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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RESULTS
The main clinical charasteristics of the patients in
the childrens’ cohort is listed in Table 1, and those of
patients in an adult cohort is listed in Table 2. The MDC
were applied to all children and adults in the study. Clinical
comparison between both cohorts of patients (i.e.,
children and adults), was also performed and the data are
presented in Table 3.
In a cohort of children, RCEs and/or PDHc deficiencies
were found in all subjects. Twelve children had a
PDHc deficiency. Molecular genetic analysis of the PDHA
and PDX genes did not reveal a mutation in any child.
Five children had Leigh syndrome, 10 children had RCE
deficiencies, and four children had combined PDHc and
RCE deficiencies. Diagnostic evaluation in these children is presented in Table 4, and results of molecular genetic
testing are available in Table 5.
In a cohort of adults the main clinical presentation of
MD was chronic progressive external ophthalmoplegioa
(CPEO) or CPEO+, where a clinical diagnosis with musculus
levator palpebrae or musculus orbicularis oculi biopsy
and EM in 16 patients. Classical mitochondrial syndromes
(CPEO, CPEO plus, MELAS, MERRF, MNGIE) were
found in 22 patients (Table 2). Twelve adults were found to
carry a diagnosis of definite MD, and 15 adults were found
to carry a probable MD. A muscle biopsy with histochemical
analysis has been performed in 30 patients, but RCEs
were measured in only 14 patients. Diagnostic evaluation
of these adult patients is presented in Table 6, and results
of molecular genetic testing are available in Table 5.
Twenty children were scored according to MDC as
a definite MD, five children as a probable MD and one child as a possible MD. The mean clinical score (I) was 3.7
(range 2-4), with a maximum score of 4 [including multisystem
involvement taken alone, as part of the clinical
score, had a mean score of 1.0 (range 0-2)]. The metabolic
and brain imaging score (II) was 3.0 (range 0-4), and the
histology score (III) was 1.8 (range 0-4). Before muscle
biopsy, the mean MDC score (I+II) was 6.6 (±1.4 SD),
and the final score (I+II+III) was 8.4 (±1.8 SD). Twenty
children (77.0%) scored a total (I+II+III) of >8, a result
that is comparable with the diagnosis of a definite MD.
Twelve adults were scored according to MDC as a
definite MD, 15 adults as a probable, and eight adults as
a possible MD. The mean clinical score (I) was 3.5 (range
2-4), with a maximum score of 4 [including multisystem
involvement, which taken alone, had a mean score of 1.4
(range 0-3)]. The metabolic and brain imaging score (II)
was 0.4 (range 0-3), and the histology score (III) was 2.6
(range 0-4). Before muscle biopsy, the mean MDC score
(I+II) was 3.8 (±1.2), and the final score (I+II+III) was
6.5 (± 2.0). Twelve adults (35.0%) scored a total (I+II+III)
of >8, a result that is comparable with the diagnosis of a
definite MD. If we also include in this group of patients the
patients with CPEO who were not genetically confirmed,
the number of definite MD patients would be increased
to 22 (63.0%).
Of 24 children evaluated with brain MRI imaging,
five children (20%) had MRI signs of Leigh syndrome.
Morphological brain MRI changes, which are not classified
in MDC, but might be in accordance with the diagnosis of
an MD, have been found in the following: eight (33.0%)
children with delayed myelination, seven (29.0%) children
with cerebral atrophy, two (8.0%) children with cerebellum
changes, and in six (25.0%) children in whom neuronal
migration disorders were found. In summary, brain MRI
morphological changes, which can be an imaging clue for
the diagnosis of MD, were found in 17/24 (71.0%) children. Variability of results of the MRS spectrum was large
in children with MD. No statistically significant difference
at relaxation time TE 35 ms was found in N-acetyl aspartate,
myoinositol and cholin ratios between basal ganglia
and white matter between children with MD and children
in a control group. Lactate peak was found in one child
with Leigh syndrome and complex I plus IV deficiency
at 1.33 ppm. However, statistically significant metabolic
differences were found between basal ganglia and white
matter in a healthy control group, leading us to conclude
that the MRS spectrum was well performed.
Follow-up of this group of children with brain MRI
has been important to show the “normalization” of myelination
in these children after several years of active disease,
to evaluate the progression of morphological changes
in Leigh syndrome, and revealed new neuronal migration
disorders previously not found on brain MRI images (Table
7). Figure 1 demonstrates the progression of Leigh syndrome
in an 18-year-old girl with a pathogenic homozygous
mutation c.626C>T (p.Ser209Leu) on the MTFMT
gene (OMIM #614947).
We concluded this phase of the study with a comparison
of the clinical characteristics of MD in children
and adults (Table 3). Mitochondrial diseases in children
have revealed a chronic course with metabolic decompensation
with increased serum lactate and often negative
genetic analysis. However, MDs in adults have also
presented a slow but chronic progression over the years
and this has been more often related to mitochondrial genome
rearrangements with normal serum lactate. Nuclear
mitochondrial gene mutations can have a different clinical
presentation depending on whether patients are children
or adults. Figure 2 demonstrates brain MRI changes in an
adult with a pathogenic homozygous mutation p.Ser282fs
on the SURF1 gene, a pathogenic variant that usually presents
in childhood as Leigh syndrome (OMIM #256000).
Finally, we analyzed positive results of molecular
genetic analysis methods for different groups of patients scored by Nijmegen MDC (Table 8). Positive molecular
genetic results were in the great majority (17/19) in accordance
with definite diagnosis of MD. Results also showed
that NGS methods are beneficial to discriminate molecular
mimicry and determining a diagnosis in cases of possible
and probable groups of patients with MD (Tables 5 and 8).
Despite a limited number of patients with mtDNA clinical
syndromes, buccal swabs for mtDNA isolation are a
promising noninvasive option instead of muscle biopsies
(Table 8).
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