American journal ofPatbology, Vol. 136, No. 6, June 1990
Copyright (© American Association ofPathologists
Animal Model of Human Disease Maple Syrup Urine Disease (Branched Chain Ketoaciduria)
Peter A. W. Harper, Peter J. Healy, and Julie A. Dennis From the Veterinary Laboratories, Elizabeth MacArthur Agricultural Institute, Department ofAgriculture and Fisheries, New South Wales, Australia
Pathologically, status spongiosus,5 failure of myelination, sponginess attributed to edema without myelin breakdown,6 increased cerebral water content, and reduction in total brain lipid content76 have been described.
Animal Model
Biologic Features Maple Syrup Urine Disease (MSUD) was first described in 1954 as a familial disease of progressive neurologic dysfunction occurring in infants in the first weeks of life, and accompanied by a maple syrup odor to the urine.1 The disorder was subsequently recognized to be associated with extreme elevations of the branched chain amino acids (BCAAs) leucine, isoleucine, and valine.2 Demonstration that the branched chain keto acids (BCKAs) were also present in excess suggested that the catabolic pathway of the BCAAs was intercepted at the point of oxidative decarboxylation of their respective keto acids.3 Clinically, five different phenotypes are generally recognized: classic, intermittent, intermediate, thiamine-responsive, and E3 (dihydrolipoyl dehydrogenase) deficiency.4 The classic type is inherited in an autosomal recessive manner.4 The infant appears normal at birth but by the end of the first week of life the typical patient fails to thrive, feeds poorly, vomits, and develops convulsions, generalized rigidity, stupor, and hypotonia, and if untreated, becomes progressively more lethargic, falls into a coma, and dies. An odor of maple syrup is frequently noted, and persistent dramatic elevations in plasma and urinary BCAAs and BCKAs are present.4 Plasma BCAA concentrations as high as 5.0 mmol/l (millimolar) for leucine and 1.0 mmol/l for both isoleucine and valine have been recorded.4
Recently, a disease of neonatal Poll Hereford calves characterized by the development of severe neurologic symptoms in the first week of life, a variable maple syrup odor to the urine, and extreme elevations of the plasma BCAAs has been described.9 The calves are born normally, are suckled by their dams, and within 12 to 48 hours develop central nervous system (CNS) depression, lethargy, and a "scruffy" unclean coat, although some calves are dull from birth. Dullness is followed by periodic recumbency with limb extension, occasional tremors, and disorganized limb paddling. There is hyper- to hypotonia, and periodic opisthotonus, progressing to coma and death within 48 to 72 hours. Severely affected calves have hyperesthesia, tetany, rigidity, apparent blindness, and extreme elevations of temperature. Maple syrup urine diseas has been diagnosed as a cause of stillbirth, and pre-suckle serum from affected calves has elevations of the BCAAs.1' Plasma leucine, isoleucine, and valine concentrations of 1.836, 1.608, and 0.480 mmol/l, respectively have been reported,9'10 and there is marked reduction in the activity of Publication sponsored by the Registry of Comparative Pathology, Armed Forces Institute of Pathology and supported by Grant RR-00301 from the Division of Research Resources, NIH, under the auspices of Universities Associated for Research and Education in Pathology, Inc., and by Hazleton Laboratories America, Inc. Address reprint requests to Dr. Peter A. W. Harper, Veterinary Laboratories, Department of Agriculture and Fisheries of New South Wales, Menangle, NSW, 2568, Australia.
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1446 Harper, Healy, and Dennis AJPJune 1990, Vol. 136, No. 6
CNS (Figure 1), without evidence of myelin deficiency. Ultrastructural examination has confirmed the presence of myelin edema, with splitting of the myelin sheath at the intraperiod line1' (Figure 2). Breeding studies suggest that the disease is inherited in an autosomal recessive manner.10 The recognition of bovine MSUD appears to have resolved some inconsistencies regarding the diagnosis of so-called bovine neuraxial edema.12'13
Comparison With Human Disease
Figure 1. White matter of the cerebellum from an MSUDaffected Poll Hereford calf demonstrating severe status spongiosus due to vacuolation of the myelin sheath (H & E, X 100).
the branched chain ketoacid decarboxylase complex in cultured skin fibroblasts.'0 Pathologically, the disease is characterized by diffuse status spongiosus, particularly of the white matter of the
Maple syrup urine disease in Poll Hereford calves appears analagous to the classic type of infantile MSUD. In humans, the pregnancy and immediate neonatal period appear uneventful, suggesting regulation of the concentrations of the BCAAs and BCKAs by the placenta and maternal circulation.'4 The majority of calves have a similar history, although the observation of prenatal MSUD presenting as stillbirth, and elevated BCAAs at birth, suggests that maternal regulation of the foetal concentrations of the BCAAs and BCKAs is less efficient in the bovine. With the consumption and absorption of milk high in the BCAAs, the failure of oxidative decarboxylation of the BCKAs, and subsequent build-up of excessive metabolites, there is rapid onset of neurologic disease, presumably due to 'toxic' effects of the metabolites on brain function.14 The presence of severe myelin edema early in the course of the disease indicates that the 'toxic' effect is accompanied by or mediated via a disturbance of the fluid retention mechanisms of the myelin sheath.
;--f
Figure 2. White matter of the cerebellum of an MSUD-affected calf; illustrating myelin edema, with splitting of the myelin sheath at the intraperiod line (X 7560).
Maple Syrup Urine Disease
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AJPJune 1990, Vol. 136, No. 6
Usefulness of the Model Bovine MSUD provides a useful model for the study of the pathogenesis of the CNS lesions of classic MSUD, and potentially for comparative study of the dietary modification and other clinical procedures used in the therapy of MSUD.
5.
6. 7.
Availability A herd of obligate heterozygotes for bovine MSUD has been established at the Elizabeth MacArthur Agricultural Institute, Menangle, N.S.W., Australia.
References 1. Menkes JH, Hurst PL, Craig JM: New syndrome: Progressive familial infantile cerebral dysfunction associated with an unusual urinary substance. Pediatrics 1954, 14:462-467 2. Westall RG, Dancis J, Miller S: Maple sugar urine disease. Am J Dis Child 1957, 94:571-572 3. Menkes JH: Maple syrup urine disease: Isolation and identification of organic acids in the urine. Pediatrics 1959, 23:
348-350 4. Tanaka K, Rosenberg LE: Disorders of branched chain amino acids and organic acid metabolism, The Metabolic
8.
Basis of Inherited Disease. 5th edition. Edited by JB Stanbury, JB Wyngaarden, DS Frederickson, JL Goldstein, MS Brown. New York, McGraw-Hill, 1985, p 451 Diezel PB, Martin K: Die Ahornsirupkrankheit mit familiarem Befall. Virchows Arch [A] 1964, 337:425-445 Silberman J, Dancis J, Feigin I: Neuropathological observations in maple syrup urine disease. Arch Neurol 1961, 5:351 363 Prensky AL, Moser HW: Brain lipids, proteolipids and free amino acids in maple syrup urine disease. J Neurochem 1966,13:863-874 Prensky AL, Carr S, Moser HW: Development of myelin in inherited disorders of amino acid metabolism. Arch Neurol
1968,19:552-558 9. Harper PAW, Healy PJ, Dennis JA: Maple syrup urine disease as a cause of spongiform encephalopathy in calves. Vet Rec 1986,119:62-65 10. Harper PAW, Dennis JA, Healy PJ, Brown GK: Maple syrup urine disease in calves: A clinical, pathological and biochemical study. Aust Vet J 1989, 66:46-49 11. Harper PAW, Healy PJ, Dennis JA: Ultrastructural findings in maple syrup urine disease in Poll Hereford calves. Acta Neuropathol 1986, 71:316-320 12. Healy PJ, Harper PAW, Dennis JA: Diagnosis of neuraxial oedema. Aust Vet J 1986, 63:95 13. Cordy DR, Richards WCC, Stormont C: Hereditary neuraxial oedema of Hereford calves. Pathol Vet 1969, 6:487-501 14. Dancis J, Levitz M: Abnormalities of branched chain amino acid metabolism, The Metabolic Basis of Inherited Disease. 4th edition. Edited by J Stanbury, J Wyngaarden, D Frederickson. New York, McGraw-Hill, 1979, p 403
Copyright (© American Association ofPathologists
Animal Model of Human Disease Maple Syrup Urine Disease (Branched Chain Ketoaciduria)
Peter A. W. Harper, Peter J. Healy, and Julie A. Dennis From the Veterinary Laboratories, Elizabeth MacArthur Agricultural Institute, Department ofAgriculture and Fisheries, New South Wales, Australia
Pathologically, status spongiosus,5 failure of myelination, sponginess attributed to edema without myelin breakdown,6 increased cerebral water content, and reduction in total brain lipid content76 have been described.
Animal Model
Biologic Features Maple Syrup Urine Disease (MSUD) was first described in 1954 as a familial disease of progressive neurologic dysfunction occurring in infants in the first weeks of life, and accompanied by a maple syrup odor to the urine.1 The disorder was subsequently recognized to be associated with extreme elevations of the branched chain amino acids (BCAAs) leucine, isoleucine, and valine.2 Demonstration that the branched chain keto acids (BCKAs) were also present in excess suggested that the catabolic pathway of the BCAAs was intercepted at the point of oxidative decarboxylation of their respective keto acids.3 Clinically, five different phenotypes are generally recognized: classic, intermittent, intermediate, thiamine-responsive, and E3 (dihydrolipoyl dehydrogenase) deficiency.4 The classic type is inherited in an autosomal recessive manner.4 The infant appears normal at birth but by the end of the first week of life the typical patient fails to thrive, feeds poorly, vomits, and develops convulsions, generalized rigidity, stupor, and hypotonia, and if untreated, becomes progressively more lethargic, falls into a coma, and dies. An odor of maple syrup is frequently noted, and persistent dramatic elevations in plasma and urinary BCAAs and BCKAs are present.4 Plasma BCAA concentrations as high as 5.0 mmol/l (millimolar) for leucine and 1.0 mmol/l for both isoleucine and valine have been recorded.4
Recently, a disease of neonatal Poll Hereford calves characterized by the development of severe neurologic symptoms in the first week of life, a variable maple syrup odor to the urine, and extreme elevations of the plasma BCAAs has been described.9 The calves are born normally, are suckled by their dams, and within 12 to 48 hours develop central nervous system (CNS) depression, lethargy, and a "scruffy" unclean coat, although some calves are dull from birth. Dullness is followed by periodic recumbency with limb extension, occasional tremors, and disorganized limb paddling. There is hyper- to hypotonia, and periodic opisthotonus, progressing to coma and death within 48 to 72 hours. Severely affected calves have hyperesthesia, tetany, rigidity, apparent blindness, and extreme elevations of temperature. Maple syrup urine diseas has been diagnosed as a cause of stillbirth, and pre-suckle serum from affected calves has elevations of the BCAAs.1' Plasma leucine, isoleucine, and valine concentrations of 1.836, 1.608, and 0.480 mmol/l, respectively have been reported,9'10 and there is marked reduction in the activity of Publication sponsored by the Registry of Comparative Pathology, Armed Forces Institute of Pathology and supported by Grant RR-00301 from the Division of Research Resources, NIH, under the auspices of Universities Associated for Research and Education in Pathology, Inc., and by Hazleton Laboratories America, Inc. Address reprint requests to Dr. Peter A. W. Harper, Veterinary Laboratories, Department of Agriculture and Fisheries of New South Wales, Menangle, NSW, 2568, Australia.
1445
1446 Harper, Healy, and Dennis AJPJune 1990, Vol. 136, No. 6
CNS (Figure 1), without evidence of myelin deficiency. Ultrastructural examination has confirmed the presence of myelin edema, with splitting of the myelin sheath at the intraperiod line1' (Figure 2). Breeding studies suggest that the disease is inherited in an autosomal recessive manner.10 The recognition of bovine MSUD appears to have resolved some inconsistencies regarding the diagnosis of so-called bovine neuraxial edema.12'13
Comparison With Human Disease
Figure 1. White matter of the cerebellum from an MSUDaffected Poll Hereford calf demonstrating severe status spongiosus due to vacuolation of the myelin sheath (H & E, X 100).
the branched chain ketoacid decarboxylase complex in cultured skin fibroblasts.'0 Pathologically, the disease is characterized by diffuse status spongiosus, particularly of the white matter of the
Maple syrup urine disease in Poll Hereford calves appears analagous to the classic type of infantile MSUD. In humans, the pregnancy and immediate neonatal period appear uneventful, suggesting regulation of the concentrations of the BCAAs and BCKAs by the placenta and maternal circulation.'4 The majority of calves have a similar history, although the observation of prenatal MSUD presenting as stillbirth, and elevated BCAAs at birth, suggests that maternal regulation of the foetal concentrations of the BCAAs and BCKAs is less efficient in the bovine. With the consumption and absorption of milk high in the BCAAs, the failure of oxidative decarboxylation of the BCKAs, and subsequent build-up of excessive metabolites, there is rapid onset of neurologic disease, presumably due to 'toxic' effects of the metabolites on brain function.14 The presence of severe myelin edema early in the course of the disease indicates that the 'toxic' effect is accompanied by or mediated via a disturbance of the fluid retention mechanisms of the myelin sheath.
;--f
Figure 2. White matter of the cerebellum of an MSUD-affected calf; illustrating myelin edema, with splitting of the myelin sheath at the intraperiod line (X 7560).
Maple Syrup Urine Disease
1447
AJPJune 1990, Vol. 136, No. 6
Usefulness of the Model Bovine MSUD provides a useful model for the study of the pathogenesis of the CNS lesions of classic MSUD, and potentially for comparative study of the dietary modification and other clinical procedures used in the therapy of MSUD.
5.
6. 7.
Availability A herd of obligate heterozygotes for bovine MSUD has been established at the Elizabeth MacArthur Agricultural Institute, Menangle, N.S.W., Australia.
References 1. Menkes JH, Hurst PL, Craig JM: New syndrome: Progressive familial infantile cerebral dysfunction associated with an unusual urinary substance. Pediatrics 1954, 14:462-467 2. Westall RG, Dancis J, Miller S: Maple sugar urine disease. Am J Dis Child 1957, 94:571-572 3. Menkes JH: Maple syrup urine disease: Isolation and identification of organic acids in the urine. Pediatrics 1959, 23:
348-350 4. Tanaka K, Rosenberg LE: Disorders of branched chain amino acids and organic acid metabolism, The Metabolic
8.
Basis of Inherited Disease. 5th edition. Edited by JB Stanbury, JB Wyngaarden, DS Frederickson, JL Goldstein, MS Brown. New York, McGraw-Hill, 1985, p 451 Diezel PB, Martin K: Die Ahornsirupkrankheit mit familiarem Befall. Virchows Arch [A] 1964, 337:425-445 Silberman J, Dancis J, Feigin I: Neuropathological observations in maple syrup urine disease. Arch Neurol 1961, 5:351 363 Prensky AL, Moser HW: Brain lipids, proteolipids and free amino acids in maple syrup urine disease. J Neurochem 1966,13:863-874 Prensky AL, Carr S, Moser HW: Development of myelin in inherited disorders of amino acid metabolism. Arch Neurol
1968,19:552-558 9. Harper PAW, Healy PJ, Dennis JA: Maple syrup urine disease as a cause of spongiform encephalopathy in calves. Vet Rec 1986,119:62-65 10. Harper PAW, Dennis JA, Healy PJ, Brown GK: Maple syrup urine disease in calves: A clinical, pathological and biochemical study. Aust Vet J 1989, 66:46-49 11. Harper PAW, Healy PJ, Dennis JA: Ultrastructural findings in maple syrup urine disease in Poll Hereford calves. Acta Neuropathol 1986, 71:316-320 12. Healy PJ, Harper PAW, Dennis JA: Diagnosis of neuraxial oedema. Aust Vet J 1986, 63:95 13. Cordy DR, Richards WCC, Stormont C: Hereditary neuraxial oedema of Hereford calves. Pathol Vet 1969, 6:487-501 14. Dancis J, Levitz M: Abnormalities of branched chain amino acid metabolism, The Metabolic Basis of Inherited Disease. 4th edition. Edited by J Stanbury, J Wyngaarden, D Frederickson. New York, McGraw-Hill, 1979, p 403
