Lafora disease

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A 10-month-old male infant presented with massive hepatomegaly. There was no history of jaundice, fever, weight loss, blood in stool, or acholic stool. He was born at full term without any complications, and the newborn screening test results were normal. The maternal perinatal history was unremarkable for infections, previous blood transfusion, or intravenous drug use. Family history was negative for jaundice, early infantile death, neurodegenerative disorder, or ctl-antitrypsin deficiency. Physical examination revealed normal growth and vital signs, no icterus, lymphadenopathy, ascites, splenomegaly, or other systemic abnormal findings. Firm, nontender hepatomegaly was noted 8 cm below the right costal margin, Laboratory results included a total bilirubin level of 0.5 mg/ dL (9 (mu)mol/L); aspartate aminotransferase, 956 U/L (reference range, 0-50 U/L); alanine aminotransferase, 287 U/L (reference range, 0-45U/L); gamma-glutamyltransferase, 216 U/L (reference range, 5-32 U/L); and alkaline phosphatase, 321 U/L (reference range, 170-580 U/L). Urine was negative for reducing substances. Results for complete blood count, prothrombin time, partial thromboplastin time, total protein, albumin, serum ferritin, cholesterol, and lactate dehydrogenase were all within normal limits. The hepatitis antibody panel (hepatitis B and C, cytomegalovirus, and Epstein-Barr virus) was negative.

A percutaneous needle biopsy of the liver showed loss of normal hepatic architecture, bridging fibrosis, and micronodule formation that was confirmed by trichrome stain. Many scattered hepatocytes showed glassy refractile cytoplasmic inclusions (Figure, A), which stained positively with periodic acid-Schiff (Figure, B) and were generally sensitive to diastase digestion. These inclusions appeared light blue with Alcian blue stain and showed coarsely clumped staining with colloidal iron stain (Figure, C). An ultrastructural evaluation of formalin-fixed tissue showed hepatocytes filled with rarefied fibrillar material interspersed with microfoci of normal glycogen (Figure, D). A diagnosis of glycogen storage disease, type IV, was rendered.

Type IV glycogen storage disease (type IV GSD), also known as Andersen disease or amylopectinosis, is a rare autosomal-recessive disorder caused by the deficiency of glycogen branching enzyme. The gene for this enzyme is located on chromosome 3p14. Although the clinical manifestations of this disorder are variable, the most common and classic form is characterized by progressive hepatic fibrosis in the first 18 months of life, resulting in hepatosplenomegaly and failure to thrive and death by the age of 5 years. Patients with a rare nonprogressive variant do not develop cirrhosis and survive to adulthood.1 Patients with the neuromuscular form of the disease may (1) present at birth with severe hypotonia, muscle atrophy, and neuronal involvement resulting in death during the neonatal period; (2) present in late childhood with myopathy or cardiomyopathy; or (3) present as adults with central and peripheral nervous system dysfunction.

Tissue deposition of amylopectin-like material can be demonstrated in the liver, heart, muscle, skin, intestine, brain, spinal cord, and peripheral nerve of affected patients. The definitive diagnosis rests on the demonstration of the deficiency of branching enzyme activity in liver, muscle, cultured skin fibroblasts, or leukocytes. Electron microscopy of the affected organs demonstrates in addition to a and P glycogen, amylopectin-like material, which is fibrillar and poorly soluble in buffers. Prenatal diagnosis is possible by measuring the enzyme activity in cultured amniocytes or chorionic villi.2 A study measuring the residual branching enzyme activity in patients with type IV GSD showed no difference between patients with the nonprogressive hepatic form and those with the classic progressive and early neonatal fatal types.1 The authors of this study suggested that caution should be used when counseling patients regarding the prognosis of type IV GSD based on the analysis of enzyme activity. These patients should be carefully monitored for evidence of progression before recommending liver transplantation.

The differential diagnosis of type IV GSD includes Lafora disease, since the liver biopsy can show similar inclusions. Although the inclusions in this disorder stain positively with the colloidal iron stain, they are not as coarsely clumped as in type IV GSD. Also, patients with Lafora disease typically present in late childhood or adolescence with the characteristic clinical triad of epilepsy, myoclonus, and dementia.

There is no specific treatment available for type IV GSD. Orthotopic liver transplantation has resulted in improved patient outcome because metabolic sequelae, such as cardiomyopathy and skeletal myopathy, have not developed in most cases. Postoperative heart biopsies from patients have shown minimal amylopectin deposits up to 45 years following transplantation. Failure of liver transplantation to diminish cardiac deposits of amylopectin leading to death has been reported3; however, multiorgan transplantation has been suggested in cases with severe multiorgan involvement.

References

1. McConkie-Rosell A, Wilson C, Piccoli DA, et al. Clinical and laboratory findings in four patients with the non-progressive hepatic form of type lV glycogen storage disease. j Inherit Metab Dis. 1996; 19:51-58.

2. Brown BI, Brown DH. Branching enzyme activity of cultured amniocytes and chorionic villi: prenatal testing for type IV glycogen storage disease. Am J Hum Genet 1989;44:378-381.

3. Rosenthal P, Podesta L, Grier R, et al. Failure of liver transplantation to diminish cardiac deposits of amylopectin and leukocyte inclusions in type IV glycogen storage disease. Liver Transpl Surg. 1995;1:373-376.

Sunati Sahoo, MD; Andrea K. Blumberg, MD; Elizabeth Sengupta, MD; John Hart, MD

Accepted for publication January 2, 2002.

From the Department of Pathology, The University of Chicago Hospitals, Chicago, Ill (Drs Sahoo, Sengupta, and Hart); and the Department of Pathology, Memorial Regional Hospital, Hollywood, Fla (Dr Blumberg).

Reprints: John Hart, MD, Department of Pathology, The University of Chicago Hospitals, 5841 S Maryland Ave, MC 6101, Chicago, IL 60637 (e-mail: jhart@uchospitals.edu).

Copyright College of American Pathologists May 2002
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