Atypical phenotype in a boy with a maple syrup urine disease

Abstract

Maple syrup urine disease (MSUD) is a metabolic disorder due to a block in the decarboxylation step in the catabolic pathways of the branched-chain amino acids (BCAAs). We describe an atypical presentation in an infant male. The patient presented with psychomotor retardation, profound hypotonia and elevated plasma levels of BCAAs, but no elevation of alloisoleucine. Cranial magnetic resonance imaging showed prominent diffuse CSF spaces, delayed myelin maturation and symmetrical signal abnormality within the globi pallidi, midbrain, dorsal pons and medulla. The cerebellar white matter was specifically spared. A mitochondrial disorder was suggested. After correction of feeding problems with G-tube feeds, his high BCAAs persisted and, on fourth analysis, alloisoleucine was seen. Subsequent fibroblast enzyme and mutation analysis confirmed MSUD due to E(1)-alpha subunit deficiency. After starting dietary treatment, there was no significant improvement in his hypotonia or his psychomotor development. However, the high signal within the globi pallidi had resolved. MSUD may have diverse clinical presentations, and should be considered in children who present with chronic psychomotor delay but no acute encephalopathic episodes. BCAA levels may not be very high, alloisoleucine may not always be detected in MSUD even with severe enzyme deficiency, and imaging may be misleading if seen in the chronic phase only.

Challenges in Diagnosing Intermediate Maple Syrup Urine Disease by Newborn Screening and Functional Validation of Genomic Results Imperative for Reproductive Family Planning

“…Dramatic neuroimaging findings in the early stages may not correlate with eventual clinical outcomes [4], as demonstrated in our patient's significant initial MRI abnormalities that were subsequently resolved with optimal dietary interventions and excellent compliance. This case further substantiates the reversibility of neurological insults sustained during acute decompensation, also reported in other patients where complete resolution of neuroimaging abnormalities has occurred concurrently with normalisation of BCAA levels [13].…”

Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders

“…As a consequence, NAA deficiency in MSUD may result in defective myelination. Indeed, myelination differences are frequently observed in MSUD patients on magnetic resonance imaging (MRI) scans [ 56 , 57 , 58 , 59 , 60 , 61 ]. Additional evidence from histological and electrophysiological data also demonstrated myelin destruction and axonal degeneration in a MSUD case [ 62 ].…”

Second-Tier Test for Quantification of Alloisoleucine and Branched-Chain Amino Acids in Dried Blood Spots to Improve Newborn Screening for Maple Syrup Urine Disease (MSUD)

“…This method is sensitive, requires a small sample size, and is faster than previously published protocols using either an HPLC separation of derivatized amino acids (7,13 ) or GC-MS (14 ). This method is also an improvement over traditional methods that apply ion exchange chromatography and postcolumn ninhydrin derivatization, because allo-Ile at near normal concentrations is difficult to distinguish from other nearby eluting ninhydrin-sensitive amines, a complication that may be problematic in some cases (15 ).…”

“…Three cases were published whose combined concentration of the isobaric amino acids Leu, Ile, allo-Ile, and OHPro (XLE-OHPro) in the newborn screening samples (344, 325, and 209 mol/L, respectively) were below the cutoff applied by the performing laboratory (4,15 ). The 2 patients described by Bhattacharya et al (17 ) were affected with the intermediate-severity form of MSUD, which often only reveals abnormal metabolites during metabolic stress.…”