Number of patients: | 36 |
males | 21 (60.0) |
females | 15 (40.0) |
Age: | |
range | 23–79 |
average±SD | 58±13 |
Age at diagnosis of MD: | |
<18 years | 16 (46.0) |
18–45 years | 9 (26.0) |
>45 years | 10 (28.0) |
First clinical symptoms: | |
ptosis | 14 (40.0) |
exercise intolerance | 15 (43.0) |
developmental delay | 2 (5.0) |
stroke | 1 (3.0) |
vision deterioration | 1 (3.0) |
rapidly progressive dementia | 1 (3.0) |
epilepsy | 1 (3.0) |
Nijmegen MD clinical criteria: | |
unlikely | 0 (0.0) |
possible | 8 (23.0) |
probable | 15 (43.0) |
definite MD | 12 (34.0) |
Clinical mitochondrial diagnosis: | |
CPEO | 8 (23.0) |
CPEO plus | 8 (23.0) |
MELAS | 2 (5.0) |
MERRF | 3 (9.0) |
MNGIE | 1 (3.0) |
mitochondrial myopathy | 7 (20.0) |
unspecific encephalomyopathy | 5 (14.0) |
adult Leigh syndrome | 1 (3.0) |
Number of patients | 26 |
males | 12 (46.0) |
females | 14 (54.0) |
Age: | |
range | 0.5–18.5 |
average±SD | 7.3±5.1 |
Age at diagnosis of MD: | |
neonatal presentation | 10 (39.0) |
>2 years | 11 (42.0) |
<2 years | 5 (19.0) |
First clinical symptoms: | |
severe central hypotonia | 8 (31.0) |
psychomotor regression | 9 (35.0) |
exercise intolerance | 5 (19.0) |
seizures | 4 (15.0 |
Nijmegen MD clinical criteria: | |
unlikely | 0 (0.0) |
possible | 1 (4.0) |
probable | 5 (19.0) |
definite MD | 20 (77.0) |
Clinical mitochondrial diagnosis: | |
Leigh or Leigh-like syndrome | 5 (19.0) |
unspecific encephalomyopathy | 16 (62.0) |
myopathy | 5 (19.0) |
Main clinical signs | encephalomyopaathy | neuromuscular |
Serum lactate measurements | increased in 80.0% | increased in 14.0% |
Changes in brain imaging | common | rare |
Muscle histology | less informative | more informative |
Genetic analysis | nuclear defects | mtDNA defects |
Metabolic decompensation | more common | almost never |
MD syndrome suspected | rarely | common |
Multisystemic signs | common | common |
Number of patients | 26 |
Laboratory: | |
increased lactate serum (>2.2 mmol/L) | 20 (77.0) |
increased pyruvate serum (>80.0 nmol/L) | 14 (54.0) |
increased lactate in CSF (>1.8 mmol/L) | 5 (19.0) |
abnormal amino acids in plasma | 1 (4.0) |
abnormal organic acids in urine | 7 (27.0) |
abnormal acyl-carnitine profile | 0 (0.0) |
Electrophysiology: | |
EMG: | 14 |
myopathic | 3 (22.0) |
neuropathic | 2 (14.0) |
normal | 9 (64.0) |
EEG: | 16 |
focal | 4 (25.0) |
multifocal | 3 (19.0) |
hypsarrhythmia | 1 (6.0) |
3T MRI imaging: | 24 |
Leigh or Leigh-like syndrome | 5 (21.0) |
cerebral atrophy | 7 (29.0) |
dysmielination | 8 (33.0) |
neuronal migration disorder | 6 (25.0) |
cerebellar hypoplasia | 2 (8.0) |
ischemic lesion | 1 (4.0) |
normal | 4 (16.0) |
Muscle biopsy: | 26 |
COX negative fibers | 7 (27.0) |
ragged-red fibers | 0 (0.0) |
abnormal mitochondria on EM | 7 (27.0) |
normal results | 1 (4.0) |
OXPHOS and PDHc biochemical | 26 |
measurements: | 12 (46.0) |
PDHc deficiency | 6 (23.0) |
single OXPHOS deficiency | 4 (15.0) |
combined OXPHOS deficiency | 4 (15) |
combine PDHc and OXPHOS deficiency |
Number of children analyzed | 26 (100.0) |
Molecular genetic methods: | |
nuclear DNA muscle (Sanger) | 3 (12.0) |
nuclear and mtDNA blood (CES, PCR, Sanger | 23 (88.0) |
Results: | |
TK2 p.Ala181Val, OMIM #609560 | 3 |
SCO2 p.Glu140Lys, OMIM #604377 | 1 |
MTFMT p.Ser209Leu, OMIM #614947 | 1 |
SCL16A2 p.Gly327Arg, OMIM #300523 | 2 |
CHAT p.Thr354Met, p.Ser694Cys, | 1 |
OMIM #254210 | |
CES normal | 3/6 |
E1α PDHc mutation analysis negative | 12/12 |
common mtDNA mutation analysis negative | 23/26 |
Number of adults analyzed | 27 (77.0) |
Molecular genetic methods: | |
mtDNA muscle (PCR, Southern blotting) | 13 (48.0) |
mtDNA buccal swab (NGS) | 15 (56.0) |
nuclear DNA blood (CES) | 19 (70.0) |
Results: | |
mtDNA point mutation: | 4 (15.0) |
mt.12213G>A | 1 |
mt.8344A>G, OMIM #545000 | 3 |
mtDNA large deletion | 4 (15.0) |
mtDNA VUS | 2 (7.0) |
nuclear defects | 3 (11.0) |
C10orf1 p.Arg374Gln, OMIM #609286 | 1 |
SLC25A4 p.Ala123Asp, OMIM #615418 | 1 |
SURF1 p.Ser282fs, OMIM #256000 | 1 |
nuclear DNA VUS | 3 (11.0) |
1 | PDHc | – | No data | 11 | Normal |
2 | PDHc | – | No data | 17 | Normal |
3 | complex IV | 6 months | Cerebral atrophy F-T; delayed myelination; nucleus caudatus atrophy; callosal hypogenesis | 5 | Progression of nucleus caudatus atrophy; dysmyelination; cerbral atrophy F-T; callosal hypogenesis |
4 | complex II+PDHc | 1 year | Delayed myelination; callosal hypoplasia; bilateral polymicrogyria of operculum | 3 | Normal myelination; callosal hypoplasia; bilateral polymicrogyria of operculum |
5 | PDHc | 1 year | Cerebral atrophy F-T; delayed myelination; bilateral GM heterotopia along LV | 4 | Less cerebral atrophy; normal mye-lination; bilateral GM heterotopia along LV |
6 | PDHc | – | Lost data | 7 | Mild cerebral atrophy F-T; callosal hypoplasia; atrophy of cerebellar padunculi (wide 4th ventricle) |
7 | complex I+IV | 4 years | Leigh syndrome | 18 | Leigh syndrome-progression; nucleus caudatus atrophy; bilateral high T2 signal in putamen and mesencephalon |
8 | PDHc | – | Lost data | 7 | Mild cerebral atrophy |
9 | complex IV+PDHc | 6 months | Mild cerebral atrophy F-P | 7 | Mild cerebral atrophy F-P |
Laboratory: | |
increased lactate in serum | 5 (14.0) |
positive ischemic test | 0 |
amino acids in plasma/organic acids in urine | 0 |
CSF analysis | 0 |
Electrophysiology: | |
EMG: | 31 |
myopathic | 19 (61.0) |
neuropathic | 2 (6.0) |
normal | 10 (33.0) |
EEG: | 16 |
normal patterns | 6 (38.0) |
abnormal (slow waves or epileptic discharges) | 10 (62.0) |
VEPs: abnormal | 5 |
BERA: normal | 2 |
Brain imaging: | 8 |
unspecific abnormalities on CT | 3 (38.0) |
unspecific abnormalities on MRI | 3 (38.0) |
stroke-like episodes on MRI | 2 (24.0) |
Muscle biopsy: | 30 |
COX negative fibers | 10 (33.0) |
ragged-red fibers | 16 (53.0) |
blue ragged fibers | 3 (10.0) |
abnormal mitochondria on EM | 20 (67.0) |
normal results | 4 (13.0) |
OXPHOS biochemical measurements: | 14 |
normal enzyme activities | 8 (58.0) |
single deficiency | 3 (21.0) |
combined deficiency | 3 (21.0) |
Average | Range | Average | Range | |
---|---|---|---|---|
Clinical signs and symptoms (I) | 2.9 | 1–4 | 3.7 | 2–4 |
Multisystem disease: | 1.0 | 0–2 | 1.0 | 0–2 |
metabolic/imaging studies (II) | 0.4 | 0–2 | 3 | 0–4 |
morphology: muscle biopsy (III) | 2.6 | 0–4 | 1.8 | 0–4 |
I + II | 3.2 | ±1.3 | 6.6 | ±1.4 |
I + II + III | 6.0 | ±1.9 | 8.4 | ±1.8 |
Molecular genetic analysis (number of cases): | unlikely | possible | probable | definite |
WES blood | 0 | 1 | 1 | 8 |
mtDNA muscle | 0 | 0 | 0 | 8 |
mtDNA buccal swab | 0 | 0 | 0 | 1 |