Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations.

BACKGROUND: Juvenile amyotrophic lateral sclerosis (ALS) with basophilic inclusions is a form of ALS characterized by protein deposits in motor neurons that are morphologically and tinctorially distinct from those of classic sporadic ALS. The nosologic position of this type of ALS in the molecular pathologic and genetic classification of ALS is unknown. METHODS: We identified neuropathologically 4 patients with juvenile ALS with basophilic inclusions and tested the hypothesis that specific RNA binding protein pathology may define this type of ALS. Immunohistochemical findings prompted us to sequence the fused in sarcoma (FUS) gene. RESULTS: Motor symptoms began between ages 17 and 22. Disease progression was rapid without dementia. No family history was identified. Basophilic inclusions were strongly positive for FUS protein but negative for TAR DNA binding protein 43 (TDP-43). Granular and compact FUS deposits were identified in glia and neuronal cytoplasm and nuclei. Ultrastructure of aggregates was in keeping with origin from fragmented rough endoplasmic reticulum. Sequencing of all 15 exons of the FUS gene in 3 patients revealed a novel deletion mutation (c.1554_1557delACAG) in 1 individual and the c.1574C>T (P525L) mutation in 2 others. CONCLUSION: Juvenile ALS with basophilic inclusions is a FUS proteinopathy and should be classified as ALS-FUS. The FUS c.1574C>T (P525L) and c.1554_1557delACAG mutations are associated with this distinct phenotype. The molecular genetic relationship with frontotemporal lobar degeneration with FUS pathology remains to be clarified.

TARDBP in amyotrophic lateral sclerosis: identification of a novel variant but absence of copy number variation.

BACKGROUND: Mutations in the gene encoding TDP-43 have been identified in both familial and sporadic amyotrophic lateral sclerosis (ALS). METHODS: A mutation screen and copy number analysis in a motor neuron disease clinic cohort was conducted to characterise the genetic contribution of TARDBP. RESULTS: A novel missense mutation in a highly conserved region of TDP-43 was identified in a patient with sporadic ALS. The mutation is in close vicinity to previously identified changes. Copy number variation abnormalities were not detected. CONCLUSIONS: The findings stress the importance of TDP-43 in the pathogenesis of sporadic ALS.

Candidate screening of the bovine and feline spinal muscular atrophy genes reveals no evidence for involvement in human motor neuron disorders.

Spinal muscular atrophy (SMA) is a devastating neuromuscular disease characterised by progressive loss of spinal motor neurons. Mutations in the genes underlying spontaneous bovine and feline models of SMA have recently been described. The clinical and pathological features of these disorders are similar to human forms of SMA making both genes excellent candidates in patients with motor neuron loss of no known aetiology. Here we report that a screen for mutations in coding regions and splice sites of the LIX1 and FVT1 genes in a cohort of 96 non-5q SMA patients and 119 familial and sporadic Amyotrophic Lateral Sclerosis patients identified no obvious pathogenic changes. This study indicates that mutations in these genes do not contribute significantly to the cause of motor neuron diseases in the human population.

Chronic antidopaminergic medication might affect amygdala structure in patients with schizophrenia.

BACKGROUND: Recently amygdala enlargement has been reported in patients with schizophrenia like psychosis of epilepsy. The effect of antipsychotic medication on amygdala structure has not been investigated so far. There is theoretical evidence to support the assumption that dopaminergic neurotransmission might affect neuronal plasticity. METHODS: In order to analyze the influence of chronic antidopaminergic medication on amygdala structure we compared amygdala volumes in patients with schizophrenia like psychosis of epilepsy (POE) treated with neuroleptic medication (n = 11) to patients with POE not treated with such medication (n = 15), patients with epilepsy alone (n = 24) and healthy control subjects (n = 20). RESULTS: Analyzing our data with a factorial ANOVA approach, we found a significant effect of the factor medication in that patients treated with antipsychotic medication displayed a "normalization" of the increased amygdala volumes observed in the untreated patient group. CONCLUSION: This observation supports the assumption that antidopaminergic medication might affect the amygdala structure.

Psychopathological profile in patients with severe bilateral hippocampal atrophy and temporal lobe epilepsy: evidence in support of the Geschwind syndrome?

Bilateral symmetrical hippocampal atrophy (BHA) has been implicated as a possible causal element in various neuropsychiatric disorders, in particular depressive disorder and schizophrenia. To test the hypothesis that bilateral symmetrical severe volume loss of the hippocampi is of causal relevance to these psychiatric syndromes rather than an epiphenomenon we assessed the psychopathology in a group of patients with temporal lobe epilepsy (TLE) and very severe bilateral symmetrical hippocampal atrophy and compared it with that of a patient control group. Patients with TLE and hippocampal volumes smaller than three standard deviations below the mean of a control population were identified and compared with a matched patient population with normal hippocampal volumes. Psychopathology was assessed by blinded trained psychiatrists using the Present State Examination and Neurobehavioral Inventory. The prevalence of psychiatric syndromes was high in both patient groups; however, there was no significant difference between the two groups. With use of the more specific Neurobehavioral Inventory a psychopathological pattern reminiscent of the Geschwind syndrome emerged when patients with BHA were characterized by caregivers. While BHA does not result in an increased prevalence of specific psychiatric syndromes, specific symptoms that characterize the Geschwind syndrome like hypergraphia and hyposexuality might be pathogenically related to hippocampal atrophy.

Support after cot death: the CONI programme in action.

After a previous cot death, most parents approach the next baby with anxiety as well as joy. The Care of Next Infant (CONI). Programme offers structured support to the parents antenatally and through the first months of the baby's life Key features are weekly visits from the family health visitor, and providing the family with an apnoea monitor or weighing scales and a daily diary to record symptoms. Parents are taught resuscitation skills and the significance of temperature, smoking and positioning the baby on the back or side. Additional support is available from the general practitioner and paediatrician. Evaluation shows that most parents and health professionals consider this a useful scheme and that parents feel reassured by the extra support and advice.