Maple Syrup Urine Disease, Mild Variant

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Retrieved

2019-09-22

Source

Omim

Trials

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Genes

DBT, BCKDHB, BCKDHA, BCAT2, PPM1K, DLD, ARID4B, BDNF, CTSD, SERPINE1, TNS3, CACNA2D2, MKRN3, UMOD, SPN, NME1, PAH, NBN, MEA1, IL1B, GPR4, GLI2, F2, MECP2

Drugs

Glycine, L-alanine, L-arginine, L-aspartic acid, L -cysteine, L-cystine, L- glutamic acid, L-histidine, L-lysine monohydrate, L -methionine, L- phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan, L-tyrosine, taurine, Sodium phenylbutyrate ( BUPHENYL, AMMONAPS )

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A number sign (#) is used with this entry because of evidence that a mild variant of maple syrup urine disease (MSUDMV) is caused by homozygous mutation in the PPM1K gene (611065) on chromosome 4q22. One such family has been reported.

Description

The mild variant of MSUD is characterized by increased plasma levels of branched-chain amino acids (BCAA) apparent at birth. Treatment with a low-protein diet free of BCAA can result in normal psychomotor development and lack of metabolic episodes; however, plasma levels of BCAA may remain elevated (summary by Oyarzabal et al., 2013).

For a general description and a discussion of genetic heterogeneity of maple syrup urine disease, see 248600.

Clinical Features

Oyarzabal et al. (2013) reported a 21-year-old woman with a mild variant of maple syrup urine disease. Newborn screening had detected increased blood concentrations of leucine and isoleucine, and cultured fibroblasts showed decreased leucine decarboxylation activity (14% of control values). She was started on an MSUD diet, and showed normal psychomotor development without metabolic episodes. At age 21, she worked as a nurse and had an IQ of 90. Brain MRI was normal, but blood levels of branched-chain amino and keto acids remained mildly increased.

Inheritance

The transmission pattern in the patient with MSUDMV reported by Oyarzabal et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a 21-year-old woman with a mild variant of maple syrup urine disease, Oyarzabal et al. (2013) identified a homozygous truncating mutation in the PPM1K gene (611065.0001). Her unaffected father was heterozygous for the mutation, and the proband had uniparental disomy of chromosome 4. The mutant protein was not detected in patient cells or in COS-7 cells transfected with the mutation, suggesting that it is prone to degradation and consistent with a loss of function. Transfection of patient cells with wildtype PPM1K resulted in an increase in activity of the branched-chain alpha-keto acid dehydrogenase (BCKDH) complex. In addition, patient cells showed a 2-fold increase in reactive oxygen species compared to control, suggesting an increase in metabolic stress.

Animal Model

Lu et al. (2009) found that Pp2cm-deficient mice developed defects in the catabolism of branched-chain amino acids and showed a metabolic phenotype similar to human maple syrup urine disease, with an increase in plasma concentrations of branched-chain amino acids. Pp2cm-null mice on a high protein diet showed increased neonatal lethality and increased oxidative stress.