Subgroup comparison according to clinical phenotype and serostatus in autoimmune encephalitis: a multicenter retrospective study.

BACKGROUND AND PURPOSE: Autoimmune encephalitides (AE) include a spectrum of neurological disorders whose diagnosis revolves around the detection of neuronal antibodies (Abs). Consensus-based diagnostic criteria (AE-DC) allow clinic-serological subgrouping of AE, with unclear prognostic implications. The impact of AE-DC on patients' management was studied, focusing on the subgroup of Ab-negative-AE. METHODS: This was a retrospective multicenter study on patients fulfilling AE-DC. All patients underwent Ab testing with commercial cell-based assays (CBAs) and, when available, in-house assays (immunohistochemistry, live/fixed CBAs, neuronal cultures) that contributed to defining final categories. Patients were classified as Ab-positive-AE [N-methyl-d-aspartate-receptor encephalitis (NMDAR-E), Ab-positive limbic encephalitis (LE), definite-AE] or Ab-negative-AE (Ab-negative-LE, probable-AE, possible-AE). RESULTS: Commercial CBAs detected neuronal Abs in 70/118 (59.3%) patients. Testing 37/48 Ab-negative cases, in-house assays identified Abs in 11 patients (29.7%). A hundred and eighteen patients fulfilled the AE-DC, 81 (68.6%) with Ab-positive-AE (Ab-positive-LE, 40; NMDAR-E, 32; definite-AE, nine) and 37 (31.4%) with Ab-negative-AE (Ab-negative-LE, 17; probable/possible-AE, 20). Clinical phenotypes were similar in Ab-positive-LE versus Ab-negative-LE. Twenty-four/118 (20.3%) patients had tumors, and 19/118 (16.1%) relapsed, regardless of being Ab-positive or Ab-negative. Ab-positive-AE patients were treated earlier than Ab-negative-AE patients (P = 0.045), responded more frequently to treatments (92.3% vs. 65.6%, P < 0.001) and received second-line therapies more often (33.3% vs. 10.8%, P = 0.01). Delays in first-line therapy initiation were associated with poor response (P = 0.022; odds ratio 1.02; confidence interval 1.00-1.04). CONCLUSIONS: In-house diagnostics improved Ab detection allowing better patient management but was available in a patient subgroup only, implying possible Ab-positive-AE underestimation. Notwithstanding this limitation, our findings suggest that Ab-negative-AE and Ab-positive-AE patients share similar oncological profiles, warranting appropriate tumor screening. Ab-negative-AE patients risk worse responses due to delayed and less aggressive treatments.

P450c17 deficiency: clinical and molecular characterization of six patients.

CONTEXT: The characteristics of P450c17 deficiency include 46,XY disorder of sex development, hypertension, hypokalemia, and lack of pubertal development. OBJECTIVE: To better understand this rare enzymatic deficiency, we analyzed the CYP17A1 gene in six affected patients. DESIGN AND PATIENTS: We examined six patients, five 46,XY, and one 46,XX (age 9-29 yr) with complete lack of masculinization (female infantile external genitalia, no uterus) and delayed puberty, respectively, and different degrees of hypertension. MAIN OUTCOME MEASUREMENTS: Genotype-phenotype correlation was measured. RESULTS: Four homozygote mutations were identified by direct sequencing of the CYP17A1 gene corresponding to an alanin 302-proline (A302P) exchange; the loss of lysine 327 (K327del); the deletion of glutamate 331 (E331del); and the replacement of arginine 416 with a histidine (R416H). Both P450c17 activities were abolished in all the mutant proteins, except one, when expressed in COS1 cells. The E331del-mutated P450c17 retained 17alpha-hydroxylase activity. The mutant proteins were normally expressed, suggesting that the loss of enzymatic activity is not due to defects of synthesis, stability, or localization of P450c17 proteins. CONCLUSION: These studies confirm lack of masculinization in 46,XY individuals as the pathognomic sign of the complete P450c17 deficiency. In XX individuals P450c17 deficiency should be considered in cases of delayed puberty. Age of onset and the severity of hypertension do not seem to be constant. Careful examination of long-term follow-ups in two of our patients suggested to us that estrogen treatment in P450c17-deficient patients might worsen the enzymatic defect, leading to aggravation of the hypertension.

Anticuerpos IgG-NMO en la neuromielitis óptica: a propósito de 2 casos / NMO-IgG antibodies in neuromyelitis optica: a report of 2 cases

Introducción. La neuromielitis óptica es una enfermedad inflamatoria desmielinizante que afecta de forma exclusiva al nervio óptico y a la médula espinal. Recientemente se ha descrito que los anticuerpos IgG-NMO, detectados mediante inmunofluorescencia indirecta, son altamente específicos para el diagnóstico, aunque también están presentes en formas clínicas incompletas. El antígeno responsable de la respuesta parece ser un canal acuoso, la aquaporina- 4. Caso clínico. Describimos la detección en nuestro laboratorio de anticuerpos IgG-NMO en dos pacientes, uno con neuromielitis óptica y otro con mielitis recurrente y afectación subclínica del nervio óptico. Conclusiones. Mediante doble marcaje, la microscopía confocal mostró que los anticuerpos de ambos pacientes se colocalizaban con el de un anticuerpo policlonal contra la aquaporina-4 (AU)

Introduction: Neuromyelitis optica is an inflammatory demyelination disease that selectively affects optic nerves and spinal cord. Recently it has been described that the NMO-IgG antibodies, are highly specific for the diagnosis, although they are also present in partial forms of the disease. The antigen responsible for this immune response seems to be aquaporin-4 water channel. Clinical case: We describe the detection in our laboratory of NMO-IgG antibodies in two patients, one of them with a neuromyelitis optica and the other one with a recurrent myelitis and subclinical involvement of the optic nerve. Conclusions: By using dual immunostaining, confocal microscopy showed that the antibodies of both patients colocalized with that of an anti-aquaporin-4 (AU)

Friedreich's ataxia: clinical heterogeneity in two sisters.

Diagnostic evaluation of two sisters affected by ataxia, with similar age of onset, revealed a characteristic trinucleotide expansion in the Friedreich's ataxia (FRDA) locus and two different phenotypic presentations. At onset the elder sister had retained deep tendon reflexes (FARR), while the younger sister presented classic FRDA. The GAA expansion in the patients' alleles proved to be similar in both siblings, ruling out that age at onset and clinical heterogeneity could be due to different FRDA mutations. On the whole, clinical and genetic data on these patients confirmed that FARR is a variant phenotype of FRDA.

[NMO-IgG antibodies in neuromyelitis optica: a report of 2 cases]. / Anticuerpos IgG-NMO en la neuromielitis óptica: a propósito de 2 casos.

INTRODUCTION: Neuromyelitis optica is an inflammatory demyelination disease that selectively affects optic nerves and spinal cord. Recently it has been described that the NMO-IgG antibodies, are highly specific for the diagnosis, although they are also present in partial forms of the disease. The antigen responsible for this immune response seems to be aquaporin-4 water channel. CLINICAL CASE: We describe the detection in our laboratory of NMO-IgG antibodies in two patients, one of them with a neuromyelitis optica and the other one with a recurrent myelitis and subclinical involvement of the optic nerve. CONCLUSIONS: By using dual immunostaining, confocal microscopy showed that the antibodies of both patients colocalized with that of an anti-aquaporin-4.

Prevalence of inherited ataxias in the province of Padua, Italy.

Few population studies are available on epidemiological indexes of hereditary ataxias. An investigation on the prevalence rate of these movement disorders is in progress for the Veneto region, the main area of northeast Italy with a population of 4,490,586 inhabitants. The first results of this epidemiological survey concern the province of Padua, which numbers 845,203 residents (January 1, 2002). The prevalence rate of inherited ataxias has been estimated at 93.3 cases per million inhabitants. The most common types appeared to be the autosomal dominant forms, namely spinocerebellar ataxia type 1 and 2, with a prevalence of 24 per 1,000,000. In the same population, with a prevalence rate of 6 per 1,000,000, Friedreich's ataxia was defined as the prominent recessive autosomal form. There were very rare cases of ataxia telangiectasia, ataxia with vitamin E deficiency and cerebellar ataxia with congenital muscular dystrophy, a recently identified autosomal recessive disease.