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

Physicians have become accustomed to thinking of certain inborn errors of metabolism (e.g., 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 metabolic defect is expressed in the cytosol, endoplasmic reticulum, and Golgi apparatus. These could be conveniently thought of as "prelysosomal" disorders. At least six of these entities are characterized by hypoglycosylation of many glycoconjugates, and have been designated as the carbohydrate-deficient glycoprotein syndromes. Given the ubiquity of the products of N-glycosylation in the cellular economy, it is not surprising that these defects in metabolism 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 features or cerebellar hypoplasia, attesting to the antenatal expression of these disorders. The most frequently recognized phenotype (several hundred cases worldwide) has been designated carbohydrate-deficient glycoprotein syndrome type la, and results from mutations in phosphomannomutase, a cytosolic enzyme involved in the synthesis of the lipid-linked oligosaccharide that is eventually attached to nascent glycoproteins through the amide group of asparagine residues. All forms of carbohydrate-deficient glycoprotein syndrome express an excess of hypoglycosylated isoforms of circulating transferrin, which serves as a useful screening tool. Physicians should consider screening for carbohydrate-deficient glycoprotein syndrome in individuals with delayed development, seizures, strokelike episodes, cerebellar hypoplasia, and demyelinating neuropathy with or without other signs of multisystem disease.