Table 3.
Phenotypic, metabolic, and MRI spectrum in children with a mutation in ECHS1 in the heterozygous state (c.476A>G (p.Gln159Arg; rs375032130) or c.817A>G (p.Lys273Glu; rs565090080).
| Patient | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 |
|---|---|---|---|---|---|---|---|---|---|---|---|
| Ethnicity | Romanian parents | Iraqi-Turkish Jewish/mother Iraqi -Libyan Jewish | Japanese and American parents | Netherlands parents | German parents | French-Canadian parents | NL | NL | Italian parents | Belgian parents | Greek parents |
| Genetic mutation | c.476A>G/c.817A>G | c.433C>T/c.476A>G | c.176A>G/ c.476A>G |
c.161G>A/c.817A>G | c.229G>C/c.476A>G | c.538A>C/c.476A>G | c.518C>T/c.817A>G | c.476A>G/c.538A>G; | c.476A>G/c.139G>A | c.239C>T/c.817A>C | c.476A>C/ c.542G>T |
| Protein effect | p.Gln159Arg/p.Lys273Glu | p.Leu145Phe/ p.Gln159Arg |
p.Asn59Ser/ p.Gln159Arg |
p.Arg54His/ p.Lys273Glu |
p.Glu77Gln/ p.Gln159Arg |
p.Thr180Ala/p.Gln159Arg | p.Ala173Val/ p.Lys273Glu |
p.Gln159Arg/ p.Thr180Ala |
p.Gln159Arg/p.Val47Met | p.Pro80Leu/p.Lys273Glu | p.Gln159Arg/p.Arg181Leu |
| Allele source | c.476A>G mother c.817A>G father |
NL | c.476A>G mother c.176A>G father |
ND | c.476A>G mother father- ND |
c.538A>C mother father NA |
c.518C>T father c.817A>G mother |
Parents- heterozygous for variants | c.476A > G father c.139G > A mother |
NL | NL |
| Sibling (sex, mutation) | F, dead/c.476A>G/c.817A>G | No | F, dead in 1st day of life: respiratory failure, severe lactic acidosis; mutation NL | NL | M, alive, c.229G>C/= (p.Glu77Gln/=) (heterozygous carrier) |
NL | NL | NL | NL | NL | NL |
| Sex | F | F | F | M | F | F | M | F | M | M | F |
| Age of onset | 3 mo | early infancy | birth | birth | 11 mo | 1 mo | 8 ys | 17 mo | birth | 35 mo | 8 mo |
| First neurological signs/symptoms | hypotonia | hypotonia | hypotonia | hypotonia | fist-clenching, teeth-gnashing, horizontal nystagmus | development delay or regression | dyskinesias | hypotonia, lower limbs-flexed on the trunk | lower limb paroxysmal dystonia | encephalopathy | |
| Neurologic involvement/characteristics | microcephaly, hypotonia dystonia, spasticity, nystagmus, seizure, inconsolable crying, optic atrophy, global developmental delay, hearing loss? | microcephaly, hypotonia, global developmental delay, optic atrophy, hearing loss | deafness | microcephaly, hypotonia, dystonia, spasticity, inconsolable crying, global developmental regress | dystonia, developmental delay, spastic, nystagmus, hearing loss, optic atrophy | microcephaly, hypotonia, dystonia, nystagmus, optic atrophy, hearing loss | dyskinesias, dystonia | hypotonia, dystonia global developmental delay | hypotonia, limbs spasticity, hearing loss | dystonia, spasticity, mild developmental delay | microcephaly, nystagmus, severe development delay optic atrophy, hearing loss |
| Seizure, age of onset | Yes, 6 mo | No | Yes | Yes, 1.3 ys | Yes | Yes / + | No | No | No | No | No |
| Feeding difficulties | Yes | Yes | NL | yes | NL | NL | No | NL | NL | No | Yes |
| Cardiomyopathy/Cardiac involvement | HCM | transient hypertrophy of the interventricular septum | HCM, cardiac failure | No | No | NL | NL | No | LVH | No | No |
| Outcome alive/death (age) | Alive 6 ys | Alive at 7 ys | Death at 4 mo | Death at 7.5 ys | Alive at 31 ys | Alive at 12 ys | Alive at 8 ys | Alive at 4.5 ys | Death at 62 d | Alive 6 ys | Death 9 ys |
| Metabolic workup | |||||||||||
| Plasma Lactate | High | High | High | ND | High | N | N | High | High | N | High |
| Plasma Pyruvate | High | NL | NL | NL | N | NL | N | N | |||
| Alanine | N | High | NL | NL | NL | NL | N | NL | High | N | N |
| Urinary organic acids | NL | NL | metabolic profiling (amino acid analysis, urine organic acid analysis, acylcarnitine analysis) was unremarkable | NL | NL | severe ketosis and hyperlactaturia (resolved with treatment) | N | normal plasma amino acids, urine organic, and amino acid analysis | NL | NL | NL |
| 2-methyl-2,3-dihydroxybutyric acid | High | High | N | NL | N | NL | N | NL | High | N | N |
| MRI changes | brain atrophy, hyperintensity within putamen, cavitation at this level, extensive diffuse white matter changes | atrophy of the cerebellum and brain stem, mild ventricular dilatation, generalized atrophy of the grey matter, thinning of the corpus callosum |
moderate brain atrophy, low intensity in cerebral white matter | Extensive brain atrophy, widening of the subarachnoid space and of the ventricular system | no atrophy, hyperintensity in nucleus caudatus and putamen | cerebellar atrophy, hyperintense T2-weighted images in the putamen, globus palidus, caudate nuclei | regions of increased T2 and FLAIR signal and of hypointense T1 signal in the globus pallidus bilaterally with mild diffusion restriction | globus pallidus, putamen, caudate nuclei, basal ganglia T2 hyperintensity | asymmetric ventricular dilatation, partial agenesis of the posterior part of the corpus callosum, basal ganglia, a slight increase of T2 WM signal intensity, germinal cyst in the thalamo-caudate notch | asymmetric cavitation of globus pallidus, bilateral T2-WI hyperintensity, restricted diffusion | globus pallidus, caudate nuclei T2 hyperintensity |
| References | Our case | [27] | [4] | [4] | [4] | [28] | [29] | [30] | [31] | [32] | [32] |
d: day; mo: months; ys: years. M: male; F: female; HCM: hypertrophic cardiomyopathy; LVH: left ventricular hypertrophy; NL: not listed; N: normal; WM: white matter.