Alternative titles; symbolsEMPF▼ DescriptionEncephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1) is characterized by delayed psychomot...
Alternative titles; symbols
Encephalopathy due to defective mitochondrial and peroxisomal fission-1 (EMPF1) is characterized by delayed psychomotor development and hypotonia that may lead to death in childhood. Many patients develop refractory seizures, consistent with an epileptic encephalopathy, and thereafter show neurologic decline. The age at onset, features, and severity are variable, and some patients may not have clinical evidence of mitochondrial or peroxisomal dysfunction (summary by Sheffer et al., 2016; Fahrner et al., 2016).
Genetic Heterogeneity of Encephalopathy Due to Defective Mitochondrial And Peroxisomal Fission
See also EMPF2 (617086), caused by mutation in the MFF gene (614785) on chromosome 2q36.
▼ Clinical Features
Waterham et al. (2007) reported a newborn girl, born of unrelated Caucasian parents of British ancestry, with a systemic disorder resulting in death in infancy. The mother noted diminished fetal movements during pregnancy. After birth, the infant was well for several days, but presented in the first week of life with poor feeding and neurologic impairment, including hypotonia, little spontaneous movement, no tendon reflexes, no response to light stimulation, and poor visual fixation. She was mildly dysmorphic, with microcephaly, deep-set eyes, and a pointed chin. Optic discs were pale and cupped, and MRI showed an abnormal gyral pattern in both frontal lobes that extended to the perisylvian areas and was associated with dysmyelination. Laboratory studies showed persistent lactic acidemia and mildly elevated plasma concentration of very long-chain fatty acids. She died suddenly at 37 days of age. Studies of patient fibroblasts did not show defects in mitochondrial oxidative phosphorylation or in mitochondrial complex activities, and muscle biopsy was essentially normal with no ragged-red fibers. However, immunofluorescence microscopic analyses showed fewer peroxisomes in fibroblasts compared to controls, and the peroxisomes varied markedly in size and were frequently arranged in rows. This arrangement was similar to that seen in mammalian cells overexpressing dominant-negative mutant DLP1 or those with DLP1 expression that had been downregulated owing to RNA interference (Koch et al., 2003; Li and Gould, 2003). Because such mammalian cells also showed a defect in mitochondrial fission (Smirnova et al., 2001; Yoon et al., 2001), Waterham et al. (2007) studied the mitochondria of fibroblasts from the patient using a fluorescent mitochondrial probe. Mitochondria in the patient's fibroblasts were elongated, tangled, tubular structures concentrated predominantly around the nucleus.
Sheffer et al. (2016) reported a 2-year-old boy, born of unrelated Arab parents, with a severe neurologic disorder characterized by neonatal hypotonia and respiratory insufficiency, delayed psychomotor development, and insensitivity to pain. At age 2 years, he could crawl, but not stand or speak. He had postnatal microcephaly, poor overall growth, athetoid movements, drooling, broad thumbs and big toes, and reduced muscle tone; there were no significant dysmorphic features. Brain imaging suggested delayed myelination. Plasma lactate was mildly increased, and patient fibroblasts showed isolated mitochondrial complex IV deficiency, as well as decreased ATP production and oxygen consumption (decreased by 30 and 40%, respectively). Mitochondria isolated from patient fibroblasts showed an elongated morphology, but peroxisomes appeared normal and there was no biochemical evidence of a peroxisomal defect.
Vanstone et al. (2016) reported a 7-year-old boy, born of unrelated Caucasian parents, with severely delayed psychomotor development and onset of refractory epilepsy at about 1 year of age. He had clonic, focal, and generalized tonic-clonic seizures, and experienced several episodes of status epilepticus. He was nonambulatory and had few words. He did not have significant dysmorphic features, and brain imaging was normal. Skeletal muscle biopsy showed the presence of concentric cristae and/or increased dense granules in some mitochondria, and many subsarcolemmal mitochondrial aggregates on electron microscopy. Confocal microscopy of patient fibroblasts showed hyperfusion of the mitochondrial network. However, respiratory chain enzymologies in muscle and skin fibroblasts and lactate/pyruvate ratio in fibroblasts were normal, as was serum lactate. There was no evidence of peroxisomal dysfunction. Vanstone et al. (2016) noted the diagnostic difficulties given that this patient had no clinical evidence of mitochondrial dysfunction on standard screening tests, and suggested that the disorder may result from abnormal mitochondrial distribution within neurons.
Fahrner et al. (2016) reported 2 unrelated boys who presented at 4 to 5 years of age with epileptic encephalopathy and subsequent neurologic decline after normal early development. Both children had metabolic insults prior to the sudden onset of status epilepticus: one patient developed seizures 2 weeks following a DTaP booster vaccination, whereas the other developed seizures after a viral illness and minor head trauma. Both had refractory epilepsy followed by developmental regression and progressive neurologic decline. One child had difficulty walking, dysphasia, and cognitive decline. The second child was wheelchair-bound with profound global developmental delay, myoclonus, and hypertonia; he had a tracheostomy and G-tube. Both patients continued to have seizures, and brain imaging showed progressive diffuse cerebral atrophy, particularly affecting the hippocampus, as well as nonspecific signal changes in the thalamus. Serum lactate was normal, and muscle biopsy of 1 patient was normal.
Chao et al. (2016) reported a boy with EMPF1 manifest as global developmental delay, hypotonia, and status epilepticus. He had normal development until 5 months of age, when he developed seizures followed by neurodevelopmental regression. Brain imaging showed progressive cerebral volume loss, demyelination, thinning of the corpus callosum, and T2-weighted hyperintense lesions in the cortex. Serum lactate levels were initially normal, but became elevated around 4 years of age. Muscle biopsy showed mild reduction of mitochondrial respiratory chain activities and mitochondrial pleomorphism. He died at 5 years of age due to severe status epilepticus with respiratory failure.
Vandeleur et al. (2019) reported a female infant who was microcephalic and had failure to thrive at 4 months of age. At 6 months of age, she had gross motor delay, truncal hypotonia, increased startle response, decreased visual tracking, and lactic acidosis. A brain MRI showed reduced white matter volume. At 8 months of age, she had poor feeding, diarrhea, and reduced urine output, and an echocardiogram showed a dilated left ventricle, reduced ejection fraction, and reduced shortening fraction. She died at 8 months of age of congestive heart failure and cardiogenic shock. Postmortem evaluation showed mitochondrial cardiomyopathy characterized by abnormal cardiac myocytes with enlarged mitochondria. Neuropathology showed accumulation of intracellular organelles, such as mitochondria, in the midbrain, cerebellum, and pons, as well as reduction in myelination in the subcortical white matter.
Autosomal Recessive Inheritance
Yoon et al. (2016) reported 2 infant sibs, born of unrelated Filipino parents with EMPF resulting in death in infancy. Both presented at birth with profound hypotonia, absent respiratory effort, no spontaneous movements, and absent deep tendon reflexes. Brain imaging was normal in 1 infant, whereas it showed a profound hypoxic-ischemic insult in the other. Laboratory studies did not show increased serum lactate or biochemical evidence of a peroxisomal disorder. The patients died at ages 8 days and 3 weeks. Postmortem examination showed intracytoplasmic hyaline eosinophilic round globules in neurons in both the brain and spinal cord. Electron microscopy of hippocampal neurons and Purkinje cells of the cerebellum showed multiple giant mitochondria that contained elongated cristae arranged parallel to each other. Giant mitochondria were not identified in glial or nonneuronal cells. The spinal cord showed reduced myelin content and the posterior nerve roots were poorly myelinated; peripheral nerves also showed poor myelination with a marked reduction in numbers of myelinated axons. Examination of skeletal muscle showed no abnormalities. The myelination defects in the peripheral nervous system were consistent with the absence of deep tendon reflexes and profound muscle weakness in both patients. Whole-exome sequencing identified compound heterozygous truncating mutations in the DNM1L gene (603850.0004 and 603850.0005) in both sibs, consistent with a complete loss of function. Sural nerve samples revealed absent DNM1L protein in both patients compared to an age-matched control. Each unaffected parent was heterozygous for 1 of the mutations. The findings confirmed the central role of DNM1L and mitochondrial fission in normal human development and survival. Yoon et al. (2016) noted the autosomal recessive inheritance pattern in this family, resulting from loss-of-function mutations, which differed from previously reported patients with de novo heterozygous mutations in the DNM1L gene that presumably resulted in a gain of function.
Nasca et al. (2016) reported 2 brothers, aged 16 and 3 years, with a slowly progressive neurologic disorder characterized by delayed psychomotor development that became apparent at about 1 year of age. The patients had strabismus, oculomotor apraxia, dysarthria, dysmetria, hyperreflexia, pyramidal signs, and severe walking difficulties. Brain imaging of the older brother showed minor abnormalities in the subthalamic nucleus. Fibroblasts derived from the older patient showed isolated partial complex IV deficiency (53% of controls) and decreased mtDNA content (about 50% of controls), but muscle samples showed normal activities of all mitochondrial respiratory chain enzymes. Laboratory studies showed increased lactate beginning at age 12 years in the older brother; serum lactate was normal in the younger brother. There was no biochemical evidence of a peroxisomal defect. Targeted sequencing of a gene panel identified compound heterozygous mutations in the DNM1L gene: S36G (603850.0007) and a truncating mutation (603850.0005). Each unaffected parent carried 1 of the mutations in heterozygous state. Although immunofluorescence studies showed impairment of both mitochondria and peroxisomal dynamics, routine laboratory studies in the patients were not informative for these defects.
▼ Molecular Genetics
In a newborn girl with a systemic lethal disorder and abnormal peroxisomes and mitochondria in fibroblast studies, Waterham et al. (2007) identified a de novo heterozygous mutation in the DNM1L gene (A395D; 603850.0001). The mutation was associated with a severe defect in the fission of both mitochondria and peroxisomes, indicating a dominant-negative effect.
In a 7-year-old boy, born of unrelated Caucasian parents, with EMPF1, Vanstone et al. (2016) identified a de novo heterozygous missense mutation in the DNM1L gene (G362D; 603850.0002). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing.
In a 2-year-old boy, born of unrelated Arab parents, with EMPF1, Sheffer et al. (2016) identified a de novo heterozygous missense mutation in the DNM1L gene (G362S; 603850.0003). The mutation was found by exome sequencing and confirmed by Sanger sequencing. Transfection of the mutation into fibroblasts caused significantly altered mitochondrial morphology, with bulky clusters of mitochondria concentrated in a small area of the cell and absent in the remaining part. Transfected cells were also 60% smaller than control cells.
In 2 unrelated boys with onset of EMPF1 in childhood after normal early development, Fahrner et al. (2016) identified a de novo heterozygous missense mutation in the DNM1L gene (R403C; 603850.0006). The mutations were found by whole-exome sequencing. In vitro functional expression studies in mouse cells and yeast showed that the R403C mutation resulted in impaired self-assembly, decreased colocalization to the mitochondria, and defective mitochondrial fission in a dominant-negative manner. Fahrner et al. (2016) noted that higher-order oligomerization of DNM1L is critical for proper function because it facilitates recruitment to the mitochondrial surface and enhances GTP hydrolysis activity. The effects of this mutation were not as severe as those of A395D (603850.0001), which may explain the later onset of symptoms in these children.
In a boy with EMPF1, Chao et al. (2016) identified a de novo heterozygous missense mutation in the DNM1L gene (G350R; 603850.0008). The mutation, which was found by whole-exome sequencing, was not present in the father, but was present in maternal blood at a low level (6 to 8%), suggesting somatic mosaicism. Expression of the G350R mutation in Drosophila resulted in increased peroxisomal size, altered cellular distribution, decreased number of total peroxisomes per cell, abnormal mitochondrial morphology, and abnormal mitochondrial trafficking, with a dominant-negative effect.
In a female infant with EMPF1, Vandeleur et al. (2019) identified a de novo heterozygous missense mutation in the DNM1L gene (E410K; 603850.0011). The mutation was identified by trio whole-exome sequencing and confirmed by Sanger sequencing.