ABSTRACT
Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive neurological dysfunction. To date, only supportive care aimed to halt the progressive neurodegeneration is available for the treatment. Recently, an improvement of neurological signs during short-term treatment with betamethasone has been reported. To date, the molecular and biochemical mechanisms by which the steroid produces such effects have not yet been elucidated. Therefore, a review of the literature was carried out to define the potential molecular and functional targets of the steroid effects in A-T. Glucocorticoids (GCs) are capable of diffusing into the CNS by crossing the blood-brain barrier (BBB) where they exert effects on the suppression of inflammation or as antioxidant. GCs have been shown to protect post-mitotic neurons from apoptosis. Eventually, GCs may also modulate synaptic plasticity. A better understanding of the mechanisms of action of GCs in the brain is needed, because in A-T during the initial phase of cell loss the neurological impairment may be rescued by interfering in the biochemical pathways. This would open a new window of intervention in this so far incurable disease.
Subject(s)
Ataxia Telangiectasia/drug therapy , Ataxia Telangiectasia/physiopathology , Betamethasone/therapeutic use , Cell Cycle Proteins/physiology , DNA-Binding Proteins/physiology , Glucocorticoids/therapeutic use , Nerve Degeneration/drug therapy , Neuronal Plasticity/drug effects , Protein Serine-Threonine Kinases/physiology , Tumor Suppressor Proteins/physiology , Ataxia Telangiectasia/genetics , Ataxia Telangiectasia Mutated Proteins , Betamethasone/pharmacology , Cell Cycle Proteins/genetics , DNA-Binding Proteins/genetics , Glucocorticoids/physiology , Humans , Models, Genetic , Oxidative Stress/physiology , Protein Serine-Threonine Kinases/genetics , Tumor Suppressor Proteins/geneticsABSTRACT
Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM 607721), recently related to the invariant c.4A>G missense change in SHOC2, is characterized by features reminiscent of Noonan syndrome. Ectodermal involvement, short stature associated with growth hormone (GH) deficiency (GHD), and cognitive deficits are common features. We report on a patient with molecularly confirmed NS/LAH exhibiting severe short stature associated with GH insensitivity (GHI), and chronic complex tics, a neurological feature never described before in this syndrome. IGF1 generation test revealed only a blunted increase in IGF1 after exogenous GH treatment, revealing mild GH insensitivity associated with proper STAT5 activation. Most common causes of secondary tics in childhood were excluded.