An exploratory open-label multicentre phase I/II trial evaluating the safety and efficacy of postnatal or prenatal and postnatal administration of allogeneic expanded fetal mesenchymal stem cells for the treatment of severe osteogenesis imperfecta in infants and fetuses: the BOOSTB4 trial protocol.

INTRODUCTION: Severe osteogenesis imperfecta (OI) is a debilitating disease with no cure or sufficiently effective treatment. Mesenchymal stem cells (MSCs) have good safety profile, show promising effects and can form bone. The Boost Brittle Bones Before Birth (BOOSTB4) trial evaluates administration of allogeneic expanded human first trimester fetal liver MSCs (BOOST cells) for OI type 3 or severe type 4. METHODS AND ANALYSIS: BOOSTB4 is an exploratory, open-label, multiple dose, phase I/II clinical trial evaluating safety and efficacy of postnatal (n=15) or prenatal and postnatal (n=3, originally n=15) administration of BOOST cells for the treatment of severe OI compared with a combination of historical (1-5/subject) and untreated prospective controls (≤30). Infants<18 months of age (originally<12 months) and singleton pregnant women whose fetus has severe OI with confirmed glycine substitution in COL1A1 or COL1A2 can be included in the trial.Each subject receives four intravenous doses of 3×106/kg BOOST cells at 4 month intervals, with 48 (doses 1-2) or 24 (doses 3-4) hours in-patient follow-up, primary follow-up at 6 and 12 months after the last dose and long-term follow-up yearly until 10 years after the first dose. Prenatal subjects receive the first dose via ultrasound-guided injection into the umbilical vein within the fetal liver (16+0 to 35+6 weeks), and three doses postnatally.The primary outcome measures are safety and tolerability of repeated BOOST cell administration. The secondary outcome measures are number of fractures from baseline to primary and long-term follow-up, growth, change in bone mineral density, clinical OI status and biochemical bone turnover. ETHICS AND DISSEMINATION: The trial is approved by Competent Authorities in Sweden, the UK and the Netherlands (postnatal only). Results from the trial will be disseminated via CTIS, ClinicalTrials.gov and in scientific open-access scientific journals. TRIAL REGISTRATION NUMBERS: EudraCT 2015-003699-60, EUCT: 2023-504593-38-00, NCT03706482.

Non-collagen pathogenic variants resulting in the osteogenesis imperfecta phenotype in children: a single-country observational cohort study.

BACKGROUND/OBJECTIVES: In England, children (0-18 years) with severe, complex and atypical osteogenesis imperfecta (OI) are managed by four centres (Birmingham, Bristol, London, Sheffield) in a 'Highly Specialised Service' (HSS OI); affected children with a genetic origin for their disease that is not in COL1A1 or COL1A2 form the majority of the 'atypical' group, which has set criteria for entry into the service. We have used the data from the service to assess the range and frequency of non-collagen pathogenic variants resulting in OI in a single country. METHODS: Children with atypical OI were identified through the HSS OI service database. All genetic testing for children with OI in the service were undertaken at the Sheffield Diagnostic Genetics Service. Variant data were extracted and matched to individual patients. This study was done as part of a service evaluation project registered with the Sheffield Children's Hospital Clinical Governance Department. RESULTS: One hundred of 337 children in the HSS met the 'atypical' criteria. Eighty have had genetic testing undertaken; 72 had genetic changes detected, 67 in 13 genes known to be causative for OI. The most frequently affected genes were IFITM5 (22), P3H1 (12), SERPINF1 (8) and BMP1 (6). CONCLUSION: Among children with more severe forms of OI (approximately one-third of all children with OI), around 20% have pathogenic variants in non-collagen genes. IFITM5 was the most commonly affected gene, followed by genes within the P3H1 complex. These data provide additional information regarding the likelihood of different genetic origins of the disease in children with OI, which may influence clinical care.

Living with osteogenesis imperfecta: A qualitative study exploring experiences and psychosocial impact from the perspective of patients, parents and professionals.

BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic condition characterised by increased bone fragility. Recurrent fractures, pain and fatigue have a considerable impact on many aspects of the life of a person affected with OI and their families. OBJECTIVE: To improve our understanding of the impact of OI on the daily lives of individuals and families and consider how the condition is managed so that support needs can be better addressed. METHODS: Semi-structured qualitative interviews (n = 56) were conducted with adults affected with OI, with (n = 9) and without children (n = 8), parents of children affected with OI (n = 8), health professionals (n = 29) and patient advocates (n = 2). Interviews were digitally recorded, transcribed verbatim and analysed using thematic analysis. RESULTS: Three overarching themes are described: OI is not just a physical condition, parenting and family functioning and managing the condition. Fractures, chronic pain and tiredness impact on daily life and emotional well-being. For parents with OI, pain, tiredness and mobility issues can limit interactions and activities with their children. Specialist paediatric health services for OI were highly valued. The need for more emotional support and improved coordination of adult health services was highlighted. CONCLUSIONS: Our findings allow a better understanding of the day-to-day experiences of individuals and families affected with OI. Supporting emotional well-being needs greater attention from policy makers and researchers. Improvements to the coordination of health services for adults with OI are needed and an in-depth exploration of young people's support needs is warranted with research focused on support through the teenage years.

Psychiatric comorbidity is common in dystonia and other movement disorders.

OBJECTIVE: To determine rates of psychiatric comorbidity in a clinical sample of childhood movement disorders (MDs). DESIGN: Cohort study. SETTING: Tertiary children's hospital MD clinics in Sydney, Australia and London, UK. PATIENTS: Cases were children with tic MDs (n=158) and non-tic MDs (n=102), including 66 children with dystonia. Comparison was made with emergency department controls (n=100), neurology controls with peripheral neuropathy or epilepsy (n=37), and community controls (n=10 438). INTERVENTIONS: On-line development and well-being assessment which was additionally clinically rated by experienced child psychiatrists. MAIN OUTCOME MEASURES: Diagnostic schedule and manual of mental disorders-5 criteria for psychiatric diagnoses. RESULTS: Psychiatric comorbidity in the non-tic MD cohort (39.2%) was comparable to the tic cohort (41.8%) (not significant). Psychiatric comorbidity in the non-tic MD cohort was greater than the emergency control group (18%, p<0.0001) and the community cohort (9.5%, p<0.00001), but not the neurology controls (29.7%, p=0.31). Almost half of the patients within the tic cohort with psychiatric comorbidity were receiving medical psychiatric treatment (45.5%) or psychology interventions (43.9%), compared with only 22.5% and 15.0%, respectively, of the non-tic MD cohort with psychiatric comorbidity. CONCLUSIONS: Psychiatric comorbidity is common in non-tic MDs such as dystonia. These psychiatric comorbidities appear to be under-recognised and undertreated.

Intraoperative electrophysiology during single-level selective dorsal rhizotomy: technique, stimulation threshold, and response data in a series of 145 patients.

OBJECTIVE: Selective dorsal rhizotomy (SDR) is effective at permanently reducing spasticity in children with spastic cerebral palsy. The value of intraoperative neurophysiological monitoring in this procedure remains controversial, and its robustness has been questioned. This study describes the authors' institutional electrophysiological technique (based on the technique of Park et al.), intraoperative findings, robustness, value to the procedure, and occurrence of new motor or sphincter deficits. METHODS: The authors analyzed electrophysiological data of all children who underwent SDR at their center between September 2013 and February 2019. All patients underwent bilateral SDR through a single-level laminotomy at the conus and with transection of about 60% of the L2-S2 afferent rootlets (guided by intraoperative electrophysiology) and about 50% of L1 afferent roots (nonselectively). RESULTS: One hundred forty-five patients underwent SDR (64% male, mean age 6 years and 7 months, range 2 years and 9 months to 14 years and 10 months). Dorsal roots were distinguished from ventral roots anatomically and electrophysiologically, by assessing responses on free-running electromyography (EMG) and determining stimulation thresholds (≥ 0.2 mA in all dorsal rootlets). Root level was determined anatomically and electrophysiologically by assessing electromyographic response to stimulation. Median stimulation threshold was lower in sacral compared to lumbar roots (p < 0.001), and 16% higher on the first operated (right) side (p = 0.023), but unrelated to age, sex, or functional status. Similarly, responses to tetanic stimulation were consistent: 87% were graded 3+ or 4+, with similar distributions between sides. This was also unrelated to age, sex, and functional status. The L2-S2 rootlets were divided (median 60%, range 50%-67%), guided by response to tetanic stimulation at threshold amplitude. No new motor or sphincter deficits were observed, suggesting sparing of ventral roots and sphincteric innervation, respectively. CONCLUSIONS: This electrophysiological technique appears robust and reproducible, allowing reliable identification of afferent nerve roots, definition of root levels, and guidance for rootlet division. Only a direct comparative study will establish whether intraoperative electrophysiology during SDR minimizes risk of new motor or sphincter worsening and/or maximizes functional outcome.

Pharmacological management of abnormal tone and movement in cerebral palsy.

BACKGROUND: The evidence base to guide the pharmacological management of tone and abnormal movements in cerebral palsy (CP) is limited, as is an understanding of routine clinical practice in the UK. We aimed to establish details of motor phenotype and current pharmacological management of a representative cohort across a network of UK tertiary centres. METHODS: Prospective multicentre review of specialist motor disorder clinics at nine UK centres, collecting data on clinical features and pharmacological management of children and young people (CYP) with CP over a single calendar month. RESULTS: Data were collected from 275 CYP with CP reviewed over the calendar month of October 2017. Isolated dystonia or spasticity was infrequently seen, with a mixed picture of dystonia and spasticity ± choreoathetosis identified in 194/275 (70.5%) of CYP. A comorbid diagnosis of epilepsy was present in 103/275 (37.4%). The most commonly used medications for abnormal tone/movement were baclofen, trihexyphenidyl, gabapentin, diazepam and clonidine. Medication use appeared to be influenced separately by the presence of dystonia or spasticity. Botulinum toxin use was common (62.2%). A smaller proportion of children (12.4%) had undergone a previous neurosurgical procedure for tone/movement management. CONCLUSIONS: CYP with CP frequently present with a complex movement phenotype and comorbid epilepsy. They have multiple therapy, medical and surgical management regimens. Future trials of therapeutic, pharmacological or surgical interventions in this population must adequately encompass this complexity in order to be translatable to clinical practice.

Stakeholder views and attitudes towards prenatal and postnatal transplantation of fetal mesenchymal stem cells to treat Osteogenesis Imperfecta.

The Boost Brittle Bones Before Birth (BOOSTB4) clinical trial is investigating the safety and efficacy of transplanting fetal derived mesenchymal stromal cells (MSCs) prenatally and/or in early postnatal life to treat severe Osteogenesis Imperfecta (OI). This study aimed to explore stakeholder views to understand perceived benefits or concerns, identify ethical issues and establish protocols for support and counselling. Semi-structured qualitative interviews were conducted with three groups; 1. Adults affected with OI, with and without children, and parents of children affected with OI; 2. Health professionals who work with patients with OI; 3. Patient advocates from relevant patient support groups. Interviews were digitally recorded, transcribed verbatim and analysed using thematic analysis. Interviews with 56 participants revealed generally positive views towards using fetal MSC transplantation to treat OI. Early treatment was considered advantageous for preventing fractures and reducing severity and could bring psychological benefits for parents. Common concerns were procedure safety, short/long-term side effects and whether transplantation would be effective. Difficulties inherent in decision-making were frequently discussed, as treatment efficacy is unknown and, by necessity, parents will make decisions at a time when they are vulnerable. Support needs may differ where there is a family history of OI compared to an unexpected diagnosis of OI. Explaining fetal MSC transplantation in a way that all parents can understand, clear expectation setting, psychological support and time for reflection during the decision-making process will be crucial to allow parents to make informed decisions about participation in the BOOSTB4 clinical trial.

Exploring the impact of Osteogenesis Imperfecta on families: A mixed-methods systematic review.

BACKGROUND: Osteogenesis Imperfecta (OI) is a rare genetic condition whose key characteristic is increased bone fragility. OI has the potential to impact upon all family members, making it important to consider the challenges families face, how they cope and their support needs as the affected individual moves from childhood through to adult life. OBJECTIVE: To conduct a mixed-methods systematic review investigating the experiences of families when a family member is affected with OI. METHODS: A systematic search of seven electronic databases, relevant patient organisation websites and reference lists was conducted. Data extraction was performed for all studies that met the eligibility and quality criteria. Results were synthesised following the principles of thematic analysis. RESULTS: One mixed-method, six qualitative and six quantitative studies were included in the review. Three overarching themes were identified through thematic analysis: Impact of OI on the psychosocial wellbeing of families, impact on family life and evolving roles and relationships. Fear of fractures and the uncertainty of when the next fracture will occur are key issues that permeate all areas of family life and impact upon all family members. CONCLUSION: The experiences, coping strategies and support needs of families affected by OI were highly variable and changed over time. Future research should address the need for adaptive health and education interventions that support all family members.

The clinical syndrome of dystonia with anarthria/aphonia.

OBJECTIVES: In dystonia the formulation of a clinical syndrome is paramount to refine the list of etiologies. We here describe the rare association of dystonia with anarthria/aphonia, by examining a large cohort of patients, to provide a narrow field of underlying conditions and a practical algorithmic approach to reach diagnosis. METHODS: We retrospectively reviewed cases, which were evaluated between 2005 and 2014, to identify those with dystonia combined with marked anarthria and/or aphonia. We reviewed demographic information, clinical characteristics, as well as clinico-genetic investigations. We evaluated video material where available. RESULTS: From 860 cases with dystonia as the predominant motor feature, we identified 32 cases (3.7%) with anarthria/aphonia. Age at neurological symptom onset was variable, but the majority of cases (n = 20) developed symptoms within their first eight years of life. A conclusive diagnosis was reached in 27 cases. Monoamine neurotransmitter disorders, neurodegeneration with brain iron accumulation syndromes, hypomyelination with atrophy of the basal ganglia and cerebellum, and syndromes with inborn errors of metabolism were the most common diagnoses. Brain MRI was crucial for reaching a diagnosis by examining the structural integrity of the basal ganglia, the cerebral cortex, brain myelination and whether there was abnormal metal deposition. Pathophysiological mechanisms underlying anarthria/aphonia included dystonia, corticobulbar involvement, apraxia and abnormalities of brain development. CONCLUSIONS: The spectrum of conditions that may present with the syndrome of dystonia with anarthria/aphonia is broad. Various causes may account for the profound speech disturbance. A practical brain MRI-based algorithm is provided to aid the diagnostic procedure.

Pediatric Herpes Simplex Virus Encephalitis Complicated by N-Methyl-D-aspartate Receptor Antibody Encephalitis.

N-methyl-D-aspartate receptor antibodies (NMDAR-Abs) can contribute to neurological relapse after herpes simplex virus encephalitis (HSE). We describe a child with NMDAR-Ab encephalitis after HSE, which was recognized and treated early. We discuss the case in the context of existing reports, and we propose a modified immunotherapy strategy to minimize risk of viral reactivation.