Table 1.
Genetic and Clinical Findings in Subjects with Bi-allelic MDH2 Variants
| Subject 1 | Subject 2 | Subject 3 | |
|---|---|---|---|
| Gender | male | male | male |
| Family history | no | no | no |
| Consanguinity | no | no | no |
| Age at last clinical examination | 4.5 years | died at 1.5 years | 7.5 years (lost view) |
| MDH2 mutations | c.398C>T (p.Pro133Leu) | c.398C>T (p.Pro133Leu) | c.109G>A (p.Gly37Arg) |
| c.620C>T (p.Pro207Leu) | c.596delG (p.Gly199Alafs∗10) | c.398C>T (p.Pro133Leu) | |
| Age at onset | 5 months | neonatal | neonatal |
| Initial symptom | hypotonia, no head control | seizures | hypotonia |
| Refractory epilepsy | + (partial, afterward myoclonic; onset at 7 months) | + (generalized tonic and spasms; onset at 2 months) | + (myoclonic epilepsy and generalized tonic; onset ?) |
| Hypotonia | + (marked, mainly axial and in the lower limbs) | + (axial) | + |
| Developmental delay | + | + | + |
| Head control | 10 months | not acquired at 6 months | 12 months |
| Sitting position | 18 months | not acquired at 12 months | − |
| Crawling | 18 months | not acquired at 12 months | no |
| Good eye contact | yes | yes | no |
| Language | not acquired | babbling at 12 months | not acquired |
| Muscle weakness | + | + | + |
| Failure to thrive | + | − | + |
| Age at onset | 7 months | − | ? |
| Gastrostomy (age) | + (3 years) | − | + (?) |
| Last examination | 4 years | 18 months | 7.5 years |
| Length | < −2 SDs | + 1 SD | −2 SDs |
| Head circumference | < −2 SDs | + 1 SD | +2 SDs |
| Weight | < −3 SDs | + 1 SD | −2.5 SDs |
| Movement disorders | dystonia and dyskinesia | − | dystonia |
| Obstinate constipation | + | + | − |
| Ophthalmologic examination (age) | retinitis pigmentosa (4 years), strabismus (5 months) | strabismus (1 year) | ? |
| Pyramidal signs | + | + | − |
| Deep tendon reflexes | decreased | N | − |
| Plantar responses | bilateral extensor | bilateral extensor after 1 year | normal |
| Other findings | − | − | two supernumerary nipples, von Willebrand disease, CCAM |
| Ketogenic diet (onset) | + (3 years) | + (18 months) | + (3 years) |
| Response to Ketogenic diet | reduction epileptic seizure frequency | reduction epileptic seizure frequency | ? |
| Evolution | alive at 5 years | died at 1.5 years (secondary to metabolic decompensation) | alive at 12 years |
| Brain MRI abnormalities | + (atrophy of the anterior part of the CC, delayed myelination of the frontal white matter, frontal and parietal atrophy, elevated lactic acid peak on MRS) | + (delayed myelination of the genu of the CC, cortical and subcortical atrophy of the frontal lobes) | + (cerebral cortical and subcortical atrophy, cerebellar atrophy, elevated lactic acid peak on MRS) |
| Lactate Concentration | |||
| Plasma (N < 2.20 mmol/l) | elevated (3.0) | elevated (5.7) | elevated (2.8) |
| L/P ratio (N < 18) | elevated (63) | elevated (23) | elevated (20) |
| CSF (N < 2.10 mmol/l) | elevated (2.48) | elevated (3.3) | ND |
| Krebs Cycle Intermediates | |||
| Malate (N < 7 μmol/mmol creatine) | elevated (56) | elevated (15–38) | ND |
| Fumarate (N < 14 μmol/mmol creatine) | elevated (20) | N or elevated (9–55) | N |
| Succinate | N | N | N |
| RC Activity | |||
| Muscle | N | ND | N |
| Liver | reduced CV activity | ND | ND |
| Fibroblasts | N | ND | reduced CI activity |
Abbreviations are as follows: +, present; −, absent; ?, unknown; N, normal; ND, not done; SD, standard deviation; CCAM, congenital cystic adenomatoid malformation; MRS, magnetic resonance spectroscopy; CC, corpus callosum; L/P, lactate/pyruvate; CSF, cerebrospinal fluid; RC, respiratory chain; CV, complex V; and CI, complex I.