The metabolomic signature of Leber’s hereditary optic neuropathy reveals endoplasmic reticulum stress

Leber’s hereditary optic neuropathy (MIM#535000), the commonest mitochondrial DNA-related disease, is caused by mutations affecting mitochondrial complex I. The clinical expression of the disorder, usually occurring in young adults, is typically characterized by subacute, usually sequential, bilateral visual loss, resulting from the degeneration of retinal ganglion cells. As the precise action of mitochondrial DNA mutations on the overall cell metabolism in Leber’s hereditary optic neuropathy is unknown, we investigated the metabolomic profile of the disease. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites in fibroblasts from 16 patients with Leber’s hereditary optic neuropathy and eight healthy control subjects. Latent variable-based statistical methods were used to identify discriminating metabolites. One hundred and twenty-four of the metabolites were considered to be accurately quantified. A supervised orthogonal partial least squares discriminant analysis model separating patients with Leber’s hereditary optic neuropathy from control subjects showed good predictive capability (Q2cumulated = 0.57). Thirty-eight metabolites appeared to be the most significant variables, defining a Leber’s hereditary optic neuropathy metabolic signature that revealed decreased concentrations of all proteinogenic amino acids, spermidine, putrescine, isovaleryl-carnitine, propionyl-carnitine and five sphingomyelin species, together with increased concentrations of 10 phosphatidylcholine species. This signature was not reproduced by the inhibition of complex I with rotenone or piericidin A in control fibroblasts. The importance of sphingomyelins and phosphatidylcholines in the Leber’s hereditary optic neuropathy signature, together with the decreased amino acid pool, suggested an involvement of the endoplasmic reticulum. This was confirmed by the significantly increased phosphorylation of PERK and eIF2α, as well as the greater expression of C/EBP homologous protein and the increased XBP1 splicing, in fibroblasts from affected patients, all these changes being reversed by the endoplasmic reticulum stress inhibitor, TUDCA (tauroursodeoxycholic acid). Thus, our metabolomic analysis reveals a pharmacologically-reversible endoplasmic reticulum stress in complex I-related Leber’s hereditary optic neuropathy fibroblasts, a finding that may open up new therapeutic perspectives for the treatment of Leber’s hereditary optic neuropathy with endoplasmic reticulum-targeting drugs.

Brain 2016

Why are acute ischemic stroke patients not receiving IV tPA? Results from a national registry

ABSTRACT

Objective: To determine patient and hospital characteristics associated with not providing IV tissue plasminogen activator (tPA) to eligible patients with acute ischemic stroke (AIS) in clinical practice.

Methods: We performed a retrospective cohort study of patients with AIS arriving within 2 hours of onset to hospitals participating in Get With The Guidelines–Stroke without documented contraindications to IV tPA from April 2003 through December 2011, comparing those who received tPA to those who did not. Multivariable generalized estimating equation logistic regression modeling identified factors associated with not receiving tPA.

Results: Of 61,698 eligible patients with AIS presenting within 2 hours of onset (median age 73 years, 51% female, 74% non-Hispanic white, median NIH Stroke Scale score 11, interquartile range 6–18), 15,282 (25%) were not treated with tPA within 3 hours. Failure to give tPA decreased over time from 55% in 2003 to 2005 to 18% in 2010 to 2011 (p< 0.0001). After adjustment for all covariates, including stroke severity, factors associated with failure to treat included older age, female sex, nonwhite race, diabetes mellitus, prior stroke, atrial fibrillation, prosthetic heart valve, NIH Stroke Scale score <5, arrival off-hours and not via emergency medical services, longer onset-to-arrival and door-to-CT times, earlier calendar year, and arrival at rural, nonteaching, non–stroke center hospitals located in the South or Midwest.

Conclusions: Overall, about one-quarter of eligible patients with AIS presenting within 2 hours of stroke onset failed to receive tPA treatment. Thrombolysis has improved dramatically over time and is strongly associated with stroke center certification. Additionally, some groups, including older patients, milder strokes, women, and minorities, may be undertreated.

Neurology 2016

SIGMAR1 mutation associated with autosomal recessive Silver-like syndrome

ABSTRACT

Objective: To describe the genetic and clinical features of a simplex patient with distal hereditary motor neuropathy (dHMN) and lower limb spasticity (Silver-like syndrome) due to a mutation in the sigma nonopioid intracellular receptor–1 gene (SIGMAR1) and review the phenotypic spectrum of mutations in this gene.

Methods: We used whole-exome sequencing to investigate the proband. The variants of interest were investigated for segregation in the family using Sanger sequencing. Subsequently, a larger cohort of 16 unrelated dHMN patients was specifically screened for SIGMAR1 mutations.

Results: In the proband, we identified a homozygous missense variant (c.194T>A, p.Leu65Gln) in exon 2 ofSIGMAR1 as the probable causative mutation. Pathogenicity is supported by evolutionary conservation, in silico analyses, and the strong phenotypic similarities with previously reported cases carrying coding sequence mutations in SIGMAR1. No other mutations were identified in 16 additional patients with dHMN.

Conclusions: We suggest that coding sequence mutations in SIGMAR1 present clinically with a combination of dHMN and pyramidal tract signs, with or without spasticity, in the lower limbs. Preferential involvement of extensor muscles of the upper limbs may be a distinctive feature of the disease. These observations should be confirmed in future studies.

Neurology 2016

A genome-wide association study in multiple system atrophy

ABSTRACT

Objective: To identify genetic variants that play a role in the pathogenesis of multiple system atrophy (MSA), we undertook a genome-wide association study (GWAS).

Methods: We performed a GWAS with >5 million genotyped and imputed single nucleotide polymorphisms (SNPs) in 918 patients with MSA of European ancestry and 3,864 controls. MSA cases were collected from North American and European centers, one third of which were neuropathologically confirmed.

Results: We found no significant loci after stringent multiple testing correction. A number of regions emerged as potentially interesting for follow-up at p < 1 × 10⁻⁶, including SNPs in the genes FBXO47, ELOVL7, EDN1, andMAPT. Contrary to previous reports, we found no association of the genes SNCA and COQ2 with MSA.

Conclusions: We present a GWAS in MSA. We have identified several potentially interesting gene loci, including theMAPT locus, whose significance will have to be evaluated in a larger sample set. Common genetic variation in SNCAand COQ2 does not seem to be associated with MSA. In the future, additional samples of well-characterized patients with MSA will need to be collected to perform a larger MSA GWAS, but this initial study forms the basis for these next steps.

Neurology 2016

Mechanisms of memory impairment in epilepsy depend on age at disease onset

ABSTRACT

Objective: In this study, we aimed to uncover distinct antecedents of autobiographic memory dysfunction in patients with epilepsy with early (childhood/adolescence) vs late (adulthood) disease onset.

Methods: One hundred sixty-six adults participated: 92 patients with focal epilepsy, whose cognitive and psychiatric functioning were compared to that of 74 healthy controls. Predictors of autobiographic memory deficit were contrasted between patients with early-onset (n = 47) vs late-onset (n = 45) epilepsy.

Results: Overall, people with epilepsy performed significantly worse on measures of both semantic and episodic autobiographic memory and showed markedly high rates of depressive symptoms and disorders (p < 0.001). Reduced autobiographic memory in patients with early-onset epilepsy was associated with young age at onset, more frequent seizures, and reduced working memory. In contrast, the difficulty that patients with late-onset epilepsy had in recalling autobiographic information was linked to depression and the presence of an MRI-identified lesion.

Conclusions: This study reveals that memory deficits in people with focal epilepsy have differing antecedents depending on the timing of the disease onset. While neurobiological factors strongly underpin reduced autobiographic function in patients with early-onset epilepsy, psychological maladjustment gives rise to the impairments seen in patients with late-onset epilepsy. More broadly, these findings support the practice of subtyping patients according to distinct clinical characteristics to find individualized predictors of cognitive dysfunction.

Neurology 2016

Progressive solitary sclerosis Gradual motor impairment from a single CNS demyelinating lesion

ABSTRACT

Objective: To report patients with progressive motor impairment resulting from an isolated CNS demyelinating lesion in cerebral, brainstem, or spinal cord white matter that we call progressive solitary sclerosis.

Methods: Thirty patients were identified with (1) progressive motor impairment for over 1 year with a single radiologically identified CNS demyelinating lesion along corticospinal tracts, (2) absence of other demyelinating CNS lesions, and (3) no history of relapses affecting other CNS pathways. Twenty-five were followed prospectively in our multiple sclerosis (MS) clinic and 5 were identified retrospectively from our progressive MS database. Patients were excluded if an alternative etiology for progressive motor impairment was found. Multiple brain and spinal cord MRI were reviewed by a neuroradiologist blinded to the clinical details.

Results: The patients' median age was 48.5 years (range 23–71) and 15 (50%) were women. The median follow-up from symptom onset was 100 months (range 15–343 months). All had insidiously progressive upper motor neuron weakness attributable to the solitary demyelinating lesion found on MRI. Clinical presentations were hemiparesis/monoparesis (n = 24), quadriparesis (n = 5), and paraparesis (n = 1). Solitary MRI lesions involved cervical spinal cord (n = 18), cervico-medullary/brainstem region (n = 6), thoracic spinal cord (n = 4), and subcortical white matter (n = 2). CSF abnormalities consistent with MS were found in 13 of 26 (50%). Demyelinating disease was confirmed pathologically in 2 (biopsy, 1; autopsy, 1).

Conclusions: Progressive solitary sclerosis results from an isolated CNS demyelinating lesion. Future revisions to MS diagnostic criteria could incorporate this presentation of demyelinating disease.

Neurology 2016

Thyroid function and the risk of dementia The Rotterdam Study

ABSTRACT

Objective: To study the role of thyroid function in dementia, cognitive function, and subclinical vascular brain disease with MRI.

Methods: Analyses were performed within the Rotterdam Study (baseline 1997), a prospective, population-based cohort. We evaluated the association of thyroid-stimulating hormone (TSH) and free thyroxine with incident dementia using Cox models adjusted for age, sex, cardiovascular risk factors, and education. Absolute risks were calculated accounting for death as a competing risk factor. Associations of thyroid function with cognitive test scores and subclinical vascular brain disease (white matter lesions, lacunes, and microbleeds) were assessed with linear or logistic regression. Additionally, we stratified by sex and restricted analyses to normal thyroid function.

Results: We included 9,446 participants with a mean age of 65 years. During follow-up (mean 8.0 years), 601 participants had developed dementia. Higher TSH was associated with lower dementia risk in both the full and normal ranges of thyroid function (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.83–0.98; and HR 0.76, 95% CI 0.64–0.91, respectively). This association was independent of cardiovascular risk factors. Dementia risk was higher in individuals with higher free thyroxine (HR 1.04, 95% CI 1.01–1.07). Absolute 10-year dementia risk decreased from 15% to 10% with higher TSH in older women. Higher TSH was associated with better global cognitive scores (p = 0.021). Thyroid function was not related to subclinical vascular brain disease as indicated by MRI.

Conclusions: High and high-normal thyroid function is associated with increased dementia risk. Thyroid function is not related to vascular brain disease as assessed by MRI, suggesting a role for thyroid hormone in nonvascular pathways leading to dementia.

Neurology 2016