Nuclear Envelope Alterations in Myotonic Dystrophy Type 1 Patient-Derived Fibroblasts

Myotonic dystrophy type 1 (DM1) is a hereditary and multisystemic disease characterized by myotonia, progressive distal muscle weakness and atrophy. The molecular mechanisms underlying this disease are still poorly characterized, although there are some hypotheses that envisage to explain the multisystemic features observed in DM1. An emergent hypothesis is that nuclear envelope (NE) dysfunction may contribute to muscular dystrophies, particularly to DM1. Therefore, the main objective of the present study was to evaluate the nuclear profile of DM1 patient-derived and control fibroblasts and to determine the protein levels and subcellular distribution of relevant NE proteins in these cell lines. Our results demonstrated that DM1 patient-derived fibroblasts exhibited altered intracellular protein levels of lamin A/C, LAP1, SUN1, nesprin-1 and nesprin-2 when compared with the control fibroblasts. In addition, the results showed an altered location of these NE proteins accompanied by the presence of nuclear deformations (blebs, lobes and/or invaginations) and an increased number of nuclear inclusions. Regarding the nuclear profile, DM1 patient-derived fibroblasts had a larger nuclear area and a higher number of deformed nuclei and micronuclei than control-derived fibroblasts. These results reinforce the evidence that NE dysfunction is a highly relevant pathological characteristic observed in DM1.

Case Report: Christianson Syndrome Caused by SLC9A6 Mutation: From Case to Genotype-Phenotype Analysis

Christianson syndrome (CS) is an X-linked neurodevelopmental syndrome characterized by microcephaly, epilepsy, ataxia, and severe generalized developmental delay. Pathogenic mutations in the SLC9A6 gene, which encodes the Na+/H+ exchanger protein member 6 (NHE6), are associated with CS and autism spectrum disorder in males. In this study, whole exome sequencing (WES) and Sanger sequencing revealed a novel de novo frameshift variant c.1548_1549insT of SLC9A6 in a 14-month-old boy with early-onset seizures. According to The American College of Medical Genetics and Genomics (ACMG)/the Association for Molecular Pathology (AMP) guidelines, the variant was classified as pathogenic. The proband presented with several core symptoms of typical epilepsy, including microcephaly, motor delay, distal muscle weakness, micrognathia, occasional unprovoked laughter, swallowing and speech difficulties. Electroencephalography (EEG) showed spikes-slow waves in frontal pole, frontal, anterior temporal and frontal midline point areas. Gesell development schedules (GDS) indicated generalized developmental delay. We also summarized all the reported variants and analyzed the correlation of genotype and phenotype of CS. Our study extends the mutation spectrum of the SLC9A6 gene, and it might imply that the phenotypes of CS are not correlated with SLC9A6 genotypes.

EFFECT OF LOWER LIMB PROXIMAL TO DISTAL MUSCLE IMBALANCE CORRECTION ON FUNCTIONAL PES PLANUS DEFORMITY IN YOUNG ADULTS

The pes planus deformity is seen more in adults. Pes planus or low foot medial longitudinal arch, contributes to lower extremity injury due to the muscular imbalance. This deformity causes proximal to distal muscle imbalance in lower limb. Effective correction of muscle imbalance is prime important in correction of pes planus. The purpose of the study was to find the effect of exercise in pes planus to correct the imbalance, improve the condition & prevent the injuries along with the long-term effect of the pes planus deformity. To study and find the effect of lower limb proximal to distal muscle imbalance correction in pes planus deformity in young adults. 40 people with functional pes planus deformity were randomly assigned to a group that received the baseline treatment for the muscle imbalance along with the intrinsic muscle strengthening exercises (experimental group) or a group that received only intrinsic muscle strengthening exercises (control group). Each group received 6 weeks treatment. Statistical analysis were performed using paired t test and unpaired t test. In pre-intervention, there was no statistically significant difference seen with p values for the navicular drop test for the right leg and left leg 0.1127, 0.1504 respectively. Ink test p values for the right leg, left leg 0.4184, 0.8719 respectively. While on comparing the post-interventional values using the unpaired t test, revealed that there was extremely significant difference seen with p value for both legs the navicular drop test was 0.0001 and for the ink test (right leg=0.0008, left leg=0.0318). Our study reported that muscular imbalance corrective exercises along with the intrinsic muscle strengthening was more effective in improving the condition and muscle imbalance caused by the pes planus. So, muscular imbalance corrective exercises and intrinsic muscle strengthening exercises should be recommended to correct the deformity or prevent the abnormalities in people with functional pes planus.

Large-gap Peripheral Nerve Repair Using Xenogeneic Transplants in Primates

Early surgical intervention is required to successfully treat severe, large-gap peripheral nerve injuries. However, all existing treatments have shortcomings, and for large-gap injuries (≥4 cm), there is no reported alternative to autologous nerve. We report preclinical repair of large (4 cm), complete transectional radial nerve damage in Rhesus macaques using viable, whole sciatic nerve from genetically engineered, designated pathogen free porcine donors. Porcine nerves are physiologically similar to human nerves, contain neurotrophic growth factors and a matrix-rich scaffold, and offer greater clinical availability. We demonstrate regeneration of the transected nerve, distal muscle reinnervation, and recovery of conduction velocity and compound muscle action potential across xenogeneic transplants resulting in functional recovery comparable to autologous controls. We also show the lack of systemic porcine cell migration and the elimination of detectable transplanted porcine tissue. Our findings support the safety and efficacy of neural porcine therapeutics and the broader clinical potential of xenotransplantation.

Identification of a Homozygous Deletion within FGD4 in a Charcot-Marie-Tooth type 4H Family by Exome Sequencing

Charcot-Marie-Tooth (CMT) disease is a group of clinically and genetically heterogeneous peripheral neuropathies by causing distal muscle weakness, sensory impairment, hyporeflexia, and skeletal deformities. Both of sequence and copy number variations (CNVs) of over 80 genes have been described in CMT patients so far, and FGD4 variants are among the uncommon causes of the disease. In this article, we present four siblings with early-onset CMT, who were found to carry a novel homozygous deletion within FGD4 gene by exome sequencing. Since CNVs of CMT-related genes other than PMP22 have been rarely described in literature and they are prone to be overlooked by next generation sequencing, this report confirms the importance of paying additional attention to these variants to increase diagnostic yield in CMT.

Neuromuscular and Neuroendocrinological Features Associated With ZC4H2-Related Arthrogryposis Multiplex Congenita in a Sicilian Family: A Case Report

Wieacker-Wolff syndrome (WWS) is an X-linked Arthrogryposis Multiplex Congenita (AMC) disorder associated with broad neurodevelopmental impairment. The genetic basis of WWS lies in hemizygous pathogenic variants in ZC4H2, encoding a C4H2 type zinc-finger nuclear factor abundantly expressed in the developing human brain. The main clinical features described in WWS families carrying ZC4H2 pathogenic variants encompass having a short stature, microcephaly, birth respiratory distress, arthrogryposis, hypotonia, distal muscle weakness, and broad neurodevelopmental delay. We hereby report a Sicilian family with a boy clinically diagnosed with WWS and genetically investigated with exome sequencing (ES), leading to the identification of a c.593G>A (p. R198Q) hemizygous pathogenic variant in the ZC4H2 gene. During the first year of life, the onset of central hypoadrenalism led to recurrent hypoglycemic events, which likely contributed to seizure susceptibility. Also, muscle biopsy studies confirmed a pathology of the muscle tissue and revealed peculiar abnormalities of the neuromuscular junction. In conclusion, we expand the phenotypic spectrum of the WWS-related neurodevelopmental disorders and discuss the role of ZC4H2 in the context of the potential neuroendocrinological and neuromuscular features associated with this condition.

A rare case of hypokalaemia and hypophosphataemia secondary to geophagia

We report a case of severe hypokalaemia and moderate hypophosphataemia from clay ingestion. A 60-year-old woman presented with flaccid paralysis. Investigations revealed a serum potassium level of 1.8 mmol/L, phosphate level of 0.56 mmol/L and creatine kinase level of 30 747 IU/L. She had marked proximal and distal muscle weakness due to severe hypokalaemia and concurrent hypophosphataemia, which likely contributed to the onset of rhabdomyolysis. The patient subsequently admitted to significant pica, most likely secondary to an associated iron deficiency. We conclude that the ingested clay acted as a potassium and phosphate binder. Although we did not investigate the content of the clay in this case, it has been reported that clay can bind potassium in vitro and is rich in minerals such as aluminium that could play a role in the binding of phosphate, although the exact mechanism remains unclear. The patient recovered fully and outpatient follow-up at 6 months and again at 40 months confirmed no electrolyte abnormality, myopathy nor any further geophagia.

Clinical and genetic analysis of a case with centronuclear myopathy caused by SPEG gene mutation: a case report and literature review

Background Centronuclear myopathy (CNM), a subtype of congenital myopathy (CM), is a group of clinical and genetically heterogeneous muscle disorders. Since the discovery of the SPEG gene and disease-causing variants, only a few additional patients have been reported. Case presentation The child, a 13-year-old female, had delayed motor development since childhood, weakness of both lower extremities for 10 years, gait swinging, and a positive Gower sign. Her distal muscle strength of both lower extremities was grade IV. The electromyography showed myogenic damage and electromyographic changes. Her 11-year-old sister had a similar muscle weakness phenotype. Gene sequencing revealed that both sisters had SPEG compound heterozygous mutations, and the mutation sites were c.3715 + 4C > T and c.3588delC, which were derived from their parents. These variant sites have not been reported before. The muscle biopsy showed the nucleic (> 20% of fibers) were located in the center of the cell, the average diameter of type I myofibers was slightly smaller than that of type II myofibers, and the pathology of type I myofibers was dominant, which agreed with the pathological changes of centronuclear myopathy. Conclusions The clinical phenotypes of CNM patients caused by mutations at different sites of the SPEG gene are also different. In this case, there was no cardiomyopathy. This study expanded the number of CNM cases and the mutation spectrum of the SPEG gene to provide references for prenatal diagnosis and genetic counseling.

Anatomical study of the teres major muscle: description of an additional distal muscle slip

Background Understanding muscle and tendon anatomy is of tremendous importance to achieve optimal surgical execution and results in tendon transfers around the shoulder. The aim of this study was to introduce and describe an additional distal muscle slip of the teres major (TM). Methods Sixteen fresh-frozen cadaver shoulders were dissected with the deltopectoral approach. The ventral latissimus dorsi (LD) tendon was harvested, and the shoulders were analyzed for the presence/absence of a distal teres major slip (dTMs) and its dimensions and relationship with the TM and LD tendons. Results The dTMs was identified in 12 shoulders (75%). It was always distal to the TM tendon and visible during the deltopectoral approach. There was a clear separation between the TM proximally and dTMs tendon distally. At the humeral insertion, both tendons had a common epimyseal sheet around the teres major and inserted continuously at the humerus. The mean width of the dTMs tendon at the insertion was 13 ± 4 mm (range, 7–22 mm). The total lengths of the dTMs tendon and LD tendon were 40 ± 7 mm (range, 25–57 mm) and 69 ± 7 mm (range, 57–79 mm), respectively (p < 0.001). The dTMs muscle showed direct adhesions in ten shoulders (83%) with the LD muscle. Conclusions This is the first macroscopic description of an additional distal slip of the teres major muscle. The dTMs has a separate (distal) but continuous (mediolateral) insertion at the humerus within a common epimyseal sheet around the TM. The dTMs tendon is visible during the deltopectoral approach and can therefore provide a lead structure, particularly in ventral LD transfers with the deltopectoral approach.