Maple Syrup Urine Disease (MSUD)

Branched-chain ketoacid dehydrogenase (BCKD) deficiency

Branched-chain ketoaciduria

E71.0, Maple-syrup-urine disease

Amino acidemia

Elevated leucine, isoleucine, alloisoleucine, and valine along with an elevated (leucine+isoleucine)/alanine ratio

Tandem mass spectrometry (MS/MS); sensitivity=94.2%; specificity=99.9%; milder or variant forms of the disease can be missed by newborn screening [Schulze: 2003] [Puckett: 2010]

With treatment, normal IQ and development can occur if treatment is initiated before permanent damage is incurred from the initial and subsequent metabolic crises. Long-term management may consist of a protein/BCAA restricted diet, supplementation of deficient amino acids, and a general avoidance of metabolic stress. One variant may be responsive to thiamine. However, proper metabolic control is difficult to achieve. Patients with MSUD remain at high risk for metabolic crises that can result in cognitive impairment, executive dysfunction, emotional strain, and social dependence. [Strauss: 2020] Treatment of metabolic crises should be initiated by a metabolic specialist to rapidly reduce plasma leucine by reversal of catabolism and, in some cases, dialysis.

Without treatment, profound developmental delays and neurologic disturbances such as seizures and ataxia can be expected. In Classic MSUD, symptoms typically occur in the first few days of life after an initial symptom-free period. One of the first signs can be cerumen smelling of maple syrup, followed by irritability, excessive sleepiness, poor feeding, vomiting, and tachypnea. The characteristic maple syrup-odor urine coincides with worsening encephalopathy, and finally, brain edema with increased intracranial pressure can lead to cerebellar herniation, compression of the brainstem, coma, and death. Because of the rapid onset, severe symptoms may be present before screening results are reported or treatment begins.

Untreated Intermediate and Intermittent MSUD can have much more variable presentations, including later onset of symptoms with typically less severe neurological impairment and, in some cases, metabolic decompensation. These other forms may present with anorexia, poor growth, irritability, or developmental delay in late infancy or childhood. Urine may also have a maple syrup odor, especially during metabolic crises. Symptoms and metabolic crisis episodes may be precipitated by illnesses or other triggers, such as fasting. [Strauss: 2020]

The incidence of MSUD in the USA is approximately 1:198,000. [Therrell: 2014]

Autosomal recessive

• Urgently contact the family and evaluate the infant for poor feeding, lethargy, irregular breathing pattern, or other symptoms described above.
• Provide emergency treatment and referral for lethargy, tachypnea, alternating hypertonia/hypotonia, or seizures. See ACT Sheet for Maple Syrup Urine Disease (ACMG) ( 369 KB).
• Discontinue breast or cow milk formula feeding and substitute with a special BCAA-free MSUD formula.

• To confirm the diagnosis, work with Newborn Screening Services (see ID providers [22]).
• The diagnosis is confirmed by measurement of plasma amino acids (elevated leucine, isoleucine, alloleucine, valine) and urine organic acid analysis (abnormal branched-chain ketoacids). Hydroxyprolinemia, a benign condition, can cause abnormal newborn screening for MSUD since hydroxyproline has the same mass/charge ratio of leucine/isoleucine. [Strauss: 2006]
• Molecular genetic testing can confirm the diagnosis by identifying the causative gene variant but should not delay treatment in symptomatic patients. Associated genes include BCKDHA, BCKDHB, and DBT.

• For evaluation and ongoing collaborative management, particularly for dietary management and prompt management of illnesses resulting in metabolic stress (i.e., fever, vomiting, poor oral intake), consult Biochemical Genetics (Metabolics) (see ID providers [2]).
• Educate the family about signs, symptoms, and the need for urgent care if the infant becomes ill. See Maple Syrup Urine Disease - Information for Parents (STAR-G).
• Facilitate Genetic Testing and Counseling (see ID providers [9]) for the family.
• Support initiation and maintenance of dietary restriction of BCAAs (found in animal and vegetable food sources) and use of medical formulas. Provide protein as essential, and non-essential amino acids and supplementation with isoleucine or valine as needed. Consider thiamine for children with the thiamine-responsive variant.
• See newborns readily when illness occurs since that is the primary cause of decompensation.
• Refer infants at risk for developmental delays for assessment and support to Early Intervention for Children with Disabilities/Delays (see ID providers [149]).