Maple Syrup Urine Disease

A number sign (#) is used with this entry because maple syrup urine disease (MSUD) can be caused by homozygous or compound heterozygous mutation in at least 3 genes: BCKDHA (608348) on chromosome 19q13, BCKDHB (248611) on chromosome 6q14, and DBT (248610) on chromosome 1p21. These genes encode 2 of the catalytic components of the branched-chain alpha-keto acid dehydrogenase complex (BCKDC), which catalyzes the catabolism of the branched-chain amino acids, leucine, isoleucine, and valine.

Mutation in the third component, E3 (DLD; 238331), on chromosome 7q31, causes an overlapping but more severe phenotype known as DLD deficiency (DLDD; 246900). DLD deficiency is sometimes referred to as MSUD3.

Nomenclature

Maple syrup urine disease caused by mutation in the E1-alpha subunit gene is referred to as MSUD type IA; that caused by a mutation in the E1-beta subunit gene as type IB; and that caused by defect in the E2 subunit gene as type II. The phenotype caused by mutation in the E3 subunit is sometimes referred to as MSUD type III (Chuang and Shih, 2001), but that disorder is more commonly referred to as E3 or dihydrolipoamide dehydrogenase deficiency (246900) (summary by Hong et al., 1996). See also a mild variant of MSUD (MSUDMV; 615135), caused by mutation in the regulatory gene PPM1K (611065).

Description

The major clinical features of maple syrup urine disease are mental and physical retardation, feeding problems, and a maple syrup odor to the urine. The keto acids of the branched-chain amino acids are present in the urine, resulting from a block in oxidative decarboxylation. There are 5 clinical subtypes of MSUD: the 'classic' neonatal severe form, an 'intermediate' form, an 'intermittent' form, a 'thiamine-responsive' form, and an 'E3-deficient with lactic acidosis' form (246900). All of these subtypes can be caused by mutations in any of the 4 genes mentioned above, except for the E3-deficient form, which is caused only by mutation in the E3 gene (Chuang and Shih, 2001).

Clinical Features

Classic Severe MSUD

Menkes et al. (1954) reported a familial syndrome in which 4 sibs had progressive infantile cerebral dysfunction associated with an unusual urinary substance. Onset was in the first week of life, with death by 3 months of age. The urine had an odor resembling maple syrup. Referring to the syndrome as 'maple syrup urine disease,' Westall et al. (1957) found that the levels of branched-chain amino acids, leucine, isoleucine, and valine, were greatly elevated. Menkes (1959) isolated and identified the corresponding keto acids in the urine of affected patients, suggesting that the catabolic pathways of the branched-chain amino acids were blocked at the decarboxylation step. Dancis et al. (1960) also referred to the disorder as 'branched-chain ketoaciduria.'

In classic MSUD, which is the most common form of the disorder, 50% or more of the keto acids are derived from leucine, and the activity of the BCKD complex is less than 2% of normal. Affected newborns appear normal at birth, with symptoms developing between 4 and 7 days of age. The infants show lethargy, weight loss, metabolic derangement, and progressive neurologic signs of altering hypotonia and hypertonia, reflecting a severe encephalopathy. Seizures and coma usually occur, followed by death if untreated (Chuang and Shih, 2001).

Wong et al. (1972) reported a case of classic MSUD. DiGeorge et al. (1982) made important observations on the course of classic MSUD in the first 4 days of life when an affected child was on a diet devoid of branched-chain amino acids. Although the branched-chain amino acids were normal in cord blood, serum leucine was significantly elevated by 4 to 14 hours of age and rose progressively thereafter, permitting an accurate and early diagnosis. However, Shih (1984) emphasized that classic MSUD may be missed in newborn screening because of slow rise of blood leucine levels.

Frezal et al. (1985) observed a family in which 2 different forms of MSUD occurred in the same family. The proposita had an acute neonatal form; 2 of her sisters had an almost asymptomatic form which the authors thought represented compound heterozygosity for the classic mutant and a partial variant. The proband did not respond to thiamine.

Kaplan et al. (1989) described psychometric testing on 9 girls and 7 boys with MSUD. They concluded that prospective or early treatment significantly improves the intellectual outcome and that poor biochemical control may adversely affect performance.

Van Calcar et al. (1992) described a 25-year-old woman with classic MSUD who was diagnosed at the age of 11 days and was successfully treated with dietary restrictions. She was followed closely during a pregnancy, with delivery of a healthy baby whose length and weight were at the 5th centile.

Intermediate MSUD

Schulman et al. (1970) first described intermediate MSUD in a 19-month-old patient who was being evaluated for mental retardation. She had normal physical growth but severe developmental delay. She had mild systemic acidosis and markedly increased levels of plasma branched-chain amino acids and urinary branched-chain keto acids. Protein restriction was effective, but thiamine administration was not. The patient had 15 to 25% residual BCKD activity in leukocytes and fibroblasts. Kalyanaraman et al. (1972) reported 2 patients with the intermediate form of MSUD manifesting as hyperkinetic behavior and mental retardation.

Chhabria et al. (1979) reported a neonate who presented with ophthalmoplegia and was later found to have intermediate MSUD with residual BCKD complex activity. They noted that 2 similar cases with MSUD and ophthalmoplegia had previously been reported.

Gonzalez-Rios et al. (1985) reported a boy with intermediate MSUD who presented at age 10 months in ketoacidotic coma, with a history of irritability, poor feeding, and growth and developmental delay. branched chain amino acid restriction resulted in normal growth and development by age 42 months, but thiamine was not effective. The authors determined that the defect was in the catalytic activity of the E1 component of the BCKD complex, but there was some residual enzyme activity.

Schadewaldt et al. (2001) determined whole-body L-leucine oxidation in MSUD patients. In 4 patients with classic MSUD, L-leucine oxidation was too low to be measurable. In 2 females with a severe variant form of the disease, L-leucine oxidation was about 4% of control. In 6 milder variants, including intermediates, the estimates for residual whole-body L-leucine oxidation ranged from 19 to 86% (59 +/- 24%) of control, and were substantially higher than the residual branched-chain 2-oxo acid dehydrogenase complex activities in the patients' fibroblasts (10 to 25% of control).

Intermittent MSUD

Morris et al. (1961) reported a 24-month-old female with intermittent MSUD. She was asymptomatic until age 16 months when she had recurrent episodic ataxia, lethargy, semicoma, and elevated urinary branched-chain keto acids following otitis media. Similarly, her younger brother was normal until about age 10 months when he had an acute episode. Dietary protein restriction was effective (see also Morris et al., 1966).

In 2 sibs of each of 2 families, Dancis et al. (1967) observed intermittent MSUD. The children suffered from a transient neurologic disorder associated with elevation of branched-chain amino acids and keto acids in the urine as well as a distinctive odor to the urine. One sib of each family died during an attack. Late onset of symptoms and clinical normality between attacks differentiated the condition from classic MSUD. In addition, the level of leukocyte BCKD complex activity seemed to be higher than in the classic form of the disease.

Two Norwegian families with the intermittent form were described by Goedde et al. (1970). They noted that in the intermittent form, only 1 parent shows decreased enzyme activity. Van der Horst and Wadman (1971) described an intermittent form with severe episodes of acidosis with mental retardation that was partially reversed on dietary therapy. Other cases of intermittent MSUD were reported by Kiil and Rokkones (1964), Valman et al. (1973), and Indo et al. (1988).

Thiamine-responsive MSUD

Scriver et al. (1971) described a variant of MSUD in which the hyperaminoacidemia was completely corrected by thiamine hydrochloride (10 mg per day) with dietary restriction (see also Scriver et al., 1985). Duran et al. (1978) and Duran and Wadman (1985) reported successful treatment of MSUD with thiamine administration.

Chuang et al. (1982) found that BCKDH complex activity in thiamine-responsive MSUD is about 30 to 40% the normal rate. Further studies showed that the primary defect in thiamine-responsive MSUD is reduced affinity of the mutant BCKD for thiamine pyrophosphate.

In 2 cases of MSUD responsive to thiamine administration, Zhang et al. (1990) found that the sequence of the gene for the E1-alpha subunit was normal. The result was considered consistent with any of the following possibilities: that the thiamine-binding site involves the E1-beta subunit, that the binding site is on E1-alpha, but a mutation elsewhere in the complex alters the affinity of the thiamine-binding site by an allosteric interaction, or that the clinical response to thiamine is due to stabilization of the enzyme that has a mutation in either the E1-beta or the E2 protein.

Fenugreek Tea

In a report from Tunisia, Monastiri et al. (1997) noted that since maple syrup is largely unknown by Mediterranean populations, the odor of the urine in MSUD is more reminiscent of fenugreek (Trigonella foenum graecum L.) than of maple syrup. Fenugreek beans are traditionally used by Mediterranean populations as an infusion for sick persons (Boukef et al., 1982), and its fragrant smell is disagreeable and well known in that area. Monastiri et al. (1997) suggested that physicians in Mediterranean countries should keep in mind that a fenugreek odor of urine with neurologic distress in newborn infants, without a history of fenugreek ingestion by the mother of the baby, should raise a suspicion of MSUD.

Sewell et al. (1999) described a case of 'pseudo-maple syrup urine disease' caused by drinking fenugreek tea. The 5-week-old Egyptian infant had a 10-minute episode of unconsciousness while drinking bottled tea. He recovered spontaneously, but the parents nevertheless sought medical attention. On examination, the child was found to exude an aroma similar to that of Maggi (a widely available flavoring), and a spontaneously voided urine sample had a similar aroma. The parents indicated that the child had been given herbal tea (Helba tea) to reduce flatulence and prevent fever. This tea contains seeds of fenugreek. Analysis of the infant's urine revealed the presence of sotolone, the compound responsible for the aroma in maple syrup urine disease (Podebrad et al., 1999). Tea prepared from fenugreek seeds was found to contain sotolone. Bartley et al. (1981) had reported a similar case. Since herbal teas are popular as home remedies, particularly in Middle Eastern countries, physicians should use caution when they are presented with young infants from such countries, to avoid unnecessary and costly investigations.

Clinical Management

Bodner-Leidecker et al. (2000) reported a patient with classic MSUD who had orthotopic liver transplantation at age 7 years due to a terminal liver failure triggered by a hepatitis A infection. The patient was maintained on an unrestricted diet, and plasma concentrations of branched-chain L-amino and 2-oxo acids were stable, yet at moderately increased levels (2- to 3-fold of control). L-alloisoleucine concentrations, however, remained remarkably elevated (greater than 5-fold of control). In vivo catabolism showed normal rates of L-alloisoleucine and leucine elimination. Bodner-Leidecker et al. (2000) suggested that the enhanced substrate supply from extrahepatic sources was responsible for the elevation of plasma concentrations.

Morton et al. (2002) reported 35 Mennonite patients with MSUD and homozygosity for the Y393N mutation (608348.0001) in the BCKDHA gene and 1 non-Mennonite patient who was compound heterozygous for the Y393N mutation and a splice-site mutation. Eighteen affected neonates were identified between 12 and 24 hours of age using amino acid analysis of plasma or whole blood collected on filter paper. None of the infants identified before 3 days of age and managed according to the protocol suggested by the authors became ill during the neonatal period. MSUD was diagnosed after age 3 days in 18 infants, all of whom had the characteristic maple syrup-like odor and had neurologic deficits, including dystonic posturing, seizures, and cerebral edema. Follow-up of all 36 patients showed that the overall rate of hospitalization after the neonatal period was only 0.56 days per patient per year (25% of which were accounted for by 2 patients), and all showed uniformly good developmental outcomes. Four patients developed life-threatening cerebral edema as a consequence of infection and metabolism intoxication, but all recovered. Morton et al. (2002) presented a detailed treatment protocol for MSUD that was designed to inhibit endogenous protein catabolism, sustain protein synthesis, prevent amino acid deficiencies, and maintain normal serum osmolarity. The authors emphasized the importance of diagnosis within the first days of life and concluded that classic MSUD can be properly managed to allow a benign neonatal course, normal growth and development, and low hospitalization rates.

Heterogeneity

Genetic Heterogeneity

Lyons et al. (1973) sought genetic heterogeneity in maple syrup urine disease by the study of heterokaryons derived from cultured fibroblasts of different patients. Fibroblasts from one patient consistently complemented those from other particular patients by increasing the level of BCKD. Correlation with clinical expression could not be made. Singh et al. (1977) and Jinno et al. (1984) likewise did complementation analysis to answer the question of genetic heterogeneity. Jinno et al. (1984) demonstrated the usefulness of lymphoid cell lines in such studies and found 2 complementation groups. Unlike the earlier 2 studies, the 2 groups corresponded to clinical groups: 3 cell lines were from patients with the variant type and 2 were from patients with the classic type.

Indo et al. (1988) found altered BCKDH complex enzyme activity and kinetics that appeared to correspond with MSUD phenotype: classic, intermediate, and intermittent types of MSUD demonstrated increasing levels of complex activity, and were associated with sigmoidal, near-sigmoidal, and hyperbolic kinetics, respectively.

By Northern and Western blot analysis of the E1-alpha and E2 proteins in cell cultures from 7 unrelated MSUD patients, Fisher et al. (1989) demonstrated several distinct molecular phenotypes according to mRNA and protein-subunit contents, demonstrating the genetic complexity of MSUD.

Molecular Genetics

Mutations in the E1-alpha Subunit Gene

In a patient with classic MSUD, Zhang et al. (1989, 1991) identified a mutation in the gene encoding the E1-alpha subunit (608348.0001). Chuang et al. (1994) later identified a second mutation in the BCKDHA gene in this patient (608348.0002). Each parent was heterozygous for 1 of the mutations.

In 3 of 4 unrelated Hispanic-Mexican patients with intermediate MSUD, Chuang et al. (1995) identified a homozygous mutation in the BCKDHA gene (608348.0003). The fourth patient was homozygous for a different mutation in the same gene (608348.0004).

Patel and Harris (1995) provided a schematic representation of 7 point mutations, 1 small deletion, and 1 small insertion reported in the BCKDHA gene.

Mutations in the E1-beta Subunit Gene

In a patient with classic maple syrup urine disease, Nobukuni et al. (1991) identified a homozygous 11-bp deletion in exon 1 of the E1-beta gene (248611.0001). In 6 of 7 Ashkenazi Jewish patients with classic MSUD, Edelmann et al. (2001) identified homozygosity or compound heterozygosity for the same mutation in the BCKDHB gene (R183P; 248611.0002). The authors found that approximately 33% (10 of 34) of families with MSUD followed in their clinic in New York were of Ashkenazi Jewish descent. Large-scale population screening of Ashkenazi Jewish individuals for the R183P mutation revealed that the carrier frequency of the mutant allele was approximately 1 in 113 persons.

In 3 unrelated Israeli patients with classic MSUD, Chuang et al. (2004) identified homozygous or compound heterozygous mutations in the BCKDHB gene (248611.0003-248611.0006). Functional expression studies in E. coli showed that the different mutations had variable expression but no residual enzyme activity.

Mutations in the E2 Component Gene

In a case of classic MSUD, Herring et al. (1991) identified a 124-bp deletion in the DBT gene encoding the E2 component of the BCKDH complex (248610.0001).

In a cell line from a patient with thiamine-responsive MSUD, Fisher et al. (1991) identified compound heterozygosity for mutations in the DBT gene (248610.0002 and 248610.0003).

In several Japanese patients with the intermediate form of MSUD, Tsuruta et al. (1998) identified homozygosity or compound heterozygosity for mutations in the DBT gene (248610.0005-248610.0008).

Genotype/Phenotype Correlations

Nellis et al. (2003) evaluated and compared the clinical course of 11 unrelated patients with MSUD, including 3 with mutations in the E1-alpha gene, 5 with mutations in the E1-beta gene, and 3 with mutations in the E2 gene (2 were sibs). All had residual BCKD activity less than 3% of control values. All patients except 2, 1 with E1-alpha and 1 with an E1-beta mutations, had documented episodes of metabolic decompensation. IQ greater than 90 was observed in 70% of patients. Patients with mutations in the E1-alpha gene tended to have decreased IQs compared to other patients. In general, however, the results indicated no significant impact of 1 mutant locus to another in determining clinical outcome. The most important factor in determining outcome was early identification and institution of a protein-modified diet.

Among 15 patients with variant forms of MSUD, Flaschker et al. (2007) found that more severe phenotypes tended to be associated with mutations in the BCKDHA gene, whereas milder variants tended to be associated with mutations in the BCKDHB and DBT genes.

Population Genetics

In a mobile, urban, predominantly white population of New England, Levy (1973) found a frequency of MSUD of 1 in 290,000 on newborn screening. The highest reported frequency of MSUD was observed among the Old Order Mennonites of Pennsylvania (Auerbach and DiGeorge, 1973; Naylor, 1980; Marshall and DiGeorge, 1981). In conservative Mennonites of eastern Pennsylvania, classic MSUD has a frequency as high as 1 in 176 births (DiGeorge et al., 1982). Matsuda et al. (1990) demonstrated the specific defect in the Mennonite cases (see 608348.0001). Chuang and Shih (2001) noted a worldwide incidence of MSUD of 1 in 185,000 live births.

Using complementation assays in cells from 63 individuals with clinically diagnosed MSUD, Nellis and Danner (2001) found that 33% of the cases were caused by mutations in the E1-alpha gene, 38% by mutations in the E1-beta gene, and 19% by mutations in the E2 gene. Ten percent of the tested cell lines gave ambiguous results by showing no complementation or restoration of activity with 2 gene products.

In 11 children with MSUD from a Gypsy community in southern Portugal, Quental et al. (2008) identified a homozygous 1-bp deletion (117delC; 608348.0009) in the BCKDHA gene. By haplotype analysis, Quental et al. (2009) showed that the 117delC mutation is a founder mutation in Portuguese Gypsies with a carrier frequency estimated to be 1.4%. An unrelated Spanish patient with the deletion who was not of Gypsy origin did not share the haplotype, indicating that it occurred independently. The deletion occurs within a poly-C tract and may represent a mutation hotspot in the BCKDHA gene.

Feuchtbaum et al. (2012) reported the birth rates of selected metabolic, endocrine, hemoglobin, and cystic fibrosis disorders for specific racial/ethnic groups in a total of 2,282,138 newborns born between 2005 and 2010 in California who were screened using a blood sample collected via heel stick. Screening of 21,973 individuals of Middle Eastern ancestry gave an estimated birth prevalence for maple syrup urine disease of approximately 14 per 100,000 births; of 61,120 individuals of Filipino ancestry, approximately 2 per 100,000 births; and of 1,183,044 Hispanic individuals, approximately 1 per 100,000 births. Results for other ethnic groups were less than 1 per 100,000 births.

Animal Model

In polled Hereford calves with maple syrup urine disease, Zhang et al. (1991) demonstrated a C-to-T substitution in the E1-alpha gene that introduced a stop codon into the leader peptide of the protein.

Gortz et al. (2003) found that spontaneous network activity in primary dissociated embryonic rat neurons was reversibly reduced or blocked by increased extracellular leucine or alpha-ketoisocaproate in a dose-dependent fashion. In contrast, resting potential, various membrane currents, and intracellular calcium were unaffected by the substances. Gortz et al. (2003) concluded that an abnormality of release or imbalance of concentration of glutaminergic/GABAergic neurotransmitters causes the acute neuronal dysfunction in maple syrup urine disease.

In a large N-ethyl-N-nitrosourea (ENU)-induced mouse mutagenesis program, Wu et al. (2004) identified a phenotype characterized by striking elevation of serum branched chain amino acids and a moderate increase in arginine. Clinically, the affected mice also showed failure to thrive, weakness, decreased spontaneous movement, and thin hair, features seen in humans with maple syrup urine disease. In the affected mice, Wu et al. (2004) identified a homozygous T-to-C transition in the 5-prime splicing site consensus sequence of exon 2 and intron 2 of the Bcat2 gene (113530), resulting in deletion of exon 2. RT-PCR showed markedly reduced amounts of Bcat2 mRNA in muscle and liver compared to controls. The authors noted that exon 2 contains the mitochondrial targeting leader sequence. A diet low in branched chain amino acids resulted in clinical improvement in the mice.