Carbohydrate-deficient glycoprotein (CDG) syndromes are genetic diseases that are due to defects in the glycosylation of glycoproteins (Jaeken et al. 1993, 1997b). With one exception (Billette de Villemeur et al. 1995), all reported patients presented moderate to severe brain disease (Jaeken and Casaer 1997). The diagnosis is usually made by isoelectrofocusing of serum transferrin showing different patterns of cathodal shift due to the deficiency of the terminal sialic acid (Jaeken et al. 1984; Stibler and Jaeken 1990). The majority of patients show the so-called type I pattern characterized by an increase of di-and asialotransferrin. About 70% of patients with the type I pattern have a deficiency of phosphomannomutase (PMM)(type IA)(Van Schaftingen and Jaeken 1995; Jaeken et al. 1997a), the enzyme catalyzing the second step in the conversion of fructose 6-phosphate to GDP-mannose (fig. 1), and mutations in the PMM2 gene have been found in all patients with a PMM deficiency (Matthijs et al. 1997a, 1998). Among the patients from which we analyzed the fibroblasts (Van Schaftingen and Jaeken 1995; Jaeken et al. 1997a; Matthijs et al. 1997b),∼ 30 did not show PMM deficiency. On the rationale that type I glycosylation pattern may be due to other enzymatic defects in the pathway leading to GDP-mannose, the activity of phosphomannose isomerase, which catalyzes its first step, was systematically analyzed in the samples from the latter patients. As shown in table 1, three of them showed a marked deficiency in this enzyme, whereas PMM activity was normal. Experiments in which extracts were mixed indicated that the deficiency was not due to the presence of an inhibitor. As reported elsewhere (Van Schaftingen and Jaeken 1995), PMI activity was normal in PMM-deficient patients. For patient C, the PMI deficiency was independently found at about the same time by other investigators (Niehues et al., 1998). This patient, who had a similar liver disease associated with protein-losing enteropathy (Freeze et al. 1997; Niehues et al., 1998) as patient A (see below) was not further investigated in the present study. The parents of patient B, but not of patient A, were available for testing; surprisingly, normal activities of PMI were found