Maple syrup urine disease

A 6-day-old infant is admitted from the emergency department due to an abnormal metabolic screening (elevated leucine at 2250 µmol/L and valine), without metabolic acidosis. The infant alternates between periods of sleep and wakefulness and exhibits irritability and mild hypertonicity in the limbs.

A transfontanellar ultrasound revealed a diffuse increase in the echogenicity of the deep and central white matter, with hyper-echogenic thalami and caudate nuclei, suggesting a possible metabolic disorder (Figures 1a and 1b).

Brain MRI demonstrated bilateral and symmetric diffusion restriction in regions of advanced myelination—perirolandic area, pre and postcentral white matter (Figure 2a), central region of the semioval centres (Figure 2b), posterior limb of the internal capsule, ventrolateral thalamic nucleus (Figures 2c and 3a), dorsal brainstem (Figure 2d), cerebellar peduncles, and dentate nuclei (Figures 2e and 3b)—, along with hypointensity on T1-weighted (Figures 4a and 4b) and hyperintensity on T2-weighted sequences (Figure 5b), consistent with cytotoxic/intramyelinic oedema. Diffusion-weighted imaging (DWI) showed increased diffusion in the frontal, parieto-occipital, and cerebellar white matter, with mild cortical sulcal prominence, particularly in the frontal lobes (Figure 5a), suggesting vasogenic oedema.

The magnetic resonance spectroscopy revealed a reduced N-acetylaspartate (NAA) peak, consistent with neuroaxonal loss, without pathological lactate or long-chain amino acid (0.9–1.0 ppm) peaks (Figure 6).

These findings suggested classic maple syrup urine disease.

Background

Maple syrup urine disease (MSUD) is a rare autosomal-recessive disorder (1:180,000) caused by a deficiency in the branched-chain ketoacid dehydrogenase complex. This leads to an accumulation of branched-chain amino acids (BCAAs)—leucine, isoleucine, and valine—in the plasma, urine, and cerebrospinal fluid [1]. MSUD is classified into several forms: Classic, Intermediate, Intermittent, Thiamine-responsive, and E3-deficient [2].

Clinical Perspective

The accumulation of BCAAs in the brain disrupts amino acid synthesis, resulting in cerebral oedema and abnormal myelination. Classic MSUD presents in neonates after an initial asymptomatic period, with symptoms such as feeding, vomiting, weight loss, and lethargy [2]. Without treatment, the condition can lead to mental retardation, spastic paralysis, cortical blindness, and death. Laboratory tests reveal metabolic acidosis and elevated BCAAs in plasma [1].

Imaging Perspective

MRI plays a crucial role in diagnosing MSUD, often revealing characteristic findings before genetic tests or mass spectrometry confirm the diagnosis [2]. In the acute phase, brain MRI typically demonstrates symmetrical diffusion restriction (hyperintensity on DWI and hypointensity on the apparent diffusion coefficient (ADC) map) and T2 hyperintensity in the myelinated regions of full-term neonates, such as the globus pallidus, thalamus, internal capsule, brainstem, and cerebellar white matter, due to intramyelinic oedema [2,3]. Additionally, it can reveal diffuse vasogenic-interstitial oedema in unmyelinated areas [1]. Both findings were seen in our patient. DWI is superior in depicting the extent of brain injury in MSUD [1]. Magnetic resonance spectroscopy typically identifies a characteristic BCAA methyl peak at 0.9–1.0 ppm, although this was not observed in our case [1].

Outcome

Early diagnosis and intervention are essential to prevent neurological damage. If untreated, the classic form of MSUD leads to death within weeks [2]. Treatment includes acute supportive care, including haemodialysis, glucocorticoids, oxygen, and intravenous fluids, along with long-term dietary modification using a formula that eliminates BCAAs [1,3]. With appropriate treatment, MRI findings typically improve. Liver transplantation has been shown to prevent further brain damage and enhance outcomes. However, despite treatment, most patients still experience some degree of neurological impairment, such as developmental delays [2].

Take Home Message / Teaching Points

• Maple syrup urine disease (MSUD) is a rare metabolic disorder with nonspecific early clinical signs. MRI should be promptly performed in neonates with symptoms like poor feeding, vomiting, and lethargy.
• MRI findings typically show bilateral diffusion restriction in myelinated brain regions, which is crucial for early diagnosis and management.

Written informed patient consent for publication has been obtained.