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Intermediate maple syrup urine disease

Orpha number ORPHA268162
Synonym(s) Intermediate BCKD deficiency
Intermediate MSUD
Intermediate branched-chain 2-ketoacid dehydrogenase deficiency
Prevalence 1-9 / 1 000 000
Inheritance Autosomal recessive
Age of onset Infancy
Neonatal
ICD-10
  • E71.0
ICD-O -
OMIM
UMLS
  • C1621920
MeSH -
MedDRA -
SNOMED CT
  • 405287008

Summary

Intermediate maple syrup urine disease (MSUD; see this term) is a milder form of MSUD characterized by persistently raised branched-chain amino and keto-acids, but fewer or no acute episodes of decompensation.

The estimated birth prevalence of MSUD is 1/ 150,000. Perhaps 30% of cases are the intermediate type.

Symptom onset of intermediate MSUD varies between the early months and the early years of childhood. Infants may have feeding problems, poor growth, maple syrup odor in urine and developmental delay. Older children usually present with learning difficulties. Like classic MSUD (see this term), catabolic stress can result in acute decompensation with anorexia, vomiting, ataxia (in infants/toddlers), cognitive impairment, sleep disturbances, hallucinations, hyperactivity, mood swings, acute dystonia, choreoathetosis (in adults), stupor, coma and cerebral edema if untreated.

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 intermediate MSUD mutations in BCKDHB and DBT predominate. A mutation in the PPM1K gene (4q22.1) was found in one case.

Intermediate MSUD can be diagnosed by tandem mass spectrometry newborn screening. Otherwise, plasma amino acid analysis is diagnostic. Plasma leucine levels are increased while isoleucine and valine levels may be normal or increased. Patients have 3-30% BCKAD activity so their plasma BCAA levels are not as high as those seen in classic MSUD (see this term). Molecular genetic testing can identify a disease causing mutation, equally confirming diagnosis.

Differential diagnoses of the presenting symptoms include other inborn errors of intermediary metabolism such as NAGS deficiency, ornithine transcarbamylase deficiency, argininosuccinic aciduria (and other urea cycle defects), neonatal glycine encephalopathy, propionic methylmalonic academia, and ketoacidosis due to beta-ketothiolase deficiency (see these terms).

Prenatal diagnosis is possible in families with a known disease-causing mutation.

Intermediate MSUD is inherited autosomal recessively and genetic counseling is possible.

Treatment of intermediate MSUD is similar to classic MSUD. Infants require high calorie BCAA-free formulas, dietary leucine restriction and close outpatient monitoring at a metabolic clinic. Management of acute decompensation requires aggressive enhancement of protein anabolism using glucose plus insulin, intravenous lipids, plasma amino acid monitoring, and isoleucine and valine supplements. Patients must adhere to a strict life-long diet to avoid episodes of acute decompensation. Special monitoring during pregnancy is vital.

With early diagnosis and appropriate therapy the prognosis is good, but because the disorder is mild, diagnostic delay is common and some neurological damage may be sustained.

Expert reviewer(s)

  • Dr Bridget WILCKEN

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Detailed information

Clinical genetics review
  • EN (2013)
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