Background
Maple syrup urine disease (MSUD) is a rare metabolic disorder of autosomal recessive inheritance caused by decreased activity of the branched-chain α-ketoacid dehydrogenase (BCKD) complex. The first cases of MSUD were described by Menkes et al. [
1] in 1954. The incidence of MSUD is 1 in 185,000 births throughout the world, and the incidence rate may be higher in some ethnic and racial groups [
2]. The deficiency of BCKD causes the corresponding branched-chain keto acids (BCKAs) formed by branched-chain amino acid (BCAA) transaminase to be unable to oxidize decarboxylic acid, resulting in the accumulation of BCAAs (including leucine, isoleucine and valine) and BCKAs. Within the brain, glutamate serves as a neurotransmitter within the central nervous system and plays important roles in brain development and cognitive functions. Disorders of BCAA metabolism can cause abnormalities in glutamate synthesis, leading to various neurological problems in patients. The accumulation of leucine is highly neurotoxic. Elevated levels of leucine can affect water homeostasis within the subcortical grey matter, causing swelling within the brain, altering nitrogen homeostasis, further depleting glutamate levels, and increasing oxidative stress [
3]. Furthermore, the BCAAs and BCKAs that accumulate in MSUD trigger apoptosis in glial and neuronal cells in a dose- and time-dependent manner [
4]. The accumulation of BCAAs and BCKAs induces ketoacidosis, developmental disturbances, neurological impairment and coma and may be fatal if untreated [
5]. We analysed the clinical data of 1 case to improve the understanding of the disease and the level of diagnosis and treatment.
Discussion and conclusions
On the basis of the activity of BCKD and clinical manifestations, most studies have classified MSUD into five forms: a classic form, intermediate form, intermittent form, thiamine-responsive form and fatty acid amide dehydrogenase deficiency form. The classic form is the most serious and common phenotype, which shows onset in early neonates with poor prognosis and can rapidly develop into respiratory failure, coma and even death. The clinical onset of MSUD usually occurs within the first week after birth but lacks specific symptoms. The standard treatment of MSUD is mainly a special diet and thiamine intake, while patients with severe MSUD need dialysis and plasma exchange. BCAA-free enteral formula plays an essential role in restoring and maintaining metabolic homeostasis in MSUD, and patients should avoid the ingestion of BCAA-containing exogenous protein and liquid to prevent catabolism and the accumulation of endogenous BCAAs and BCKAs [
7]. Thiamine pyrophosphate (TPP) is a co-factor for the multi-subunit enzyme BCKD, and thiamine supplementation is an adjunctive therapy to be considered in the treatment regime for MSUD. Patients with MSUD for whom supplemental thiamine provides increased dietary BCAA tolerance (or decreased plasma BCAAs on constant dietary intake) appear to be individuals with some residual BCKD activity [
8], especially those with DBT gene mutations [
9]. In our study, the boy was admitted to the hospital due to drowsiness and poor appetite at the age of 11 days. The clinical symptoms, examination indexes and head MRI of the child were significantly improved with BCAA-free enteral formula and thiamine diet. Based on the clinical presentation, progression of the disease and effectivity of thiamine, the patient might be classified as having a thiamine-responsive form of MSUD.
To date, at least 4 genes (BCKDHA, BCKDHB, DLD and DBT) have been reported to be the causative gene for MSUD [
2]. According to the mutation types of the BCKDHA, BCKDHB, DBT and DLD genes, MSUD can also be divided into four genotypes: IA, IB, II and III. Among them, BCKDHA and BCKDHB mutations are the most common, and DLD gene mutations are rarely reported. Furthermore, there have been 88 BCKDHA, 85 BCKDHB, 21 DLD and 71 DBT mutations listed in the Human Gene Mutation Database (HGMD) [
10]. Mitsubuchi et al. [
11] considered that type IA and IB tended to be of the classic MSUD type and that all thiamine-responsive MSUDs are type II, with patients that have mild clinical manifestations [
8]. This child suffering from a DBT gene mutation, with mild clinical manifestations, improved obviously after timely supplementation with thiamine, which is consistent with the above view. In this case, the child had a homozygous mutation of the DBT gene, c.1132C > T (p.378X), and both parents had the heterozygous mutation of c.1132C > T (p.378X), which has not yet been reported. The grandmothers of the father and mother were sisters, and the c.1132C > T mutation of the DBT gene was familial. However, the parents of the child denied that there was a similar disease in the family, which provided new thinking about the study of this disease.
MSUD is a disorder of branched-chain amino acid metabolism, with BCAAs and BCKAs accumulating in the blood and intracranially, and BCKAs can be excreted in the urine. Therefore, blood tandem mass spectrometry, urinary organic acid analysis and head MRI are helpful for early diagnosis. Blood tandem mass spectrometry always showed elevations of leucine, isoleucine and valine, and leucine was more significant. Schadewaldt et al. [
12] proposed that the elevation of isoleucine is more specific for the diagnosis of MSUD, but the determination of isoleucine has not been widely used. In the acute phase, the accumulation of BCAAs and BCKAs affected the tricarboxylic acid cycle, thereby interfering with the energy metabolism of brain cells, leading to the dysfunction of the Na
+/K
+ ATP pump and diffuse cerebral oedema [
13]. In the chronic phase, cavernous degeneration and myelin sheath formation disorder occurred in white matter due to the accumulation of BCAAs and BCKAs. The symmetrical central gyrus, basal ganglia, thalamus, dentate nucleus, and cerebral foot of the brain were damaged [
14]. Therefore, blood tandem mass spectrometry can detect an increase in branched-chain amino acids before the symptoms of encephalopathy and craniographic changes occur in patients with MSUD [
15]. In this case, the clinical manifestations and related tests and examinations were very important for us to make a timely diagnoses of MSUD. Timely diagnosis is beneficial for early intervention to improve the prognosis.
Conclusion
In view of the clinical data of the patient, prompt diagnosis and treatment were essential to improve prognosis. Blood tandem mass spectrometry, urinary organic acid analysis and head MRI were crucial for the timely diagnosis. Furthermore, we identified a novel mutation of the DBT gene (c.1132C > T (p.378X)), and BCAA-free nutrition and a thiamine diet were effective to improve the blood level of BCAAs. This case provides an important reference for the diagnosis and treatment of MSUD.
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