Novel missense variants cause intermediate phenotypes in the phenotypic spectrum of SLC5A6-related disorders.

SLC5A6 encodes the sodium-dependent multivitamin transporter, a transmembrane protein that uptakes biotin, pantothenic acid, and lipoic acid. Biallelic SLC5A6 variants cause sodium-dependent multivitamin transporter deficiency (SMVTD) and childhood-onset biotin-responsive peripheral motor neuropathy (COMNB), which both respond well to replacement therapy with the above three nutrients. SMVTD usually presents with various symptoms in multiple organs, such as gastrointestinal hemorrhage, brain atrophy, and global developmental delay, at birth or in infancy. Without nutrient replacement therapy, SMVTD can be lethal in early childhood. COMNB is clinically milder and has a later onset than SMVTD, at approximately 10 years of age. COMNB symptoms are mostly limited to peripheral motor neuropathy. Here we report three patients from one Japanese family harboring novel compound heterozygous missense variants in SLC5A6, namely NM_021095.4:c.[221C>T];[642G>C] p.[(Ser74Phe)];[(Gln214His)]. Both variants were predicted to be deleterious through multiple lines of evidence, including amino acid conservation, in silico predictions of pathogenicity, and protein structure considerations. Drosophila analysis also showed c.221C>T to be pathogenic. All three patients had congenital brain cysts on neonatal cranial imaging, but no other morphological abnormalities. They also had a mild motor developmental delay that almost completely resolved despite no treatment. In terms of severity, their phenotypes were intermediate between SMVTD and COMNB. From these findings we propose a new SLC5A6-related disorder, spontaneously remitting developmental delay with brain cysts (SRDDBC) whose phenotypic severity is between that of SMVTD and COMNB. Further clinical and genetic evidence is needed to support our suggestion.

[A case of pulmonary aspergilloma successfully treated with transbronchial intracavitary itraconazole].

A 74-year-old woman given a diagnosis of chronic necrotizing pulmonary aspergillosis in February, 2007 was treated by intravenous voriconazole (VRCZ) and her conditions improved. Then it was switched to oral VRCZ and continued treatment. However, a fungus ball remained, and (1-3)-beta-D-glucan values increased, which had previously been within normal limit. Therefore transbronchial intracavitary itraconazole therapy was performed twice a week, for a total of 9 times (715 mg) from June, 2007. The fungus ball disappeared at the time of the fourth injection, and (1-3)-beta-D-glucan values decreased gradually. Intravenous ITCZ was administered for two weeks from July, 2007, after which it was switched to oral ITCZ 400 mg/day and treatment was continued without recurrence. Though intracavitary ITCZ therapy caused temporary fever and elevation of CRP, we were able to perform the treatment safely and confirm the elevation of enough serum ITCZ concentrations. This is the first case of pulmonary aspergilloma successfully and safely treated with transbronchial intracavitary itraconazole.