RESUMEN
Buschke-Ollendorff syndrome is a rare autosomal dominant condition caused by pathogenic variants in LEMD3 and characterized by connective tissue nevi and sclerotic bone abnormalities known as osteopoikilosis. The bone phenotype in Buschke-Ollendorff syndrome including osteopoikilosis remains unclear. We investigated bone turnover markers, pelvis and crura X-rays; lumbar spine and femoral neck DXA; bone activity by NaF-PET/CT, bone structure by µCT and dynamic histomorphometry in adults with Buschke-Ollendorff syndrome. Two women aged 25 and 47 years with a BMI of 30 and 32 kg/m2, respectively, were included in the investigation. Bone turnover markers were within normal range. aBMD Z-scores were comparable to that of controls in the lumbar spine and increased at the hip. Radiographies exposed spotted areas in crura and pelvis, and NaF-PET/CT exposed abnormal pattern of irregular shaped NaF uptake in the entire skeleton. In both biopsies, µCT showed trabecular structure comparable to that of controls with stellate shaped sclerotic noduli within the cavity and on the endocortex. Histomorphometric analyses of the sclerotic lesions revealed compact lamellar bone with a normal bone remodeling rate, but partly replaced by modeling-based bone formation. Woven bone was not observed in the nodules. Therefore, while bone turnover and BMD were largely within normal reference range in patients with the Buschke-Ollendorff syndrome, osteosclerotic lesions appear to emerge due to modeling-based bone formation with secondary bone remodeling. These observations indicate that LEMD3 may be important for the activation of bone lining cells leading to modeling-based bone formation.
Asunto(s)
Osteopoiquilosis , Adulto , Hueso Cortical , Femenino , Humanos , Osteogénesis , Osteopoiquilosis/diagnóstico por imagen , Osteopoiquilosis/genética , Tomografía Computarizada por Tomografía de Emisión de Positrones , Enfermedades Cutáneas GenéticasRESUMEN
Carriers of the mitochondrial mutation m.3243A>G presents highly variable phenotypes including mitochondrial encephalomyopathy, lactoacidosis and stroke-like episodes (MELAS). We conducted a follow-up study to evaluate changes in leucocyte heteroplasmy and the clinical phenotypes in m.3243A>G carriers. Leucocyte heteroplasmy was determined by next generation sequencing covered by 100 000X reads in 32 individuals with a median follow-up of 10.2 years. Ten-year clinical follow-up is reported in 46 individuals. The annual leucocyte mutation level declined by -0.7 (±0.4) percentage points/year (P < .0001), and correlated with the level of the initial sample (ρ = -0.92, P < .0001). Eleven of 46 m.3243A>G carriers died and clinical symptoms progressed. This longitudinal study shows the decline in leucocyte m.3243A>G heteroplasmy associates with the level of the initial sample. Further, there was a high mortality among carriers.
Asunto(s)
ADN Mitocondrial/genética , Secuenciación de Nucleótidos de Alto Rendimiento , Síndrome MELAS/genética , Niño , Femenino , Estudios de Seguimiento , Heterocigoto , Humanos , Leucocitos/metabolismo , Leucocitos/patología , Síndrome MELAS/patología , Masculino , Mutación , Fenotipo , Estudios ProspectivosRESUMEN
BACKGROUND AND PURPOSE: Over the last three decades mitochondrial dysfunction has been postulated to be a potential mechanism in migraine pathogenesis. The lifetime prevalence of migraine in persons carrying the 3243A>G mutation in mitochondrial DNA was investigated. METHODS: In this cross-sectional study, 57 mDNA 3243A>G mutation carriers between May 2012 and October 2014 were included. As a control group, a population-based cohort from our epidemiological studies on migraine in Danes was used. History of headache and migraine was obtained by telephone interview, based on a validated semi-structured questionnaire, performed by trained physicians. RESULTS: The prevalence of migraine is significantly higher in persons carrying the 3243A>G mutation than in controls (58% vs. 18%; P < 0.001). This applies for both subforms of migraine, migraine without aura (47% vs. 12%; P < 0.001) and migraine with aura (18% vs. 6%; P < 0.001), and in females (58% vs. 24%; P < 0.001) and males (58% vs. 12%; P < 0.001) for any migraine. CONCLUSIONS: A high prevalence of migraine in persons with the mDNA 3243A>G mutation was found. This finding suggests a clinical association between a monogenetically inherited disorder of mitochondrial dysfunction and susceptibility to migraine. Mitochondrial DNA aberrations may contribute to the pathogenesis of migraine.
Asunto(s)
ADN Mitocondrial/genética , Trastornos Migrañosos/epidemiología , Trastornos Migrañosos/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Dinamarca/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Prevalencia , Adulto JovenRESUMEN
INTRODUCTION: Short-stature homeobox (SHOX) gene haploinsufficiency may cause skeletal dysplasia including Léri-Weill Dyschondrosteosis (LWD), a clinical entity characterised by the triad of low height, mesomelic disproportion and Madelung's deformity of the wrist. Bone microarchitecture and estimated strength in adult SHOX mutation carriers have not been examined. METHODS: Twenty-two subjects with a SHOX mutation including 7 males and 15 females with a median age of 38.8 [21.1-52.2] years were recruited from five unrelated families. The control group consisted of 22 healthy subjects matched on age and sex. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry. Bone geometry, volumetric density, microarchitecture and finite element estimated (FEA) bone strength were measured using high-resolution peripheral quantitative computed tomography (HR-pQCT). A full region of interest (ROI) image analysis and height-matched ROI analyses adjusting for differences in body height between the two groups were performed. RESULTS: Areal BMD and T-scores showed no significant differences between cases and controls. Total radius area was smaller in cases than controls (207 [176-263] vs. 273 [226-298] mm, p<0.01). Radius cortical bone area (74 ± 20 vs. 58 ± 17 mm(2), p=0.01) and thickness (1.16 ± 0.30 vs. 0.84 ± 0.26 mm, p<0.01) as well as total density (428 ± 99 vs. 328 ± 72 mg/cm(3), p<0.01) were higher in SHOX mutation carriers compared to controls. Radius trabecular bone area (119 [103-192] vs. 202 [168-247] mm(2), p<0.01) and trabecular number (1.61 [1.46-2.07] vs. 1.89 [1.73-2.08] mm(-1), p=0.01) were smaller in SHOX mutation carriers. Tibia trabecular thickness was lower in cases (0.067 ± 0.012 vs. 0.076 ± 0.012 mm, p=0.01). These results remained significant after adjustment for differences in body height and when restricting analyses to females. There were no differences in BMD, radius and tibia cortical porosity or FEA failure load between groups. A segment of cortical bone defect was identified in the distal radius adjacent to ulna in five unrelated SHOX mutation carriers. CONCLUSION: Subjects with a SHOX mutation presented with a different bone geometry in radius and tibia while there were no differences in BMD or failure load compared to controls, suggesting that mutations in SHOX gene may have an impact on bone microarchitecture albeit not bone strength.
Asunto(s)
Proteínas de Homeodominio/genética , Mutación , Radio (Anatomía)/diagnóstico por imagen , Absorciometría de Fotón , Adulto , Densidad Ósea , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteína de la Caja Homeótica de Baja Estatura , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
BACKGROUND: The 3243A-->G is a common pathogenic mitochondrial DNA (mtDNA) point mutation causing a variety of different phenotypes. Segregation of this mutation to different tissues during embryonic life and postnatally is still enigmatic. OBJECTIVE: To investigate the tissue distribution of this mutation. METHODS: In 65 individuals from nine families segregating the 3243A-->G mutation, the mutation load (% mutated mtDNA) was determined in various tissues. Mutation load was measured in two to four cell types--blood leucocytes, buccal cells, skeletal muscle cells, and urine epithelial cells (UEC)--derived from all three embryogenic germ layers. RESULTS: There was a significant correlation among mutation loads in the four tissues (r = 0.80-0.89, p<0.0001). With blood serving as reference, the mutation load was increased by 16% in buccal mucosa, by 31% in UEC, and by 37% in muscle. There were significant differences between the mitotic tissues blood, buccal mucosa, and UEC (p<0.0001), but no difference between UEC and muscle. Using the present data as a cross sectional investigation, a negative correlation of age with the mutation load was found in blood, while the mutation load in muscle did not change with time; 75% of the children presented with higher mutation loads than their mothers in mitotic tissues but not in the post-mitotic muscle. CONCLUSIONS: There appears to be a uniform distribution of mutant mtDNA throughout the three germ layers in embryogenesis. The significant differences between mutation loads of the individual tissue types indicate tissue specific segregation of the 3243A-->G mtDNA later in embryogenesis.