DNM1L‐related encephalopathy in infancy with Leigh syndrome‐like phenotype and suppression‐burst

Dynamin 1-like (DNM1L), a member of the dynamin superfamily of GTPases, mediates mitochondrial and peroxisomal division, and dominant-negative mutation of DNM1L in mammalian cells leads to a defect in mitochondrial fission (1, 2). In human, a heterozygous dominant-negative mutation in DNM1L has been reported in infants with severe encephalopathy. Here, we report a patient with hypotonia and infantile spasms with suppression-burst on EEG, showing biochemically mitochondrial dysfunction and pathologically Leigh syndrome (LS). Whole exome sequencing (WES) analysis identified a de novo novel DNM1L mutation. Our patient is a 6-month-old male infant, who presented severe hypotonia, infantile spasms with suppression-burst and a high level of lactate in cerebrospinal fluid (Table S1, Supporting information). Serial magnetic resonance imaging of brain showed progressive atrophy. His development was profoundly delayed, and he attained no developmental milestones before his death at 18 months of age. We performed brain pathology, measurement of mitochondrial respiratory chain complexes (MRC) activities, immunocytochemistry of cultured fibroblasts and WES analysis. Brain pathology showed LS features, such as symmetrical neuronal necrosis with vascular proliferation in cerebral cortex, basal ganglia, and brainstem (Fig. 1f–h). Assay of muscle tissue showed low crude activities of MRC, however, significantly reduced activities of less than 20% of citrate synthase ratio were noted in respiratory chain complexes I, III, and IV. WES analysis revealed a de novo missense mutation of c.1217T>C, p.Leu406Ser in DNM1L gene (Fig. 1i–j). Immunocytochemistry showed defects of fission in peroxisomes and mitochondria (Fig. 1l–m). DNM1L is the only member of the family implicated in mitochondrial fission and also implicated in the fission of peroxisomes. The DNM1L central domain and GTPase domain are thought to play an important role in forming the severe encephalopathy in early infancy. Most previous patients showed no significant changes of the MRC activities in both biopsied skeletal muscle tissues and cultured fibroblasts. The abnormal DNM1L protein may not directly influent MRC activities, especially in cultured fibroblast. Some, but not all, patients with DNM1L mutations have exhibited lactic acidosis and/or respiratory chain deficiencies in muscle (Table S1). Interestingly, four of five patients with missense mutation. We reviewed the clinicopathological features of six patients with DNM1L-encephalopathy in infancy from the literatures and our patient (Table S2). All patients showed initial symptoms at the neonatal or infantile period, and cytopathologically mitochondria fission deficit. Most of them exhibited severe developmental delay, epilepsy and early death. Most patients with DNM1L-related encephalopathy have commonly possessed a heterozygous de novo mutation in the central domain of DNM1L gene and showed severe developmental delay and/or abnormal brain development (2). Clinical features of our patient were partial in common with previously reported patients, such as severe hypotonia, developmental delay, elevated lactate in serum and CSF and early infantile death. Moreover, the DNM1L mutation (c.1217T>C, p.Leu406Ser) in our patient locates in the central domain of DNM1L gene, a similar region to the previous description. The DNM1L mutation in our patient may act as a dominant-negative manner by interfering with helical polymerization, because of the same domain containing the reported mutation (3). The common dysfunction of the mitochondrial and peroxisome fission also supports this pathogenesis. On the other hand, the sibling patients with recessive loss-of-function mutations (c.261dup and c.385_386del) of the GTPase domain of DNM1L gene exhibited a severe lethal phenotype (4). The both mutations can predict the frame-shift transcription and the premature termination, and result in complete functional null, because of resembling drp1 (homology of human DNM1L)-null mice phenotypes of embryonic lethality (5). However, drp1-heterozygous mice markedly reduced Drp1 expression level are normal in birth, growth, and mating like human heterozygous parents of the patients (6). Drp1 is highly expressed in the brain and plays a major role in developing brain (5). Drp1-null brain development is inhibited and its synapse shows no existence of mitochondria (5). DNM1L-mutation position and its inherited manner may be the useful information for the clinical severity of the disease.