Reviewer's report
Title:Macro-AST: Misleading Finding in an Adolescent with MCAD-deficiency
Version: 1Date:25 May 2012
Reviewer: Terry Derks
Reviewer's report:
It is an interesting observation (macro-AST in an MCADD-patient) and the
possibility of macro-AST deserves attention in every patient with unexplained
increased AST concentrations.
Major Compulsory Revisions
- This case report brings up several questions. This reviewer questions the
novelty of this observation, including the interpretation of the findings. Macro-AST
is a phenomenon, which was already described > 25 years ago. The prevalence
in the general population is 0.5-2.5% (Ref: summarized by Lee et al. Dig Dis Sci
2011). In the group of inborn errors of metabolism MCADD is probably relatively
prevalent. As there is no generally agreed protocol for follow-up of these patients,
the rate of detecting this abnormality/variation depends on the rate we perform
this test. Any form of routine investigation carries a risk of finding abnormalities,
of which macro-AST is just one example.
- This reviewer feels that some relationships are presented to be causal. This
needs to be motivated by the authors, or changed. The abstract contains an
example: “AST was probably……due to an allergic disposition.” This is a
hypothesis and cannot be stated firmly, unless the type of Ig in this
complex-formation was identified. As long as the authors do not report this, it is
speculative. Moreover, the correlation between clinical symptoms and signs of
atopy/allergy do not strongly correlate with serum concentrations of IgE (Ref:
Sampson HA. J Allergy Clin Immunol 2004). DO the authors know whether the
prevalence of macro-enzymes is positively correlated with blood concentrations
of Ig’s, irrespective of the type (IgA, IgG, IgG, IgE)? In other words: are increased
concentrations necessary to make these macro-complexes? Another thought: in
many cases, especially in strong allergy, there is a genetic/familial predisposition.
Were there family members with increased IgE and macro-AST, too?
- The general……MCAD-deficiency”. Together with a sentence in the discussion,
the impression has been given, that the ideas of the general practitioner were not
right, or even strange. However, the authors do not state exactly WHY AST was
determined in the first place. But subsequently, the next step to study the
possibility of macro-AST can only be taken AFTER exclusion of organ damage.
Therefore this reviewer thinks (based on what was written in the manuscript) that
this was a very good decision from the general practitioner to refer the child, but
irrespective of this finding. This also is related to point, that there is no general
follow-up protocol.
- This reviewer disagrees that the occasional finding of macro-AST in one
MCADD-case should be an argument of regular consulting a metabolic specialist.
The relative rarity of the disease and the fact that we did not yet describe the full
natural history of the disorder are the main arguments for regular follow-up.
Then, obviously regular (which is clearly different from frequent!) follow up
ensures that we will describe the phenotype to the best of our capacities and pick
up abnormalities as soon as they occur.
- “In anabolism……function occur”. This is not true. In most MCADD-patients
acylcarnitines, urinary organic acids determined by GC-MS and free fatty acid
profile (whenever performed) remain abnormal, also in anabolism. In the case
presentation, the authors also mention de abnormality of medium-chain length
acylcarnitines.
- There are several reasons to address the possibility of organ damage very
carefully. Firstly, because of the metabolite profiles in MCAD-deficient patients.
There is many experimental evidence from in vitro studies and animal models,
that these metabolites may lead to mitochondrial dysfunction and/or oxidative
damage. Secondly, because there are no large follow-up studies of well-defined
cohorts of MCAD-deficient patients until late adulthood. Thirdly, other inborn
errors of mitochondrial fatty acid oxidation demonstrate that later in life,
involvement of other organs may be predominant (for instance the muscle in
LCHADD, associated with hyper-CK).
Minor Essential Revisions
Abstract:
- Spells: It should not be encouraged the use of this word, as for many
pediatricians it is closely linked to Fallot’s Tetralogy. In the Background the
authors use the word ‘decompensation’, which seems more appropriate to me.
Background:
- “This is……during catabolism/fasting”. The pathophysiology of hypoglycemia in
these patients is probably more complex than explained by the authors. I would
like to refer to many mechanistic studies in knock-out mouse models, but also
nice case reports (like for instance Bougneres et. al. J Pediatr 1981).
Conclusion:
- Adolescence instead of adolescene.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests.
Reviewer's report
Title:Macro-AST: Misleading Finding in an Adolescent with MCAD-deficiency
Version: 1Date:25 May 2012
Reviewer: Terry Derks
Reviewer's report:
It is an interesting observation (macro-AST in an MCADD-patient) and the
possibility of macro-AST deserves attention in every patient with unexplained
increased AST concentrations.
Major Compulsory Revisions
- This case report brings up several questions. This reviewer questions the
novelty of this observation, including the interpretation of the findings. Macro-AST
is a phenomenon, which was already described > 25 years ago. The prevalence
in the general population is 0.5-2.5% (Ref: summarized by Lee et al. Dig Dis Sci
2011). In the group of inborn errors of metabolism MCADD is probably relatively
prevalent. As there is no generally agreed protocol for follow-up of these patients,
the rate of detecting this abnormality/variation depends on the rate we perform
this test. Any form of routine investigation carries a risk of finding abnormalities,
of which macro-AST is just one example.
- This reviewer feels that some relationships are presented to be causal. This
needs to be motivated by the authors, or changed. The abstract contains an
example: “AST was probably……due to an allergic disposition.” This is a
hypothesis and cannot be stated firmly, unless the type of Ig in this
complex-formation was identified. As long as the authors do not report this, it is
speculative. Moreover, the correlation between clinical symptoms and signs of
atopy/allergy do not strongly correlate with serum concentrations of IgE (Ref:
Sampson HA. J Allergy Clin Immunol 2004). DO the authors know whether the
prevalence of macro-enzymes is positively correlated with blood concentrations
of Ig’s, irrespective of the type (IgA, IgG, IgG, IgE)? In other words: are increased
concentrations necessary to make these macro-complexes? Another thought: in
many cases, especially in strong allergy, there is a genetic/familial predisposition.
Were there family members with increased IgE and macro-AST, too?
- The general……MCAD-deficiency”. Together with a sentence in the discussion,
the impression has been given, that the ideas of the general practitioner were not
right, or even strange. However, the authors do not state exactly WHY AST was
determined in the first place. But subsequently, the next step to study the
possibility of macro-AST can only be taken AFTER exclusion of organ damage.
Therefore this reviewer thinks (based on what was written in the manuscript) that
this was a very good decision from the general practitioner to refer the child, but
irrespective of this finding. This also is related to point, that there is no general
follow-up protocol.
- This reviewer disagrees that the occasional finding of macro-AST in one
MCADD-case should be an argument of regular consulting a metabolic specialist.
The relative rarity of the disease and the fact that we did not yet describe the full
natural history of the disorder are the main arguments for regular follow-up.
Then, obviously regular (which is clearly different from frequent!) follow up
ensures that we will describe the phenotype to the best of our capacities and pick
up abnormalities as soon as they occur.
- “In anabolism……function occur”. This is not true. In most MCADD-patients
acylcarnitines, urinary organic acids determined by GC-MS and free fatty acid
profile (whenever performed) remain abnormal, also in anabolism. In the case
presentation, the authors also mention de abnormality of medium-chain length
acylcarnitines.
- There are several reasons to address the possibility of organ damage very
carefully. Firstly, because of the metabolite profiles in MCAD-deficient patients.
There is many experimental evidence from in vitro studies and animal models,
that these metabolites may lead to mitochondrial dysfunction and/or oxidative
damage. Secondly, because there are no large follow-up studies of well-defined
cohorts of MCAD-deficient patients until late adulthood. Thirdly, other inborn
errors of mitochondrial fatty acid oxidation demonstrate that later in life,
involvement of other organs may be predominant (for instance the muscle in
LCHADD, associated with hyper-CK).
Minor Essential Revisions
Abstract:
- Spells: It should not be encouraged the use of this word, as for many
pediatricians it is closely linked to Fallot’s Tetralogy. In the Background the
authors use the word ‘decompensation’, which seems more appropriate to me.
Background:
- “This is……during catabolism/fasting”. The pathophysiology of hypoglycemia in
these patients is probably more complex than explained by the authors. I would
like to refer to many mechanistic studies in knock-out mouse models, but also
nice case reports (like for instance Bougneres et. al. J Pediatr 1981).
Conclusion:
- Adolescence instead of adolescene.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests.
Please review this paper.
user
Reviewer's report
Title:Macro-AST: Misleading Finding in an Adolescent with MCAD-deficiency
Version: 1Date:25 May 2012
Reviewer: Terry Derks
Reviewer's report:
It is an interesting observation (macro-AST in an MCADD-patient) and the
possibility of macro-AST deserves attention in every patient with unexplained
increased AST concentrations.
Major Compulsory Revisions
- This case report brings up several questions. This reviewer questions the
novelty of this observation, including the interpretation of the findings. Macro-AST
is a phenomenon, which was already described > 25 years ago. The prevalence
in the general population is 0.5-2.5% (Ref: summarized by Lee et al. Dig Dis Sci
2011). In the group of inborn errors of metabolism MCADD is probably relatively
prevalent. As there is no generally agreed protocol for follow-up of these patients,
the rate of detecting this abnormality/variation depends on the rate we perform
this test. Any form of routine investigation carries a risk of finding abnormalities,
of which macro-AST is just one example.
- This reviewer feels that some relationships are presented to be causal. This
needs to be motivated by the authors, or changed. The abstract contains an
example: “AST was probably……due to an allergic disposition.” This is a
hypothesis and cannot be stated firmly, unless the type of Ig in this
complex-formation was identified. As long as the authors do not report this, it is
speculative. Moreover, the correlation between clinical symptoms and signs of
atopy/allergy do not strongly correlate with serum concentrations of IgE (Ref:
Sampson HA. J Allergy Clin Immunol 2004). DO the authors know whether the
prevalence of macro-enzymes is positively correlated with blood concentrations
of Ig’s, irrespective of the type (IgA, IgG, IgG, IgE)? In other words: are increased
concentrations necessary to make these macro-complexes? Another thought: in
many cases, especially in strong allergy, there is a genetic/familial predisposition.
Were there family members with increased IgE and macro-AST, too?
- The general……MCAD-deficiency”. Together with a sentence in the discussion,
the impression has been given, that the ideas of the general practitioner were not
right, or even strange. However, the authors do not state exactly WHY AST was
determined in the first place. But subsequently, the next step to study the
possibility of macro-AST can only be taken AFTER exclusion of organ damage.
Therefore this reviewer thinks (based on what was written in the manuscript) that
this was a very good decision from the general practitioner to refer the child, but
irrespective of this finding. This also is related to point, that there is no general
follow-up protocol.
- This reviewer disagrees that the occasional finding of macro-AST in one
MCADD-case should be an argument of regular consulting a metabolic specialist.
The relative rarity of the disease and the fact that we did not yet describe the full
natural history of the disorder are the main arguments for regular follow-up.
Then, obviously regular (which is clearly different from frequent!) follow up
ensures that we will describe the phenotype to the best of our capacities and pick
up abnormalities as soon as they occur.
- “In anabolism……function occur”. This is not true. In most MCADD-patients
acylcarnitines, urinary organic acids determined by GC-MS and free fatty acid
profile (whenever performed) remain abnormal, also in anabolism. In the case
presentation, the authors also mention de abnormality of medium-chain length
acylcarnitines.
- There are several reasons to address the possibility of organ damage very
carefully. Firstly, because of the metabolite profiles in MCAD-deficient patients.
There is many experimental evidence from in vitro studies and animal models,
that these metabolites may lead to mitochondrial dysfunction and/or oxidative
damage. Secondly, because there are no large follow-up studies of well-defined
cohorts of MCAD-deficient patients until late adulthood. Thirdly, other inborn
errors of mitochondrial fatty acid oxidation demonstrate that later in life,
involvement of other organs may be predominant (for instance the muscle in
LCHADD, associated with hyper-CK).
Minor Essential Revisions
Abstract:
- Spells: It should not be encouraged the use of this word, as for many
pediatricians it is closely linked to Fallot’s Tetralogy. In the Background the
authors use the word ‘decompensation’, which seems more appropriate to me.
Background:
- “This is……during catabolism/fasting”. The pathophysiology of hypoglycemia in
these patients is probably more complex than explained by the authors. I would
like to refer to many mechanistic studies in knock-out mouse models, but also
nice case reports (like for instance Bougneres et. al. J Pediatr 1981).
Conclusion:
- Adolescence instead of adolescene.
Level of interest: An article whose findings are important to those with closely
related research interests
Quality of written English: Acceptable
Statistical review: No, the manuscript does not need to be seen by a
statistician.
Declaration of competing interests:
I declare that I have no competing interests.
assistant