OBJECTIVETo describe a patient with a multifocal demyelinating motor neuropathy with onset in childhood and a mutation in phosphatase and tensin homolog (PTEN), a tumor suppressor gene associated ...with inherited tumor susceptibility conditions, macrocephaly, autism, ataxia, tremor, and epilepsy. Functional implications of this protein have been investigated in Parkinson and Alzheimer diseases.
METHODSWe performed whole-exome sequencing in the patientʼs genomic DNA validated by Sanger sequencing. Immunoblotting, in vitro enzymatic assay, and label-free shotgun proteomic profiling were performed in the patientʼs fibroblasts.
RESULTSThe predominant clinical presentation of the patient was a childhood onset, asymmetric progressive multifocal motor neuropathy. In addition, he presented with macrocephaly, autism spectrum disorder, and skin hamartomas, considered as clinical criteria for PTEN-related hamartoma tumor syndrome. Extensive tumor screening did not detect any malignancies. We detected a novel de novo heterozygous c.269T>C, p.(Phe90Ser) PTEN variant, which was absent in both parents. The pathogenicity of the variant is supported by altered expression of several PTEN-associated proteins involved in tumorigenesis. Moreover, fibroblasts showed a defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4-trisphosphate. In support of our findings, focal hypermyelination leading to peripheral neuropathy has been reported in PTEN-deficient mice.
CONCLUSIONWe describe a novel phenotype, PTEN-associated multifocal demyelinating motor neuropathy with a skin hamartoma syndrome. A similar mechanism may potentially underlie other forms of Charcot-Marie-Tooth disease with involvement of the phosphatidylinositol pathway.
Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy leading to severe metabolic disturbances in infants, which recover spontaneously after 6‐months of age. ...RIRCD is associated with the homoplasmic m.14674T>C mitochondrial DNA mutation; however, only ~ 1/100 carriers develop the disease. We studied 27 affected and 15 unaffected individuals from 19 families and found additional heterozygous mutations in nuclear genes interacting with mt‐tRNAGlu including EARS2 and TRMU in the majority of affected individuals, but not in healthy carriers of m.14674T>C, supporting a digenic inheritance. Our transcriptomic and proteomic analysis of patient muscle suggests a stepwise mechanism where first, the integrated stress response associated with increased FGF21 and GDF15 expression enhances the metabolism modulated by serine biosynthesis, one carbon metabolism, TCA lipid oxidation and amino acid availability, while in the second step mTOR activation leads to increased mitochondrial biogenesis. Our data suggest that the spontaneous recovery in infants with digenic mutations may be modulated by the above described changes. Similar mechanisms may explain the variable penetrance and tissue specificity of other mtDNA mutations and highlight the potential role of amino acids in improving mitochondrial disease.
Synopsis
Reversible infantile respiratory chain deficiency (RIRCD) is a rare mitochondrial myopathy associated with homoplasmic mutation in mt‐tRNAGlu. Heterozygous mutations in nuclear genes interacting with mt‐tRNAGlu induce the integrated stress response (ISR) and metabolic rearrangements that reduce penetrance and promote spontaneous RIRCD recovery in infants.
Nuclear gene variants that affect glutamate/glutamine metabolism or mt‐tRNAGlu aminoacylation contribute to manifestation of RIRCD, when co‐occurring with the mtDNA m.14674T>C variant.
Analysis of diseased muscles reveals that recovery from RIRCD occurs in a stepwise manner in infants.
During phase one, ISR signaling increases FGF21 and GDF15 expression and enhances lipid and amino acid metabolism.
In a second phase, patients present activation of mTOR, leading to increased mitochondrial biogenesis.
ISR and increased mitochondria number facilitate a metabolic shift that improves amino acid availability and contribute to the spontaneous recovery in phase three.
Heterozygous mutations in nuclear genes interacting with mt‐tRNAGlu induce the integrated stress response and metabolic rearrangements, reducing penetrance and promoting spontaneous recovery in a rare mitochondrial myopathy.
Bacterial DNA activates mouse macrophages, B cells, and dendritic cells in a TLR9-dependent manner. Although short ssCpG-containing phosphodiester oligonucleotides (PO-ODN) can mimic the action of ...bacterial DNA on macrophages, they are much less immunostimulatory than Escherichia coli DNA. In this study we have assessed the structural differences between E. coli DNA and PO-ODN, which may explain the high activity of bacterial DNA on macrophages. DNA length was found to be the most important variable. Double-strandedness was not responsible for the increased activity of long DNA. DNA adenine methyltransferase (Dam) and DNA cytosine methyltransferase (Dcm) methylation of E. coli DNA did not enhance macrophage NO production. The presence of two CpG motifs on one molecule only marginally improved activity at low concentration, suggesting that ligand-mediated TLR9 cross-linking was not involved. The major contribution was from DNA length. Synthetic ODN >44 nt attained the same levels of activity as bacterial DNA. The response of macrophages to CpG DNA requires endocytic uptake. The length dependence of the CpG ODN response was found to correlate with the presence in macrophages of a length-dependent uptake process for DNA. This transport system was absent from B cells and fibroblasts.
Intra-articular synovial sarcoma Friedman, Michael V.; Kyriakos, Michael; Matava, Matthew J. ...
Skeletal radiology,
06/2013, Letnik:
42, Številka:
6
Journal Article
Recenzirano
A case of right knee intra-articular synovial sarcoma in a 26-year-old man is reported. The patient had experienced 12 to 18 months of chronic posterior right knee pain with flexion contracture of ...the leg. Magnetic resonance imaging (MRI) examination demonstrated nonspecific characteristics of a well-circumscribed, homogeneous mass within the posterior lateral compartment of the knee joint. The mass was isointense and hyperintense to muscle on T1- and T2-weighted sequences respectively, and initially clinically diagnosed as a localized tenosynovial giant cell tumor. However, histological examination showed the lesion to be a synovial sarcoma arising from the synovium of the knee joint. Synovial sarcoma may have a nonspecific MR appearance, especially when less than 5 cm in size, often simulating a less aggressive process. Primary intra-articular origin may predispose to earlier presentation, and therefore, radiological evaluation of smaller masses. Nonspecific MR characteristics of small, intra-articular masses provide a diagnostic dilemma. Synovial sarcoma should be considered in the differential diagnosis when distinguishing MR characteristics of other common joint-centered entities are not present.
This resource presents a step-by-step, four-phase model for developing effective prereferral intervention teams and presents methods for evaluating the effectiveness of a prereferral intervention ...program.
Background Hemodialysis access by autogenous arteriovenous fistulas (AVFs) is generally recommended due to lower mortality, morbidity, and cost vs graft and catheter use. Many dialysis patients lack ...the common superficial veins used for standard AVF options and require transposition of a deep vein for autogenous dialysis access through a long open incision (open/AVF-T). These operations may require prolonged time for healing, thus extending catheter-based dialysis. We report our experience with minimally invasive techniques for creating AVF-Ts using an endoscopic procedure (endo/AVF-T). Methods We reviewed our vascular access database of consecutive access operations to identify consecutive patients with endo/AVF-Ts. For comparison, we also reviewed the immediate preceding traditional open/AVF-T operations that we previously reported. We evaluated demographics, time to access use, and primary, assisted, and cumulative patency. Results We identified 100 consecutive endo/AVF-T operations attempted, and 98 were technically successful. The analysis excluded two conversions to successful open/AVF-T. The mean age of the 98 patients in the endo/AVF-T study group was 60 years (range, 22-94 years), 59 (60.2%) were women, 48 (49.0%) were diabetic, 20 (20.4%) were obese, and 52 (53.1%) had had previous access surgery. Mean time to initial use of the access for endo/AVF-Ts was 6 weeks for primary and 12 weeks for staged transpositions. Mean follow-up was 14 months (range, 1-30 months). The 12- and 24-month cumulative patencies were 95.5% and 88.6%. The 78 traditional open/AVF-T operations from our previous report were reviewed for comparison. The mean age was 62 years (range, 18-83 years), 57 (73.1%) were women, 44 (56.4%) were diabetic, 15 (19.2%) were obese, and 46 (59.0%) had previous access surgery. Mean time to initial use of the access for open/AVF-Ts was 8 weeks for primary and 16 weeks for staged operations. Mean follow-up was 18 months (range, 3-48 months). The 12- and 24-month cumulative patencies were 96.0 and 88.9%. No grafts were used in any patient during the study period. Conclusion Time to access use was less with endoscopic AVF-T ( P < .01) for both primary and staged operations. Primary, assisted, and cumulative patency rates were the same for open and technically successful endoscopic transpositions. Endoscopic AVF-Ts offer a viable alternative to open AVF-Ts.
PDF
