Autosomal recessive mutations in the nuclear Twinkle (C10orf2) gene cause a mitochondrial DNA depletion syndrome (MDS) characterized by early onset hepatoencephalopathy.
We report a severe, early onset encephalopathy and multisystem failure case caused by novel recessive Twinkle gene mutations. Patient clinical, laboratory, and pathological features are reported and Twinkle-associated MDS literature reviewed.
Typical presentation includes symptom onset before age six months, failure to thrive, psychomotor regression, epileptic encephalopathy, sensory axonal neuropathy, cholestatic liver dysfunction, and occasionally, renal tubulopathy, movement disorders, and ophthalmoplegia. Death is typical before age four years.
In the differential diagnosis of early onset encephalopathy and multisystem failure, MDS should be considered.
Whitehead MT, Wien M, Lee B, Bass N, Gropman A. Black Toenail Sign in MELAS Syndrome. Pediatr Neurol. 2017 Oct;75:61-65.
Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) syndrome is a mitochondrial disorder often causing progressive brain injury that is not confined to large arterial territories. Severe insults ultimately lead to gyral necrosis affecting the cortex and juxtacortical white matter; the neuroimaging correlate is partial gyral signal suppression on T2/FLAIR sequences that resemble black toenails. We aimed to characterize the imaging features and the natural history of MELAS-related gyral necrosis.
Materials and Methods
Databases at two children's hospitals were searched for brain magnetic resonance imaging studies of individuals with MELAS. Examinations with motion artifact and those lacking T2/FLAIR sequences were excluded. The location, the cumulative number, and the maximum transverse diameter of necrotic gyral lesions were assessed using T2-weighted images and T2/FLAIR sequences. Wilcoxon signed-rank test was employed to evaluate the relationship between disease duration and the number of necrotic lesions.
One hundred twenty-four examinations from patients with 14 unique MELAS patients (16 ± 3 years) were evaluated. Six of the eight patients who developed brain lesions also developed gyral necroses (mean 13, range 0 to 44). Necrotic lesions varied in maximal diameter from 4 to 25 mm. Cumulative necrotic lesions correlated with disease duration (P < 0.001).
The black toenail sign signifying gyral necrosis is a common imaging feature in individuals with MELAS syndrome. The extent of gyral necrosis correlates with disease duration.
Multifocal cortical/subcortical lesions have developed in both cerebral hemispheres, without regard to large arterial territories. Lesions are hyperintense on T2WI (A), and many demonstrate partial signal suppression on T2/FLAIR resembling black toenails (arrows, B), representing gyral necroses.