Intermittent Maple Syrup Urine Disease

Intermittent maple syrup urine disease (intermittent MSUD) is a mild form of MSUD (see this term) where patients (when well) are asymptomatic with normal levels of branched-chain amino acids (BCAAs) but with catabolic stress are at risk of acute decompensation with ketoacidosis, which can lead to cerebral edema and coma if untreated.

Epidemiology

MSUD has an estimated incidence of 1/150,000 live births. There is no data to suggest what number of patients has intermittent MSUD but it is probably underdiagnosed.

Clinical description

Unlike classic MSUD (see this term), patients with intermittent MSUD show normal growth and intellectual development during infancy and childhood. They may develop symptoms (mainly in childhood) with any catabolic stress (i.e. fasting, dehydration, fever, infections or pregnancy (in adults)). These precipitating factors can lead to a potentially fatal episode of acute decompensation with anorexia, nausea, vomiting, lethargy, ataxia (in infants/toddlers), cognitive impairment, sleep disturbances, hallucinations, hyperactivity, mood swings, acute dystonia, and choreoathetosis (in adults), that can progress to stupor, coma and cerebral edema. Intelligence and development are not usually affected by these episodes.

Etiology

MSUD is due to mutations in genes encoding 3 of the 4 subunits of the branched-chain 2-ketoacid dehydrogenase (BCKAD) complex. The genes are BCKDHA (19q13.1-q13.2), encoding E1a, BCKDHB (6q14.1), encoding E1b, and DBT (1p31), encoding E2 respectively. Mutations lead to an accumulation of BCAAs (especially leucine) and branched-chain alpha-ketoacids. In intermittent MSUD, mutations in DBT may predominate.

Diagnostic methods

Intermittent MSUD may be missed on tandem mass spectrometry newborn screening. BCAA levels are usually normal or only slightly elevated, except during times of physiological stress when the biochemical profile is similar to classic MSUD. Ketonuria and gas chromatography-mass spectrometry can also identify branched-chain alpha ketoacids (BCKAs) in the urine during decompensation only.

Differential diagnosis

Differential diagnoses of the presenting symptoms may 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 acidemia and beta-ketothiolase deficiency (see these terms).

Antenatal diagnosis

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

Genetic counseling

Inheritance is autosomal recessive and genetic counseling is possible.

Management and treatment

Patients with intermittent MSUD tolerate a normal intake of leucine and treatment is not necessary. However, they need regular review at a metabolic clinic and a management strategy to avoid acute decompensation including a high-energy, low-protein diet during illness. Management of acute decompensation requires aggressive enhancement of protein anabolism which may include using glucose plus insulin, intravenous lipids, plasma amino acid monitoring, and isoleucine and valine supplements.

Prognosis

The prognosis is good if metabolic control is maintained during times of stress and any episodes of acute decompensation are immediately treated.