Late-onset sensory-motor axonal neuropathy, a novel SLC12A6-related phenotype.

We describe five families from different regions in Norway with a late-onset autosomal-dominant hereditary polyneuropathy sharing a heterozygous variant in the SLC12A6 gene. Mutations in the same gene have previously been described in infants with autosomal-recessive hereditary motor and sensory neuropathy with corpus callosum agenesis and mental retardation (Andermann syndrome), and in a few case reports describing dominantly acting de novo mutations, most of them with onset in childhood. The phenotypes in our families demonstrated heterogeneity. Some of our patients only had subtle to moderate symptoms and some individuals even no complaints. None had CNS manifestations. Clinical and neurophysiological evaluations revealed a predominant sensory axonal polyneuropathy with slight to moderate motor components. In all 10 patients the identical SLC12A6 missense variant, NM_001365088.1 c.1655G>A p.(Gly552Asp), was identified. For functional characterization, the mutant potassium chloride cotransporter 3 was modelled in Xenopus oocytes. This revealed a significant reduction in potassium influx for the p.(Gly552Asp) substitution. Our findings further expand the spectrum of SLC12A6 disease, from biallelic hereditary motor and sensory neuropathy with corpus callosum agenesis and mental retardation and monoallelic early-onset hereditary motor and sensory neuropathy caused by de novo mutations, to late-onset autosomal-dominant axonal neuropathy with predominant sensory deficits.

Long-term post-concussion symptoms. / Langvarige plager etter hjernerystelse.

Concussion is common and usually resolves without complications. However, persistent symptoms occur in 10-15 % of patients. These post-concussion symptoms are predominantly somatic, cognitive and emotional. The condition is most common in those with previous somatic and mental health issues. The causes underlying long-term post-concussion symptoms are unclear, but a biopsychosocial explanatory model is currently regarded as the most appropriate basis for diagnosis and treatment. This clinical review article is based on key literature and our own clinical experiences with patients who have these long-term post-concussion symptoms.

Therapeutic drug monitoring of gabapentin in various indications.

OBJECTIVES: Gabapentin has been increasingly used in various indications in recent years. Despite variable pharmacokinetics, therapeutic drug monitoring (TDM) is scarcely described in other indications than epilepsy. The aim of the study was to investigate the use and pharmacokinetic variability of gabapentin in epilepsy and non-epilepsy indications and to further evaluate the use of TDM in patients with restless legs syndrome (RLS). MATERIALS & METHODS: Population-based data from the Norwegian Prescription Database, retrospective TDM data from the section for Clinical Pharmacology, the National Center for Epilepsy, Norway, and prospective observational data on patients with RLS were used. RESULTS: The use of gabapentin increased by 30% from 2014 to 2017 (32 181 to 42 675 users). TDM data from 120 patients showed a 22-fold pharmacokinetic variability in concentration/dose ratios, and this ratio was elevated in elderly patients (≥65 years). The majority of elderly used gabapentin for non-epilepsy indications. In patients with RLS, intake in the evening/night only was common due to nocturnal symptoms, in contrast to regular dosing regimens in epilepsy. Thus, drug fasting concentrations do not reflect concentrations at the time of required therapeutic effect. TDM was still found useful in most patients to support dosage increase or evaluate adverse effects. CONCLUSION: Due to extensive pharmacokinetic variability, TDM can benefit patients using gabapentin. Challenges with applying TDM in new indications such as RLS include different dosage regimens and consequently different interpretation of serum concentrations. Thus, TDM should be requested on clear clinical grounds and the service tailored according to the therapeutic indication.

[Sleep-related movement disorders]. / Søvnrelaterte bevegelsesforstyrrelser.

BACKGROUND: Restless legs syndrome is a common cause of sleep problems; the condition is often associated with periodic limb movement during sleep. The syndrome is probably under-diagnosed and under-treated. MATERIAL AND METHODS: The article is based on literature identified through a search in PubMed, a review of international recommendations and our own clinical experience. RESULTS: The restless leg syndrome is common, with a prevalence of about 10 %. Many of these patients are affected by sleep disturbances and have periodic limb movement during sleep (PLMS). Restless legs and the associated sleep disturbances can be effectively treated with dopaminagonists. Because of the augmentation risk, the lowest necessary dose should be maintained. PLMS also occurs in other sleep disorders. Periodic limb movement disorder (PLMD) is defined as PLMS combined with sleep disturbances and/or sleepiness during daytime without a known cause. The clinical relevance of PLMD for sleep disturbances is not clear. INTERPRETATION: The restless legs syndrome is a common cause of sleep disturbance; good treatment options are available.

[Restless legs]. / Rastløse bein.

BACKGROUND: Restless legs syndrome is a common and not fully appreciated disorder. Improved treatment options require knowledge about the condition. MATERIAL AND METHODS: The article is based on a literature search on Medline, PubMed and Scirus for the years 1988-2003 with the keyword "restless legs". RESULTS AND INTERPRETATION: Restless legs syndrome is a chronic condition defined as an irresistible desire to move one's limbs, usually associated with paraesthesia/dysaesthesia and motor restlessness. The symptoms start or worsen at rest and improve with activity. The prevalence is between 5% and 15%. 80% of patients suffer from periodic limb movements in sleep. A current hypothesis is that the condition results from a deficiency of iron that lead to the underlying dopaminergic abnormalities. Therapeutically, studies have confirmed the effect of levodopa and dopamine agonists; dopamine agonists seem to imply less risk of side effects.