Carbohydrate-deficient glycoprotein syndrome type 1 (CDG1 or Jaeken syndrome) is the prototype of a class of genetic multisystem disorders characterized by defective glycosylation of glycoconjugates. It is mostly a severe disorder which presents neonatally. There is a severe encephalopathy with axial hypotonia, abnormal eye movements and pronounced psychomotor retardation, as well as a peripheral neuropathy, cerebellar hypoplasia and retinitis pigmentosa. The patients show a peculiar distribution of subcutaneous fat, nipple retraction and hypogonadism. There is a 20% lethality in the first years of life due to severe infections, liver insufficiency or cardiomyopathy. CDG1 shows an autosomal recessive mode of inheritance and has been mapped to chromosome 16p. Most patients show a deficiency of phosphomannomutase (PMM)8, an enzyme necessary for the synthesis of GDP-mannose. We have cloned the PMM1 gene, which is on chromosome 22q13 (ref.9). We now report the identification of a second human PMM gene, PMM2, which is located on 16p13 and which encodes a protein with 66% identity to PMM1. We found eleven different missense mutations in PMM2 in 16 CDG1 patients from different geographical origins and with a documented phosphomannomutase deficiency. Our results give conclusive support to the biochemical finding that the phosphomannomutase deficiency is the basis for CDG1.

We report the sequence of a human cDNA that encodes a 46 kDa transmembrane protein homologous to bacterial transporters for phosphate esters. This protein presents at its carboxy terminus the consensus motif for retention in the endoplasmic reticulum. Northern blots of rat tissues indicate that the corresponding mRNA is mostly expressed in liver and kidney. In two patients with glycogen storage disease type lb, mutations were observed that either replaced a conserved Gly to Cys or introduced a premature stop codon. The encoded protein is therefore most likely the glucose 6-phosphate translocase that is functionally associated with glucose-6-phosphatase.

Neutropenia and neutrophil dysfunction cause serious infections and inflammatory bowel disease in glycogen storage disease Ib (GSD-Ib). Our discovery that accumulating 1,5-anhydroglucitol-6-phosphate causes neutropenia in a G6PC3-deficient mouse model and in the two rare diseases (GSD-Ib and G6PC3-deficiency) led us to repurpose the widely used antidiabetic drug empagliflozin, an inhibitor of the renal glucose co-transporter SGLT2. Off-label use of empagliflozin in four GSD-Ib patients with incomplete response to granulocyte colony stimulating factor (GCSF) treatment decreased serum 1,5-anhydroglucitol and neutrophil 1,5-anhydroglucitol-6-phosphate levels within one month. Clinically, symptoms of frequent infections, mucosal lesions, and inflammatory bowel disease resolved, and no symptomatic hypoglycemia was observed. GCSF could be discontinued in two patients and tapered down - by 57 and 81%, respectively - in the other two. The fluctuating neutrophil numbers in all patients were increased and stabilized. We further show the improved neutrophil function: we show a normal oxidative burst (in three of three patients tested, 3/3), a corrected protein glycosylation (2/2), as well as a normal neutrophil chemotaxis (1/1), and bactericidal activity (1/1) under treatment. In conclusion, the glucose lowering drug empagliflozin, used for the frequent and acquired disease type 2 diabetes, was successfully repurposed for treating neutropenia and neutrophil dysfunction in the rare inherited metabolic disorder GSD-Ib without causing symptomatic hypoglycemia. We ascribe this to an improvement of the neutrophil function due to the reduction of the intracellular concentration of 1,5-anhydroglucitol-6-phosphate.