder due to pathogenic variants in the sphingomyelin phosphodiesterase 1 gene. It can lead to death in early childhood in its most severe form. According to previous registries, the birth prevalence of ASMD is nearly 0.4-0.6 per 100,000 live births. The diagnosis of ASMD is usually delayed or missed due to the wide variability of clinical manifestations of the disease. Until recently, the management of ASMD patients was based on symptomatic treatments and supportive care; however, the introduction of enzyme replacement therapy (ERT) has revolutionized the management landscape of ASMD. ERT with a recombinant human Acid Sphingomyelinase Enzyme administered intravenously demonstrated a significant improvement in the non-neuronopathic type of ASMD in phase 2/3 trials. In June 2022, the European Medical Agency granted the ERT, olipudase alfa, marketing authorization. The prevalence of inherited metabolic disorders, including lysosomal storage diseases, is relatively higher in the Arab world than in the rest of the world due to the high consanguinity rate. In this study, we aim to review the current landscape of ASMD in the Gulf Cooperation Council countries and gather insights from experts regarding the roadmap to diagnosis, prevalence, and management approaches of ASMD in the region.

Antenatal corticosteroids in Singapore: a clinical and scientific assessment.

Preterm birth (PTB; delivery prior to 37 weeks' gestation) is the leading cause of early childhood death in Singapore today. Approximately 9% of Singaporean babies are born preterm; the PTB rate is likely to increase given the increased use of assisted reproduction technologies, changes in the incidence of gestational diabetes/high body mass index and the ageing maternal population. Antenatal administration of dexamethasone phosphate is a key component of the obstetric management of Singaporean women who are at risk of imminent preterm labour. Dexamethasone improves preterm outcomes by crossing the placenta to functionally mature the fetal lung. The dexamethasone regimen used in Singapore today affords a very high maternofetal drug exposure over a brief period of time. Drawing on clinical and experimental data, we reviewed the pharmacokinetic profile and pharmacodynamic effects of dexamethasone treatment regimen in Singapore, with a view to creating a development pipeline for optimising this critically important antenatal therapy.

RECURRENT LUNG INFECTIONS IN A HETEROZYGOUS CARRIER OF NOVEL NSMCE3 MUTATION.

<h3>Introduction</h3> Several biallelic missense mutations in NSMCE3 lead to chromosome breakage syndrome (LICS), which presents with early-onset lung disease, pneumonia, B- and T- cell dysfunction and resultant death in early childhood. The protein product of NSMCE3 helps bridge and stabilize the SMC5/6 complex, which plays a crucial role in DNA double-strand break repair and is thought to help suppress viral infections. <h3>Case Description</h3> A 5-year-old male with atopic dermatitis and reactive airway disease presented for evaluation of recurrent sinopulmonary infections. In one year, he had three episodes of acute otitis media and five viral upper respiratory infections, complicated by multiple bacterial pneumonias. Initial immunologic workup showed low CD8+ T-cells that subsequently normalized. He also had marginally-low IgM, but showed intact humoral response to HiB vaccine and Pneumovax. Three years later, he experienced two more episodes of bacterial pneumonia, one requiring two rounds of antibiotics for clinical improvement. Genetic testing (Invitae Primary Immunodeficiency Panel) showed a heterozygous variant of uncertain significance, a deletion-insertion mutation of the NSMCE3 gene (nucleotides 41 and 42 are deleted and two cytosines inserted, which changes glutamine to proline at the 14th amino acid position in the protein product). <h3>Discussion</h3> In most cases, heterozygous carriers can compensate for a defective allele. Our patient has a missense mutation in one NSMCE3 allele, which may affect the protein product's conformation. Since this protein functions in DNA repair and known mutations have been associated with pneumonia and viral infections, we hypothesize that his reduced level of normal protein may underlie his recurrent pneumonias.

Inequalities in adverse birth outcomes and survival in early childhood: birth cohort in South Korea

Abstract Background Adverse birth outcomes (ABOs) are considered the most common factor of deaths in early childhood. Inequalities in child mortality occur due to interactions between intrinsic and socio-environmental factors related to socioeconomic disadvantage. There are, however, few studies investigating the impact of ABOs on mortality in terms of parental SEP. Methods Using the Under-5 Infant Birth-Death Cohort Data in Korea, a pooled retrospective birth cohort of all children born in 2012-2014 was built (N = 1,356,584). We analyzed neonatal, post-neonatal, and childhood mortality by ABOs and with the interaction of parental SEP using the Cox proportional hazard regression model for survival analyses. We further stratified the analysis both by parental SEP and child age. Multiple logistic regression was performed to confirm the social inequalities in ABO itself. Results After adjusting for covariates, children born with ABOs presented higher risk of mortality for all periods. For post-neonatal period, lower maternal education showed significant interaction effect with LBW (HR = 0.57; 95% CI = [0.39-0.85]), PTB (HR = 0.53; 95% CI = [0.33-0.86]), LBW &amp; PTB ([HR = 0.67; 95% CI = [0.54-0.83]) while lower paternal education (HR = 0.67; 95% CI = [0.54-0.82]) and maternal unemployment (HR = 0.80; 95% CI = [0.63-0.99]) showed significance for babies with LBW &amp; PTB. However, stratification analyses suggested that the impact of ABOs on mortality was greater for children born to lower parental SEP in neonatal period. Meanwhile apparent social inequalities in ABOs were suggested from regression analyses. Conclusions We confirmed social inequalities in the incidence of ABOs as well as mortalities from ABOs. However, the difference in mortality between babies with and without ABOs was greater for advantaged children. Policies to reduce the mortality of children with ABOs as well as those of healthy children among socioeconomically disadvantaged families are required. Key messages • Social inequalities in mortality from ABOs were apparent especially in the neonatal period while the incidence of ABOs itself was greater among children from disadvantaged families. • Disadvantaged children are more likely to die not only from ABOs but also from other socio-environmental determinants, especially in the post-neonatal period than their counterparts.

The Effect of a Pex3 Mutation on Hearing and Lipid Content of the Inner Ear.

Peroxisome biogenesis disorders (due to PEX gene mutations) are associated with symptoms that range in severity and can lead to early childhood death, but a common feature is hearing impairment. In this study, mice carrying Pex3 mutations were found to show normal auditory development followed by an early-onset progressive increase in auditory response thresholds. The only structural defect detected in the cochlea at four weeks old was the disruption of synapses below inner hair cells. A conditional approach was used to establish that Pex3 expression is required locally within the cochlea for normal hearing, rather than hearing loss being due to systemic effects. A lipidomics analysis of the inner ear revealed a local reduction in plasmalogens in the Pex3 mouse mutants, comparable to the systemic plasmalogen reduction reported in human peroxisome biogenesis disorders. Thus, mice with Pex3 mutations may be a useful tool to understand the physiological basis of peroxisome biogenesis disorders.

Role of innate errors of immunity in the group of children with fatal outcomes during the first year of life

In the modern world, inborn errors of immunity (IEIs), or primary immunodeficiencies (PIDs), are among of the main causes of childhood disability and mortality, determining the demographic state of mankind not only at present, but also in the future. In the Sverdlovsk Region over the past 5 years, there were about 30% of children who died from severe combined primary immunodeficiency. This retrospective study is devoted to the study of the nosological profile of mortality in the children with immune-dependent disorders in the Sverdlovsk Region, as well as to assess information significance of extrachromosomal circular DNA molecules (TREC and KREC) analysis. Some anamnestic data on the course of prenatal period in the current and previous pregnancies were considered the signs of suggested diagnosis of primary immunodeficiencies, i.e., threats of pregnancy loss at the early terms, documented cases of early childhood death, persistent viral and bacterial infections in the mother, complicated course of pregnancy in the mother, as well as some clinical manifestations, including fungal-bacterial sepsis, generalized viral infection, repair disorders, reduced physiological tolerance accompanied by autoimmune organ damage and uncontrolled systemic inflammation. The study demonstrated a wide range of nosological entities of innate errors of immunity in the structure of early childhood mortality, including both classical forms of primary immunodeficiencies and the disorders not directly related to innate errors of immunity, but those showing phenotypically pronounced immunodeficiency and their immediate role in statistical deviations. Among the main criteria that may presume possible presence of an immune-dependent pathology in the early neonatal period we considered the molecular markers of naive T and B cells (TREC and KREC, respectively) revealed in 70% of the cases studied, with, at least, one of these indexes found to be reduced. It is important to understand that primary immunodeficiencies are not as rare as previously thought. Therefore, it is necessary to carry out timely and high-quality diagnostics, in order to avoid unavoidable deaths.

Triosephosphate isomerase deficiency in an infant

Triosephosphate isomerase deficiency is an autosomal recessive disorder characterized by progressive neuromuscular degeneration, seizure, dystonia, weak muscles, cardiomyopathy, hemolytic anemia, and death in early childhood. In the glycolytic pathway, dihydroxy acetone phosphate (DHAP) is converted to glyceraldehyde-3-phosphate by an enzymatic reaction. The reaction is catalyzed by the TPI enzyme. In TPI deficiency, erythrocyte viability is reduced due to insufficient anaerobic respiration and DHAP accumulation causes toxic effects on cells. A 2-month-old boy initially presented with infection and moderate anemia. Respiratory distress and neurological symptoms developed shortly thereafter. He was followed up with a mechanical ventilator for a long time. A homozygous pathogenic variant in the TPI1 gene was detected in the genetic analysis performed due to the progressive neurodegeneration and the need of intermittent erythrocyte transfusion in the follow-up. Here, an infant case with triosephosphate isomerase enzyme deficiency is presented.

Chemically modified recombinant human sulfamidase (SOBI003) in mucopolysaccharidosis IIIA patients: Results from an open, non-controlled, multicenter study.

Mucopolysaccharidosis IIIA (MPS IIIA) is an inherited lysosomal storage disorder caused by mutations in the N-sulfoglucosamine sulfohydrolase gene that result in deficient enzymatic degradation of heparan sulfate (HS), resulting in progressive neurodegeneration in early childhood and premature death. A chemically modified variant of recombinant human sulfamidase, SOBI003, has shown to cross the blood-brain barrier (BBB) in mice and achieve pharmacologically relevant levels in cerebrospinal fluid (CSF). We report on a phase 1/2, open-label, first-in-human (FIH) study (NCT03423186) and its extension study (NCT03811028) to evaluate the long-term safety, tolerability, pharmacokinetics/pharmacodynamics (PK/PD) and clinical efficacy of SOBI003 in patients with MPS IIIA for up to 104 weeks. Six patients aged 1-6 years with confirmed MPS IIIA with developmental age ≥ 12 months received weekly intravenous injections of SOBI003 at 3 mg/kg (Cohort 1, n = 3) or 10 mg/kg (Cohort 2, n = 3). During the extension study, the individual dose of SOBI003 could be adjusted up to 20 mg/kg at the discretion of the investigator. SOBI003 was generally well tolerated. Serum concentrations of SOBI003 increased in proportion to dose, and presence in CSF confirmed that SOBI003 crosses the BBB. Anti-drug antibodies (ADA) were detected in serum and CSF in all patients, with subsequent reductions in serum SOBI003 exposure at high ADA titers. SOBI003 exerted a clear PD effect: a mean reduction in HS levels in CSF of 79% was recorded at the last assessment, together with reductions in HS levels in serum and urine. Neurocognitive development age-equivalent scores showed a stabilization of cognition for all patients, whereas no clear overall clinical effect was observed on adaptive behavior, sleep pattern or quality of life. SOBI003 was well tolerated when administered as weekly intravenous infusions at doses of up to 20 mg/kg for up to 104 weeks. ADA development was common and likely affected both PK and PD parameters. SOBI003 crossed the BBB and showed pharmacological activity on HS in CSF.

Mortality in patients with alpha-mannosidosis: a review of patients’ data and the literature

BackgroundAlpha-mannosidosis is a rare autosomal recessive lysosomal storage disorder (LSD) caused by reduced activity of alpha-mannosidase. Clinical manifestations include skeletal dysmorphism, mental impairment, hearing loss and recurrent infections. The severe type of the disease leads to early childhood death, while patients with milder forms can live into adulthood. There are no mortality studies to date. This study aimed to investigate the age at death and the causes of death of patients with alpha-mannosidosis who had not received disease-modifying treatment.MethodsClinicians and LSD patient organisations (POs) from 33 countries were invited to complete a questionnaire between April–May 2021. Cause of death and age at death was available for 15 patients. A literature review identified seven deceased patients that met the inclusion criteria.ResultsMedian age at death for patients reported by clinicians/POs was 45 years (mean 40.3 ± 13.2, range 18–56, n = 15); 53% were female. One death occurred during the patient’s second decade of life, and 14 out of 15 deaths (93.3%) during or after the patients’ third decade, including four (26.7%) during their sixth decade. Median age at death for patients identified from the literature was 4.3 years (mean 15.7 ± 17.0, range 2.2–41, n = 7); two were female. Four of the seven patients (57.1%) died within the first decade of life.Seven of 15 deaths (46.7%) reported by clinicians/POs were recorded as pneumonia and three (20.0%) as cancer. Other causes of death included acute renal failure due to sepsis after intestinal perforation, decrease of red blood cells of unknown origin, kidney failure with systemic lupus erythematosus, aortic valve insufficiency leading to heart failure, and dehydration due to catatonia. Three out of seven causes of death (42.9%) reported in the literature were associated with septicaemia, two (28.6%) with respiratory failure and one to pneumonia following aspiration.ConclusionsThis study suggests that pneumonia has been the primary cause of death during recent decades in untreated patients with alpha-mannosidosis, followed by cancer. Determining the causes of mortality and life expectancy in these patients is crucial to further improve our understanding of the natural history of alpha-mannosidosis.

Incidence of respiratory virus illness and hospitalizations in a Panama and El Salvador birth cohort, 2014–2018

SummaryBackgroundRespiratory viruses remain a key cause of early childhood illness, hospitalization, and death globally.The recent pandemic has rekindled interest in the control of respiratory viruses among paediatric populations. We estimate the burden of such viruses among children <2 years.MethodsEnrolled neonates were followed until two years of age. Weekly active symptom monitoring for the development of acute respiratory illnesses (ARI) defined as cough, rhinorrhoea, difficulty breathing, asthenia, anorexia, irritability, or vomiting was conducted. When the child had ARI and fever, nasopharyngeal swabbing was performed, and samples were tested through singleplex RT-PCR. Incidence of respiratory viruses was calculated by dividing the number of laboratory-confirmed detections by the person-time accrued during weeks when that virus was detectable through national surveillance then corrected for under-ascertainment among untested children.FindingsDuring December 2014–November 2017, 1567 enrolled neonates contributed 2,186.9 person-years (py). Six in ten (64·4%) children developed ARI (total 2493 episodes). Among children <2 years, incidence of respiratory syncytial virus (RSV)-associated ARI episodes (21·0, 95%CI 19·3–22·8, per 100py) and rhinovirus-associated (20·5, 95%CI 20·4–20·7) were similar and higher than parainfluenza 1–3-associated (14·2, 95%CI 12·2–16·1), human metapneumovirus-associated (9·2, 95%CI 7·7–10·8), influenza-associated (5·9, 95%CI 4·4–7·5), and adenovirus-associated ARI episodes (5·1, 95%CI 5·0–5·2). Children aged <3 months had the highest rates of RSV ARI (49·1, 95%CI 44·0–54·1 per 100py) followed by children aged 3–5 (25·1, 95%CI 20·1–30·0), 6–11 (17·6, 95%CI 13·2–21·9), and 12–23 months (11·9, 95%CI 10·8–12·9). One in ten children with RSV was referred to the hospital (2·5, 95%CI 2·1–2·8, per 100py).InterpretationChildren frequently developed viral ARI and a substantive proportion required hospital care. Such findings suggest the importance of exploring the value of new interventions and increasing uptake of existing prevention measures to mitigate burden of epidemic-prone respiratory viruses.FundingThe study was supported by the Centers for Disease Control and Prevention.

Efficacy and Safety of a Krabbe Disease Gene Therapy.

Krabbe disease is a lysosomal storage disease caused by mutations in the gene that encodes galactosylceramidase, in which galactosylsphingosine (psychosine) accumulation drives demyelination in the central and peripheral nervous systems, ultimately progressing to death in early childhood. Gene therapy, alone or in combination with transplant, has been developed for almost two decades in mouse models, with increasing therapeutic benefit paralleling the improvement of next-generation adeno-associated virus (AAV) vectors. This effort has recently shown remarkable efficacy in the canine model of the disease by two different groups that used either systemic or cerebrospinal fluid (CSF) administration of AAVrh10 or AAV9. Building on our experience developing CSF-delivered, AAV-based drug products for a variety of neurodegenerative disorders, we conducted efficacy, pharmacology, and safety studies of AAVhu68 delivered to the CSF in two relevant natural Krabbe animal models, and in nonhuman primates. In newborn Twitcher mice, the highest dose (1 × 1011 genome copies [GC]) of AAVhu68.hGALC injected into the lateral ventricle led to a median survival of 130 days compared to 40.5 days in vehicle-treated mice. When this dose was administered intravenously, the median survival was 49 days. A single intracisterna magna injection of AAVhu68.cGALC at 3 × 1013 GC into presymptomatic Krabbe dogs increased survival for up to 85 weeks compared to 12 weeks in controls. It prevented psychosine accumulation in the CSF, preserved peripheral nerve myelination, ambulation, and decreased brain neuroinflammation and demyelination, although some regions remained abnormal. In a Good Laboratory Practice-compliant toxicology study, we administered the clinical candidate into the cisterna magna of 18 juvenile rhesus macaques at 3 doses that displayed efficacy in mice. We observed no dose-limiting toxicity and sporadic minimal degeneration of dorsal root ganglia (DRG) neurons. Our studies demonstrate the efficacy, scalability, and safety of a single cisterna magna AAVhu68 administration to treat Krabbe disease. ClinicalTrials.Gov ID: NCT04771416.