RESUMEN
We report clinical and biochemical finding from three unrelated patients presenting ONCE (Optic Neuropathy, Cardiomyopathy and Encephalopathy with lactic acidosis and combined oxidative phosphorylation deficiency) syndrome. Whole-exome sequencing (WES) of the three patients and the healthy sister of one of them was used to identify the carry gene. Clinical and biochemical findings were used to filter variants, and molecular, in silico and genetic studies were performed to characterize the candidate variants. Mitochondrial DNA (mtDNA) defects involving mutations, deletions or depletion were discarded, whereas WES uncovered a double homozygous mutation in the MTO1 gene (NM_001123226:c.1510C>T, p.R504C, and c.1669G>A, p.V557M) in two of the patients and the homozygous mutation p.R504C in the other. Therefore, our data confirm p.R504C as pathogenic mutation responsible of ONCE syndrome, and p.V557M as a rare polymorphic variant.
Asunto(s)
Anomalías Múltiples/genética , Proteínas Portadoras/genética , Predisposición Genética a la Enfermedad/genética , Mutación Missense , Polimorfismo de Nucleótido Simple , Anomalías Múltiples/patología , Acidosis Láctica , Adolescente , Secuencia de Aminoácidos , Encefalopatías , Cardiomiopatías , Exoma/genética , Salud de la Familia , Femenino , Homocigoto , Humanos , Masculino , Enfermedades Mitocondriales , Enfermedades del Nervio Óptico , Linaje , Proteínas de Unión al ARN , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Síndrome , Adulto JovenRESUMEN
BACKGROUND: Individuals with pathogenic variants in SATB2 display intellectual disability, speech and behavioral disorders, dental abnormalities and often features of Pierre Robin sequence. SATB2 encodes a transcription factor thought to play a role in bone remodeling. The primary aim of our study was to systematically review the skeletal manifestations of SATB2-associated syndrome. For this purpose, we performed a non-interventional, multicenter cohort study, from 2017 to 2018. We included 19 patients, 9 females and 10 males ranging in age from 2 to 19 years-old. The following data were collected prospectively for each patient: clinical data, bone markers and calcium and phosphate metabolism parameters, skeletal X-rays and bone mineral density. RESULTS: Digitiform impressions were present in 8/14 patients (57%). Vertebral compression fractures affected 6/17 patients (35%). Skeletal demineralization (16/17, 94%) and cortical thinning of vertebrae (15/17) were the most frequent radiological features at the spine. Long bones were generally demineralized (18/19). The distal phalanges were short, thick and abnormally shaped. C-telopeptide (CTX) and Alkaline phosphatase levels were in the upper normal values and osteocalcin and serum procollagen type 1 amino-terminal propeptide (P1NP) were both increased. Vitamin D insufficiency was frequent (66.7%). CONCLUSION: We conclude that SATB2 pathogenic variants are responsible for skeletal demineralization and osteoporosis. We found increased levels of bone formation markers, supporting the key role of SATB2 in osteoblast differentiation. These results support the need for bone evaluation in children and adult patients with SATB2-associated syndrome (SAS).
Asunto(s)
Fracturas por Compresión , Proteínas de Unión a la Región de Fijación a la Matriz , Fracturas de la Columna Vertebral , Factores de Transcripción , Adolescente , Adulto , Biomarcadores , Densidad Ósea/genética , Huesos , Niño , Preescolar , Estudios de Cohortes , Femenino , Fracturas por Compresión/genética , Fracturas por Compresión/metabolismo , Fracturas por Compresión/patología , Humanos , Masculino , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Estudios Prospectivos , Fracturas de la Columna Vertebral/genética , Fracturas de la Columna Vertebral/metabolismo , Fracturas de la Columna Vertebral/patología , Síndrome , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Adulto JovenRESUMEN
STXBP1 (MUNC18.1), encoding syntaxin binding protein 1, has been reported in Ohtahara syndrome, a rare epileptic encephalopathy with suppression burst pattern on EEG, in patients with infantile spasms and in a few patients with nonsyndromic mental retardation without epilepsy. We report a patient who presented late onset infantile spasms. Epilepsy was controlled but the patient developed severe mental delay. A first diagnosis of mitochondrial disease was based on clinical presentation and on a partial deficit of respiratory chain complex IV, but molecular screening for mitochondrial genes was negative. The sequencing of STXBP1 gene found a de novo nonsense mutation (c.585C>G/p.Tyr195X). This observation widens the clinical spectrum linked to STXBP1 mutations with the description of a patient with late onset infantile spasms. It raises the question of the value of epilepsy genes screening in patients with uncertain, partial or unconfirmed mitochondrial dysfunction.
Asunto(s)
Codón sin Sentido , Complejo IV de Transporte de Electrones/genética , Discapacidad Intelectual/genética , Proteínas Munc18/genética , Espasmos Infantiles/genética , Ondas Encefálicas , Humanos , Lactante , Discapacidad Intelectual/diagnóstico , Síndrome de Lennox-Gastaut , Masculino , Espasmos Infantiles/diagnósticoRESUMEN
The removal of 13 polycyclic aromatic hydrocarbons, 7 polychlorobiphenyls and nonylphenol was measured during the continuous anaerobic digestion of five different sludge samples. The reactors were fed with one of the following: primary/secondary sludge (PS/SS), thermally treated PS, cellulose-added SS, or SS augmented with dissolved and colloidal matter (DCM). These various feeding conditions induced variable levels of micropollutant bioavailability (assumed to limit their biodegradation) and overall metabolism (supposed to be linked to micropollutant metabolism throughout co-metabolism). On the one hand, overall metabolism was higher with secondary sludge than with primary and the same was observed for micropollutant removal. However, when overall metabolism was enhanced thanks to cellulose addition, a negative influence on micropollutant removal was observed. This suggests that either the co-metabolic synergy would be linked to a specific metabolism or co-metabolism was not the limiting factor in this case. On the other hand, micropollutant bioavailability was presumably diminished by thermal treatment and increased by DCM addition. In both cases, micropollutant removal was reduced. These results suggest that neither overall metabolism nor bioavailability would absolutely limit micropollutant removal. Each phenomenon might alternatively predominate depending on the feed characteristics.