Neurodegeneration With Brain Iron Accumulation 6

A number sign (#) is used with this entry because of evidence that neurodegeneration with brain iron accumulation-6 (NBIA6) is caused by homozygous or compound heterozygous mutation in the COASY gene (609855) on chromosome 17q21.

Description

Neurodegeneration with brain iron accumulation refers to a group of neurodegenerative disorders characterized by progressive motor and cognitive dysfunction beginning in childhood or young adulthood. Patients show extrapyramidal motor signs, such as spasticity, dystonia, and parkinsonism. Brain imaging shows iron accumulation in the basal ganglia (summary by Dusi et al., 2014).

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

Clinical Features

Dusi et al. (2014) reported 2 unrelated Italian patients, 1 of whom was born of consanguineous parents, with neurodegeneration with brain iron accumulation. Both had normal psychomotor development until about 2 years of age, when they developed toe walking as well as difficulty walking. This progressed to spastic paraplegia or tetraplegia, resulting in wheelchair use in the teenage years. Both patients also developed progressive cognitive impairment (IQ in the 40s). At age 15 years, the first patient showed mild oromandibular dystonia with dysarthria and spastic dystonic paraparesis. She lost the ability to walk at age 20. At age 25, she had a severe spastic bradykinetic-rigid syndrome with mild dystonia, distal areflexia, and mild axonal neuropathy. She also had behavioral disturbances with obsessive-compulsive symptoms and depression. Brain MRI showed bilateral hypointensity in the globus pallidus associated with a central region of hyperintensity in the anteromedial portion. The second patient had a similar disease course, with progressive motor impairment resulting in loss of ambulation at age 15 years. At age 17, he showed mild oromandibular dystonia with dysarthria, spastic-dystonic tetraparesis, and parkinsonian features. He also had distal amyotrophy, areflexia, and pes cavus. Behavioral abnormalities included obsessive-compulsive behavior and complex motor tics. Brain MRI showed progressive iron accumulation in the caudate, putamina, thalami, and globi pallidi. The brain imaging in these patients was consistent with the 'eye of the tiger' sign.

Evers et al. (2017) reported 2 sibs, born of unrelated Turkish parents, with a phenotype similar to that reported by Dusi et al. (2014). The patients presented in the first months of life with global developmental delay. Both achieved walking between 2 and 3 years of age, but gait was ataxic and broad-based with later onset of spasticity, hyperreflexia, and pyramidal signs. The patients had severely impaired intellectual development with poor speech and behavioral abnormalities, including obsessive-compulsive symptoms and self-injurious behavior. Both also had microcephaly (-1.9 to -3.2 SD) and short stature (-3 to -4.2 SD). One patient had severe hyperopia. Brain imaging in the first years of life showed T2-weighted hyperintensities and swelling of the caudate, putamen, thalamus, and anterior limb of the internal capsule, as well as a thin corpus callosum. Subtle abnormalities in the globus pallidus appeared a few years later. The cerebellum was normal. Laboratory investigations showed increased levels of free carnitines and low levels of long-chain acylcarnitines.

Inheritance

The transmission pattern of NBIA6 in the families reported by Dusi et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a 25-year-old woman, born of consanguineous Italian parents, with neurodegeneration with brain iron accumulation, Dusi et al. (2014) identified a homozygous missense mutation in the COASY gene (R499C; 609855.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. An unrelated Italian patient with a similar disorder was compound heterozygous for R499C and a nonsense mutation (Q59X; 609855.0002). This patient was ascertained from a cohort of 280 NBIA-affected individuals in whom the COASY gene was sequenced. In vitro functional expression assays showed that the R499C mutant protein had lost DPCK enzymatic activity. Fibroblasts of both patients showed decreased levels of acetyl coenzyme A (CoA) and significantly decreased de novo production of CoA and dephospho-CoA, at about 20% of controls, consistent with a loss of function. The findings indicated that a defect in CoA biosynthesis can cause NBIA. This was the second inborn error of CoA biosynthesis to be implicated in NBIA, the first being NBIA1 (234200), which is caused by mutation in the PANK2 gene (606157).

In 2 sibs, born of unrelated Turkish parents, with NBIA6, Evers et al. (2017) identified compound heterozygosity for 2 missense mutations in the COASY gene: the previously identified R499C mutation and A214V (609855.0003). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants were not performed.