Search

COQ7 encodes a hydroxylase responsible for the penultimate step of coenzyme Q10 (CoQ10) biosynthesis in mitochondria. CoQ10 is essential for multiple cellular functions, including mitochondrial oxidative phosphorylation, lipid metabolism, and reactive oxygen species homeostasis. Mutations in COQ7 have been previously associated with primary coenzyme Q10 deficiency, a clinically heterogeneous multisystemic mitochondrial disorder. We identified COQ7 biallelic variants in nine families diagnosed with distal hereditary motor neuropathy (dHMN) with upper neuron involvement, expending the clinical phenotype associated with defects in this gene. A recurrent p.Met1? change was identified in five families from Brazil with evidence of a founder effect. Fibroblasts isolated from patients revealed a substantial depletion of COQ7 protein levels, indicating protein instability leading to loss of enzyme function. HPLC assay showed that fibroblasts from patients had reduced levels of CoQ10, and abnormal accumulation of the biosynthetic precursor DMQ10. Accordingly, fibroblasts from patients displayed significantly decreased oxygen consumption rates in patients, suggesting mitochondrial respiration deficiency. iPSC-derived motor neurons from patient fibroblasts showed significantly increased levels of extracellular neurofilament light protein, indicating axonal degeneration. Our findings indicate a molecular pathway involving CoQ10 biosynthesis deficiency and mitochondrial dysfunction in patients with dHMN. Further studies will be important to evaluate the potential benefits of CoQ10 supplementation in the clinical outcome of the disease.

In recent years, flip chip technology becomes more and more important with benefits of thin package profile, reduction of package outline, and excellent electrical and thermal performance by connection of copper pillar bumps (CuP) or C4 solder bumps. In order to fill the die gap to prevent voids problem, two encapsulated solutions could be applied: capillary underfill (CUF) and molded underfill (MUF). In general comparison, CUF means to dispense underfill first to fill in die gap then proceed over-molding afterward; and MUF is directly fill under and above die by mold compound. The advantages of MUF solution are low cost and high throughput, however, it will suffer other assembly issues such as solder extrusion and solder crack, and might result in potential function failure. To form these kinds of defects, we suspected that solder will plastically deform under thermal stress treatment, which comes from unbalance mold transfer pressure and material expansion stress during thermal process. In this article, we have tried to investigate the mechanism of solder crack through molding recipe DOE (Design of Experiment) and mold flow simulation. The test vehicle is 12 × 12 mm2 FCCSP, with 6 × 5 mm2 die size. The bump type is copper pillar bump and pitch/size are 126 um and 35 × 60 um2, respectively. The molding recipe has been evaluated by cross section, and it revealed that molding transfer time and molding temperature are directions toward improvement of solder crack issue.

•Foot deformities are frequently observed in Charcot-Marie-Tooth disease patients.•Surgical management is variable among centres.•During the workshop current surgical approaches were reviewed.•Recommendations for foot surgery in CMT patients were agreed by the participants.

In order to better understand the pathogenesis of demyelination in P

Anogenital distance (AGD) is a marker for endocrine disruption in animal studies in which decreased male AGD has been associated with testicular dysfunction. The objective of the study was to investigate whether anogenital distance could distinguish men with obstructive azoospermia (OA) from those with nonobstructive azoospermia (NOA). To accomplish this, azoospermic men were recruited and evaluated at a men's reproductive health clinic in Houston, TX. Anogenital distance (the distance from the posterior aspect of the scrotum to the anal verge) and penile length (PL) were measured using digital calipers. Testis size was estimated by physical examination. Logistic regression was used to compare AGD lengths in men with OA and men with NOA. A total of 69 OA men (mean age: 44.2 ± 9.2) and 29 NOA men (mean age: 32.8 ± 4.8) were recruited. The NOA men possessed significantly shorter mean AGD than the men with OA (AGD: 36.3 vs. 41.9 mm, p = 0.01). An AGD of less than 30 mm, had a 91% specificity in accurately classifying NOA. Moreover, after adjustment for age, race, and BMI, an AGD of less than 30 mm yielded a significantly increased odds of NOA compared to OA (OR 5.6, 95% CI 1.0, 30.7). In summary, AGD may provide a novel metric for assessing testicular function in men and in distinguishing OA from NOA.

Study Type--Therapy (case series) Level of Evidence 4. What's known on the subject? and What does the study add? Anogenital distance (AGD) is a marker of genital development and adult testicular function. To date, there is no data on the clinical utility of using such an anthropomorphic variable. About 30% of men will have no improvement in semen parameters after varicocele repair. It is currently difficult to assess which patients are most likely to benefit from surgical repair. The present study showed that men with a longer AGD had a higher likelihood of improvement after varicocelectomy. As such, AGD may allow clinicians to better counsel men on the efficacy of varicocele repair.• To investigate whether anogenital distance (AGD) can identify men most likely to show improved semen parameters after varicocele ligation, as AGD has been shown to correlate with intrinsic adult testicular function.• Men with varicoceles who were evaluated at a men's reproductive health clinic in Houston were recruited. • AGD (the distance from the posterior aspect of the scrotum to the anal verge) was measured using digital callipers. • Logistic regression was used to compare outcomes after stratifying men based on AGD.• In all, 46 men with a mean (sd) age of 33.1 (6.3) years with postoperative semen data were recruited. • Semen concentration, motility, and total motile sperm count all showed significant improvement postoperatively (P0.01). • While 48% of men with a shorter AGD had improvements in sperm concentration postoperatively, 84% of men with a longer AGD improved (P = 0.01). • There was a trend toward a lower percentage of men (62% vs 84%) with shorter AGDs showing improvements in total motile sperm count (P = 0.09).• AGD may provide a novel metric to assess intrinsic testicular function and predict efficacy of varicocele repair.

Classification of neuropathies into Charcot-Marie-Tooth syndrome (CMT, hereditary motor and sensory neuropathy) or purely motor neuropathies is relatively easy in single patients but subtle sensory findings can vary in different affected individuals in a family. We examined the extent of sensory involvement in different individuals in two new X-linked neuropathy syndromes (CMTX3 and dSMAX) and in some dominantly inherited mainly motor neuropathies. CMTX3 is a mild X- linked recessive CMT phenotype linked to Xq26-28. dSMAX (distal spinal muscular atrophy linked to Xq13-21). We describe a new family linked to this locus that has some sensory findings which could also be described as a motor and sensory neuropathy i.e. a form of CMT. In our dominant distal hereditary motor neuropathy (HMN) family linked to chromosome 7 (dHMN1) we also found some affected individuals with sensory signs as well as reduced sensory action potentials. In reported HMN families with known mutations in GARS, SETX, HSPB1 and HSPB8 genes and in many of our HMN families with unknown gene mutations, there is sensory involvement producing a CMT phenotype in some individuals. These disorders do not easily fit into traditional hereditary neuropathy classifications and should be recognised as CMT/HMN overlap syndromes. Recognition of overlap syndromes may assist development of more accurate gene screening paradigms.

Twelve laboratories from the United States, Canada, France, Italy and Switzerland participated in a workshop to compare assays used to measure anti-GM1 antibodies, and to discuss the clinical significance of these antibodies. A panel of test samples containing varying amounts of anti-GM1 antibody was prepared by mixing varied proportions of normal serum with a serum containing a monoclonal IgM antibody that bound GM1 ganglioside. Enzyme-linked immunosorbent assay (ELISA) data were supplied by eight laboratories and ten laboratories classified the sera as negative, weakly or strongly positive. Most laboratories correctly identified the two samples that contained the highest quantities of antibody, but there was considerable disagreement on the classification of the three samples with moderate or small amounts of antibody. The sensitivity of the assays varied considerably. The more sensitive assays did not use detergent in the washing buffers, and incubated the human serum with the antigen at 4 degrees C overnight. Several investigators have identified a subset of patients with lower motor neuron disease or multifocal neuropathy who have high titers of anti-GM1 antibodies. Many patients with neurological and non-neurological diseases have low to moderate levels of anti-GM1 antibodies, and the significance of these antibodies is unclear. There was general agreement that standardization of the ELISA assays is urgently required, and that distribution of a reference high-titered antiserum would facilitate this process.

Ten patients with neuropathy and IgM M-proteins that bind to the myelin-associated glycoprotein (MAG) were studied to determine whether the M-proteins bind to common regions of MAG and whether the reactive determinants contain carbohydrate residues. The M-protein of one patient was biotinylated, and binding to human MAG was quantitated by enzyme-linked immunosorbent assay (ELISA) by using avidin-biotin-peroxidase complexes. Serum from the same patient and nine others, but not from controls, competed with the biotinylated M-protein for binding to human MAG. Bovine MAG was digested with staph protease or cleaved with cyanogen bromide, and the resultant fragments were separated by electrophoresis and were transferred onto nitrocellulose sheets. Serum from all patients immunostained the peptide fragments identically. Bovine MAG was deglycosylated by trifluoromethanesulfonic acid, and binding of the M-proteins to MAG and to deglycosylated MAG was tested by immunoblotting. None of the patient's M-proteins bound to deglycosylated MAG. Deglycosylated MAG was visualized by using a mouse monoclonal antibody, GEN-S3, directed at the polypeptide core of MAG. The effectiveness of deglycosylation was ascertained by electrophoresis and by binding of biotinylated concanavalin A. These data and the observed identical species specificity of the M-proteins suggest that the respective anti-MAG M-proteins all bind to the same region in MAG and that the reactive determinants may contain carbohydrate moieties.