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 thiamine challenge in all individuals with MSUD except those known to be homozygous 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 thiamine supplementation to assess thiamine responsiveness (“thiamine challenge”), although several studies (F.114, F.113, F.82, F.109, F.127) have shown that thiamine 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 thiamine responsive (G.49). Some sources (G.3, F.66) have indicated that thiamine 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 thiamine response would be expected in only a minority of cases.
There was consensus (83% of MD and 100% of RD respondents either agreed or completely agreed) that all patients with MSUD should be evaluated for thiamine responsiveness.
There was not consensus (83% of MD, but only 73% of RD respondents) that thiamine responsiveness should be evaluated only after BCAA have stabilized.
There was no consensus among respondents in response to all statements regarding a thiamine challenge.
100% of MD (compared with 54% of RD) respondents agreed that a thiamine response would be expected only in those individuals with partial BCKD activity.
83% of MD (compared with 54% of RD) respondents agreed that 100mg thiamine was an adequate dosage for eliciting a thiamine response.
100% of MD (compared with 64% of RD) respondents agreed that 4 weeks was a sufficient time interval for assessing a thiamine response.
Comments: several RD respondents stated that they had no experience with administering a thiamine challenge
Initiate a thiamine challenge with a dosage 50-200 mg/day
The recommended dosages range from 10-1000 mg/day for one to four weeks. Because it is a water-soluble vitamin, reported thiamine 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 thiamine-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 thiamine.
There was not consensus (83% of MD and 73% of RD respondents) agreed that a dosage of 100 mg was appropriate for evaluating thiamine responsiveness.
Comments: one MD suggested that a higher dosage may be needed in some individuals.
There was not consensus (83% of MD and 54% of RD respondents) agreed that a dosage of 100mg was appropriate for evaluating thiamine responsiveness.
Comments: one MD felt that a response may be seen with a lower dosage in some individuals.
Evaluate response to thiamine challenge over a one month period by assessing plasma BCAA and/or tolerance for dietary BCAA.
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 thiamine. 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 thiamine response by quantifying exhaled CO2 from the metabolism of labeled leucine (increased leucine catabolism).
There was no consensus (76% of MD and 67% of RD respondents agreed) that the duration of the thiamine challenge should be at least one month unless a clear response is seen earlier..
Comments: On MD suggested that a longer trial may be necessary. One RD stated that monitoring diet was important as major changes could confound results.
There was near consensus (100% MD and 64% RD respondents agreed) that 4 weeks was sufficient time to determine a thiamine response.
Maintain thiamine supplementation and appropriate dietary BCAA restriction in thiamin-responsive individuals.
No studies have reported thiamine 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 thiamine supplementation was increased systematically from 10mg to 100mg to 1000mg per day.
There was no consensus (67% of MD and 64% of RD respondents agreed) that some continued BCAA restriction in thiamine-responsive individuals was necessary.