Clinical Course of Atopic Dermatitis in an Adult with Amyotrophic Lateral Sclerosis: Aetiological Implications of Voluntary Movements and Dermatitis Severity.

is missing (Short communication).

Overexpression of Dok-7 in skeletal muscle enhances neuromuscular transmission with structural alterations of neuromuscular junctions: Implications in robustness of neuromuscular transmission.

Neuromuscular junctions (NMJs) are cholinergic synapses characterized by ultrastructural specializations, including the presynaptic active zones, the acetylcholine (ACh) release sites of the motor nerve terminal, and the postsynaptic junctional folds of muscle membrane, where ACh receptors (AChRs) cluster for efficient neuromuscular transmission. The formation and maintenance of NMJs are governed by the muscle-specific receptor tyrosine kinase MuSK. We had previously demonstrated that the muscle cytoplasmic protein Dok-7 is an essential activator of MuSK, and its activation and NMJ formation are enhanced in the Dok-7 transgenic (Tg) mice, in which Dok-7 is specifically overexpressed in skeletal muscle. Although Dok-7 Tg mice develop abnormally large NMJs but show normal motor function, the forced expression of Dok-7 in the muscle improves impaired motor activity in mouse models of neuromuscular disorders with NMJ defects. However, the effect of Dok-7 overexpression in skeletal muscle on ultrastructure and neuromuscular transmission of NMJs is yet to be studied. Here, we investigated the structural and electrophysiological properties of NMJs in the diaphragm muscle of 8-week-old Dok-7 Tg mice. The areas of the presynaptic motor nerve terminals and postsynaptic muscle membrane of NMJs were 2.7 and 4.3 times greater in Dok-7 Tg mice than in WT mice, respectively. Electrophysiological analyses revealed that neuromuscular transmission via NMJs in Dok-7 Tg mice was significantly enhanced but not proportionally with the increased size of the synaptic contact. Consistent with this, the densities of active zones and synaptic vesicles (ACh carriers) in the presynaptic motor nerve terminals were reduced. In addition, the density and size of postsynaptic junctional folds in the muscle membrane were also reduced. Moreover, terminal Schwann cells exhibited significantly greater penetration of their processes into the synaptic clefts, which connect the pre- and post-synaptic specializations. Together, our findings demonstrate that transgenic overexpression of Dok-7 in the skeletal muscle enhances neuromuscular transmission with significant enlargement and ultrastructural alterations of NMJs, the latter of which might prevent toxic overactivation of AChRs at the abnormally enlarged NMJs.

Protein-anchoring strategy for delivering acetylcholinesterase to the neuromuscular junction.

Acetylcholinesterase (AChE) at the neuromuscular junction (NMJ) is anchored to the synaptic basal lamina via a triple helical collagen Q (ColQ). Congenital defects of ColQ cause endplate AChE deficiency and myasthenic syndrome. A single intravenous administration of adeno-associated virus serotype 8 (AAV8)-COLQ to Colq(-/-) mice recovered motor functions, synaptic transmission, as well as the morphology of the NMJ. ColQ-tailed AChE was specifically anchored to NMJ and its amount was restored to 89% of the wild type. We next characterized the molecular basis of this efficient recovery. We first confirmed that ColQ-tailed AChE can be specifically targeted to NMJ by an in vitro overlay assay in Colq(-/-) mice muscle sections. We then injected AAV1-COLQ-IRES-EGFP into the left tibialis anterior and detected AChE in noninjected limbs. Furthermore, the in vivo injection of recombinant ColQ-tailed AChE protein complex into the gluteus maximus muscle of Colq(-/-) mice led to accumulation of AChE in noninjected forelimbs. We demonstrated for the first time in vivo that the ColQ protein contains a tissue-targeting signal that is sufficient for anchoring itself to the NMJ. We propose that the protein-anchoring strategy is potentially applicable to a broad spectrum of diseases affecting extracellular matrix molecules.

Increased T-cell immunity against aquaporin-4 and proteolipid protein in neuromyelitis optica.

In neuromyelitis optica (NMO), B-cell autoimmunity to aquaporin-4 (AQP4) has been shown to be essential. However, the role of T cells remains ambiguous. Here, we first showed an increase in CD69+ activated T cells in PBMCs during NMO relapses. Next, T-cell responses to AQP4 and myelin peptides were studied in 12 NM0 patients, 10 multiple sclerosis (MS) patients and 10 healthy subjects (HS). Four hours after adding 1 of 28 overlapping AQP4 peptides, a mixture of AQP4 peptides (AQP4-M) or one of six distinct myelin peptides to 2-day cultured PBMC, CD69 expression on CD4+ T cells was examined. Data were analyzed by paired t-test, frequency of samples with 3-fold increase of CD69 on CD4+ cells (fSI3) and mean stimulation index (mSI). The T-cell response to AQP4-M was significantly increased in NMO (fSI3 = 10/12, mSI = 5.50), with AQP4 (11-30) and AQP4 (91-110) representing the two major epitopes (AQP4 (11-30), fSI3 = 11/12, mSI = 16.0 and AQP4 (91-110), fSI3 = 11/12, mSI = 13.0). Significant but less extensive responses to these two epitopes were also observed in MS and HS. Significant reactivities against AQP4 (21-40), AQP4 (61-80), AQP4 (101-120), AQP4 (171-190) and AQP4 (211-230) were exclusively found in NMO. In addition, responses to AQP4 (81-100) were higher and more frequently detected in NMO, without reaching statistical significance. Interestingly, among the six myelin peptides studied, proteolipid protein (95-116) induced a significant T-cell response in NMO (fSI3 = 7/12, mSI = 4.60). Our study suggests that cellular as well as humoral responses to AQP4 are necessary for NMO development and that the immune response to myelin protein may contribute to disease pathogenesis.

Tranilast for advanced heart failure in patients with muscular dystrophy: a single-arm, open-label, multicenter study.

BACKGROUND: The transient receptor potential cation channel subfamily V member 2 (TRPV2) is a stretch-sensitive calcium channel. TRPV2 overexpression in the sarcolemma of skeletal and cardiac myocytes causes calcium influx into the cytoplasm, which triggers myocyte degeneration. In animal models of cardiomyopathy and muscular dystrophy (MD), TRPV2 inhibition was effective against heart failure and motor function. Our previous pilot study showed that tranilast, a TRPV2 inhibitor, reduced brain natriuretic peptide (BNP) levels in two MD patients with advanced heart failure. Thus, this single-arm, open-label, multicenter study aimed to evaluate the safety and efficacy of tranilast for heart failure. METHODS: The study enrolled MD patients with advanced heart failure whose serum BNP levels were > 100 pg/mL despite receiving standard cardioprotective therapy. Tranilast was administered orally at 100 mg, thrice daily. The primary endpoint was the change in log (BNP) (Δlog [BNP]) at 6 months from baseline. The null hypothesis was determined based on a previous multicenter study of carvedilol results in a mean population Δlog (BNP) of 0.18. TRPV2 expression on peripheral blood mononuclear cell surface, cardiac events, total mortality, left ventricular fractional shortening, human atrial natriuretic peptide, cardiac troponin T, and creatine kinase, and pinch strength were also assessed. RESULTS: Because of the poor general condition of many patients, only 18 of 34 patients were included and 13 patients could be treated according to the protocol throughout the 6-month period. However, there were no serious adverse events related to tranilast except diarrhea, a known adverse effect, and the drug was administered safely. TRPV2 expression on the mononuclear cell surface was elevated at baseline and reduced after treatment. Cardiac biomarkers such as BNP, human atrial natriuretic peptide, and fractional shortening remained stable, suggesting a protective effect against the progression of heart failure. In the per protocol set group, Δlog [BNP] was - 0.2 and significantly lower than that in the null hypothesis. CONCLUSIONS: Tranilast is safe and effective in inhibiting TRPV2 expression, even in MD patients with advanced heart failure. Further trials are needed to evaluate the efficacy of tranilast in preventing myocardial damage, heart failure, motor impairment, and respiratory failure. Clinical trial registration The study was registered in the UMIN Clinical Trials Registry (UMIN-CTR: UMIN000031965, URL: http://www.umin.ac.jp/ctr/ ) [March 30, 2018] and the Japan Registry of Clinical Trials (jRCT, registration number: jRCTs031180038, URL: https://jrct.niph.go.jp/ ) [November 12, 2021]. Patient registration was started in December 19, 2018.

[A Japanese family with POMT2-related limb girdle muscular dystrophy].

Mutations in the gene encoding the protein O-mannosyl-transferase 2 (POMT2) are known to cause autosomal recessive limb girdle muscular dystrophy type 14 (LGMDR14). No Japanese patient with LGMDR14 has been reported previously. Here, we report three patients with LGMDR14 in one family. The first and second patients harbored a novel homozygous mutation of c.1568A>G, while the third harbored a compound heterozygous mutation of c.1568A>G and c.869C>T. The novel c.1568A>G mutation is classified as likely pathogenic by the guideline of the American College of Medical Genetics and Genomics. Similar to previous cases, all three patients presented difficulty walking and cognitive impairment, and the hamstring muscles were severely affected. Although eye abnormality has only been reported in one previous case, two our patients showed eye abnormalities. As POMT2 enzymatic activity has been demonstrated in the mammalian retina, an eye abnormality may represent a phenotype associated with POMT2 mutation.

A web-based questionnaire survey on the influence of coronavirus disease-19 on the care of patients with muscular dystrophy.

To clarify the influence of coronavirus disease-19 (COVID-19) on the care of muscular dystrophy patients, we performed a questionnaire survey that was posted on the internet on May 11, 2020. By the end of July 2020, 542 responses had been collected. Approximately 30% of patients postponed regular consultations, and one-quarter of patients who received consultation more than once a month used telephone consultations. Two of 84 patients with Duchenne muscular dystrophy had reduced their steroid doses. A shortage of ventilator accessories and infection protection equipment occurred following the onset of COVID-19, and this shortage had a serious impact on medical care and infection prevention measures. Reductions in rehabilitation and other services, and avoidance of outings, led to a decrease in exercise and an increase in caregiver burden. Inpatients were restricted from going out and visiting family members. More than 20% of patients reported physical or mental complaints; however, few required treatment. COVID-19 has seriously affected the activities and quality of life of patients with muscular dystrophy. We will continue this survey and analyze the longitudinal changes.

Effect of dietary fatty acid composition on Th1/Th2 polarization in lymphocytes.

BACKGROUND: It has become increasingly clear that polyunsaturated fatty acids (PUFAs) have immunomodulatory effects. However, the intake of these fatty acids used in animal studies often greatly exceeds dietary human intake. Whether differences in the composition of fatty acids that are consumed in amounts consistent with normal dietary intake can influence immune function remains uncertain. METHODS: We manufactured 3 types of liquid diet, related to modified fatty acid composition (omega-6/omega-3 = 0.25, 2.27 and 42.9), but excluding eicosapentaenoic acid and docosahexaenoic acid, based upon a liquid diet used clinically in humans. We assessed CD3-stimulated cytokine production of splenocytes in female BALB/c mice (n = 4 per group) fed 1 of 3 liquid diets for 4 weeks. We also measured the cytokine production of peripheral blood mononuclear cells stimulated with phorbol myristate acetate and ionomycin in humans at the end of a 4-week period of consumption of 2 different liquid diets (omega-6/omega-3 = 3 and 44). RESULTS: We found that the ratio of interfero omega-gamma (IFN-gamma) / interleukin-4 (IL-4) was significantly higher in mice fed the omega-3 rich diet than in others. In humans, IFN-gamma / IL-4 was significantly higher after the omega-3 versus the omega-6 enhanced diet. CONCLUSIONS: Differences in the composition of omega-3 and omega-6 PUFAs induces a shift in the Th1/Th2 balance in both mouse and human lymphocytes, even when ingested in normal dietary amounts. An omega-3 rich diet containing alpha-linolenic acid modulates immune function.

The Cross-Sectional Area of Paraspinal Muscles Predicts the Efficacy of Deep Drain Stimulation for Camptocormia.

BACKGROUND: Camptocormia, a disturbance of posture, is a well-described clinical feature of PD and other parkinsonian syndromes. Previous reports have shown that DBS of the subthalamic nucleus (STN) or globus pallidus internus is effective in treating camptocormia. However, the efficacy of DBS for camptocormia varies. OBJECTIVE: To determine a clinical marker for selecting an appropriate therapy for camptocormia, a disabling manifestation of Parkinson's disease (PD) that has a variable response to systemic and local therapies. METHODS: We obtained pre-operative lumbar magnetic resonance imaging of 14 consecutive PD patients with camptocormia who underwent subthalamic nucleus deep brain stimulation (STN-DBS) in this retrospective-designed study. Lumbar MRI was performed three to six months prior to the operation. We measured the cross-sectional area (CSA) and width of each participant's paraspinal muscles. RESULTS: Four (28.6%) patients were effective (EF), five (35.7%) were partially effective (PE), and five (35.7%) were non-effective (NE) to STN-DBS. The lumbar paraspinal CSA and width were significantly larger in the EF group than in the PE and NE groups. CONCLUSIONS: The CSA of paraspinal muscles and erector spinae width can be good predictive markers for improving camptocormia in patients with PD after deep brain stimulation.

R-spondin 2 promotes acetylcholine receptor clustering at the neuromuscular junction via Lgr5.

At the neuromuscular junction (NMJ), acetylcholine receptor (AChR) clustering is mediated by spinal motor neuron (SMN)-derived agrin and its receptors on the muscle, the low-density lipoprotein receptor-related protein 4 (LRP4) and muscle-specific receptor tyrosine kinase (MuSK). Additionally, AChR clustering is mediated by the components of the Wnt pathway. Laser capture microdissection of SMNs revealed that a secreted activator of Wnt signaling, R-spondin 2 (Rspo2), is highly expressed in SMNs. We found that Rspo2 is enriched at the NMJ, and that Rspo2 induces MuSK phosphorylation and AChR clustering. Rspo2 requires Wnt ligands, but not agrin, for promoting AChR clustering in cultured myotubes. Leucine-rich repeat-containing G-protein coupled receptor 5 (Lgr5), an Rspo2 receptor, is also accumulated at the NMJ, and is associated with MuSK via LRP4. Lgr5 is required for Rspo2-mediated AChR clustering in myotubes. In Rspo2-knockout mice, the number and density of AChRs at the NMJ are reduced. The Rspo2-knockout diaphragm has an altered ultrastructure with widened synaptic clefts and sparse synaptic vesicles. Frequency of miniature endplate currents is markedly reduced in Rspo2-knockout mice. To conclude, we demonstrate that Rspo2 and its receptor Lgr5 are Wnt-dependent and agrin-independent regulators of AChR clustering at the NMJ.

The Effectiveness of the Stereotactic Burr Hole Technique for Deep Brain Stimulation.

Deep brain stimulation (DBS) is performed by burr hole surgery. In microelectrode recording by multi-channel parallel probe, because all microelectrodes do not always fit in the burr hole, additional drilling to enlarge the hole is occasionally required, which is time consuming and more invasive. We report a stereotactic burr hole technique to avoid additional drilling, and the efficacy of this novel technique compared with the conventional procedure. Ten patients (20 burr holes) that received DBS were retrospectively analyzed (5 in the conventional burr hole group and 5 in the stereotactic burr hole group). In the stereotactic burr hole technique, the combination of the instrument stop slide of a Leksell frame and the Midas Rex perforator with a 14-mm perforator bit was attached to the instrument carrier slide of the arc in order to trephine under stereoguidance. The efficacy of this technique was assessed by the number of additional drillings. Factors associated with additional drilling were investigated including the angle and skull thickness around the entry points. Four of the 10 burr holes required additional drilling in the conventional burr hole group, whereas no additional drilling was required in the stereotactic burr hole group (p = 0.043). The thicknesses in the additional drilling group were 10.9 ± 0.9 mm compared to 9.1 ± 1.2 mm (p = 0.029) in the non-additional drilling group. There were no differences in the angles between the two groups. The stereotactic burr hole technique contributes to safe and exact DBS, particularly in patients with thick skulls.

[Left-sided metamorphopsia of the face and simple objects caused by an infarction at the right side of the splenium of the corpus callosum].

A 78-year-old woman noticed that people's eyes and the right nasal foramens located in her left visual field looked smaller than those observed in the right. The woman reported no change in shape regarding facial outlines or scenic objects. Magnetic resonance imaging revealed an acute infarction of the right side of the splenium of the corpus callosum. Close examination revealed that her metamorphopsia affected the left side of her visual field, especially influencing facial components, particularly the eye. The woman had similar reactions to photographs of several kinds of animals, realistic portraits of humans, and caricatured humans. Meanwhile, presentings caricature human face at a 90° rotation elicited metamorphopsia in eyebrows located on the left side of a picture, but not the eyes. She also reported a change of shape or color tone for geometric objects. The patient's only symptom was metamorphopsia, and she did not show any other neurological defects such as callosal disconnection syndrome. Furthermore, objects that were affected by the patient's metamorphopsia (e.g. facial component especially the eye, and simple geometric figures) may be easy images to use in order to detect this type of distorted vision.

Thymic myoid cells as a myasthenogenic antigen and antigen-presenting cells.

We investigated immune property of a myoid cell line, established from Fisher rat thymus. Immunization of syngeneic rats with the myoid cells induced anti-rat acetylcholine receptor (AChR). Implantation of them into the thymus failed to induce typical thymic pathology of human myasthenia gravis (MG) or anti-AChR responses. We also demonstrated that the myoid cells were able to present exogenous antigens to T cells and induce antigen-specific T cell proliferation. These results suggest that myoid cells have the potential antigenicity to induce anti-AChR and the functions of antigen-presenting cells, but their expansion in the thymus may not directly cause MG.

Selective adsorption of human CD4 T cells.

The pathogenesis of most autoimmune diseases directly involves CD4(+) helper T cells. To remove CD4(+) T cells selectively from the circulation, we designed a new column in which an anti-CD4 monoclonal antibody was immobilized on the activated substance. Nearly 90% of CD4(+) T cells were selectively adsorbed from whole blood with a single passage through the column in vitro, resulting in depletion of the antigen-specific T cell responses. We conclude that this new column would be potentially useful for treatment of T cell-mediated autoimmune diseases.

[The effects of repetitive transcranial magnetic stimulation (rTMS) in the patients with Parkinson's disease].

The 1-Hz rTMS of 320 stimuli with an intensity of 90% of motor threshold was applied over the vertex of the skull using a round coil in a day. The effects of short-term (treated in 5 successive days) treatment was examined in 6 patients and long-term (treated in every one or two weeks for six months) treatment was examined in five. Unified Parkinson's Disease Rating Scale (UPDRS), motor evoked potential threshold (MT) and cortical silent period (SP) were recorded before and one day after the short-term treatment. In the long-term treatment, same recordings were obtained in every two months. After the short-term treatment, the total UPDRS scores was reduced from 37 +/- 3.3 (mean +/- S.E.) to 31 +/- 3.1 and the SP duration was prolonged from 98.9 +/- 24.7 to 106 +/- 22.0 significantly (P < 0.05 by Wilcoxon Matched Pairs Teat). After the long-term treatment, both total UPDRS scores and MEP threshold was reduced from 33 +/- 5.8 to 30 +/- 5.3 and from 75 +/- 7.2 to 69 +/- 5.7, respectively two months after the initiation of the treatment. Both values reduced continuously until the end of treatment, and a significant linear correlation was noted (r = 0.98) between them. Our results show the beneficial effects of rTMS and suggest the possible mechanism that the alteration of brain excitability induced by rTMS mediate therapeutic effects in patients with Parkinson's disease.

[A case of Alexander disease suspected juvenile-onset and exacerbating after long stationary state].

We report the case of a 40-year-old woman with Alexander disease. She experienced single seizure as 1-year-old, and became less active after that. Her academic records in elementary school were poor. However, she graduated from junior college and was later employed as a clerk for a short duration. Her parents, who lived with her noticed her apathy when she was 38, and gait disturbance soon after. At the age of 40, she was admitted to a hospital because of a fall and was referred to us. Brain magnetic resonance imaging (MRI) showed significant leukodystrophy with frontal predominance, and cervical MRI revealed mild cervical cord atrophy with dilated central canal. We performed genetic analysis and found the R79H variant of the gene encoding the glial fibrillary acidic protein. The patient was diagnosed with Alexander disease and suspedted juvenile-onset on the basis of the genetic analysis and MRI findings. Patients with juvenile Alexander disease have been previously reported to have variable survival, ranging from the early teens to the 20's and 30's. Our patient may suggest that natural history of this disease is more variable than previously thought.

Neuroleptic malignant syndrome (parkinsonism-hyperpyrexia syndrome) after deep brain stimulation of the subthalamic nucleus.

Neuroleptic malignant syndrome (NMS), also called parkinsonism-hyperpyrexia syndrome (PHS), is a severe, general, sometimes fatal, physical reaction, induced by sudden and strong blockade of dopamine receptors. When subthalamic nucleus (STN)-deep brain stimulation (DBS) is used on patients with Parkinson disease (PD), dopaminergic medications are transiently stopped prior to the procedure, and a reduction in the use of drugs is routinely attempted after the procedure. Although a sudden stop or abrupt reduction of dopaminergic medications may set the stage for NMS/PHS, only three cases have been reported after STN-DBS surgery. Here, we describe a 75-year-old woman with PD who experienced delayed onset, yet fatal, PHS after STN-DBS. Although STN-DBS might prevent or suppress PHS, its protective effect is not always complete. We must be aware that fatal PHS can occur when the use of medication for PD is reduced or altered, even when patients are under continuous STN stimulation.

Subacute motor axonal neuropathy associated with the IgG anti-GalNAc-GD1a antibody.

A 14-year-old boy developed a distinct asymmetrical muscle atrophy and weakness with no sensory disturbance in the lower extremities after enteritis. He had an elevated titre of the IgG antibody against GalNAc-GD1a, but none of the others. A nerve conduction study revealed motor axonopathy. Intravenous immunoglobulin therapy improved the status gradually, with low titres of IgG anti-GalNAc-GD1a.

[Transient blindsight (type 2) after surgery for posterior cerebral artery aneurysm--case report].

In a 47-year-old woman experiencing pulsatile headache, radiological examination revealed a large right posterior cerebral artery (PCA) aneurysm. Preoperative neurological examination showed bilateral papilledema, but no visual disturbance. Cerebral angiography revealed that the aneurysm originated from the ambient segment of the PCA, and the posterior temporal, calcarine, and parieto-occipital arteries were all branched from the aneurysmal dome. Clipping of the feeding PCA trunk was performed via a left subtemporal approach. As a result of left occipital lobe infarction due to calcarine artery occlusion, right upper quadrant hemianopsia appeared after surgery, as confirmed by Goldman's perimetry. Other cerebral infarctions were identified in the junction between the left posterior internal capsule and thalamus, in the left posterior corpus callosum, and in the posterior base of the left temporal lobe due to the occlusion of the posterolateral thalamoperforating, posterior pericallosal, and posterior temporal arteries, respectively. The aneurysm was thrombosed and headache and papilledema subsided. The patient was able to detect the motion of a subject in a blind field, but consciousness of sight was absent. She was able to unconsciously move her finger toward a small penlight, and insert a paper into a slot with variable angles in the blind field. These phenomena disappeared within 4 months of the surgery. The results to forced choice tasks with figures (circle, cross, square, triangle, and star) and colors (red, blue, yellow, and green) were below chance levels. The present case was thus diagnosed as blindsight type 2 (gnosopsia) associated with awareness, probably due to transient activation of the dorsal "what" pathway among numerous visual processes.

Aberrant neuromuscular junctions and delayed terminal muscle fiber maturation in alpha-dystroglycanopathies.

Recent studies have revealed an association between post-translational modification of alpha-dystroglycan (alpha-DG) and certain congenital muscular dystrophies known as secondary alpha-dystroglycanopathies (alpha-DGpathies). Fukuyama-type congenital muscular dystrophy (FCMD) is classified as a secondary alpha-DGpathy because the responsible gene, fukutin, is a putative glycosyltransferase for alpha-DG. To investigate the pathophysiology of secondary alpha-DGpathies, we profiled gene expression in skeletal muscle from FCMD patients. cDNA microarray analysis and quantitative real-time polymerase chain reaction showed that expression of developmentally regulated genes, including myosin heavy chain (MYH) and myogenic transcription factors (MRF4, myogenin and MyoD), in FCMD muscle fibers is inconsistent with dystrophy and active muscle regeneration, instead more of implicating maturational arrest. FCMD skeletal muscle contained mainly immature type 2C fibers positive for immature-type MYH. These characteristics are distinct from Duchenne muscular dystrophy, suggesting that another mechanism in addition to dystrophy accounts for the FCMD skeletal muscle lesion. Immunohistochemical analysis revealed morphologically aberrant neuromuscular junctions (NMJs) lacking MRF4 co-localization. Hypoglycosylated alpha-DG indicated a lack of aggregation, and acetylcholine receptor (AChR) clustering was compromised in FCMD and the myodystrophy mouse, another model of secondary alpha-DGpathy. Electron microscopy showed aberrant NMJs and neural terminals, as well as myotubes with maturational defects. Functional analysis of NMJs of alpha-DGpathy showed decreased miniature endplate potential and higher sensitivities to d-Tubocurarine, suggesting aberrant or collapsed formation of NMJs. Because alpha-DG aggregation and subsequent clustering of AChR are crucial for NMJ formation, hypoglycosylation of alpha-DG results in aberrant NMJ formation and delayed muscle terminal maturation in secondary alpha-DGpathies. Although severe necrotic degeneration or wasting of skeletal muscle fibers is the main cause of congenital muscular dystrophies, maturational delay of muscle fibers also underlies the etiology of secondary alpha-DGpathies.