In this article, the author reviews developments in neurodegeneration and brain iron accumulation (NBIA). The previous extensive contributions of Schiffmann and Swaiman regarding neurodegeneration and brain iron accumulation (formerly known as Hallervorden-Spatz syndrome) and the childhood differential diagnosis have been extended to adults by genetic studies of pantothenate kinase 2 (PANK2). Phenotypes of PANK2 are variable, with many later onset cases or others with slower progression due to differences in inherited kinase function. Several other additional uncommon inherited diseases affecting brain iron metabolism have been discovered in addition to PANK2, which are also associated with brain iron accumulation: PLA2G6 associated neurodegeneration, neuroferritinopathy, and aceruloplasminemia. Much smaller amounts of iron accumulation have also been associated with neurodegenerative disorders such as Alzheimer disease, Parkinson disease, and multiple sclerosis. Neurodegeneration with brain iron accumulation may encompass a larger number of disorders.
Historical note and terminology
Pantothenate kinase-associated neurodegeneration (PKAN) was discovered in 1922. Several reports have discussed Julius Hallervorden's unethical scientific activities during World War II (78; 77). As a result, pantothenate kinase-associated neurodegeneration and neurodegeneration with brain iron accumulation type 1 (NBIA type 1) have replaced the Hallervorden-Spatz eponym (19; 55; 27). Since discovery of the gene for pantothenate kinase 2 as a cause of the classic young onset neurodegeneration with brain iron accumulation type 1 syndrome (100), it has been shown that a significant number of cases of less typical and later onset disease lack the gene or have a genetic mutation resulting in lesser defects in the enzyme (27; 89; 26). The term neurodegeneration with brain iron accumulation type 1 (NBIA-1) has also been in use as an alternative name for HSS for some time. The NBIA family of disorders also includes PLA2G6 associated neurodegeneration (PLAN), neuroferritinopathy (15; 11), and aceruloplasminemia (40). Brain iron accumulation may also be present in common neurodegenerative disorders such as multiple sclerosis (06) and Alzheimer and Parkinson diseases (68; 99; 23; 70).
In the original report, the prominent pathologic characteristics associated with a presumably consistent clinical pattern were described. Since then, a spectrum of conditions included under this designation have been reported, detailed, and rearranged in order to provide useful subclassifications. The massive iron deposition in the globus pallidus and substantia nigra, the autosomal recessive genetic transmission, and the clinical manifestations (80) generally set apart the classic form of pantothenate kinase-associated neurodegeneration from other neurodegenerative and extrapyramidal conditions. The classic phenotypic features of pantothenate kinase-associated neurodegeneration include early onset and rapidly progressive disease. The atypical presentations include later onset in the second or third decade, slower progression and speech and psychiatric disorders along with the extrapyramidal and corticospinal tract features of the classic form (32; 27).
After many years of efforts to find a specific gene abnormality, the gene PANK2 was found to be defective in some patients with neurodegeneration with brain iron accumulation type 1 (100a). The defective gene results in the deficiency of the enzyme pantothenate kinase. All of the patients with the typical classic form and one-third of the patients with an atypical form of the disease were found to have mutations in PANK2 (27). A genotyping study of 72 patients with clinical profiles of PKAN syndrome of NBIA and MR imaging revealed PANK2 mutations in 48, but none were found in 24 other cases. Of the 72, 17 were atypical as their onset was in the second or third decade of life. For 7 of the 24 PANK2-negative cases, onset was in the first decade (26). As in other studies, clinical phenotypes of patients without PANK2 deficiency featured dystonia, corticospinal tract abnormalities and cognitive decline. More studies (58; 26) found that up to 90% of PKAN patients had spasticity and cognitive decline compared to 30% reported by Hayflick and colleagues (27).
The initial case report consisted of members of a family of 12 children. Three children died in infancy, and 4 were in good health. The remaining 5, all girls, manifested clinical involvement between 7 years and 9 years of age. Initial symptoms were predominantly those of gait difficulties associated with rigidity of the legs and deformity of the feet. In retrospect, the findings were consistent with dystonia. The girls manifested progressive intellectual loss and dysarthria. Two developed atrophy of the distal muscles, and 1 experienced corticospinal tract impairment. Each girl of a pair of twins exhibited gray-brown skin pigmentation. One of the girls experienced increased muscle tone of the neck (presumably dystonia), swallowing difficulties, and choreoathetotic movements. The girls all died between the ages of 16 years and 27 years (96). Gross rust-brown pigmentation of the globus pallidus and the zona reticulata of the substantia nigra were evident during neuropathologic study.
Subsequently, 3 brothers were reported who developed athetotic movements, tremors, visual difficulties associated with optic atrophy, and corticospinal tract findings at 9 years to 10 years of age (36). The oldest boy died at age 26 years with similar findings on neuropathology.
A number of other cases were reported (96), including a case by Messing, suggesting that the diagnosis could be made in the presence of intellectual deterioration, extrapyramidal movement disorder, and optic atrophy (49; 50). Through the years, familial cases were reported with more or less parallel clinical and neuropathologic findings to the original patients of Hallervorden and Spatz.
A number of new genes have been found, including PLA2G6, FAHN, C19ORF12, ATP13A2, FTL, CP, DCAF17, and COASY (21). Their phenotypes will be outlined in the next section.