Description of Two Families with New Mutations in Familial Cerebral Cavernous Malformations Genes.

Cerebral cavernous malformations (CCMs) are dilated aberrant leaky capillaries located in the Central Nervous System. Familial CCM is an autosomal dominant inherited disorder related to mutations in KRIT1, Malcavernin or PDCD10. We show two unrelated families presenting familial CCM due to two new mutations in KRIT1 and PDCD10, producing truncated proteins. Clinical phenotype was highly variable among patients from asymptomatic individuals to diplopia, seizures or severe intracranial hemorrhage. PDCD10 patients usually show a more aggressive course and they frequently showed multiple meningiomas. This work provides evidence for the pathogenicity of two new mutations in CCM genes and supports previous findings regarding familial CCM and multiple meningiomas.

Autoimmune GFAP astrocytopathy presenting with remarkable CNS hyperexcitability and oculogyric crises.

The autoimmune GFAP astrocytopathy has been associated with meningoencephalomyelitis that usually responds to glucocorticoids. We report a 20-year-old man that developed an acute and severe meningoencephalomyelitis with remarkable CNS hyperexcitability and oculogyric crises. CSF analysis showed hypoglycorrhachia, pleocytosis, elevated ADA, and CSF-immunofluorescence characteristic of autoimmune GFAP astrocytopathy. MRI showed lesions at thalamus, corpus-callosum, dorsal pons and dentate nucleus with associated myelitis. Immunotherapy led to a full recovery, although MRI activity was observed at follow-up. CNS hyperexcitability, typically seen in other immune-mediated syndromes, represents a novel presenting form to be included as part of the clinical spectrum of this entity.

Management of an outbreak of botulism with benign clinical presentation.

Botulism is a life-threatening presynaptic disorder of the neuromuscular transmission produced by the neurotoxin elaborated by the botulinum neurotoxin-producing clostridia. We describe the management of a case series of 14 patients, members of 5 different families that were exposed to home-canned tuna and developed symptoms compatible with a mild clinical presentation of foodborne botulism. The electrophysiological study of the index case represented a reliable diagnostic test as it demonstrated a slight presynaptic dysfunction of the neuromuscular junction. Definite diagnosis was later confirmed by microbiological tests. Out of 14, only 3 patients presenting with a shorter period from symptom onset and with signs of multiple cranial neuropathies received botulinum antitoxin. All the patients remained stable and recovered progressively. Treatment with antitoxin may not be necessary in patients with late-presenting disease and mild and stable clinical picture.

Vemurafenib as first-line therapy in BRAF-V600E-mutant Erdheim-Chester disease with CNS involvement.

Erdheim-Chester disease (ECD) is a rare histiocytosis that may affect the central nervous system (CNS). Infiltration by the disease occurs throughout the neuroaxis, usually involving the dentate nucleus and the pons, manifested as a pyramido-cerebellar syndrome. CNS involvement is an adverse prognostic factor which warrants prompt evaluation and treatment. BRAF mutation occurs in more than half of the cases and has become central in the therapeutic approach. There is rapidly growing evidence that BRAF inhibitors such as vemurafenib or dabrafenib are effective in treating CNS-spread disease. We present a patient with BRAF-V600E-mutant ECD with a classical pyramido-ataxic onset of disease who improved after prompt diagnosis with vemurafenib treatment as first-line therapy.

Parkinsonism and spastic paraplegia type 7: Expanding the spectrum of mitochondrial Parkinsonism.

BACKGROUND: Pathogenic variants in the spastic paraplegia type 7 gene cause a complicated hereditary spastic paraplegia phenotype associated with classical features of mitochondrial diseases, including ataxia, progressive external ophthalmoplegia, and deletions of mitochondrial DNA. OBJECTIVES: To better characterize spastic paraplegia type 7 disease with a clinical, genetic, and functional analysis of a Spanish cohort of spastic paraplegia type 7 patients. METHODS: Genetic analysis was performed in patients suspecting hereditary spastic paraplegia and in 1 patient with parkinsonism and Pisa syndrome, through next-generation sequencing, whole-exome sequencing, targeted Sanger sequencing, and multiplex ligation-dependent probe analysis, and blood mitochondrial DNA levels determined by quantitative polymerase chain reaction. RESULTS: Thirty-five patients were found to carry homozygous or compound heterozygous pathogenic variants in the spastic paraplegia type 7 gene. Mean age at onset was 40 years (range, 12-63); 63% of spastic paraplegia type 7 patients were male, and three-quarters of all patients had at least one allele with the c.1529C>T (p.Ala510Val) mutation. Eighty percent of the cohort showed a complicated phenotype, combining ataxia and progressive external ophthalmoplegia (65% and 26%, respectively). Parkinsonism was observed in 21% of cases. Analysis of blood mitochondrial DNA indicated that both patients and carriers of spastic paraplegia type 7 pathogenic variants had markedly lower levels of mitochondrial DNA than control subjects (228 per haploid nuclear DNA vs. 176 vs. 573, respectively; P < 0.001). CONCLUSIONS: Parkinsonism is a frequent finding in spastic paraplegia type 7 patients. Spastic paraplegia type 7 pathogenic variants impair mitochondrial DNA homeostasis irrespective of the number of mutant alleles, type of variant, and patient or carrier status. Thus, spastic paraplegia type 7 supports mitochondrial DNA maintenance, and variants in the gene may cause parkinsonism owing to mitochondrial DNA abnormalities. Moreover, mitochondrial DNA blood analysis could be a useful biomarker to detect at risk families. © 2019 International Parkinson and Movement Disorder Society.

Clinical response to thalidomide in the treatment of intracranial tuberculomas: case report.

We describe a patient with multiple intracranial tuberculomas resistant to standard care with antituberculosis drugs and corticosteroids who responded well to thalidomide. Adjunctive thalidomide may have a role in the management of refractory intracranial tuberculomas, although it should be used conservatively owing to its potential adverse events.

Funciones y organización de un comité de neurooncología en un hospital con servicio de neurocirugía / Functions and organisation of a neuro-oncology committee in hospitals with a neurosurgery service

El Grupo de Trabajo de Neurooncología (GTNO) de la SENEC ha encargado a los miembros del comité de neurooncología del Hospital Universitario Donostia de San Sebastián (España) la elaboración del presente documento, para que sirva como Guía del consenso establecido en el seno del GTNO y recomendación propuesta en todos los hospitales, públicos o privados, que manejan esta patología. Es obligado la constitución y funcionamiento normalizado de comités de neurooncología en todos los centros con servicio de neurocirugía, y lo expuesto a continuación debe contemplarse a la luz de las condiciones particulares de los mismos, con las variaciones pertinentes según los recursos diagnósticos y terapéuticos. Nos presentan a continuación el ejemplo de la constitución, funcionamiento y experiencia que han contraído en más de 8 años de trabajo multidisciplinar en pacientes con tumores cerebrales (AU)

The Neuro-Oncology Study Group (NOSG) at SENEC has commissioned the elaboration of the present document to the Neuro-Oncology Committee at Donostia University Hospital. It is intended to serve as a NOSG Consensus Guide and a proposed recommendation for the management of his pathological conditionatallSpanishHospitals,bothpublicandprivate.Neuro-Oncology Committees must be established and active at all centres with a Neurosurgery Service, taking into account the specific diagnostic and therapeutic capacity available. The work presents an example of the constitution, functioning and experience of such a Committee, drawing on 8 years of multidisciplinary work with brain tumour patients (AU)

[Functions and organisation of a neuro-oncology committee in hospitals with a neurosurgery service]. / Funciones y organización de un comité de neurooncología en un hospital con servicio de neurocirugía.

The Neuro-Oncology Study Group (NOSG) at SENEC has commissioned the elaboration of the present document to the Neuro-Oncology Committee at Donostia University Hospital. It is intended to serve as a NOSG Consensus Guide and a proposed recommendation for the management of this pathological condition at all Spanish Hospitals, both public and private. Neuro-Oncology Committees must be established and active at all centres with a Neurosurgery Service, taking into account the specific diagnostic and therapeutic capacity available. The work presents an example of the constitution, functioning and experience of such a Committee, drawing on 8 years of multidisciplinary work with brain tumour patients.

Does the severity of the LGMD2A phenotype in compound heterozygotes depend on the combination of mutations?

INTRODUCTION: Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by a deficiency of calpain-3/p94. Although the symptoms in most LGMD2A patients are generally homogeneous, some variation in the severity and progression of the disease has been reported. METHODS: We describe 2 patients who carry the same combination of compound heterozygous mutations (pG222R/pR748Q) and whose symptoms are exceptionally benign compared to homozygotes with each missense mutation. RESULTS: The benign phenotype observed in association with the combined pG222R and pR748Q mutations suggested that it may result from a compensatory effect of compound heterozygosity rather than the individual mutations themselves. Our analyses revealed that these two mutations exert different effects on the protease activity of calpain-3, suggesting "molecular complementation" in these patients. CONCLUSION: We propose several hypotheses to explain how this specific combination of mutations may rescue the normal proteolytic activity of calpain-3, resulting in an exceptionally benign phenotype.

Mutations in progranulin gene: clinical, pathological, and ribonucleic acid expression findings.

BACKGROUND: There is an increasing interest in the clinico-pathological correlation of mutations in progranulin (PGRN) and frontotemporal lobar degeneration (FTLD) complex diseases. We aim to study the PGRN expression variability in patients with different clinical features for a better understanding of its roles in FTLD disease. METHODS: We sequenced the PGRN gene in 72 patients suffering from FTLD (25 familial and 47 sporadic cases) and in 24 asymptomatic at-risk relatives. We also analyzed PGRN expression in blood by quantitative real-time polymerase chain reaction from 37 patients, 8 asymptomatic mutation carriers, and 10 control subjects as well as in brain tissue from 16 patients and 9 control subjects. RESULTS: Four novel mutations were associated with familial and sporadic FTLD and familial dementia associated with amyotrophic lateral sclerosis. We identified a close association between the IVS6-1G>A mutation in PGRN and corticobasal syndrome. Brain tissue was available for carriers of two of the four mutations (IVS6-1 G>A and P357HfsX3). Immunohistochemical analysis revealed ubiquitin- and TDP-43positive and tau/alpha-synuclein negative immunoreactive neuronal intranuclear inclusions. The relative expression of PGRN in the clinical sample was significantly lower in carriers of the IVS6-1 G>A than in control subjects. CONCLUSIONS: Progranulopathies are a major cause of the main phenotypes included in the FTLD complex. According to our results, the level of expression of PGRN in blood could be a useful marker both for diagnostics of part of the spectrum of FTLD conditions and for monitoring future treatments that might boost the level of PGRN in this disorder.

Familial prion diseases in the Basque Country (Spain).

In 1995, a surveillance system for prion diseases was set up in the Basque Country, an autonomous region in northern Spain (2.1 million inhabitants). In the period from January 1993 to December 2003, we diagnosed 21 patients with familial prion diseases prospectively and another 4 patients retrospectively. They represent 35% of all the cases referred to the epidemiological registry. Two main possible explanations for this unusual high incidence of familial prion diseases are proposed: first, comprehensive case ascertainment by public health neurologists; second, a probable cluster of the D178N mutation within families of Basque origin related to a still unconfirmed common ancestor. Further genetic and genealogical studies should resolve this issue.

A common haplotype associated with the Basque 2362AG --> TCATCT mutation in the muscular calpain-3 gene.

Limb-girdle muscular dystrophy type 2A (LGMD2A) is caused by any of over 150 mutations in the calpain-3 (CAPN3) gene. Of those, 2362AG --> TCATCT is particularly prevalent in Basque patients, and this mutation was hypothesized to have arisen in the Basque Country. To explore the natural history of this mutation, we genotyped 65 Basque and non-Basque patients with LGMD2A who carry the 2362AG --> TCATCT mutation for four microsatellites within or flanking the gene. A particular haplotype was found in three-fourths of the patients and was assumed to be ancestral. From the average number of recombinations and mutations accumulated from this ancestral haplotype, the age of the 2362AG ----> TCATCT mutation was estimated to be 50 generations (i.e., 1,250 years), which is more recent than the Paleolithic Basque heritage. The subsequent spread of the 2362AG --> TCATCT mutation can be related to gene flow out of the Basque Country, even across a cultural border.