In vivo Functional Consequences of Human THRA Variants Expressed in the Zebrafish.

BACKGROUND: Heterozygous mutations in the thyroid hormone receptor alpha (THRA) gene cause resistance to thyroid hormone alpha (RTHα), a disease characterized by variable manifestations reminiscent of untreated congenital hypothyroidism but a raised triiodothyronine/thyroxine ratio and normal thyrotropin levels. It was recently described that zebrafish embryos expressing a dominant negative (DN) form of thraa recapitulate the key features of RTHα, and that zebrafish and human receptors are functionally interchangeable. METHODS: This study expressed several human thyroid hormone receptor alpha (hTRα) variants in zebrafish embryos and analyzed the resulting phenotypes. RESULTS: All hTRα-injected embryos showed variable defects, including cerebral and cardiac edema likely caused by an aberrant looping during heart development, anemia, and an incomplete formation of the vascular network. Moreover, the hTRα-injected embryos presented severe defects of motorneurons and craniofacial development, thus affecting their autonomous feeding and swimming behaviors. Surprisingly, expression of all hTRα mutants had no detectable effect on thyrotropin beta and thyrotropin-releasing hormone transcripts, indicating that their DN action is limited on the thyroid hormone reception beta 2 targets at the hypothalamic/pituitary level in vivo. As previously described in vitro, treatment with high triiodothyronine doses can efficiently revert the observed defects only in embryos injected with missense hTRα variants. CONCLUSION: Injection of human THRA variants in zebrafish embryos causes tissue-specific defects recapitulating most of the RTHα clinical and biochemical manifestations. The described manipulation of zebrafish embryos represents a novel in vivo model to screen the functional consequences of THRA variants and the rescue potential of new therapeutic compounds.

Esclerosis Lateral Amiotrófica, presentación atípica / Atypical presentation of Amyotrophic lateral sclerosis

La esclerosis lateral amiotrófica (ELA) es una enfermedad neurodegenerativa, progresiva, con desenlace fatal, que afecta a neuronas motoras de la médula espinal, tronco cerebral y corteza motora. Se produce un fracaso del sistema motor que dirige, regula y mantiene la musculatura esquelética, responsable de la capacidad para moverse y relacionarse con el entorno. Presentamos el caso de un hombre de 58 años de edad con diagnóstico de ELA, con sintomatología inicial atípica que dificultó el juicio clínico final, resaltando en el diagnóstico diferencial la miopatía por cuerpos de inclusión (AU)

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative fatal disease that affects motor neurons in the spinal cord, brain stem and motor cortex. It produces a failure of the motor system that directs, adjusts and maintains skeletal muscles, responsible for the ability to move and interact with the environment. We report the case of a 58-year-old male diagnosed with ALS, with atypical initial symptoms that hindered the final clinical judgement, and where inclusion body myopathy stood out during the differential diagnosis (AU)

Congenital hypotonia: clinical and developmental assessment.

Identifying the underlying cause of congenital hypotonia remains difficult, despite advances in diagnostic laboratory and imaging techniques. Clinical evaluation strategies and standardized developmental tests can assist in differentiating hypotonia resulting from primary involvement of the upper motoneuron (central hypotonia) versus that involving the lower motoneuron and motor unit (peripheral hypotonia). This is especially important in infants with idiopathic hypotonia. This review outlines and describes the components of the clinical assessment: detailed infant and family history, clinical techniques and characteristics for differentiating hypotonia of central versus peripheral origin, and clinical evaluation (muscle tone, primitive reflexes, deep tendon reflexes, etc). Recent research that has contributed to the differential diagnosis of congenital hypotonia is reviewed and directions for future research are provided. Ideally, the assessment of infants with congenital hypotonia is best accomplished by an interdisciplinary team of developmental specialists including pediatricians, medical geneticists, child neurologists, and physical or occupational therapists.

Neonatal lower motor neuron syndrome associated with maternal neuropathy with anti-GM1 IgG.

The authors report a newborn with motor neuropathy associated with anti-GM1 antibodies from an affected mother. This finding suggests that the disorder was due to transplacental transfer of pathogenic antibodies.