Neurological aspects of the Angelman syndrome

Angelman syndrome (AS) has emerged as an important neurogenetic syndrome due to its relatively high prevalence and easier confirmation of the diagnosis by improved genetic testing. In infancy, nonspecific clinical features of AS pose diagnostic challenges to the neurologist and these include any combination of microcephaly, seizure disorder, global developmental delay or an ataxic/hypotonic cerebral palsy-like picture. In later childhood, however, absent speech, excessively happy behavior, ataxia and jerky movements usually present as a recognizable clinical syndrome. Brain MRI shows nonspecific or normal findings but occasionally the characteristic EEG patterns alone can lead to the correct diagnosis. The physical, clinical and behavioral aspects appear to be attributable to localized CNS dysfunction of the ubiquitin ligase gene, UBE3A, located at 15q11.2. In certain brain regions, UBE3A normally has mono-allelic expression from the maternally derived chromosome 15. Several distinct genetic mechanisms can inactivate or disrupt the maternally derived UBE3A: chromosome microdeletions, paternal uniparental disomy, imprinting defects and intragenic UBE3A mutations. Those with the deletion type of AS are the most prevalent (about 70% of cases) and appear to have a more severe clinical phenotype. The unique epileptic patterns and distinct behavioral features may be related to multiple actions of UBE3A, possibly occurring during, as well as after, the time of neuronal development.     

Neurological aspects in antiphospholipid syndrome]

Antiphospholipid syndrome is considered to be a cause of an acquired hypercoagulable state leading to stroke and transient ischemic attack. Antiphospholipid antibodies (aPL) comprise a heterogeneous group of autoantibodies. Among them, lupus anticoagulant (LA) and beta 2-glycoprotein I dependent anticardiolipin antibody (beta 2-GPI aCL) are important and commonly measured. Recently, LA has been considered to be closely related to phosphatidylserine anti-prothrombin antibody. APL is an independent risk factor for first-ever ischemic stroke and a prognostic marker of recurrent stroke. The precipitating factors for the occurrence of stroke are the presence of beta 2-GPI-dependent aCL, a GPL aCL level of more than 40, and the simultaneous presence of lupus anticoagulant. Several mechanisms are believed to be involved in the thrombotic process in patients with antiphospholipid antibodies. Human activated protein C functions as a potent anticoagulant in human plasma by inhibiting the activity of coagulation cofactors Va and VIIIa. Activation of protein C is impaired in patients with aPL. Recently, the presence of aPL has been considered to be contributory factor for the development of atherosclerotic lesions. Transgenic mouse lacking the LDL receptor develop accelerated arteriosclerosis upon immunization with beta 2-GPL Several therapeutic options are available for the prevention of ischemic stroke in patients with aPL, such as antiplatelet, anticoagulant, and immunosuppressive therapy. The rate of recurrence in patients undergoing antiplatelet and anticoagulation combination therapy was found to be lower than that in patients receiving other forms of therapy. The WARSS-APASS collaborative study showed that there was no difference in the recurrence rate between aPL patients receiving antiplatelet or anticoagulation therapy alone. APL has been investigated in other neurological disorders such as multiple sclerosis, chorea, migraine and convulsion. The association of aPL with multiple sclerosis remains debatable. APL could be a contributory factor for the development of convulsion, but not for migraine.     

Neurological aspects of osteopetrosis

The osteopetroses are caused by reduced activity of osteoclasts which results in defective remodelling of bone and increased bone density. They range from a devastating neurometabolic disease, through severe malignant infantile osteopetrosis (OP) to two more benign conditions principally affecting adults [autosomal dominant OP (ADO I and II)]. In many patients the disease is caused by defects in either the proton pump [the a3 subunit of vacuolar-type H(+)-ATPase, encoded by the gene variously termed ATP6i or TCIRG1] or the ClC-7 chloride channel (ClCN7 gene). These pumps are responsible for acidifying the bone surface beneath the osteoclast. Although generally thought of as bone diseases, the most serious consequences of the osteopetroses are seen in the nervous system. Cranial nerves, blood vessels and the spinal cord are compressed by either gradual occlusion or lack of growth of skull foramina. Most patients with OP have some degree of optic atrophy and many children with severe forms of autosomal recessive OP are rendered blind; optic decompression is frequently attempted to prevent the latter. Auditory, facial and trigeminal nerves may also be affected, and hydrocephalus can develop. Stenosis of both arterial supply (internal carotid and vertebral arteries) and venous drainage may occur. The least understood form of the disease is neuronopathic OP [OP and infantile neuroaxonal dystrophy, MIM (Mendelian inheritance in man) 600329] which causes rapid neurodegeneration and death within the first year. Although characterized by the finding of widespread axonal spheroids and accumulation of ceroid lipofuscin, the biochemical basis of this disease remains unknown. The neurological complications of this disease and other variants are presented in the context of the latest classification of the disease.     

Neurological aspects of infantile autism

Childhood autism is not usually considered as a neurological disease although frequent antecedents of ante, peri and postnatal injuries are found in its antecedents. Several symptoms of autism particularly in the early development, resemble the signs observed in frontal, temporal, striatal and brainstem dysfunctioning. These cerebral structures are connected with the central dopaminergic system which may be disturbed in autistic children. Such hypotheses suggest the necessary elaboration of an infant and child "behavioral neurology".     

Neurological aspects of mycoplasmal infection

Mycoplasmal infections may be complicated by a wide variety of systemic syndromes, including neurological disorders. Circumstantial evidence suggests that these are immunologically-induced. A detailed study of five patients with proven mycoplasma pneumoniae and central nervous system signs showed that immunological factors were involved and suggested that the neurological symptoms were due to a vasculopathy.     

Neurological aspects of Fabry's disease

Fabry disease is a rare X-linked disorder caused by deficient activity of the lysosomal enzyme alpha-galactosidase A. Progressive accumulation in lysosomes of the undegraded glycosphingolipids leads to a multi-system disease with dermatological, ocular, renal, cardiac, and neurological manifestations. Peripheral nerve involvement, neuropathic pain and chronic acroparesthesiae, are frequent and early-onset signs revealing the disease. They are due to the involvement of small nerve fiber, thus explaining the normality of electroneuromyography. Cochleo-vestibular and autonomic nervous system involvement is frequent. Besides rare aseptic meningitis, central nervous system involvement is essentially represented by cerebrovascular events (stroke, transient ischemic attack). Affecting essentially the posterior circulation, their etiologies have to be clarified: progressive stenosis of small vessels with globotriasocylceramide deposits, arterial remodeling, endothelial dysfunction, pro-thrombotic state, cerebral hypoperfusion consecutive to dysautonaumy, cardiac embolism. MRI shows numerous silent lesions, increasing with age, mainly in small perforant arteries (periventricular white matter, brainstem, cerebellum, basal ganglia). Pulvinar calcifications, due to an increase in cerebral hyperperfusion, could be specific of Fabry disease. Positon tomography analysis shows a reduced cerebral flow velocity and impaired cerebral autoregulation, secondary to the glycosphingolipid storage in vascular endothelial cells. Enzyme replacement therapy has to be carefully monitored.     

Neurological aspects of vergence eye movements

This review of vergence eye movements emphasizes the importance of performing a more rigorous examination of vergence at the bedside. Furthermore, recent experimental studies have better defined the physiological organization of brain-stem neurons that generate immediate premotor vergence commands. We emphasize analogies with the saccadic system and suggest that there are common organizational features of models for the generation of saccadic and of vergence movements. Finally, using the paradigm of spectacle-corrected anisometropia, we have demonstrated a remarkable adaptive capability that assures proper ocular alignment with changes of gaze.     

Neurological aspects of organophosphate poisoning.

Besides their well-known anticholinesterase action resulting in a typical acute cholinergic crisis, organophosphorus (OP) agents are capable of producing several subacute or chronic neurological syndromes. The acute over-stimulation at the neuromuscular junction results in muscle fiber necrosis. The significance of this OP-induced myopathy in human intoxication is unknown. Organophosphate-induced delayed neuropathy (OPIDN) arises 1-3 weeks after exposure to some OP compounds all capable of remarkably inhibiting a distinct esterase called neuropathy target esterase (NTE) during a critical time period. An experimental hen model has been designed to screen new OP compounds as to their delayed neurotoxic effects. The recently described intermediate syndrome emerges 1-4 days after an apparently well-treated cholinergic crisis. It main clinical features are sudden respiratory paralysis, cranial motor nerve palsies, and proximal limb muscle and neck flexor weakness. Whether or not this is a separate entity in OP agent toxicology remains to be seen. Further studies are required to further determine its clinical and paraclinical characteristics and the actual type of underlying neuromuscular dysfunction involved.