Myelin protein zero mutation-related hereditary neuropathies: Neuropathological insight from a new nerve biopsy cohort.

Myelin protein zero (MPZ/P0) is a major structural protein of peripheral nerve myelin. Disease-associated variants in the MPZ gene cause a wide phenotypic spectrum of inherited peripheral neuropathies. Previous nerve biopsy studies showed evidence for subtype-specific morphological features. Here, we aimed at enhancing the understanding of these subtype-specific features and pathophysiological aspects of MPZ neuropathies. We examined archival material from two Central European centers and systematically determined genetic, clinical, and neuropathological features of 21 patients with MPZ mutations compared to 16 controls. Cases were grouped based on nerve conduction data into congenital hypomyelinating neuropathy (CHN; n = 2), demyelinating Charcot-Marie-Tooth (CMT type 1; n = 11), intermediate (CMTi; n = 3), and axonal CMT (type 2; n = 5). Six cases had combined muscle and nerve biopsies and one underwent autopsy. We detected four MPZ gene variants not previously described in patients with neuropathy. Light and electron microscopy of nerve biopsies confirmed fewer myelinated fibers, more onion bulbs and reduced regeneration in demyelinating CMT1 compared to CMT2/CMTi. In addition, we observed significantly more denervated Schwann cells, more collagen pockets, fewer unmyelinated axons per Schwann cell unit and a higher density of Schwann cell nuclei in CMT1 compared to CMT2/CMTi. CHN was characterized by basal lamina onion bulb formation, a further increase in Schwann cell density and hypomyelination. Most late onset axonal neuropathy patients showed microangiopathy. In the autopsy case, we observed prominent neuromatous hyperinnervation of the spinal meninges. In four of the six muscle biopsies, we found marked structural mitochondrial abnormalities. These results show that MPZ alterations not only affect myelinated nerve fibers, leading to either primarily demyelinating or axonal changes, but also affect non-myelinated nerve fibers. The autopsy case offers insight into spinal nerve root pathology in MPZ neuropathy. Finally, our data suggest a peculiar association of MPZ mutations with mitochondrial alterations in muscle.

Effects of a 6-week, whole-body vibration strength-training on depression symptoms, endocrinological and neurobiological parameters in adolescent inpatients experiencing a major depressive episode (the "Balancing Vibrations Study"): study protocol for a randomized placebo-controlled trial.

BACKGROUND: Moderate to vigorous endurance and strength-training exercise was suggested as a treatment option for major depression. However, there is little evidence to support this suggestion in adolescent patients. The present study investigates the effects of a whole-body vibration strength-training intervention on symptoms in medication-naïve adolescent inpatients experiencing a major depressive episode. Potential underlying endocrinological and neurobiological mechanisms are explored. METHODS/DESIGN: A double-blinded randomized controlled trial is conducted at the University Hospital of Cologne in Germany, comparing a 6-week, whole-body vibration strength-training with a 6-week placebo-intervention, as add-on therapy to inpatient treatment as usual. Forty-one subjects (13-18 years of age) will be included in each of the two groups. The study is powered to detect (α = .05, ß = .2) a medium effect size difference between the two groups (d = .5) in terms of patients' change in the Children's Depression Rating Scale raw-score, from baseline until the end of the intervention. As secondary endpoints, the effects of exercise treatment on patients' cortisol awakening response as well as on brain-derived neurotrophic factor, insulin-like growth factor 1 and inflammatory markers (tumor necrosis factor-alpha, interleukin-6 and C-reactive protein) serum levels will be assessed. DISCUSSION: This study will provide evidence on the effectiveness of whole-body vibration strength-training as an add-on therapy in adolescent inpatients experiencing a major depressive episode. After completion of data collection, the present study will be the largest randomized controlled trial so far to investigate the effectiveness of an exercise intervention in inpatient adolescents suffering from a major depressive episode. Moreover, the present study may help to determine the underlying mechanisms of potential anti-depressant effects of exercise in depressed adolescent inpatients. TRIAL REGISTRATION: DRKS.de, German Clinical Trials Register (DRKS), Identifier: DRKS00011772 . Registered on 20 March 2017.

Morphological spectrum and clinical features of myopathies with tubular aggregates.

Tubular aggregates (TAs) are aggregates of densely packed tubules in human skeletal muscle fibers with particular histochemical and ultrastructural features that most probably arise from the sarcoplasmic reticulum. Some studies have shown an additional mitochondrial origin of TAs. We studied the histopathological spectrum and clinical features in a large cohort of patients with TAs in their muscle biopsy (106 biopsies), derived from our muscle biopsy archive (15,412 biopsies in total). In particular, we examined light microscopic, enzyme histochemical, immunohistochemical and ultrastructural features in the muscle biopsies, as well as the patients' clinical data. We found TAs in 0.5% of all muscle biopsies. Based on the size of TAs, we identified two sub-groups: (1) myopathies with large TAs (29 biopsies) in type 2 fibers and sometimes also in type 1 fibers, absence of any other associated disorder, and a familial history in half of the cases, and (2) myopathies with small TAs (77 biopsies), exclusively in type 2 fibers, presence of another associated disease in the majority of patients and mostly no familial history. In the sub-group with large TAs, we observed a high variability of ultrastructural changes. The most frequent clinical symptom in both groups was limb muscle weakness. No significant differences in clinical presentation, age at onset or disease duration at the time of biopsy were found between the two groups. In conclusion, myopathies with TAs can be sub-divided into a group with large TAs, probably corresponding to the so-called primary TA myopathies, and into a group with small TAs as a feature of another underlying condition.