Mutations in COQ2 in Familial and Sporadic Multiple-System Atrophy

Nejm, june 2013

BACKGROUND

Multiple-system atrophy is an intractable neurodegenerative disease characterized by autonomic failure in addition to various combinations of parkinsonism, cerebellar ataxia, and pyramidal dysfunction. Although multiple-system atrophy is widely considered to be a nongenetic disorder, we previously identified multiplex families with this disease, which indicates the involvement of genetic components.

METHODS

In combination with linkage analysis, we performed whole-genome sequencing of a sample obtained from a member of a multiplex family in whom multiple-system atrophy had been diagnosed on autopsy. We also performed mutational analysis of samples from members of five other multiplex families and from a Japanese series (363 patients and two sets of controls, one of 520 persons and one of 2383 persons), a European series (223 patients and 315 controls), and a North American series (172 patients and 294 controls). On the basis of these analyses, we used a yeast complementation assay and measured enzyme activity of parahydroxybenzoate-polyprenyl transferase. This enzyme is encoded by the gene COQ2 and is essential for the biosynthesis of coenzyme Q10. Levels of coenzyme Q10 in lymphoblastoid cells and brain tissue were measured on high-performance liquid chromatography.

RESULTS

We identified a homozygous mutation (M78V-V343A/M78V-V343A) and compound heterozygous mutations (R337X/V343A) in COQ2 in two multiplex families. Furthermore, we found that a common variant (V343A) and multiple rare variants in COQ2, all of which are functionally impaired, are associated with sporadic multiple-system atrophy. The V343A variant was exclusively observed in the Japanese population.

CONCLUSIONS

Functionally impaired variants of COQ2 were associated with an increased risk of multiple-system atrophy in multiplex families and patients with sporadic disease, providing evidence of a role of impaired COQ2 activities in the pathogenesis of this disease. (Funded by the Japan Society for the Promotion of Science and others.)

Froment Sign

Froment's sign is a special test of the wrist. It tests for palsy of the ulnar nerve, specifically, the action of adductor pollicis.  Froment sign can also refer to cogwheel effect seen inessential tremor.

segni di Trousseau e Chvostek

Chvostek sign (fonte: Youtube)

Trousseau Sign (fonte: youtube)

N Engl J Med. 2013 May 23;368(21):1992-2003. doi: 10.1056/NEJMoa1215993. Epub 2013 May 8.

Ataxia, dementia, and hypogonadotropism caused by disordered ubiquitination.

Margolin DH, Kousi M, Chan YM, Lim ET, Schmahmann JD, Hadjivassiliou M, Hall JE, Adam I, Dwyer A, Plummer L, Aldrin SV,O'Rourke J, Kirby A, Lage K, Milunsky A, Milunsky JM, Chan J, Hedley-Whyte ET, Daly MJ, Katsanis N, Seminara SB.

Source

Department of Neurology, Massachusetts General Hospital, Boston 02115, USA.

Abstract

BACKGROUND:

The combination of ataxia and hypogonadism was first described more than a century ago, but its genetic basis has remained elusive.

METHODS:

We performed whole-exome sequencing in a patient with ataxia and hypogonadotropic hypogonadism, followed by targeted sequencing of candidate genes in similarly affected patients. Neurologic and reproductive endocrine phenotypes were characterized in detail. The effects of sequence variants and the presence of an epistatic interaction were tested in a zebrafish model.

RESULTS:

Digenic homozygous mutations in RNF216 and OTUD4, which encode a ubiquitin E3 ligase and a deubiquitinase, respectively, were found in three affected siblings in a consanguineous family. Additional screening identified compound heterozygous truncating mutations in RNF216 in an unrelated patient and single heterozygous deleterious mutations in four other patients. Knockdown of rnf216 or otud4 in zebrafish embryos induced defects in the eye, optic tectum, and cerebellum; combinatorial suppression of both genes exacerbated these phenotypes, which were rescued by nonmutant, but not mutant, human RNF216 or OTUD4 messenger RNA. All patients had progressive ataxia and dementia. Neuronal loss was observed in cerebellar pathways and the hippocampus; surviving hippocampal neurons contained ubiquitin-immunoreactive intranuclear inclusions. Defects were detected at the hypothalamic and pituitary levels of the reproductive endocrine axis.

CONCLUSIONS:

The syndrome of hypogonadotropic hypogonadism, ataxia, and dementia can be caused by inactivating mutations in RNF216 or by the combination of mutations in RNF216 and OTUD4. These findings link disordered ubiquitination to neurodegeneration and reproductive dysfunction and highlight the power of whole-exome sequencing in combination with functional studies to unveil genetic interactions that cause disease. (Funded by the National Institutes of Health and others.).

SLA

Genome-wide association analyses in Han Chinese identify two new susceptibility loci for amyotrophic lateral sclerosis

To identify susceptibility genes for amyotrophic lateral sclerosis (ALS), we conducted a genome-wide association study (GWAS) in 506 individuals with sporadic ALS and 1,859 controls of Han Chinese ancestry. Ninety top SNPs suggested by the current GWAS and 6 SNPs identified by previous GWAS were analyzed in an independent cohort of 706 individuals with ALS and 1,777 controls of Han Chinese ancestry. We discovered two new susceptibility loci for ALS at 1q32 (CAMK1G, rs6703183, Pcombined = 2.92 × 10⁻⁸, odds ratio (OR) = 1.31) and 22p11 (CABIN1 andSUSD2, rs8141797, Pcombined = 2.35 × 10⁻⁹, OR = 1.52). These two loci explain 12.48% of the overall variance in disease risk in the Han Chinese population. We found no association evidence for the previously reported loci in the Han Chinese population, suggesting genetic heterogeneity of disease susceptibility for ALS between ancestry groups. Our study identifies two new susceptibility loci and suggests new pathogenic mechanisms of ALS (Nature Genetics 45; 2013).

Pine-Nut Syndrome

una "chicca neurologica" disponibile nella casella condivisa...


Pinemouth syndrome (PMS), otherwise known as pine nut syndrome, is a relatively new condition. At least several thousand cases have now been described in the literature. The author describes the PMS toxidrome, offers a preliminary case definition, and discusses current best evidence regarding the etiology and risk factors related to the development of PMS. A clinically compatible case of PMSmust include taste disturbance, usually characterized as bitter or metallic, following the ingestion of affected pine nuts by 1 to 3 days. Affected nuts would appear to include all, or some portion, of nuts harvested from species Pinus armandii (Chinese white pine), but could include nuts from other species. The specific toxin that is apparently present in affected nuts has not yet been isolated, and the mechanism of toxicity and factors determining PMS susceptibility need to be further detailed. There are no proven therapies for PMS. The only treatment is to cease ingesting implicated nuts and to wait for symptoms to abate.

ci sono tanto di criteri diagnostici!!!

Linee guida AAN

sono uscite le linee guida su

"Periprocedural Management of Antithrombotic Medications in Patients with Ischemic Cerebrovascular Disease"

sono disponibili in casella condivisa.

buona lettura