Familial clustering of primary lateral sclerosis and amyotrophic lateral sclerosis: Supplementary evidence for a continuum.

BACKGROUND AND PURPOSE: Primary lateral sclerosis (PLS) is a motor neuron disorder characterized by a pure upper motor neuron degeneration in the bulbar and spinal regions. The key difference with amyotrophic lateral sclerosis (ALS) is the lower motor neuron system integrity. Despite important literature on this disease, the pathophysiology of PLS remains unknown, and the link with ALS still balances between a continuum and a separate entity from ALS. METHODS: We report nine families in which both PLS and ALS cases occurred, in general among first-degree relatives. RESULTS: The patients with PLS and ALS had a typical disease presentation. Genetic studies revealed mutations in SQSMT1, TBK1, and TREM2 genes in two PLS patients and one ALS patient. CONCLUSIONS: These results strongly support a phenotypic continuum between PLS and ALS.

Effect of familial clustering in the genetic screening of 235 French ALS families.

OBJECTIVES: To determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cases and the phenotype of the disease may help identify the pathogenic genes involved. METHODS: We conducted a targeted next-generation sequencing analysis on 235 French familial ALS (FALS), unrelated probands to identify mutations in 30 genes linked to the disease. The genealogy, that is, number of cases and generations with ALS, gender, age, site of onset and the duration of the disease were analysed. RESULTS: Regarding the number of generations, 49 pedigrees had only one affected generation, 152 had two affected generations and 34 had at least three affected generations. Among the 149 pedigrees (63.4%) for which a deleterious variant was found, an abnormal G4C2 expansion in C9orf72 was found in 98 cases as well as SOD1, TARBP or FUS mutations in 30, 9 and 7 cases, respectively. Considering pedigrees from the number of generations, abnormal G4C2 expansion in C9orf72 was more frequent in pedigrees with pairs of affected ALS cases, which represented 65.2% of our cohort. SOD1 mutation involved all types of pedigrees. No TARDBP nor FUS mutation was present in monogenerational pedigrees. TARDBP mutation predominated in bigenerational pedigrees with at least three cases and FUS mutation in multigenerational pedigrees with more than seven cases, on average, and with an age of onset younger than 45 years. CONCLUSION: Our results suggest that familial clustering, phenotypes and genotypes are interconnected in FALS, and thus it might be possible to target the genetic screening from the familial architecture and the phenotype of ALS cases.

Single-fiber studies for assigning pathogenicity of eight mitochondrial DNA variants associated with mitochondrial diseases.

Whole mitochondrial DNA (mtDNA) sequencing is now systematically used in clinical laboratories to screen patients with a phenotype suggestive of mitochondrial disease. Next Generation Sequencing (NGS) has significantly increased the number of identified pathogenic mtDNA variants. Simultaneously, the number of variants of unknown significance (VUS) has increased even more, thus challenging their interpretation. Correct classification of the variants' pathogenicity is essential for optimal patient management, including treatment and genetic counseling. Here, we used single muscle fiber studies to characterize eight heteroplasmic mtDNA variants, among which were three novel variants. By applying the pathogenicity scoring system, we classified four variants as "definitely pathogenic" (m.590A>G, m.9166T>C, m.12293G>A, and m.15958A>T). Two variants remain "possibly pathogenic" (m.4327T>C and m.5672T>C) but should these be reported in a different family, they would be reclassified as "definitely pathogenic." We also illustrate the contribution of single-fiber studies to the diagnostic approach in patients harboring pathogenic variants with low level heteroplasmy.

Brain computer interface with the P300 speller: Usability for disabled people with amyotrophic lateral sclerosis.

OBJECTIVES: Amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease, restricts patients' communication capacity a few years after onset. A proof-of-concept of brain-computer interface (BCI) has shown promise in ALS and "locked-in" patients, mostly in pre-clinical studies or with only a few patients, but performance was estimated not high enough to support adoption by people with physical limitation of speech. Here, we evaluated a visual BCI device in a clinical study to determine whether disabled people with multiple deficiencies related to ALS would be able to use BCI to communicate in a daily environment. METHODS: After clinical evaluation of physical, cognitive and language capacities, 20 patients with ALS were included. The P300 speller BCI system consisted of electroencephalography acquisition connected to real-time processing software and separate keyboard-display control software. It was equipped with original features such as optimal stopping of flashes and word prediction. The study consisted of two 3-block sessions (copy spelling, free spelling and free use) with the system in several modes of operation to evaluate its usability in terms of effectiveness, efficiency and satisfaction. RESULTS: The system was effective in that all participants successfully achieved all spelling tasks and was efficient in that 65% of participants selected more than 95% of the correct symbols. The mean number of correct symbols selected per minute ranged from 3.6 (without word prediction) to 5.04 (with word prediction). Participants expressed satisfaction: the mean score was 8.7 on a 10-point visual analog scale assessing comfort, ease of use and utility. Patients quickly learned how to operate the system, which did not require much learning effort. CONCLUSION: With its word prediction and optimal stopping of flashes, which improves information transfer rate, the BCI system may be competitive with alternative communication systems such as eye-trackers. Remaining requirements to improve the device for suitable ergonomic use are in progress.

[Management of amyotrophic lateral sclerosis]. / Prise en charge du patient atteint de sclérose latérale amyotrophique. Une dimension rééducative indispensable pour la prévention des troubles et pour l'adaptation.

Management Of amyotrophic lateral Sclerosis Management of amyotrophic lateral sclerosis starts with diagnosis announcement which is straightaway followed by initiating neuroprotective treatment (riluzole). A quarterly-based management is proposed, coordinated by an ALS center in close collaboration with the general practitioner, home care organization, and a dedicated health network. Key point for efficiency of global care is to develop a coordination with a multidisciplinary approach, including the involvement of neurologist and physicians from different medical specialties, nurse practitioners, physical and occupational therapists, speech language therapists, dietitians and psychologists. The assessments follow-up concern mainly motor impairments and physical disability, adaptations, nutritional and respiratory functions. Associated symptoms such as pain, spasticity, mood disorders have to be recognized and treated. Decisions about nutritional and respiratory assistive devices require a collaborative approach involving specialized practitioners and paramedical professionals. These decisions have to be anticipated (advanced directives) in agreement with the patient, the family and the trusted person. Along the disease's management, patients and their family may have support from a psychologist. Finally, home care organization requires the intervention of a social worker.

Prise en charge du patient atteint de sclérose latérale amyotrophique. La prise en charge de la sclérose latérale amyotrophique (SLA) débute dès l'annonce diagnostique, et le traitement par le riluzole doit être instauré immédiatement. La prise en charge est multidisciplinaire, au mieux coordonnée par un centre SLA en articulation avec le médecin traitant et un réseau de santé dédié. Elle nécessite des bilans trimestriels. Les points clés de la surveillance portent sur les troubles moteurs, nutritionnels et respiratoires. La dimension rééducative (kinésithérapie, orthophonie, ergothérapie) est indispensable, ayant pour but la prévention et l'adaptation. Les symptômes associés doivent être reconnus, évalués et traités régulièrement. Les décisions de suppléance des fonctions vitales, nutritionnelle et respiratoire, nécessitent une démarche collégiale impliquant des professionnels médicaux et paramédicaux spécialisés. Ces décisions doivent être anticipées (directives anticipées) en concertation avec le patient, sa famille et la personne de confiance. Le patient et sa famille doivent pouvoir avoir accès, de l'annonce de la maladie à la fin de vie, à un suivi psychologique parallèlement à la relation médicale. L'organisation des soins au domicile nécessite une coordination professionnalisée du parcours de soins et l'intervention d'un assistant socio-éducatif.

Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia.

Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative syndrome hallmarked by adult-onset loss of motor neurons. We performed exome sequencing of 252 familial ALS (fALS) and 827 control individuals. Gene-based rare variant analysis identified an exome-wide significant enrichment of eight loss-of-function (LoF) mutations in TBK1 (encoding TANK-binding kinase 1) in 13 fALS pedigrees. No enrichment of LoF mutations was observed in a targeted mutation screen of 1,010 sporadic ALS and 650 additional control individuals. Linkage analysis in four families gave an aggregate LOD score of 4.6. In vitro experiments confirmed the loss of expression of TBK1 LoF mutant alleles, or loss of interaction of the C-terminal TBK1 coiled-coil domain (CCD2) mutants with the TBK1 adaptor protein optineurin, which has been shown to be involved in ALS pathogenesis. We conclude that haploinsufficiency of TBK1 causes ALS and fronto-temporal dementia.

Safety of home parenteral nutrition in patients with amyotrophic lateral sclerosis: a French national survey.

We carried out a retrospective multicentre study to assess the safety of home parenteral nutrition (HPN) in patients with ALS. We reviewed the case records of patients from French ALS centres treated with HPN by central venous catheter (CVC) using an implantable port between January 2005 and October 2009. Seventy-three patients received HPN for a total of 11,908 catheter days. Twenty-seven patients experienced a total of 37 CVC related complications resulting in an incidence rate of 3.11 CVC complications/1000 catheter days, including 1.93 septic complications and 1.09 mechanical complications/1000 catheter days. Metabolic complications were frequent but without serious consequences on mortality. The use of the catheter for intravenous therapies in addition to HPN was identified as a septicaemia's risk factor (relative risk (RR) = 2.54, confidence interval (CI) 1.56-4.14, p = 0.04). In conclusion, HPN is an alternative procedure to PEG in advanced ALS patients. The incidence of complications appears to be comparable to data from the literature on HPN in other diseases. A prospective study comparing HPN and radiologic inserted gastrostomy (RIG) would allow comparison of the relative risk-benefit and survival of these procedures. The relation of CVC and RIG placement timing and the complications' occurrence should also be investigated.

Do patients having a decrease in SNAP amplitude during the course of MMN present with a different condition?

A decrease in sensory nerve action potentials (SNAP) amplitude has been recently reported in some patients during the course of multifocal motor neuropathy with conduction blocks (MMNCB). It is not known if those patients have different clinical expression and disability when compared with typical MMNCB. Clinical, biological and electrophysiological assessments were performed in 15 patients fitting the diagnosis criteria of MMNCB, including normal SNAP amplitude at initial examination. Patients presenting with nerve entrapment or associated disease causative of sensory neuropathy were excluded. Median time of follow-up was 3 years (1-17 years). At the last examination, four patients had at least one SNAP amplitude below 50% of normal value. None had clinically objective sensory loss. Clinical and electrophysiological data obtained at the last examination were compared between patients with normal SNAP amplitude and patients with decreased SNAP amplitude. No difference between both population in term of age, sex, disease duration, anti-GM1 antibody titers, CSF data and number of conduction blocks was noted. In contrast, patients with decreased SNAP amplitude had worse overall neuropathy limitation scale (ONLS) scores (7 vs. 2; p = 0.02), a higher number of affected nerves (12.5 vs. 4; p = 0.018), a higher number of affected limb regions (6 vs. 2; p = 0.019) and lower median CMAP amplitude (2 mV vs. 6.5 mV; p = 0.04). They were all dependent on higher doses of IVIg (1.4 g/(kg 4 weeks vs. 0.6; p = 0.018). A reduction in SNAP amplitude during the course of MMNCB is associated with a more severe disease and a more prominent axonal loss. This result needs to be confirmed in a larger cohort.