Loss-of-function of EBP50 is a new cause of hereditary peripheral neuropathy: EBP50 functions in peripheral nerve system

Finding causative genetic mutations is important in the diagnosis and treatment of hereditary peripheral neuropathies. This study was conducted to find new genes involved in the pathophysiology of hereditary peripheral neuropathy. We identified a new mutation in the EBP50 gene, which is co-segregated with neuropathic phenotypes, including motor and sensory deficit in a family with Charcot–Marie–Tooth disease. EBP50 is known to be important for the formation of microvilli in epithelial cells, and the discovery of this gene mutation allowed us to study the function of EBP50 in the nervous system. EBP50 was strongly expressed in the nodal and paranodal regions of sciatic nerve fibers, where Schwann cell microvilli contact the axolemma, and at the growth tips of primary Schwann cells. In addition, EBP50 expression was decreased in mouse models of peripheral neuropathy. Knockout mice were used to study EBP50 function in the peripheral nervous system. Interestingly motor function deficit and abnormal histology of nerve fibers were observed in EBP50^+/− heterozygous mice at 12 months of age, but not 3 months. in vitro studies using Schwann cells showed that NRG1-induced AKT activation and migration were significantly reduced in cells overexpressing the I325V mutant of EBP50 or cells with knocked-down EBP50 expression. In conclusion, we show for the first time that loss of function due to EBP50 gene deficiency or mutation can cause peripheral neuropathy.     

Frequency,entity and determinants of fatigue in Charcot–Marie–Tooth disease

Background and purpose

Fatigue, a disabling symptom in many neuromuscular disorders, has been reported also in Charcot–Marie–Tooth disease (CMT). The presence of fatigue and its correlations in CMT was investigated.

Methods

The Modified Fatigue Impact Scale (MFIS) was administered to CMT patients from the Italian Registry and a control group. An MFIS score >38 indicated abnormal fatigue. The correlation with disease severity and clinical characteristics, the Hospital Anxiety and Depression Scale and Epworth Sleepiness Scale scores, and drug use was analysed.

Results

Data were collected from 251 CMT patients (136 women) and 57 controls. MFIS total (mean ± standard deviation 32 ± 18.3, median 33), physical (18.9 ± 9.7, 20) and psychosocial (2.9 ± 2.4, 3) scores in CMT patients were significantly higher than controls. Abnormal fatigue occurred in 36% of the patients who, compared to patients with normal scores, had more severe disease (median CMT Examination Score 9 vs. 7), more frequent use of foot orthotics (22% vs. 11%), need of support for walking (21% vs. 8%), hand disability (70% vs. 52%) and positive sensory symptoms (56% vs. 36%). Patients with abnormal fatigue had significantly increased frequency of anxiety/depression/general distress (Hospital Anxiety and Depression Scale), somnolence (Epworth Sleepiness Scale), obesity (body mass index ≥ 30) and use of anxiolytic/antidepressant or anti-inflammatory/analgesic drugs.

Conclusions

Fatigue is a relevant symptom in CMT as 36% of our series had scores indicating abnormal fatigue. It correlated with disease severity but also with anxiety, depression, sleepiness and obesity, indicating different components in the generation of fatigue. CMT patients' management must include treatment of fatigue and of its different generators, including general distress, sleepiness and obesity.     

Sister Marie Joseph nodule and Krükenberg's tumor: rare association revealing a gastric adenocarcinoma

It was about a 61-year-old patient who presented an indurated and painless umbilical swelling surrounded by ulcerated plaque and an abdominal arch progressing for 8 months. Abdomino-pelvic ultrasound and abdominal-pelvic CT scan revealed in right ovarian the presence of a mass with a cystic''s tissue, a thickness with a subcutaneous infiltration of the umbilical region and the diffuse infiltration of gastric parietal mesenteric fat. Histology of the ovarian mass confirmed Krükenberg''s tumor and that of the Sister Marie-Joseph''s nodule confirmed umbilical skin metastasis. The primary was a well differentiated gastric adenocarcinoma. The death occurred after the first chemotherapy treatment. The association of Krükenberg''s tumor with Sister Marie-Joseph''s nodule, rare and unusual, has been revealing of a gastric adenocarcinoma which up to now was unknown and asymptomatic.