Jeffrey Statland

Primary lateral sclerosis.

The spectrum of motor neuron diseases ranges from disorders that clinically are limited to lower motor neurons to those that exclusively affect upper motor neurons. Primary lateral sclerosis (PLS) is the designation for the syndrome of progressive upper motor neuron dysfunction when no other etiology is identified. Distinction between PLS and the more common amyotrophic lateral sclerosis (ALS) relies primarily on recognition of their symptoms and signs, as well as on ancillary, although non‐specific, laboratory data. In this review, we survey the history of PLS from the initial descriptions to the present. We discuss the role of laboratory, electrodiagnostic, and imaging studies in excluding other diagnoses; the findings from major case series of PLS patients; and proposed diagnostic criteria. Consistent differences are evident in patients classified as PLS compared to those with ALS, indicating that, despite its limitations, this clinical designation retains important utility. Muscle Nerve, 2007

Somatodendritic Kv7/KCNQ/M Channels Control Interspike Interval in Hippocampal Interneurons

The M-current (IM), 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, IM controls action potential (AP) accommodation and contributes to the medium-duration afterhyperpolarization, but the role of IM in control of interneuron excitability remains unclear. Here, we investigated IM in 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 the IM amplitude present during relaxation from −30 to −50 mV and reduced the holding current (Ihold). In addition, 0.5 mm tetraethylammonium reduced IM, suggesting that IM was composed of Kv7.2-containing channels. In contrast, the Kv7 channel opener retigabine increased IM amplitude and Ihold. 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 incorporated IM, somatodendritic placement of Kv7 channels best reproduced experimentally measured IM. 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.

Cell type-specific dependence of muscarinic signalling in mouse hippocampal stratum oriens interneurones

Cholinergic signalling is critically involved in learning and memory processes in the hippocampus, but the postsynaptic impact of cholinergic modulation on morphologically defined subtypes of hippocampal interneurones remains unclear. We investigated the influence of muscarinic receptor (mAChR) activation on stratum oriens interneurones using whole‐cell patch clamp recordings from hippocampal slices in vitro. Upon somatic depolarization, mAChR activation consistently enhanced firing frequency and produced large, sustained afterdepolarizations (ADPs) of stratum oriens–lacunosum moleculare (O‐LM) interneurones. In contrast, stratum oriens cell types with axon arborization patterns different from O‐LM cells not only lacked large muscarinic ADPs but also appeared to exhibit distinct responses to mAChR activation. The ADP in O‐LM cells, mediated by M1/M3 receptors, was associated with inhibition of an M current, inhibition of a slow calcium‐activated potassium current, and activation of a calcium‐dependent non‐selective cationic current (ICAT). An examination of ionic conductances generated by firing revealed that calcium entry through ICAT controls the emergence of the mAChR‐mediated ADP. Our results indicate that cholinergic specializations are present within anatomically distinct subpopulations of hippocampal interneurones, suggesting that there may be organizing principles to cholinergic control of GABA release in the hippocampus.

Mexiletine for Symptoms and Signs of Myotonia in Nondystrophic Myotonia: A Randomized Controlled Trial

CONTEXT Nondystrophic myotonias (NDMs) are rare diseases caused by mutations in skeletal muscle ion channels. Patients experience delayed muscle relaxation causing functionally limiting stiffness and pain. Mexiletine-induced sodium channel blockade reduced myotonia in small studies; however, as is common in rare diseases, larger studies of safety and efficacy have not previously been considered feasible. OBJECTIVE To determine the effects of mexiletine for symptoms and signs of myotonia in patients with NDMs. DESIGN, SETTING, AND PARTICIPANTS A randomized, double-blind, placebo-controlled 2-period crossover study at 7 neuromuscular referral centers in 4 countries of 59 patients with NDMs conducted between December 23, 2008, and March 30, 2011, as part of the National Institutes of Health-funded Rare Disease Clinical Research Network. INTERVENTION Oral 200-mg mexiletine or placebo capsules 3 times daily for 4 weeks, followed by the opposite intervention for 4 weeks, with 1-week washout in between. MAIN OUTCOME MEASURES Patient-reported severity score of stiffness recorded on an interactive voice response (IVR) diary (scale of 1 = minimal to 9 = worst ever experienced). Secondary end points included IVR-reported changes in pain, weakness, and tiredness; clinical myotonia assessment; quantitative measure of handgrip myotonia; and Individualized Neuromuscular Quality of Life summary quality of life score (INQOL-QOL, percentage of maximal detrimental impact). RESULTS Mexiletine significantly improved patient-reported severity score stiffness on the IVR diary. Because of a statistically significant interaction between treatment and period for this outcome, primary end point is presented by period (period 1 means were 2.53 for mexiletine and 4.21 for placebo; difference, -1.68; 95% CI, -2.66 to -0.706; P < .001; period 2 means were 1.60 for mexiletine and 5.27 for placebo; difference, -3.68; 95% CI, -3.85 to -0.139; P = .04). Mexiletine improved the INQOL-QOL score (mexiletine, 14.0 vs placebo, 16.7; difference, -2.69; 95% CI, -4.07 to -1.30; P < .001) and decreased handgrip myotonia on clinical examination (mexiletine, 0.164 seconds vs placebo, 0.494 seconds; difference, -0.330; 95% CI, -0.633 to -0.142; P < .001). The most common adverse effect was gastrointestinal (9 mexiletine and 1 placebo). Two participants experienced transient cardiac effects that did not require stopping the study (1 in each group). One serious adverse event was determined to be not study related. CONCLUSION In this preliminary study of patients with NDMs, the use of mexiletine compared with placebo resulted in improved patient-reported stiffness over 4 weeks of treatment, despite some concern about the maintenance of blinding. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00832000.

Muscarinic receptor activation tunes mouse stratum oriens interneurones to amplify spike reliability

Cholinergic activation of hippocampal targets can initiate and sustain network oscillations in vivo and in vitro, yet the impact of cholinergic modulation on the oscillatory properties of interneurones remains virtually unexplored. Using whole cell current clamp recordings in acute hippocampal slices, we investigated the influence of muscarinic receptor (mAChR) activation on the oscillatory properties of CA1 stratum oriens (SO) interneurones in vitro. In response to suprathreshold oscillatory input, mAChR activation increased spike reliability and precision, and extended the bandwidth that interneurone firing phase‐locked. These suprathreshold effects were largest at theta frequencies, indicating that mAChR activation tunes active conductances to enhance firing reliability and precision to theta frequency input. Muscarinic tuning of the intrinsic oscillatory properties of interneurones is a novel mechanism that may be crucial for the genesis of the theta rhythm.

Primary lateral sclerosis: A heterogeneous disorder composed of different subtypes?

Objective: To determine identifiable subgroups of patients with primary lateral sclerosis (PLS) with distinct clinical features as a first step in identifying patients likely to have the same disorder. Methods: Twenty-five patients meeting previously proposed diagnostic criteria for PLS were seen for examination, measurement of gait and finger tapping speed, and physiologic tests to assess motor pathways. Motor cortex excitability and central motor conduction time were assessed with transcranial magnetic stimulation. Brainstem motor pathways were assessed by the acoustic startle reflex. MRS was performed in a subgroup of patients to assess metabolites in the motor cortex. Results: Fifty-six percent of the patients with PLS had a similar pattern of symptom progression, which the authors termed ascending. In these patients spasticity began in the legs and progressed slowly and steadily. Spasticity in the arms developed 3.6 years after the legs, on average, and speech impairment followed 1.5 years later. Motor evoked potentials were absent. MRS showed a mean reduction of N-acetylaspartate/creatinine in the motor cortex. The remaining patients with PLS had heterogeneous patterns of symptom progression and physiology. Conclusions: Patients with PLS with an ascending progression of symptoms form a distinct clinical subgroup that may be amenable to investigations of etiology and treatment.

Facioscapulohumeral muscular dystrophy: molecular pathological advances and future directions.

PURPOSE OF REVIEW Recent advances have provided a model for understanding the underlying molecular genetic changes in facioscapulohumeral muscular dystrophy (FSHD). This review will highlight our current understanding and future research directions. RECENT FINDINGS FSHD typically results from contraction of a critical number of D4Z4 repeats in a macrosatellite repeat array on chromosome 4q35. Contraction leads to loss of DNA methylation and heterochromatin markers in the 4q35 D4Z4 region, resulting in relaxation of the chromatin structure and release of DUX4 repression. DUX4, a retrogene contained in the D4Z4 repeats, is normally epigenetically silenced in somatic cells. Stable expression of DUX4, however, can only occur in the presence of a permissive genetic background, which contains a polyadenylation signal sequence that stabilizes DUX4 mRNA. Expression of DUX4 mRNA and protein occurs at low frequency but in high abundance in FSHD myotube nuclei. DUX4 expression in transfection studies induces apoptosis and interferes with myogenesis. SUMMARY FSHD results from a unique combination of genetic and epigenetic changes on 4q35 leading to release of repression of DUX4, causing disease in a toxic gain-of-function manner. Questions remain regarding the normal function of DUX4 and how expression of DUX4 in somatic cells leads to FSHD.

Risk of functional impairment in Facioscapulohumeral muscular dystrophy

Introduction: Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent muscular dystrophies. Nevertheless, little is known about the risk of developing functional impairment. Here we determine the 6‐year risk of functional impairment in FSHD. Methods: A retrospective cohort of 313 genetically confirmed, clinically affected FSHD participants in a United States registry between January 2002 and June 2011. Our main outcome was wheelchair (WC) use. Results: The 6‐year risk of WC use was 24.0% (95% confidence interval 18.6–29.3). The distribution of WC risk was bimodal, with a peak in the second decade associated with large D4Z4 contractions, followed by an age‐related increase in risk. Other functional categories showed moderate risk. Prevalence of hearing aid use and difficulty pronouncing words was increased in large D4Z4 contractions. Conclusions: The 6‐year risk of functional impairment in FSHD is moderate, and early WC use is associated with large D4Z4 contractions. Muscle Nerve 49:520–527, 2014

Coats syndrome in facioscapulohumeral dystrophy type 1 Frequency and D4Z4 contraction size

Objective: To investigate the frequency of Coats syndrome and its association with D4Z4 contraction size in patients with facioscapulohumeral muscular dystrophy type 1 (FSHD1). Methods: We searched a North American FSHD registry and the University of Rochester (UR) FSHD research database, reviewed the literature, and sent surveys to 14 FSHD referral centers in the United States and overseas to identify patients with genetically confirmed FSHD1 with a diagnosis of Coats syndrome. Results: Out of 357 genetically confirmed patients in a North American FSHD registry and 51 patients in the UR database, 3 patients had a self-reported history of Coats disease (0.8%; 95% confidence interval 0.2%–2.2%). In total, we identified 14 patients with FSHD with known genetic contraction size and Coats syndrome confirmed by ophthalmologic examination: 10 from our survey and 4 from the literature. The median age at diagnosis of Coats syndrome was 10 years (interquartile range 14 years). The median D4Z4 fragment size was 13 kilobases (kb) (interquartile range 1 kb). One patient was mosaic (55% 11 kb, and 45% 78 kb). Conclusions: Coats syndrome is a rare extramuscular complication of FSHD1 associated with large D4Z4 contractions. Closer surveillance for retinal complications is warranted in patients with D4Z4 fragments ≤15 kb.

Targeting protein homeostasis in sporadic inclusion body myositis

Augmenting the heat shock response with arimoclomol ameliorates pathology in cellular and animal models of inclusion body myositis. Targeting protein dyshomeostasis in myopathy Sporadic inclusion body myositis (sIBM) is a debilitating adult myopathy that is difficult to treat. Although both inflammation and protein dyshomeostasis have been implicated in sIBM pathogenesis, treatments have only targeted the inflammatory component, and all have failed in clinical trials. In a new study, Ahmed et al. tested the effects of targeting protein dyshomeostasis using arimoclomol, a co-inducer of the heat shock response. In rat myoblast cell culture, arimoclomol reduced key pathological features of IBM. In mutant valosin-containing protein (VCP) mice, which develop an inclusion body myopathy, treatment with arimoclomol ameliorated disease pathology and improved muscle function. The authors then treated a small number of sIBM patients with arimoclomol and showed that it was safe and well tolerated. Sporadic inclusion body myositis (sIBM) is the commonest severe myopathy in patients more than 50 years of age. Previous therapeutic trials have targeted the inflammatory features of sIBM but all have failed. Because protein dyshomeostasis may also play a role in sIBM, we tested the effects of targeting this feature of the disease. Using rat myoblast cultures, we found that up-regulation of the heat shock response with arimoclomol reduced key pathological markers of sIBM in vitro. Furthermore, in mutant valosin-containing protein (VCP) mice, which develop an inclusion body myopathy, treatment with arimoclomol ameliorated disease pathology and improved muscle function. We therefore evaluated arimoclomol in an investigator-led, randomized, double-blind, placebo-controlled, proof-of-concept trial in sIBM patients and showed that arimoclomol was safe and well tolerated. Although arimoclomol improved some IBM-like pathology in the mutant VCP mouse, we did not see statistically significant evidence of efficacy in the proof-of-concept patient trial.