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Journal of Pediatric Gastroenterology & Nutrition:
Selected Summaries

New Diagnosis and Treatment of Congenital Hepatic Fibrosis

Freeze, Hudson H.

Section Editor(s): Braegger, Christian M.D.; Büller, Hans M.D.; Thomas, Adrian M.D.; Bishop, Warren P. M.D.; Haber, Barbara Anne M.D.; Lichtman, Steven N. M.D.; Shneider, Benjamin L. M.D.

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Author Information

ESPGHAN (Braegger, Büller, Thomas); NASPGN (Bishop, Haber, Lichtman, Shneider)

The Burnham Institute; 10901 North Torrey Pines Road; La Jolla, CA 92037, U.S.A.

A Novel Disorder of N-Glycosylation Due to Phosphomannose Isomerase Deficiency. de Koning TJ, Dorland L, van Diggelen OP, Boonman AMC, de Jong GJ, van Noort WL, De Schryver J, et al. Biochem Biophys Res Commun 1998;245:38-42.

Phosphomannose Isomerase Deficiency: A Carbohydrate-Deficient Glycoprotein Syndrome with Hepatic-Intestinal Presentation. Jaeken J, Matthijs G, Saudubray J-M, Dionisi-Visi C, Bertini E, de Lonlay P, Henri H, et al. Am J Hum Genet 1998;62:1535-9.

Summary: In these two articles, the authors identify a deficiency in protein N-glycosylation as the cause of congenital hepatic fibrosis that can also be associated with hypoalbuminemia, protein-losing enteropathy, and hypoglycemia. In another article (J Clin Invest 1998;101:1414-20), a simple, effective treatment of these inherited disorders is described. In the first article, three teenaged siblings had recurrent bouts of vomiting and diarrhea with persistently low serum albumin. All had elevated aminotransaminases during the episodes. Biopsy specimens in one of the patients showed histologic features of congenital hepatic fibrosis. Mental and psychomotor development were normal, and none of the patients showed dysmorphic features. The second article describes one patient, a boy, who had chronic diarrhea, hypoglycemia, histologic features of congenital hepatic fibrosis and protein-losing enteropathy with decreased levels of factor XI, antithrombin III, protein C, and protein S. Duodenal specimens revealed partial villous atrophy, and he had frequent episodes of bacterial and viral gastroenteritis. Gross motor development was mildly retarded. He died at 4 years of age of unknown causes.

In all these patients, isoelectric focusing (IEF) analysis of serum transferrin showed increased asialotransferrin and disialotransferrin, which are indicators of insufficient N-glycosylation. Direct compositional analysis confirmed the absence of sugar chains from some transferrin molecules. Identical abnormal transferrin patterns are also seen in patients with carbohydrate-deficient glycoprotein Syndrome (CDGS) type I, but these patients have severe psychomotor and mental retardation. Phosphomannomutase (PMM, mannose-6-P←→mannose-1-P) is deficient in these patients with CDGS type Ia, but the activity of this enzyme was normal in the cases described in these articles. The absence of sugar chains in transferrin suggest that a defect in the early portion of the glycosylation pathway was responsible for the altered transferrin. In vitro assay of leukocytes, fibroblasts, and liver tissue from the three siblings showed a deficiency in phosphomannose isomerase (PMI, fructose-6-P←→mannose-6-P). The same deficiency was seen in the patient described in the second article. In addition, Jaeken et al. identified two mutations in the human PMI gene that changed key conserved amino acids near the active site of the enzyme. Determination of PMI deficiency establishes a novel glycosylation disorder, CDGS type Ib. It is biochemically indistinguishable from CDGS type Ia, but the clinical presentation is entirely different.

Comment: Congenital hepatic fibrosis (CHF) is a rare recessive condition characterized by hepatomegaly and portal hypertension and is often associated with polycystic kidney disease. Fibrous tissue is seen linking portal tracts with multiple bile ducts. The underlying defects of this idiopathic disorder have remained unknown, but these studies show that PMI deficiency can now be considered to be one cause of CHF. The disorder is readily diagnosed using the serum transferrin IEF test. Most important, CHF is eminently treatable with simple dietary supplements of mannose (J Clin Invest 1998;101:1414-20).

In addition to these articles, assorted abstracts (J Inherit Metab Dis 1998;21:96-7) and emerging unpublished data describe a group of patients with similar and overlapping clinical features that include one or more of the following: elevated transaminases, hepatomegaly, fibrosis of the portal areas, mild ductal plate malformation, episodes of severe liver failure, Caroli syndrome, thromboses, reduced coagulation factors, and hypoalbuminemia. In addition, they have hypoglycemia, severe gastrointestinal involvement with chronic diarrhea, severe cyclic vomiting, and protein-losing enteropathy. Findings in neurologic examinations are mostly normal, and there is little, if any, cognitive deficiency.

These complex multisystemic lesions all result from defective protein glycosylation that is easily detected using transferrin as an indicator. In most cases, thrombosis and reduced levels of liver-derived serum glycoproteins prompt serum transferrin IEF analysis. Normally, transferrin has two N-linked sugar chains, each with two negatively charged sialic acids, producing tetrasialotransferrin. Absence of one or both oligosaccharide chains leads to molecules with only 2- or 0-sialic acids-that is, disialotransferrin or asialotransferrin, respectively. Many other glycoproteins are affected similarly and have unoccupied glycosylation sites. The powerful but underused IEF test is the first step in detecting PMI deficiency, which is then confirmed by direct PMI assay in leukocytes.

Phosphomannose isomerase converts fructose-6-P to mannose-6-P, which is eventually converted into guanosine diphosphate-mannose and dolichol-P-mannose, the immediate precursors of mannose-based glycosylation found in every cell. PMI links glucose metabolism (glycolysis) to protein glycosylation, but mannose-6-P can also be formed directly from mannose by hexokinase. Mannose is delivered from the blood to cells through a high-affinity, mannose-specific, facilitated diffusion transporter that is insensitive to normal glucose concentrations (J Biol Chem 1996;271:9417-21). (The mannose transporter should not be confused with the mannose-6-P/insulin-like growth factor-II receptor that binds mannose-6-P-containing glycoproteins.) Protein glycosylation in cultured cells preferentially uses mannose delivered through the facilitated diffusion transporter over that derived from glucose (J Biol Chem 1997;272:23123-9).

Deficiency of PMI causes a significant decrease in protein glycosylation, but it does not abolish all glycosylation, because residual enzymatic activity and/or exogenous mannose can be used when it is available. The severity of the clinical condition may depend on the availability of mannose in the diet. This simple hypothesis was proved by providing daily doses of mannose to another patient (J Clin Invest 1998;101:1414-20). Mannose reversed all of the biochemical indicators and clinical symptoms in this patient over the course of several months (J Pediatr 1998;133:593-600). After 2 years of mannose therapy, he remains symptom-free without significant side-effects (Harms, Marquardt, Freeze, unpublished results, 1999). Mannose therapy also led to improvement in recently diagnosed patients who have been taking mannose for shorter times (J Inherit Metab Dis 1998;21:96). In one case, the clinical manifestations seemed to improve at 3 months of age after introducing solid food (mannose?) into the diet. Very little is known about the availability of mannose in the human diet, but different quantities of dietary mannose may well explain the variable and episodic manifestations seen, even among siblings.

The simple transferrin IEF analysis may hold the key for detecting many other potential defects in glycoprotein synthesis, not only defects in PMI. Mutations in more than 30 genes involved in glycosylation precursor synthesis and N-linked oligosaccharide processing could cause altered glycosylation of multiple serum glycoproteins, critical cell surface receptors, and cell adhesion molecules critical to normal development (J Pediatr 1998;133:593-600). Because glycosyltransferases are themselves glycoproteins, their activity may be reduced as a result of primary mutations in earlier steps in the pathway. It is difficult to predict the probable symptoms resulting from the complex cascade and even more difficult to speculate about specific mechanisms and developmental windows that account for the deleterious effects. Glycosylation is ubiquitous and 0.5% to 1% of the expressed human genes may be involved in sugar chain synthesis or recognition.

In addition to PMI deficiency, there are three known metabolic glycosylation defects that cause abnormal transferrin IEF patterns. The clinical presentations of various forms of CDGS (Adv Pediatr 1997;44:109-140) are different from those of PMI deficiency, because these patients have dysmorphic characteristics with skeletal abnormalities and peripheral neuropathy. They have profound mental and psychomotor retardation. The most prevalent form of CDGS, type Ia, is caused by a deficiency in PMM (man-6-P←→man-1-P). PMM and PMI are only a single metabolic step away from each other, and defects in both generate identical underglycosylated transferrin molecules, but the overall clinical presentations are different. PMM- and PMI-deficient patients display hematologic and hepatic problems. Some PMM-deficient patients also have renal cysts. Although preliminary results suggest that mannose may help PMM-deficient patients, none has improved with mannose therapy (J Pediatr 1998;133:593-600).

In at least two articles, two families are described including five patients whose symptoms included CHF, protein-losing enteropathy, and thrombosis. All but one of these patients died (J Pediatr 1986;108:61-5; Acta Paediatr Scand 1980;69:571-4). The combination of these symptoms suggests PMI deficiency, and the one surviving sibling has now been confirmed to have abnormal transferrin IEF results and PMI deficiency (Freeze, Kjaergaard, Skovby, unpublished observations, 1999).

The potentially fatal prognosis and benefits of mannose therapy for PMI-deficient patients mandate that any patient with congenital hepatic fibrosis, idiopathic coagulopathies, and hypoglycemia be tested for glycosylation abnormalities using the transferrin IEF test. Because these symptoms may not only result from a PMI deficiency, abnormal transferrin IEF results may reveal other unknown glycosylation defects. This both broadens and complicates the clinical picture. Although the effects and symptoms of glycosylation deficiency are multisystemic, the central role of the liver in protein N-glycosylation makes it the most likely organ to display these adverse effects.

Information for patients and families who have glycosylation deficiencies can be obtained through the CDG Family Network (http://www.cdgs.com). Mannose therapy trials are ongoing in the United States and are open to all documented CDGS patients. Contact the author for information on diagnosis and therapy.

Hudson H. Freeze

The Burnham Institute; 10901 North Torrey Pines Road; La Jolla, CA 92037, U.S.A.

© 1999 Lippincott Williams & Wilkins, Inc.

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