Branched-chain ketoacyl dehydrogenase deficiency: Maple syrup disease

Abstract

Classic maple syrup disease can be managed to allow a benign neonatal course, normal growth, and low hospitalization rates. The majority of affected infants that are prospectively managed have good neurodevelopmental outcome; however, acute metabolic intoxication and neurologic deterioration can develop rapidly at any age. Each episode is associated with a risk for cerebral edema, cerebrovascular compromise, and brain herniation. High plasma leucine and, possibly, alpha-ketoisocaproate are the principal neurotoxins in maple syrup disease. Plasma levels rise rapidly in association with net protein catabolism provoked by common infections and injuries. Transient periods of maple syrup disease encephalopathy appear fully reversible, leaving no clinically detectable neurologic sequelae. In contrast, prolonged amino acid imbalance, particularly if occurring during the critical period of brain development, leads to neuronal hypoplasia, a paucity of synapses, and undermyelination. Stagnated maturation and inadequate nutritional maintenance of brain structure have lifelong neurologic and behavioral consequences. Core elements of effective long-term therapy include screening and identification of asymptomatic newborns, frequent plasma amino acid monitoring, careful attention to branched-chain amino acid nurtriture, prevention of cerebral essential amino acid deficiencies, adequate provision of essential omega-3 class fatty acids and micronutrients deficient in commercial formulas, methods for home monitoring of metabolic control, and a commitment to lifelong therapy. Recognizing the risk for acute leucine intoxication depends on anticipating effects of common childhood infection and physiologic stresses on whole body protein turnover. Successful management of metabolic decompensation is based on the use of home sick-day regimens, rapid availability of branched-chain amino acid-free hyperalimentation solutions for hospitalized children, prevention of hyponatremia in patients with leucinosis, and frequent adjustments of intravenous therapies guided by plasma amino acid levels and indices of metabolic and clinical response.

Domino liver transplantation in maple syrup urine disease

“…The outcome is potentially favorable when the patients are kept on carefully supervised long-term therapy, but even with successful treatment late complications including brain damage or death are possible, 1 and there is increasing awareness of chronic psychological burden in older patients with MSUD. 2 Liver transplantation has been performed for several years in metabolic disorders that directly cause hepatic dysfunction, such as Wilson disease 3 and tyrosinemia. 4 More recently, as the methodology and success rates improved, liver transplantation has been performed in metabolic disorders which do not cause hepatic failure, but in which the pathophysiology includes deficiency of an enzyme normally expressed exclusively in the liver, such as the urea cycle disorders, including ornithine transcarbamoylase deficiency, carbamyl phosphate synthetase deficiency, and citrullinemia.…”

Developmental Defects of Caenorhabditis elegans Lacking Branched-chain α-Ketoacid Dehydrogenase Are Mainly Caused by Monomethyl Branched-chain Fatty Acid Deficiency

“…In addition, elevated BCAAs and branched-chain ␣-ketoacids induce mitochondrial dysfunction and oxidative stresses, which could contribute to the neurological damage of MSUD (10 -12). In accordance with this, MSUD is managed with lifelong dietary intervention (5,13). Alternatively, liver transplantation partially restores BCKDH activity, normalizes BCAA levels, and eliminates the need for long-term dietary restriction (14).…”

“…If untreated, patients can develop life-threatening cerebral edema within 10 days of life. MSUD also has a chronic effect on the central nervous system, resulting in dysmyelination and mental retardation in young patients (5,6).…”

“…The neurotoxicity of MSUD has been attributed mainly to increased plasma leucine and its derivative, ␣-ketoisocaproic acid (5). They compete with other large neutral amino acids for transportation across the blood-brain barrier by the LAT1 amino acid transporter, causing decreased levels of large neutral amino acids that are precursors for key neuronal factors such as dopamine and serotonin, in the brain in humans (5), classic MSUD mice (7), and rats (8).…”

“…They compete with other large neutral amino acids for transportation across the blood-brain barrier by the LAT1 amino acid transporter, causing decreased levels of large neutral amino acids that are precursors for key neuronal factors such as dopamine and serotonin, in the brain in humans (5), classic MSUD mice (7), and rats (8). Increased ␣-ketoisocaproic acid depletes glutamate, affecting transamination in the brain and causing dehydrating stress on astrocytes (5,9). In addition, elevated BCAAs and branched-chain ␣-ketoacids induce mitochondrial dysfunction and oxidative stresses, which could contribute to the neurological damage of MSUD (10 -12).…”