Annals of neurology
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Annals of neurology · Jan 2008
Case ReportsMemory enhancement induced by hypothalamic/fornix deep brain stimulation.
Bilateral hypothalamic deep brain stimulation was performed to treat a patient with morbid obesity. We observed, quite unexpectedly, that stimulation evoked detailed autobiographical memories. ⋯ Electroencephalographic source localization showed that hypothalamic deep brain stimulation drove activity in mesial temporal lobe structures. This shows that hypothalamic stimulation in this patient modulates limbic activity and improves certain memory functions.
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Annals of neurology · Jan 2008
5-(N-ethyl-N-isopropyl)-amiloride enhances SMN2 exon 7 inclusion and protein expression in spinal muscular atrophy cells.
Spinal muscular atrophy (SMA) is a common inherited neuromuscular disorder caused by homozygous loss of function of the survival motor neuron 1 (SMN1) gene. All SMA patients carry at least one copy of a nearly identical SMN2 gene. However, a critical nucleotide change in SMN2 results in alternative splicing and exclusion of exon 7 in the majority of SMN2 messenger RNA (mRNA), thus producing a low level of functional SMN protein. Increasing SMN protein production by promoting SMN2 exon 7 inclusion could be a therapeutic approach for SMA. It has been shown that cellular pH microenvironment can modulate pre-mRNA alternative splicing in vivo. In this study, we tested whether inhibitors of the Na+/H+ exchanger can modulate the exon 7 splicing of SMN2 mRNA METHODS: We treated SMA lymphoid cell lines with Na+/H+ exchanger inhibitors and then measured SMN2 exon 7 splicing by reverse transcriptase polymerase chain reaction and SMN protein production by Western blotting and immunofluorescence ⋯ Our finding that EIPA, an inhibitor of the Na+/H+ exchanger, can increase SMN protein expression in SMA cells provides a new direction for the development of drugs for SMA treatment. However, further translational studies are needed to determine whether this finding is applicable for SMA treatment or just a proof of cellular pH effect on SMN splicing.
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Annals of neurology · Dec 2007
Case ReportsLong-term course and mutational spectrum of spatacsin-linked spastic paraplegia.
Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of neurodegenerative disorders resulting in progressive spasticity of the lower limbs. One form of autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) was linked to chromosomal region 15q13-21 (SPG11) and associated with mutations in the spatacsin gene. We assessed the long-term course and the mutational spectrum of spatacsin-associated ARHSP with TCC. ⋯ We demonstrate that not only frameshift and nonsense mutations but also splice mutations result in SPG11. Mutations are distributed throughout the spatacsin gene and emerge as major cause for ARHSP with TCC associated with severe motor and cognitive impairment. The clinical phenotype and the ultrastructural analysis suggest a disturbed axonal transport of long projecting neurons.