Excerpt from Hallervorden-Spatz Disease

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Background

Hallervorden-Spatz disease (HSD) is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. Onset is most commonly in late childhood or early adolescence, but cases with adult onset have been described (Jankovic, 1985). The disease can be familial or sporadic. When familial, it is inherited recessively and has been linked to chromosome 20 (Taylor, 1996). Recently, a mutation in the pantothenate kinase (PANK2) gene on band 20p13 has been described in patients with typical HSD (Zhou, 2001).

Hallervorden and Spatz first described the disease in 1922 as a form of familial brain degeneration characterized by iron deposition in the brain. Recently concerns have been raised regarding reports of Hallervorden and Spatz's association with Nazi activities in Germany, and some even suggested changing the name of the syndrome to neuroaxonal dystrophy (Harper, 1996). The term "neurodegeneration with brain iron accumulation type1" (NBIA-1) has been used in more recent publications (Neumann, 2000).

Pathophysiology

The exact pathophysiology of the disease 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 pathogenesis 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 (Perry, 1985). 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.

Recently, a role for mutation in the PANK2 gene (band 20p13) in the pathogenesis of the disease 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 (Hayflick, 2001).

Pathologic evaluation reveals characteristic rust-brown discoloration of the globus pallidus and SN pars reticulata secondary to iron deposition (Swaiman, 1991; Halliday, 1995). 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 known as 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 but also in cerebral cortex
• Accumulation of pigment, mostly containing iron
• Ceroid lipofuscin and neuromelanin containing iron in the areas mainly affected as mentioned above

Iron deposition may be found both 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. 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 (Neumann, 2000).

Frequency

United States

The exact frequency of HSD is not known.

Mortality/Morbidity

HSD is relentlessly progressive. The course is characterized by progressive dementia, corticospinal signs (eg, spasticity, hyperreflexia), and extrapyramidal signs including rigidity, dystonia, and choreoathetosis. Affected individuals typically die in the second or third decade. The course of the disease usually proceeds over 10-12 years, but case reports describe patients surviving 30 years (Saito, 2000; Hickman, 2001).

Race

No particular race is more susceptible than others to HSD. The disease is rare and has been reported in all races.

Sex

The disease is equally common in both sexes.

Age

Age of onset is usually in early adolescence; however, presentations in adulthood and infancy have been reported (Jankovic, 1985; Grimes, 2000; Cooper, 2000). The classic presentation is in the late part of the first decade or early part of the second decade, when the individual is aged 7-15 years.

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