Maple Syrup Urine Disease

Clinical characteristics.

Maple syrup urine disease (MSUD) is categorized as classic (severe), intermediate, or intermittent. Neonates with classic MSUD are born asymptomatic but without treatment follow a predictable course:

• 12–24 hours: Elevated concentrations of branched-chain amino acids (BCAAs; leucine, isoleucine, and valine) and alloisoleucine, as well as a generalized disturbance of amino acid concentration ratios, are present in blood and the maple syrup odor can be detected in cerumen;
• Two to three days: Early and nonspecific signs of metabolic intoxication (i.e., irritability, hypersomnolence, anorexia) are accompanied by the presence of branched-chain alpha-ketoacids, acetoacetate, and beta-hydroxybutyrate in urine;
• Four to six days: Worsening encephalopathy manifests as lethargy, apnea, opisthotonos, and reflexive "fencing" or "bicycling" movements as the sweet maple syrup odor becomes apparent in urine;
• Seven to ten days: Severe intoxication culminates in critical cerebral edema, coma, and central respiratory failure.

Individuals with intermediate MSUD have partial branched-chain alpha-ketoacid dehydrogenase deficiency that manifests only intermittently or responds to dietary thiamine therapy; these individuals can experience severe metabolic intoxication and encephalopathy in the face of sufficient catabolic stress. In the era of newborn screening (NBS), the prompt initiation of treatment of asymptomatic infants detected by NBS means that most individuals who would have developed neonatal manifestations of MSUD remain asymptomatic with continued treatment compliance.

Diagnosis/testing.

Suggestive biochemical findings on NBS include whole-blood concentration ratios of (leucine + isoleucine) to alanine and phenylalanine that are above the cutoff values for the particular screening lab. Follow-up plasma amino acid analysis typically demonstrates elevated concentrations of BCAAs and alloisoleucine. The diagnosis of MSUD is confirmed by identification of biallelic pathogenic variants in BCKDHA, BCKDHB, or DBT.

Management.

Treatment of manifestations: Treatment consists of dietary leucine restriction, BCAA-free medical foods, judicious supplementation with isoleucine and valine, and frequent clinical and biochemical monitoring. A BCAA-restricted diet fortified with prescription medical foods can maintain average plasma BCAA concentrations within standard reference intervals and preserves the ratios among them. Use of a "sick-day" formula recipe (devoid of leucine and enriched with calories, isoleucine, valine, and BCAA-free amino acids) combined with rapid and frequent amino acid monitoring allows many catabolic illnesses to be managed in the outpatient setting. Acute metabolic decompensation is corrected by treating the precipitating stress while delivering sufficient calories, insulin, free amino acids, isoleucine, and valine to achieve sustained net protein synthesis in tissues. Some centers use hemodialysis/hemofiltration to remove BCAAs from the extracellular compartment, but this intervention does not alone establish net protein accretion. Brain edema is a common complication of metabolic encephalopathy and requires careful management in an intensive care setting. Adolescents and adults with MSUD are at increased risk for attention-deficit/hyperactivity disorder, depression, and anxiety disorders and can be treated successfully with standard psychostimulant and antidepressant medications.

Prevention of primary manifestations: Transplantation of allogeneic liver tissue affords affected individuals an unrestricted diet and protects them from metabolic crises, but does not reverse preexisting psychomotor disability or mental illness. In those who have not undergone liver transplantation, strict and consistent metabolic control can decrease the risk of developing neuropsychiatric morbidities. Consider a trial of enteral thiamine to determine if an affected individual may have thiamine-responsive disease.

Prevention of secondary complications: Any trauma care or surgical procedures should be approached in consultation with a metabolic specialist.

Surveillance: Weekly or twice-weekly assessment of amino acid profile for rapidly growing infants; weekly amino acid profile assessment in children, adolescents, and adults; routine monitoring of calcium, magnesium, zinc, folate, selenium, and omega-3 essential fatty acid levels; at least monthly visit with a metabolic specialist in infancy; assessment of developmental milestones at each visit or as needed.

Evaluation of relatives at risk: It can be determined if newborn sibs of an affected individual (who have not been tested prenatally) are affected (1) by plasma amino acid analysis at approximately 24 hours of life; or (2) by molecular genetic testing of umbilical cord blood if the family-specific pathogenic variants have been identified. Early diagnosis may allow management of asymptomatic infants out of hospital by experienced providers. Before confirmatory molecular testing is complete, at-risk neonates can be managed with an MSUD prescription diet if serial plasma amino acid profiles provide evidence of MSUD.

Pregnancy management: For women with MSUD, metabolic control should be rigorously maintained before and throughout pregnancy by frequent monitoring of plasma amino acid concentrations and dietary adjustments to avoid the likely teratogenic effects of elevated maternal leucine plasma concentration. Fetal growth should be monitored to detect any signs of essential amino acid deficiency. The catabolic stress of labor, involutional changes of the uterus, and internal sequestration of blood are potential sources of metabolic decompensation of the affected mother. Appropriate monitoring of the affected mother at a metabolic referral center at the time of delivery and in the postpartum period are recommended.

Genetic counseling.

MSUD is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being unaffected and a carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk relatives and prenatal diagnosis for pregnancies at increased risk are possible if the pathogenic variants have been identified in an affected family member.

Establishing the Diagnosis

The diagnosis of MSUD in a proband with suggestive metabolic/biochemical findings is established by identification of biallelic pathogenic variants in one of the genes listed in Table 1 or – in limited instances – by significantly reduced activity of the BCKD enzyme in cultured fibroblasts, leukocytes, or biopsied liver tissue. Because of its relatively high sensitivity, molecular genetic testing can obviate the need for enzymatic testing and, thus, is increasingly the preferred confirmatory test for MSUD.

Note: In vitro measurements of BCKD activity do not correlate with measurements of in vivo leucine oxidation [Schadewaldt et al 2001], dietary leucine tolerance [Strauss et al 2010], or in vivo response to BCKD-activating medications [Brunetti-Pierri et al 2011]. Therefore, the authors do not find measurements of BCKD enzyme activity clinically useful.

Clinical Description

Traditionally, the metabolic phenotype of maple syrup urine disease (MSUD) is termed classic or intermediate on the basis of residual branched-chain alpha-ketoacid dehydrogenase (BCKD) enzyme activity. Rarely, affected individuals have partial BCKD enzyme deficiency that manifests only intermittently or responds to dietary thiamine therapy (see Table 2). Phenotypic distinctions are not absolute: individuals with intermediate or intermittent forms of MSUD can experience severe metabolic intoxication and encephalopathy if physiologic stress is sufficient to overwhelm residual BCKD activity or this activity is reduced by transient changes in the phosphorylation state of the enzyme complex. Even in persons with relatively high baseline residual BCKD enzyme activity, episodes of metabolic intoxication can be fatal.

Metabolic considerations in establishing MSUD phenotype:

• Dietary leucine tolerance. Leucine tolerance is defined as the weight-adjusted daily leucine intake that is sufficient for normal growth and maintains plasma leucine concentration within the normal range (reference mean ±2 SDs). In persons with classic MSUD, in vivo oxidation and urinary losses of branched-chain amino acids (BCAAs) are negligible [Schadewaldt et al 1999b, Levy 2001]. Thus, leucine tolerance reflects a balance between unmeasured protein losses (e.g., sloughed skin, hair, and nails) and the net accretion of body protein, which in turn is linked to growth rate [Strauss et al 2010]. During metabolic crises, changes of plasma leucine mirror whole-body protein turnover, which can be quantified if one assumes the human body is 10%-12% protein, protein is about 10% leucine by weight, and free leucine (molecular weight 131 mg/mmol) is evenly distributed in total body water [Garrow et al 1965, Filho et al 1997].
• Plasma concentration ratios of BCAAs. The wild type BCKD complex maintains stringent stoichiometric relationships among the three BCAAs, such that plasma concentration ratios (µmol/L:µmol/L) of leucine to isoleucine (Leu/Iso) and valine to leucine (Val/Leu) remain close to 2.0 in diverse physiologic contexts, including overnight fasting, protein loading, and catabolic illness. In contrast, these concentration ratios vary across several orders of magnitude in individuals with classic MSUD [Strauss et al 2006]. Individuals with intermediate forms of MSUD are less vulnerable to these volatile changes of plasma BCAA concentrations and less likely to experience prolonged essential amino acid deficiencies.
• Plasma alloisoleucine. Alloisoleucine is a chemical derivative of isoleucine and represents the most sensitive and specific diagnostic marker for all forms of MSUD. Plasma alloisoleucine is <5 µmol/L in healthy infants, children, and adults, and exceeds this value in 94% and 99.9% of samples from individuals with intermediate and classic forms of MSUD, respectively [Schadewaldt et al 1999a].
• Rapidity and severity of decompensation during illness. The risk for metabolic crisis in any ill person with MSUD depends on residual in vivo BCKD enzyme activity in relation to the net liberation of free leucine from protein catabolism. Thus, individuals with residual in vivo BCKD enzyme activity enjoy a higher leucine tolerance when well and also tend to have slower and less severe elevations of plasma leucine concentrations during illnesses.

Classic MSUD Phenotype

Maple syrup odor is evident in cerumen soon after birth and in urine by age five to seven days. In untreated neonates, ketonuria, irritability, and poor feeding occur within 48 hours of delivery. Lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling" are evident by age four to five days and are followed by coma and central respiratory failure. Preemptive detection of affected newborns, before they exhibit neurologic signs of MSUD, significantly reduces lifetime risk of intellectual disability, mental illness, and global functional impairment [Strauss et al 2012, Muelly et al 2013, Strauss et al 2020].

Following the neonatal period, acute metabolic intoxication (leucinosis) and neurologic deterioration can develop rapidly at any age as a result of net protein degradation precipitated by infection, surgery, injury, or psychological stress (see Figure 1). In infants and toddlers, leucinosis causes nausea, anorexia, altered level of consciousness, acute dystonia, and ataxia. Neurologic signs of intoxication in older individuals vary and can include cognitive impairment, hyperactivity, sleep disturbances, hallucinations, mood swings, focal dystonia, choreoathetosis, and ataxia. As plasma concentrations of leucine and alpha-ketoisocaproic acid (aKIC) increase, individuals become increasingly stuporous and may progress to coma. In persons of all ages with MSUD, nausea and vomiting are common during crisis and often necessitate hospitalization [Morton et al 2002].

Figure 1.

Serial plasma leucine measurements over a 62-day NICU course in a Mennonite newborn with trisomy 21 and classic MSUD. Plasma leucine levels rise predictably as a result of net protein catabolism provoked by a variety of physiologic stresses, including (more...)

Each episode of acute leucinosis is associated with a risk for cerebral edema (see Figure 2) [Levin et al 1993] and death [Strauss et al 2020]. Mechanisms of brain edema in MSUD are not completely understood. Plasma leucine concentration correlates only indirectly with the degree of swelling; severe cerebral edema and neurologic impairment are more directly related to the rate of change of plasma leucine and concomitant decreases in blood osmolarity. During the evolution of leucinosis, cerebral vasopressin release may be provoked by both acute hyperosmolarity (from the accumulation of BCAAs, ketoacids, ketone bodies, and free fatty acids in the circulation) and vomiting. Renal excretion of branched-chain alpha-ketoacids (BCKAs) is accompanied by obligate urine sodium loss, and when this coincides with renal free water retention (antidiuresis), administration of hypotonic or even isotonic fluids can result in hyponatremia and critical brain edema [Strauss & Morton 2003].

Figure 2

A. Coronal T₂-weighted MRI from a Mennonite boy age five years during an acute metabolic crisis. Diffuse gray matter swelling and signal hyperintensity (on T₂-weighted and FLAIR images) involve the cortical mantle, basal ganglia nuclei, hippocampus, and (more...)

Transient periods of MSUD encephalopathy appear fully reversible, provided no global or focal ischemic brain damage occurs. In contrast, prolonged amino acid imbalances, particularly if they occur during the early years of brain development, lead to structural and functional neurologic abnormalities that have morbid long-term psychomotor consequences [Carecchio et al 2011, Shellmer et al 2011, Muelly et al 2013, Strauss et al 2020].

Neonatal screening and sophisticated enteral and parenteral treatment protocols (see Management) have significantly improved neurologic outcomes for persons with classic MSUD [Strauss et al 2010, Muelly et al 2013, Strauss et al 2020], but risks of acute brain injury or death are always present, and the long-term neuropsychiatric prognosis is guarded. In two longitudinal studies of individuals with classic MSUD [Muelly et al 2013, Strauss et al 2020], an asymptomatic neonatal course and stringent longitudinal biochemical control proved fundamental to optimizing long-term cognitive outcome and mental health.

• Early developmental milestones. Children with MSUD who are diagnosed during the neonatal period and managed prospectively under stringent dietary control can achieve major developmental milestones along time courses similar to their unaffected sibs [Strauss et al 2020].
• Cognitive function. Among individuals with classic MSUD (n = 81, ages 3.6-51.1 years), full scale intelligence quotient (FSIQ) correlates with birthdate (r_s = 0.39, p = 0.0044) and is on average 20%-40% lower in affected individuals as compared to their unaffected sibs [Strauss et al 2020]. This difference is most striking for affected individuals born before the advent of newborn screening (NBS) (FSIQ of 62 ± 17, range 40-99). FSIQ correlates directly with the frequency of amino acid monitoring and inversely with both average lifetime plasma leucine and its concentration ratio to valine [Muelly et al 2013]. Prolonged neonatal encephalopathy is the single strongest predictor of neurocognitive disability and global functional impairment [Muelly et al 2013, Strauss et al 2020].
• Mood and anxiety. Among individuals with classic MSUD who complete appropriate objective testing, the probability of affective illness (depression, anxiety, and panic disorder) is between 83% and 100% by age 35 years [Muelly et al 2013, Strauss et al 2020]. Newborns who were encephalopathic at the time of diagnosis are five and ten times more likely, respectively, to later suffer from anxiety and depression (see Table 3) [Muelly et al 2013].
• Attention and hyperactivity. Cumulative lifetime incidence of attention-deficit/hyperactivity disorder (ADHD) exceeds 50% among individuals with MSUD on dietary therapy and may be even higher among those who underwent liver transplantation [Muelly et al 2013].
• Movement disorders. Among 17 adults with MSUD (mean age 27.5 years), 12 (70.6%) had a movement disorder (primarily tremor, dystonia, or a combination of both) on clinical examination [Carecchio et al 2011]. Parkinsonism and simple motor tics were also observed. Pyramidal signs were present in 11 affected individuals (64.7%), and a spastic-dystonic gait was observed in six (35.2%). In the authors' experience, such motor disabilities are rare in individuals with MSUD who are managed appropriately from the neonatal period but common among those who did not have the advantage of NBS [Strauss et al 2020].

Table 3.

Lifetime Relative Risk of Each Finding Based on Condition at the Time of Diagnosis

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Ill vs. Well at Diagnosis	Relative Risk	Fisher's Exact p
Depression	10.3	0.001
Anxiety	5.1	0.007
Global assessment of functioning <70	4.0	0.05
Full scale intelligence quotient <70	2.9	0.20
Attention-deficit/hyperactivity	1.4	0.28

Muelly et al [2013]

The relative risk in this table compares the likelihood of developing the finding if the affected individual was ill at the time of diagnosis versus if the affected individual was well at the time of diagnosis.

Liver transplantation appears to prevent catastrophic brain injuries that can occur during metabolic intoxication [Mazariegos et al 2012] and arrests the progression of neurocognitive impairment [Shellmer et al 2011], but does not reverse preexisting cognitive disability or psychiatric illness [Strauss et al 2020]. Neuropsychiatric morbidity and neurochemistry are similar among individuals with MSUD who have and have not undergone liver transplantation [Muelly et al 2013, Strauss et al 2020].

Non-central nervous system involvement in MSUD can include:

• Iatrogenic essential amino acid deficiency. Anemia, acrodermatitis, hair loss, growth failure, arrested head growth, anorexia, and lassitude are complications of chronic deficiency of leucine, isoleucine, or valine [Puzenat et al 2004]. Iatrogenic cerebral essential amino acid deficiency can be a cause of significant neurologic morbidity in any individual ingesting a diet low in natural protein and high in prescription medical protein [Strauss et al 2010, Manoli et al 2016].
• Recurrent oroesophageal candidiasis. Candida infections are common in hospitalized persons with MSUD and may result from T-cell inhibitory effects of elevated plasma leucine [Hidayat et al 2003] or iatrogenic immunodeficiency as a result of inadequate BCAA intake.

Pathophysiology

BCKD has four subunit components (E1a, E1b, E2, and E3). Pathogenic variants in both alleles encoding any subunit can result in decreased activity of the enzyme complex and the accumulation of BCAAs and corresponding BCKAs in tissues and plasma [Nellis et al 2003, Chuang et al 2004] (see Nomenclature).

For more information on the pathophysiology of MSUD click here (pdf).

Genotype-Phenotype Correlations

The severity of the MSUD metabolic phenotype is determined by the amount of residual BCKD enzyme activity relative to dietary BCAA excess and the large demands for BCAA oxidation that accompany fasting, illness, or other catabolic stresses [Strauss et al 2010]. Although there are some established relationships between genotype and biochemical phenotype (i.e., classic vs intermediate), clinical and functional outcomes (e.g., FSIQ, psychiatric illness, executive dysfunction) cannot be predicted from genotype [Strauss et al 2020]. Individuals with the same MSUD genotype may vary considerably in their cerebral response to metabolic crisis – some being more vulnerable than others to the complications of metabolic encephalopathy, brain edema, and mental illness – and long-term outcomes are largely related to the timing and quality of metabolic control.

Nomenclature

Biochemical derangement caused by biallelic pathogenic variants in BCKDHA encoding BCKA decarboxylase (E1) alpha subunit is sometimes referred to as MSUD type 1A. Biochemical derangement caused by biallelic pathogenic variants in BCKDHB encoding BCKA decarboxylase (E1) beta subunit is sometimes referred to as MSUD type 1B, and biallelic pathogenic variants in DBT encoding dihydrolipoyl transacylase (E2) subunit are sometimes referred to as MSUD type 2. All three are clinically indistinguishable biochemically.

Note: Dihydrolipoamide dehydrogenase deficiency, caused by biallelic pathogenic variants in DLD encoding the E3 subunit (lipoamide dehydrogenase) of BCKD, is sometimes referred to as MSUD type 3, although the phenotype is easily distinguishable from MSUD (see Differential Diagnosis).

Prevalence

MSUD is rare in most populations, with incidence estimates of 1:185,000 live births [Chuang & Shih 2001, Nellis et al 2003].

As a result of a founder variant (c.1312T>A) in BCKDHA (E1a), certain Mennonite populations of Pennsylvania, Kentucky, New York, Indiana, Wisconsin, Michigan, Iowa, and Missouri have a carrier frequency for classic MSUD as high as one in ten and a disease incidence of approximately one in 380 live births [Puffenberger 2003] (see Molecular Genetics).