Fabry disease results from deficient alpha-galactosidase A (alpha-Gal A) activity and the pathologic accumulation of the globotriaosylceramide (GL-3) and related glycosphingolipids, primarily in vascular endothelial lysosomes. Treatment is currently palliative, and affected patients generally die in their 40s or 50s. Preclinical studies of recombinant human alpha-Gal A (r-halphaGalA) infusions in knockout mice demonstrated reduction of GL-3 in tissues and plasma, providing rationale for a phase 1/2 clinical trial. Here, we report a single-center, open-label, dose-ranging study of r-halphaGalA treatment in 15 patients, each of whom received five infusions at one of five dose regimens. Intravenously administered r-halphaGalA was cleared from the circulation in a dose-dependent manner, via both saturable and non-saturable pathways. Rapid and marked reductions in plasma and tissue GL-3 were observed biochemically, histologically, and/or ultrastructurally. Clearance of plasma GL-3 was dose-dependent. In patients with pre- and posttreatment biopsies, mean GL-3 content decreased 84% in liver (n=13), was markedly reduced in kidney in four of five patients, and after five doses was modestly lowered in the endomyocardium of four of seven patients. GL-3 deposits were cleared to near normal or were markedly reduced in the vascular endothelium of liver, skin, heart, and kidney, on the basis of light- and electron-microscopic evaluation. In addition, patients reported less pain, increased ability to sweat, and improved quality-of-life measures. Infusions were well tolerated; four patients experienced mild-to-moderate reactions, suggestive of hypersensitivity, that were managed conservatively. Of 15 patients, 8 (53%) developed IgG antibodies to r-halphaGalA; however, the antibodies were not neutralizing, as indicated by unchanged pharmacokinetic values for infusions 1 and 5. This study provides the basis for a phase 3 trial of enzyme-replacement therapy for Fabry disease.
Juvenile hyaline fibromatosis (JHF) and infantile systemic hyalinosis (ISH) are autosomal recessive syndromes of unknown etiology characterized by multiple, recurring subcutaneous tumors, gingival hypertrophy, joint contractures, osteolysis, and osteoporosis. Both are believed to be allelic disorders; ISH is distinguished from JHF by its more severe phenotype, which includes hyaline deposits in multiple organs, recurrent infections, and death within the first 2 years of life. Using the previously reported chromosome 4q21 JHF disease locus as a guide for candidate-gene identification, we identified and characterized JHF and ISH disease-causing mutations in the capillary morphogenesis factor-2 gene (CMG2). Although CMG2 encodes a protein upregulated in endothelial cells during capillary formation and was recently shown to function as an anthrax-toxin receptor, its physiologic role is unclear. Two ISH family-specific truncating mutations, E220X and the 1-bp insertion P357insC that results in translation of an out-of-frame stop codon, were generated by site-directed mutagenesis and were shown to delete the CMG-2 transmembrane and/or cytosolic domains, respectively. An ISH compound mutation, I189T, is predicted to create a novel and destabilizing internal cavity within the protein. The JHF family-specific homoallelic missense mutation G105D destabilizes a von Willebrand factor A extracellular domain alpha-helix, whereas the other mutation, L329R, occurs within the transmembrane domain of the protein. Finally, and possibly providing insight into the pathophysiology of these diseases, analysis of fibroblasts derived from patients with JHF or ISH suggests that CMG2 mutations abrogate normal cell interactions with the extracellular matrix.
The manifestations of many congenital and acquired conditions can be seen in the ribs of children. Normal variants are usually clinically insignificant; they are occasionally palpated at clinical examination or detected incidentally at chest radiography. Signs of abnormality can appear in the ribs as variations in number, size, mineralization, and shape. These changes can be focal or generalized. Abnormalities detected in the ribs may be the initial indication of previously unsuspected systemic disease. The ribs can yield important diagnostic clues in the work-up of patients with congenital bone dysplasias, acquired metabolic diseases, iatrogenic conditions, trauma (especially child abuse), infection, and neoplasms. Routine evaluation of the ribs on every chest radiograph is important so that valuable diagnostic data will not be overlooked. The diagnostic information obtained from evaluation of the ribs can help tailor the radiologic and laboratory studies that may be necessary to complete a patient's diagnostic work-up.
The art of interpreting skull radiographs is slowly being lost as trainees in radiology see fewer plain radiographs and depend more heavily on computed tomography and magnetic resonance imaging. Nevertheless, skull radiographs still provide significant information that is helpful in finding pathologic conditions and appreciating their extents. Abnormalities in the skull may be reflected as variations in the density, size, and shape of the skull, as well as skull defects. Skeletal dysplasias may manifest as a generalized decrease in calvarial density (hypophosphatasia, osteogenesis imperfecta), a generalized increase in calvarial density (osteopetrosis), or a focal increase in density (frontometaphyseal dysplasia). Diffusely decreased or increased calvarial density is usually associated with a process that affects the entire skeleton. Therefore, correct differentiation among these dysplasias depends on other concurrent features. Decreased size of the cranial vault at birth generally implies an underlying insult to the brain, including fetal alcohol syndrome and the so-called TORCH infections (toxoplasmosis, rubella, cytomegalovirus infection, herpes simplex). Macrocephaly may result from skeletal dysplasia or an increase in the intracranial volume (eg, due to underlying anomalies of the brain such as hydrocephalus).
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