The subcellular distribution of alpha-tocopherol has been studied in rat liver. Lysosomal membranes were found to be considerably enriched in alpha-tocopherol with 6300 pmol/mg membrane protein, whereas mitochondrial membranes and microsomes contained 530 and 200 pmol/mg membrane protein, respectively. The 37-fold higher specific content of alpha-tocopherol in lysosomal membranes relative to homogenate indicates that lysosomes could be a target of cellular pathology in vitamin E deficiency states.
Morquio disease (MPS IVA) is an autosomal recessive disorder caused by a deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) activity. Patients commonly present in early infancy with growth failure, spondyloepiphyseal dysplasia, corneal opacification, and keratan sulfaturia, but milder forms have been described. We report on a patient who grew normally until age 5 years. Her keratan sulfaturia was not detected until adolescence, and she now has changes restricted largely to the axial skeleton. She has experienced only mildly impaired vision. At age 22, thin-layer chromatography of purified glycosaminoglycans showed some keratan sulfaturia. GALNS activity in fibroblast homogenate supernatants was 20 +/- 5% of controls (as compared to 5 +/- 3% of controls in severe MPS IVA, P < .003). Kinetic analysis of residual fibroblast GALNS activity in patient and parents revealed decreased K(m) and increased Vmax in the mother and daughter, but not in the father, compatible with compound heterozygosity. GALNS exons were amplified from patient genomic DNA and screened by SSCP. Two missense mutations, a C to T transition at position 335 (predicting R94C) and a T to G transversion at position 344 (predicting F97V), were found on sequencing an abnormally migrating exon 3 amplicon. Digestion of the amplicon with FokI and AccI restriction enzymes (specific for the R94C and F97V mutations, respectively) confirmed heterozygosity. In fibroblast transfection experiments, heterozygous R94C and F97V mutants independently expressed as severe and mild GALNS deficiency, respectively. We interpret these findings to indicate that our patient bears heteroallelic GALNS missense mutations, leading to GALNS deficiency and mild MPS IVA. Our findings expand the clinical and biochemical phenotype of MPS IVA, but full delineation of the genotype-phenotype relationship requires further study of native and transfected mutant cell lines.
Introduction: Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory process that has been linked to abnormal cytotoxic T-cell and natural killer (NK) cell function. We report on the first case of severe combined immunodeficiency (SCID) caused by a CD3δ mutation presenting with HLH in a female of Mennonite descent.
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