High-dose pyridoxine treatment for inherited glycosylphosphatidylinositol deficiency.

OBJECTIVE: We aimed to assess the efficacy and safety of high-dose pyridoxine treatment for seizures and its effects on development in patients with inherited glycosylphosphatidylinositol deficiencies (IGDs). METHODS: In this prospective open-label multicenter pilot study, we enrolled patients diagnosed with IGDs using flow cytometry and/or genetic tests. The patients received oral pyridoxine (20-30 mg/kg/day) for 1 year, in addition to previous treatment. RESULTS: All nine enrolled patients (mean age: 66.3 ± 44.3 months) exhibited marked decreases in levels of CD16, a glycosylphosphatidylinositol-anchored protein, on blood granulocytes. The underlying genetic causes of IGDs were PIGO, PIGL, and unknown gene mutations in two, two, and five patients, respectively. Six patients experienced seizures, while all patients presented with developmental delay (mean developmental age: 11.1 ± 8.1 months). Seizure frequencies were markedly (>50%) and drastically (>90%) reduced in three and one patients who experienced seizures, respectively. None of the patients presented with seizure exacerbation. Eight of nine patients exhibited modest improvements in development (P = 0.14). No adverse events were observed except for mild transient diarrhea in one patient. CONCLUSION: One year of daily high-dose pyridoxine treatment was effective in the treatment of seizures in more than half of our patients with IGDs and modestly improved development in the majority of them. Moreover, such treatment was reasonably safe. These findings indicate that high-dose pyridoxine treatment may be effective against seizures in patients with IGDs, although further studies are required to confirm our findings. (University Hospital Medical Information Network Clinical Trials Registry [UMIN-CTR] number: UMIN000024185.).

Null mutation in PGAP1 impairing Gpi-anchor maturation in patients with intellectual disability and encephalopathy.

Many eukaryotic cell-surface proteins are anchored to the membrane via glycosylphosphatidylinositol (GPI). There are at least 26 genes involved in biosynthesis and remodeling of GPI anchors. Hypomorphic coding mutations in seven of these genes have been reported to cause decreased expression of GPI anchored proteins (GPI-APs) on the cell surface and to cause autosomal-recessive forms of intellectual disability (ARID). We performed homozygosity mapping and exome sequencing in a family with encephalopathy and non-specific ARID and identified a homozygous 3 bp deletion (p.Leu197del) in the GPI remodeling gene PGAP1. PGAP1 was not described in association with a human phenotype before. PGAP1 is a deacylase that removes an acyl-chain from the inositol of GPI anchors in the endoplasmic reticulum immediately after attachment of GPI to proteins. In silico prediction and molecular modeling strongly suggested a pathogenic effect of the identified deletion. The expression levels of GPI-APs on B lymphoblastoid cells derived from an affected person were normal. However, when those cells were incubated with phosphatidylinositol-specific phospholipase C (PI-PLC), GPI-APs were cleaved and released from B lymphoblastoid cells from healthy individuals whereas GPI-APs on the cells from the affected person were totally resistant. Transfection with wild type PGAP1 cDNA restored the PI-PLC sensitivity. These results indicate that GPI-APs were expressed with abnormal GPI structure due to a null mutation in the remodeling gene PGAP1. Our results add PGAP1 to the growing list of GPI abnormalities and indicate that not only the cell surface expression levels of GPI-APs but also the fine structure of GPI-anchors is important for the normal neurological development.

A comparative study on compositional changes and Knoop hardness measurement of the cavity floor prepared by Er:YAG laser irradiation and mechanical bur cavity.

OBJECTIVE: This present study was performed to compare the compositional changes of human dentin and, Knoop hardness of the cavity floor prepared by Er:YAG laser irradiation with that of the conventional bur cavity. BACKGROUND DATA: There are still no reports on the compositional changes of dental hard tissues and microhardness of the cavity floor prepared by Er:YAG laser irradiation. MATERIALS AND METHODS: Fifteen laser and 15 bur cavities were cross-sectioned, and subjected to atomic analysis by SEM-EDX and Knoop hardness testing. Statistical analyses were performed using the Mann-Whitney U test; a value of p < 0.01 was considered significant. Cross sections of the remaining five laser and five bur cavities were examined by light microscopy and then by SEM. RESULTS: The results showed that the quantities of Ca (Ca weight %) and P (P weight %) were increased significantly in the laser cavities, but no significant differences were found between the Ca/P ratio and Knoop hardness number of laser and bur cavities. The results of SEM observation revealed that the lased cavity surface was irregular, and there was also the absence of a smear layer; the orifice of dentinal tubules was exposed. CONCLUSION: Er:YAG laser device produces minimal thermal induced changes of dental hard tissue compositions; Ca/P ratio and Knoop hardness of the lased cavity floor was almost similar to the bur cavities.

Compositional and structural changes of human dentin following caries removal by Er,Cr:YSGG laser irradiation in primary teeth.

In this in vitro study, the compositional and structural changes of human dentin, and knoop harness of cavity floor following the removal of dental caries by Er,Cr:YSGG laser irradiation in primary teeth was compared with that of the conventional bur cavity. The results confirmed that laser irradiation revealed minimal thermal damage to the surrounding tissues, minimal thermal induced changes of dental hard tissue compositions, and favorable surface characteristic.

Microleakage of composite resin restoration in cavities prepared by Er,Cr:YSGG laser irradiation and etched bur cavities in primary teeth.

In this in vitro study, the surface alterations of enamel and dentin in cavities prepared by Er,Cr:YSGG laser irradiation was investigated by scanning electron microscopy and compared to the microleakage degree after composite resin restoration with etched bur cavities in human primary teeth. The results confirmed that laser cavity surface facilitated a good adhesion with the restorative materials; the acid etch step can be easily avoided with the laser treatment.