Neuromuscular Junction Disorders

The neuromuscular junction (NMJ) is a critical component of the motor unit that is made up of the distal, unmyelinated nerve terminal, synaptic space, and end-plate region of the muscle fiber. Contraction of muscle fiber involves a coordinated series of steps that ultimately generates an action potential at the muscle end plate (also known as an end-plate potential). Normally the end-plate potential substantially exceeds the threshold necessary to trigger an action potential in the muscle fiber, and this difference is termed the safety factor of neuromuscular transmission. Disorders that affect the NMJ reduce this safety factor, a change that results in fatigable weakness.

The Pathological Features of Common Hereditary Mitochondrial Dynamics Neuropathy

ObjectivesMitofusin 2 and ganglioside-induced differentiation-associated protein 1 are two main mitochondrial dynamics-related proteins. Dysfunction of these two proteins leads to different subtypes of Charcot–Marie–Tooth disease type 2A (CMT2A) and CMT2K. This study aims to report the pathological difference between CMT2A and CMT2K in a large cohort.MethodsThirty patients with molecularly confirmed CMT2A and nine with CMT2K were identified by next-generation sequencing. Sural nerve biopsies were performed in 29 patients.ResultsThe patients with both diseases showed length-dependent neuropathy with distal weakness, sensory loss, and no deep tendon reflex. Optic neuropathy appeared in 3/30 (10%) patients with CMT2A. Tendon contracture appeared in 4/9 (50.0%) patients with CMT2K. Sural biopsy revealed the loss of both myelinated and unmyelinated nerve fibers. Closely packed, irregularly oriented neurofilaments were observed in axons of unmyelinated nerve fibers in both diseases. Another important finding was the ubiquitous presence of smaller, rounded, and fragmented mitochondria in CMT2A and elongated mitochondria in CMT2K in the myelinated and unmyelinated axons.ConclusionThis study confirmed large diversity in phenotypes between CMT2A and CMT2K. Mitochondrial dynamics-related variations can induce different mitochondrial morphological changes and neurofilament accumulation in axons.

Peripheral sensory neuropathies – pain loss vs. pain gain

Peripheral sensory neurons are afferent neurons that innervate the skin, joints, bones, muscles, and mucosal tissues. By converting different stimuli into action potentials, they transmit signals for the sensing of temperature, touch, pressure, or pain. This review discusses the known Mendelian disorders which affect pain sensing in humans. For painlessness, these disorders can be classified as developmental, neurodegenerative, or functional, where pain-sensing neurons (nociceptors) are present but cannot be activated or produce action potentials. Affected patients suffer from numbness with recurrent injuries, burns, and poorly healing wounds. For Mendelian disorders of excess pain, aberrant overactivity of nociceptors is a hallmark and leads to paroxysmal or continuous pain states. Again, the effect can be functional or, as in small fiber neuropathies, can be accompanied by degeneration of small unmyelinated nerve fibers in the skin. About 20 different genes are known to cause Mendelian pain disorders and the molecules involved are of general interest for human pain research and as analgesic targets. Comprehensive genetic testing is the key to early diagnosis and adaptation of clinical management.

C-Fiber Assays in the Cornea vs. Skin

C-fibers are unmyelinated nerve fibers that transmit high threshold mechanical, thermal, and chemical signals that are associated with pain sensations. This review examines current literature on measuring altered peripheral nerve morphology and discusses the most relevant aspects of corneal microscopy, especially whether corneal imaging presents significant method advantages over skin biopsy. Given its relative merits, corneal confocal microscopy would seem to be a more practical and patient-centric approach than utilizing skin biopsies.

Endometriotic lesions

Endometriosis is a complex gynaecological condition affecting women of reproductive age. It is characterised by the presence of lesions containing endometrial glands and stroma outside the uterus. The disease is typically associated with pelvic pain (including dysmenorrhoea and dyspareunia), infertility and bowel-related symptoms. Endometriotic lesions have a highly variable presentation and most commonly occur in the abdominal cavity. These lesions are broadly classified into peritoneal, ovarian and deep infiltrating endometriosis. There have been observations of increased density of nerve fibres and neurological molecules in the endometriotic lesions compared to the uninvolved peritoneum of women without endometriosis and the presence of unmyelinated nerve fibres were higher near the glands. The lesion sites are characterised by a range of immunological alterations, and specific immune cell populations have also been known to synthesise and secrete neurogenic factors. Endometriotic lesions are capable of producing prostaglandins which are direct generators of pain and are capable of inducing inflammation. Diagnosing the disease involves direct visualisation of the lesions through a laparoscopic or laparotomy, which is followed by histopathological examination of biopsied or excised lesions. The staging of endometriosis due to its complexity is highly variable as presentation and gaps in knowledge pose a great challenge in the classification of the disease. The medical management of endometriosis aims at providing adequate analgesia and suppression of the activity of the lesion. A better understanding of endometriotic lesion relationships between innervations and specific clinical characteristics may elucidate aspects of pain mechanisms and infertility in endometriosis and facilitate the development of novel therapeutic approaches.