Maple syrup urine disease (MSUD) is an inherited metabolic dysfunction that leads to an accumulation of the branched-chain amino acids (BCAAs) and the corresponding branched-chain 2-keto acids (BCKAs) (Chuang & Shih, 2001). This occurs due to a deficiency of branched-chain l-2-keto acid dehydrogenase complex (BCKD) activity. To a lesser extent, specific hydroxyl derivatives also accumulate (Treacy et al., 1992). The buildup of these compounds within the central nervous system (CNS) results in pronounced neurological dysfunction that may include manifestation of convulsions, seizures, ataxia, psychomotor delay, mental retardation, and, in some instances, coma. Rare in prevalence, MSUD has an occurrence of 1 in 185,000 worldwide (Chuang & Shih, 2001). However, higher incidence rates of roughly 1 in 200 births have been noted in Mennonite settlements throughout the Midwest purportedly due to a founder effect (Mitsubuchi et al., 1992).
There is no cure for the disorder. Treatment is commonly focused on dietary/nutritional management in combination with more targeted interventions to further regulate the accumulative compounds. To this end, peritoneal dialysis, exchange transfusion, hemodialysis, hemofiltration, hemodiafiltration, and/or administration of a large dose of thiamine are all options for treatment. Beyond this, treatment is focused on addressing the residuals of neurological dysfunction.
MSUD is an inherited disorder. It represents a metabolic flaw that results from a severe deficiency of BCKD activity (Bridi, 2003). The by-product of this dysfunction is system-based accumulation of the BCAAs leucine, isoleucine, and valine, and the corresponding BCKAs l-2-ketoisocaproic, l-2-ketoisovaleric, and l-2-keto-3-methylvaleric acids (Chuang & Shih, 2001; Yeman, 1986). The hydroxyl derivatives l-2-hydroxyisocaproic, l-2-hydroxyisovaleric, and l-2-hydroxy-3 methylvaleric acids, produced by the reduction of their respective l-2-keto acids, also accumulate but to a lesser degree (Treacy et al., 1992). Ketoacidosis manifests and represents a clinical feature of MSUD (Nyhan, 1984).
From a neuropathological standpoint, MSUD impact is multifaceted and generally diffuse. In the initial stages, the cerebral peduncles and the dorsal part of the brainstem are primarily involved. The discussed accumulation contributes to demyelination, edema, reduced brain uptake of essential amino acids, brain energy deficiency, and neuronal apoptosis (Aráujo et al., 2001; Jouvet et al., 2000; Pilla et al., 2003). In patients who die, generalized spongy CNS degeneration is noted (Gascon, Ozand, & Cohen, 2007).
Neurotransmitter disturbance is also a common outcome of the presentation (Tavares et al., 2000). In animal models, specific disturbances are in the form of reduced brain tissue concentrations of glutamate, aspartate, and GABA (Dodd et al., 1992). Cerebral edema is also commonly noted with preferential targeting of the pyramidal tracts of the spinal cord and the white matter of the cerebral hemispheres, corpus callosum, and dentate nuclei (Chuang & Shih, 2001).
Beyond aforementioned metabolic features, MSUD is manifested as heterogeneous clinical phenotypes, ranging from classical to mild variants (Schadewaldt & Wendel, 1997). Although the features may vary from person to person, the salient features that have been most commonly noted in classical MSUD include ketoacidosis, failure to thrive, poor feeding, apnea, ataxia, seizures, coma, psychomotor delay, and mental retardation presenting in the neonatal period (Nyhan, 1984). Variability across other forms has been proposed as being possibly due to the distinct residual enzyme activity that itself may vary. In fact, MSUD patients can be divided into five different clinical and biochemical phenotypes (Chuang & Shih, 2001).
Acutely sick children or adults with MSUD first present with muscle fatigue, epigastric pain, vomiting, and increased confusion (Korein, Sansaricq, Kalmijn, Honig, & Lange, 1994; Riviello, Rezvani, DiGeorge, & Foley, 1991). Neurological sequelae are present in most patients having been linked to both white matter demyelination and diffuse subcortical gray matter edema (Korein et al., 1994; Riviello et al., 1991). Dystonia, stupor, hallucination, and sleep disturbances may present. There is a high prevalence of ataxia and psychomotor delay (Nyhan, 1984). Cognitively, mental retardation is commonly seen over the long term. Even in those who have milder neurological involvement, learning disabilities are seen at higher rates of incidence (Chuang & Shih, 2001). Death during acute metabolic decompensation results from central transtentorial herniation.
MSUD must be ruled out in any case of neonatal lethargy progressing to coma; with altering tone changes; in the absence of changes in blood pH, glucose, and ammonia; and regardless of the presence of an infection (Gascon et al., 2007). Definitive diagnosis is accomplished through urinalysis or evaluation of the plasma. Diagnostic findings are that of elevated L-leucine, isoleucine, and valine.
Electroencephalogram (EEG) and neuroimaging can also have a role in diagnostics in terms of identifying CNS involvement as opposed to confirming MSUD. EEG often presents with a characteristic sharp wave pattern described as comb-like. It is an essential tool given the relative prevalence of seizures in this population, even when the disorder is controlled.
On MRI, white matter attenuation may be seen fairly early on. Edema may be observed in the deep cerebellum, the dorsal part of the brainstem, the cerebral peduncles, and the dorsal limb of the internal capsule initially and then spreads to include the central white matter, particularly of the frontal lobes (Gascon et al., 2007).
Neuropsychological assessment is essential once children come of age to determine the nature and extent of any presenting neurocognitive deficits. Domains of impairment may vary. Assessment should also seek to evaluate academic domains as children would naturally be at greater risk for learning disabilities.
Treatment begins with identification of the presentation. Given classical MSUD presents in the neonatal period with metabolic decompensation that may prove fatal or contribute to various neurological sequelae and psychomotor retardation, management of this decompensation as early as possible is essential. This is attempted by suppressing catabolism and facilitating the incorporation of free amino acids in body protein by drip infusion of balanced electrolytes and hypertonic glucose solution in combination with nutritional management and nasogastric feeding with or without insulin administration (Berry et al., 1991; Parini et al., 1991; Townsend & Kerr, 1982; Wendel, Langenbeck, Lombeck, & Bremer, 1982). Peritoneal dialysis, hemodialysis, exchange transfusion, hemodiafiltration, and/or administration of a large dose of thiamine to enhance the residual activity of branched-chain ketoacid dehydrogenase complex may be utilized in an attempt to remove the accumulating toxic metabolites (Rutledge et al., 1990; Thompson, Butt, Shann et al., 1991; Thompson, Francis, & Halliday, 1991). Beyond management of the biochemical components of the presentation, treatment is symptom based and related to standard practices of addressing those residuals. For example, learning disabilities may be addressed through special education services or other classroom or educational adaptations.
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This article is a revision of the previous edition article by Dean J. Danner, volume 3, pp 34–39, © 2003, Elsevier Inc. Abstract Maple syrup urine