Association of corneal nerve loss with markers of axonal ion channel dysfunction in type 1 diabetes.

OBJECTIVE: Corneal confocal microscopy (CCM) has been identified as a non-invasive technique to assess corneal nerve fiber morphology. It is not known how corneal nerve changes relate to measures of peripheral nerve function in diabetic peripheral neuropathy (DPN). The present study investigates the relationship between nerve structure and function in DPN. METHODS: Fifty participants with type 1 diabetes (T1DM) and 29 healthy controls underwent CCM to assess corneal nerve fiber density (CNFD), branch density (CNBD), fiber length (CNFL), total branch density (CTBD), nerve fractal dimension (CNFrD) and inferior whorl length (IWL). The severity of DPN was assessed as Total Neuropathy Score (TNS). Motor nerve axonal excitability tests were conducted to assess axonal function. RESULTS: Significant correlations were noted between CNFD (rho = -0.783; P < 0.01) or superexcitability (rho = 0.435; P < 0.01) and TNS. CNFrD was significantly correlated with peak response to stimulus (r = 0.414; P < 0.01) and superexcitability (r = -0.467; P < 0.01) measurements. CONCLUSION: Corneal nerve loss demonstrates a significant association with axonal ion channel dysfunction in T1DM. SIGNIFICANCE: Detection of altered corneal nerve morphology may lead to the earlier diagnosis of DPN.

Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy.

Stroke-like episodes (SLE) occur in phosphomannomutase deficiency (PMM2-CDG), and may complicate the course of channelopathies related to Familial Hemiplegic Migraine (FHM) caused by mutations in CACNA1A (encoding CaV2.1 channel). The underlying pathomechanisms are unknown. We analyze clinical variables to detect risk factors for SLE in a series of 43 PMM2-CDG patients. We explore the hypothesis of abnormal CaV2.1 function due to aberrant N-glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp, N-glycosylation blockade and mutagenesis. Nine SLE were identified. Neuroimages showed no signs of stroke. Comparison of characteristics between SLE positive versus negative patients' group showed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or CACNA1A channelopathies show similarities. Hypoglycosylation of both CaV2.1 subunits (α1A and α2α) induced gain-of-function effects on channel gating that mirrored those reported for pathogenic CACNA1A mutations linked to FHM and ataxia. Unoccupied N-glycosylation site N283 at α1A contributes to a gain-of-function by lessening CaV2.1 inactivation. Hypoglycosylation of the α2δ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the CaV2.1 channel. CaV2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant CaV2.1 N-glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.

Imaging alterations in skeletal muscle channelopathies: a study in 15 patients.

Skeletal muscle channelopathies (SMC), including non dystrophic myotonias (NDM) and periodic paralyses (PP), are characterized by considerable clinical overlap and clinical features not always allow addressing molecular diagnosis. Muscle imaging has been shown to be useful for differential diagnosis in neuromuscular disorders, however it has been relatively poorly investigated in SMC. We studied 15 patients affected by genetically confirmed SMC (NDM = 9, PP = 6) through muscle MRI or CT of thighs and legs, including 11 patients mutated in SCN4A gene, 2 in CACNA1S and 2 in CLCN1. Mean age at muscle imaging was 45.2 ± 18 years (range 22-70). Overall, fatty infiltration was found in thigh muscles in 8 (53%) patients and in leg muscles in 10 (60%). All patients mutated in CLCN1 and CACNA1S had abnormal thigh and/or leg muscle MRI, regardless the disease duration. On the contrary normal thigh and leg muscle MRI or CT scans were observed in 4/15 (27%) patients, all mutated in SCN4A. Variable degrees of fatty changes were found in patients mutated in SCN4A, CACNA1S and CLCN1. No differences on overall score of fatty infiltration were detected between NDM and PP (p-value = 0.953) neither between presence or absence of permanent weakness (p-value = 0.951). Our data confirm the presence of muscle fatty changes in the majority of SMC patients, although without any specific pattern of involvement. However muscle MRI may be a useful tool for longitudinal follow-up of SMC patients, in particular to evaluate the occurrence and the progression of fixed myopathy.

Muscle ultrasound measurements and functional muscle parameters in non-dystrophic myotonias suggest structural muscle changes.

Patients with non-dystrophic myotonias, including chloride (myotonia congenita) and sodium channelopathies (paramyotonia congenita/potassium aggravated myotonias), may show muscular hypertrophy in combination with some histopathological abnormalities. However, the extent of muscle changes has never been assessed objectively in a large group genetically confirmed patients. This study quantitatively determines echo intensities, thicknesses, ranges-of-motion and force of four skeletal muscles in 63 genetically confirmed patients. The main findings revealed elevated echo intensities in all muscles except the rectus femoris (+1.3-2.2SD, p<0.0001), and hypertrophy in the arms (+0.5-0.9SD, p<0.01). Muscle echo intensities were inversely correlated to the corresponding ranges-of-motion (biceps brachii: r= -0.43; p<0.001, forearm flexors: r= -0.47; p<0.001, rectus femoris: r= -0.40; p=0.001, and tibial anterior: r= -0.27; p=0.04) and correlated positively to age (r=0.22; p=0.05). The echo intensity of the forearm flexors was inversely correlated to their muscles' force (r= -0.30; p=0.02). Together, these data suggest that non-dystrophic myotonias may lead to structural muscle changes.