CLINICAL EXPERIENCE OF NEUROLOGICAL
MITOCHONDRIAL DISEASES IN CHILDREN AND ADULTS:
A SINGLE-CENTER STUDY
Rogac M, Neubauer D, Leonardis L, Pecaric N, Meznaric M, Maver A,
Sperl W, Garavaglia BM, Lamantea E, Peterlin B
*Corresponding Author: Mihael Rogac, M.D., Ph.D., Clinical Institute of Genomic Medicine, University
Medical Center Ljubljana, Slajmerjeva 4, 1000 Ljubljana, Slovenia. Tel: +386-1-522-6078. Fax:
+386-1-540-1137. E-mail: mihael.rogac@kclj.si
page: 5
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DISCUSSION
Slovenia is a small European high-income country
with 2.1 million inhabitants and an estimated prevalence
of MD of three per 100,000 inhabitants, a finding that is
in accordance with other population studies of MD prevalence
[2]. Determining a diagnosis of MD is a complex
algorithm due to its extremely heterogeneous character,
genetic diversity and complex laboratory diagnostic methods.
With the majority of our mitochondrial patients we still have to use a laborious approach with muscle biopsies
in the end. Obviously, in the genomic era, the new diagnostic
algorithms will improve the diagnostic approach,
and influence the development of new standards for early
diagnosis and possible treatment [3,9,20].
Our study has mostly been done on unspecific encephalomyopathies
in children and neuromuscular patients
in adults. Thirty-one percent of cases were defined by CES
in both our cohorts. Clinical-exome sequencing has been
used when a pathology in the mitochondrial genome was
not suspected or was excluded. In almost all of the children
in the study, a diagnosis of MD was first suspected, based
on the results of metabolic deviations in plasma, urine or
CSF or abnormal brain MRI. In adults, an MD diagnosis
has still been defined by muscle histology findings. Twenty
of 30 adult patients had abnormal mitochondria on EM and
16/30 adult patients presented ragged-red fibers. Therefore,
clinical knowledge, metabolic investigations, brain
imaging and muscle biopsies have still been valuable in
our clinical scenario until 2018. Promising potential of
whole-exome sequencing (WES) as a first diagnostic option
in finding mutations in genes related to mitochondrial
dys-functions will probably reverse the classical diagnostic
approach [21,22].
Our clinical and diagnostic patient data were put together
according to MDC scoring. It has previously been
demonstrated that a high MDC scores increases the likelihood
of finding a genetic diagnosis by WES [23,24].
Witters et al. [8] found that the combined metabolic findings
and imaging sub scores were higher in mitochondrial
patients who were diagnosed when Sanger sequencing
was used as a genetic analysis tool, and where a cliniciandirected
genetic analysis to a target gene was based on a
clinical phenotype. The MDC scores are still found very
useful in the clinical diagnosis of MDs. The MDC scores
are helpful in interpreting exome-sequencing results or
deciding on the need to perform a muscle biopsy [8]. The
importance of MDC scoring and recognizing the patient’s
clinical phenotype is in accordance with what we found
in our clinical data. Moreover, in our cohort, MDC score
was used to conduct muscle biopsy not molecular genetic
studies. Twenty of 26 children and 22/36 adults in our
cohort reached a score of a definite MD. In all children,
a diagnosis was confirmed by RCEs and PDHc activities
measurements and when a high MDC score was reached
before a muscle biopsy. Molecular genetic diagnosis was
confirmed in 5/26 children. In adults a diagnosis of MD
was confirmed in six patients with measurements of RCE
activities, and reached a confirmation in 11 patients by
molecular genetic analysis. Sixteen of 36 patients had
CPEO syndrome, which is still challenging to diagnose
at the genetic level [25]. The MDC score was found to
be a useful tool for determining whether a muscle biopsy
was used in both cohorts of patients, as well as for affirming
the certainty of a diagnosis. In future, the MDC
score might be also useful in using WES results to reach
a diagnosis of a definite MD before performing a muscle
biopsy, especially in children.
Next-generation sequencing methods are becomig
the first diagnostic tool in the genomic era. Whole-genome
sequencing (WGS) of blood DNA is also going to contribute
as the first-line method for diagnosing a primary MD
[3]. Whole-genome sequencing has overtaken WES as
the preferred NGS method for DNA sequencing [26-28].
Whole-genome sequencing is better for detecting copy
number variations (CNVs), single nucleotide variants,
insertions/deletions, and in principle, microRNA (miRNA)
variants. However, even with WES, results are not going
to be so straightforward. Four scenarios of molecular
results are possible for diagnoses derived from the WES
approach [9]. At the very least, a skin biopsy and fibroblast-
related studies will be needed to evaluate variances of
unknown significance (VUS) or new candidate genes. For
now, the results of CES in our cohort of patients, gave us
a promising yield (positive in 7/22 or 31.0% cases) compared
to a yield of 39.0-55.0% in centers abroad [23,29].
Next-generation sequencing methods can also discriminate
molecular mimicry or confirm a molecular diagnosis, even
in cases of probable or possible groups of MD (Table
8). Buccal swabs for mtDNA isolation are showing us a
potential as a noninvasive approach to diagnose mtDNA
pathogenic variations, but we had a limited number of
suspected mtDNA syndrome cases (Table 8).
Large mitochondrial centers are searching for a geno-
type-phenotype correlation in neuroimaging of MDs
[30-32]. Mitochondrial diseases are not only commonly
described as multi-systemic diseases, but also demonstrate
neuroradiological changes in several functional
systems of the central nervous system. Pathognomonic
MRI changes for MDs can be found in the cerebral cortex,
white matter, basal ganglia, cerebellum and brainstem
[31]. The same is true in neuroimaging of MDs, as the
meaning of pleitropy is known in genetics. For example,
it is true that one pathognomonic MRI characteristic
can be a result of many genes related to mitochondrial
dysfunction. A genetic cause of Leigh sydnrome can
also be found in 75 genes [33]. Nevertheless, through
our study, we can demonstrate that in 71.0% of children
with MD we have found brain MRI changes that can be
a clue to a diagnosis of MD. Therefore, we can suggest
that MRI is still the diagnostic tool of choice in selected
cases that serves to provide at least one piece of the puzzle,
particularly if we have a genetic result of VUS or
negative results by WES. Magnetic resonance imaging also demonstrates that MD has the dynamic nature of a
chronic disease (Table 7) (Figure 1). Some of the brain
MRI characteristics present as a degree of cortical atrophy,
dysmyelination and/or basal ganglia hyperintensities
can change over a period of several years of follow-up
(Table 7) (Figure 1).
One of the diagnostic problems in MDs is diagnostic
mimicry. Clinical presentation of MD can present
as a metabolic, neurodegenerative, neuromuscular or
neuroin-flammatory diseases [34,35]. When we suspect
a primary MD, another molecular cause can be found
and mitochondrial dysfunction is only secondary [36].
This is demonstrated by the example of two clinical cases
with pathogenic variants in a gene for a congenital myasthenic
syndrome and Allan-Herndon-Dudley syndrome of
triiodo-thyronine resistance that have been found by CES.
In these cases, even muscle morphology and OXPHOS
measurements of a skeletal muscle specimen and brain
MRI have been misleading. We emphasize how important
WES is in the differentiation of rare neurogenetic diseases
mimicking as an MD.
In conclusion, MDs have remained a very heterogeneous
group of neurometabolic diseases on a clinical,
biochemical and genetic level of diagnostics. The goal of
being noninvasive and cost-efficient is guiding us to choose
a new way of the “gene-to-function” approach, instead of
the old way as the “function-to-gene” approach. Solving
the diagnostic puzzle(s) in either way is still a challenging
task. For clinical purposes, the MDC has been a valuable
tool in the diagnosis of MDs in children and adults. Obviously,
the NGS methods are likely to contribute to end
many diagnostic odysseys.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
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