Table 1
Clinical characteristics in our cohort of children with mitochondrial diseases.
| Clinical Characteristics | n (%) |
|---|---|
| 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) |
[i] MD: mitochondrial disease; Nijmegen MDC: mitochondrial disease criteria.
Table 2
Clinical characteristic in our cohort of adult mitochondrial patients.
| Clinical Characteristics | n (%) |
|---|---|
| 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) |
[i] CPEO: chronic progressive external ophthalmoplegia; MELAS: mitrochondrial encephalomyopathy, lactic acidosis and stroke-like episodes; MERRF: myoclonic epilepsy with ragged-red fibers; MNGIE: mitochondrial neugastrointestinal encephalopathy.
Table 3
Comparison of mitochondrial diseases between children and adults in our cohort of patients.
| Parameters | Children (<18 years) n = 26 | Adults n = 36 |
|---|---|---|
| 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 |
[i] mtDNA: mitochondrial DNA; MD: mitochondrial disease.
Table 4
Diagnostic investigations in our cohort of children with mitochondrial diseases.
| Diagnostic Investigations | n (%) |
|---|---|
| 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 |
[i] CSF: cerebralspinal fluid; EMG: electromyography; EEG: encephalomyography; COX: cytochrome oxidase; EM: electron microscopy; OXPHOS: oxidative phosphorylation; PDHc: pyruvate deydrogenase complex.
Table 5
Results of molecular genetic analysis in both our cohorts of mitochondrial patients.
| Molecular Genetic Analysis | n (%) |
|---|---|
| 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) |
[i] CES: clinical-exome sequencing; PCR: polymerase chain reaction; Sanger: Sanger sequencing; PDHc: pyruvate dehydrogenase complex; VUS: variant of unknown significance.
Table 6
Diagnostic investigations in our cohort of adult mitochondrial patients.
| Diagnostic Investigations in Our Cohort | n (%) |
|---|---|
| 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) |
[i] CSF: cerebralspinal fluid; EMG: electromyography; EEG: encephalomyography; VEPs: visual-evoked potentials; BERA: brainstem-evoked response audiometry; CT: computed tomography; MRI: magnetic resonance imaging; COX: cytochrome oxidase; EM: electron microscopy; OXPHOS: oxidative phosphorylation.
Table 7
Brain magnetic resonance imaging morphological changes in children with mitochondrial encephalomyopathies at follow-up.
| Case | Enzyme Deficiency | Age of First MRI (diagnostic) | First Brain MRI Results | Age of Last MRI (follow-up in years) | Last Brain MRI Results |
|---|---|---|---|---|---|
| 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 |
[i] PHDc: pyruvate dehydrogenase complex; F-T: frontotemporal region; F-P: frontoparietal region; GM: brain grey matter; LV: lateral ventricle.
Figure 1
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).
*: progression of nucleus caudatus atrophy and T2-weighted hyperintensities; +: T2-weighted hyperintensities in putamen bilaterally.
Figure 2
Brain MRI morphological changes in an adult with a pathogenic homozygous mutation p.Ser282fs on the SURF1 gene, which is usually presented in childhood as Leigh syndrome (OMIM #256000). *: round T2-weighted hyperintensities in cerebral peduncles; +: T2-weighted periaqueductal hyperintensities; #: significant cerebral atrophy in occipital lobes. =: dilatations of Virchow-Robin spaces in basal ganglia bilaterally.
Table 8
Yield of different diagnostic approaches used in Nijmegen mitochondrial disease criteria and positive molecular genetic analysis results in different groups of patients (children and adults) according to the Nijmegen mitochondrial disease criteria.
| Nijmegen MDC | Adults | Children | ||
|---|---|---|---|---|
| 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 |
[i] Nijmegen MDC: Nijmegen mitochondrial disease criteria; WES: whole-exome sequencing; mtDNA: mitochondrial DNA.