Thiamin pyrophosphate is a co-factor for the multi-subunit enzyme, branched chain a-ketoacid dehydrogenase (BCKD) and is an adjunct to be considered in the treatment regime for MSUD. Because it is a water-soluble vitamin, reported thiamin dosages have varied from 10-1000 mg/day and have been given for extended periods of time in both the newborn period and later without any reported toxic side-effects. Patients with MSUD for whom supplemental thiamin has increased dietary branched chain amino acid (BCAA) tolerance (or decreased plasma BCAA on a constant dietary intake), appear to be only those with some residual BCKD activity, especially those with E2 mutations. Patients should be continued on a BCAA restricted diet during the assessment of the thiamin response, as well as during long-term supplementation. Studies have reported a thiamin response is apparent within one month.
Perform a thiamin challenge in all individuals with MSUD except those known to be homozyfous for the1312T>A mutation or other mutations resulting in less than 3% BCKD enzyme activity.
There are no publications that evaluate specific criteria for initiating thiamin supplementation to assess thiamin responsiveness (“thiamin challenge”), although several studies (F.114, F.113, F.82, F.109, F.127) have shown that thiamin response is significant only in individuals who have some residual enzyme activity and/or have mutations in the E2 (versus E1) subunit. Patients with the (1312T>A) mutation, which codes for an E1 subunit with 0-3% activity, are not thiamin responsive (G.49). Some sources (G.3, F.66) have indicated that thiamin was routinely given to all patients with MSUD, and given at the initiation of dietary treatment before plasma BCAA concentrations were reduced to the treatment range. However, with approximately 80% of all cases of MSUD having the classical form, with 0-3% BCKD activity (G.50), a thiamin response would be expected in only a minority of cases.
In the Delphi 1, 82% either agreed or completely agreed that all patients with MSUD should be evaluated for thiamin responsiveness. There was no consensus whether thiamin responsiveness should be evaluated only after BCAA have stabilized. There was a discrepancy between the responses from the metabolic dietitians and the physicians in the Delphi 2. Physicians agreed that responders would be only those patients with partial BCKD activity (100%). The dietitians commented that they had little experience with the thiamin challenge.
Initiate a thiamin challenge with a dosage 50-200mg/day
The recommended dosages range from 10-1000 mg/day for one to four weeks. Because it is a water-soluble vitamin, reported thiamin dosages up to 1000 mg/day have been given for extended periods of time in both the newborn period and later without any reported toxic side-effects (Y.2). The initial thiamin-responsive patient required only 10 mg/day to show a response (F.119). A systematic study (F.109) of 4 children between 17 mos and 9 years found that 150-200 mg per day was sufficient to decrease plasma BCAA by 37-66% in four weeks in three of the four children. In this study, one child, with <1% BCKD activity did not respond to the thiamin.
76% (Delphi 1) and 59% (Delphi 2) agreed that a dosage of 100 mg was appropriate for testing responsiveness. There was a discrepancy between the responses from the metabolic dietitians and the physicians in the Delphi 2. Physicians agreed that a dosage of 100mg thiamin would be adequate (83%). The dietitians commented that they had little experience with the thiamin challenge.
Evaluate response to thiamin challenge over a one month period by assessing plasma BCAA and/or tolerance for dietary BCAA.
Evidence: A systematic study (F.109) of 4 children between 17 mos and 9 years found that 150-200 mg per day was sufficient to decrease plasma BCAA by 37-66% in four weeks in three of the four children. In this study, one child with <1% BCKD activity did not respond to the thiamin. Response has been assessed by a drop in blood levels of BCAA and BCKA on a defined intake of BCAA or an increase in BCAA tolerance (G.43). Research studies (F.101) have shown that it is possible to evaluate thiamin response by quantifying exhaled CO2 from the metabolism of labeled leucine (increased leucine catabolism).
71% (Delphi 1) and 76% (Delphi 2)agreed that the duration of a trial of thiamin responsiveness should be at least one month unless a clear response is seen sooner
Maintain thiamin supplementation and appropriate dietary BCAA restriction in thiamin-responsive individuals.
No studies have reported thiamin supplementation as the sole treatment for MSUD; all patients had some restriction of dietary BCAA. A single study (F.113) demonstrated that complete BCAA normalization was not possible without dietary BCAA restriction even when thiamin supplementation was increased systematically from 10mg to 100mg to 1000mg
The need for some continued BCAA restriction in thiamin responders was agreed to by 65% of those taking the Delphi 2.