Table 1.
Clinical Features of Individuals with TMTC3 Variants
| I-V-1 | II-V-1 | II-V-2 | III-IV-2 | IV-IV-1 | IV-IV-2 | V-IV-1 | V-IV-2 | VI-IV-1 | |
|---|---|---|---|---|---|---|---|---|---|
| cDNA mutations | c.1462delA, c.2617C>T | c.1959_1960insTT | c.1959_1960insTT | c.1686_1701del | c.199C>G | c.199C>G | c.3G>A | c.3G>A | c.1151G>A, c.2521dupA |
| Proteins variants | p.Arg488Glufs∗6, p.Gln873∗ | p.Arg654Leufs∗6 | p.Arg654Leufs∗6 | p.Phe562Leufs∗8 | p.His67Asp | p.His67Asp | p.Met1? | p.Met1? | p.Gly384Glu, p.Ile841Asnfs∗4 |
| Gender | female | female | female | male | female | male | male | female | male |
| Country of origin | Egypt | Yemen | Yemen | Egypt | Lebanon | Lebanon | Turkey | Turkey | US |
| Consanguinity | + | + | + | + | + | + | + | + | − |
| Weight at birth (kg) | NA | NA | NA | 2 | 3.55 | 3.63 | 3.45 | 2.6 | 2.7 |
| Length at birth (cm) | NA | NA | NA | 47 | 55 | 53 | NA | NA | NA |
| HC at birth (SD) | NA | NA | NA | −1 | −1 | +1 | NA | NA | NA |
| Psychomotor Development | |||||||||
| Gross motor skillsa | delayed | delayed | delayed | delayed | delayed | delayed | delayed | delayed | delayed |
| Fine motor skillsa | delayed | delayed | delayed | absent | delayed | delayed | delayed | delayed | delayed |
| Languagea | delayed | delayed | delayed | absent | absent | absent | delayed | delayed | absent |
| Sociala | delayed | delayed | delayed | delayed | delayed | delayed | delayed | delayed | delayed |
| Neurological Examination | |||||||||
| HC at last examination (cm) | 41 (−7.5 SDs) | NA | NA | 39.5 (−4 SDs) | 46 (−1.34 SDs) | 46.5 (−0.22 SD) | 49.5 (−1 SD) | 45 (−2 SDs) | 53 (+1.5 SDs) |
| Age at diagnosis | NA | NA | NA | 6 months | 18 months | 6 months | 1 month | 5 months | prenatal: encephalocele on ultrasound |
| Hypotonia | + | + | + | + | + | + | + | + | + |
| Intellectual disability | + | + | + | + | + | + | + | + | + |
| Autistic-like behavior | NA | + | + | − | NA | NA | − | − | NA |
| Seizures | |||||||||
| Onset | 4 months | 6 months | 8 months | 7 months | − | − | − | 5 months | 6 months |
| Type | GTC | GTC | GTC | myoclonic | − | − | − | GTC | infantile spasms |
| Frequency | weekly | weekly | under control | infrequent | − | − | − | weekly | daily |
| Ophthalmologic Findings | |||||||||
| Cataract | − | + (L) | NA | − | − | − | + (R) | − | − |
| Micropthalmia | − | − | NA | − | − | − | + (L) | − | − |
| Buphthalmos | − | − | NA | − | − | − | − | − | − |
| Megalocornea | − | − | NA | − | − | − | − | − | − |
| Optic atrophy | − | + | NA | − | − | − | − | − | − |
| Retinal dysplasia | − | − | NA | − | − | − | − | − | − |
| Other Systemic Findings | |||||||||
| Cardiovascular | NA | − | NA | − | − | − | NA | − | − |
| Respiratory | NA | − | NA | RD at birth | − | − | NA | − | − |
| Musculoskeletal | NA | − | NA | club feet | club feet | − | NA | contractures of elbow | G-tube feeding due to hypotonia |
| Genitourinary | NA | unilateral pubic adhesion | − | − | − | − | NA | − | − |
| Other | − | − | occipital lipoma | squint | − | − | facial asymmetry | hypertelorismus, strabismus, sacral hemangioma | squint |
| MRI | |||||||||
| Agyria | + | + | + | + | − | − | − | − | − (PMG) |
| Cobblestone lissencephaly | + | + | + | + | − | − | + | + | + |
| Ventriculomegaly | + | + | + | − | + | + | + | − | + |
| Encephalocele | + (occipital) | − | − | − | − | − | − | − | + (occipital) |
| Corpus callosum | hypoplasia | − | − | hypoplasia | hypoplasia | hypoplasia | − | − | partial hypoplasia |
| Brainstem | dysplasia, hypoplasia | hypoplasia | hypoplasia | hypoplasia | hypoplasia | hypoplasia | − | − | − |
| Cerebellum | dysplasia | hypoplasia | hypoplasia | hypoplasia | dysplasia | dysplasia | − | − | − |
| Retrocerebellar cysts | − | − | − | + | − | − | − | − | − |
| Investigations | |||||||||
| CPK level (units/liter) | normal | NA | NA | normal | normal | normal | normal | elevated (650) | elevated (1,025) |
| Other metabolic findings | NA | normal | increased GGT and ALP | normal | normal | normal | normal | normal | normal |
| VEP/ERG | NA | NA | NA | normal | NA | NA | NA | NA | normal |
| EMG | normal | NA | NA | normal | NA | NA | NA | NA | NA |
| Muscle biopsy | NA | NA | NA | NA | NA | NA | NA | NA | mild myopathic change, increased interstitial collagen, fiber-size variation |
Abbreviations: ALP, alkaline phosphatase; CPK, creatine phosphokinase; EMG, electromyography; GGT, gamma glutamate transferase; GTC, generalized tonic clonic; HC, head circumference; L, left; NA, not available; PMG, polymicrogyria; R, right; RD, respiratory distress; and VEP/ERG, visual evoked potential and electroretinogram.
a
Normal, delayed, or absent.