Background
Hallervorden-Spatz disease (HSD) is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. Hallervorden and Spatz first described the disease, in 1922, as a form of familial brain degeneration characterized by iron deposition in the brain. The term neurodegeneration with brain iron accumulation type 1 (NBIA-1), instead of HSD, eventually came to be used for this condition,[1] although the most recent term for the disorder is pantothenate kinase-associated neurodegeneration (see the image below). (See Etiology.)[2]
Magnetic resonance imaging (MRI) has increased the likelihood of antemortem diagnosis of Hallervorden-Spatz (HSD) disease. The typical MRI reveals bilaterally symmetrical, hyperintense signal changes in the anterior medial globus pallidus, with surrounding hypointensity in the globus pallidus, on T2-weighted images. These imaging features, which are fairly diagnostic of HSD, have been termed the eye-of-the-tiger sign. The hyperintensity represents pathologic changes, including gliosis, demyelination, neuronal loss, and axonal swelling. The surrounding hypointensity is due to loss of signal secondary to iron deposition. Onset most commonly occurs in late childhood or early adolescence. The classic presentation is in the late part of the first decade or the early part of the second decade, when the individual is between ages 7 and 15 years. However, the disease has been reported in infancy, and cases with adult onset have been described as well. (See Presentation and Workup.)[3, 4, 5]
HSD is relentlessly progressive. The course is characterized by progressive dementia, corticospinal signs (eg, spasticity, hyperreflexia), and extrapyramidal signs, including rigidity, dystonia, and choreoathetosis. The course of the disease usually proceeds over 10-12 years and affected individuals typically die in the second or third decade, but case reports describe patients surviving 30 years. (See Presentation and Prognosis.)[6, 7]
The disease can be familial or sporadic. When familial, HSD is inherited recessively; it has been linked to chromosome 20.[8] A mutation in the pantothenate kinase (PANK2) gene on band 20p13 has been described in patients with typical HSD. (See Etiology.)[9]
Patient education
The Web site of the NBIA Disorders Association (formerly, the Hallervorden-Spatz Syndrome Association) is helpful.
Etiology
The exact etiology of HSD is not known. One suggestion states that abnormal peroxidation of lipofuscin to neuromelanin and deficient cysteine dioxygenase lead to abnormal iron accumulation in the brain. While portions of the globus pallidus and pars reticulata of substantia nigra (SN) have high iron content in healthy individuals, individuals with HSD have excess amounts of iron deposited in these areas.
However, the exact role of iron in the etiology of this disease remains unknown. Also, whether the deposition of iron in basal ganglia in HSD is the cause or consequence of neuronal loss and gliosis is not clear. Decreased activity of the enzyme cysteine dioxygenase was demonstrated in one affected child.[10] This was postulated to lead to accumulation of cysteine in the basal ganglia, since cysteine can chelate iron and thus result in its deposition. However, these findings were not confirmed in adult patients.
A role for mutation in the PANK2 gene (band 20p13) in the etiology of HSD has been proposed. Deficiency of pantothenate kinase may lead to accumulation of cysteine and cysteine-containing compounds in the basal ganglia. This causes chelation of iron in the globus pallidus and free radical generation as a result of rapid auto-oxidation of cysteine in the presence of iron.[11] Mutations in the PANK2 gene account for most HSD cases. Such mutations result in an autosomal recessive inborn error of coenzyme A metabolism called pantothenate kinase ̶ associated neurodegeneration.[12, 13, 14, 15]
Pathologic evaluation reveals characteristic rust-brown discoloration of the globus pallidus and SN pars reticulata secondary to iron deposition.[16, 17] Generalized atrophy of the brain may be noted, with the caudate nuclei, SN, and tegmentum decreased in size. Microscopically, the characteristic changes include the following:
- Variable loss of neurons, myelinated fibers, and gliosis in globus pallidus and SN, which may appear spongiotic when severe
- Widely disseminated rounded or oval, nonnucleated structures called spheroids (also known as axon schollen or neuroaxonal dystrophy); these represent swollen axons with vacuolated cytoplasm and are found most abundantly in the pallidonigral system, although they are also present in the cerebral cortex
- Accumulation of pigment, mostly containing iron
- Ceroid lipofuscin and neuromelanin containing iron, in the areas mainly affected (mentioned above)
Iron deposition may be found intracellularly and extracellularly and frequently is centered on vessels. These changes are found to a lesser degree in other parts of the brain and in the spinal cord. The presence of spheroids suggests a link between HSD and infantile neuroaxonal dystrophy; however, no clinical or genetic relationship has been reported between the 2 diseases. Tau-positive neurofibrillary tangles and alpha-synuclein–positive Lewy bodies may be found in cortical and subcortical regions in patients with a prolonged clinical course.[1]
Prognosis
The clinical course of HSD is variable. In most patients, the disease has a progressive course extending over several years, leading to death in early childhood. Some patients experience rapid deterioration of function secondary to dystonia, rigidity, dysphagia, and respiratory compromise and die within 1-2 years of disease onset. Other patients undergo a slower progression or even plateau for many years and may continue to function into the third decade of life.[7]
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