Newly Characterized Forms of Neurodegeneration with Brain Iron Accumulation

Abstract

Neurodegeneration with brain iron accumulation (NBIA) comprises a group of brain iron deposition syndromes that lead to mixed extrapyramidal features and progressive dementia. Historically, many patients with clinical and radiologic features of NBIA have not had a clearly identifiable molecular cause. Recent discoveries have shown that mutations in C19orf12 or WDR45 can lead to NBIA. C19orf12 mutations are inherited in an autosomal recessive manner, and lead to a syndrome similar to that caused by mutations in PANK2 or PLA2G6. In contrast, WDR45 mutations lead to a distinct form of NBIA characterized by spasticity and intellectual disability in childhood followed by the subacute onset of dystonia-parkinsonism in adulthood. WDR45 mutations act in an X-linked dominant manner. Although the function of C19orf12 is largely unknown, WDR45 plays a key role in autophagy. Each of these new forms of NBIA thus leads to a distinct clinical syndrome and together they implicate new cellular pathways in the pathogenesis of these disorders.

Lessons from a pair of siblings with BPAN

“…1,3,7,10,12,15 Here we have demonstrated that although hemizygous germline variants in males are not universally lethal as it was originally presumed, they can result in a more severe phenotype. The direct clinical comparison of the two siblings here described revealed a more significant neurodevelopmental compromise at all ages in the male proband compared with his sister.…”

“…Its clinical course is described as biphasic with an initial presentation during childhood, as spastic quadriplegia or static encephalopathy with early developmental delay with or without seizures, followed by dementia in adulthood and the development of parkinsonism and dystonia. 1,4,[7][8][9][10][11] Heterozygous variants in the WD repeat-containing protein 45 gene (WDR45, OMIM: 300526) located in Xp11.23 lead to decreased autophagic activity and the BPAN phenotype. 12 All well-described cases of BPAN in the literature have been sporadic with a clear female predominance supporting an X-linked dominant pattern of inheritance with proposed lethality in males with germline variants.…”

“…[1][2][3][4][5][6] Beta-propeller protein-associated neurodegeneration (BPAN, NBIA5, OMIM: 300894) has been estimated to account for~7% of all cases of NBIA. 7 Besides being the only type of NBIA with an X-linked dominant pattern of inheritance, BPAN has distinctive clinical and brain imaging findings.…”

Nomenclature of genetic movement disorders: Recommendations of the international Parkinson and movement disorder society task force

“…Neurodegeneration with brain iron accumulation (NBIA) characterizes a number of progressive neurological disorders with the hallmark of iron deposition on MRI in several brain regions, most consistently the globus pallidus . Most of these are genetically determined although some patients, particularly with neurological symptoms beginning in mid to late adult life, have sporadic disorders of uncertain origin.…”

“…Neurodegeneration with brain iron accumulation (NBIA) characterizes a number of progressive neurological disorders with the hallmark of iron deposition on MRI in several brain regions, most consistently the globus pallidus. 214 Most of these are genetically determined although some patients, particularly with neurological symptoms beginning in mid to late adult life, have sporadic disorders of uncertain origin. Movement disorders, particularly dystonia and parkinsonism, dominate the clinical manifestations, but other common features include spasticity, ataxia, cognitive and psychiatric disturbances, and oculomotor abnormalities, optic nerve, retinal, and peripheral nerve involvement.…”