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1.
Calcif Tissue Int ; 2024 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-38836890

RESUMEN

Osteogenesis imperfecta (OI) is a Mendelian connective tissue disorder associated with increased bone fragility and other clinical manifestations most commonly due to abnormalities in production, structure, or post-translational modification of type I collagen. Until recently, most research in OI has focused on the pediatric population and much less attention has been directed at the effects of OI in the adult population. This is a narrative review of the literature focusing on the skeletal as well as non-skeletal manifestations in adults with OI that may affect the aging individual. We found evidence to suggest that OI is a systemic disease which involves not only the skeleton, but also the cardiopulmonary and gastrointestinal system, soft tissues, tendons, muscle, and joints, hearing, eyesight, dental health, and women's health in OI and potentially adds negative affect to health-related quality of life. We aim to guide clinicians as well as draw attention to obvious knowledge gaps and the need for further research in adult OI.

2.
Am J Hum Genet ; 107(5): 989-999, 2020 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-33053334

RESUMEN

Osteogenesis imperfecta (OI) is characterized primarily by susceptibility to fractures with or without bone deformation. OI is genetically heterogeneous: over 20 genetic causes are recognized. We identified bi-allelic pathogenic KDELR2 variants as a cause of OI in four families. KDELR2 encodes KDEL endoplasmic reticulum protein retention receptor 2, which recycles ER-resident proteins with a KDEL-like peptide from the cis-Golgi to the ER through COPI retrograde transport. Analysis of patient primary fibroblasts showed intracellular decrease of HSP47 and FKBP65 along with reduced procollagen type I in culture media. Electron microscopy identified an abnormal quality of secreted collagen fibrils with increased amount of HSP47 bound to monomeric and multimeric collagen molecules. Mapping the identified KDELR2 variants onto the crystal structure of G. gallus KDELR2 indicated that these lead to an inactive receptor resulting in impaired KDELR2-mediated Golgi-ER transport. Therefore, in KDELR2-deficient individuals, OI most likely occurs because of the inability of HSP47 to bind KDELR2 and dissociate from collagen type I. Instead, HSP47 remains bound to collagen molecules extracellularly, disrupting fiber formation. This highlights the importance of intracellular recycling of ER-resident molecular chaperones for collagen type I and bone metabolism and a crucial role of HSP47 in the KDELR2-associated pathogenic mechanism leading to OI.


Asunto(s)
Huesos/metabolismo , Colágeno Tipo I/metabolismo , Proteínas del Choque Térmico HSP47/metabolismo , Osteogénesis Imperfecta/genética , Proteínas de Transporte Vesicular/metabolismo , Adulto , Alelos , Secuencia de Aminoácidos , Animales , Sitios de Unión , Huesos/patología , Pollos , Preescolar , Colágeno Tipo I/química , Colágeno Tipo I/genética , Retículo Endoplásmico/metabolismo , Retículo Endoplásmico/patología , Femenino , Fibroblastos/metabolismo , Fibroblastos/patología , Expresión Génica , Aparato de Golgi/metabolismo , Aparato de Golgi/patología , Proteínas del Choque Térmico HSP47/química , Proteínas del Choque Térmico HSP47/genética , Humanos , Lactante , Masculino , Osteogénesis Imperfecta/diagnóstico , Osteogénesis Imperfecta/metabolismo , Osteogénesis Imperfecta/patología , Linaje , Cultivo Primario de Células , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Estructura Secundaria de Proteína , Transporte de Proteínas , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Proteínas de Transporte Vesicular/química , Proteínas de Transporte Vesicular/genética
3.
Am J Hum Genet ; 105(4): 836-843, 2019 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-31564437

RESUMEN

Osteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, OI-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated WNT signaling could benefit individuals with MESD-associated OI.


Asunto(s)
Chaperonas Moleculares/genética , Mutación , Osteogénesis Imperfecta/genética , Animales , Femenino , Genes Recesivos , Células HEK293 , Humanos , Proteína-5 Relacionada con Receptor de Lipoproteína de Baja Densidad/metabolismo , Proteína-6 Relacionada a Receptor de Lipoproteína de Baja Densidad/metabolismo , Masculino , Ratones , Linaje , Fenotipo , Vía de Señalización Wnt
4.
Osteoporos Int ; 33(7): 1601-1611, 2022 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-35435480

RESUMEN

We assessed lower-limb geometry in adults with X-linked hypophosphatemia (XLH) and controls. We found large differences in multiple measures including femoral and tibial torsion, bowing and cross-sectional area and acetabular version and coverage which may contribute to clinical problems such as osteoarthritis, fractures and altered gait common in XLH. PURPOSE: Individuals with X-linked hypophosphatemia (XLH) are at risk of lower-limb deformities and early onset of osteoarthritis. These two factors may be linked, as altered biomechanics is a risk factor for osteoarthritis. This exploratory evaluation aims at providing clues and concepts for this association to facilitate future larger-scale and longitudinal studies on that aspect. METHODS: For this observational study, 13 patients with XLH, aged 18-65 years (6 female), were compared with sex-, age- and weight-matched healthy individuals at a single German research centre. Femoral and hip joint geometry, including femoral and tibial torsion and femoral and tibial shaft bowing, bone cross-sectional area (CSA) and acetabular version and coverage were measured from magnetic resonance imaging (MRI) scans. RESULTS: Total femoral torsion was 29° lower in individuals with XLH than in controls (p < 0.001), mainly resulting from lower intertrochanteric torsion (ITT) (p < 0.001). Femoral lateral and frontal bowing, tibial frontal bowing, mechanical axis, femoral mechanical-anatomical angle, acetabular version and acetabular coverage were all greater and tibial torsion lower in individuals with XLH as compared to controls (all p < 0.05). Greater femoral total and marrow cavity CSA, greater tibial marrow cavity CSA and lower cortical CSA were observed in XLH (all p < 0.05). DISCUSSION: We observed large differences in clinically relevant measures of tibia and particularly femur bone geometry in individuals with XLH compared to controls. These differences may plausibly contribute to clinical manifestations of XLH such as early-onset osteoarthritis, pseudofractures and altered gait and therefore should be considered when planning corrective surgeries.


Asunto(s)
Raquitismo Hipofosfatémico Familiar , Osteoartritis , Adulto , Raquitismo Hipofosfatémico Familiar/complicaciones , Raquitismo Hipofosfatémico Familiar/patología , Femenino , Fémur/patología , Humanos , Extremidad Inferior , Tibia/diagnóstico por imagen , Tibia/patología
5.
J Clin Densitom ; 25(3): 334-342, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35168895

RESUMEN

Children and adolescents with cerebral palsy (CP) are at increased risk of low trauma fractures (LTF) due to low bone mineral content (BMC). The risk of LTFs might be overestimated by only age - and sex adjusted Z-scores for BMC because Z-score based DXA techniques do not take into account other relevant parameters like height, muscle and fat mass. This study aimed to present an update of the functional muscle-bone unit-algorithm (uFMBU-A) to evaluate bone health in children with CP in order to predict the risk of LTF taking into account the parameters sex, age, height, muscle and fat mass. We performed a monocentric retrospective analysis of 177 DXA-scans of children and adolescents with CP aged 8-19. Six of these 177 patients had sustained at least 1 LTF. Age-, sex- and size adjusted Z-scores of total body less head (TBLH)-BMC, lean body mass and fat mass were calculated. The uFMBU-A was applied to the study group and results were compared with established Z-score based DXA-measurements and algorithm based diagnostic techniques concerning the prediction of LTF risk. The uFMBU-A had the greatest diagnostic odds ratio (13.3 [95% CI 2.41; 72.9]) of the evaluated predictors with a sensitivity of 50.0% (95% CI 11.8; 88.2), specifity of 93% (95% CI 88.1; 96.3). The uFMBU-A was the most accurate method of the evaluated parameters to predict LTF in children with CP and is recommended when evaluating bone health.


Asunto(s)
Parálisis Cerebral , Fracturas Osteoporóticas , Absorciometría de Fotón/métodos , Adolescente , Densidad Ósea/fisiología , Parálisis Cerebral/diagnóstico por imagen , Niño , Humanos , Músculos , Estudios Retrospectivos
6.
J Musculoskelet Neuronal Interact ; 22(2): 284-291, 2022 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35642707

RESUMEN

The results of three cases with infantile-onset Pompe disease participating in a rehabilitation program with home-based vibration training will be presented. In this retrospective observational case study, the cases participated in the neuromuscular training program "Auf die Beine", which combines two blocks of intensive, goal directed training with 6 months of home-based whole body vibration (WBV). Assessments by the means of a dual-energy X-ray absorptiometry and grip strength were applied at multiple points throughout the program. Two cases showed an increase in lean mass index of +0.319 kg/m2, +0.721 kg/m2 and bone mineral content of +0.028 kg/m2, +0.031 kg/m2 over one year. Additionally physiotherapeutic therapy goals could be achieved. In the remaining child lean mass index did not change, bone mineral content decreased by -0.03 kg. The neuromuscular rehabilitation program "Auf die Beine" has shown to be safe and effective in two of three cases for muscle and bone mass gain as well as in achievement of physiotherapeutic goals. To summarize, WBV is an innovative therapy in a rehabilitation concept, which might be helpful in Pompe disease, but further studies with larger cohorts are needed.


Asunto(s)
Enfermedad del Almacenamiento de Glucógeno Tipo II , Vibración , Absorciometría de Fotón , Niño , Humanos , Modalidades de Fisioterapia , Estudios Retrospectivos , Vibración/uso terapéutico
7.
Neuropediatrics ; 51(6): 407-416, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33065752

RESUMEN

BACKGROUND: The efficacy of interventions for cerebral palsy (CP) has been frequently investigated with inconclusive results and motor function measured by the Gross Motor Function Measure (GMFM-66) is common. OBJECTIVE: In this observational analysis, we quantify the GMFM-66 change scores of the second and third year of a multimodal rehabilitation program (interval rehabilitation including home-based, vibration-assisted training) in children with CP. METHODS: The study was a retrospective analysis of children with CP (2-13 years) participating for a second (n = 262) and third year (n = 86) in the rehabilitation program with GMFM-66 scores at start (M0), after 4 months (M4) of intensive training, and after 8 months of follow-up (M12). A method was previously developed to differentiate between possible treatment effects and expected development under standard of care for GMFM-66 scores using Cohen's d effect size (ES; size of difference). RESULTS: After the treatment phase of 4 months (M4) in the second year, 125 of 262 children were responder (ES ≥ 0.2) and 137 children nonresponder (ES < 0.2); mean ES for nonresponder was -0.212 (trivial) and for responder 0.836 (large). After M4 in the third year, 43 children of 86 were responder (ES = 0.881 [large]) and 43 nonresponder (ES = -0.124 [trivial]). DISCUSSION AND CONCLUSION: Repeated rehabilitation shows a large additional treatment effect to standard of care in 50% of children which is likely due to the intervention, because in the follow-up period (standard of care), no additional treatment effect was observed and the children followed their expected development.


Asunto(s)
Parálisis Cerebral/rehabilitación , Actividad Motora , Modalidades de Fisioterapia , Niño , Femenino , Humanos , Masculino , Índice de Severidad de la Enfermedad , Resultado del Tratamiento
8.
Dev Med Child Neurol ; 61(10): 1168-1174, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-30927269

RESUMEN

AIM: To evaluate the diagnostic performance of anthropometric indicators to identify undernutrition in children with cerebral palsy (CP). METHOD: The present study was a monocentric retrospective analysis of prospectively collected data among children and adolescents with CP participating in a rehabilitation program. Undernutrition was defined as a z-score for dual-energy X-ray absorptiometry (DXA) determined body fat percentage less or equal to -2.0. The cut-off values for body mass index (BMI) of the World Health Organization (WHO) and the Centers for Disease Control and Prevention (CDC), and the cut-off values for BMI and height for age of the Robert Koch Institut (RKI) were evaluated. RESULTS: In total, 329 children with CP (181 males, 148 females, Gross Motor Function Classification System levels I-V) were eligible for analysis. The mean age was 12 years 4 months (SD 2y 9mo). The BMI cut-off values showed the following sensitivities and specificities: WHO, sensitivity of 0.474 (95% confidence interval [CI] 0.244-0.711), specificity of 0.897 (95% CI: 0.857-0.928); CDC, sensitivity of 0.632 (95% CI: 0.384-0.837), specificity of 0.819 (95% CI: 0.772-0.861); RKI, sensitivity of 0.789 (95% CI: 0.544-0.939), specificity of 0.732 (95% CI: 0.679-0.781); and for height for age, sensitivity of 0.263 (95% CI: 0.091-0.512), specificity of 0.668 (95% CI: 0.612-0.720). INTERPRETATION: BMI had a high specificity but very low sensitivity in identifying undernutrition in children with CP. Z-scores for height for age had even lower specificity and sensitivity and seemed not to be appropriate for predicting undernutrition in children with CP. WHAT THIS PAPER ADDS: Body mass index (BMI) z-scores had a high specificity but very low sensitivity in identifying undernutrition in children with cerebral palsy (CP). Height z-scores were not appropriate for predicting undernutrition in children with CP. Undernutrition assessed by BMI was overestimated in children with CP versus when assessed by dual-energy X-ray absorptiometry (DXA).


MEDICIONES ANTROPOMÉTRICAS PARA IDENTIFICAR DESNUTRICIÓN EN NIÑOS CON PARÁLISIS CEREBRAL: OBJETIVO: Evaluar el rendimiento diagnóstico de los indicadores antropométricos para identificar la desnutrición en niños con parálisis cerebral (PC). MÉTODO: El presente estudio realizado en un solo centro de atención, fue un análisis retrospectivo de datos recopilados prospectivamente entre niños y adolescentes con PC que participan en un programa de rehabilitación. La desnutrición se definió como una puntuación z para la absorciometría de rayos X de energía dual (DXA), y porcentaje de grasa corporal determinado menor o igual a -2,0. Fueron evaluados los valores de corte para el índice de masa corporal (IMC) de la Organización Mundial de la Salud (OMS) y los Centros para el Control y la Prevención de Enfermedades (CDC), y los valores de corte para el IMC y la altura para la edad del Robert Koch Institut (RKI). RESULTADOS: En total, 329 niños con PC (181 varones, 148 mujeres, con niveles I - V del Sistema de clasificación de la función motora gruesa) fueron elegibles para el análisis. La edad media fue de 12 años 4 meses (DS 2a 9m). Los valores de corte del IMC mostraron las siguientes sensibilidades y especificidades: OMS, sensibilidad de 0,474 (intervalo de confianza del 95% [IC] 0,244-0,711), especificidad de 0,897 (IC del 95%: 0,857-0,928); CDC, sensibilidad de 0,632 (IC del 95%: 0,384 a 0,837), especificidad de 0,819 (IC del 95%: 0,772 a 0,861); RKI, sensibilidad de 0,789 (IC 95% 0,544-0,939), especificidad de 0,732 (IC 95% 0,679-0,781); y para la altura para la edad, la sensibilidad de 0,263 (IC del 95%: 0,091 a 0,512), la especificidad de 0,668 (IC del 95%: 0,612 a 0,720). INTERPRETACIÓN: El IMC tenía una alta especificidad, pero una sensibilidad muy baja para identificar la desnutrición en niños con PC. Las puntuaciones Z para la altura para la edad tenían una especificidad y sensibilidad aún más bajas y no parecían ser adecuadas para predecir la desnutrición en niños con PC.


MEDIDAS ANTROPOMÉTRICAS PARA IDENTIFICAR SUBNUTRIÇÃO EM CRIANÇAS COM PARALISIA CEREBRAL: OBJETIVO: Avaliar o desempenho diagnóstico de indicadores antropométricos para avaliar subnutrição em crianças com paralisia cerebral (PC). MÉTODO: O presente estudo foi uma análise monocêntrica retrospectiva de dados coletados prospectivamente entre crianças e adolescentes com PC que participavam de um programa de reabilitação. A subnutrição foi definida como um escore z para porcentagem de gordura corporal determinada por absorciometria de dupla energia de raio-X (DXA) menor ou igual a -2.0. Os valores de corte para o índice de massa corporal IMC) da Organização Mundial de Saúde (OMS) e dos Centros para Controle e Prevenção de Doenças (CCPD), e os valores de corte para IMC e altura por idade do Robert Koch Institut (RKI) foram avaliados. RESULTADOS: No total, 329 crianças com PC (181 do sexo masculino, 148 do sexo feminino, níveis do Sistema de Classificação da Função Motora Grossa I-V) foram elegíveis para análise. A média de idade foi 12 anos e 4 meses (DP 2a 9m). Os valores de corte do IMC mostraram as seguintes sensibilidades e especificidades: OMS, sensibilidade de 0,474 (intervalo de confiança [IC] a 95% 0,244-0,711), especificidade de 0,897 (IC 95% 0,857-0,928); CCPD, sensibilidade de 0,632 (IC 95% 0,384-0,837), especifididade de 0,819 (IC 95% 0,772-0,861); RKI, sensibilidade de 0,789 (IC 95% 0,544-0,939), especificidade de 0,732 (IC 95% 0,679-0,781); e de altura por idade, sensibilidade de 0,263 (IC 95% 0,091-0,512), especificidade de 0,668 (IC 95% 0,612-0,720). INTERPRETAÇÃO: O IMC teve alta especificidade mas sensibilidade muito baixa para identificar subnutrição em crianças com PC. Os escores z para altura por idade tiveram especificidade ainda menor e não pareceram apropriados para predizer subnutrição em crianças com PC.


Asunto(s)
Parálisis Cerebral/complicaciones , Trastornos de la Nutrición del Niño/diagnóstico , Antropometría , Índice de Masa Corporal , Niño , Trastornos de la Nutrición del Niño/complicaciones , Femenino , Humanos , Masculino , Estudios Retrospectivos , Sensibilidad y Especificidad
9.
Eur J Pediatr ; 178(6): 811-822, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30877384

RESUMEN

The purpose of this study was to create growth-percentiles for Caucasian children with cerebral palsy (CP). The studied parameters were height and age. In a retrospective analysis, we converted measurements collected in our center to create disorder-specific percentiles of normative data. Patients were stratified due to sex (male and female) and to mobility levels using the gross motor function classification system (GMFCS) (A = walking; GMFCS I-III, B = non walking; GMFCS IV-V) into four groups. In total, 2363 measurements in patients 0-18 years were collected. The mean age for group "Am" was 6.8 years (n = 862), group "Bm" 7.6 years (n = 563), group "Af" 7.7 years (n = 600), and group "Bf" 8.2 years (n = 366). The created percentiles for all groups were below the reference percentiles for healthy Caucasian children (KiGGS). The median curve for children with GMFCS levels I-III is slightly above the 3rd percentile, whereas the 50th percentile for GMFCS levels IV-V is mostly below the 3rd KiGGS centile.Conclusion: In conclusion, children with cerebral palsy are smaller than healthy children. The difference between 50th percentile of CP patients compared to healthy children supports the need for the use of disorder-specific growth charts. Those charts can help clinicians differentiate growth disorders in patients with CP. What is Known: • Children with cerebral palsy are shorter than healthy children and height is influenced by level of ambulation. • Currently, only reference percentiles of American children with mixed ethical backgrounds are available to evaluate growth. What is New: • This paper presents disorder-specific reference percentiles for longitudinal growth of Caucasian children with cerebral palsy depending on motor function. • These percentiles allow to asses longitudinal growth in children with cerebral palsy to detect other additional diseases impairing growth.


Asunto(s)
Parálisis Cerebral/fisiopatología , Desarrollo Infantil , Gráficos de Crecimiento , Caminata , Adolescente , Adulto , Estatura , Estudios de Casos y Controles , Niño , Preescolar , Femenino , Humanos , Masculino , Estudios Retrospectivos , Población Blanca , Adulto Joven
10.
J Clin Densitom ; 22(2): 229-235, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-30309730

RESUMEN

INTRODUCTION/BACKGROUND: Osteogenesis imperfecta is a hereditary connective tissue disorder, resulting in low bone mass and high bone fragility. Dual-energy X-ray absorptiometry (DXA) and in adulthood also the trabecular bone score (TBS) are well established to assess bone health and fracture risk. The purpose of this investigation was to assess the usefulness of TBS in respect to different treatment regimes in children with osteogenesis imperfecta. Changes of areal bone mineral density (aBMD) and TBS using DXA scans of children treated with antiresorptive therapies were evaluated. METHODOLOGY: DXA scans (aBMD, TBS) of 8 children with OI were evaluated. The scans were taken during a 1 yr period of treatment with bisphosphonates and during 1 yr pilot trial using denosumab. Changes of aBMD and TBS during both treatment regimens were compared. RESULTS: During bisphosphonate treatment aBMD increased about 6.2%, while TBS increased about 2.1%. The difference between aBMD and TBS before and after bisphosphonate treatment was not significant (p = 0.25). During denosumab treatment aBMD increased around 25.1%, while TBS increased 6.7%. The change of aBMD was significant (p = 0.007), as was the difference between aBMD and TBS (p < 0.001). CONCLUSIONS: Denosumab had a significant effect on both aBMD and TBS but was significantly more pronounced in aBMD. These results suggest a stronger effect of denosumab on cortical bone and the growth plate in comparison to bisphosphonates. Beside the lack of paediatric reference data and the small sample size, the results suggest TBS to be a useful tool for monitoring skeletal changes during development, growth, and antiresorptive therapy in children with OI.


Asunto(s)
Conservadores de la Densidad Ósea/uso terapéutico , Hueso Esponjoso/diagnóstico por imagen , Hueso Cortical/diagnóstico por imagen , Denosumab/uso terapéutico , Difosfonatos/uso terapéutico , Vértebras Lumbares/diagnóstico por imagen , Osteogénesis Imperfecta/tratamiento farmacológico , Absorciometría de Fotón , Densidad Ósea , Niño , Preescolar , Femenino , Placa de Crecimiento/diagnóstico por imagen , Humanos , Masculino , Osteogénesis Imperfecta/diagnóstico por imagen , Resultado del Tratamiento
11.
Klin Padiatr ; 231(6): 304-312, 2019 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-31724139

RESUMEN

BACKGROUND: Physiotherapy, including vibration-assisted therapy, has been proven to be effective for patients with ataxic cerebral palsy. Herewith, we studied the effect of a functional, goal-oriented interval rehabilitation program, including vibration-assisted home-training on the motor function of children with congenital ataxias. PATIENTS: 45 children (mean age 7.7 years, SD 4.70) with ataxia, having received a 6-month home-based side-alternating vibration-assisted therapy combined with intensive, goal-oriented, functional rehabilitation intervals, were included in the study, classified according to the progressive or non-progressive ataxia character. METHOD: Retrospective analysis of the prospectively collected data of the registry of the Cologne rehabilitation program "Auf die Beine". Motor abilities have been assessed prior to the intervention (M0), after 6 months of home-training (M6) as well as in a follow-up 6 months later (M12). We performed a gait analysis, a 1-minute walking test (1-MWT), and the Gross Motor Function Measure (GMFM-66). RESULTS: The GMFM-66 improvement (M6-M0 vs. M12-M6) was statistically significant with median improvement of 2.4 points (non-progressive) and 2.9 points (progressive) respectively, and clinically relevant. The 1-MWT improvement was statistically significant and clinically relevant for non-progressive ataxia. CONCLUSION: The intensive training, including vibration-assisted therapy significantly improved the motor function of children with ataxia. Six months later the skills were preserved in children with progressive ataxia and could be further developed in non-progressive forms.


Asunto(s)
Ataxia/rehabilitación , Parálisis Cerebral/rehabilitación , Modalidades de Fisioterapia , Vibración/uso terapéutico , Niño , Femenino , Humanos , Masculino , Destreza Motora , Estudios Retrospectivos , Resultado del Tratamiento
12.
Z Rheumatol ; 78(7): 636-644, 2019 Sep.
Artículo en Alemán | MEDLINE | ID: mdl-31338681

RESUMEN

BACKGROUND: In juvenile idiopathic arthritis and related chronic inflammatory diseases, proinflammatory cytokines inhibit bone formation and stimulate bone resorption. Anti-inflammatory drugs, such as glucocorticoids and nonsteroidal antirheumatic drugs (NSARD) have as a side effect the potential to inhibit growth and maintenance of bone. These issues are of particular importance for the growing skeleton in childhood and adolescence. OBJECTIVE: This article presents a narrative overview about the dimension of the problem, a critical evaluation of diagnostic procedures and a discussion of available countermeasures. METHODS: A systematic literature search was carried out and the available evidence was evaluated based on the authors' knowledge and clinical experience as experts in the field. RESULTS AND CONCLUSION: In recent years solid data have been accumulated with respect to the interpretation of bone mineral density (BMD) measurements in children and adolescents. Based on these data from the literature and given that the radiation exposure is also very low, it is now possible to clinically apply BMD measurements in this population using dual energy X­ray absorption (DXA) technology for risk evaluation and diagnosis, taking the respective phase of development and body length into consideration. Dynamic measurements over time appear to be especially valuable in the context of individual clinical data. Hence, BMD measurements can be helpful in monitoring bone health, especially in juvenile idiopathic arthritis and other related inflammatory diseases. Apart from the specific indications for extended diagnostics and bone targeted pharmacological treatment, this method can also contribute to the management of preventive measures, such as sufficient calcium and vitamin D intake and targeted exercise interventions. Even in times of extremely effective antirheumatic drugs, children with chronic inflammatory diseases still bear a risk for bone health.


Asunto(s)
Artritis Juvenil , Densidad Ósea , Huesos/efectos de los fármacos , Glucocorticoides/efectos adversos , Absorciometría de Fotón , Adolescente , Artritis Juvenil/complicaciones , Artritis Juvenil/tratamiento farmacológico , Huesos/fisiología , Niño , Fracturas Óseas , Glucocorticoides/uso terapéutico , Humanos , Radiografía
13.
Am J Hum Genet ; 96(3): 432-9, 2015 Mar 05.
Artículo en Inglés | MEDLINE | ID: mdl-25683121

RESUMEN

As a result of a whole-exome sequencing study, we report three mutant alleles in SEC24D, a gene encoding a component of the COPII complex involved in protein export from the ER: the truncating mutation c.613C>T (p.Gln205(∗)) and the missense mutations c.3044C>T (p.Ser1015Phe, located in a cargo-binding pocket) and c.2933A>C (p.Gln978Pro, located in the gelsolin-like domain). Three individuals from two families affected by a similar skeletal phenotype were each compound heterozygous for two of these mutant alleles, with c.3044C>T being embedded in a 14 Mb founder haplotype shared by all three. The affected individuals were a 7-year-old boy with a phenotype most closely resembling Cole-Carpenter syndrome and two fetuses initially suspected to have a severe type of osteogenesis imperfecta. All three displayed a severely disturbed ossification of the skull and multiple fractures with prenatal onset. The 7-year-old boy had short stature and craniofacial malformations including macrocephaly, midface hypoplasia, micrognathia, frontal bossing, and down-slanting palpebral fissures. Electron and immunofluorescence microscopy of skin fibroblasts of this individual revealed that ER export of procollagen was inefficient and that ER tubules were dilated, faithfully reproducing the cellular phenotype of individuals with cranio-lentico-sutural dysplasia (CLSD). CLSD is caused by SEC23A mutations and displays a largely overlapping craniofacial phenotype, but it is not characterized by generalized bone fragility and presented with cataracts in the original family described. The cellular and morphological phenotypes we report are in concordance with the phenotypes described for the Sec24d-deficient fish mutants vbi (medaka) and bulldog (zebrafish).


Asunto(s)
Craneosinostosis/genética , Anomalías del Ojo/genética , Hidrocefalia/genética , Osteogénesis Imperfecta/genética , Proteínas de Transporte Vesicular/genética , Alelos , Animales , Huesos/patología , Niño , Retículo Endoplásmico/metabolismo , Femenino , Heterocigoto , Humanos , Masculino , Mutación Missense , Linaje , Fenotipo , Conformación Proteica , Análisis de Secuencia de ADN , Proteínas de Transporte Vesicular/metabolismo , Pez Cebra/genética
14.
Pediatr Endocrinol Rev ; 15(Suppl 1): 123-129, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29292876

RESUMEN

Osteogenesis imperfecta (OI) is a rare hereditary skeletal disease leading to recurrent fractures, short stature and impaired mobility. The phenotype varies from mildly affected patients to perinatal lethal forms. In most cases an impaired collagen production due to mutations in COL1A1 or COL1A2 cause this hereditary bone fragility syndrome with an autosomal dominant inheritance. Currently an interdisciplinary therapeutic approach with antiresorptive drugs, physiotherapy and surgical procedures is the state of the art therapy. The effect of such a therapy is evaluated by measuring different surrogate parameters like areal bone mineral density or by using different mobility tests or questionnaires. Up till now the impact of these parameters on quality of life of the patients is not evaluated. Currently pharmacological strategies are based on antiresorptive treatment with bisphosphonates. In this trial we investigated the effect of an antiresorptive therapy with the monoclonal antibody denosumab decreasing the activity of osteoclasts. Denosumab was administered subcutaneously in a dose of 1mg/kg body weight in 10 children with OI (5-10 years of age) every 12 weeks for 48 weeks. Areal bone mineral density, mobility, pain scores and quality of life were measured. The results showed a good effect of the treatment on bone mineral density but this improvement showed no correlation to pain and quality of life. In conclusion further trials have to define parameters to assess interventions which influence activities of daily life of the patients. An interdisciplinary approach including physicians, basic researchers and patient organisation is needed to focus research on topics improving quality of life of patients with severe skeletal diseases.


Asunto(s)
Denosumab/uso terapéutico , Osteogénesis Imperfecta , Densidad Ósea , Conservadores de la Densidad Ósea , Niño , Preescolar , Humanos , Osteogénesis Imperfecta/tratamiento farmacológico , Calidad de Vida
15.
Am J Hum Genet ; 92(4): 565-74, 2013 Apr 04.
Artículo en Inglés | MEDLINE | ID: mdl-23499309

RESUMEN

We report that hypofunctional alleles of WNT1 cause autosomal-recessive osteogenesis imperfecta, a congenital disorder characterized by reduced bone mass and recurrent fractures. In consanguineous families, we identified five homozygous mutations in WNT1: one frameshift mutation, two missense mutations, one splice-site mutation, and one nonsense mutation. In addition, in a family affected by dominantly inherited early-onset osteoporosis, a heterozygous WNT1 missense mutation was identified in affected individuals. Initial functional analysis revealed that altered WNT1 proteins fail to activate canonical LRP5-mediated WNT-regulated ß-catenin signaling. Furthermore, osteoblasts cultured in vitro showed enhanced Wnt1 expression with advancing differentiation, indicating a role of WNT1 in osteoblast function and bone development. Our finding that homozygous and heterozygous variants in WNT1 predispose to low-bone-mass phenotypes might advance the development of more effective therapeutic strategies for congenital forms of bone fragility, as well as for common forms of age-related osteoporosis.


Asunto(s)
Densidad Ósea/genética , Huesos/patología , Mutación/genética , Osteogénesis Imperfecta/genética , Osteoporosis/genética , Proteína Wnt1/genética , Animales , Secuencia de Bases , Células Cultivadas , Niño , Preescolar , Femenino , Heterocigoto , Humanos , Recién Nacido , Proteínas Relacionadas con Receptor de LDL/genética , Masculino , Ratones , Ratones Endogámicos C57BL , Datos de Secuencia Molecular , Osteoblastos/metabolismo , Osteoblastos/patología , Osteogénesis Imperfecta/patología , Osteoporosis/patología , Linaje , Fenotipo , Embarazo
16.
J Clin Densitom ; 19(2): 208-15, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26059565

RESUMEN

Conventional lateral spine and hand radiographs are the standard tools to evaluate vertebral morphometry and bone age in children. Beside bone mineral density analyses, dual-energy X-ray absorptiometry (DXA) measurements with lower radiation exposure provide high-resolution scans which are not approved for diagnostic purposes. Data about the comparability of conventional radiographs and DXA in children are missing yet. The purpose of the trial was to evaluate whether conventional hand and spine radiographs can be replaced by DXA scans to diminish radiation exposure. Thirty-eight children with osteogenesis imperfecta or secondary osteoporosis or short stature (male, n=20; age, 5.0-17.0 yr) were included and assessed once by additional DXA (GE iDXA) of the spine or the left hand. Intraclass correlation coefficients (ICCs) were used to express agreement between X-ray and iDXA assessment. Evaluation of the spine morphometry showed reasonable agreement between iDXA and radiography (ICC for fish-shape, 0.75; for wedge-shape, 0.65; and for compression fractures, 0.70). Bone age determination showed excellent agreement between iDXA and radiography (ICC, 0.97). IDXA-scans of the spine in a pediatric population should be used not only to assess bone mineral density but also to evaluate anatomic structures and vertebral morphometry. Therefore, iDXA can replace some radiographs in children with skeletal diseases.


Asunto(s)
Absorciometría de Fotón/métodos , Osteogénesis Imperfecta/diagnóstico , Osteoporosis/diagnóstico , Radiografía/métodos , Columna Vertebral/diagnóstico por imagen , Adolescente , Determinación de la Edad por el Esqueleto/métodos , Estatura , Densidad Ósea , Desarrollo Óseo , Niño , Preescolar , Investigación sobre la Eficacia Comparativa , Femenino , Alemania , Humanos , Masculino , Salud Radiológica/métodos , Reproducibilidad de los Resultados
17.
Am J Hum Genet ; 91(2): 349-57, 2012 Aug 10.
Artículo en Inglés | MEDLINE | ID: mdl-22863195

RESUMEN

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous disorder associated with bone fragility and susceptibility to fractures after minimal trauma. OI type V has an autosomal-dominant pattern of inheritance and is not caused by mutations in the type I collagen genes COL1A1 and COL1A2. The most remarkable and pathognomonic feature, observed in ~65% of affected individuals, is a predisposition to develop hyperplastic callus after fractures or surgical interventions. To identify the molecular cause of OI type V, we performed whole-exome sequencing in a female with OI type V and her unaffected parents and searched for de novo mutations. We found a heterozygous de novo mutation in the 5'-untranslated region of IFITM5 (the gene encoding Interferon induced transmembrane protein 5), 14 bp upstream of the annotated translation initiation codon (c.-14C>T). Subsequently, we identified an identical heterozygous de novo mutation in a second individual with OI type V by Sanger sequencing, thereby confirming that this is the causal mutation for the phenotype. IFITM5 is a protein that is highly enriched in osteoblasts and has a putative function in bone formation and osteoblast maturation. The mutation c.-14C>T introduces an upstream start codon that is in frame with the reference open-reading frame of IFITM5 and is embedded into a stronger Kozak consensus sequence for translation initiation than the annotated start codon. In vitro, eukaryotic cells were able to recognize this start codon, and they used it instead of the reference translation initiation signal. This suggests that five amino acids (Met-Ala-Leu-Glu-Pro) are added to the N terminus and alter IFITM5 function in individuals with the mutation.


Asunto(s)
Proteínas de la Membrana/genética , Osteogénesis Imperfecta/genética , Regiones no Traducidas 5'/genética , Absorciometría de Fotón , Secuencia de Aminoácidos , Secuencia de Bases , Niño , Codón Iniciador/genética , Biología Computacional , Difosfonatos/uso terapéutico , Exoma/genética , Femenino , Humanos , Lactante , Datos de Secuencia Molecular , Osteogénesis Imperfecta/diagnóstico por imagen , Osteogénesis Imperfecta/tratamiento farmacológico , Mutación Puntual/genética , Análisis de Secuencia de ADN
18.
Am J Hum Genet ; 90(4): 661-74, 2012 Apr 06.
Artículo en Inglés | MEDLINE | ID: mdl-22482805

RESUMEN

Bone morphogenetic protein 1 (BMP1) is an astacin metalloprotease with important cellular functions and diverse substrates, including extracellular-matrix proteins and antagonists of some TGFß superfamily members. Combining whole-exome sequencing and filtering for homozygous stretches of identified variants, we found a homozygous causative BMP1 mutation, c.34G>C, in a consanguineous family affected by increased bone mineral density and multiple recurrent fractures. The mutation is located within the BMP1 signal peptide and leads to impaired secretion and an alteration in posttranslational modification. We also characterize a zebrafish bone mutant harboring lesions in bmp1a, demonstrating conservation of BMP1 function in osteogenesis across species. Genetic, biochemical, and histological analyses of this mutant and a comparison to a second, similar locus reveal that Bmp1a is critically required for mature-collagen generation, downstream of osteoblast maturation, in bone. We thus define the molecular and cellular bases of BMP1-dependent osteogenesis and show the importance of this protein for bone formation and stability.


Asunto(s)
Proteína Morfogenética Ósea 1/fisiología , Osteogénesis/genética , Osteogénesis/fisiología , Animales , Secuencia de Bases , Conservadores de la Densidad Ósea/uso terapéutico , Proteína Morfogenética Ósea 1/genética , Proteína Morfogenética Ósea 1/metabolismo , Huesos/metabolismo , Diferenciación Celular , Preescolar , Colágeno/biosíntesis , Difosfonatos/uso terapéutico , Exoma , Femenino , Fracturas Óseas/tratamiento farmacológico , Fracturas Óseas/prevención & control , Sitios Genéticos , Proteínas de Choque Térmico , Humanos , Masculino , Datos de Secuencia Molecular , Mutación , Osteoblastos/efectos de los fármacos , Osteoblastos/fisiología , Osteogénesis/efectos de los fármacos , Fragmentos de Péptidos , Procesamiento Proteico-Postraduccional , Pez Cebra/genética , Pez Cebra/metabolismo
19.
Wien Med Wochenschr ; 165(13-14): 278-84, 2015 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-26055811

RESUMEN

Osteogenesis imperfecta is a rare hereditary disease mostly caused by mutations impairing collagen synthesis and modification. Recently recessive forms have been described influencing differentiation and activity of osteoblasts and osteoclasts. Most prominent signs are fractures due to low traumata and deformities of long bones and vertebrae. Additional patients can be affected by dwarfism, scoliosis Dentinogenesis imperfecta, deafness and a blueish discoloration of the sclera. During childhood state of the art medical treatment are i.v. bisphosphonates to increase bone mass and to reduce fracture rate. Surgical interventions are needed to treat fractures, to correct deformities and should always be accompanied by physiotherapeutic and rehabilitative interventions.


Asunto(s)
Osteogénesis Imperfecta/fisiopatología , Osteogénesis Imperfecta/terapia , Colágeno Tipo I/genética , Cadena alfa 1 del Colágeno Tipo I , Terapia Combinada , Análisis Mutacional de ADN , Difosfonatos/administración & dosificación , Femenino , Fijación de Fractura , Fracturas Espontáneas/genética , Fracturas Espontáneas/fisiopatología , Fracturas Espontáneas/terapia , Tamización de Portadores Genéticos , Humanos , Lactante , Recién Nacido , Infusiones Intravenosas , Masculino , Osteoblastos/fisiología , Osteoclastos/fisiología , Osteogénesis Imperfecta/genética , Modalidades de Fisioterapia
20.
Am J Hum Genet ; 88(3): 362-71, 2011 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-21353196

RESUMEN

Osteogenesis imperfecta (OI) is a heterogeneous genetic disorder characterized by bone fragility and susceptibility to fractures after minimal trauma. After mutations in all known OI genes had been excluded by Sanger sequencing, we applied next-generation sequencing to analyze the exome of a single individual who has a severe form of the disease and whose parents are second cousins. A total of 26,922 variations from the human reference genome sequence were subjected to several filtering steps. In addition, we extracted the genotypes of all dbSNP130-annotated SNPs from the exome sequencing data and used these 299,494 genotypes as markers for the genome-wide identification of homozygous regions. A single homozygous truncating mutation, affecting SERPINF1 on chromosome 17p13.3, that was embedded into a homozygous stretch of 2.99 Mb remained. The mutation was also homozygous in the affected brother of the index patient. Subsequently, we identified homozygosity for two different truncating SERPINF1 mutations in two unrelated patients with OI and parental consanguinity. All four individuals with SERPINF1 mutations have severe OI. Fractures of long bones and severe vertebral compression fractures with resulting deformities were observed as early as the first year of life in these individuals. Collagen analyses with cultured dermal fibroblasts displayed no evidence for impaired collagen folding, posttranslational modification, or secretion. SERPINF1 encodes pigment epithelium-derived factor (PEDF), a secreted glycoprotein of the serpin superfamily. PEDF is a multifunctional protein and one of the strongest inhibitors of angiogenesis currently known in humans. Our data provide genetic evidence for PEDF involvement in human bone homeostasis.


Asunto(s)
Exones/genética , Proteínas del Ojo/genética , Genes Recesivos/genética , Mutación/genética , Factores de Crecimiento Nervioso/genética , Osteogénesis Imperfecta/genética , Serpinas/genética , Adolescente , Secuencia de Bases , Niño , Preescolar , Análisis Mutacional de ADN , Homocigoto , Humanos , Lactante , Datos de Secuencia Molecular , Osteogénesis Imperfecta/diagnóstico por imagen , Radiografía
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