Periodic paralyses (PPs) are rare neuromuscular disorders caused by mutations in skeletal muscle sodium, calcium, and potassium channel genes. PPs include hypokalemic paralysis, hyperkalemic paralysis, and Andersen‐Tawil syndrome. Common features of PP include autosomal dominant inheritance, onset typically in the first or second decades, episodic attacks of flaccid weakness, which are often triggered by diet or rest after exercise. Diagnosis is based on the characteristic clinic presentation then confirmed by genetic testing. In the absence of an identified genetic mutation, documented low or high potassium levels during attacks or a decrement on long exercise testing support diagnosis. The treatment approach should include both management of acute attacks and prevention of attacks. Treatments include behavioral interventions directed at avoidance of triggers, modification of potassium levels, diuretics, and carbonic anhydrase inhibitors. Muscle Nerve 57: 522–530, 2018

Primary lateral sclerosis (PLS) is a neurodegenerative disorder of the adult motor system. Characterised by a slowly progressive upper motor neuron syndrome, the diagnosis is clinical, after exclusion of structural, neurodegenerative and metabolic mimics. Differentiation of PLS from upper motor neuron-predominant forms of amyotrophic lateral sclerosis remains a significant challenge in the early symptomatic phase of both disorders, with ongoing debate as to whether they form a clinical and histopathological continuum. Current diagnostic criteria for PLS may be a barrier to therapeutic development, requiring long delays between symptom onset and formal diagnosis. While new technologies sensitive to both upper and lower motor neuron involvement may ultimately resolve controversies in the diagnosis of PLS, we present updated consensus diagnostic criteria with the aim of reducing diagnostic delay, optimising therapeutic trial design and catalysing the development of disease-modifying therapy.

Objective To identify preferred neurofilament assays and clinically validate serum neurofilament light (NfL) and phosphorylated neurofilament heavy (pNfH) as prognostic and potential pharmacodynamic biomarkers relevant to amyotrophic lateral sclerosis (ALS) therapy development. Methods In this prospective, multicenter, longitudinal observational study of patients with ALS (n = 229), primary lateral sclerosis (n = 20), and progressive muscular atrophy (n = 11), biological specimens were collected, processed, and stored according to strict standard operating procedures (SOPs). Neurofilament assays were performed in a blinded manner by independent contract research organizations. Results For serum NfL and pNfH measured using the Simoa assay, there were no missing data (i.e., technical replicates below the lower limit of detection were not encountered). For the Iron Horse and Euroimmun pNfH assays, such missingness was encountered in ∼4% and ∼10% of serum samples, respectively. Mean coefficients of variation for NfL in serum and CSF were both ∼3%. Mean coefficients of variation for pNfH in serum and CSF were ∼4%–5% and ∼2%–3%, respectively, in all assays. Baseline serum NfL concentration, but not pNfH, predicted the future Revised ALS Functional Rating Scale (ALSFRS-R) slope and survival. Incorporation of baseline serum NfL into mixed effects models of ALSFRS-R slopes yields an estimated sample size saving of ∼8%. Depending on the method used to estimate effect size, use of serum NfL (and perhaps pNfH) as pharmacodynamic biomarkers, instead of the ALSFRS-R slope, yields significantly larger sample size savings. Conclusions Serum NfL may be considered a clinically validated prognostic biomarker for ALS. Serum NfL (and perhaps pNfH), quantified using the Simoa assay, has potential utility as a pharmacodynamic biomarker of treatment effect.

The M-current (I_M), comprised of Kv7 channels, is a voltage-activated K⁺conductance that plays a key role in the control of cell excitability. In hippocampal principal cells,I_Mcontrols action potential (AP) accommodation and contributes to the medium-duration afterhyperpolarization, but the role ofI_Min control of interneuron excitability remains unclear. Here, we investigatedI_Min hippocampal stratum oriens (SO) interneurons, both from wild-type and transgenic mice in which green fluorescent protein (GFP) was expressed in somatostatin-containing interneurons. Somatodendritic expression of Kv7.2 or Kv7.3 subunits was colocalized in a subset of GFP+ SO interneurons, corresponding to oriens-lacunosum moleculare (O-LM) cells. Under voltage clamp (VC) conditions at −30 mV, the Kv7 channel antagonists linopirdine/XE-991 abolished theI_Mamplitude present during relaxation from −30 to −50 mV and reduced the holding current (I_hold). In addition, 0.5 mmtetraethylammonium reducedI_M, suggesting thatI_Mwas composed of Kv7.2-containing channels. In contrast, the Kv7 channel opener retigabine increasedI_Mamplitude andI_hold. When strongly depolarized in VC, the linopirdine-sensitive outward current activated rapidly and comprised up to 20% of the total current. In current-clamp recordings from GFP+ SO cells, linopirdine induced depolarization and increased AP frequency, whereas retigabine induced hyperpolarization and arrested firing. In multicompartment O-LM interneuron models that incorporatedI_M, somatodendritic placement of Kv7 channels best reproduced experimentally measuredI_M. The models suggest that Kv3- and Kv7-mediated channels both rapidly activate during single APs; however, Kv3 channels control rapid repolarization of the AP, whereas Kv7 channels primarily control the interspike interval.

Augmenting the heat shock response with arimoclomol ameliorates pathology in cellular and animal models of inclusion body myositis.