The disorder is now referred to as pantothenate kinase-associated neurodegeneration or PKAN.įirst described in 1922 by Julius Hallervorden and Hugo Spatz, the eponym for this disorder is no longer favored. Mutations in the gene encoding pantothenate kinase 2 cause the disorder, which includes abnormal movements, vision defects, and psychiatric problems. Hallervorden–Spatz syndrome is an autosomal recessive neurodegenerative disorder. Hayflick, in Encyclopedia of Movement Disorders, 2010 Definition and History This chapter reviews the established genetic defects leading to different NBIA subtypes, highlights phenotypic presentations to direct genetic testing, and briefly discusses the scarce available treatment options and upcoming challenges and future hopes of the field. Despite these advances, treatment to date remains mainly symptomatic. Genetic tests, combined with postmortem neuropathology, usually make for the final disease confirmation. Clinically, certain symptom combinations can suggest a specific genetic defect. Ten associated genes have been established, with many more being suggested as new technologies and data emerge. Genetics have fostered ongoing progress in elucidating underlying pathophysiologic mechanisms of NBIA disorders. Postmortem, Lewy body, TDP-43, or tau pathology has been observed. Neuropathologically, NBIA disorders usually are associated with widespread axonal spheroids and local iron accumulation in the basal ganglia. Increased nonphysiologic, nonaging-associated brain iron, most pronounced in the basal ganglia, is often termed the unifying characteristic of these clinically variable disorders, though occurrence and extent can be fluctuating or even absent. Clinical core symptoms comprise a combination of early-onset dystonia, pyramidal and extrapyramidal signs with ataxia, cognitive decline, behavioral abnormalities, and retinal and axonal neuropathy variably accompanying these core features. Neurodegeneration with brain iron accumulation (NBIA) describes a heterogeneous group of inherited rare clinical and genetic entities. Sarah Wiethoff, Henry Houlden, in Handbook of Clinical Neurology, 2018 Abstract New NBIA genes are being recognized with increasing frequency as a result of whole-exome sequencing, which is also facilitating early ascertainment of patients whose phenotype is often nonspecific.
Together, these genes account for disease in approximately 85% of patients diagnosed with an NBIA disorder.
The ultrarare NBIA disorders are caused by mutations in CoASY, ATP13A2, and FA2H (causing CoA synthase protein-associated neurodegeneration, Kufor–Rakeb disease, and fatty acid hydroxylase-associated neurodegeneration, respectively). The four most common NBIA disorders include pantothenate kinase-associated neurodegeneration (PKAN) due to mutations in PANK2, phospholipase A 2-associated neurodegeneration caused by mutation in PLA2G6, mitochondrial membrane protein-associated neurodegeneration from mutations in C19orf12, and beta-propeller protein-associated neurodegeneration due to mutations in WDR45. For the majority of NBIA disorders the genetic basis has been delineated, and clinical testing is available. These rare disorders are often first suspected when increased basal ganglia iron is observed on brain magnetic resonance imaging. Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of disorders affecting children and adults.
Penelope Hogarth, in Handbook of Clinical Neurology, 2018 Abstract