Screening for "prelysosomal disorders": Carbohydrate-deficient glycoprotein syndromes

Physicians have become accustomed to thinking of certain inborn errors of m etabolism (eg, lysosomal, peroxisomal, and mitochondrial diseases) as being associated with specific subcellular organelles. In recent years, a family of disorders of N-glycosylation has been recognized, in which the metaboli c defect is expressed in the cytosol, endoplasmic reticulum, and Golgi appa ratus. These could be conveniently thought of as "prelysosomal" disorders. At least six of these entities are characterized by hypoglycosylation of ma ny glycoconjugates, and have been designated as the carbohydrate-deficient glycoprotein syndromes. Given the ubiquity of the products of N-glycosylati on in the cellular economy, it is not surprising that these defects in meta bolism have protean clinical manifestations. Delayed development and other neurologic symptoms are wedded to variable dysfunctions of the heart, liver , and endocrine and coagulation systems. Patients can have dysmorphic featu res or cerebellar hypoplasia, attesting to the antenatal expression of thes e disorders. The most frequently recognized phenotype (several hundred case s worldwide) has been designated carbohydrate-deficient glycoprotein syndro me type la, and results from mutations in phosphomannomutase, a cytosolic e nzyme involved in the synthesis of the lipid-linked oligosaccharide that is eventually attached to nascent glycoproteins through the amide group of as paragine residues. All forms of carbohydrate-deficient glycoprotein syndrom e express an excess of hypoglycosylated isoforms of circulating transferrin , which serves as a useful screening tool. Physicians should consider scree ning for carbohydrate-deficient glycoprotein syndrome in individuals with d elayed development, seizures, strokelike episodes, cerebellar hypoplasia, a nd demyelinating neuropathy with or without other signs of multisystem dise ase.