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1.
BMJ Case Rep ; 13(12)2020 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-33318265

RESUMO

We present a 9-year-old male child having history of fractures on trivial trauma with a family history of the same. He was treated for osteogenesis imperfecta (OI; zolendronate, calcium and vitamin D) and showed clinical improvement. On evaluating his bone health using dual energy X-ray absorptiometry and peripheral quantitative CT, we found that the child had bone density within the reference range but a smaller bone mass for his height, low muscle mass and thin bones with a lower strength strain index in comparison with healthy children. Our case suggests that treatment with bisphosphonates results in increase in bone density; however, bones remain thin and the lean body mass in these children may also be low. Controlled physical activity to improve muscle health and newer approaches to improve bone geometry would result in better bone health in children with OI.


Assuntos
Absorciometria de Fóton , Densidade Óssea , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/fisiopatologia , Tomografia Computadorizada por Raios X , Conservadores da Densidade Óssea/uso terapêutico , Cálcio/uso terapêutico , Criança , Difosfonatos/uso terapêutico , Fraturas Ósseas/etiologia , Fraturas Ósseas/prevenção & controle , Humanos , Masculino , Osteogênese Imperfeita/tratamento farmacológico , Tomografia Computadorizada por Raios X/métodos , Vitamina D/uso terapêutico , Ácido Zoledrônico/uso terapêutico
2.
Reumatol. clín. (Barc.) ; 16(2,pt.2): 165-168, mar.-abr. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-194341

RESUMO

La osteogénesis imperfecta (OI) es un trastorno hereditario del tejido conectivo generalmente relacionado con mutaciones de los genes del colágeno tipoI. El diagnóstico se basa en los hallazgos clínicos y radiológicos. El manejo clínico de la OI en adultos no está del todo establecido y comprende desde la rehabilitación física y los procedimientos quirúrgicos hasta el uso de tratamientos antirresortivos y osteoformadores. El objetivo del presente trabajo ha sido analizar las características clínicas y analíticas de estos pacientes en la edad adulta, así como evaluar los diferentes tratamientos administrados. Se han revisado los casos de OI diagnosticados en nuestro centro en los últimos 12 años (2005-2017). Se describen 15 pacientes adultos con OI


Osteogenesis imperfecta (OI) is an inherited connective tissue disease. The disease has been linked to mutations in one of the type I collagen genes. The diagnosis is based on clinical and radiologic findings. The management of OI in adults is not well-established and includes physical rehabilitation, surgical procedures, the use of antiresorptive therapy and anabolic agents. The aim of the present work was to analyze the clinical and analytical characteristics of these patients in adulthood, as well as to evaluate the different treatments administered. We reviewed the cases of OI diagnosed in our center over the last 12 years (2005-2017). We describe 15 adult patients with OI


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Difosfonatos/administração & dosagem , Densitometria/métodos , Osteogênese Imperfeita/fisiopatologia , Pró-Colágeno/uso terapêutico , Estudos Retrospectivos , Esclerose/complicações , Dentinogênese , Osteoporose/complicações , Doenças Ósseas Metabólicas/complicações
3.
BMC Musculoskelet Disord ; 21(1): 6, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900144

RESUMO

BACKGROUND: Osteogenesis Imperfecta (OI) is characterized by bone fragility, and features such as blue sclerae, dentinogenesis imperfecta, hearing loss, ligamentous laxity and short stature can be present. It has long been assumed that the functional ability and quality of life of patients with OI depends primarily on the severity of skeletal deformities. However, fatigue is often mentioned in clinic by patients with all types of OI as an important modifier of their quality of life and does not always seem to be related to their functional ability. The aim of this study is to investigate whether adults with Osteogenesis Imperfecta are significantly more fatigued than the normal population. METHODS: The Fatigue Severity Scale (FSS) was distributed by mobile phone application among 151 adult patients with different OI types. Results of the FSS in the OI group were compared with two control populations from America (n = 20) and the Netherlands (n = 113). RESULTS: Ninety-nine patients (OI type 1 (n = 72), OI type 3 (n = 13), OI type 4 (n = 14) completed the FSS questionnaire. The mean FSS score of this cohort was 4.4 and significantly higher than the control populations (2.3/2.9). 65% of our cohort reported at least moderate fatigue compared with 2 control populations from America and the Netherlands. CONCLUSION: Fatigue in patients with OI is a frequently encountered problem in our expert clinic but research into this topic is sparse. This pilot study is the largest study to date investigating fatigue in patients with OI and results have been compared with two control groups. The mean FSS score of 4.4 in the OI group indicates that people with OI are generally significantly more fatigued than the control population. Further evaluation of fatigue and its influencers in a larger group of OI patients is important for future management.


Assuntos
Telefone Celular , Fadiga/diagnóstico , Aplicativos Móveis , Osteogênese Imperfeita/diagnóstico , Inquéritos e Questionários , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Efeitos Psicossociais da Doença , Estudos Transversais , Fadiga/etiologia , Fadiga/fisiopatologia , Fadiga/psicologia , Feminino , Nível de Saúde , Humanos , Masculino , Pessoa de Meia-Idade , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/fisiopatologia , Osteogênese Imperfeita/psicologia , Projetos Piloto , Valor Preditivo dos Testes , Qualidade de Vida , Índice de Gravidade de Doença , Adulto Jovem
4.
J Pediatr Orthop ; 40(1): 48-52, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31815862

RESUMO

BACKGROUND: Evaluation of the union of osteotomies and fractures in patients with osteogenesis imperfecta (OI) is a critical component of patient care. Studies of the OI patient population have so far used varied criteria to evaluate bony union. The radiographic union score for tibial fractures (RUST), which was subsequently revised to the modified RUST, is an objective standardized method of evaluating fracture healing. We sought to evaluate the reliability of the modified RUST in the setting of the tibias of patients with OI. METHODS: Tibial radiographs of 30 patients with OI fractures, or osteotomies were scored by 3 observers on 2 separate occasions. Each of the 4 cortices was given a score (1=no callus, 2=callus present, 3=bridging callus, and 4=remodeled, fracture not visible) and the modified RUST is the sum of these scores (range, 4 to 16). The interobserver and intraobserver reliabilities were evaluated using intraclass coefficients (ICC) with 95% confidence intervals. RESULTS: The ICC representing the interobserver reliability for the first iteration of scores was 0.926 (0.864 to 0.962) and for the second series was 0.915 (0.845 to 0.957). The ICCs representing the intraobserver reliability for each of the 3 reviewers for the measurements in series 1 and 2 were 0.860 (0.707 to 0.934), 0.994 (0.986 to 0.997), and 0.974 (0.946 to 0.988). CONCLUSIONS: The modified RUST has excellent interobserver and intraobserver reliability in the setting of OI despite challenges related to the poor quality of the bone and its dysplastic nature. The application and routine use of the modified RUST in the OI population will help standardize our evaluation of osteotomy and fracture healing. LEVEL OF EVIDENCE: Level III-retrospective study of nonconsecutive patients.


Assuntos
Consolidação da Fratura , Osteogênese Imperfeita/fisiopatologia , Fraturas da Tíbia/diagnóstico por imagem , Adolescente , Pré-Escolar , Feminino , Humanos , Variações Dependentes do Observador , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/cirurgia , Osteotomia , Radiografia , Reprodutibilidade dos Testes , Estudos Retrospectivos , Fraturas da Tíbia/etiologia , Fraturas da Tíbia/cirurgia , Adulto Jovem
5.
Injury ; 50(12): 2215-2219, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31653500

RESUMO

BACKGROUND: Osteogenesis imperfecta (OI) is a rare genetic bone disease associated with brittle bones and fractures. Among all known types, OI type I is the most common type and characterized by increased bone fragility, low bone mass, distinctly blue-gray sclera, and susceptibility to conductive hearing loss beginning in adolescence. Mutations in genes encoding type I collagen (COL1A1 and COL1A2) contribute to the main pathogenic mechanism of OI. METHODS: Subtle mutation of the COL1A1 gene in the proband was detected by targeted next-generation sequencing (NGS) and confirmed by Sanger sequencing. We then assessed the effect of the mutation on the splicing of the COL1A1 gene by bioinformatics prediction and hybrid minigene splicing assay (HMSA). RESULTS: A novel splice site mutation c.1821+1 G>C was discovered in the proband by NGS and further confirmed by Sanger sequencing, which was also simultaneously identified from the proband's mother and elder sister. Bioinformatics predicted that this mutation would result in a disappearance of the 5' donor splice site in intron 26, thereby leading to abnormal splicing and generation of premature stop codon. The follow-up experimental data generated by HMSA was consistent with this prediction. CONCLUSION: Our study identified a novel splice site mutation that caused OI type I in the proband by abnormal splicing and demonstrated that combined applications of NGS, bioinformatics and HMSA are comprehensive and effective methods for diagnosis and aberrant splicing study of OI.


Assuntos
Colágeno Tipo I/genética , Fraturas Ósseas , Osteogênese Imperfeita , Osteoporose , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Feminino , Fraturas Ósseas/diagnóstico , Fraturas Ósseas/fisiopatologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Anamnese , Mutação , Osteogênese Imperfeita/etnologia , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/fisiopatologia , Osteoporose/diagnóstico , Osteoporose/etiologia , Sítios de Splice de RNA , Recidiva
6.
J Pediatr Orthop ; 39(8): e641-e646, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31393309

RESUMO

BACKGROUND: Osteogenesis imperfecta (OI) is a congenital connective tissue disorder often characterized by orthopaedic complications that impact normal gait. As such, mobility is of particular interest in the OI population as it is associated with multiple aspects of participation and quality of life. The purpose of the current study was to identify and describe common gait deviations in a large sample of individuals with type I OI and speculate the etiology with a goal of improving function. METHODS: Gait analysis was performed on 44 subjects with type I (11.7±3.08 y old) and 30 typically developing controls (9.54±3.1 y old ). Spatial temporal, kinematic, and kinetic gait data were calculated from the Vicon Plug-in-Gait Model. Musculoskeletal modeling of the muscle tendon lengths (MTL) was done in OpenSim 3.3 to evaluate the MTL of the gastrocnemius and gluteus maximus. The gait deviation index, a dimensionless parameter that evaluates the deviation of 9 kinematic gait parameters from a control database, was also calculated. RESULTS: Walking speed, single support time, stride, and step length were lower and double support time was higher in the OI group. The gait deviation index score was lower and external hip rotation angle was higher in the OI group. Peak hip flexor, knee extensor and ankle plantarflexor moments, and power generation at the ankle were lower in the OI group. MTL analysis revealed no significant length discrepancies between the OI group and the typically developing group. CONCLUSIONS: Together, these findings provide a comprehensive description of gait characteristics among a group of individuals with type I OI. Such data inform clinicians about specific gait deviations in this population allowing clinicians to recommend more focused interventions. LEVEL OF EVIDENCE: Level III-case-control study.


Assuntos
Análise da Marcha , Instabilidade Articular , Articulações/fisiopatologia , Osteogênese Imperfeita , Qualidade de Vida , Adolescente , Fenômenos Biomecânicos , Estudos de Casos e Controles , Criança , Feminino , Análise da Marcha/métodos , Análise da Marcha/estatística & dados numéricos , Humanos , Instabilidade Articular/diagnóstico , Instabilidade Articular/etiologia , Masculino , Músculo Esquelético/fisiopatologia , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/fisiopatologia , Osteogênese Imperfeita/psicologia , Amplitude de Movimento Articular , Velocidade de Caminhada
7.
Bone ; 127: 646-655, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31369917

RESUMO

Osteogenesis imperfecta (OI) type I caused by the null allele of COL1A1 gene is in the majority in clinical OI cases. Currently, heterozygous Mov-13 mice generated by virus insertion in the first intron of col1a1 is the exclusive model to modulate OI type I, in spite of the gradually recovered bone mineral and mechanical properties. A newly designed heterozygous col1a1±365 OI mouse was produced in the present study by partial exons knockout (exon 2-exon 5, 365 nt of mRNA) using CRISPR/Cas9 system. The deletion resulted in generally large decrease in type I collagen synthesis due to frameshift mutation and premature chain termination, closely mimicking the pathogenic mechanism in affected individuals. And the strain possessed significantly sparse mineral scaffolds, bone loss, lowered mechanical strength and broken bone metabolism by 8 and 20 weeks compared to their littermates, suggesting a sustained skeletal weakness. Notably, the remarkable down-regulation of Yes-associated protein (YAP), one of the key coactivator in Hippo signaling pathway, was first found both in the femur and adipose derived mesenchymal stem cells (ADSCs) under osteogenic differentiation of col1a1±365 mice, which might be responsible for the reduced osteogenic potential and brittle bones. Still, further research was needed in order to illuminate the underlying mechanism.


Assuntos
Doenças do Desenvolvimento Ósseo/patologia , Osteogênese Imperfeita/patologia , Animais , Fenômenos Biomecânicos , Doenças do Desenvolvimento Ósseo/diagnóstico por imagem , Doenças do Desenvolvimento Ósseo/fisiopatologia , Osso e Ossos/metabolismo , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Calcificação Fisiológica , Diferenciação Celular , Colágeno Tipo I/genética , Modelos Animais de Doenças , Fêmur/diagnóstico por imagem , Fêmur/patologia , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Osteogênese , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/fisiopatologia , Transdução de Sinais , Microtomografia por Raio-X
8.
Biosci Rep ; 39(7)2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31239369

RESUMO

Osteogenesis imperfecta (OI) is an inherited connective tissue disorder with a broad clinical spectrum that can overlap with Ehlers-Danlos syndrome (EDS). To date, patients with both OI and EDS have rarely been reported. In the present study, we investigated a family with four members, one healthy individual, one displaying OI only, and two displaying the compound phenotype of OI and EDS, and identified the pathogenic mutations. Whole exome sequencing was applied to the proband and her brother. To verify that the mutations were responsible for the pathogenesis, conventional Sanger sequencing was performed for all members of the family. We identified a known COL1A1 (encoding collagen type I α 1 chain) mutation (c.2010delT, p.Gly671Alafs*95) in all three patients (the proband, her brother, and her mother) in this family, but also a novel heterozygous COL5A1 (encoding collagen type V α 1 chain) mutation (c.5335A>G, p.N1779D) in the region encoding the C-terminal propeptide domain in the proband and her mother, who both had the compound phenotype of OI and EDS. The results of the present study suggested that the proband and her mother presented with the compound OI-EDS phenotype caused by pathogenic mutations in COL5A1 and COL1A1.


Assuntos
Colágeno Tipo I/genética , Colágeno Tipo V/genética , Síndrome de Ehlers-Danlos/genética , Osteogênese Imperfeita/genética , Adolescente , Adulto , Criança , Síndrome de Ehlers-Danlos/fisiopatologia , Feminino , Predisposição Genética para Doença , Heterozigoto , Humanos , Masculino , Mutação , Osteogênese Imperfeita/fisiopatologia , Linhagem , Fenótipo
10.
J Food Sci ; 84(6): 1646-1650, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31116433

RESUMO

Pepino (Solanum muricatum), which is an evergreen plant native to South America, is well-known for its effects in antioxidation, antidiabetic activity, anti-inflammation, and antitumor activity. A previous study in our lab indicated that Solanum muricatum (SM) extract promoted osteogenic differentiation by upregulating Wnt and BMP signaling pathway in rat bone marrow stromal cells. The osteogenesis imperfecta (OI) mouse model was used in order to further discover the osteogenic properties of SM extract in the present research. We utilized microCT analysis to collect bone mass and microarchitectural parameters at vertebrae and at femur metaphysis in OI mice. Raman spectrometry was applied to identify change of bone mineral and matrix composition during SM treatment. Finally, collagen synthesis marker PINP and collagen degradation marker CTX were detected using enzyme immunoassay. SM extract could improve the bone mass and microarchitectural parameters both at vertebrae and at femur metaphysis. It also significantly increased the collagen content by promoting its biosynthesis and inhibiting its degradation. By using heterozygous Col1a1Jrt /+ mice as a model of OI, 6 weeks treatment of SM extract could significantly ameliorate the symptoms in OI mice. Thus, SM holds potential for developing new drugs of bone formation and bone remodeling.


Assuntos
Osteogênese Imperfeita/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Solanum/química , Animais , Densidade Óssea/efeitos dos fármacos , Colágeno/metabolismo , Modelos Animais de Doenças , Feminino , Fêmur/diagnóstico por imagem , Fêmur/efeitos dos fármacos , Fêmur/metabolismo , Humanos , Masculino , Células-Tronco Mesenquimais/efeitos dos fármacos , Células-Tronco Mesenquimais/metabolismo , Camundongos , Osteogênese/efeitos dos fármacos , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/metabolismo , Osteogênese Imperfeita/fisiopatologia , Microtomografia por Raio-X
11.
J Hum Nutr Diet ; 32(5): 619-624, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31037781

RESUMO

BACKGROUND: In several bone disorders, adequate calcium intake is a coadjuvant intervention to regular treatment. Osteogenesis imperfecta (OI) is a collagen disorder with a range of symptoms, ranging from fractures to minimum trauma, and it is typically treated with bisphosphonates. In the present study, we evaluate the impact of a nutritional intervention (NI) on dietary calcium intake and bone mineral density (BMD) in paediatric patients with OI. METHODS: A nonrandomised clinical trial was designed with a NI. Dietary calcium intake, anthropometry and clinical features were assessed at baseline, including anthropometry, basal metabolic rate (BMR), BMD. In addition, a food guidance form was developed and sent to patients by mail. After 12 months, clinical features of patients were reassessed and compared with the baseline data. RESULTS: Fifty-two children and adolescents were enrolled. Significant increases in total calcium intake (mg day-1 ), percentage of adequate calcium intake (%) and number of cups of milk ingested were observed after NI. We detected a positive correlation between the variation of BMD and milk consumption in patients treated with bisphosphonate. CONCLUSIONS: We observed an increase in calcium intake in patients with OI. This finding demonstrates the importance of nutrition therapy as part of a multidisciplinary treatment approach for bone health.


Assuntos
Densidade Óssea/fisiologia , Cálcio na Dieta/análise , Dieta/estatística & dados numéricos , Terapia Nutricional/métodos , Osteogênese Imperfeita/terapia , Adolescente , Antropometria , Criança , Dieta/métodos , Feminino , Humanos , Masculino , Osteogênese Imperfeita/fisiopatologia , Resultado do Tratamento
12.
Injury ; 50 Suppl 2: S52-S56, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30827706

RESUMO

INTRODUCTION: Patients with Osteogenesis Imperfecta (OI) Type 3 may exhibit both primitive deformities and secondary fracture malunions on a femoral level. The orthopaedic surgeon's objective is to cure the deformities in order to prevent fractures and to treat the fractures in order to prevent deformities, by using telescopic nails as the gold standard method of fixation. However, the titanium elastic nail (TEN) is indicated as a possible alternative in certain selected cases. MATERIALS AND METHODS: The Centre for Congenital Osteodystrophy of the Sapienza University of Rome follows 485 patients with osteogenesis imperfecta. For the purpose of this study, we selected 36 patients with OI type 3 (15 females and 21 males), aged between 2 and 10 years old, who were surgically treated for femur fractures with Titanium Elastic Nail (TEN) from January 2007 to December 2009. In 12 cases a single TEN was implanted, while 24 of the cases were treated by implanting 2 TENs with the Sliding Nail (SN) technique. A retrospective evaluation was carried out by analysing the data from the medical charts and dossiers related to pain symptoms, knee and hip Range of Motion (ROM), any possible complications that could cause implant revisions (infections, nail slide failure, nail migration, traumatic events following surgery, delayed consolidation, epiphysiodesis). RESULTS: At the 60th post-surgical month, the revision rate was 75%, mostly due to migration, osteolysis, nail slide failure and nail fracture. The Kaplan-Meier's survival curve analysis showed a coefficient of 0.25-60 months (confidence interval -0.31 and 0.81). DISCUSSION: The percentage of complications and the high rate of revisions recorded in our sample confirm that telescopic nail is the gold standard in the treatment of femoral fractures in patients with OI type 3. CONCLUSIONS: In patients under the age of 4, with narrow medullary canals, low life expectancy, few to nil rehabilitative prospectives or severe comorbidities, the use of TEN may be considered as a less invasive approach compared to telescopic nail surgery, however only temporarily, as it will still most probably require a surgical revision a few years down the line.


Assuntos
Fraturas do Fêmur/cirurgia , Fêmur/anormalidades , Fixação Intramedular de Fraturas/instrumentação , Consolidação da Fratura/fisiologia , Osteogênese Imperfeita/cirurgia , Pinos Ortopédicos , Criança , Pré-Escolar , Feminino , Fraturas do Fêmur/etiologia , Fraturas do Fêmur/fisiopatologia , Fêmur/cirurgia , Guias como Assunto , Humanos , Masculino , Osteogênese Imperfeita/complicações , Osteogênese Imperfeita/fisiopatologia , Reoperação , Estudos Retrospectivos , Resultado do Tratamento
13.
J Bone Miner Res ; 34(9): 1646-1659, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30908713

RESUMO

Osteogenesis imperfecta (OI) is a heritable connective tissue disorder that most often arises from type I collagen-COL1A1 and COL1A2-gene defects leading to skeletal fragility, short stature, blue-gray sclera, and muscle weakness. Relative to the skeletal fragility, muscle weakness is much less understood. Recent investigations into OI muscle weakness in both patients and mouse models have revealed the presence of an inherent muscle pathology. Understanding the mechanisms responsible for OI muscle weakness is critical, particularly in light of the extensive cross-talk between muscle and bone via mechanotransduction and biochemical signaling. In the following study we initially subjected WT and oim/oim mice, modeling severe human OI type III, to either weight-bearing (voluntary wheel-running) or non-weight-bearing (swimming) exercise regimens as a modality to improve muscle strength and ultimately bone strength. The oim/oim mice ran only 35% to 42% of the distance run by age- and sex-matched WT mice and exhibited little improvement with either exercise regimen. Upon further investigation, we determined that oim/oim gastrocnemius muscle exhibited severe mitochondrial dysfunction as characterized by a 52% to 65% decrease in mitochondrial respiration rates, alterations in markers of mitochondrial biogenesis, mitophagy, and the electron transport chain components, as well as decreased mitochondrial citrate synthase activity, relative to age- and sex-matched WT gastrocnemius muscle. Thus, mitochondrial dysfunction in the oim/oim mouse likely contributes to compromised muscle function and reduced physical activity levels. © 2019 American Society for Bone and Mineral Research.


Assuntos
Mitocôndrias/patologia , Osteogênese Imperfeita/fisiopatologia , Condicionamento Físico Animal , Animais , Biomarcadores/metabolismo , Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , DNA Mitocondrial/metabolismo , Modelos Animais de Doenças , Transporte de Elétrons , Feminino , Glicogênio/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Mitocondriais/metabolismo , Mitofagia , Músculos/ultraestrutura , Tamanho do Órgão , Biogênese de Organelas , Natação
14.
Genet Med ; 21(10): 2311-2318, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-30918359

RESUMO

PURPOSE: Osteogenesis imperfecta (OI) is a genetic connective tissue disorder that causes bone fragility. Phenotypic severity influences ability to walk, however, little is known about ambulatory characteristics of individuals with OI, especially in more severe forms. The purpose of this work was to characterize mobility in OI using standard clinical assessment tools and determine if patient characteristics could be used to predict mobility outcomes. METHODS: We collected mobility data at five clinical sites to analyze the largest cohort of individuals with OI (n = 491) to date. Linear mixed models were developed to explore relationships among subject demographics and mobility metrics. RESULTS: Results showed minor limitations in the mild group while the more severe types showed more significant limitations in all mobility metrics analyzed. Height and weight were shown to be the most significant predictors of mobility. Relationships with mobility and bisphosphonates varied with OI type and type used (oral/IV). CONCLUSION: These results are significant to understanding mobility limitations of specific types of OI and beneficial when developing rehabilitation protocols for this population. It is important for physicians, patients, and caregivers to gain insight into severity and classification of the disease and the influence of disease-related characteristics on prognosis for mobility.


Assuntos
Limitação da Mobilidade , Osteogênese Imperfeita/fisiopatologia , Osteogênese Imperfeita/reabilitação , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , América do Norte , Fenótipo , Prognóstico
15.
J Hum Genet ; 64(4): 291-296, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30692598

RESUMO

A rare form of osteogenesis imperfecta (OI) caused by Wingless-type MMTV integration site family 1 (WNT1) mutations combines central nervous system (CNS) anomalies with the characteristic increased susceptibility to fractures. We report an additional case where arachnoid cysts extend the phenotype, and that also confirms the association of intellectual disabilities with asymmetric cerebellar hypoplasia here. Interestingly, if the cerebellum is normal in this disorder, intelligence is as well, analogous to an association with similar delays in a subset of patients with sporadic unilateral cerebellar hypoplasia. Those cases typically appear to represent vascular disruptions, and we suggest that most brain anomalies in WNT1-associated OI have vascular origins related to a role for WNT1 in CNS angiogenesis. This unusual combination of benign cerebellar findings with effects on higher functions in these two situations raises the possibility that WNT1 is involved in the pathogenesis of the associated sporadic cases as well. Finally, our patient reacted poorly to pamidronate, which appears ineffective with this form of OI, so that a lack of improvement is an indication for molecular testing that includes WNT1.


Assuntos
Sistema Nervoso Central/fisiopatologia , Deficiência Intelectual/genética , Osteogênese Imperfeita/genética , Proteína Wnt1/genética , Cistos Aracnóideos/diagnóstico por imagem , Cistos Aracnóideos/fisiopatologia , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/diagnóstico por imagem , Cerebelo/anormalidades , Cerebelo/diagnóstico por imagem , Cerebelo/fisiopatologia , Deficiências do Desenvolvimento/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Lobo Frontal/diagnóstico por imagem , Lobo Frontal/fisiopatologia , Humanos , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/tratamento farmacológico , Deficiência Intelectual/fisiopatologia , Mutação , Malformações do Sistema Nervoso/diagnóstico por imagem , Malformações do Sistema Nervoso/genética , Malformações do Sistema Nervoso/fisiopatologia , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/fisiopatologia , Pamidronato/administração & dosagem , Pamidronato/efeitos adversos
16.
Orphanet J Rare Dis ; 14(1): 23, 2019 01 29.
Artigo em Inglês | MEDLINE | ID: mdl-30696467

RESUMO

BACKGROUND: Patient reported outcome (PRO) information is crucial for establishing better patient-provider communication, improving shared decision-making between clinicians and patients, assessing patient responses to therapeutic interventions, and increasing satisfaction with care. We used the Brittle Bones Disease Consortium (BBDC) Contact Registry for People with OI, managed by the Rare Disease Clinical Research Network (RDCRN) to (1) to evaluate the construct validity of the Patient-Reported Outcome Measurement Information System® (PROMIS®) to record important components of the disease experience among individuals with OI; and (2) explore the feasibility of using a registry to recruit individuals with OI to report on health status. Our long-term goal is to enhance communication of health and disease management findings back to the OI community, especially those who do not have access to major OI clinical centers. RESULTS: We demonstrated the construct validity of PROMIS instruments in OI. Our results confirm that the scores from most domains differ significantly from the general US population: individuals with OI have worse symptom burden and functioning. We found no excessive floor or ceiling effects. Our study demonstrates that the BBDC Contact Registry can be used to recruit participants for online health status surveys. However, there are numerous challenges that must be addressed: lack of self-knowledge of OI type, under-representation of men, limited ethnic diversity, and imperfect questionnaire completion rates. CONCLUSION: Our pilot study demonstrated the feasibility of using a contact registry to recruit respondents from the OI community and to obtain analyzable PROMIS data regarding disease experience. Because the results differ from the general population and avoid excessive floor and ceiling effects, PROMIS instruments can be used to assess response to therapeutic interventions in individuals with OI. Future directions will include (1) development and validation of an OI-specific patient-based classification system that aggregates persons with similar clinical characteristics and risks for complications to identify treatment needs; and (2) integrating these PRO tools into routine patient care and research studies.


Assuntos
Osteogênese Imperfeita/fisiopatologia , Doenças Raras/fisiopatologia , Adolescente , Fatores Etários , Criança , Pré-Escolar , Tomada de Decisão Clínica , Feminino , Humanos , Masculino , Projetos Piloto , Qualidade de Vida , Fatores Sexuais
17.
Genet Med ; 21(2): 275-283, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-29970925

RESUMO

PURPOSE: Osteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI. METHODS: Using data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves. RESULTS: In children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was -4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P < 0.001), age, bisphosphonate use, and rodding (P < 0.05). CONCLUSION: From the largest cohort of individuals with OI, we provide median values for height, weight, and BMI z-scores that can aid the evaluation of overall growth in the clinic setting. This study is an important first step in the generation of OI-specific growth curves.


Assuntos
Estatura/fisiologia , Peso Corporal/fisiologia , Osteogênese Imperfeita/epidemiologia , Adolescente , Adulto , Índice de Massa Corporal , Criança , Pré-Escolar , Difosfonatos/uso terapêutico , Feminino , Humanos , Masculino , América do Norte , Osteogênese Imperfeita/tratamento farmacológico , Osteogênese Imperfeita/fisiopatologia , Pamidronato/uso terapêutico , Adulto Jovem
18.
Am J Med Genet A ; 179(1): 65-70, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30289614

RESUMO

Severe forms of osteogenesis imperfecta (OI) are usually caused by mutations in genes that code for collagen Type I and frequently are associated with craniofacial abnormalities. However, the dental and craniofacial characteristics of OI caused by the p.Ser40Leu mutation in the IFITM5 gene have not been reported. We investigated a 15-year-old girl with severe OI caused by this mutation. She had marked deformations of extremity long bones. There were no clinical or radiological signs of dentinogenesis imperfecta, but one tooth was missing and several teeth were impacted. Cone beam computed tomography revealed a generalized osteopenic appearance of the craniofacial skeleton, bilateral enlargement of mandibular bodies, and areas of cortical erosions. The cranial base and skull showed a generalized granular bone pattern with a mixture of osteosclerosis and osteolysis. Sphenoid and frontal sinuses were congenitally missing. Cephalometric analysis indicated a Class III growth pattern. In this case, the IFITM5 p.Ser40Leu mutation did not affect tooth structure but was associated with deformities in craniofacial bones that resemble those in the other parts of the skeleton.


Assuntos
Anormalidades Craniofaciais/genética , Proteínas de Membrana/genética , Osteogênese Imperfeita/genética , Adolescente , Cefalometria , Anormalidades Craniofaciais/diagnóstico por imagem , Anormalidades Craniofaciais/fisiopatologia , Feminino , Humanos , Masculino , Mutação , Osteogênese Imperfeita/diagnóstico por imagem , Osteogênese Imperfeita/fisiopatologia , Fenótipo
19.
Osteoporos Int ; 30(2): 461-468, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30569229

RESUMO

In this large-sample study, we demonstrated that osteogenesis imperfecta (OI) significantly impaired the quality of life (QoL) in children. Moderate/severe OI patients had worse QoL scores than patients with mild OI. Furthermore, the QoL for OI patients was correlated with the presence of pathogenic gene mutations. INTRODUCTION: Osteogenesis imperfecta (OI) is a hereditary disease characterized by multiple fragility fractures and progressive skeletal deformities. No detailed investigations about the quality of life (QoL) have been carried out in a large sample of patients with OI. We evaluated the QoL and its influencing factors in a large and well-characterized OI cohort. METHODS: We used a validated questionnaire of PedsQL 4.0 to evaluate the health-related quality of life (HRQoL) of children and adolescents with OI. We compared HRQoL among patients with OI types I, III, and IV. The relationship between HRQoL and pathogenic mutations in candidate OI genes was investigated. We also evaluated the influencing factors of HRQoL in OI patients. RESULTS: A total of 138 children with OI and 138 healthy controls were enrolled in this study. The HRQoL scores of OI patients were 64.4 ± 30.0, 71.9 ± 22.2, 75.7 ± 24.8, 63.7 ± 24.5, and 68.9 ± 22.0 in physical, emotional, social, school functioning, and total score, respectively, which were significantly lower than those of healthy children (86.5 ± 12.7, 83.3 ± 16.0, 92.1 ± 11.8, 87.5 ± 11.8, and 87.3 ± 10.7, all p < 0.01). Moderate and severe OI (type III/IV) patients had poorer HRQoL scores than patients with mild OI (type I). Gene mutations inducing qualitative defects in type I collagen led to worse HRQoL scores than those with quantitative defects in type I collagen, except in emotional functioning. The total HRQoL score was positively correlated with family income, lumbar, and femoral bone mineral density (BMD) Z-scores and negatively correlated with disease severity and fracture frequency. CONCLUSION: HRQoL was significantly impaired in OI patients, and patients with more severe OI had poorer HRQoL scores. For the first time, we found that children with qualitative defects in type I collagen had poorer HRQoL scores than those with quantitative defects in type I collagen.


Assuntos
Osteogênese Imperfeita/reabilitação , Qualidade de Vida , Adolescente , Densidade Óssea/genética , Estudos de Casos e Controles , Criança , Pré-Escolar , Colágeno Tipo I/genética , Estudos Transversais , Feminino , Genótipo , Humanos , Masculino , Mutação , Osteogênese Imperfeita/genética , Osteogênese Imperfeita/fisiopatologia , Osteogênese Imperfeita/psicologia , Fraturas por Osteoporose/genética , Fraturas por Osteoporose/fisiopatologia , Fraturas por Osteoporose/psicologia , Fraturas por Osteoporose/reabilitação , Fenótipo , Psicometria , Índice de Gravidade de Doença , Fatores Socioeconômicos
20.
World J Pediatr ; 15(1): 4-11, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30343446

RESUMO

BACKGROUND: Bone remodeling is a lifelong process due to the balanced activity of osteoclasts (OCs), the bone-reabsorbing cells, and osteoblasts (OBs), and the bone-forming cells. This equilibrium is regulated by numerous cytokines, but it has been largely demonstrated that the RANK/RANKL/osteoprotegerin and Wnt/ß-catenin pathways play a key role in the control of osteoclastogenesis and osteoblastogenesis, respectively. The pro-osteoblastogenic activity of the Wnt/ß-catenin can be inhibited by sclerostin and Dickkopf-1 (DKK-1). RANKL, sclerostin and DKKs-1 are often up-regulated in bone diseases, and they are the target of new monoclonal antibodies. DATA SOURCES: The authors performed a systematic literature search in PubMed and EMBASE to June 2018, reviewed and selected articles, based on pre-determined selection criteria. RESULTS: We re-evaluated the role of RANKL, osteoprotegerin, sclerostin and DKK-1 in altered bone remodeling associated with some inherited and acquired pediatric diseases, such as type 1 diabetes mellitus (T1DM), alkaptonuria (AKU), hemophilia A, osteogenesis imperfecta (OI), 21-hydroxylase deficiency (21OH-D) and Prader-Willi syndrome (PWS). To do so, we considered recent clinical studies done on pediatric patients in which the roles of RANKL-RANK/osteoprotegerin and WNT-ß-catenin signaling pathways have been investigated, and for which innovative therapies for the treatment of osteopenia/osteoporosis are being developed. CONCLUSIONS: The case studies taken into account for this review demonstrated that quite frequently both bone reabsorbing and bone deposition are impaired in pediatric diseases. Furthermore, for some of them, bone damage began in childhood but only manifested with age. The use of denosumab could represent a valid alternative therapeutic approach to improve bone health in children, although further studies need to be carried out.


Assuntos
Reabsorção Óssea/fisiopatologia , Osteoprotegerina/sangue , Ligante RANK/sangue , Via de Sinalização Wnt/fisiologia , Hiperplasia Suprarrenal Congênita/sangue , Hiperplasia Suprarrenal Congênita/fisiopatologia , Alcaptonúria/sangue , Alcaptonúria/fisiopatologia , Biomarcadores/sangue , Remodelação Óssea/fisiologia , Reabsorção Óssea/sangue , Criança , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/fisiopatologia , Hemofilia A/sangue , Hemofilia A/fisiopatologia , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Osteogênese Imperfeita/sangue , Osteogênese Imperfeita/fisiopatologia , Síndrome de Prader-Willi/sangue , Síndrome de Prader-Willi/fisiopatologia , Regulação para Cima/fisiologia
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