How can we define the presymptomatic C9orf72 disease in 2022? An overview on the current definitions of preclinical and prodromal phases.

Repeat expansions in C9orf72 gene are the main genetic cause of frontotemporal dementia, amyotrophic lateral sclerosis and related phenotypes. With the advent of disease-modifying treatments, the presymptomatic disease phase is getting increasing interest as an ideal time window in which innovant therapeutic approaches could be administered. Recommendations issued from international study groups distinguish between a preclinical disease stage, during which lesions accumulate in absence of any symptoms or signs, and a prodromal stage, marked by the appearance the first subtle cognitive, behavioral, psychiatric and motor signs, before the full-blown disease. This paper summarizes the current definitions and criteria for these stages, in particular focusing on how fluid-based, neuroimaging and cognitive biomarkers can be useful to monitor disease trajectory across the presymptomatic phase, as well as to detect the earliest signs of clinical conversion. Continuous advances in the knowledge of C9orf72 pathophysiology, and the integration of biomarkers in the clinical evaluation of mutation carriers will allow a better diagnostic definition of C9orf72 disease spectrum from the earliest stages, with relevant impact on the possibility of disease prevention.

Multimodal neurometabolic investigation of the effects of zolpidem on leukoencephalopathy-related apathy.

BACKGROUND AND PURPOSE: The symptomatic effect of zolpidem on apathy has been reported in neurological disorders such as strokes and post-anoxic brain injuries, but not in white-matter disease of the brain. METHODS: A 38-year-old patient presenting with severe apathy related to a genetic leukoencephalopathy but showing marked improvement of apathy after taking 10 mg of zolpidem was studied. To understand what may mediate such a clinical effect, a multimodal neurometabolic approach using 18 F fluorodeoxyglucose positron emission tomography (FDG-PET) and a dedicated magnetic resonance spectroscopy (MRS) sequence for gamma aminobutyric acid (GABA) and glutamine + glutamate metabolism was undertaken. RESULTS: Pre-zolpidem FDG-PET showed hypometabolism in the orbitofrontal cortex, dorsolateral cortex and basal ganglia compared to healthy controls. Post-zolpidem, FDG-PET displayed increased metabolism in the orbitofrontal cortex together with improvement in the emotional and auto-activation domains of apathy. There was no improvement in the cognitive domain of apathy, and no change in metabolism in the dorsolateral frontal cortex. Post-zolpidem, MRS showed increased GABA and glutamine + glutamate levels in the frontal cortex and pallidum. CONCLUSION: Our multimodal neurometabolic study suggests that the effects of zolpidem on apathy are related to increased metabolism in the orbitofrontal cortex and basal ganglia secondary to GABA modulation. Zolpidem may improve apathy in other white-matter disorders.

Genetic forms of frontotemporal lobar degeneration: Current diagnostic approach and new directions in therapeutic strategies.

Recent advances in the genetics of neurodegenerative diseases have substantially improved our knowledge about the genetic causes of frontotemporal lobar degeneration (FTLD). Three major genes, namely progranulin (GRN), C9orf72 and MAPT, as well as several less common genes, are responsible for the majority of familial cases and for a significant proportion of sporadic forms, including FTLD with or without associated amyotrophic lateral sclerosis and some rarer clinical presentations. Plasma progranulin dosage and next-generation sequencing are currently available tools which allow the detection of a genetic cause in a more rapid and efficient way. This has important consequences for clinical practice and genetic counseling for patients and families. The ongoing investigations on some therapeutic candidates targeting different biological pathways involved in the most frequent genetic forms of FTLD, as well as a better understanding of the early pathophysiological modifications occurring during the presymptomatic phase of the disease could hopefully contribute to develop effective disease-modifying therapies. The identification of a causal mutation in a family is of outmost importance indeed to propose to presymptomatic carriers their inclusion in clinical trials with the aim to prevent or delay the onset of disease.

[Toward a preventive management Alzheimer's disease]. / Pour une prise en charge préventive de la maladie d'Alzheimer.

Dementias, and Alzheimer's disease (AD) in particular, will increasingly become a public health issue. However, three major data may change the severity of these pathologies: in young adults, simple measures of healthy lifestyle (control of vascular risk factors, physical activity and cognitive stimulation), have an impact on a future cognitive decline; the same lifestyle interventions may delay the start of the disease for elderly people potentially at-risk; finally, and for the first time, a monoclonal antibody directed against amyloid lesions has just shown a significant effect on the progression of AD in patients at an early stage of the disease. According to these results, we will have to reconsider the strategy for managing minor or severe cognitive disorders and particularly AD. Nowadays, patients start the care process too late. The solution is to act earlier, even preventively. It is necessary to improve a care offer adapted to this new situation in order to impact on the disease as soon as possible, even before the onset of symptoms, based on: 1) predictive algorithms aimed at establishing whose cognitively unimpaired individuals may further develop the disease; these algorithms will be based on demographic, family, cognitive, genomic and biological data, such as in the "Santé Cerveau" project developed in partnership with the Health Regional Agency (ARS) and the general practitioners; 2)and on some expert centers which must become "dementia prevention clinics" to test prevention measures, initiate and validate multi-domain therapeutic education programs; to disclose about the risk in response to the request of worried patients; and to propose early pharmacological treatments if these individuals are on the way to declare AD in the coming months, taking into account competition between risks. This will allow to prepare to make use of new pharmacological treatments that might be discovered.

Adult-Onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia: An MRI Study of 16 French Cases.

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia is an autosomal dominant leukoencephalopathy related to CSF1R gene mutations. A growing number of clinicoradiologic phenotypes have been described. In this study, we analyzed brain imaging findings in 16 patients with adult-onset leukoencephalopathy with axonal spheroids and pigmented glia to refine radiologic diagnostic clues. T2/FLAIR white matter hyperintensities were present in all patients with frontal or frontoparietal predilection, with asymmetric distribution in more than one-third. Brain atrophy and callosal involvement were almost constant, and corticospinal tract involvement was frequent. Moreover, deep white matter hyperintense dots on DWI and deep punctate calcifications on CT were often found. Conversely, deep gray matter nuclei, external capsules, and brain stem were rarely involved. Our series emphasized the great variability of MR imaging findings seen in adult-onset leukoencephalopathy with axonal spheroids and pigmented glia. A complete imaging screening including DWI, T2*, and CT is mandatory to accurately assess patients with suspected inherited adult-onset leukoencephalopathy.

Comparing ataxias with oculomotor apraxia: a multimodal study of AOA1, AOA2 and AT focusing on video-oculography and alpha-fetoprotein.

Whether the recessive ataxias, Ataxia with oculomotor apraxia type 1 (AOA1) and 2 (AOA2) and Ataxia telangiectasia (AT), can be distinguished by video-oculography and alpha-fetoprotein level remains unknown. We compared 40 patients with AOA1, AOA2 and AT, consecutively referred between 2008 and 2015 with 17 healthy subjects. Video-oculography revealed constant impairments in patients such as cerebellar signs, altered fixation, impaired pursuit, hypometric saccades and abnormal antisaccades. Horizontal saccade latencies could be highly increased reflecting oculomotor apraxia in one third of patients. Specific distinctive alpha-fetoprotein thresholds were determined for AOA1 (7-15 µg/L), AOA2 (15-65 µg/L) and AT (>65 µg/L). Early age onset, severe walking disability, movement disorders, sensori-motor neuropathy and cerebellar atrophy were all shared. In conclusion, alpha-fetoprotein level seems to permit a distinction while video-oculography does not and therefore is not mandatory, even if an appropriate oculomotor examination remains crucial. Our findings are that AOA1, AOA2 and AT form a particular group characterized by ataxia with complex oculomotor disturbances and elevated AFP for which the final diagnosis is relying on genetic analysis. These findings could guide genetic analysis, assist reverse-phenotyping and provide background for the interpretation of the numerous variants of unknown significance provided by next-generation sequencing.

17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression.

To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-ß deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.

Frontotemporal lobar dementia and amyotrophic lateral sclerosis associated with c9orf72 expansion.

An intronic GGGGCC repeat expansion in c9orf72 gene has been identified as the most common genetic cause of frontotemporal lobar dementia (FTLD), amyotrophic lateral sclerosis (ALS) and FTLD-ALS. The discovery of c9orf72 gene has led to important scientific progresses and has considerably changed our clinical practice over the last few years. This paper summarizes the common and less typical phenotypes associated with c9orf72 expansion, the complex pathological pattern characterized by p62/dipeptide repeat aggregates, as well as the pathological mechanisms by which the expansion might produce neurodegeneration implicating loss-of-function, RNA toxicity, RNA-binding protein sequestration and accumulation of dipeptide repeats. We also discuss the recommendations and limits for genetic testing and counseling in clinical practice.

Genetics of frontotemporal lobar degeneration: an up-date and diagnosis algorithm.

The last decade marked a turning point in the knowledge of frontotemporal lobar degenerations (FTLD). Major discoveries were made with the identification of TDP-43 and FUS, two novel key players in FTLD. The growing number of FTLD genes has considerably changed our clinical practice. The high intrafamilial variability of phenotypes underlines the necessity of a careful interview concerning the family history, regarding FTLD diseases, but also other neurodegenerative and extra-neurological disorders. Knowledge of the different genetic forms of FTLD and their associated phenotypes become essential to propose appropriate genetic diagnosis to the patients, and deliver accurate genetic counseling to their families. We propose an algorithm based on four criteria to help to pinpoint the genetic cause of FTLD: Presence of ALS in the patient or family; age at onset of FTLD; progranulin plasma level; and other disorders present in the patient or family. Presence of ALS is strongly indicative of a C9ORF72 expansion; a very early age at onset (<50 years), parkinsonism and oculomotor dysfunction are indicative of MAPT mutations; whereas hallucinations, CBDS and PNFA are indicative of PGRN mutations. A C9ORF72 repeat expansion should be searched for therefore in patients with FTLD-ALS, followed by sequencing of exon 6 of TARDBP gene in negative cases. Since C9ORF72 expansions are as frequent as PGRN mutations in patients with pure FTLD, both should be investigated, except in early familial FTLD (<50) where MAPT mutations should be searched for first. VCP, SQSTM1 and hnRNPA2B1 gene-sequencing could be proposed in patients or families presenting 'multisystem proteinopathy'. The genes currently identified explain 50-60% of familial forms of FTLD. The identification of new FTLD genes involved remains a major challenge to gain further insight into the pathology and even better clarify the classification of FTLD in the future.

Ataxia with oculomotor apraxia type 2: clinical, biological and genotype/phenotype correlation study of a cohort of 90 patients.

Ataxia with oculomotor apraxia type 2 (AOA2) is an autosomal recessive disease due to mutations in the senataxin gene, causing progressive cerebellar ataxia with peripheral neuropathy, cerebellar atrophy, occasional oculomotor apraxia and elevated alpha-feto-protein (AFP) serum level. We compiled a series of 67 previously reported and 58 novel ataxic patients who underwent senataxin gene sequencing because of suspected AOA2. An AOA2 diagnosis was established for 90 patients, originating from 15 countries worldwide, and 25 new senataxin gene mutations were found. In patients with AOA2, median AFP serum level was 31.0 microg/l at diagnosis, which was higher than the median AFP level of AOA2 negative patients: 13.8 microg/l, P = 0.0004; itself higher than the normal level (3.4 microg/l, range from 0.5 to 17.2 microg/l) because elevated AFP was one of the possible selection criteria. Polyneuropathy was found in 97.5% of AOA2 patients, cerebellar atrophy in 96%, occasional oculomotor apraxia in 51%, pyramidal signs in 20.5%, head tremor in 14%, dystonia in 13.5%, strabismus in 12.3% and chorea in 9.5%. No patient was lacking both peripheral neuropathy and cerebellar atrophy. The age at onset and presence of occasional oculomotor apraxia were negatively correlated to the progression rate of the disease (P = 0.03 and P = 0.009, respectively), whereas strabismus was positively correlated to the progression rate (P = 0.03). An increased AFP level as well as cerebellar atrophy seem to be stable in the course of the disease and to occur mostly at or before the onset of the disease. One of the two patients with a normal AFP level at diagnosis had high AFP levels 4 years later, while the other had borderline levels. The probability of missing AOA2 diagnosis, in case of sequencing senataxin gene only in non-Friedreich ataxia non-ataxia-telangiectasia ataxic patients with AFP level > or =7 microg/l, is 0.23% and the probability for a non-Friedreich ataxia non-ataxia-telangiectasia ataxic patient to be affected with AOA2 with AFP levels > or =7 microg/l is 46%. Therefore, selection of patients with an AFP level above 7 microg/l for senataxin gene sequencing is a good strategy for AOA2 diagnosis. Pyramidal signs and dystonia were more frequent and disease was less severe with missense mutations in the helicase domain of senataxin gene than with missense mutations out of helicase domain and deletion and nonsense mutations (P = 0.001, P = 0.008 and P = 0.01, respectively). The lack of pyramidal signs in most patients may be explained by masking due to severe motor neuropathy.

Chromosome 9p-linked families with frontotemporal dementia associated with motor neuron disease.

BACKGROUND: Frontotemporal dementia associated with motor neuron disease (FTD-MND) is a rare neurodegenerative disorder that may be inherited by autosomal dominant trait. No major gene has been identified but a locus was mapped on chromosome 9 (9p21.3-p13.3). METHODS: Ten French families with FTD-MND were tested for linkage to the 9p21.3-p13.3 region. We report extensive mutation screening in 9p-linked families and their clinical characteristics. RESULTS: We identified six new families with evidence for linkage to the chromosome 9p. Cumulative multipoint LOD score values were positive between markers D9S1121 and D9S301, reaching a peak of 8.0 at marker D9S248. Haplotype reconstruction defined the telomeric boundary at marker AFM218xg11, slightly narrowing the candidate interval. We found no disease-causing mutations by sequencing 29 candidate genes including IFT74 and no copy number variations in the 9p region. The mean age at onset was 57.9 +/- 10.3 years (range, 41-84), with wide heterogeneity within and among families suggesting age-dependant penetrance. The patients presented isolated FTD (32%), isolated MND (29%), or both disorders (39%). The general characteristics of the disease did not differ, except for an older age at onset and shorter disease duration in the 9p-linked compared to nonlinked families. TDP-43-positive neuronal cytoplasmic inclusions were found in cortex and spinal cord in 3 patients. CONCLUSIONS: This study increases the number of 9p-linked families now reported and shows that this locus may have a major effect on frontotemporal dementia (FTD) and motor neuron disease (MND). Considering our results, the causative gene might be implicated in at least 60% of the families with FTD-MND disorder.

Are interrupted SCA2 CAG repeat expansions responsible for parkinsonism?

BACKGROUND: Autosomal dominant parkinsonism (ADP) is caused in a large percentage of familial and sporadic cases by mutations in the LRRK2 gene, particularly G2019S. It is also caused by mutations in genes associated with autosomal dominant cerebellar ataxia (ADCA), notably CAG/CAA repeat expansions in SCA2. METHODS: We screened 164 families with ADP for expansions in the SCA2, 3, and 17 genes and for the G2019S mutation in LRRK2. The SCA2 CAG/CAA repeat expansion was sequenced to determine its structure. The phenotypes of patients with ADP caused by the SCA2, LRRK2, and unknown mutations were compared, as well as those of SCA2 patients with interrupted or uninterrupted expansions of the same size. RESULTS: Three French ADP families had SCA2 mutations. The expansions ranged from 37 to 39 repeats and were interrupted and stable upon transmission. All patients (n = 9) had levodopa-responsive parkinsonism without cerebellar signs. They had significantly more symmetric signs and less rigidity than ADP caused by the G2019S mutation in LRRK2 or by unknown mutations. Interestingly, two sisters carrying both the SCA2 and the G2019S LRRK2 mutations had markedly earlier onset than their mother with only SCA2. In contrast, similar-sized but uninterrupted repeats were associated with ADCA in which cerebellar ataxia was constant and associated only rarely with one or more mild parkinsonian signs. CONCLUSION: These results suggest that the configuration of the SCA2 CAG/CAA repeat expansions plays an important role in phenotype variability. Uninterrupted SCA2 repeat expansions found in families with autosomal dominant cerebellar ataxia result in somatic mosaicism and produce large hairpin RNAs, which may interact with double-stranded RNA-binding proteins. These characteristics are modified by interruption of the SCA2 repeat expansion as found in families with autosomal dominant parkinsonism.

Clinical and genetic features of families with frontotemporal dementia and parkinsonism linked to chromosome 17 with a P301S tau mutation.

In 9 patients with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) with a P301S tau mutation, the predominant phenotype was frontotemporal dementia in 3 and parkinsonism in 6. Comparison of the tau genotype/haplotype carrying the mutation and the initial clinical sign showed association between H1/H1 and parkinsonism and between H1/H2 and personality change. Thus, the tau haplotype carrying the mutation and the tau genotype may be related to the clinical phenotype throughout the disease course.

Muscle coenzyme Q10 deficiencies in ataxia with oculomotor apraxia 1.

APTX gene mutations responsible for ataxia-oculomotor apraxia 1 (AOA1) were identified in a family previously reported with ataxia and coenzyme Q10 (CoQ10) deficiency. We measured muscle CoQ10 levels in six patients with AOA1 and found decreased levels in five. Patients homozygous for the W279X mutation had lower values (p = 0.003). A therapeutic trial of CoQ10 may be warranted in patients with AOA1.

Predominant dystonia with marked cerebellar atrophy: a rare phenotype in familial dystonia.

BACKGROUND: Dystonia syndromes constitute a heterogeneous group of phenotypes that may be caused by different heredodegenerative, metabolic, or genetic diseases. OBJECTIVE: To describe the characteristics of an unusual dystonia-plus phenotype associated with cerebellar atrophy. METHODS: We selected patients with predominant dystonia and cerebellar atrophy among the 861 families referred to us for genetic testing from 1992 to 2003. The main secondary heredodegenerative causes and the major genes responsible for hereditary dystonias and autosomal dominant or recessive ataxias were excluded. RESULTS: We identified 12 patients in 8 families with an unusual dystonia-plus phenotype characterized by dystonia and cerebellar atrophy on brain MRI. The mean age at onset was 27.3 +/- 11.5 years (range: 9 to 42 years) and the mean disease duration 14.7 +/- 7.7 years (range: 4 to 30). At onset, dystonia was focal or multifocal, mainly affecting vocal cords (n = 8) and upper limbs (n = 2). During the disease course spasmodic dysphonia became severe in five patients, leading to complete aphonia in two. Dystonia became generalized in five. Cerebellar ataxia was limited to unsteadiness in most patients and progressed very slowly. The paucity of clinical cerebellar signs contrasted with the marked cerebellar atrophy on brain MRI in most patients. Four families with two affected sibs support the hypothesis of an autosomal recessive disorder. However, X-linked inheritance is possible since only men were affected. CONCLUSION: We have characterized an unusual familial phenotype associating dystonia and cerebellar atrophy in 12 male patients.

Valosin-containing protein gene mutations: clinical and neuropathologic features.

BACKGROUND: Hereditary inclusion body myopathy (IBMPFD) with Paget disease of bone (PDB) and frontotemporal dementia (FTD) is a rare multisystem disorder with autosomal dominant inheritance. Recently, missense mutations in the gene encoding valosin-containing protein (VCP) have been found in individuals with IBMPFD. VCP/P97, which exerts a variety of cellular functions, plays a key role in the ubiquitin-proteasome dependent degradation of cytosolic proteins and in the retrotranslocation of misfolded proteins from the endoplasmic reticulum into the cytoplasm. METHODS: The authors describe the clinical features of two kindreds in which VCP R93C and R155C missense mutations segregate and perform a histopathologic examination of brain, muscle, bone, and liver of three subjects harboring the R155C mutation. RESULTS: Frontotemporal dementia was present in 100% of affected subjects in Family F1 and 70% in Family F2, as compared with an average of 30% in previously described IBMPFD families. In contrast, PDB was a more inconstant clinical feature. Biochemical and histopathologic data are consistent with the hypothesis that VCP R155C mutation disrupts normal VCP function, leading to diffuse accumulation of ubiquitinated proteins within the cells. CONCLUSIONS: VCP mutations are present in two families in which FTD is the most prominent symptom. The histopathologic study performed in patients harboring the R155C mutation supports the hypothesis that this mutation disrupts normal VCP function, leading to diffuse accumulation of ubiquitinated proteins within the cells. IBMPFD belongs to a class of genetic diseases associated with an alteration of the ubiquitin-proteasome system.