Neurodegeneration With Brain Iron Accumulation 5

A number sign (#) is used with this entry because neurodegeneration with brain iron accumulation-5 (NBIA5) is caused by de novo heterozygous or hemizygous mutation in the WDR45 (300526) gene on chromosome Xp11.

Description

NBIA5, sometimes referred to as 'static encephalopathy of childhood with neurodegeneration in adulthood (SENDA),' is an X-linked neurodegenerative disorder characterized by global developmental delay in early childhood that is essentially static, with slow motor and cognitive gains until adolescence or early adulthood. In young adulthood, affected individuals develop progressive dystonia, parkinsonism, extrapyramidal signs, and dementia resulting in severe disability. Brain MRI shows iron accumulation in the globus pallidus and substantia nigra. A characteristic finding is T1-weighted hyperintensity surrounding a central band of hypointensity in the substantia nigra. Cerebral and cerebellar atrophy are also observed (summary by Haack et al., 2012 and Saitsu et al., 2013).

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

Clinical Features

In a review of the clinical and genetic features of various forms of NBIA, Gregory et al. (2009) identified a group of 7 patients with a distinctive form of idiopathic NBIA in whom no mutations had been found. These individuals had global developmental delay or frank mental retardation in infancy or early childhood, which remained static for at least 2 decades. Then, during their late twenties to thirties, they developed parkinsonism followed by rapid progression with dystonia, dysarthria, spastic paraparesis, and loss of ambulation. Many responded well to levodopa therapy. Neuroimaging showed abnormal iron accumulation in the substantia nigra in addition to the globus pallidus.

In reviews of NBIA, Schneider and Bhatia (2012) and Schneider and Bhatia (2013) stated that SENDA is characterized by early-onset mental retardation and spastic paraplegia that remains static until the twenties or thirties when it progresses to parkinsonism and dystonia. Variable features include eye movement abnormalities, sleep disorders, frontal release signs, and dysautonomia. Brain MRI shows brain iron accumulation in the globus pallidus and substantia nigra.

Kimura et al. (2013) reported a 39-year-old Japanese woman with SENDA. She had psychomotor retardation since childhood that remained nonprogressive until age 30 when she developed severe dystonia and gait disturbance, resulting in her being bedridden within 3 years. Brain MRI at age 33 years showed marked hypointensity in the globus pallidus and substantia nigra on T2-weighted imaging, consistent with iron deposition. T1-weighted imaging showed hyperintensity of the substantia nigra with a central band of hypointensity. Mild cerebral and cerebellar atrophy was also present. Treatment with levodopa resulted in mild clinical improvement. Reexamination at age 39 years showed clinical progression and progression of the lesions on brain imaging. Magnetic resonance spectroscopy showed increased N-acetylaspartate in the globus pallidus and substantia nigra, suggesting neuronal loss in these regions. Increased myoinositol suggested gliosis.

Saitsu et al. (2013) reported 5 unrelated women with NBIA5, including the patient reported by Kimura et al. (2013). The patients ranged in age from 28 to 51 years, and all showed a similar disease course with delayed psychomotor development in infancy or early childhood, very poor or no speech development, and nonprogressive cognitive dysfunction in childhood. More variable features early in life included seizures, broad-based gait, hand flapping, and spasticity. The phenotype was stable in each until the early twenties or thirties when the patients developed parkinsonism, rigidity, tremor, further cognitive decline, dystonia, and dysphagia. All became bedridden or wheelchair-dependent and fully dependent for all activities of daily living, and some showed aggressive behavior. Brain MRI as young adults showed iron deposition in the globus pallidus and substantia nigra, with a characteristic hyperintensity of the substantia nigra with a central band of hypointensity on T1-weighted images. Cerebral and cerebellar atrophy were also apparent. Two patients had atrophy of the retinal nerve.

Neuroradiologic Findings

In a review of the neuroradiologic findings of various forms of NBIA, Kruer et al. (2012) noted that SENDA is characterized by iron deposition in the globus pallidus and substantia nigra, as well as T1 hyperintensity of the substantia nigra with a central band of T1 hypointensity. Significant cerebral and milder cerebellar atrophy also occur.

Inheritance

NBIA5 does not follow a pattern of inheritance typical of an X-linked disorder, although molecular analysis has shown it to be X-linked dominant. Haack et al. (2012) reported 17 affected females and 3 affected males who exhibited a homogeneous phenotype. Since WDR45 is on the X chromosome, Haack et al. (2012) concluded that the males must be somatic mosaic for the mutation, which was demonstrated in 1 affected male. Presumably, males with germline WDR45 mutations are nonviable. Females may either harbor germline or somatic mutations, and several affected females had evidence of skewed X-inactivation. All of these factors may contribute to disease manifestations.

Molecular Genetics

In 20 unrelated patients with neurodegeneration with brain iron accumulation-5, Haack et al. (2012) identified 19 different hemizygous or heterozygous de novo mutations in the WDR45 gene (see, e.g., 300526.0001-300526.0002). Most of the mutations were truncating, but 2 were missense mutations affecting highly conserved residues. The mutations were located throughout the coding sequence. Initial mutations were identified by exome sequencing and all were confirmed by Sanger sequencing. There were 17 females and 3 males.

Saitsu et al. (2013) identified 5 different de novo heterozygous truncating mutations in the WDR45 gene (see, e.g., 300526.0003-300526.0005) in 5 unrelated women with NBIA5. The initial mutations were identified by exome sequencing of 2 patients. Lymphoblastoid cells from 4 of the patients showed exclusive expression of the mutant transcript, suggesting X inactivation of the wildtype allele. All patient cells showed decreased levels of the mutant proteins, suggesting protein instability. Patient cells showed impaired autophagic flux. Immunofluorescence studies showed the accumulation of autophagic structures in patient cells, consistent with improper autophagosome formation. The findings suggested that impairment of autophagy contributes to the pathogenesis of this neurodegenerative disorder.

Nomenclature

Haack et al. (2012) recommended that the term 'SENDA' not be used for this disorder, and proposed the term 'beta-propeller protein-associated neurodegeneration (BPAN).' The disorder caused by WDR45 mutation is here designated 'neurodegeneration with brain iron accumulation-5 (NBIA5).'