EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.

BACKGROUND AND PURPOSE: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. METHODS: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. RESULTS AND CONCLUSION: This paper provides updated guidelines for molecular diagnosis of two particularly complex groups of disorders, the ataxias and spastic paraplegias. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.

EFNS guidelines on the molecular diagnosis of mitochondrial disorders.

OBJECTIVES: These European Federation of Neurological Sciences (EFNS) guidelines are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics for diagnosing mitochondrial disorders (MIDs), which gain increasing attention and are more frequently diagnosed due to improved diagnostic tools. BACKGROUND: Since the publication of the first EFNS guidelines on the molecular diagnosis of inherited neurological diseases in 2001, rapid progress has been made in this field, necessitating the creation of an updated version. SEARCH STRATEGY: To collect data about the molecular diagnosis of MIDs search for literature in various electronic databases, such as Cochrane library, MEDLINE, OMIM, GENETEST or Embase, were carried out and original papers, meta-analyses, review papers, and guideline recommendations were reviewed. RESULTS: The guidelines summarise the possibilities and limitations of molecular genetic diagnosis of MIDs and provide practical recommendations and diagnostic criteria in accordance with the EFNS Scientific Committee to guide the molecular diagnostic work-up of MIDs. RECOMMENDATIONS: The proposed guidelines suggest an approach to the molecular diagnosis of MIDs in a manner accessible to general neurologists.

EFNS guidelines on the molecular diagnosis of neurogenetic disorders: general issues, Huntington's disease, Parkinson's disease and dystonias.

BACKGROUND AND PURPOSE: These EFNS guidelines on the molecular diagnosis of neurogenetic disorders are designed to provide practical help for the general neurologist to make appropriate use of molecular genetics in diagnosing neurogenetic disorders. Since the publication of the first two EFNS-guideline papers on the molecular diagnosis of neurological diseases in 2001, rapid progress has been made in this field, necessitating an updated series of guidelines. METHODS: Literature searches were performed before expert members of the task force wrote proposals, which were discussed in detail until final consensus had been reached among all task force members. RESULTS AND CONCLUSION: This paper provides updated guidelines for molecular diagnosis of Huntington's disease, Parkinson's disease and dystonias as well as a general introduction to the topic. Possibilities and limitations of molecular genetic diagnosis of these disorders are evaluated and recommendations are provided.

Early hydrocephalus in Listeria meningitis: Case report and review of the literature.

Listeria monocytogenes is a gram-positive bacterium with a predilection to infect the central nervous system, often affecting immunocompromised or elderly patients. The most common manifestations are meningitis and rhomboencephalitis. We report two cases of Listeria meningitis complicated by acute hydrocephalus several days after presentation and we further review the literature of similar cases. We conclude that acute hydrocephalus is a significant, not often recognized, complication of Listeria meningitis, usually occurring several days from onset when coverage did not include anti-Listeria antimicrobials. In high risk patients, meningitis combined with acute hydrocephalus is suggestive of LM infection.

Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic.

Pharmacokinetics of methotrexate in cerebrospinal fluid and serum after osmotic blood-brain barrier disruption in patients with brain lymphoma.

OBJECTIVE: To evaluate the pharmacokinetics of methotrexate in ventricular cerebrospinal fluid and serum after osmotic blood-brain barrier disruption and intra-arterial administration compared with intravenous or simple intra-arterial infusion in patients with primary central nervous system lymphoma. METHODS: Serum and ventricular cerebrospinal fluid were sampled after methotrexate administration in 12 patients. Blood-brain barrier disruption was induced on 2 sequential days by mannitol (25%) infusion delivered to the vertebral or internal carotid artery territories followed by intra-arterial methotrexate (dose, 1.4 g/m2; 47 treatments). Sixteen treatments were given without barrier disruption by intravenous (3.5 g/m2; nine treatments) or intra-arterial (2.8 g/m2; seven treatments) infusion. RESULTS: Ventricular cerebrospinal fluid-methotrexate peak levels after blood-brain barrier disruption of the vertebral and the internal carotid arteries territories were 19.3 +/- 2.9 and 8.5 +/- 0.7 micromol/L (P < .001), and the area under the curve from time 0 to infinity was 178.0 +/- 21.3 and 110.0 +/- 12.4 [micromol/L x h, respectively (P < .01). No significant differences were observed in serum levels. After intra-arterial infusion was performed without disruption, the serum peak level was higher than that achieved by intravenous treatment (518.2 +/- 67.7 versus 180.6 +/- 31.8 micromol/L; P < .001). No differences were observed in cerebrospinal fluid concentrations, which dropped below 1 micromol/L at 6 hours. The cerebrospinal fluid/serum ratio [AUC(%)] of methotrexate after blood-brain barrier disruption was three to four times greater than that by systemic administration. CONCLUSION: Enhanced methotrexate delivery to the central nervous system can be attained by intra-arterial administration combined with osmotic disruption of the blood-brain barrier compared with simple intra-arterial or intravenous administration.

Adult-onset Niemann-Pick type C disease. Clinical, biochemical, and genetic study.

BACKGROUND: Niemann-Pick type C disease is an autosomal recessive neurometabolic disorder of unknown origin mapped to chromosome 18q11-12 in most of the studied families. In contrast to the sphingomyelin lipidoses, in Niemann-Pick type C disease, fibroblasts are impaired in intracellular homeostatic responses to exogenous low-density lipoprotein (LDL) cholesterol. Biochemical heterogeneity of the disorder in relation to abnormal LDL processing is associated with various clinical presentations, but adult-onset Niemann-Pick type C disease is rare and has not been comprehensively characterized. OBJECTIVE: To describe clinical, biochemical, and genetic features of adult-onset Niemann-Pick type C disease in 3 siblings. DESIGN AND SETTING: Case series in a tertiary care center. PATIENTS: The 3 siblings manifested a variable combination of vertical supranuclear ophthalmoplegia, ataxia, and splenomegaly. Brain magnetic resonance imaging showed cerebellar atrophy; brainstem auditory evoked responses were unobtainable, and bone marrow examination disclosed typical foam cells. The patients were 20, 26, and 28 years old and belonged to a sibship of 13 born of consanguineous healthy parents. METHODS: Esterification of exogenous LDL cholesterol in cultured skin fibroblasts and filipin staining for free intracellular cholesterol. Polymerase chain reaction-based DNA linkage study using AC microsatellite markers D18S40, D18S44, D18S480, and D18S66. RESULTS: Fibroblasts of the 3 patients showed a 23% to 58% block in the induced cholesterol esterification after 4 1/2 hours and a mild to moderate accumulation of free cholesterol. DNA study demonstrated linkage to the major 18q11-12 Niemann-Pick type C locus and identified unaffected carriers. CONCLUSIONS: These results confirm the diagnosis of the least biochemically affected Niemann-Pick type C phenotype in this family with adult-onset disease and support a correlation between the mild laboratory and clinical findings in this age group.

Numb chin syndrome in cancer patients: etiology, response to treatment, and prognostic significance.

We retrospectively evaluated 42 consecutive cancer patients with numb chin syndrome (NCS). Breast cancer comprised 64% of the primary tumors, and lymphoproliferative neoplasms comprised 14%. A standard workup (including imaging of the brain, base of skull, and mandible, and CSF analysis) led to the diagnosis of a metastatic etiology in 89% of the patients. Fifty percent of the patients had mandibular metastases, 14% base-of-skull bone lesions, and 22% leptomeningeal seeding. NCS was a late manifestation of malignancy, associated with disease progression in 67% of the patients or heralding a relapse, which was often confined to the leptomeninges, in 31%. Although various therapeutic strategies led to resolution of NCS, median survival after its diagnosis was 5 months when due to bone metastases and 12 months if associated with leptomeningeal seeding.

Leptomeningeal metastases: analysis of 31 patients with sustained off-therapy response following combined-modality therapy.

Thirty-one (23%) of 137 patients treated for leptomeningeal metastases (LM) achieved a sustained off-therapy response of at least 6 months' duration following treatment by a standard protocol. Of the 31 patients, equal distribution was found among various tumors: lymphoma, 13/44 (29%); breast carcinoma, 10/51 (20%); and other tumors, 8/42 (19%). Neuroimaging of the neuraxis disclosed subarachnoid deposits in 70%, with unexpected findings in 55%. At withdrawal of therapy, all 13 patients with lymphomas had achieved a complete response, and for those with the other tumors, 61% had a partial response. Off-therapy relapse was unrelated to the type of attained response and occurred in nine patients (29%) after a median time of 12 months. Five patients obtained a second prolonged response, mainly by systemic therapy. All eight patients who received only systemic therapy for their LM responded to treatment, four with a complete response. All others received both systemic and intra-CSF treatment and maintained a systemic response. Delayed complications occurred in 58%, with leukoencephalopathy equally affecting patients exposed and patients not exposed to cranial irradiation. The median survival of the whole group was 23 months. We conclude that in LM (lymphomas excluded), a partial response is compatible with a prolonged off-therapy response. Since LM may respond to systemic treatment, the role of intra-CSF therapy, with its associated complications, deserves a prospective reevaluation.