Table 1.
Clinical and laboratory features.
| Individual 1 | Individual 2 | Individual 3 | |
|---|---|---|---|
| Clinical presentation | |||
| Sex | M | F | F |
| Perinatal history | NRFHR, mild temperature instability | normal | NRFHR, C/S |
| Birth weight (SD) | −2.9 | +0.5 | −1.0 |
| Age at presentation | 18 days | 9 days | 13 days |
| Feeding difficulties | + | + | + |
| Failure to thrive | + | + | + |
| Acute encephalopathy | − | - | + (hyperammonemia) |
| Chronic diarrhoea | + | - | + |
| Anaemia | + | - | + |
| Age at most recent assessment | 3 years | 14 months | 18 months |
| Age at symptom resolution | 12 months | 10 months | 15–18 months |
| Clinical status | asymptomatic | asymptomatic | asymptomatic |
| Most recent weight (SD) | −1.0 | −0.8 | +0.2 |
| Developmental status | normal | normal | normal |
| Metabolic laboratory testinga | |||
| Hyperammonemia | + (267 μmol/L) | + (90 μmol/L) | + (520 μmol/L) |
| Encephalopathy | - | - | + (seizures after EBM gavage feeds) |
| Lactic acidosis (mmol/L) | + (range: 1.0–11.0; x̅ = 3.6 mmol/L) (n = 36) | + (range: 1.2–8.5 mmol/L; x̅ = 3.5 mmol/L) (n = 17) | + (range: 3.2–5.8 mmol/L; x̅ = 4.3 mmol/L) (n = 7) |
| Plasma amino acids (μmol/L): | |||
| Alanine | 1624 (↑↑) [83–447] | 1245 (↑↑) [119–439] | 1675 (↑↑) [75–500] |
| Proline | 530 (↑) [87–375] | 439 (↑) [104–348] | 590 (↑) [20–330] |
| Glycine | 574 (↑) [133–409] | 229 [103–386] | 530 [100–550] |
| Glutamine | 1742 (↑↑) [240–1194] | 979 [303–1459] | 1725 (↑) [124–1000] |
| Citrulline | BDL (↓) | BDL ( ↓) | 2 [0–50] |
| Arginine | 19 [6–140] | 18 (↓) [30–147] | 17 (↓) [50–160] |
| Ornithine | 23 (↓) [29–168] | NR | 18 (↓) [25–250] |
| Urine orotic acid (mmol/molCr) | 7.1 (↑) [<2.0] | NR | 9.3 (↑) [1.0–3.2] |
| Urine organic acids | Increased lactic, pyruvic, 2-ethyl-3-hydroxypropionic, ethylmalonic, Krebs cycle intermediates including fumaric | Increased lactic and pyruvic acids | Increased lactic acid |
| Acylcarnitine profile | Persistent (n = 4) minor increases in C3, C3DC, C4, C6, C6OH, and C10 | Normal (n = 3) apart from trivial increases in C6OH, C3:1, and/or C3 | Normal (n = 1) |
| Plasma GDF-15 (pg/mL) | >6000 (↑↑) [<750] (age 3 weeks) | 2030 (↑↑) [<750] (7 months) | NR |
| 3952 (↑↑) (age 2 months) | |||
| 3017 (↑↑) (age 5 months) | |||
| 2731 (↑↑) (age 13 months) | |||
| Residual/subclinical laboratory findings (at most recent assessment) | lactate 2.5 mmol/L; elevated GDF-15 (2731 pg/mL) (last tested age 13 months) | lactate 2.7 mmol/L; hyperalaninemia (685 μmol/L) | lactate 3.7 mmol/L |
| Muscle biopsy | |||
| Histology and EM | Increased lipid droplets, irregular loss of sarcomeres with replacement by glycogen, large, ‘swollen’ mitochondria with abnormal figures | NR | NR |
| Complexes I–IV | normal | ||
| Primary skin fibroblasts | |||
| Complex I | NR | NR | normal |
| Complexes II–IV | normal | NR | normal |
| PDH, PC and L/P ratio | normal | NR | NR |
Reference intervals are denoted in square brackets.
BDL below detectable limit, C/S Caesarean section, EBM expressed breast milk, F female, GDF-15 growth and differentiation factor 15, L/P lactate/pyruvate, M male, NR not reported, NRFHR non-reassuring foetal heart rate, PC pyruvate carboxylase, PDH pyruvate dehydrogenase, SD standard deviations.
aSee Supplementary Fig. 1 for additional details.