Mutations in MME cause an autosomal-recessive Charcot–Marie–Tooth disease type 2

Objective

The objective of this study was to identify new causes of Charcot–Marie–Tooth (CMT) disease in patients with autosomal-recessive (AR) CMT.

Methods

To efficiently identify novel causative genes for AR-CMT, we analyzed 303 unrelated Japanese patients with CMT using whole-exome sequencing and extracted recessive variants/genes shared among multiple patients. We performed mutation screening of the newly identified membrane metalloendopeptidase (MME) gene in 354 additional patients with CMT. We clinically, genetically, pathologically, and radiologically examined 10 patients with the MME mutation.

Results

We identified recessive mutations in MME in 10 patients. The MME gene encodes neprilysin (NEP), which is well known to be one of the most prominent beta-amyloid (Aβ)-degrading enzymes. All patients had a similar phenotype consistent with late-onset axonal neuropathy. They showed muscle weakness, atrophy, and sensory disturbance in the lower extremities. All the MME mutations could be loss-of-function mutations, and we confirmed a lack/decrease of NEP protein expression in a peripheral nerve. No patients showed symptoms of dementia, and 1 patient showed no excess Aβ in Pittsburgh compound-B positron emission tomography imaging.

Interpretation

Our results indicate that loss-of-function MME mutations are the most frequent cause of adult-onset AR-CMT2 in Japan, and we propose that this new disease should be termed AR-CMT2T. A loss-of-function MME mutation did not cause early-onset Alzheimer's disease. Identifying the MME mutation responsible for AR-CMT could improve the rate of molecular diagnosis and the understanding of the molecular mechanisms of CMT. 

Ann Neurol 2016

Glial and axonal changes in systemic lupus erythematosus measured with diffusion of intracellular metabolites

Systemic lupus erythematosus is an inflammatory autoimmune disease with multi-organ involvement. Central nervous system involvement in systemic lupus erythematosus is common and results in several neurological and psychiatric symptoms that are poorly linked to standard magnetic resonance imaging outcome. Magnetic resonance imaging methods sensitive to tissue microstructural changes, such as diffusion tensor imaging and magnetization transfer imaging, show some correlation with neuropsychiatric systemic lupus erythematosus (NPSLE) symptoms. Histological examination of NPSLE brains reveals presence of cerebral oedema, loss of neurons and myelinated axons, microglial proliferation and reactive astrocytosis, microinfacrts and diffuse ischaemic changes, all of which can affect both diffusion tensor imaging and magnetization transfer imaging in a non-specific manner. Here we investigated the underlying cell-type specific microstructural alterations in the brain of patients with systemic lupus erythematosus with and without a history of central nervous system involvement. We did so combining diffusion tensor imaging with diffusion-weighted magnetic resonance spectroscopy, a powerful tool capable of characterizing cell-specific cytomorphological changes based on diffusion of intracellular metabolites. We used a 7 T magnetic resonance imaging scanner to acquire T1-weighted images, diffusion tensor imaging datasets, and single volume diffusion-weighted magnetic resonance spectroscopy data from the anterior body of the corpus callosum of 13 patients with systemic lupus erythematosus with past NPSLE, 16 patients with systemic lupus erythematosus without past NPSLE, and 19 healthy control subjects. Group comparisons were made between patients with systemic lupus erythematosus with/without past NPSLE and healthy controls on diffusion tensor imaging metrics and on diffusion coefficients of three brain metabolites: the exclusively neuronal/axonal N-acetylaspartate, and the predominantly glial creatine + phosphocreatine and choline compounds. In patients with systemic lupus erythematosus with past NPSLE, significantly higher diffusion tensor imaging mean and radial diffusivities were accompanied by a significantly higher intracellular diffusion of total creatine (0.202 ± 0.032 μm2/ms, P = 0.018) and total choline (0.142 ± 0.031 μm2/ms, P = 0.044) compared to healthy controls (0.171 ± 0.024 μm2/ms, 0.124 ± 0.018 μm2/ms, respectively). Total N-acetylaspartate, total creatine and total choline diffusion values from all patients with systemic lupus erythematosus correlated positively with systemic lupus erythematosus disease activity index score (P = 0.033, P = 0.040, P =0.008, respectively). Our results indicate that intracellular alterations, and in particular changes in glia, as evidenced by increase in the average diffusivities of total choline and total creatine, correlate with systemic lupus erythematosus activity. The higher diffusivity of total creatine and total choline in patients with NPSLE, as well as the positive correlation of these diffusivities with the systemic lupus erythematosus disease activity index are in line with cytomorphological changes in reactive glia, suggesting that the diffusivities of choline compounds and of total creatine are potentially unique markers for glial reactivity in response to inflammation.

Brain 2016

Early and protective microglial activation in Alzheimer’s disease: a prospective study using 18F-DPA-714 PET imaging

Summary

While emerging evidence suggests that neuroinflammation plays a crucial role in Alzheimer’s disease, the impact of the microglia response in Alzheimer’s disease remains a matter of debate. We aimed to study microglial activation in early Alzheimer’s disease and its impact on clinical progression using a second-generation 18-kDa translocator protein positron emission tomography radiotracer together with amyloid imaging using Pittsburgh compound B positron emission tomography. We enrolled 96 subjects, 64 patients with Alzheimer’s disease and 32 controls, from the IMABio3 study, who had both 11C-Pittsburgh compound B and 18F-DPA-714 positron emission tomography imaging. Patients with Alzheimer’s disease were classified as prodromal Alzheimer’s disease (n = 38) and Alzheimer’s disease dementia (n = 26). Translocator protein-binding was measured using a simple ratio method with cerebellar grey matter as reference tissue, taking into account regional atrophy. Images were analysed at the regional (volume of interest) and at the voxel level. Translocator protein genotyping allowed the classification of all subjects in high, mixed and low affinity binders. Thirty high+mixed affinity binders patients with Alzheimer’s disease were dichotomized into slow decliners (n =10) or fast decliners (n =20) after 2 years of follow-up. All patients with Alzheimer’s disease had an amyloid positive Pittsburgh compound B positron emission tomography. Among controls, eight had positive amyloid scans (n = 6 high+mixed affinity binders), defined as amyloidosis controls, and were analysed separately. By both volumes of interest and voxel-wise comparison, 18-kDa translocator protein-binding was higher in high affinity binders, mixed affinity binders and high+mixed affinity binders Alzheimer’s disease groups compared to controls, especially at the prodromal stage, involving the temporo-parietal cortex. Translocator protein-binding was positively correlated with Mini-Mental State Examination scores and grey matter volume, as well as with Pittsburgh compound B binding. Amyloidosis controls displayed higher translocator protein-binding than controls, especially in the frontal cortex. We found higher translocator protein-binding in slow decliners than fast decliners, with no difference in Pittsburgh compound B binding. Microglial activation appears at the prodromal and possibly at the preclinical stage of Alzheimer’s disease, and seems to play a protective role in the clinical progression of the disease at these early stages. The extent of microglial activation appears to differ between patients, and could explain the overlap in translocator protein binding values between patients with Alzheimer’s disease and amyloidosis controls.

Brain 2016

Retinal thickness measured with optical coherence tomography and risk of disability worsening in multiple sclerosis: a cohort study

Summary

Background

Most patients with multiple sclerosis without previous optic neuritis have thinner retinal layers than healthy controls. We assessed the role of peripapillary retinal nerve fibre layer (pRNFL) thickness and macular volume in eyes with no history of optic neuritis as a biomarker of disability worsening in a cohort of patients with multiple sclerosis who had at least one eye without optic neuritis available.

Methods

In this multicentre, cohort study, we collected data about patients (age ≥16 years old) with clinically isolated syndrome, relapsing-remitting multiple sclerosis, and progressive multiple sclerosis. Patients were recruited from centres in Spain, Italy, France, Germany, Czech Republic, Netherlands, Canada, and the USA, with the first cohort starting in 2008 and the latest cohort starting in 2013. We assessed disability worsening using the Expanded Disability Status Scale (EDSS). The pRNFL thickness and macular volume were assessed once at study entry (baseline) by optical coherence tomography (OCT) and was calculated as the mean value of both eyes without optic neuritis for patients without a history of optic neuritis or the value of the non-optic neuritis eye for patients with previous unilateral optic neuritis. Researchers who did the OCT at baseline were masked to EDSS results and the researchers assessing disability with EDSS were masked to OCT results. We estimated the association of pRNFL thickness or macular volume at baseline in eyes without optic neuritis with the risk of subsequent disability worsening by use of proportional hazards models that included OCT metrics and age, disease duration, disability, presence of previous unilateral optic neuritis, and use of disease-modifying therapies as covariates.

Findings

879 patients with clinically isolated syndrome (n=74), relapsing-remitting multiple sclerosis (n=664), or progressive multiple sclerosis (n=141) were included in the primary analyses. Disability worsening occurred in 252 (29%) of 879 patients with multiple sclerosis after a median follow-up of 2·0 years (range 0·5–5 years). Patients with a pRNFL of less than or equal to 87 μm or less than or equal to 88 μm (measured with Spectralis or Cirrus OCT devices) had double the risk of disability worsening at any time after the first and up to the third years of follow-up (hazard ratio 2·06, 95% CI 1·36–3·11; p=0·001), and the risk was increased by nearly four times after the third and up to the fifth years of follow-up (3·81, 1·63–8·91; p=0·002). We did not identify meaningful associations for macular volume.

Interpretation

Our results provide evidence of the usefulness of monitoring pRNFL thickness by OCT for prediction of the risk of disability worsening with time in patients with multiple sclerosis.

Lancet Neurology 2016

Serum and CSF GQ1b antibodies in isolated ophthalmologic syndromes

ABSTRACT

Objective: To establish the sensitivity and specificity of serum and CSF antibodies targeting the gangliosides GQ1b (GQ1bAb) in isolated ophthalmologic syndromes, such as acute ophthalmoplegia (AO) and optic neuritis (ON), caused by disorders other than Miller-Fisher syndrome (MFS).

Methods: We measured serum and CSF GQ1bAb in patients with MFS and with AO or ON caused by other disorders than MFS.

Results: Twenty-one patients with AO (21 serum, 9 CSF), 13 with ON (13 serum, 13 CSF), and 12 with MFS (12 serum, 10 CSF) were included in the study. There were no significant differences in age, sex, and CSF findings between the AO and MFS groups. Elevated serum GQ1b titers occurred in 11 of 12 patients with MFS but in only 1 of the 34 patients without MFS. Sensitivity was 92% (95% confidence interval [CI] 62%–100%) and specificity 97% (95% CI 85%–100%). In CSF, GQ1bAb were identified in 2 of 10 patients with MFS but in none with other disorders. Sensitivity was 20% (95% CI 2%–56%) and specificity 100% (95% CI 85%–100%).

Conclusions: Increased serum GQ1bAb are highly specific for MFS. Measurement of GQ1bAb in CSF does not improve diagnosis.

Classification of evidence: This study provides Class III evidence that serum GQ1bAb accurately distinguish MFS from other disorders (sensitivity 92%, 95% CI 62%–100%; specificity 97%, 95% CI 85%–100%).

Neurology 2016

Frontotemporal networks and behavioral symptoms in primary progressive aphasia

ABSTRACT

Objective: To determine if behavioral symptoms in patients with primary progressive aphasia (PPA) were associated with degeneration of a ventral frontotemporal network.

Methods: We used diffusion tensor imaging tractography to quantify abnormalities of the uncinate fasciculus that connects the anterior temporal lobe and the ventrolateral frontal cortex. Two additional ventral tracts were studied: the inferior fronto-occipital fasciculus and the inferior longitudinal fasciculus. We also measured cortical thickness of anterior temporal and orbitofrontal regions interconnected by these tracts. Thirty-three patients with PPA and 26 healthy controls were recruited.

Results: In keeping with the PPA diagnosis, behavioral symptoms were distinctly less prominent than the language deficits. Although all 3 tracts had structural pathology as determined by tractography, significant correlations with scores on the Frontal Behavioral Inventory were found only for the uncinate fasciculus. Cortical atrophy of the orbitofrontal and anterior temporal lobe cortex was also correlated with these scores.

Conclusions: Our findings indicate that damage to a frontotemporal network mediated by the uncinate fasciculus may underlie the emergence of behavioral symptoms in patients with PPA.

Neurology 2016

Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients

Objective

Hereditary spastic paraplegias (HSPs) are genetically driven disorders with the hallmark of progressive spastic gait disturbance. To investigate the phenotypic spectrum, prognostic factors, and genotype-specific differences, we analyzed baseline data from a continuous, prospective cohort.

Methods

We recruited 608 HSP cases from 519 families of mostly German origin. Clinical severity was assessed by the Spastic Paraplegia Rating Scale. Complicating symptoms were recorded by a standardized inventory.

Results

Family history indicated dominant (43%), recessive (10%), and simplex (47%) disease. We observed a significant male predominance, particularly in simplex cases without a genetic diagnosis. Disease severity increased with disease duration. Earlier disease onset was associated with less severe disease. Specific complicating features including cognitive impairment, extrapyramidal or peripheral motor involvement, and ataxia were associated with worse disease severity. Disease severity also depended on the genotype. HSP cases maintained the ability to walk independently for a median disease duration of 22 years. Early onset cases were able to maintain free walking significantly longer and were at less risk to become wheelchair dependent.

Interpretation

This cross-sectional cohort study provides the first large-scale data on disease manifestation, progression, and modifying factors, with relevance for counseling of HSP families and planning of future cross-sectional and natural history studies. Later age of onset, specific complicating features, and the SPG11 genotype are strongly associated with more severe disease. Future interventional studies will require stratification for modifiers of disease progression identified in this study. Prospective longitudinal studies will verify progression rates calculated in this baseline analysis. 

Ann Neurol 2016