Maple Syrup Disease

Abstract

MAPLE -APLE syrup disease is a rapidly progressive familial cerebral degenerative condition marked by the excretion of a urine possessing a sweet, maple syrup-like odor.1 The enzymatic basis for this disease is a failure in the oxidative decarboxylation of three branched-chain keto acids, the derivatives of leucine, valine, and isoleucine. As a consequence of the defect, these compounds and their amino acid analogues are excreted in large amounts, and plasma levels of branched-chain amino acids are many times higher than normal.2 Hypertonia, disturbances in respiration, and seizures appear shortly after birth and prove to be fatal within a few weeks or months in a majority of children.In analogy to the therapy for phenylketonuria, Holt et al first suggested regulating the abnormal blood levels of branchedchain amino acids by means of a completely synthetic diet in which the intake of leucine, isoleucine, valine, and methionine could be carefully controlled.3 More recently, regulation of methionine intake has been abandoned, and a more simplified diet based on small amounts of skimmed milk supplemented by arachis oil, sucrose, and L-amino acids in proportions similar to those found in a full milk diet has been devised by Westall.4 On such a regimen the rapid neurologic deterioration of infants wth maple syrup disease can be arrested, and near-normal intellectual development becomes possible.5In the untreated case surviving beyond the first two months of life, the principal ana¬ tomic alterations occur in cerebral white matter. The deposition of myelin is less ad¬ vanced than would be expected for a normal brain of comparable age, and status spongiosus, often accompanied by focal areas of astrocytosis, is evident.6-8These pathologic findings are less strik¬ ing in younger infants1; and in the instance of a 12-day-old child, the analyses of lipid class and fatty acid composition in white matter were entirely normal for the infant's age.9,ioAs it appeared likely that the early de¬ mise of this patient precluded the develop¬ ment of any abnormalities in lipid compo¬ sition, these neurochemical studies were repeated on two infants with maple syrup disease, dying between the ages of 4 and 5 months. One of these children was untreat¬ ed, while the other had been placed on a diet restricted in leucine, valine, and isoleu¬ cine during the second week of life, with plasma levels of these amino acids main¬ tained as close to normal as possible. Report of CasesDetailed case histories and pathological studies were presented in a previous publi¬ cation by one of us.8 Case 1.-This boy, the product of a normal pregnancy and delivery, developed swallowing difficulties on the sixth day of life, and seizures at eight days. Over the next few weeks neuro¬ logic symptoms became progressively more se¬ vere. The diagnosis of maple syrup disease was made at 4 months of age shortly before his death of bronchopneumonia and hyperpyrexia.On autopsy the brain was markedly edematous.

Inhibition by the branched-chain 2-oxo acids of the 2-oxoglutarate dehydrogenase complex in developing rat and human brain

“…Appell (1966 observed a decrease in the charging of tRNA in the presence ofhigh concentrations ofthe branched-chain amino acids and suggested it as a possible mechanism by which cerebral protein synthesis is affected in these patients. A marked decrease in the amounts of proteolipids and cerebrosides in brains from patients with maple-syrup-urine disease suggests an impairment in myelination (Menkes et al, 1965;Prensky et al, 1968;Prensky & Moser, 1966;Menkes & Solcher, 1967). A decrease in the biosynthesis of protein (Appel, 1966) and lipids (M. S. Patel, unpublished work as described below) is consistent with the observed decrease in the amount of myelin in brains of affected patients (Menkes et al, 1965;Prensky & Moser, 1966).…”