A 33-year-old woman with a history of FMS lasting more than 1 year was referred to our neurology clinic for the management of chronic headache and myalgia, which had initially developed during pregnancy at the age of 31 years. She had been treated with an antidepressant (duloxetine) and antiepileptic (gabapentin) for FMS, which was diagnosed on the basis of CWP lasting at least 3 months in the absence of underlying rheumatic diseases at the age of 32 years, according to the new diagnostic criteria for FMS. Her scores for widespread pain index, symptom severity, and the Fibromyalgia Impact Questionnaire (FIQ) were 10, 7, and 50.24 points, respectively. She also had 11 positive mechanical tender points at that time. Magnetic resonance imaging of the brain and cervical spine for evaluation of the chronic headache produced unremarkable findings, but she had a history of transient muscle weakness lasting for periods of no more than several seconds in her legs when she suddenly had to walk at a pedestrian crossing or a bus stop. Moderate muscular hypertrophy was seen on a physical examination, but grip release-or percussion-myotonia, or warm-up phenomenon were not at the same time. However, needle EMG revealed myotonic discharges in some of the muscles studied, although she did not have physical evidence of myotonia.

Direct DNA sequence analysis of CLCN1 revealed a heterozygous G-to-A substitution in exon 8 at position 950, causing an amino acid change at codon 317 (c.950G>A, p.Arg-317Gln) (Fig. 1A, B, and C). This previously identified mutation was found in her asymptomatic mother, but was not in her sister. However, other family members including asymptomatic father and grandparents did not agree to undergo mutation analyses. Further genetic studies were carried out to evaluate for other causes of myotonic syndrome, but no mutations were found in the genes encoding the sodium channel, voltage-gated, type IV, alpha subunit (SCN4A) or dystrophia myotonica-protein kinase (DMPK). She was diagnosed clinically with a case of RGM, because the family history was negative for clinical and electrical myotonia. However, the possibility of ADM could not be excluded due to a failure to identify a second mutation in her mutation analysis. Her headache as well as CWP improved after the administration of sodium channel blockers (lacosamide or carbamazepine) and amitriptyline.

A 37-year-old man with a history of FMS and depression was referred to the neurology clinic for the evaluation of cold-induced muscle cramps. He suffered from CWP with multiple tender points on 14 of the 18 specific regions, and had experienced psychological symptoms including insomnia, fatigue, and depression from the age of 34 years. His FIQ score was 88.8 points, and he reported a pain score of 80 mm on a visual analogue scale at that time (range, 0-100 mm). A neurologic examination revealed normal motor, sensory, and deep tendon reflexes in both arms and legs, but cold-water testing aggravated the muscle stiffness and cramps in his forearm. Needle EMG for the evaluation of muscle cramps revealed the continued presence of provoked positive sharp waves lasting for up to several seconds, and waning-only myotonic discharges in a part of his leg muscles. A detailed examination of his medical history revealed that he suffered from transient muscle weakness in his arms and legs in childhood, but that these muscle symptoms had improved with age. His younger sister had a history of episodic muscle weakness, but his elder sister and parents had not.

Mutation analysis of CLCN1 revealed a heterozygous mutation (c.1679T>C, p.Met560Thr) (Fig. 1D and E) that was not found in the asymptomatic mother and elder sister of the patient as well as in normal controls from South Korea (Fig. 1F). He was clinically diagnosed as a case of RGM with a single recessive mutation. However, the possibility of a sporadic MC or ADM could not be excluded, because mutational analyses for his father and symptomatic younger sister were not performed. Further, no additional study was carried out for identifying a second mutation such as exon deletions or duplications in CLCN1. The patient is still being treated with antiepileptic drugs (carbamazepine, pregabalin, and valproic acid), antidepressants (duloxetine and mirtazapine), mexiletine, and tramadol, but his physical and psychological symptoms have not been ameliorated.