BRANCHED-CHAIN KETOACIDURIA
MAPLE SYRUP URINE DISEASE, THIAMINE-RESPONSIVE, INCLUDED
MSUD2, INCLUDED
MAPLE SYRUP URINE DISEASE, INTERMITTENT, INCLUDED
MSUD1A, INCLUDED
MAPLE SYRUP URINE DISEASE, TYPE II, INCLUDED
MAPLE SYRUP URINE DISEASE, TYPE IA, INCLUDED
MAPLE SYRUP URINE DISEASE, INTERMEDIATE, INCLUDED
BRANCHED-CHAIN ALPHA-KETO ACID DEHYDROGENASE DEFICIENCY
MAPLE SYRUP URINE DISEASE, TYPE IB, INCLUDED
KETO ACID DECARBOXYLASE DEFICIENCY MAPLE SYRUP URINE DISEASE, CLASSIC, INCLUDED
MSUD1B, INCLUDED
BCKD DEFICIENCY
MSUD
Classic branched-chain ketoacid dehydrogenase deficiency
Classic leucinosis
Classic MSUD
Classic branched-chain ketoaciduria
Classic BCKD deficiency
MSUD is due to mutations in genes encoding the first 3 subunits of branched chain 2-ketoacid dehydrogenase (BCKAD). The genes are BCKDHA (19q13.1-q13.2), encoding E1a, BCKDHB (6q14.1), encoding E1b, and DBT (1p31), encoding E2 respectively. Mutations lead to accumulation of branched-chain amino acids (especially leucine) and branched-chain alpha-ketoacids. In classic MSUD, mutations in BCKDHA predominate [Orphanet].
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 ... 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).
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 ... - 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 fifth 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.
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 ... 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.
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 ... - 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).
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 ... 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; 608248.0009) 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.