Encephalopathy, Progressive, Early-Onset, With Brain Edema And/or Leukoencephalopathy, 1

A number sign (#) is used with this entry because of evidence that early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1) is caused by homozygous or compound heterozygous mutation in the NAXE gene (608862) on chromosome 1q22.

Description

Early-onset progressive encephalopathy with brain edema and/or leukoencephalopathy-1 (PEBEL1) is an autosomal recessive severe neurometabolic disorder characterized by rapidly progressive neurologic deterioration that is usually associated with a febrile illness. Affected infants tend to show normal early development followed by acute psychomotor regression with ataxia, hypotonia, respiratory insufficiency, and seizures, resulting in coma and death in the first years of life. Brain imaging shows multiple abnormalities, including brain edema and signal abnormalities in the cortical and subcortical regions (summary by Kremer et al., 2016).

Genetic Heterogeneity of PEBEL

See also PEBEL2 (618321), caused by mutation in the NAXD gene (615910) on chromosome 13q34.

Clinical Features

Spiegel et al. (2016) reported 5 sibs, born of consanguineous parents of Arab Muslim origin, with a lethal infantile encephalopathy. After normal early development, the infants developed progressive generalized and proximal weakness between 6 and 12 months of age, usually associated with a febrile illness. Thereafter, previous developmental milestones were lost, including all motor skills, and there was a gradual development of an encephalopathy with loss of cognitive skills. By 2 years of age, the surviving patients were bedridden and required mechanical ventilation due to respiratory muscle failure, ultimately resulting in a vegetative state. Four patients died between 1 and 3 years of age; the fifth patient was alive at age 5.5 years but on mechanical ventilation. Brain MRI was initially normal but later showed deep white matter abnormalities in the periventricular frontal and insular regions, as well as in the cerebellum, consistent with a leukoencephalopathy. Muscle biopsy, extensive laboratory testing, and activities of mitochondrial respiratory chain enzymes were all normal.

Kremer et al. (2016) reported 6 patients from 4 unrelated families with lethal infantile encephalopathy. Four patients had normal early development, whereas 2 had mild developmental delay, mostly affecting motor skills, in early infancy. Between 8 and 20 months of age, all children showed acute and severe neurologic decompensation, most often associated with a febrile illness. Features included ataxia, nystagmus, hypotonia, tetraparesis, tremor, and respiratory failure; several patients developed seizures. Some patients showed partial recovery with stabilization and an undulating course, only to relapse into further episodic neurologic decline. All had increased serum and CSF lactate. Brain imaging showed variable abnormalities, including cerebellar edema, spinal myelopathy, cerebral atrophy, and signal abnormalities in cortical and subcortical brain regions. Four patients also developed erythematous bullous skin lesions on intertriginous and perigenital areas, hands, and feet, sometimes leading to erosion and eruption of the skin. Muscle biopsies of 2 patients showed some defects in mitochondrial oxidative phosphorylation, particularly decreased complex I activity, although these values were normal in a third patient. Several patients became comatose, and all 6 died between 16 and 28 months of age. When performed, autopsy showed periventricular and cortical/subcortical encephalomalacia with massive brain edema, cystic alterations, and necrosis.

Inheritance

The transmission pattern of PEBEL in the families reported by Spiegel et al. (2016) and Kremer et al. (2016) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 5 sibs, born of consanguineous parents of Arab Muslim origin, with PEBEL, Spiegel et al. (2016) identified a homozygous missense mutation in the NAXE gene (A94D; 608862.0001). The variant, which was found by a combination of homozygosity mapping and whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed. Given the role of NAXE in the repair of hydrated NAD and NADP cofactors, Spiegel et al. (2016) hypothesized that compromised NAXE function may result in abnormal accumulation of toxic metabolites especially during illness or stress, similar to that observed in patients with vanishing white matter due to mutations in EIF2B genes (see, e.g., EIF2B1, 606686).

In 5 patients from 4 unrelated families with PEBEL, Kremer et al. (2016) identified homozygous or compound heterozygous mutations in the NAXE gene (608862.0002-608862.0007). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Fibroblasts derived from 2 unrelated patients showed significantly increased levels of the toxic metabolite cyclic-NADHX, as well as increased levels of R-NADHX and S-NADHX, compared to controls. There was also a gradual increase in these toxic metabolites after NAXE cells were exposed to heat stress. The findings confirmed deficiency of the mitochondrial NAD(P)HX repair system, resulting in the accumulation of toxic metabolites that are known to inhibit various cellular NADH dehydrogenases.