The main objective is to investigate whether the variant indeed cause mitochondrial dysfunction leading to the observed phenotype, including characterization of the pathophysiology.
ID
Source
Brief title
Condition
- Renal and urinary tract disorders congenital
- Electrolyte and fluid balance conditions
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary study parameters are:
- Mitochondrial function of patient cells compared to reference values, control
cells from healthy unrelated individuals and cells of other affected families
(obtained from collaborators)
- Response of patients to a thiazide diuretic challenge test compared to the
normal population (matched for age and gender)
- Fractional excretion of magnesium in patient urine compared to reference
values
Secondary outcome
The secondary study parameters are:
- The correlation between mitochondrial function of a patient*s fibroblasts and
the serum magnesium concentration of the patient
- Heteroplasmy level of the mtDNA variant in blood, urine and fibroblasts of
participants (i.e. what is the percentage of mtDNA carrying the abnormal
variant in different tissues)
- Score at NMDAS (Newcastle Mitochondrial Disease Adult Scale), (Schaefer et
al., 2006)
- Laboratory parameters as listed in Table 1 of the Research protocol. Results
will be retrieved from the patient record by the treating physician and
pseudonymously shared with the researchers. When the necessary evaluations are
not available, blood will be drawn for these laboratory evaluations at
Radboudumc. Values will be compared to normal reference values for each
analysis.
Background summary
Hypomagnesaemia (a serum magnesium concentration below 0.7 mmol/L) is a common
medical disorder that can lead to cramps, tiredness, seizures and in very
severe cases coma or death. Causes of hypomagnesaemia include gastro-intestinal
malabsorption or loss, use of certain drugs and specific genetic disorders.
Excessive loss of magnesium through renal magnesium wasting is a hallmark of
all the currently known genetic causes. In approximately 90% of cases, it is
possible to pinpoint the hypomagnesaemia to a specific molecular cause, while
the remainder of suspected genetic cases is still unsolved. In this study, we
aim to investigate a rare variant in the mitochondrial genome (m.4291T>C) that
might explain part of the remaining 10%. Several unrelated families with this
variant exhibit renal magnesium wasting. We hypothesize that this variant leads
to impaired mitochondrial function and subsequent dysfunction of the
mitochondrion-rich distal convoluted tubule.
Study objective
The main objective is to investigate whether the variant indeed cause
mitochondrial dysfunction leading to the observed phenotype, including
characterization of the pathophysiology.
Study design
Case series
Study burden and risks
The overall risk of the study is primarily determined by the thiazide challenge
test. The most severe complications related to administration of thiazide
compounds encompass dehydration, hypokalemia, hypo-/hypernatremia and an
allergic reaction to hydrochlorothiazide. By the choice of test (i.e. a test
that has been used in clinical practice before), the careful monitoring plan,
execution at a department with experience in thiazide challenge tests and the
supervision by an experienced nephrologist, we believe that the risk of this
study will be kept to an acceptable minimum. We do not expect any serious
adverse events to happen. The METC previously gave approval for the use of this
test in another research proposal, and the test was subsequently implemented in
clinical practice. The rest of the study carries little risk but some burden,
i.e. collecting 24-hour urine and a hospital visit of one day. During this day,
the patient would undergo three blood draws, one skin biopsy to obtain
fibroblasts, and fill out the Newcastle Mitochondrial Disease Adult Scale
together with a doctor.
Geert Grooteplein Zuid 28
Nijmegen 6525 GA
NL
Geert Grooteplein Zuid 28
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
Being a carrier of the m.4291T>C variant in the mitochondrial DNA.
Exclusion criteria
- Age below 16 years
- Lacking competency to make personal medical decisions (in Dutch:
*wilsonbekwaam*)
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 | NL70750.091.19 |