Carnitine supplementation for treating people with inborn errors of metabolism

Carnitine supplementation for inborn errors of metabolism

(Review)

Nasser M, Javaheri H, Fedorowicz Z, Noorani Z

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2012, Issue 2

http://www.thecochranelibrary.com

Carnitine supplementation for inborn errors of metabolism (Review)

Copyright © 2015 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

3METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

6RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

7AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

8REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

14APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

22HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

23DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

24INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

iCarnitine supplementation for inborn errors of metabolism (Review)


[Intervention Review]

Carnitine supplementation for inborn errors of metabolism

Mona Nasser1, Hoda Javaheri2, Zbys Fedorowicz3 , Zaman Noorani4

1Peninsula Dental School, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, UK. 2Animal Science research

Institute, Karaj, Iran. 3Bahrain Branch, Cochrane, Awali, Bahrain. 4Ciris Clinic, National Iranian Offshore Oil Company (NIOOC),

Karaj, Iran

Contact address: Mona Nasser, Peninsula Dental School, Plymouth University Peninsula Schools of Medicine and Dentistry, The John

Bull Building, Tamar Science Park„ Plymouth, PL6 8BU, UK. [email protected]. [email protected].

Editorial group: Cochrane Cystic Fibrosis and Genetic Disorders Group.

Publication status and date: Edited (no change to conclusions), published in Issue 4, 2015.

Review content assessed as up-to-date: 3 January 2012.

Citation: Nasser M, Javaheri H, Fedorowicz Z, Noorani Z. Carnitine supplementation for inborn errors of metabolism. CochraneDatabase of Systematic Reviews 2012, Issue 2. Art. No.: CD006659. DOI: 10.1002/14651858.CD006659.pub3.


A B S T R A C T

Background

Inborn errors of metabolism are genetic conditions which can lead to abnormalities in the synthesis and metabolism of proteins,

carbohydrates, or fats. It has been proposed that in some instances carnitine supplementation should be provided to infants with

a suspected metabolic disease as an interim measure, particularly whilst awaiting test results. Carnitine supplementation is used in

the treatment of primary carnitine deficiency, and also where the deficiency is a secondary complication of several inborn errors of

metabolism, such as organic acidaemias and fatty acid oxidation defects in children and adults.

Objectives

To assess the effectiveness and safety of carnitine supplementation in the treatment of inborn errors of metabolism.

Search methods

We searched the Cystic Fibrosis and Genetic Disorders Group’s Inborn Errors of Metabolism Trials Register, the Cochrane Central

Register of Controlled Trials (The Cochrane Library 2007, Issue 4) and MEDLINE via Ovid (1950 to July week 4 2007), LILACS (15/

05/2008) and Iranmedex (15/05/2008) and also the reference lists of retrieved articles.

Date of most recent search of the Group’s Inborn Errors of Metabolism Register: 27 October 2011.

Selection criteria

Randomised controlled trials and quasi-randomised controlled trials comparing carnitine supplementation (in different dose, frequency,

or duration) versus placebo in children and adults diagnosed with an inborn error of metabolism.

Data collection and analysis

Two authors independently screened and assessed the eligibility of the identified trials.

Main results

No trials were included in the review.

1Carnitine supplementation for inborn errors of metabolism (Review)


mailto:[email protected]

mailto:[email protected]

Authors’ conclusions

There are no published or ongoing randomised controlled clinical trials relevant to this review question. Therefore, in the absence of any

high level evidence, clinicians should base their decisions on clinical experience and in conjunction with preferences of the individual

where appropriate. This does not mean that carnitine is ineffective or should not be used in any inborn error of metabolism. However,

given the lack of evidence both on the effectiveness and safety of carnitine and on the necessary dose and frequency to be prescribed, the

current prescribing practice should continue to be observed and monitored with care until further evidence is available. Methodologically

sound trials, reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement, are required. It should be

considered whether placebo-controlled trials in potentially lethal diseases, e.g. carnitine transporter disorder or glutaric aciduria type I,

are ethical.

P L A I N L A N G U A G E S U M M A R Y

Carnitine supplements for treating people with inborn errors of metabolism

Inborn errors of metabolism are genetic disorders which have a wide range of symptoms. These often start at or soon after birth but may

appear first at any time during adulthood. Affected individuals may need to deal with symptoms of the disease throughout their lifetime.

Symptoms are often non-specific and may affect any organ. It can be difficult to diagnose an inborn error of metabolism. However,

early detection is important and screening of infants for some disorders, such as phenylketonuria, is routine in several countries. It is

recommended that carnitine supplements are prescribed in the diet of individuals with certain inborn errors of metabolism, along with

other standard treatments. Carnitine supplements take the form of tablet, oral liquid, paediatric liquid and injection and might be

taken with food for ease of administration. Unfortunately, we did not find any good quality trials to include in the review. This does not

mean that carnitine is ineffective or should not be used in treating inborn errors of metabolism; however, individuals receiving carnitine

should be carefully observed and monitored. Therefore, we recommend that clinicians base their decision to prescribe carnitine on

clinical experience together with individual preferences. Future trials should include patient-reported outcomes using validated and

internationally recognised scales. Any adverse events associated with the treatment should be reported. It should be carefully considered

whether placebo-controlled trials in potentially lethal diseases, e.g. carnitine transporter disorder or glutaric aciduria type I, are ethical.

B A C K G R O U N D

Inborn errors of metabolism (IEMs) are genetic conditions caused

by defects in enzymes or faulty transport proteins. They can lead

to abnormalities in the synthesis and metabolism (biochemical

procedures) of proteins, carbohydrates, or fats.

These disorders usually involve multiple organ systems; they can be

life-threatening or may include intervals without apparent symp-

toms, but with slow and progressive degeneration in health over

extended periods of time.

Aetiology and prevalence

There are over 500 inherited biochemical disorders, which vary in

age of onset, clinical severity, and often also mode of inheritance.

A number of these are quite rare (1 in 500,000), whilst the most

common disorders occur in 1 in 100 individuals (Winter 1998).

Inborn errors of metabolism are mainly caused by the lack of a

specific enzyme, or a transmembrane transporter, or similar pro-

tein; this results in a blockage of the metabolic pathway (biochem-

ical procedure) with a consequent build up of toxic metabolites

(Pollitt 1997; Seymour 1997). Carnitine helps in the consump-

tion and disposal of fat in the body and is an essential requirement

in the delivery of long-chain fatty acids for the oxidation process

which takes place in the mitochondria of the cell. Carnitine is also

involved in the removal of toxic waste products of this oxidation

process (Seymour 1997).

To limit the possibility of any serious permanent neurological dam-

age in children, the early identification of high risk individuals is

essential and should be followed by the provision of prompt and

appropriate treatment aimed at metabolic stabilization (Leonard

2006; Pollitt 1997).



http://www.consortstatement.org/







Diagnosis and symptoms

Inborn errors of metabolism have unique biochemical pheno-

types (patterns), which permit diagnoses by biochemical labora-

tory tests. However, and quite problematically, their clinical symp-

toms may often be indistinguishable from other infancy disorders

and diseases (Lepage 2006) and may even vary quite markedly

between individuals (Pollitt 1997).

Symptoms of IEMs can often be observed at or soon after birth,

or there may have been indications (complications) during preg-

nancy. However, symptoms may also first appear at any time dur-

ing life. Several disorders may be present at birth, such as early-

onset seizures, severe hypotonia (low muscle tone), ascites (accu-

mulation of fluid in the peritoneal cavity) or hydrops fetalis (se-

vere swelling in the fetus and newborn), and dysmorphic syn-

dromes (facial malformations). Even though many of the affected

babies appear reasonably healthy at birth, deterioration can oc-

cur quite rapidly and may lead to coma and even death after a

seemingly symptom-free period (Leonard 2006). As a result of this

wide variation in presentation, the differential diagnosis of IEMs

can be quite complex (Wilcken 2003). Early detection of these

metabolic abnormalities is paramount and screening of infants for

some IEMs, such as phenylketonuria, is a routine procedure in a

number of countries (Wilcken 2003).

A variety of tests may be required to make a definitive diagno-

sis, potentially involving a number of time-consuming and highly

specialised metabolic investigations; therefore, some form of in-

terim management may need to be instituted whilst awaiting test

results.

Treatment options

The severity of symptoms will generally dictate the management

strategy of IEMs. Due to the national screening programs for IEMs

in several countries, more individuals are being diagnosed, but

unfortunately some of these disorders do not have useful treat-

ment options and supportive care is indicated. They often require

changes in diet which is dependant on the specific metabolic dis-

ease. However, the majority of small molecule disorders (defects of

amino acid, organic acid and fatty acid metabolism) can be treated

by a combination of firstly removing toxic metabolites using dial-

ysis in an acute situation; secondly, reducing catabolism; and fi-

nally, by using diet to reduce the accumulation of toxic metabo-

lites, restricting and substituting precursors (the primary compo-

nent which enters a biochemical procedure) such as proteins, or

specific carbohydrates or fatty acids (Leonard 2006). For some dis-

orders, other therapies may be useful, of which one of these could

be carnitine medication.

Carnitine

Primary carnitine deficiency, due to mutations in the carnitine

transporter, is a rare disorder, but secondary carnitine deficiency

is a recognised secondary complication of several IEMs, especially

the organic acidaemia and fatty acid oxidation defects. Carnitine is

an amino acid derivative and has multiple physiological functions

in several major metabolic pathways. It plays a critical role in the

intermediary metabolism of fatty acids and the transport across

mitochondrial membranes, and in the ultimate removal of their

accumulated metabolites (Evangeliou 2003).

Even though it is estimated that only half of all IEMs can be treated

biochemically, it has been proposed that carnitine supplementa-

tion should, under some circumstances, be provided to infants

with a suspected metabolic disease as an interim measure, particu-

larly whilst awaiting test results (Chakrapani 2001). The primary

defect in many of these disorders of organic acid metabolism is

enzymatic, meaning supplementation is unlikely to correct the en-

zyme abnormality; nevertheless, L-carnitine may still represent a

useful therapeutic pathway specifically for the removal of accumu-

lated toxic metabolites in IEMs.

A Cochrane Review did not find any evidence to support the rou-

tine supplementation of parenterally fed neonates with L-carni-

tine (Cairns 2000). However, L-carnitine has been used in the

acute and long-term treatment of people with IEMs, such as dis-

orders of organic acid and fatty acid metabolism, i.e. propionic

acidaemia (PA); methylmalonic acidaemia (MMA); isovaleric aci-

daemia (IVA); and medium chain acyl-CoA (MCAD) deficiency.

The drug was approved by the Food and Drug Administration

(FDA) in the USA in 1992, and is generally considered to be a

cheap, safe and apparently effective therapeutic measure for treat-

ing IEMs (Itoh 1996; Walter 2003; Winter 2003).

O B J E C T I V E S

To evaluate the effectiveness and safety of carnitine supplementa-

tion in the treatment of IEMs.

M E T H O D S

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs). Trials with quasi-ran-

domised methods, such as alternation, were included if there was

sufficient evidence that the treatment and control groups were

similar at baseline.

Types of participants

Children and adults diagnosed with an IEM.



Types of interventions

Intravenous or oral carnitine supplementation (in different dose,

frequency, or duration) versus placebo or no supplementation.

Studies which had permitted concomitant therapy were included

provided this therapy was distributed similarly between the two

groups.

Types of outcome measures

Primary Outcomes

1. Changes in measures of growth (weight gain, body mass

index (BMI), growth velocity z score, height z score or other

indices of nutritional status and growth)

2. Measures of neuropsychological performance (e.g.

attention, verbal fluency, verbal learning and memory) by

validated instruments

3. Number of deaths or age at death in each group

Secondary Outcomes

1. Changes of eating behaviour

2. Measures of neurodevelopment by validated instruments

(e.g. measures of intelligence (intelligence quotient (IQ))

3. Muscle strength

4. Measures of endurance

5. Quality of life as assessed by any validated disease specific or

generic instrument

6. Number of hospital admissions

7. Biochemical outcomes

i) level of plasma carnitine (levels of acyl carnitine, i.e.

levels of octanoylcarnitine for medium-chain acyl-CoA

dehydrogenase deficiency) relative to age-related normal

concentrations

ii) liver function tests (change in aspartate and alanine

aminotransferase levels)

iii) changes in serum high density lipoprotein (HDL)

cholesterol levels

iv) changes in serum triglyceride concentration

v) changes in serum low density lipoprotein (LDL)

cholesterol levels

Adverse effects

We considered any clinically diagnosed toxicity and any reported

unacceptable adverse events associated with this medication.

Search methods for identification of studies

There were no language restrictions on included studies and we

have arranged to translate and report any relevant non-English

papers.

Electronic searches

We searched the Cystic Fibrosis and Genetic Disorders Group’s

Inborn Errors of Metabolism Trials Register using the terms: car-

nitine AND (other IEMs OR PKU OR hyperlip*).

The Inborn Errors of Metabolism Trials Register was compiled

from electronic searches of the Cochrane Central Register of

Controlled Trials (Clinical Trials) (updated each new issue of

The Cochrane Library), quarterly searches of MEDLINE and the

prospective handsearching of the Journal of Inherited MetabolicDisease. Unpublished work was identified by searching through

the abstract books of the Society for the Study of Inborn Errors of

Metabolism conference and the SHS Inborn Error Review Series.

For full details of all searching activities for the register, please see

the relevant section of the Cystic Fibrosis and Genetic Disorders

Group Module.

We also searched the Iranmedex databases (www.iranmedex.com)

which is a national database containing the articles published in

Iranian health care journals and LILACS on (15/05/2008) using

the term ’carnitine’.

We also searched the Cochrane Central Register of Controlled Tri-

als (Clinical Trials) and MEDLINE, details of which are provided

in Appendix 1.

Date of most recent search of the Group’s Inborn Errors of

Metabolism Register: 27 October 2011.

Searching other resources

The reference lists of any clinical trials identified were cross-

checked and the review authors’ personal databases of trial reports

were examined in an attempt to identify any other relevant trials.

In the future, we also plan to contact investigators of any included

trials by either conventional or electronic mail to ask for details of

additional published and unpublished trials.

Data collection and analysis

Selection of studies

Three authors, Mona Nasser (MN), Hoda Javaheri (HJ) and Za-

man Noorani (ZN), have independently assessed the abstracts of

trials identified from the searches for the original version of the

review in 2009. One person (MN) has screened the results from

the searches for this update.

We were not blinded to either the author or journal names. We

obtained full copies of all relevant and potentially relevant trials

(i.e. those appearing to meet the inclusion criteria) or for which

there were insufficient data in the title and abstract to make a clear

decision. We assessed the full text papers independently and re-

solved any disagreement on the eligibility of trials through discus-

sion and consensus; or if necessary through a fourth party, Zbys

Fedorowicz (ZF).



http://www.iranmedex.com

After assessment, the authors eliminated from further review any

remaining trials that did not match the inclusion criteria and noted

the reasons for their exclusion in the Characteristics of excluded

studies table.

Data extraction and management

For future updates, when we include trials in the review, we will

collect outcome data using a customised form. Two review authors

(MN and Hoda Javaheri (HJ)) will enter the extracted data into

RevMan 5.1 and sequentially and automatically check for differ-

ences (RevMan 2011). MN will hold the master copy and we will

only include data when we reach a consensus. We will discuss any

disagreement and if required, consult a third review author.

As there were no included trials, it was not possible to undertake

any data collection for this review. However, the following methods

will be used if further trials are included in a subsequent update

of this review.

Each review author will enter details of included trials separately

into the Characteristics of included studies table in RevMan 5.1

and cross-check these details.

We will extract the following details:

1. Trial methods: method of allocation; masking of

participants and outcomes; exclusion of participants after

randomisation; and proportion of follow-up losses.

2. Participants: country of origin; type and symptoms of IEM;

sample size; age; sex; inclusion and exclusion criteria.

3. Intervention: dose; frequency; duration and length of time

in follow up.

4. Control: placebo or no treatment.

5. Outcomes: primary and secondary and adverse outcomes

mentioned in the section of outcome measures.

We plan to group outcome data into those measured at one month,

at six months, at 12 months and annually thereafter. If data are

reported at other time periods we will also consider these.

Assessment of risk of bias in included studies

For future updates, when we include trials in the review, two au-

thors will independently assess the risk of bias according to the

method described in the Cochrane Handbook for Systematic Re-

views of Interventions (Higgins 2011a). Authors will compare

evaluations and discuss and resolve any inconsistencies in their

interpretation of inclusion criteria and their significance to the se-

lected trials.

We will assess the following domains as having either a low, unclear

or high risk of bias:

1. generation of the allocation sequence;

2. concealment of allocation;

3. blinding (of participants, personnel and outcome assessors);

4. incomplete outcome data;

5. selective outcome reporting.

Measures of treatment effect

Unfortunately, we have not included any relevant trials in this re-

view and we could not undertake data extraction or data synthesis.

However, we will use the following methods if further studies will

be identified in subsequent updates of this review.

We will calculate risk ratios and 95% confidence intervals for all

dichotomous primary and secondary outcomes. We will calculate

the mean differences and 95% confidence intervals for continuous

data.

Unit of analysis issues

For cross-over trials, if possible, we will undertake a paired analysis

of the data obtained to allow a within-individual comparison of the

treatment interventions as recommended by Elbourne (Elbourne

2002). If we identify cluster-randomised trials in this review, we

will analyse these data using the effective sample size approach as

described in Chapter 16 of the Cochrane Handbook for Systematic

Reviews of Interventions (Higgins 2011b).

Dealing with missing data

We plan to contact the primary investigators of the trials to obtain

any data missing from the published study reports.

Assessment of heterogeneity

Given that the review question is broad, we would expect clinical

diversity in the identified studies on this topic. If we identify a

sufficient number of studies for any individual comparison and

outcome, we will explore and attempt to quantify the inconsistency

using the I2 statistic (Higgins 2003).

We will use the following guide for the interpretation of the results:

• 0% to 40%: might not be important;

• 30% to 60%: may represent moderate heterogeneity;

• 50% to 90%: may represent substantial heterogeneity;

• 75% to 100%: considerable heterogeneity.

However, we recognize that this is a general guide to interpreting

the results and the importance of inconsistency depends on several

factors.

Assessment of reporting biases

If we identify a sufficient number of randomised controlled trials

(RCTs) (at least 10), we will attempt to assess publication bias

using a funnel plot (Egger 1997) and if asymmetry is identified,

we will also try to investigate other possible causes.

In order to evaluate outcome reporting bias, we will compare the

trial protocol (if available) and the final published paper. If we

are not able to identify the trial protocol, we aim to compare

the ’Methods’ and the ’Results’ sections of the paper and explore



whether all the outcomes that had been measured were reported

in the results of the paper.

Data synthesis

If data are available from different trials on a similar comparison

and outcome, we plan to analyse the data together. We will anal-

yse the data using a fixed-effect model. If we identify moderate,

substantial or considerable heterogeneity between trials, we will

analyse the data using a random-effects model.

Subgroup analysis and investigation of heterogeneity


any subgroup analyses for this review. However, for future updates,

if a sufficient number of trials are included and if we establish that

there are large numbers of participants in specific age groups, we

will undertake a subgroup analyses in which participants will be

categorized by age.

Sensitivity analysis


any sensitivity analyses for this review. However, in subsequent

updates of the review, if sufficient trials are available, we plan to

conduct sensitivity analyses to assess the robustness of the review

results by repeating the analysis with the following adjustments:

1. exclusion of trials with unclear or high risk of bias for

allocation concealment;

2. unclear or a high risk of bias for blinding;

3. including and excluding quasi-randomised trials; and

4. any missing data or data extraction problems.

In addition, we may undertake sensitivity analyses to examine the

effect of completeness of follow-up.

R E S U L T S

Description of studies

See: Characteristics of excluded studies and Characteristics of

studies awaiting classification.

Results of the search

The search strategy (last run in October 2008) retrieved 315

records (MEDLINE (OVID) 1950 to October Week 3 2008

[searched 28/10/08]: 227 references to studies; Cochrane Cen-

tral Register of Clinical Trials (Clinical Trials) all years [searched

28/10/08]: 88 references; Cystic Fibrosis and Genetic Disorders

Group’s Inborn Errors of Metabolism Trials Register: 0 references).

After examination of the titles and abstracts of these references, all

but 30 studies were subsequently excluded from further analysis.

Full text copies of these remaining studies were obtained and

were then subjected to further assessment. We also scrutinised the

bibliographical references of these papers (including two reviews

(Kolker 2004; Angelini 1987)) for any further potentially eligible

studies. We found two references for which we attempted to ob-

tain full text copies (Bjugstad 2000; Baric 1998).

One trial was a cross-over placebo-controlled clinical trial (

Rodriguez 1997). We translated this study from Spanish into En-

glish but unfortunately, the paper did not include sufficient de-

tails on study design and study groups. We have attempted to

contact the authors but, to date, have not received a response

yet and therefore the study is currently listed in Studies awaiting

classification. For further information on this trial, please refer to

the Characteristics of studies awaiting classification table.

The updated searches on 27 October 2011 retrieved 113 records

from the Cochrane Central Register of Clinical Trials (Clinical

Trials) and 15 records from MEDLINE (OVID). None of these

matched the inclusion criteria of the review.

Included studies

No trials are included in this review.

Excluded studies

From these studies, six studies were excluded as they were not con-

trolled clinical trials (Bohles 1991;Gillingham 2003; Lee 2005;

Schulpis 1990; Vilaseca 1993; Wolff 1986); a further ten be-

cause the included participants did not match our inclusion crite-

ria (Bhuiyan 1992; Bowyer 1989; Chazot 2003; Cruciani 2004;

Huidekoper 2006; Mayer 1989; Schmidt-S 1983; Sirtori 2000;

Yeh 1985; Zilleruelo 1989); and one because it included valproic

acid as one of the interventions in the trial (Igarashi 1990). A fur-

ther study had two parts, the first part was an RCT which included

healthy people as participants and the second part evaluated the

therapeutic effect of DL-carnitine chloride in people with hyper-

lipoproteinaemia. Unfortunately, the second part of the study was

uncontrolled and was therefore excluded (Maebashi 1978). Nine

reports were literature reviews and did not contain any reports of

randomised controlled trials relevant to this review (Angelini 1987;

Baric 1998; Bjugstad 2000; Goa 1987; Kolker 2004; Krähenbühl

1995; Morris 1998; Muller 2004; Winter 2003); and one was an

editorial and did not describe any relevant RCTs (Kelley 1994).

During the peer review process, an RCT was identified by the peer

reviewers as a potential trial to be included in our review (Ellaway

1999). However, we excluded the trial from our review as we do

not regard Rett syndrome as an IEM (this does not match our

IEM criteria) and listed it in Characteristics of excluded studies.



Risk of bias in included studies


Effects of interventions


D I S C U S S I O N

Suitable trials were not found in the literature for our objectives

to be achieved at present.

A number of studies tried to address the effectiveness and safety

of carnitine supplementation for people with an IEM. A guideline

on ’Diagnosis and management of glutaryl-CoA dehydrogenase defi-ciency (GDHD)’ partially addressed this question and states that

lysine restricted diet and carnitine supplementation had a benefi-

cial effect in people with GDHD. It can prevent secondary carni-

tine depletion, influences the progression of neurological disease

and decreases the mortality rate in these patients. However, these

results were only based on a multicenter cross-sectional study and

a synthesis of a number of case reports of people with Glutaric

acidemia type 1 and not on interventional trials (Kolker 2007;

Kolker 2006; Bjugstad 2000). The diverse nature of inborn errors

of metabolism patients also raises questions on the applicability

of results on the effectiveness of carnitine for one of the disorders

to other individuals with different disorders. A possible solution

could be grouping some of the disorders with similar characteris-

tics e.g. long chain fatty acid oxidation defects in a clinical trial.

There is a large body of research exploring and discussing the role

of carnitine in metabolic pathways and a limited number of obser-

vational and interventional studies examining the effectiveness of

dietary interventions in people with an IEM. This was also obvi-

ous in a number of other Cochrane Reviews evaluating dietary in-

terventions and nutrition supplements for people with phenylke-

tonuria (Poustie 2010; Webster 2010; Yi 2008).

For over 20 years carnitine has been used to treat fatty acid oxi-

dation defects and organic acid disorders, and has provided mod-

erate benefits in patients. Since then, carnitine has been added to

the treatment of many IEMs based on those early clinical obser-

vations without any evidence from controlled clinical trials. Re-

cently, a number of initiatives have led to improvements in re-

search on IEMs (Kolker 2007; Seymour 1997) along with calls

for more RCTs in these areas (Kruer 2008; Steiner 2005). On

the other hand, doubts have been raised on the safety of car-

nitine supplementation in some people with certain IEMs (e.g.

people with long-chain 3-hydroxyacyl-CoA dehydrogenase defi-

ciency (LCHAD)) (Winter 1998). Unfortunately, the effective-

ness of these interventions has not been addressed by high qual-

ity RCTs, thus both the effectiveness and safety of carnitine in

IEM remains an important question to be answered. The lack of

RCTs undertaken in this area could be partially due to concerns

raised on the ethical and practical aspects of undertaking a dou-

ble-blind RCT and the variability in characteristics of people with

different IEMs (Winter 1998). In this respect it would be impor-

tant that future RCTs are robust, well-designed and reported ac-

cording to the CONSORT statement. Ethical issues should be

carefully taken into consideration to decide whether it is possible

to conduct placebo-controlled trials in potentially lethal diseases,

e.g. carnitine transporter disorder or glutaric aciduria type I. For

other IEMs, such as MCAD deficiency, in which some clinicians

recommend the use of carnitine and others do not, we strongly

recommend that RCTs are conducted as soon as possible.

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

There are no published or ongoing randomised controlled clinical

trials relevant to this review question. Therefore, in the absence

of any high-level reliable evidence in the form of well-conducted

RCTs, no firm conclusions can be made about the effectiveness of

carnitine for IEMs. This does not mean that carnitine is ineffective

or should not be used in treating IEMs. However, there is a lack

of evidence on the effectiveness and safety of carnitine and the

necessary dose and frequency of carnitine to be prescribed. Hence,

current practice should continue to be observed and monitored

with care until further evidence is available, preferably, in a con-

trolled environment or in the context of a clinical trial. This could

be an individual based N-of-1 RCT or a multi-center RCT. Simi-

lar to previous Cochrane Reviews on people with phenylketonuria

(Poustie 2010; Webster 2010; Yi 2008), we recommend that peo-

ple with an IEM should preferably enter larger, rather than smaller

trials. Clinicians should base their treatment decisions on clini-

cal experience and in conjunction with patient preference where

appropriate. Moreover, clinicians should comprehensively inform

patients on the advantages and disadvantages of carnitine in IEMs

and existing uncertainties of its effectiveness and safety.

Implications for research

The results of this systematic review confirm the necessity for

further methodologically sound trials that are reported according

to the Consolidated Standards of Reporting Trials (CONSORT)

statement. Trialists should include patient-reported outcomes us-

ing validated and internationally recognised scales and ensure that

any adverse events associated with the treatment are reported. Tri-

alists should also involve the patients (or their carers) in trial design






to ensure that important and relevant factors are considered. We

have provided a research recommendation based on the EPICOT

format (Table 1) (Brown 2006). Careful consideration should be

given when deciding whether it is ethical to conduct placebo-con-

trolled trials in potentially lethal diseases, e.g. carnitine transporter

disorder or glutaric aciduria type I. In other disorders, such as

MCAD deficiency, where some clinicians recommend the use of

carnitine and others do not, it is strongly recommended that RCTs

are undertaken. Due to the low incidence of each type of IEM,

we recommend that researchers consider grouping similar IEMs

within international multi-center clinical trials.

A C K N O W L E D G E M E N T S

The authors would like to thank Tracey Remmington and Nikki

Jahnke of the Cochrane Cystic Fibrosis and Genetic Disorders

Group for their support throughout this protocol and review; also

the peer reviewers for their useful comments which were a great

help in the development of the final version of this review. We

would also like to thank Jeronimo Neto for translating the Spanish

article for us and Jordi Pardo and Arturo J Martí-Carvajal for their

help in attempting to identify the authors.

R E F E R E N C E S

References to studies excluded from this review

Angelini 1987 {published data only}

Angelini C, Trevisan C, Isaya G, Pegolo G, Vergani

L. Clinical varieties of carnitine and carnitine

palmitoyltransferase deficiency. Clinical Biochemistry 1987;

29(1):1–7.

Baric 1998 {published data only}

Baric I, Zschocke J, Christensen E, Duran M, Goodman SI,

Leonard JV, et al. Diagnosis and management of glutaric

aciduria type I. Journal of Inherited Metabolic Disease 1998;

21(4):326–40.

Bhuiyan 1992 {published data only}

Bhuiyan AK, Jackson S, Turnbull DM, Aynsley-Green A,

Leonard JV, Bartlett K. The measurement of carnitine

and acyl-carnitines: application to the investigation of

patients with suspected inherited disorders of mitochondrial

fatty acid oxidation. Clinica Chimica Acta 1992;207(3):

185–204.

Bjugstad 2000 {published data only}

Bjugstad KB, Goodman SI, Freed CR. Age at symptom

onset predicts severity of motor impairment and clinical

outcome of glutaric acidemia type 1. Journal of Pediatrics

2000;137(5):681–6.

Bohles 1991 {published data only}

Bohles H, Ullrich K, Endres W, Behbehani AW, Wendel U.

Inadequate iron availability as a possible cause of low serum

carnitine concentrations in patients with phenylketonuria.

European Journal of Pediatrics 1991;150(6):425–8.

Bowyer 1989 {published data only}

Bowyer BA, Fleming CR, Haymond MW, Miles JM. L-

carnitine: effect of intravenous administration on fuel

homeostasis in normal subjects and home-parenteral-

nutrition patients with low plasma carnitine concentrations.

American Journal of Clinical Nutrition 1989;49(4):618–23.

Chazot 2003 {published data only}

Chazot C, Blanc C, Hurot J M, Charra B, Jean G, Laurent

G. Nutritional effects of carnitine supplementation in

hemodialysis patients. Clinical Nephrology 2006;59(1):

24–30.

Cruciani 2004 {published data only}

Cruciani RA, Dvorkin E, Homel P, Culliney B, Malamud

S, Shaiova L, et al. L-carnitine supplementation for the

treatment of fatigue and depressed mood in cancer patients

with carnitine deficiency: a preliminary analysis. Annals of

the New York Academy of Sciences 2004;1033:168–76.

Ellaway 1999 {published data only}

Ellaway CJ, Peat J, Williams K, Leonard H, Christodoulou

J. Rett syndrome: randomized controlled trial of L-

carnitine. Journal of Child Neurology 1999;14(3):162–7.

Gillingham 2003 {published data only}

Gillingham MB, Connor WE, Matern D, Rinaldo P,

Burlingame T, Meeuws K, et al. Optimal dietary therapy of

long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

Molecular Genetics & Metabolism 2003;79(2):114–23.

Goa 1987 {published data only}

Goa KL, Brogden RN. l-Carnitine. A preliminary

review of its pharmacokinetics, and its therapeutic use

in ischaemic cardiac disease and primary and secondary

carnitine deficiencies in relationship to its role in fatty acid

metabolism. Drugs 1987;34(1):1–24.

Huidekoper 2006 {published data only}

Huidekoper HH, Schneider J, Westphal T, Vaz FM, Duran

M, Wijburg FA. Prolonged moderate-intensity exercise

without and with L-carnitine supplementation in patients

with MCAD deficiency. Journal of Inherited Metabolic

Disease 2006;29(5):631–6.

Igarashi 1990 {published data only}

Igarashi N, Sato T, Kyouya S. Secondary carnitine deficiency

in handicapped patients receiving valproic acid and/or

elemental diet. Acta Paediatrica Japonica 1990;32(2):

139–45.

Kelley 1994 {published data only}

Kelley RI. The role of carnitine supplementation in valproic

acid therapy. Pediatrics 1994;93(6):1174–5.

Kolker 2004 {published data only}

Kolker S, Burgard P, Okun JG, Schulze-Bergkamen A,

Assmann B, Greenberg CR, et al. Looking forward-an

evidence-based approach to glutaryl-CoA dehydrogenase



deficiency. Journal of Inherited Metabolic Disease 2004;27

(6):921–6.

Krähenbühl 1995 {published data only}

Krähenbühl S. [Carnitine: vitamin or doping?].

Therapeutische Umschau 1995;52(10):687–92.

Lee 2005 {published data only}

Lee PJ, Harrison EL, Jones MG, Jones S, Leonard JV,

Chalmers RA. L-carnitine and exercise tolerance in medium-

chain acyl-coenzyme A dehydrogenase (MCAD) deficiency:

a pilot study. Journal of Inherited Metabolic Disease 2005;28

(2):141–52.

Maebashi 1978 {published data only}

Maebashi M, Kawamura N, Sato M, Imamura A, Yoshinaga

K. Lipid-lowering effect of carnitine in patients with type-

IV hyperlipoproteinaemia. Lancet 1978;2(8094):805–7.

Mayer 1989 {published data only}

Mayer G, Graf H, Legenstein E, Linhart L, Auer B,

Lohninger A. L-carnitine substitution in patients on chronic

hemodialysis. Nephron 1989;52(4):295–9.

Morris 1998 {published data only}

Morris AA, Turnbull DM. Fatty acid oxidation defects in

muscle [abstract]. Current Opinion in Neurology 1998;11

(5):485–90.

Muller 2004 {published data only}

Muller E, Kolker S. Reduction of lysine intake while

avoiding malnutrition--major goals and major problems in

dietary treatment of glutaryl-CoA dehydrogenase deficiency.

Journal of Inherited Metabolic Disease 2004;27(6):903–10.

Schmidt-S 1983 {published data only}

Schmidt-Sommerfeld E, Penn D, Wolf H. Carnitine

deficiency in premature infants receiving total parenteral

nutrition: effect of L-carnitine supplementation. Journal of

Pediatrics 1983;102(6):931–5.

Schulpis 1990 {published data only}

Schulpis KH, Nounopoulos C, Scarpalezou A, Bouloukos

A, Missiou-Tsagarakis S. Serum carnitine level in

phenylketonuric children under dietary control in Greece.

Acta Paediatrica Scandinavica 1990;79(10):930–4.

Sirtori 2000 {published data only}

Sirtori CR, Calabresi L, Ferrara S, Pazzucconi F, Bondioli

A, Baldassarre D, et al. L-carnitine reduces plasma

lipoprotein(a) levels in patients with hyper Lp(a). Nutrition,

metabolism, and cardiovascular diseases : NMCD 2000;10

(5):247–51.

Vilaseca 1993 {published data only}

Vilaseca MA, Briones P, Ferrer I, Campistol J, Riverola

A, Castillo P, et al. Controlled diet in phenylketonuria

may cause serum carnitine deficiency. Journal of Inherited

Metabolic Disease 1993;16(1):101–4.

Winter 2003 {published data only}

Winter SC. Treatment of carnitine deficiency. Journal of

Inherited Metabolic Disease 2003;26(2-3):171–80.

Wolff 1986 {published data only}

Wolff JA, Carroll JE, Le Phuc Thuy, Prodanos C, Haas

R, Nyhan WL. Carnitine reduces fasting ketogenesis in

patients with disorders of propionate metabolism. Lancet

1986;1(8476):289–91. [MEDLINE: PUBMED 2868163]

Yeh 1985 {published data only}

Yeh YY, Cooke RJ, Zee P. Impairment of lipid emulsion

metabolism associated with carnitine insufficiency in

premature infants. Journal of Pediatric Gastroenterology &

Nutrition 1985;4(5):795–8.

Zilleruelo 1989 {published data only}

Zilleruelo G, Novak M, Hsia SL, Goldberg R, Abitbol

C, Monkus E, et al. Effect of dialysate composition on

the lipid response to L-carnitine supplementation. Kidney

International - Supplement 1989;27:S259–63.

References to studies awaiting assessment

Rodriguez 1997 {published data only}

Rodriguez DRE, Mendible A, Gomez N, Williams P,

Meneses P, Mathison Y. Drug intervention program in

dyslipemic children: Use of L-carnitine. Revista Latina De

Cardiologia - Euroamericana 1997;18(2):25–30.

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Chakrapani 2001

Chakrapani A, Cleary MA, Wraith JE. Detection of inborn

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in Childhood. Fetal and Neonatal Edition 2001;84(3):

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Egger 1997

Egger M, Davey-Smith G, Schneider M, Minder C. Bias

in meta-analysis detected by a simple, graphical test. BMJ

1997;315(7109):629–34.

Elbourne 2002

Elbourne D, Altman DG, Higgins JPT, Curtin F,

Worthington HV, Vail A. Meta-analysis involving cross-

over trials: methodological issues. International Journal of

Epidemiology 2002;31(1):140–9.

Evangeliou 2003

Evangeliou A, Vlassopoulos D. Carnitine metabolism

and deficit--when supplementation is necessary?. Current

Pharmaceutical Biotechnology 2003;4(3):211–9.

Higgins 2003

Higgins JPT, Thompson SG, Deeks JJ, Altman DG.

Measuring inconsistency in meta-analyses. BMJ 2003;327

(7414):557–60.

Higgins 2011a

Higgins JPT, Altman DG (editors). Chapter 8: Assessing

risk of bias in included studies. In: Higgins JPT, Green



S (editors). Cochrane Handbook for Systematic Reviews

of Interventions Version 5.1 [updated March 2011].

The Cochrane Collaboration, 2011. Available from

www.cochrane-handbook.org.

Higgins 2011b

Higgins JPT, Deeks JJ, Altman DG on behalf of the CSMG.

Chapter 16: Special topics in statistics. In: Higgins JPT,

Green S (editors). Cochrane Handbook of Systematic

Reviews of Interventions. Version 5.1 [updated March

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Itoh 1996

Itoh T, Ito T, Ohba S, Sugiyama N, Mizuguchi K,

Yamaguchi S, et al. Effect of carnitine administration on

glycine metabolism in patients with isovaleric acidemia:

significance of acetylcarnitine determination to estimate

the proper carnitine dose. Tohoku Journal of Experimental

Medicine 1996;179(2):101–9.

Kolker 2006

Kölker S, Garbade SF, Greenberg CR, Leonard JV,

Saudubray JM, Ribes A, et al. Natural history, outcome,

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Kolker 2007

Kolker S, Christensen E, Leonard JV, Greenberg CR,

Burlina AB, Burlina AP, et al. Guideline for the diagnosis

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Pollitt RJ, Green A, McCabe CJ, Booth A, Cooper NJ,

Leonard JV, et al. Neonatal screening for inborn errors of

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Steiner RD. Evidence based medicine in inborn errors of

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14651858.CD004731.pub3]∗ Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Angelini 1987 This study is a review and did not describe any relevant RCT or CCT

Baric 1998 This study is a review and did not describe any relevant and additional RCT or CCT

Bhuiyan 1992 This study is evaluating a method for the estimation of individual carnitine

Bjugstad 2000 This study is a review undertaking a multiple regression analysis on a number of cases, however, it did not

describe any relevant and additional RCT or CCT

Bohles 1991 This study is not controlled.

Bowyer 1989 The participants were not diagnosed with an IEM. They had low plasma carnitine concentration due to long-

term parenteral nutrition

Chazot 2003 The participants underwent hemodyalisis, and did not have an IEM

Cruciani 2004 This study included patients with cancer not individuals affected with IEM

Ellaway 1999 Rett syndrome is not an IEM.

Gillingham 2003 This study is not a controlled trial. It evaluates the effects of contemporary dietary therapy upon various bio-

chemical parameters of metabolic control and clinical outcome

Goa 1987 This study is a review and did not describe any relevant and additional RCT or CCT

Huidekoper 2006 Five participants were compared with healthy volunteers.

Igarashi 1990 The study includes valproic acid as an intervention arm.

Kelley 1994 This paper is an editorial and did not describe any relevant new RCT

Kolker 2004 This study is a narrative review and did not describe any relevant RCT or CCT

Krähenbühl 1995 This is a review and did not describe any relevant and additional RCT or CCT

Lee 2005 This study is not a controlled trial.

Maebashi 1978 The first part of the study included healthy participants and the second part of study did not have a control

group

Mayer 1989 This study included participants with chronic haemodialysis with hyperlipidaemia



(Continued)

Morris 1998 This study is a narrative review and did not describe any relevant RCT

Muller 2004 This study is a narrative review and did not describe any relevant and additional RCT or CCT

Schmidt-S 1983 The participants are premature infants and do not match our inclusion criteria

Schulpis 1990 This is an observational study and not a RCT or CCT.

Sirtori 2000 The study included people with hyperlipidaemia but they did not necessarily have an IEM

Vilaseca 1993 This study evaluated the level of serum, free, total carnitine and acylcarnitine in phenylketonuria and is not a

controlled trial

Winter 2003 This study is a narrative review and did not describe any relevant and additional RCT or CCT

Wolff 1986 This study is not a RCT or CCT.

Yeh 1985 This study is a prospective trial on premature infants and not on individuals with IEM

Zilleruelo 1989 This study did not include individuals with an IEM and only included 9 participants with end-stage renal disease

on maintenance hemodialysis treatment

CCT: controlled clinical trial

IEM: inborn error of metabolism

RCT: randomised controlled trial

Characteristics of studies awaiting assessment [ordered by study ID]

Rodriguez 1997

Methods The cross-over trial is a CCT but it is not clear whether the method of randomisation was adequate

Participants 25 Children with the average age of 9.76 years old (6 to 12 years) with primary dyslipidaemia and excluded people

with secondary dyslipidaemia

Interventions Oral carnitine (1g (10cc), 3 times a day) (Group A) versus placebo (Group B) for 8 weeks, at which point the

participants had a 15 days washout period and another 8 weeks of treatment: oral carnine (Group B) versus placebo

(Group A)

Outcomes Biochemical variables (serum LDL, total cholesterol, cholestrol-HDL, glycaemia, uric acid, creatinine, triglycerides,

hemoglobin, level of plasma carnitine)

Anthropometric variables (weight, height, body mass index (BMI), measures of circumferences waist/thigh, the

cutaneous pleats (sub scapular, brachial pleat))

Changes in eating behaviour, treatment tolerances (patient satisfaction)



Rodriguez 1997 (Continued)

Notes The number of participants allocated in each group and some methodological details are not clear. We have contacted

the trialists but have not yet received a response

BMI: body mass index


HDL: high-density lipoprotein

LDL: low-density lipoprotein



D A T A A N D A N A L Y S E S

This review has no analyses.

A D D I T I O N A L T A B L E S

Table 1. Research Recommendation based on a gap in the evidence on carnitine supplementation for Inborn errors of

metabolism

Core Elements Issues to Consider Status of research for this review

Evidence (E) What is the current state of evidence A systematic review that did not identify any RCT or

CCT

Population (P) Diagnosis, disease stage, comorbidity, risk factor, sex,

age,

ethnic group, specific inclusion or exclusion criteria,

clinical

setting

Patients with IEM (either focused on a specific IEM

or similar IEMs would be grouped e.g. long-chain fatty

acid oxidation defects), Sex: men and Female

Intervention (I) Type, frequency, dose, duration, prognostic factor Intravenous or oral carnitine supplementation (in dif-

ferent dose, frequency, or duration), Compliance would

be recorded

Comparison (C) Type, frequency, dose, duration, prognostic factor Placebo or no supplementation

Outcome (O) Which clinical or patient related outcomes will the re-

searcher

need to measure, improve, influence or accomplish?

Which

methods of measurement should be used?

Changes in measures of growth, Measures of neuropsy-

chological performance, Number of deaths or age at

death in each group would be reported along with the

adverse effects associated with the administration of

Carnitine

Time Stamp (T) Date of literature search or recommendation 10 Oct 2008

Study Type What is the most appropriate study design to address

the

proposed question?

Randomised controlled trial (parallel or cross over),

Methods: Concealment Clear.

Blindness: Patients, therapist, trialists, outcomes asses-

sors blind.

Setting: in hospital or outpatient care with follow up


IEM: inborn error of metabolism

RCT: randomised controlled trial



A P P E N D I C E S

Appendix 1. Details of the Search Strategies for each database

Database Date of search Search Strategy

Clinical Trials 28/10/ 2008 #13-Hydroxy-3-methylglutaric aciduria

#2Abetalipoproteinemia

#3Acatalasia

#4Renal Tubular Acidosis

#5(Adrenal Hyperplasia NEAR/10 (hereditary or congenital or famil-

ial or inborn or inherited))

#6Adrenoleukodystrophy

#7Albinism

#8Alkaptonuria

#9alpha-Mannosidosis

#10Amino acidopath*

#11Amyloid Neuropath*

#12argininaemia

#13beta-Mannosidosis

#14Biotinidase deficiency

#15Ketothiolase deficiency

#16Carbamoyl-Phosphate Synthase I Deficiency

#17Carbohydrate-Deficient Glycoprotein Syndrome

#18(Cerebral Amyloid Angiopathy NEAR/10 (hereditary or congen-

ital or familial or inborn or inherited))

#19Cholesterol Ester Storage Disease

#20Rhizomelic Chondrodysplasia Punctata

#21Citrullinemia

#22adrenal hyperplasia

#23Crigler-Najjar Syndrome

#24Cystinuria

#25Cytochrome-c Oxidase Deficiency

#26Fabry* Disease

#27hypercholesterolaemia

#28Fanconi Syndrome

#29fatty acid metabolism

#30fatty acid oxidation

#31Fructose Intolerance

#32Fructose NEAR/10 Metabolism

#33Fructose-1,6-Diphosphatase Deficiency

#34Fucosidosis

#35Galactosaemia

#36Galactosemia

#37Gangliosidoses

#38Gangliosidosis

#39Gaucher

#40gilbert NEAR/5 disease



(Continued)

#41Glucosephosphate Dehydrogenase Deficiency

#42Glutaric aciduria

#43Glycogen Storage Disease

#44Renal Glycosuria

#45Gout

#46Hartnup NEAR/5 Disease

#47Hemochromatosis

#48Hepatolenticular Degeneration

#49Histidinaemia

#50Holocarboxylase Synthetase Deficiency

#51Homocystinuria

#52Hyperargininemia

#53(Hyperbilirubinemia NEAR/10 (hereditary or congenital or fa-

milial or inborn or inherited))

#54(Hyperglycinemia NEAR/10 Nonketotic)

#55Hyperhomocysteinemia

#56Hyperlipidemia

#57Hyperlipoproteinemia

#58Hyperlysinemia

#59(Hyperoxaluria NEAR/10 Primary)

#60hyperprolinaemia

#61Hypoalphalipoproteinemia

#62Hypobetalipoproteinemia

#63Hypokalemic Periodic Paralysis

#64Hypolipoproteinemia

#65(Hypophosphatemia NEAR/10 (hereditary or congenital or fa-


#66Hypophosphatasia

#67Hypophosphatemic Rickets

#68X-Linked Ichthyosis

#69Isovaleric acidaemia

#70Chronic Idiopathic Jaundice

#71Lactose Intolerance

#72Lecithin Acyltransferase Deficiency

#73Leigh Disease

#74Lesch-Nyhan Syndrome

#75Leukodystrophy

#76Lipidoses

#77Lysosomal Storage Disease*

#78Mannosidase Deficiency Disease*

#79Mannosidosis

#80Maple Syrup Urine

#81Medium-chain acyl-CoA dehydrogenase

#82MELAS

#83MERRF

#84Methylmalonic aciduria

#85Mineralocorticoid Excess Syndrome NEAR/10 apparent

#86mitochondrial b-oxidation



(Continued)

#87mitochondrial long-chain

#88Mucolipidoses

#89Mucopolysaccharidoses

#90Mucopolysaccharidosis

#91Multicarboxylase deficienc*

#92Multiple acyl CoA dehydrogenase deficiency

#93Multiple Carboxylase Deficiency

#94Multiple Sulfatase Deficiency

#95Neuronal Ceroid-Lipofuscinoses

#96Niemann-Pick

#97Oculocerebrorenal Syndrome

#98organic acidaemia*

#99organic aciduria*

#100Ornithine Carbamoyltransferase Deficiency

#101(Peroxisomal NEAR/10 (disease or disorder))

#102Phenylketonuria

#103Porphyria

#104Progeria

#105Propionic acidaemia

#106Pseudohypoaldosteronism

#107Pseudohypoparathyroidism

#108Purine-Pyrimidine Metabolism

#109(Pyruvate Carboxylase Deficiency NEAR/10 Disease)

#110(Pyruvate Dehydrogenase Complex Deficiency NEAR/10 Dis-

ease)

#111(Pyruvate Metabolism NEAR/10 (hereditary or congenital or

familial or inborn or inherited))

#112Refsum Disease

#113Renal Aminoaciduria*

#114(Renal Tubular Transport NEAR/10 (hereditary or congenital or

familial or inborn or inherited))

#115Sandhoff Disease

#116SCAD deficiency

#117Sea-Blue Histiocyte Syndrome

#118Sialic Acid Storage Disease

#119Sjogren-Larsson Syndrome

#120Smith-Lemli-Opitz Syndrome

#121Sphingolipidoses

#122(Steroid Metabolism NEAR/10 (hereditary or congenital or fa-


#123Sulfatidosis

#124Tangier Disease

#125Tyrosinaemia

#126Wolman Disease

#127(Xanthomatosis NEAR/10 Cerebrotendinous)

#128Zellweger Syndrome

#129MeSH descriptor Metabolism, Inborn Errors explode all trees

#130(#1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9



(Continued)

OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #

17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24 OR

#25 OR #26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32



#48 OR #49 OR #50 OR #51 OR #52 OR #53 OR #54 OR #55



#71 OR #72 OR #73 OR #74 OR #75 OR #76 OR #77 OR #78



#94 OR #95 OR #96 OR #97 OR #98 OR #99 OR #100 OR #101

OR #102 OR #103 OR #104 OR #105 OR #106 OR #107 OR #

108 OR #109 OR #110 OR #111 OR #112 OR #113 OR #114 OR

#115 OR #116 OR #117 OR #118 OR #119 OR #120 OR #121

OR #122 OR #123 OR #124 OR #125 OR #126 OR #127 OR #

128 OR #129)

#131levocarnitine

#132carnitine

#133L-carnitine

#134(#131 OR #132 OR #133)

#135(#130 AND #134)

MEDLINE via Ovid (1950 to 28/10/

2008)

28/10/2008 1 randomized controlled trial.pt. (267719)

2 controlled clinical trial.pt. (80501)

3 randomized.ab. (175733)

4 placebo.ab. (110727)

5 drug therapy.fs. (1311086)

6 randomly.ab. (127547)

7 trial.ab. (183149)

8 groups.ab. (883669)

9 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 (2370962)

10 (animals not (humans and animals)).sh. (3279583)

11 9 not 10 (2011516)

12 3-Hydroxy-3-methylglutaric aciduria.tw. (46)

13 Abetalipoproteinemia.tw. (285)

14 Acatalasia.tw. (23)

15 Renal Tubular Acidosis.tw. (1737)

16 (Adrenal Hyperplasia adj10 (hereditary or congenital or familial or

inborn or inherited)).tw. (2938)

17 Adrenoleukodystrophy.tw. (1405)

18 Albinism.tw. (1524)

19 Alkaptonuria.tw. (479)

20 alpha-Mannosidosis.tw. (128)

21 Amino acidopath$.tw. (35)

22 Amyloid Neuropath$.tw. (131)

23 argininaemia.tw. (7)

24 beta-Mannosidosis.tw. (97)

25 Biotinidase deficiency.tw. (236)



(Continued)

26 Ketothiolase deficiency.tw. (60)

27 Carbamoyl-Phosphate Synthase I Deficiency.tw. (2)

28 Carbohydrate-Deficient Glycoprotein Syndrome.tw. (208)

29 (Cerebral Amyloid Angiopathy adj10 (hereditary or congenital or

familial or inborn or inherited)).tw. (73)

30 Cholesterol Ester Storage Disease.tw. (54)

31 Rhizomelic Chondrodysplasia Punctata.tw. (176)

32 Citrullinemia.tw. (264)

33 adrenal hyperplasia.tw. (3803)

34 Crigler-Najjar Syndrome.tw. (244)

35 Cystinuria.tw. (1002)

36 Cytochrome-c Oxidase Deficiency.tw. (266)

37 Fabry$ Disease.tw. (1856)

38 hypercholesterolaemia.tw. (3316)

39 Fanconi Syndrome.tw. (857)

40 fatty acid metabolism.tw. (2973)

41 fatty acid oxidation.tw. (3917)

42 Fructose Intolerance.tw. (341)

43 (Fructose adj10 Metabolism).tw. (914)

44 Fructose-1,6-Diphosphatase Deficiency.tw. (56)

45 Fucosidosis.tw. (256)

46 Galactosaemia.tw. (320)

47 Galactosemia.tw. (1077)

48 Gangliosidoses.tw. (165)

49 Gangliosidosis.tw. (1055)

50 Gaucher.tw. (1837)

51 (gilbert adj5 disease).tw. (19)

52 Glucosephosphate Dehydrogenase Deficiency.tw. (23)

53 Glutaric aciduria.tw. (343)

54 Glycogen Storage Disease.tw. (1606)

55 Renal Glycosuria.tw. (162)

56 Gout.tw. (6106)

57 (Hartnup adj5 Disease).tw. (98)

58 Hemochromatosis.tw. (4667)

59 Hepatolenticular Degeneration.tw. (493)

60 Histidinaemia.tw. (60)

61 Holocarboxylase Synthetase Deficiency.tw. (51)

62 Homocystinuria.tw. (1231)

63 Hyperargininemia.tw. (71)

64 (Hyperbilirubinemia adj10 (hereditary or congenital or familial or


65 (Hyperglycinemia adj10 Nonketotic).tw. (188)

66 Hyperhomocysteinemia.tw. (2910)

67 Hyperlipidemia.tw. (10393)

68 Hyperlipoproteinemia.tw. (2873)

69 Hyperlysinemia.tw. (43)

70 (Hyperoxaluria adj10 Primary).tw. (751)

71 hyperprolinaemia.tw. (35)



(Continued)

72 Hypoalphalipoproteinemia.tw. (200)

73 Hypobetalipoproteinemia.tw. (234)

74 Hypokalemic Periodic Paralysis.tw. (375)

75 Hypolipoproteinemia.tw. (23)

76 (Hypophosphatemia adj10 (hereditary or congenital or familial or


77 Hypophosphatasia.tw. (530)

78 Hypophosphatemic Rickets.tw. (508)

79 X-Linked Ichthyosis.tw. (282)

80 Isovaleric acidaemia.tw. (31)

81 Chronic Idiopathic Jaundice.tw. (65)

82 Lactose Intolerance.tw. (841)

83 Lecithin Acyltransferase Deficiency.tw. (0)

84 Leigh Disease.tw. (117)

85 Lesch-Nyhan Syndrome.tw. (623)

86 Leukodystrophy.tw. (1782)

87 Lipidoses.tw. (143)

88 Lysosomal Storage Disease$.tw. (1398)

89 Mannosidase Deficiency Disease$.tw. (0)

90 Mannosidosis.tw. (447)

91 Maple Syrup Urine.tw. (723)

92 Medium-chain acyl-CoA dehydrogenase.tw. (624)

93 MELAS.tw. (1105)

94 MERRF.tw. (343)

95 Methylmalonic aciduria.tw. (319)

96 (Mineralocorticoid Excess Syndrome adj10 apparent).tw. (32)

97 mitochondrial b-oxidation.tw. (2)

98 mitochondrial long-chain.tw. (62)

99 Mucolipidoses.tw. (90)

100 Mucopolysaccharidoses.tw. (679)

101 Mucopolysaccharidosis.tw. (1919)

102 Multicarboxylase deficienc$.tw. (1)

103 Multiple acyl CoA dehydrogenase deficiency.tw. (49)

104 Multiple Carboxylase Deficiency.tw. (121)

105 Multiple Sulfatase Deficiency.tw. (92)

106 Neuronal Ceroid-Lipofuscinoses.tw. (363)

107 Niemann-Pick.tw. (1564)

108 Oculocerebrorenal Syndrome.tw. (106)

109 organic acidaemia$.tw. (39)

110 organic aciduria$.tw. (311)

111 Ornithine Carbamoyltransferase Deficiency.tw. (42)

112 (Peroxisomal adj10 (disease or disorder)).tw. (428)

113 Phenylketonuria.tw. (4275)

114 Porphyria.tw. (6321)

115 Progeria.tw. (636)

116 Propionic acidaemia.tw. (111)

117 Pseudohypoaldosteronism.tw. (401)

118 Pseudohypoparathyroidism.tw. (1013)



(Continued)

119 Purine-Pyrimidine Metabolism.tw. (9)

120 (Pyruvate Carboxylase Deficiency adj10 Disease).tw. (7)

121 (Pyruvate Dehydrogenase Complex Deficiency adj10 Disease).

tw. (1)

122 (Pyruvate Metabolism adj10 (hereditary or congenital or familial

or inborn or inherited)).tw. (8)

123 Refsum Disease.tw. (212)

124 Renal Aminoaciduria$.tw. (9)

125 (Renal Tubular Transport adj10 (hereditary or congenital or fa-

milial or inborn or inherited)).tw. (14)

126 Sandhoff Disease.tw. (245)

127 SCAD deficiency.tw. (42)

128 Sea-Blue Histiocyte Syndrome.tw. (41)

129 Sialic Acid Storage Disease.tw. (77)

130 Sjogren-Larsson Syndrome.tw. (257)

131 Smith-Lemli-Opitz Syndrome.tw. (534)

132 Sphingolipidoses.tw. (138)

133 (Steroid Metabolism adj10 (hereditary or congenital or familial

or inborn or inherited)).tw. (13)

134 Sulfatidosis.tw. (13)

135 Tangier Disease.tw. (419)

136 Tyrosinaemia.tw. (187)

137 Wolman Disease.tw. (84)

138 (Xanthomatosis adj10 Cerebrotendinous).tw. (430)

139 Zellweger Syndrome.tw. (599)

140 exp metabolism, inborn errors/ or exp amino acid metabolism,

inborn errors/ or exp amino acid transport disorders, inborn/ or exp

amyloidosis, familial/ or exp brain diseases, metabolic, inborn/ or exp

carbohydrate metabolism, inborn errors/ or exp cytochrome-c oxi-

dase deficiency/ or exp hyperbilirubinemia, hereditary/ or exp lipid

metabolism, inborn errors/ or exp lysosomal storage diseases/ or exp

metal metabolism, inborn errors/ or exp peroxisomal disorders/ or exp

porphyrias/ or exp progeria/ or exp purine-pyrimidine metabolism,

inborn errors/ or exp renal tubular transport, inborn errors/ or exp

steroid metabolism, inborn errors/ (124515)

141 or/12-140 (159671)

142 levocarnitine.tw. (47)

143 carnitine.tw. (8489)

144 L-carnitine.tw. (2595)

145 exp Carnitine/ (6706)

146 or/142-145 (9950)

147 11 and 141 and 146 (305)

MEDLINE via Ovid (1950 to July week 4

2007)

10 Oct 2008 1 RANDOMIZED CONTROLLED TRIAL.pt. (267369)

2 CONTROLLED CLINICAL TRIAL.pt. (80428)

3 RANDOMIZED CONTROLLED TRIALS.sh. (0)

4 RANDOM ALLOCATION.sh. (63132)

5 DOUBLE BLIND METHOD.sh. (100865)

6 SINGLE BLIND METHOD.sh. (12612)



(Continued)

7 or/1-6 (401918)

8 (ANIMALS not HUMAN).sh. (4360195)

9 7 not 8 (364590)

10 CLINICAL TRIAL.pt. (459949)

11 exp Clinical Trial/ (567966)

12 (clin$ adj25 trial$).ti,ab. (167797)

13 ((singl$ or doubl$ or trebl$ or tripl$) adj25 (blind$ or mask$)).ti,

ab. (105799)

14 PLACEBOS.sh. (28238)

15 placebo$.ti,ab. (121110)

16 random$.ti,ab. (473183)

17 RESEARCH DESIGN.sh. (54761)

18 or/10-17 (1001547)

19 18 not 8 (890483)

20 19 not 9 (538260)

21 COMPARATIVE STUDY.sh. (1439860)

22 exp EVALUATION STUDIES/ (111837)

23 FOLLOW UP STUDIES.sh. (381719)

24 PROSPECTIVE STUDIES.sh. (254647)

25 (control$ or prospectiv$ or volunteer$).ti,ab. (2166497)

26 or/21-25 (3666472)

27 26 not 8 (2610816)

28 27 not (9 or 20) (2109014)

29 9 or 20 or 28 (3011864)

30 exp Rett Syndrome/ (1363)

31 Rett syndrome.tw. (1609)

32 (levocarnitine or carnitine or L-carnitine).tw. (8879)

33 30 or 31 (1801)

34 33 and 32 and 29 (7)

35 from 34 keep 1-7 (7)

W H A T ’ S N E W

Last assessed as up-to-date: 3 January 2012.

Date Event Description

13 April 2015 Amended Contact details updated.



H I S T O R Y

Protocol first published: Issue 3, 2007

Review first published: Issue 2, 2009

Date Event Description

3 January 2012 New search has been performed The search retrieved 113 records from the Cochrane

Central Register of Clinical Trials (Clinical Trials) and

15 records from MEDLINE (OVID). None of these

matched the inclusion criteria of the review

3 January 2012 New citation required but conclusions have not changed The methods section has been updated.

C O N T R I B U T I O N S O F A U T H O R S

Mona Nasser (MN) is responsible for co-ordinating the review.

MN and Hoda Javaheri (HJ) and Zaman Noorani (ZN) are responsible for screening search results and screening retrieved papers

against inclusion criteria.

MN and Hoda Javaheri (HJ) are responsible for appraising the quality of papers.

MN is responsible for organising the retrieval of papers and writing to authors of papers for additional information.

MN and HJ are responsible for data management of the review including extracting data from papers and entering data into RevMan

5.1.

MN and Zbys Fedorowicz (ZF) are responsible for obtaining and screening data on unpublished studies.

MN and ZF are responsible for the interpretation and analysis of data.

MN, ZM, HJ and ZF are responsible for writing the protocol and the review.

MN conceived the idea for the review and will be the guarantor for the review.

D E C L A R A T I O N S O F I N T E R E S T

There are no financial conflicts of interest and the review authors declare that they do not have any associations with any parties who

may have vested interests in the results of this review.



D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

The section of ’Assessment of risk of bias in included studies’ has been modified in light of the release of the new RevMan 5.1

software and the publication of the new Cochrane Handbook for Systematic Review of Interventions 5.0.0 produced by the Cochrane

Collaboration.

In the update of the review, we deleted the following sentence from ’Data extraction and management’ as we were concerned that it

might result in losing important data:

If appropriate, we will transform data obtained from visual analogue scales and any categorical outcomes into dichotomous data prior

to analysis in order to pool data from other trials with already dichotomous data or other categorizations.

I N D E X T E R M SMedical Subject Headings (MeSH)

∗Dietary Supplements; Carnitine [∗administration & dosage]; Metabolism, Inborn Errors [∗therapy]; Vitamin B Complex

[∗administration & dosage]

MeSH check words

Humans; Infant



Documents

Carnitine supplementation for treating people with inborn errors of metabolism