Table 1.
Clinical, biochemical and molecular data of 11 patients with pathogenic variants in PDHc related genes.
| Data and symptom(s) |
Patient KI (p) |
Patient KW (b) |
Patient SzO (p) |
Patient BF (p) |
Patient KBS (m) |
Patient PM (p) |
Patient GP (p) |
Patient KG (p) |
Patient PM (p) |
Patient ZJ (p) |
Patient PZ (p) |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Patient no. |
1 |
2 |
3 |
4 |
5 |
6 |
7 |
8 |
9 |
10 |
11 |
| Family no. | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | ||
| Sex | M | M | F | M | F | M | F | F | F | F | F |
| Age of onset | 2 y | ND | Neonatal | Neonatal | 2 y | 15 m | 3 m | 7 m | Birth | 4 m | 1.5 y |
| Age at diagnosis | 8.5 | ND | 2 | 4 y | ND | 8 y | 2.5 y | 4.5 y | 25 y | 2 y | 9 y |
| Neurological findings | |||||||||||
| Psychomotor retardation/developmental delay | No | No | Yes | Yes | No | Yes | Yes | Yes | Yes | Yes | Yes |
| Developmental delay (> 3 y) | No | No | Yes | No | ND | Yes | Yes | Yes | Yes | Yes | |
| Dysarthria | No | No | Nd | Yes | Yes | Yes | ND | ND | ND | ND | Yes |
| Microcephaly | No | ND | No | ND | No | No | Yes | Yes | Yes | Yes | No |
| Seizures | No | ND | No | No | No | No | Yes | Yes | No | Yes | No |
| Ataxia | No | ND | Yes | Yes | Yes | Yes | ND | No | ND | No | No |
| Hypotonia/hypertonia | No | ND | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes | Yes |
| Peripheral neuropathy | Yes | ND | ND | ND | Yes | Yes | ND | ND | ND | ND | No |
| Brain malformations | |||||||||||
| Brain atrophy | ND | ND | No | Yes | No | ND | Yes | ND | Yes | Yes | Yes |
| Corpus callosum hypoplasia | ND | ND | No | ND | No | ND | Yes | Yes | ND | Yes | Yes |
| Cerebellum atrophy | ND | ND | No | No | No | No | ND | No | ND | VH | VH |
| Demyelinisation | ND | ND | No | Yes | No | ND | ND | ND | ND | ND | Yes |
| Basal ganglia abnormalities | ND | ND | Yes | ND | No | ND | ND | ND | ND | ND | Yes |
| Brain stem involvement | ND | ND | Yes | ND | No | ND | ND | ND | ND | ND | ND |
| Ocular findings | |||||||||||
| Nystagmus | No | No | Yes | No | No | No | ND | No | Yes | No | No |
| Ptosis | No | No | No | No | No | No | ND | No | Yes | No | Yes |
| Oculomotor apraxia | No | No | Yes | No | No | Yes | ND | No | Yes | No | No |
| Biochemical findings | |||||||||||
| Blood lactate (fasting) [mg/dL] | 42.66 | NA | 26 | 20.8 | 47.4 | 62 | 36.2–65.6 | 39 | 42 | 54 | 104 |
| Blood pyruvate (fasting) [mg/dL] | 2.2 | NA | 2 | 1.7 | 2.3 | 3.7 | NA | 2.8 | NA | NA | NA |
| Blood lactate (after carbohydrate) [mg/dL] | 39 | NA | 25 | 29.6 | NA | 92 | NA | NA | 51 | 53 | NA |
| Blood pyruvate (after carbohydrate) [mg/dL] | 2.6 | NA | 1.5 | 2.1 | NA | 4.1 | NA | NA | NA | 4.5 | NA |
| Blood lactate/pyruvate ratio | 18 | NA | 13 | 12 | 20.7 | 17 | NA | 14 | 7.5 | 12 | NA |
| CSF lactate [mg/dL] | 40 | NA | NA | NA | NA | 67 | 75 | 47 | 87 | NA | 58.8 |
| Alanine [μmol/dL] | NA | NA | 559 | 180 | NA | 238 | 952 | NA | 222–1338 | 806 | 407 |
| GC/MS urine | LA, PA, 2-KGA | NA | NA | 2-KGA, LA | NA | 2-KGA, LA | LA, 2-KGA | NA | 2-KGA, LA | 2-KGA, LA, MMA | Normal |
| pH | NA | NA | 7.43 | 7.49 | NA | 7.46 | NA | 7.374 | 7,368 | 7.3 | 7.39 |
| pO2 [mmHg] | NA | NA | 117 | 86.5 | NA | 83.5 | NA | 81.6 | NA | 121 | 92.3 |
| pCO2 [mmHg] | NA | NA | 26,3 | 21.5 | NA | 26.7 | NA | 25.6 | 35.7 | 18.7 | 32.1 |
| Muscle biochemistry | |||||||||||
| Complex I | NA | NA | NA | NA | NA | 10 | NA | 12.2 | 11.6 | < 3.0 | 5.9 |
| Complex II | NA | NA | NA | NA | NA | 7.6 | NA | 6.5 | 3.5 | 7.3 | 3.4 |
| Complex II + III | NA | NA | NA | NA | NA | 4.7 | NA | 4 | 5.5 | < 3.0 | 3.6 |
| Complex III | NA | NA | NA | NA | NA | 44.7 | NA | 69.2 | 47.5 | 71.9 | 72 |
| Complex IV | NA | NA | NA | NA | NA | 10 | NA | 6.1 | 19.5 | 5.2 | 3.9 |
| SC | NA | NA | NA | NA | NA | 275 | NA | 211.4 | 122.6 | 513.8 | 268.2 |
| E1α [% of mean reference] | NA | NA | NA | 52.5 | NA | 0 | NA | 38.5 | NA | 20.9 | 59.7 |
| Muscle histology and histochemistry | |||||||||||
| Variability of fiber size | No | ND | ND | ND | ND | Yes | ND | Yes | ND | No | Yes |
| Lipid accumulation | No | ND | ND | ND | ND | Yes | ND | No | Yes | Yes | No |
| Predominance of fibers type I | No | ND | ND | ND | ND | No | ND | Yes | ND | Yes | Yes |
| Clinical diagnosis | |||||||||||
| Clinical diagnosis prior to genetic testing | Guillain-Barre syndrome |
Family study |
Family study |
PDHc deficiency |
Ataxia | PDHc deficiency |
Leigh syndrome |
Mitochondrial encephalopathy | Mitochondrial encephalomyopathy | PDHc deficiency |
Leigh syndrome |
| Nijmegen score | 4 | 3 | 5 | 3 | 2 | 3 | 4 | 3 | 6 | 3 | 6 |
| Type of PDHc | PDH E1α subunit |
PDH E1α subunit | PDH E1α subunit | PDH E1α subunit | PDH E1α subunit | PDH E1α subunit | PDH E1α subunit | PDH E1α subunit |
PDH E1α subunit |
PDH E1α subunit |
PDH E3 subunit |
| Neurological phenotype (final assigning) | |||||||||||
| Neonatal encephalopathy with lactic acidosis | x | x | x | x | |||||||
| Basal ganglia abnormalities (Leigh-like) | x | x | |||||||||
| Chronic/progressive neurologic deterioration | x | x | x | ||||||||
| Intermittent ataxia | x | x | |||||||||
| Molecular genetics | |||||||||||
| DNA source (tissue) | Blood | Blood | Blood | Blood | Blood | Blood | Blood | Muscle | Muscle | Muscle | Muscle |
| Molecular test | WES | Sanger | Sanger | Sanger | Sanger | Sanger | WES | Sanger | WES | Sanger | WES |
| Mutated gene | PDHA1 | PDHA1 | PDHA1 | PDHA1 | PDHA1 | PDHA1 | PDHA1 | PDHA1 | PDHA1 | PDHA1 | DLD |
| Nucleotide exchange | c.262C > T | c.262C > T | c.464T > C | c.787C > G | c.787C > G | c.787C > G | c.856_859dupACTT | c.904C > T | c.933_935delAAG | c. 934_940delAGTAAGA | c.1123G > A |
| Amino acid exchange | p.R88C | p.R88C | p.M155 T | p.R263G | p.R263G | p.R263G | p.Arg288Leufs*10 | p.R302C | p.Arg311del | p.S312Vfs*12 | p.E375K |
| Localization of mutation | Exon 3 | Exon 3 | Exon 5 | Exon 8 | Exon 8 | Exon 8 | Exon 9 | Exon 10 | Exon 10 | Exon 10 | Exon 11 |
| Mutation type | Missense | Missense | Missense | Missense | Missense | Missense | Frameshift | Missense | Inframe deletion | Frameshift | Missense |
| Mutation status | Known | Known | Novel | Known | Known | Known | Novel | Known | Known | Known | Known |
| Mutation inheritance | Maternal | Maternal | Maternal | Maternal | Na | Na | De novo | De novo | De novo | Na | Parental |
| Familial history | |||||||||||
| Affected relative | Brother | Brother | No | Mother, uncle | Son, brother | NA | No | No | No | NA | No |
p - proband; b - brother; m - mother; y - year; m - month; 2-KGA - ketoglutaric acid; LA - lactic acid; MMA - methylmalonic acid, NA - not analysed; ND - no data; PA - pyruvic acid, Sanger - Sanger sequencing; VH - vermis hypoplasia; WES – whole-exome sequencing.