Neurodegeneration With Brain Iron Accumulation 7

A number sign (#) is used with this entry because of evidence that neurodegeneration with brain iron accumulation-7 (NBIA7) is caused by compound heterozygous mutation in the REPS1 gene (614825) on chromosome 6q23. One such family has been reported.

For a general phenotypic description and a discussion of genetic heterogeneity of NBIA, see NBIA1 (234200).

Clinical Features

Drecourt et al. (2018) reported 2 sisters, born of unrelated French parents, with a neurodegenerative disorder. The older sister, who was more severely affected, presented with speech and motor delay in the first year of life. She walked at age 18 months, but later developed truncal hypotonia, progressive cerebellar ataxia, and pyramidal syndrome, resulting in the loss of ambulation at age 9 years. At this time, she showed nystagmus, dysarthria, dysmetria, spasticity of the lower limbs, and pes cavus. Brain imaging showed progressive cerebellar and cerebral atrophy, thin corpus callosum, and T2-weighted evidence of brain iron accumulation in the globus pallidi and peduncles. She gradually lost the ability to stand and hold her head, had swallowing difficulties and dystonia, and died at age 20 years. Her younger sister had a similar but milder disease course. At age 14 years, she could walk with aid, swim, use an indoor bicycle, and hold a pencil.

Inheritance

The transmission pattern of NBIA7 in the family reported by Drecourt et al. (2018) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sisters, born of unrelated French parents, with NBIA7, Drecourt et al. (2018) identified compound heterozygous missense mutations in the REPS1 gene (V78L, 614825.0001 and A113E, 614825.0002). Both mutations occurred in the EH1 domain, a conserved region that interacts with RALBP1 (605801) to form the endosome recycling compartment. The variants, which were found by exome sequencing, segregated with the disorder in the family. Patient fibroblasts showed a significant increase (10- to 30-fold change) in cellular iron content when incubated with iron compared to controls, and wildtype RESP1 was able to return the iron content to control levels. In response to high iron, patient cells showed a normal and appropriate decrease in transferrin receptor (TFRC; 190010) mRNA levels, but the amount of TFRC did not decrease in patient cells, suggesting impaired posttranslational lysosomal-based degradation of TFRC. Patient cells showed impaired transferrin (190000) and TFRC trafficking and recycling compared to controls, with clustering at the surface and in the perinuclear region, as well as abnormally enlarged lysosomes. Patient cells also showed decreased palmitoylation of TFRC, which is necessary for regulating TFRC endocytosis. Addition of the antimalarial agent artesunate rescued abnormal TFRC palmitoylation and decreased iron content in cultured patient fibroblasts. Similar findings were observed in studies of cells from NBIA patients due to mutations in other NBIA-associated genes. Drecourt et al. (2018) concluded that certain forms of NBIA result from defective endosomal recycling and should be regarded as a disorder of cellular trafficking.