Maple Syrup Urine Disease
Summary
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.
Diagnosis
Maple syrup urine disease (MSUD) is caused by decreased activity of the branched-chain alpha-ketoacid dehydrogenase complex (BCKD), the second enzymatic step in the degradative pathway of the branched-chain amino acids (BCAAs), which includes leucine, isoleucine, and valine.
Scenario 1. Abnormal newborn screening (NBS) result
- NBS for MSUD is primarily based on quantification of the ratios of (leucine + isoleucine) to alanine and phenylalanine concentrations on dry blood spots.
- A positive screening value (i.e., those above the cutoff reported by the screening laboratory) require follow-up biochemical testing with quantitative plasma amino acid and alloisoleucine analyses. If either is abnormal, treatment (see Management) and testing to establish the diagnosis (see Establishing the Diagnosis) should be initiated concurrently.Note: Individual states set standards for positive or suspected positive screens.
- Because leucine-isoleucine and hydroxyproline cannot be differentiated by mass spectrometry, neonates with isolated hydroxyprolinemia will screen positive for MSUD, but confirmatory amino acid analysis will show only increased hydroxyproline (a false positive newborn screening result).
- Neonates and infants suspected of having MSUD should never be challenged with higher than normal protein intake during the diagnostic process (see Management). This practice is dangerous; modern diagnostic methods make it unnecessary.
Scenario 2. A symptomatic individual with either atypical findings or untreated infantile-onset MSUD (resulting from any of the following: NBS not performed, false negative NBS result, or caregivers not compliant with recommended treatment following a positive NBS result)
Supportive clinical and laboratory findings can include the following.
Clinical findings
- Untreated infant:
- Maple syrup odor in cerumen, the first clinical sign of MSUD, is detectable 12 hours after birth.
- Signs of deepening encephalopathy including lethargy, intermittent apnea, opisthotonus, and stereotyped movements such as "fencing" and "bicycling" are evident by age four to five days.
- Coma and central respiratory failure may occur by age seven to ten days, sometimes before newborn screening results are available.
- Untreated older individuals with milder variants of MSUD:
- Anorexia
- Poor growth
- Irritability
- Developmental delays later in infancy or childhood
- Acute hyperleucinemia, ketonuria, and encephalopathy if stressed by fasting, dehydration, or infectious illness
Laboratory findings
- Elevated plasma concentrations of BCAAs and alloisoleucine
- Urinary excretion of BCKDs and branched-chain alpha-ketoacids (BCKAs) in infants older than 48-72 hours on an unrestricted diet
- Ketonuria detected by standard urine test stripsKetonuria in a newborn should always prompt investigation for metabolic disorders.
- Absence of hypoglycemia and hyperammonemia
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.
Molecular Genetic Testing Approaches
Scenario 1. Abnormal newborn screening (NBS) result. When NBS results and other laboratory findings suggest the diagnosis of MSUD, the preferred molecular genetic testing approach is use of a multigene panel that contains BCKDHA, BCKDHB, and DBT. In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
- Sequence analysis detects small intragenic deletions/insertions and missense, nonsense, and splice site variants. Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected.
- For this disorder, a multigene panel that also includes deletion/duplication analysis is recommended (see Table 1).
For an introduction to multigene panels click here. More detailed information for clinicians ordering genetic tests can be found here.
Scenario 2. A symptomatic individual with atypical findings or untreated infantile-onset MSUD (resulting from NBS not performed or false negative NBS result). When the diagnosis of MSUD has not been considered, comprehensive genomic testing (which does not require the clinician to determine which gene[s] are likely involved) is the best option. Exome sequencing is most commonly used; genome sequencing is also possible. If exome sequencing is not diagnostic, exome array (when clinically available) may be considered to detect (multi)exon deletions or duplications that cannot be detected by sequence analysis.
For an introduction to comprehensive genomic testing click here. More detailed information for clinicians ordering genomic testing can be found here.
Table 1.
Molecular Genetic Testing Used in Maple Syrup Urine Disease
| Gene 1, 2 | Proportion of MSUD Attributed to Pathogenic Variants in Gene | Proportion of Pathogenic Variants 3 Detectable by Method | |
|---|---|---|---|
| Sequence analysis 4 | Gene-targeted deletion/duplication analysis 5 | ||
| BCKDHA | 45% | ~92% | ~8% 6, 7 |
| BCKDHB | 35% | ~93% | ~7% |
| DBT | 20% | ~86% | ~14% 8 |
| Unknown 9, 10 | NA | ||
- 1.
Genes are listed in alphabetic order.
- 2.
See Table A. Genes and Databases for chromosome locus and protein.
- 3.
See Molecular Genetics for information on allelic variants detected in this gene.
- 4.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods that may be used include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications. Gene-targeted deletion/duplication testing will detect deletions ranging from a single exon to the whole gene; however, breakpoints of large deletions and/or deletion of adjacent genes may not be detected by these methods.
- 6.
Quental et al [2008]
- 7.
Rodríguez-Pombo et al [2006]
- 8.
Herring et al [1992]
- 9.
Inactivating variants of BCKDK in humans are associated with BCAA deficiency, autism, epilepsy, and intellectual disability that may respond to dietary treatment [Novarino et al 2012].
- 10.
Defects of PPM1K may account for a subset of human MSUD but to date no cases have been reported.
Clinical Characteristics
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.
Table 2.
Clinical Phenotypes of Maple Syrup Urine Disease
| Type | Age of Onset 1 | Clinical Features | Biochemical Signs 2 | % with Normal BCKD Activity 3 |
|---|---|---|---|---|
| Classic | Neonatal |
|
| 0%-2% |
| Intermediate | Variable |
| Similar to classic phenotype, though quantitatively less severe | 3%-30% |
| Intermittent | Variable |
|
| 5%-20% |
| Thiamine-responsive | Variable | Similar to intermediate phenotype | Improvement of leucine tolerance & biochemical profile w/thiamine therapy | 2%-40% |
BCAAs = branched-chain amino acids; BCKAs = branched-chain alpha-ketoacids
- 1.
All infants with classic MSUD present during the neonatal period. For other forms, age of presentation depends on several variables, including dietary protein and calorie intake, growth rate, number and severity of infectious illnesses, and rarely, dietary thiamine intake.
- 2.
Biochemical signs should always be interpreted in the context of dietary leucine tolerance and prevailing clinical circumstances. Dietary leucine tolerance (in mg/kg/day) is defined as the steady-state leucine intake that permits normal growth and maintains plasma leucine concentration within the normal range.
- 3.
The authors do not rely on tissue measurements of decarboxylation activity but classify affected individuals based on their leucine tolerance and metabolic response to illness. Decarboxylation data are from Chuang & Shih [2001].
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 (rs = 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
| 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.
Intermediate MSUD
Similar principles govern the acute and chronic management of classic and intermediate forms of MSUD (see Management), and the distinction between them is not absolute (see Genotype-Phenotype Correlations) [Strauss et al 2020]. Individuals with residual BCKD activity (i.e., 3%-30% ex vivo) may appear well during the neonatal period but nevertheless have maple syrup odor in cerumen and a consistently abnormal plasma amino acid profile (see Table 2). Individuals with intermediate MSUD can present with feeding problems, poor growth, and developmental delay during infancy, or may present much later in life with apparently nonsyndromic intellectual disability [Chuang & Shih 2001]. The majority of persons with intermediate MSUD are detected by NBS, although detection later in childhood can occur in settings where newborns are not tested for MSUD. When followed longitudinally, individuals with intermediate forms of MSUD have plasma BCAA concentrations similar to those observed in individuals with the classic form, but tolerate more dietary leucine and require less nutritional support to reverse episodes of metabolic intoxication [Strauss et al 2020]. Children and adults with intermediate MSUD can nevertheless develop severe leucinosis and brain swelling if subjected to sufficient catabolic stress.
Intermittent MSUD
Children with the intermittent form of MSUD have normal growth and intellectual development throughout infancy and early childhood. When they are well, they generally tolerate a normal leucine intake, and plasma amino acid and urine organic acid profiles are normal or show only mild elevations of BCAAs. During infections or other physiologic stress, they can develop the clinical and biochemical features of classic MSUD, in rare cases culminating in coma and death [Chuang & Shih 2001]. These individuals may escape detection by NBS.
Thiamine-Responsive MSUD
It is not known with certainty if individuals with true thiamine-responsive MSUD exist. In general, such putative individuals have residual ex vivo BCKD enzyme activity of up to 40% normal and are not ill in the neonatal period, but present later in life with a clinical course similar to intermediate MSUD. To date, no person with "thiamine-responsive" MSUD has been treated solely with thiamine. Rather, they are treated with a combination of thiamine (doses ranging from 10 to 1,000 mg/day) and dietary BCAA restriction, making the in vivo contribution of thiamine impossible to discern [Chuang et al 2004]. Based on in vitro data, Chuang et al [2006] provided a biochemical model of thiamine responsiveness linked to specific pathogenic variants in the E2 subunit of BCKD. It is therefore reasonable to try thiamine supplementation under controlled dietary conditions in any individual with MSUD who has verified BCKDHB pathogenic variants.
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).
Differential Diagnosis
Entities to exclude in the encephalopathic neonate include birth asphyxia, hypoglycemia, status epilepticus, kernicterus, meningitis, and encephalitis. The few inborn errors of metabolism that present with neonatal encephalopathy include the following:
- Hyperketosis syndromes (e.g., beta-ketothiolase deficiency [OMIM 203750])
- Urea cycle defects (see Urea Cycle Disorders Overview)
- Glycine encephalopathy (nonketotic hyperglycinemia)
- Propionic acidemia or isolated methylmalonic acidemia (rarely)
Among these, MSUD is unique for the sweet odor of cerumen and a positive urine dinitrophenylhydrazine test. Laboratory testing that includes quantitative plasma amino acids, plasma or whole-blood alloisoleucine, serum acylcarnitines, urine organic acids, plasma ammonia concentration, and serum lactate concentration distinguishes among these possibilities. In particular, quantitative analysis of plasma amino acids is generally sufficient to diagnosis MSUD expeditiously.
4,5-dimethyl-3-hydroxy-2[5H]-furanone (sotolone), which is thought to be responsible for the characteristic odor of MSUD [Podebrad et al 1999], is also found in maple syrup, fenugreek, and lovage. Maternal ingestion of fenugreek during pregnancy has resulted in false suspicion of MSUD [Korman et al 2001]. Topical benzoin, commonly used in NICUs, also gives off a strong sweet odor.
Note: Pathogenic variants in DLD, the gene encoding the E3 subunit, are associated with dihydrolipoamide dehydrogenase deficiency, which produces a different phenotype. Affected infants have hypotonia, developmental delay, dystonia/chorea, and a Leigh-type encephalopathy. BCKD enzyme activity is 0%-25% of control activity. Moderate elevations of plasma concentration of BCAAs, lactic acidemia, and hyperalaninemia are observed. In most cases, the disorder is lethal in infants.
Management
Evaluations Following Initial Diagnosis
When maple syrup urine disease (MSUD) is suspected during the diagnostic evaluation (i.e., due to elevated concentration of leucine, isoleucine, valine, and/or alloisoleucine), metabolic treatment should be initiated immediately.
Development and evaluation of treatment plans, training and education of affected individuals and their families, and avoidance of side effects of dietary treatment (i.e., malnutrition, growth failure) require a multidisciplinary approach to care with oversight and expertise from a specialized metabolic center. Consensus nutritional guidelines have been published [Frazier et al 2014] (full text) and two peer-reviewed articles provide general guidelines about the comprehensive treatment and monitoring of MSUD: see Strauss et al [2010] (full text), Strauss et al [2020] (full text).
To establish the extent of disease and needs in an individual following initial diagnosis of MSUD, the evaluations summarized in Table 4 (if not performed as part of the evaluation that led to diagnosis) are recommended.
Table 4.
Recommended Evaluations Following Initial Diagnosis of Maple Syrup Urine Disease
| Evaluation/System | Comment |
|---|---|
| Consultation w/metabolic physician / biochemical geneticist & specialist metabolic dietician 1 |
|
| Gastrointestinal/feeding | Swallow study as needed for symptomatic persons w/feeding difficulties &/or concern for aspiration |
| Developmental assessment | Consider referral to a developmental pediatrician. |
| Consultation w/neurologist | As needed for those w/neurologic findings |
| Consultation w/psychiatrist | For those w/signs of ADHD, anxiety, or depression |
| Consultation w/psychologist &/or social worker | To ensure understanding of the diagnosis & assess parental/patient's coping skills & resources |
| Consultation w/physical therapist, occupational therapist, & speech therapist | As needed when developmental delays are present |
ADHD = attention-deficit/hyperactivity disorder; BCAAs = branched-chain amino acids (leucine, isoleucine, and valine)
- 1.
After a new diagnosis of MSUD in an infant or child, the closest hospital and local pediatrician should also be informed.
- 2.
The following plasma concentration ratios are the most representative of amino acid regulation: leucine:isoleucine, leucine:valine, leucine:tyrosine, leucine:phenylalanine, leucine:glutamate, and leucine:alanine (mol:mol) [Mazariegos et al 2012].
- 3.
In MSUD, plasma leucine concentration has the strongest reciprocal relationship to plasma alanine and glutamine concentrations (Spearman correlation coefficient -0.86 and -0.62, respectively; p < 0.0001; see Figure 3) [Strauss et al 2010].
- 4.
Severe branched-chain alpha-ketoacid dehydrogenase (BCKD) deficiency (classic MSUD) affects amino acid homeostasis at multiple levels and causes frequent and variable disturbances of plasma amino acid concentration ratios.
- 5.
In milder intermediate forms of MSUD, plasma BCAAs may be chronically elevated while plasma amino acid concentration ratios tend to be preserved.
Figure 3.
Plasma amino values between ages four and 26 months from a child with classic MSUD show a strong reciprocal relationship between leucine (gray diamonds) and alanine (white circles) (Spearman correlation coefficient= -0.86; p<0.0001).
Strauss et al [2010]; republished with permission of Elsevier.
Treatment of Manifestations
All children with MSUD and feeding difficulties require supervision of a specialist metabolic dietitian with experience in managing the diet of those with MSUD.
The main principles of treatment are age-appropriate tolerance of leucine, isoleucine, and valine, with stable plasma branched-chain amino acid (BCAA) concentrations and BCAA concentration ratios, while avoiding deficiencies of essential amino acids, fatty acids, and micronutrients (see Table 5).
Table 5.
Routine Daily Treatment in Individuals with Maple Syrup Urine Disease
| Age | Principle/ Manifestation | Treatment | Consideration/Other |
|---|---|---|---|
| Neonate/ Infant | Leucine restriction, titrated to leucine tolerance 1 | BCAA-free powder formula | Leucine tolerance for neonates is 65-85 mg/kg/day |
| Natural protein as a source of essential & nonessential amino acids: 2-3 g/kg/day 2 |
| ||
| Maintenance of adequate isoleucine & valine supplements | 10 mg/mL solutions of isoleucine, valine, & leucine in distilled water |
| |
| Child/ Adult | Leucine restriction, titrated to leucine tolerance 1 | Leucine tolerance:
|
|
| Maintenance of adequate isoleucine & valine supplements | Maintain a plasma leucine-to-valine concentration ratio (mol:mol) of 0.5 or fewer and a leucine-to-isoleucine ratio of approximately 2.0 |
| |
| Neuropsychiatric morbidity 7 | Standard psychostimulant & antidepressant medications as needed | ||
| All ages | Normal age- & weight-adjusted energy intake | See Table 6 for patients from birth to age 4 yrs. | Information in Table 6 derived from Mennonite children birth to age 4 yrs w/classic MSUD |
| Addressing ↑ energy/caloric demands | Fundoplication, gastrostomy, or jejunostomy to address feeding issues as needed in neurologically affected persons |
| |
| Gross motor delay |
|
BCAAs = branched-chain amino acids (leucine, isoleucine, and valine)
- 1.
The dietary requirement for BCAAs varies as a function of age, growth rate, calorie intake, illness, and residual in vivo branched-chain alpha-ketoacid dehydrogenase (BCKD) enzyme activity.
- 2.
For asymptomatic individuals; see Table 6 and Table 7 for acute management recommendations.
- 3.
For rapidly growing infants, monitoring weekly or twice weekly is recommended.
- 4.
Strauss et al [2010]
- 5.
Valine has a low affinity for the blood-brain barrier LAT1 transporter, which makes it especially vulnerable to competitive inhibition by leucine.
- 6.
Muelly et al [2013]
- 7.
Which may include ADHD, depression, or anxiety
Figure 4.
Leucine (A), energy (B), and total protein (C) intakes of 15 stable Mennonite infants with classic MSUD on dietary management
Strauss et al [2010]; republished with permission of Elsevier.
Table 6.
Mean and 25th to 75th Percentile Range Nutrient Intakes (per kg-day) by Age Group
| Nutrient | Age in Months (# of Persons) | ||||||
|---|---|---|---|---|---|---|---|
| 0-2 (31) | 3-5 (18) | 6-8 (21) | 9-12 (18) | 13-18 (21) | 19-24 (18) | 25-36 (32) | |
| Mean Nutrient Intake per kg-day (25th to 75th %ile range) | |||||||
| Leucine (mg) | 72 (64-84) | 58 (47-68) | 44 (37-51) | 35 (30-41) | 33 (26-39) | 27 (22-28) | 21 (20-25) |
| Energy (kcal) | 111 (103-119) | 99 (94-107) | 89 (82-99) | 78 (71-87) | 67 (55-77) | 57 (49-71) | 38 (39-51) |
| Total protein (g) | 2.4 (2.1-2.6) | 2.3 (1.9-2.6) | 2.2 (1.8-2.5) | 2.0 (1.5-2.5) | 2.1 (1.8-2.4) | 2 (1.7-2.3) | 1.5 (1.5-2.9) |
| Leucine/energy ratio (mg/kcal) | 0.65 (0.57-0.72) | 0.58 (0.48-0.66) | 0.50 (0.43-0.56) | 0.46 (0.37-0.53) | 0.50 (0.43-0.58) | 0.48 (0.38-0.58) | 0.54 (0.44-0.55) |
Strauss et al [2010]; with permission from Elsevier
Data derived from Mennonite children from birth to age 4 years with classic MSUD
Mild illness. If an affected individual is clinically well despite an intercurrent infectious illness or febrile reaction to vaccinations, emergency outpatient management may be considered (see Table 7). If emergency outpatient treatment can be performed adequately and safely and if the child does not develop concerning symptoms during the illness, maintenance treatment and diet should be reintroduced stepwise over the next 48 (to 72) hours (see Table 5).
Table 7.
Emergency Outpatient Treatment in Individuals with Maple Syrup Urine Disease
| Manifestation/Concern | Treatment | Consideration/Other |
|---|---|---|
| Mildly increased catabolism 1 | ↑ calorie intake & ↓ dietary leucine intake by using BCAA-free amino acid protein supplementation 2 orally or via tube feed. |
|
| ↑ supplements of isoleucine & valine, 20-40 mg/kg/day each. | Measurement of plasma or whole-blood amino acids every 24-48 hrs | |
| Fever | Administration of antipyretics (acetaminophen, ibuprofen) if temperatures rises >38.5°C | |
| Occasional vomiting | Antiemetics 4 |
BCAA = branched-chain amino acid; BCKAs = branched-chain alpha-ketoacids; DNPH = dinitrophenylhydrazine
- 1.
Fever <38.5°C (101°F), enteral or gastrostomy tube feeding tolerated without recurrent vomiting or diarrhea, and absence of neurologic symptoms (altered consciousness, irritability, hypotonia)
- 2.
High-calorie BCAA-free "sick day" formulas
- 3.
Alterations in mentation/alertness, fever, and enteral feeding tolerance, with any new or evolving clinical features discussed with the designated center of expertise for inherited metabolic diseases
- 4.
Some classes of antiemetics can be used safely on an occasional basis to temporarily improve enteral tolerance of food and beverages at home or during transfer to hospital.
Acute decompensation. Dietary indiscretion causes plasma BCAAs to increase but only rarely results in acute decompensation and encephalopathy. In contrast, infections and injuries trigger a large endogenous mobilization of muscle protein and can precipitate metabolic crisis and hospitalization.
Acute manifestations (e.g., lethargy, encephalopathy, seizures, or progressive coma) should be managed symptomatically and with generous caloric support in a hospital setting (see Table 8). Correction of metabolic decompensation is predicated on treating the underlying cause of the decompensation and establishing net protein accretion.
Table 8.
Acute Inpatient Treatment in Individuals with Maple Syrup Urine Disease
| Principle Goal/ Manifestation | Treatment/Monitoring during Acute Treatment | Consideration/Other |
|---|---|---|
| To correct metabolic derangements due to MSUD 1 | ||
| ↓ plasma leucine concentration by 500-1,000 µmol/L per 24 hrs. | Provide 1.5x-3x EER as dextrose (50%-70%) & lipid (30%-50%). | When central access allows, use 25% dextrose solutions to minimize complications of hypervolemia. |
| Continuous insulin infusion: 0.02-0.15 U/kg/hr | Titrate insulin infusion to maintain blood glucose 100-160 mg/dL | |
| Total protein intake (enteral + parenteral): 2.0-3.5 g/kg/day as BCAA-free amino acids |
| |
| Isoleucine & valine supplements (enteral + parenteral): 20-120 mg/kg per day each; titrate to plasma concentrations of 400-800 µmol/L | For parenteral administration, isoleucine & valine are each prepared as separate 1% solutions in normal saline | |
| Consider renal replacement therapies in clinical settings w/appropriate resources & expertise 4 |
| |
| To prevent iatrogenic electrolyte abnormalities, 8, 9 which can → cerebral edema & intracranial hypertension | ||
| Maintain serum osmolality in normal reference range (275-300 mOsm/kg H2O). | Establish euvolemia using isotonic sodium chloride solutions | |
| Measure serum osmolality & electrolytes every 6-12 hours | Prevent serum osmolality from decreasing >5 mOsm/kg H2O per day (0.20 mOsm/kg H2O per hour) | |
| Monitor for other laboratory abnormalities. | Serum (&/or point-of-care) glucose every 4-6 hrs | |
| Plasma amino acids, serum phosphorus, & magnesium every 12-24 hrs | Hospitals admitting patients w/MSUD encephalopathy should be able to perform plasma amino acid testing around the clock. | |
| Serum lipase, amylase, & transaminases every 24-48 hours | ||
| Manage cerebral edema. | Monitor for signs of intracranial hypertension & impending brain herniation. | Management in an intensive care setting w/consultation by neurologist &/or neurointensivist is recommended |
| For obtunded individuals w/cerebral edema, consider endotracheal intubation for airway protection & neurosurgical consultation to consider measures incl e.g., intracranial pressure monitoring & active CSF drainage. | Acute neuroimaging may be indicated in some circumstances. 10 | |
| Treat symptomatic hypo-osmolality or worsening signs of intracranial hypertension using the following agents alone or in sequence: mannitol 0.5-1 mg/kg per dose; hypertonic (3%) saline 2-3 mEq/kg per dose; furosemide 0.5-1.0 mg/kg per dose | In those w/moderate-to-severe encephalopathy, consider administration of hypertonic (3%) saline drip: 5-15 mEq/kg per day sodium chloride titrated to serum osmolality 290-300 mOsm/kg H2O, serum sodium 138-145 mEq/L, & serum osmolality change <0.2 mOsm/kg H2O per hr (5 mOsm/kg H2O per day) | |
| General measures | ||
| Identify & treat precipitating catabolic stress (e.g., infection, dehydration, trauma). | Low clinical threshold for empiric administration of antibiotics when signs of infection are present |
|
| Schedule antipyretics (e.g., acetaminophen, ibuprofen, ketorolac) to control fever | Ketorolac contraindicated in those who are dehydrated, known to have kidney disease, or taking other medications that affect renal perfusion | |
| Antiemetics to control nausea & vomiting | Consider scheduled intravenous ondansetron 0.15 mg/kg per dose every 6-8 hours | |
| Limit use of glucocorticoids & vasoactive catecholaminergic agents | ||
| Other complications | ||
| Acute pancreatitis 11 |
| |
| Dystonia assoc w/metabolic crisis 13 | Enteral tyrosine at 100-400 mg/kg/day | Tyrosine dissolves poorly in aqueous solution, so enteral administration is typically required |
BCAAs = branch-chain amino acids (leucine, isoleucine, and valine); EER = estimated energy expenditure
- 1.
Establish central venous access; where regional expertise allows, the authors recommend placement of a peripheral intravenous central catheter (PICC) or other form of central line for treatment of metabolic intoxication.
- 2.
Parenteral MSUD amino acid solutions are the preferred protein source for individuals with MSUD who have severe metabolic encephalopathy; however, such parenteral solutions are available from a very limited number of specialty pharmacies and often prove difficult to procure in a timely manner.
- 3.
Nyhan et al [1998], Morton et al [2002]
- 4.
Nutritional therapy alone can effectively reduce even extremely elevated plasma concentrations of leucine in persons with MSUD of any age and under a wide variety of clinical circumstances [Morton et al 2002, Strauss & Morton 2003]. However, numerous publications have shown that renal replacement methods can achieve rapid corrections of branched-chain amino acids (BCAAs) and branched-chain alpha-ketoacids (BCKAs) during the acute phase of MSUD crisis [Jouvet et al 1997, Schaefer et al 1999, Yoshino et al 1999, Jouvet et al 2001, Puliyanda et al 2002].
- 5.
Schaefer et al [1999]
- 6.
A combined approach to therapy, using hemodialysis with simultaneous anabolic nutritional therapy was shown to be highly effective in one neonate with classic MSUD [Puliyanda et al 2002].
- 7.
Dialysis without simultaneous management of the underlying disturbance of protein turnover is analogous to treating diabetic ketoacidosis with invasive removal of glucose and ketones rather than insulin infusion. In both conditions, effective treatment depends not only on lowering concentrations of pathologic metabolites, but also on controlling the underlying metabolic derangement (in this case ongoing protein degradation due to catabolism).
- 8.
Most commonly associated with high intravenous fluid, glucose, and insulin infusions.
- 9.
The most commonly encountered biochemical complications of treatment are hyperglycemia, hypoglyemia, hyponatremia, hypokalemia, and hypophosphatemia.
- 10.
During episodes of acute encephalopathy, individuals with MSUD are typically too unstable for magnetic resonance imaging. Cranial CT scan is used to evaluate for major indices of cerebral edema, such as decreased volume of cerebral ventricles and basal fluid spaces, or reduced gray-white discrimination (see Figure 2). New scanners are designed for portable use in the intensive care setting.
- 11.
Signs and symptoms typically include epigastric or mid-back pain, anorexia, and/or vomiting, developing in two to three days into treatment of a metabolic decompensation.
- 12.
Kahler et al [1994]
- 13.
During acute metabolic crisis, newborns, infants, and children with MSUD can develop acute focal or generalized dystonic posturing attributed to an increased plasma leucine:tyrosine concentration ratio, restricted brain tyrosine uptake, and reduced cerebral dopamine synthesis [Morton et al 2002, Zinnanti et al 2009].
Prevention of Primary Manifestations
Table 9.
Prevention of Primary Manifestations in Individuals with Maple Syrup Urine Disease
| Manifestation/ Situation | Prevention | Considerations/Other |
|---|---|---|
| Metabolic cure | Orthotopic liver transplantation |
|
| Neuropsychiatric morbidity | Strict & consistent metabolic control 4 | |
| Potential thiamine responsiveness 5 | Consider a 4-wk trial of enteral thiamine (50-100 mg/day, divided 2x/day) | Significant changes in dietary therapy (e.g., BCAA or calorie intake) during treatment period confounds interpretation of a specific thiamine effect. |
BCAA = branched-chain amino acid; EBV = Epstein-Barr virus
- 1.
Wendel et al [1999], Bodner-Leidecker et al [2000], Strauss et al [2006], Mazariegos et al [2012]
- 2.
Strauss et al [2020]
- 3.
Shellmer et al [2011], Mazariegos et al [2012]
- 4.
Muelly et al [2013]
- 5.
The existence of "thiamine-responsive" branched-chain alpha-ketoacid dehydrogenase (BCKD) mutants is controversial.
Prevention of Secondary Complications
Any trauma care or surgical procedures should be approached in consultation with a metabolic specialist.
Surveillance
Table 10.
Recommended Surveillance for Individuals with Maple Syrup Urine Disease
| Manifestation | Evaluation | Frequency/Comment |
|---|---|---|
| Control of amino acid & other nutrient levels 1 | Full amino acid profile (either from plasma or filter paper) |
|
| Measurement of calcium, magnesium, zinc, folate, selenium & omega-3 essential fatty acid | As indicated based on clinical signs of deficiency | |
| Visit w/metabolic specialist | At least monthly in infancy | |
| Delayed acquisition of developmental milestones | Monitor developmental milestones 4,5 | At each visit or as needed |
- 1.
See Goals of laboratory monitoring (following) for target concentrations for various amino acids and other nutrients.
- 2.
The frequency of amino acid monitoring varies by age, metabolic stability, compliance, and regional clinical practice.
- 3.
The frequency of amino acid monitoring correlates directly with metabolic control [Strauss et al 2020] and long-term measures of intelligence [Muelly et al 2013].
- 4.
The Denver Developmental Screening Test II or a comparable tool is useful for monitoring development of infants and young children with MSUD.
- 5.
School-age children, adolescents, and adults should have neurocognitive testing if indicated by school performance or behavior problems [Shellmer et al 2011, Muelly et al 2013].
Goals of laboratory monitoring
- Plasma leucine concentration: 150-300 µmol/L with an age-appropriate intake
- Plasma isoleucine concentration approximately equal to plasma leucine concentration
- Plasma valine concentration at least twofold plasma leucine concentration
- Indices of calcium, magnesium, zinc, folate, selenium, and omega-3 essential fatty acid sufficiency
Evaluation of Relatives at Risk
Early diagnosis of at-risk sibs of an affected individual may allow asymptomatic infants to be managed out of the hospital by experienced providers.
Newborn at-risk sibs who have not undergone prenatal testing can be tested in one of two ways:
- Plasma amino acid analysis of a sample obtained at approximately 24 hours of life. In some laboratories, samples obtained earlier can yield false negative results.
- If the pathogenic variants have been identified in the family, a cord blood sample can be used for molecular genetic testing.
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.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
Pregnancy Management
With the advent of newborn screening and preventive care, more women with MSUD are surviving to child-bearing age. Successful delivery of a healthy baby is possible for women with classic MSUD [Van Calcar et al 1992, Grünewald et al 1998]. Two women who had biallelic pathogenic BCKDHA variants became pregnant following liver transplantation. Each delivered a healthy baby after remaining on immunosuppressant medication (sirolimus) but observing no special dietary restrictions during pregnancy [Strauss et al 2020].
Elevated maternal leucine plasma concentration, like elevated maternal phenylalanine plasma concentration, is likely teratogenic. If a woman with MSUD is planning a pregnancy, metabolic control should be maintained in a rigorous fashion preceding and throughout gestation. Keeping the maternal plasma levels of the branched-chain amino acids between 100 and 300 μmol/L is compatible with delivery of a normal infant [Grünewald et al 1998].
During the development of the placenta and fetus, maternal BCAA and protein requirements increase, and frequent monitoring of plasma amino acid concentrations and fetal growth may be necessary to avoid essential amino acid deficiencies [Grünewald et al 1998].
The postpartum period is dangerous for the affected mother. Catabolic stress of labor, involutional changes of the uterus, and internal sequestration of blood are potential sources of metabolic decompensation [Chuang & Shih 2001]. Appropriate monitoring at a metabolic referral center is advised at the time of delivery.
Therapies Under Investigation
Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions.