To survey the clinical and biochemical characteristics of individuals diagnosed with OCTN2, CPT2, CACT or BKT deficiency or suspected with OCTN2 deficiency after NBS in the Netherlands to aid the decision on whether or not to include these disorders…
ID
Source
Brief title
Condition
- Inborn errors of metabolism
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The main study outcome is survey of OCTN2, CPT2, CACT or BKT deficiency in the
Netherlands based on the following study parameters:
- Clinical data; Medical history, current clinical state, physical examination.
- Biochemical data; Laboratory assays performed in the context of diagnosis, eg
acylcarinitine profile, protein activity, gene analysis, glucose/ketone level,
CK level.
- Additional testing; All additional tests performed in the context of
evaluation of the disorder, eg electrocardiogram, cardiac ultrasound, imaging.
Secondary outcome
Sensitivity, specificity, positive predictive value and negative predictive
value of novel functional assay, measuring OCTN2 transporter activity in
cultured skin fibroblasts and lymfocytes.
Background summary
OCTN2 deficiency, CPT2 deficiency, CACT deficiency and BKT deficiency are all
inborn errors of metabolism that result in impairment of oxidation of long
chain fatty acids or their products (ketone bodies). They all have a varying
clinical spectrum ranging from asymptomatic *individuals* to patients
presenting with hypoglycemia, neurodevelopmental delay, (cardio)myopathy and/or
cardiac arrhythmia which may lead to sudden death. Currently, CPT2, CACT and
BKT deficiency are only diagnosed after symptoms have arisen, OCTN2 deficiency
can also be identified in the Dutch newborn screening (NBS) program as a
secondary finding when the acylcarnitine profile is obtained to detect other
inborn errors of fatty acid metabolism. It is considered an unintended finding.
For all four conditions, it is currently unclear whether all individuals that
would be identified by NBS should be considered patients and if treatment is
necessary, or whether, at least a subset of the identified individuals have a
benign biochemical and genetic variant and will remain asymptomatic. Cases or
case series in the literature often lack detailed information, are relatively
old or not representative of the situation in the Netherlands.
For OCTN2 deficiency, an additional obstacle in the workup of newborns with low
carnitine levels in NBS is the fact that these levels can reflect maternal
levels as a consequence of placental transmission of carnitine. In this case
the true levels of the newborn are initially unclear, diagnosis is not yet
possible and retesting needs to be performed a few weeks later. The low levels
of carnitine in newborns may reflect primary carnitine deficiency in the
mother, or more rarely, another inborn error of metabolism (IEM) resulting in
low carnitine. These mothers are almost all asymptomatic and whether these
incidentally discovered deficiencies represent a true health risk and require
treatment and follow-up is unclear. A comprehensive guideline as to how
physicians should act upon the finding of a low carnitine level in NBS does not
yet exist in the Netherlands. For OCTN2, CPT2, CACT and BKT deficiency a full
overview of the characteristics of all (current and historical) patients in the
Netherlands is necessary to be able to come to an informed decision whether or
not to include these disorders in the Netherlands newborn screening program.
Study objective
To survey the clinical and biochemical characteristics of individuals diagnosed
with OCTN2, CPT2, CACT or BKT deficiency or suspected with OCTN2 deficiency
after NBS in the Netherlands to aid the decision on whether or not to include
these disorders in the newborn screening program.
Study design
Retrospective and prospective cohort study
Study burden and risks
Participation in this study bears no significant risks, as most collected data
are obtained as part of standard care. In addition to the blood sample taken
for regular care 2ml blood is taken. For adults this will be a blood sample of
5ml blood.
Furthermore, the study is aimed towards improvement of newborn screening,
optimizing health benefit and limiting unnecessary referrals, treatment and
anxiety. To improve the newborn screening program, it is essential and
inevitable to include children that underwent newborn screening in its current
form (since 2007). Additionally, for CPT2/CACT and BKT-deficiency, it is
essential and inevitable to include children that are diagnosed with these
disorders, in order to achieve a complete picture of these disorders in the
Netherlands.
Lundlaan 6
Utrecht 3584 EA
NL
Lundlaan 6
Utrecht 3584 EA
NL
Listed location countries
Age
Inclusion criteria
• OCTN2 deficiency, confirmed by reduced carnitine transporter activity in
cultured fibroblasts and/or mutations in the SLC22A5 gene.
• Subject referred to academic centre for OCTN2 deficiency because of low
carnitine level in NBS.
• Mother analysed in academic centre for OCTN2 deficiency due to low carnitine
level in infant*s NBS.
• CPT2 deficiency, confirmed by reduced Carnitine palmitoyltransferase II
activity in lymphocytes or cultured fibroblasts and/or biallelic mutations in
the CPT2 gene.
• CACT deficiency, confirmed by carnitine acylcarnitine translocase activity in
cultured fibroblasts and/or biallelic mutations in the SLC25A20 gene.
• BKT deficiency, confirmed by reduced 2-methylacetoacetyl-CoA thiolase
activity in cultured fibroblasts and/or biallelic mutations in the ACAT1 gene.
Exclusion criteria
No exclusion criteria. All subjects that meet inclusion criteria are elligible
for inclusion
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL67683.041.19 |