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1.
BMJ Open ; 14(6): e079767, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38834319

RESUMEN

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.


Asunto(s)
Trasplante de Células Madre Mesenquimatosas , Osteogénesis Imperfecta , Humanos , Osteogénesis Imperfecta/terapia , Femenino , Embarazo , Trasplante de Células Madre Mesenquimatosas/métodos , Lactante , Ensayos Clínicos Fase I como Asunto , Estudios Multicéntricos como Asunto , Recién Nacido , Ensayos Clínicos Fase II como Asunto , Células Madre Mesenquimatosas , Resultado del Tratamiento , Masculino , Células Madre Fetales/trasplante
2.
Hum Mol Genet ; 32(4): 580-594, 2023 01 27.
Artículo en Inglés | MEDLINE | ID: mdl-36067010

RESUMEN

DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mammalian target of rapamycin (mTOR) pathway and is commonly implicated in sporadic and familial focal epilepsies, both non-lesional and in association with focal cortical dysplasia. Germline pathogenic variants are typically heterozygous and inactivating. We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5. Cases were identified clinically. Available records, including magnetic resonance imaging and electroencephalography, were reviewed. Genetic testing was performed by whole exome and whole-genome sequencing and cascade screening. In addition, immunohistochemistry was performed on skin biopsy. The phenotype was identified in nine children, eight of which are described in detail herein. Six of the children were of Irish Traveller, two of Tunisian and one of Lebanese origin. The Irish Traveller children shared the same DEPDC5 germline homozygous missense variant (p.Thr337Arg), whereas the Lebanese and Tunisian children shared a different germline homozygous variant (p.Arg806Cys). Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in keeping with other mTOR-opathies. Eye and cardiac involvement and severe neutropenia were also observed in one or more patients. Five of the children died in infancy or childhood; the other four are currently aged between 5 months and 6 years. Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway. The clinical, histopathological and genetic evidence supports a causal role for the homozygous DEPDC5 variants, expanding our understanding of the biology of this gene.


Asunto(s)
Epilepsias Parciales , Síndromes Epilépticos , Megalencefalia , Polimicrogiria , Humanos , Mutación , Proteínas Activadoras de GTPasa/genética , Serina-Treonina Quinasas TOR/genética , Epilepsias Parciales/genética , Megalencefalia/genética
3.
Nat Commun ; 13(1): 6324, 2022 11 07.
Artículo en Inglés | MEDLINE | ID: mdl-36344503

RESUMEN

Diagnostic whole genome sequencing (WGS) is increasingly used in rare diseases. However, standard, semi-automated WGS analysis may overlook diagnoses in complex disorders. Here, we show that specialist multidisciplinary analysis of WGS, following an initial 'no primary findings' (NPF) report, improves diagnostic rates and alters management. We undertook WGS in 102 adults with diagnostically challenging primary mitochondrial disease phenotypes. NPF cases were reviewed by a genomic medicine team, thus enabling bespoke informatic approaches, co-ordinated phenotypic validation, and functional work. We enhanced the diagnostic rate from 16.7% to 31.4%, with management implications for all new diagnoses, and detected strong candidate disease-causing variants in a further 3.9% of patients. This approach presents a standardised model of care that supports mainstream clinicians and enhances diagnostic equity for complex disorders, thereby facilitating access to the potential benefits of genomic healthcare. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project: http://www.genomicsengland.co.uk .


Asunto(s)
Genoma , Enfermedades Raras , Humanos , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Secuenciación Completa del Genoma , Fenotipo
4.
Front Cell Dev Biol ; 10: 783762, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35295849

RESUMEN

The hereditary ataxias are a heterogenous group of disorders with an increasing number of causative genes being described. Due to the clinical and genetic heterogeneity seen in these conditions, the majority of such individuals endure a diagnostic odyssey or remain undiagnosed. Defining the molecular etiology can bring insights into the responsible molecular pathways and eventually the identification of therapeutic targets. Here, we describe the identification of biallelic variants in the GEMIN5 gene among seven unrelated families with nine affected individuals presenting with spastic ataxia and cerebellar atrophy. GEMIN5, an RNA-binding protein, has been shown to regulate transcription and translation machinery. GEMIN5 is a component of small nuclear ribonucleoprotein (snRNP) complexes and helps in the assembly of the spliceosome complexes. We found that biallelic GEMIN5 variants cause structural abnormalities in the encoded protein and reduce expression of snRNP complex proteins in patient cells compared with unaffected controls. Finally, knocking out endogenous Gemin5 in mice caused early embryonic lethality, suggesting that Gemin5 expression is crucial for normal development. Our work further expands on the phenotypic spectrum associated with GEMIN5-related disease and implicates the role of GEMIN5 among patients with spastic ataxia, cerebellar atrophy, and motor predominant developmental delay.

5.
J Med Genet ; 59(8): 810-816, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-34462290

RESUMEN

BACKGROUND: Secreted protein, acidic, cysteine rich (SPARC)-related osteogenesis imperfecta (OI), also referred to as OI type XVII, was first described in 2015, since then there has been only one further report of this form of OI. SPARC is located on chromosome 5 between bands q31 and q33. The encoded protein is necessary for calcification of the collagen in bone, synthesis of extracellular matrix and the promotion of changes to cell shape. METHODS: We describe a further two patients with previously unreported homozygous SPARC variants with OI: one splice site; one nonsense pathogenic variant. We present detailed information on the clinical and radiological phenotype and correlate this with their genotype. There are only two previous reports by Mendozo-Londono et al and Hayat et al with clinical descriptions of patients with SPARC variants. RESULTS: From the data we have obtained, common clinical features in individuals with OI type XVII caused by SPARC variants include scoliosis (5/5), vertebral compression fractures (5/5), multiple long bone fractures (5/5) and delayed motor development (3/3). Interestingly, 2/4 patients also had abnormal brain MRI, including high subcortical white matter changes, abnormal fluid-attenuated inversion in the para-atrial white matter and a large spinal canal from T10 to L1. Of significance, both patients reported here presented with significant neuromuscular weakness prompting early workup. CONCLUSION: Common phenotypic expressions include delayed motor development with neuromuscular weakness, scoliosis and multiple fractures. The data presented here broaden the phenotypic spectrum establishing similar patterns of neuromuscular presentation with a presumed diagnosis of 'myopathy'.


Asunto(s)
Fracturas por Compresión , Osteogénesis Imperfecta , Escoliosis , Fracturas de la Columna Vertebral , Colágeno Tipo I/genética , Humanos , Mutación , Osteogénesis Imperfecta/genética , Osteogénesis Imperfecta/patología , Osteonectina/genética , Fenotipo
6.
Arch Dis Child ; 107(5): 486-490, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-34750202

RESUMEN

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.


Asunto(s)
Osteogénesis Imperfecta , Estudios de Cohortes , Pruebas Genéticas , Humanos , Mutación , Osteogénesis Imperfecta/diagnóstico , Osteogénesis Imperfecta/genética , Fenotipo
7.
Disabil Health J ; 15(1): 101168, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-34266787

RESUMEN

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.


Asunto(s)
Personas con Discapacidad , Osteogénesis Imperfecta , Adolescente , Adulto , Niño , Emociones , Humanos , Osteogénesis Imperfecta/complicaciones , Osteogénesis Imperfecta/psicología , Padres/psicología , Investigación Cualitativa
8.
Am J Hum Genet ; 108(9): 1710-1724, 2021 09 02.
Artículo en Inglés | MEDLINE | ID: mdl-34450031

RESUMEN

Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/- mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/- mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/- mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.


Asunto(s)
Huesos/metabolismo , Proteína Coat de Complejo I/genética , Proteína Coatómero/genética , Discapacidades del Desarrollo/genética , Discapacidad Intelectual/genética , Osteoporosis/genética , Animales , Ácido Ascórbico/farmacología , Huesos/efectos de los fármacos , Huesos/patología , Encéfalo/diagnóstico por imagen , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Niño , Preescolar , Proteína Coat de Complejo I/deficiencia , Proteína Coatómero/química , Proteína Coatómero/deficiencia , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/metabolismo , Discapacidades del Desarrollo/patología , Embrión no Mamífero , Retículo Endoplásmico/efectos de los fármacos , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/patología , Femenino , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Fibroblastos/patología , Regulación del Desarrollo de la Expresión Génica , Aparato de Golgi , Haploinsuficiencia , Humanos , Discapacidad Intelectual/diagnóstico por imagen , Discapacidad Intelectual/metabolismo , Discapacidad Intelectual/patología , Masculino , Ratones , Osteoporosis/tratamiento farmacológico , Osteoporosis/metabolismo , Osteoporosis/patología , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/metabolismo , Índice de Severidad de la Enfermedad , Pez Cebra
9.
Epilepsia ; 61(10): 2224-2233, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32875551

RESUMEN

OBJECTIVE: To characterize a cohort of children with epilepsia partialis continua (EPC) and develop a diagnostic algorithm incorporating key differential diagnoses. METHODS: Children presenting with EPC to a tertiary pediatric neurology center between 2002 and 2019 were characterized. RESULTS: Fifty-four children fulfilled EPC criteria. Median age at onset was 7 years (range 0.6-15), with median follow-up of 4.3 years (range 0.2-16). The diagnosis was Rasmussen encephalitis (RE) in 30 of 54 (56%), a mitochondrial disorder in 12 of 54 (22.2%), and magnetic resonance imaging (MRI) lesion-positive focal epilepsy in 6 of 54 (11.1%). No diagnosis was made in 5 of 54 (9%). Children with mitochondrial disorders developed EPC earlier; each additional year at presentation reduced the odds of a mitochondrial diagnosis by 26% (P = .02). Preceding developmental concerns (odds ratio [OR] 22, P < .001), no seizures prior to EPC (OR 22, P < .001), bilateral slowing on electroencephalogram (EEG) (OR 26, P < .001), and increased cerebrospinal fluid (CSF) protein level (OR 16) predicted a mitochondrial disorder. Asymmetry or hemiatrophy was evident on MRI at presentation with EPC in 18 of 30 (60%) children with RE, and in the remainder at a median of 6 months (range 3-15) after EPC onset. The first diagnostic test is brain MRI. Hemiatrophy may permit a diagnosis of RE with unilateral clinical and EEG findings. For children in whom a diagnosis of RE cannot be made on first scan but the clinical and radiological presentation resembles RE, repeat imaging every 6 months is recommended to detect progressive unicortical hemiatrophy, and brain biopsy should be considered. Evidence of intrathecal inflammation (oligoclonal bands and raised neopterin) can be supportive. In children with bihemispheric EPC, rapid polymerase gamma testing is recommended and if negative, sequencing mtDNA and whole-exome sequencing on blood-derived DNA should be performed. SIGNIFICANCE: Children presenting with EPC due to a mitochondrial disorder show clinical features distinguishing them from RE and structural epilepsies. A diagnostic algorithm for children with EPC will allow targeted investigation and timely diagnosis.


Asunto(s)
Algoritmos , Encefalitis/diagnóstico por imagen , Epilepsia Parcial Continua/diagnóstico por imagen , Enfermedades Mitocondriales/diagnóstico por imagen , Adolescente , Niño , Preescolar , Estudios de Cohortes , Diagnóstico Diferencial , Electroencefalografía/métodos , Encefalitis/fisiopatología , Epilepsia Parcial Continua/fisiopatología , Femenino , Humanos , Lactante , Imagen por Resonancia Magnética/métodos , Masculino , Enfermedades Mitocondriales/fisiopatología
10.
Am J Hum Genet ; 106(4): 484-495, 2020 04 02.
Artículo en Inglés | MEDLINE | ID: mdl-32220290

RESUMEN

Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10 different bi-allelic PIGK variants. PIGK encodes a component of the GPI transamidase complex, which attaches the GPI anchor to proteins. Clinical features found in most individuals include global developmental delay and/or intellectual disability, hypotonia, cerebellar ataxia, cerebellar atrophy, and facial dysmorphisms. The majority of the individuals have epilepsy. Two individuals have slightly decreased levels of serum alkaline phosphatase, while eight do not. Flow cytometric analysis of blood and fibroblasts from affected individuals showed decreased cell surface presence of GPI-APs. The overexpression of wild-type (WT) PIGK in fibroblasts rescued the levels of cell surface GPI-APs. In a knockout cell line, transfection with WT PIGK also rescued the GPI-AP levels, but transfection with the two tested mutant variants did not. Our study not only expands the clinical and known genetic spectrum of IGDs, but it also expands the genetic differential diagnosis for cerebellar atrophy. Given the fact that cerebellar atrophy is seen in other IGDs, flow cytometry for GPI-APs should be considered in the work-ups of individuals presenting this feature.


Asunto(s)
Aciltransferasas/genética , Moléculas de Adhesión Celular/genética , Enfermedades Cerebelosas/genética , Epilepsia/genética , Variación Genética/genética , Hipotonía Muscular/genética , Trastornos del Neurodesarrollo/genética , Anomalías Múltiples/genética , Alelos , Femenino , Humanos , Discapacidad Intelectual/genética , Masculino , Malformaciones del Sistema Nervioso/genética , Linaje , Síndrome
11.
J Peripher Nerv Syst ; 25(2): 117-124, 2020 06.
Artículo en Inglés | MEDLINE | ID: mdl-32096284

RESUMEN

KIF1A-related disorders (KRD) were first described in 2011 and the phenotypic spectrum has subsequently expanded to encompass a range of central and peripheral nervous system involvement. Here we present a case series demonstrating the range of clinical, neurophysiological, and radiological features which may occur in childhood-onset KRD. We report on all the children and young people seen at a single large tertiary centre. Data were collected through a retrospective case-notes review. Twelve individuals from 10 families were identified. Eight different mutations were present, including four novel mutations. Two patients displayed a very severe phenotype including congenital contractures, severe spasticity and/or dystonia, dysautonomia, severe sensorimotor polyneuropathy and optic atrophy, significant white matter changes on brain MRI, respiratory insufficiency, and complete lack of neurodevelopmental progress. The remaining 10 patients represented a spectrum of severity with common features including a movement disorder with spasticity and/or dystonia, subtle features of dysautonomia, sensory axonal neuropathy, varying degrees of optic atrophy and of learning and/or behavioural difficulties, and subtle or absent-but sometimes progressive-changes in white matter on MRI. Epilepsy was common among the more severely affected children. This case series demonstrates that KRD comprise a range of neurological disorders, with both the milder and the more severe forms combining central and peripheral (including autonomic) nervous system deficits.


Asunto(s)
Enfermedades del Sistema Nervioso Central , Distonía , Cinesinas/genética , Enfermedades del Sistema Nervioso Periférico , Disautonomías Primarias , Paraplejía Espástica Hereditaria , Adulto , Enfermedades del Sistema Nervioso Central/diagnóstico , Enfermedades del Sistema Nervioso Central/genética , Enfermedades del Sistema Nervioso Central/patología , Enfermedades del Sistema Nervioso Central/fisiopatología , Niño , Distonía/diagnóstico , Distonía/genética , Distonía/patología , Distonía/fisiopatología , Femenino , Humanos , Lactante , Masculino , Enfermedades del Sistema Nervioso Periférico/diagnóstico , Enfermedades del Sistema Nervioso Periférico/genética , Enfermedades del Sistema Nervioso Periférico/patología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Disautonomías Primarias/diagnóstico , Disautonomías Primarias/genética , Disautonomías Primarias/patología , Disautonomías Primarias/fisiopatología , Estudios Retrospectivos , Paraplejía Espástica Hereditaria/diagnóstico , Paraplejía Espástica Hereditaria/genética , Paraplejía Espástica Hereditaria/patología , Paraplejía Espástica Hereditaria/fisiopatología , Adulto Joven
12.
Neuromuscul Disord ; 30(2): 120-127, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32001147

RESUMEN

Our aim was to identify clinical outcomes, serological features and possible prognostic indicators of paediatric myasthenia gravis (MG). We collected 74 MG patients with disease onset before the age of 16 years (73% pre-pubertal onset defined as ≤10 years), seen regularly at two UK specialist centres, over a period of 11 years. The cohort was multi-ethnic, with a high number of non-Caucasians (52%). Ocular presentation was seen in 38 (51%) and only 8 (21%) of these generalised. Fifty-two (70%) patients had antibodies to the acetylcholine receptor (AChR) measured by radioimmunoprecipitation, 10 (14%) had antibodies only to clustered AChRs detected by a cell based assay, 3 (4%) had muscle-specific kinase and one (1%) low-density lipoprotein receptor-related protein 4 antibody. Only 8 (11%) had no detectable antibodies. Seventeen patients attained drug free remission (Kaplan Meyer survival curve estimates 25% by 7 years). Several factors were associated with a higher likelihood of free remission: onset age ≤10 years, Asian and Caucasian races, lack of AChR antibodies on RIA, and normal repetitive nerve stimulation at diagnosis. However, in a multifactorial regression analysis, the antibody status was the only significant predictor for drug free remission, with 60% of patients with antibodies only to clustered AChR achieving this outcome. Complete drug free remission is not uncommon in paediatric MG and several factors appear to influence this outcome with antibody status being the most important. These factors can be easily evaluated at diagnosis, and may help to determine whose patients are likely to require more intensive treatments.


Asunto(s)
Autoanticuerpos/sangre , Progresión de la Enfermedad , Miastenia Gravis , Evaluación de Resultado en la Atención de Salud , Receptores Colinérgicos/inmunología , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Niño , Preescolar , Femenino , Estudios de Seguimiento , Humanos , Masculino , Miastenia Gravis/sangre , Miastenia Gravis/tratamiento farmacológico , Miastenia Gravis/etnología , Miastenia Gravis/fisiopatología , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Prevalencia , Pronóstico , Inducción de Remisión , Estudios Retrospectivos , Índice de Severidad de la Enfermedad , Factores Sexuales , Reino Unido/etnología , Adulto Joven
13.
Eur J Hum Genet ; 27(8): 1244-1253, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-30918362

RESUMEN

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.


Asunto(s)
Células Madre Fetales/trasplante , Trasplante de Células Madre Mesenquimatosas/métodos , Células Madre Mesenquimatosas/citología , Osteogénesis Imperfecta/terapia , Trasplante de Células Madre/métodos , Adulto , Actitud , Niño , Femenino , Humanos , Masculino , Trasplante de Células Madre Mesenquimatosas/psicología , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Padres/psicología , Trasplante de Células Madre/psicología , Adulto Joven
14.
Disabil Health J ; 12(3): 340-349, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-30638886

RESUMEN

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.


Asunto(s)
Adaptación Psicológica , Personas con Discapacidad , Familia , Fracturas Óseas , Osteogénesis Imperfecta , Familia/psicología , Miedo , Fracturas Óseas/etiología , Fracturas Óseas/psicología , Necesidades y Demandas de Servicios de Salud , Humanos , Osteogénesis Imperfecta/psicología , Incertidumbre
15.
PLoS One ; 13(7): e0199756, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29969469

RESUMEN

BACKGROUND: Mitochondrial and neurogenetic diseases can present diagnostic challenges. We investigated if near infrared spectroscopy with the vascular occlusion test is able to differentiate between children with mitochondrial disease and children with neurogenetic disease or healthy controls. METHODS: Prospective observational study conducted in a tertiary children's hospital. RESULTS: Forty-three children with mitochondrial disease (including both genetically confirmed primary mitochondrial disease and cases with biochemical evidence of mitochondrial dysfunction), 19 children with non-mitochondrial neurogenetic disease and 13 healthy controls were recruited. The delta tissue oxygen index (ΔTOI) values showed greater variability amongst children with mitochondrial disease and neurogenetic disease than healthy controls despite the median ΔTOI being similar (median 14.1 and 18.8, t-test, p = 0.16). A low ΔTOI identifies cases with a higher probability of mitochondrial disease or neurogenetic disease compared to healthy controls (positive likelihood ratio: 3.67; 95%CI:1.01-13). A high ΔTOI with the near infrared spectroscopy with vascular occlusion test identifies cases with a lower probability of having a disease (negative likelihood ratio: 0.51; 95%CI:0.36-0.74). CONCLUSION: Near infrared spectroscopy with vascular occlusion test might be able to discriminate children with mitochondrial disease and neurogenetic disease from healthy controls.


Asunto(s)
Biomarcadores/análisis , Predisposición Genética a la Enfermedad , Enfermedades Mitocondriales/diagnóstico , Enfermedades del Sistema Nervioso/diagnóstico , Enfermedades del Sistema Nervioso/genética , Espectroscopía Infrarroja Corta/métodos , Enfermedades Vasculares/fisiopatología , Adolescente , Estudios de Casos y Controles , Niño , Femenino , Humanos , Masculino , Enfermedades Mitocondriales/diagnóstico por imagen , Enfermedades Mitocondriales/metabolismo , Enfermedades del Sistema Nervioso/diagnóstico por imagen , Enfermedades del Sistema Nervioso/metabolismo , Consumo de Oxígeno , Estudios Prospectivos , Enfermedades Vasculares/diagnóstico por imagen
16.
Genet Med ; 20(11): 1430-1437, 2018 11.
Artículo en Inglés | MEDLINE | ID: mdl-29595812

RESUMEN

PURPOSE: Unexpected fetal abnormalities occur in 2-5% of pregnancies. While traditional cytogenetic and microarray approaches achieve diagnosis in around 40% of cases, lack of diagnosis in others impedes parental counseling, informed decision making, and pregnancy management. Postnatally exome sequencing yields high diagnostic rates, but relies on careful phenotyping to interpret genotype results. Here we used a multidisciplinary approach to explore the utility of rapid fetal exome sequencing for prenatal diagnosis using skeletal dysplasias as an exemplar. METHODS: Parents in pregnancies undergoing invasive testing because of sonographic fetal abnormalities, where multidisciplinary review considered skeletal dysplasia a likely etiology, were consented for exome trio sequencing (both parents and fetus). Variant interpretation focused on a virtual panel of 240 genes known to cause skeletal dysplasias. RESULTS: Definitive molecular diagnosis was made in 13/16 (81%) cases. In some cases, fetal ultrasound findings alone were of sufficient severity for parents to opt for termination. In others, molecular diagnosis informed accurate prediction of outcome, improved parental counseling, and enabled parents to terminate or continue the pregnancy with certainty. CONCLUSION: Trio sequencing with expert multidisciplinary review for case selection and data interpretation yields timely, high diagnostic rates in fetuses presenting with unexpected skeletal abnormalities. This improves parental counseling and pregnancy management.


Asunto(s)
Exoma/genética , Asesoramiento Genético/métodos , Osteocondrodisplasias/genética , Diagnóstico Prenatal/métodos , Estudios de Cohortes , Toma de Decisiones , Femenino , Feto/diagnóstico por imagen , Feto/fisiopatología , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Osteocondrodisplasias/diagnóstico , Osteocondrodisplasias/diagnóstico por imagen , Osteocondrodisplasias/fisiopatología , Padres , Patología Molecular/métodos , Embarazo , Ultrasonografía Prenatal
17.
BMC Med Genet ; 19(1): 8, 2018 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-29329516

RESUMEN

BACKGROUND: Osteogenesis imperfecta (OI) is a rare primarily autosomal dominant condition in which the connective tissues of bones, ligaments and sclerae do not form properly. Typically, mutations in COL1A1 and COL1A2 genes lead to the defective formation or quantity of type I collagen, the principle matrix in these tissues. Molecular genetic studies have now elucidated multiple genetic subtypes of the disorder but little literature exists on the risk of retinal tears and detachments in OI. CASE PRESENTATION: We report the first case of a child with a rare recessive type of OI, subtype VIII, resulting from a P3H1 (also known as LEPRE1) gene mutation presenting with bilateral giant retinal tears and the surgical challenges encountered in performing retinal detachment repair due to scleral thinning. The P3H1 gene encodes for prolyl 3-hydroxylase 1 which is involved in the post-translational modification of not only collagen type I but also types II and V which when mutated may result in pathological posterior vitreous detachment (PVD) and giant retinal tear detachments. CONCLUSIONS: Genetic analyses are increasingly important in such cases and may guide patient monitoring and potential prophylactic treatment, known to significantly reduce the probability of giant retinal tear detachments in other high-risk collagenopathies such as Stickler Syndrome Type I.


Asunto(s)
Colágeno Tipo I/genética , Osteogénesis Imperfecta/diagnóstico , Osteogénesis Imperfecta/genética , Perforaciones de la Retina/genética , Niño , Cadena alfa 1 del Colágeno Tipo I , Colágeno Tipo II/genética , Colágeno Tipo V/genética , Genes Recesivos , Pruebas Genéticas , Humanos , Masculino , Glicoproteínas de Membrana/genética , Osteogénesis Imperfecta/complicaciones , Prolil Hidroxilasas , Procesamiento Proteico-Postraduccional , Proteoglicanos/genética , Desprendimiento de Retina/etiología , Desprendimiento de Retina/genética , Perforaciones de la Retina/etiología
18.
Neurology ; 89(10): 1035-1042, 2017 Sep 05.
Artículo en Inglés | MEDLINE | ID: mdl-28794249

RESUMEN

OBJECTIVE: To define a distinct SCN1A developmental and epileptic encephalopathy with early onset, profound impairment, and movement disorder. METHODS: A case series of 9 children were identified with a profound developmental and epileptic encephalopathy and SCN1A mutation. RESULTS: We identified 9 children 3 to 12 years of age; 7 were male. Seizure onset was at 6 to 12 weeks with hemiclonic seizures, bilateral tonic-clonic seizures, or spasms. All children had profound developmental impairment and were nonverbal and nonambulatory, and 7 of 9 required a gastrostomy. A hyperkinetic movement disorder occurred in all and was characterized by dystonia and choreoathetosis with prominent oral dyskinesia and onset from 2 to 20 months of age. Eight had a recurrent missense SCN1A mutation, p.Thr226Met. The remaining child had the missense mutation p.Pro1345Ser. The mutation arose de novo in 8 of 9; for the remaining case, the mother was negative and the father was unavailable. CONCLUSIONS: Here, we present a phenotype-genotype correlation for SCN1A. We describe a distinct SCN1A phenotype, early infantile SCN1A encephalopathy, which is readily distinguishable from the well-recognized entities of Dravet syndrome and genetic epilepsy with febrile seizures plus. This disorder has an earlier age at onset, profound developmental impairment, and a distinctive hyperkinetic movement disorder, setting it apart from Dravet syndrome. Remarkably, 8 of 9 children had the recurrent missense mutation p.Thr226Met.


Asunto(s)
Discapacidades del Desarrollo/genética , Epilepsia/genética , Hipercinesia/genética , Mutación Missense , Canal de Sodio Activado por Voltaje NAV1.1/genética , Edad de Inicio , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Niño , Preescolar , Discapacidades del Desarrollo/diagnóstico por imagen , Discapacidades del Desarrollo/fisiopatología , Epilepsias Mioclónicas/genética , Epilepsias Mioclónicas/fisiopatología , Epilepsia/diagnóstico por imagen , Epilepsia/fisiopatología , Femenino , Humanos , Hipercinesia/diagnóstico por imagen , Hipercinesia/fisiopatología , Masculino , Fenotipo
19.
BMJ Case Rep ; 2013: 200838, 2013 Oct 07.
Artículo en Inglés | MEDLINE | ID: mdl-24099834

RESUMEN

Wernicke's encephalopathy is a triad of ophthalmoplegia, ataxia and confusion seen in alcoholics with dietary vitamin B1 (thiamine) deficiency. A rare genetic defect of thiamine transporter-2 may lead to similar clinical features, biotin-thiamine responsive basal ganglia disease (BTBGD). A 15-year-old girl developed rapid onset ptosis and ophthalmoplegia evolving into a subacute encephalopathy. Neuroimaging demonstrated symmetrical basal ganglia and mid-brain lesions reminiscent of Leigh's subacute necrotising encephalomyelopathy. Oral biotin and thiamine were started, and symptoms improved dramatically the next day. The therapeutic response suggested SLC19A3, encoding thiamine transporter-2, as a strong candidate gene and Sanger sequencing revealed a novel homozygous c.517A>G;p.Asn173Asp mutation, which segregated with disease within the family. BTBGD is a potentially treatable neurological disorder and should be considered in the differential diagnosis of Leigh syndrome and Wernicke's encephalopathy. Since delayed treatment results in permanent neurological dysfunction or death, prompt diagnosis and early initiation of biotin and thiamine therapy are essential.


Asunto(s)
Biotina/uso terapéutico , Tiamina/uso terapéutico , Encefalopatía de Wernicke/diagnóstico , Encefalopatía de Wernicke/tratamiento farmacológico , Adolescente , Biopsia , Diagnóstico Diferencial , Diagnóstico por Imagen , Femenino , Humanos , Encefalopatía de Wernicke/genética
20.
Neuromuscul Disord ; 23(11): 883-91, 2013 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-23831158

RESUMEN

Mutations in DOK7 are a common cause of congenital myasthenia. Treatment with ephedrine or salbutamol is effective, but diagnosis is often delayed. The aim of our study was to find early clues to the diagnosis of DOK7 congenital myasthenic syndrome. We included 23 children of 20 families. Onset of symptoms ranged from birth to age 3 years. 13 presented at birth with feeding difficulties, 11 with stridor (documented vocal cord palsy in 7), 3/11 with hypotonia/poor head control. Weakness was more pronounced proximally in all, axial in early presenting infants. Muscle biopsy showed non-specific features in 15/16, type 1 fibre predominance in 14/16, areas devoid of oxidative enzyme activity in 7/16. Muscle imaging was normal in 8/10, 2/10 showed mild non-specific changes. A diagnostic clue suggesting CMS rather than myopathy was the discrepancy between muscle imaging or histology findings compared with the degree of weakness. Repetitive nerve stimulation and stimulation single fibre electromyography were pathological in 9/17 and 13/14, respectively. In conclusion, stridor and feeding difficulties at birth or progressive weakness despite normal milestones in infancy point to the diagnosis and should lead to neurophysiological and genetic investigation. Fatigability can be absent or easily missed in the first years of life.


Asunto(s)
Proteínas Musculares/genética , Síndromes Miasténicos Congénitos/diagnóstico , Niño , Humanos , Síndromes Miasténicos Congénitos/genética
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