C9orf72 hexanucleotide repeat expansions as the causative mutation for chromosome 9p21-linked amyotrophic lateral sclerosis and frontotemporal dementia.

OBJECTIVE: To further assess the presence of a large hexanucleotide repeat expansion in the first intron of the C9orf72 gene identified as the genetic cause of chromosome 9p21-linked amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD) in 4 unrelated families with a conclusive linkage to c9ALS/FTD. DESIGN: A repeat-primed polymerase chain reaction assay. SETTING: Academic research. PARTICIPANTS: Affected and unaffected individuals from 4 ALS/FTD families. MAIN OUTCOME MEASURE: The amplified C9orf72 repeat expansion. RESULTS: We show that the repeat is expanded in and segregated perfectly with the disease in these 4 pedigrees. CONCLUSION: Our findings further confirm the C9orf72 hexanucleotide repeat expansion as the causative mutation for c9ALS/FTD and strengthen the hypothesis that ALS and FTD belong to the same disease spectrum.

Exome sequencing reveals SPG11 mutations causing juvenile ALS.

We report here the description of a nonconsanguineous family with 2 affected individuals with a recessively inherited juvenile motor neuron disease. Exome sequencing of these 2 affected individuals led us to identify 2 compound heterozygous deletions leading to a frameshift and a premature stop codon in the SPG11 gene. One of these deletions, c.5199delA in exon 30, has not been previously reported. Interestingly, these deletions are associated with an intrafamilial phenotypic heterogeneity as one affected has atypical juvenile amyotrophic lateral sclerosis (ALS) and the other has classical hereditary spastic paraplegia with thin corpus callosum. Our findings confirm SPG11 as a genetic cause of juvenile amyotrophic lateral sclerosis and indicate that SPG11 mutations could be associated with 2 different clinical phenotypes within the same family.

The Hedgehog pathway promotes blood-brain barrier integrity and CNS immune quiescence.

The blood-brain barrier (BBB) is composed of tightly bound endothelial cells (ECs) and perivascular astrocytes that regulate central nervous system (CNS) homeostasis. We showed that astrocytes secrete Sonic hedgehog and that BBB ECs express Hedgehog (Hh) receptors, which together promote BBB formation and integrity during embryonic development and adulthood. Using pharmacological inhibition and genetic inactivation of the Hh signaling pathway in ECs, we also demonstrated a critical role of the Hh pathway in promoting the immune quiescence of BBB ECs by decreasing the expression of proinflammatory mediators and the adhesion and migration of leukocytes, in vivo and in vitro. Overall, the Hh pathway provides a barrier-promoting effect and an endogenous anti-inflammatory balance to CNS-directed immune attacks, as occurs in multiple sclerosis.

Association of long ATXN2 CAG repeat sizes with increased risk of amyotrophic lateral sclerosis.

OBJECTIVE: To analyze the ataxin 2 (ATXN2) CAG repeat size in a cohort of patients with amyotrophic lateral sclerosis (ALS) and healthy controls. Large (CAG)(n) alleles of the ATXN2 gene (27-33 repeats) were recently reported to be associated with an increased risk of ALS. DESIGN: Case-control study. SETTING: France and Quebec, Canada. PARTICIPANTS: A total of 556 case patients with ALS and 471 healthy controls; both groups of participants are of French or French-Canadian origin. RESULTS: We observed a significant association between ATXN2 high-length alleles (≥29 CAG repeats) and ALS in French and French-Canadian ALS populations. Furthermore, we identified spinocerebellar ataxia type 2-pathogenic polyglutamine expansions (≥32 CAG repeats) in both familial and sporadic ALS cases. CONCLUSIONS: Altogether, our findings support ATXN2 high-length repeats as a risk factor for ALS and further indicate a genetic link between spinocerebellar ataxia type 2 and ALS.

Decompressive craniectomy is not an independent risk factor for communicating hydrocephalus in patients with increased intracranial pressure.

BACKGROUND: It was recently suggested that communicating hydrocephalus is an almost universal finding after hemicraniectomy and that early cranioplasty may prevent the need for permanent cerebrospinal fluid diversion in these patients. OBJECTIVE: To conduct a study in an attempt to verify these findings. METHODS: The medical records of all patients who underwent decompressive craniectomy for medically refractory elevated intracranial pressure between 2001 and 2009 were retrospectively reviewed. Patients with subarachnoid hemorrhage, intraventricular hemorrhage, or head trauma were excluded. Hydrocephalus was classified as internal or external and as clinically significant or asymptomatic. RESULTS: The patient population consisted of 17 patients, 8 men and 9 women, with a median age of 44 years (range, 27-53 years). Etiologies included malignant middle cerebral artery territory infarction in 12 patients, hemorrhagic transformation of ischemic cerebrovascular accident in 2 patients, dural sinus thrombosis in 2 patients, and hemorrhagic cerebrovascular accident in 1 patient. The extent of craniectomy ranged from a large bone flap in 4 patients to a standard hemicraniectomy in 13 patients. Two patients died and 1 was lost to follow-up during the acute stage. The remaining 14 patients underwent cranioplasty after a median interval of 21 days (range, 3-42 days). In none of these patients did clinically significant hydrocephalus develop requiring cerebrospinal fluid diversion. Asymptomatic extra-axial cerebrospinal fluid collections developed in 2 patients that resolved spontaneously after cranioplasty. CONCLUSION: Our results suggest that, contrary to some beliefs, hydrocephalus does not frequently occur after decompressive craniectomy.