Encephalopathy Due To Defective Mitochondrial And Peroxisomal Fission 2

A number sign (#) is used with this entry because of evidence that encephalopathy due to defective mitochondrial and peroxisomal fission-2 (EMPF2) is caused by homozygous or compound heterozygous mutation in the MFF gene (614785) on chromosome 2q36.

Description

Encephalopathy due to defective mitochondrial and peroxisomal fission-2 is an autosomal recessive disorder characterized by delayed psychomotor development, severe hypotonia with inability to walk, microcephaly, and abnormal signals in the basal ganglia. More variable features include early-onset seizures, optic atrophy, and peripheral neuropathy (summary by Koch et al., 2016).

For a discussion of genetic heterogeneity of EMPF, see EMPF1 (614388).

Clinical Features

Shamseldin et al. (2012) reported 2 brothers, born of consanguineous Saudi Arabian parents, with EMPF2. The proband was a 4.5-year-old boy with delayed psychomotor development. He was unable to walk, but could stand supported and say a few words. He had borderline microcephaly, pale optic discs, and mild hypertonia with brisk reflexes, but no clonus. Brain MRI showed abnormal intensity of the globus pallidus. Lactate levels and mitochondrial respiratory chain complex profiles on skin fibroblasts were normal. He had a younger brother who showed similar developmental delay. Patient fibroblasts showed an abnormal tubular appearance of mitochondria and peroxisomes, suggesting a defect in the balance of fission and fusion in these organelles.

Koch et al. (2016) reported 3 patients, including an Austrian boy and 2 sibs born of consanguineous Turkish parents, with EMPF2. All had onset of severe seizures within the first year of life, and EEG showed hypsarrhythmia, consistent with an epileptic encephalopathy. The patients had severely delayed psychomotor development or regression of milestones after onset of seizures. Other features included microcephaly, severe hypotonia with inability to sit, spasticity, hyperreflexia, visual impairment, external ophthalmoparesis, and lack of verbal communication. More variable features included pale optic discs, loss of vision, swallowing difficulties necessitating gastric tube feeding, and electrophysiologic evidence of a peripheral neuropathy. Brain imaging performed between 14 and 24 months of age showed signal abnormalities in the basal ganglia and thalamus, reminiscent of Leigh syndrome (256000), as well as progressive cerebellar atrophy. One patient developed abnormal signals in the optic radiations. One patient died of respiratory failure at age 3 years; he had never acquired trunk control. The other 2 patients were severely hypotonic without trunk control at ages 7 and 4 years, respectively. Plasma lactate tended to be normal, but was sometimes increased. Mitochondrial respiratory chain activities were normal in skeletal muscle, and laboratory studies did not show evidence of peroxisomal dysfunction. However, patient fibroblasts showed abnormally elongated peroxisomes and mitochondria compared to controls, suggestive of a fission defect.

Inheritance

The transmission pattern of EMPF2 in the families reported by Koch et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 brothers, born of consanguineous Saudi Arabian parents, with EMPF2, Shamseldin et al. (2012) identified a homozygous nonsense mutation in the MFF gene (Q64X; 614785.0001). The mutation was identified by exome sequencing and confirmed by Sanger sequencing.

In 3 patients from 2 unrelated families with EMPF2, Koch et al. (2016) identified homozygous or compound heterozygous truncating mutations in the MFF gene (614785.0002-614785.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Western blot analysis of patient fibroblasts showed normal levels of DRP1 (DNM1L; 603850), but there was abnormal diffuse intracellular localization of DRP1, suggesting that it was not properly recruited to mitochondrial fission nodes.