eMedicine Specialties > Neurology > Movement and Neurodegenerative Diseases
Hallervorden-Spatz Disease
Updated: Dec 7, 2006
Introduction
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.
Clinical
History
Clinical manifestations vary from patient to patient.
- The symptoms usually begin in the first decade with a motor disorder of extrapyramidal type and gait difficulty. Symptoms including rigidity of extremities, slowness of movement, dystonia, choreoathetosis, and tremor dominate the clinical picture.
- In some patients, extrapyramidal dysfunction may be delayed for several years, as spasticity and dysarthria may be the presenting symptoms.
- Dystonia is a prominent and early feature.
- Significant speech disturbances can occur early on.
- Dysphagia is common and is due to rigidity and corticobulbar involvement.
- Dementia is present in most individuals with HSD.
- Visual impairment from optic atrophy or retinal degeneration is not uncommon and can be the presenting symptom of the disease, although this is rare.
- Seizures have been described (Swaiman, 1991).
Physical
Physical examination reveals signs consistent with extrapyramidal and corticospinal dysfunction. In addition to rigidity, dystonia, and chorea, patients may experience spasticity, brisk reflexes, and extensor plantar responses.
- Based on the common clinical features, the following diagnostic criteria for HSD have been proposed (Swaiman, 1991). All of the obligate findings and at least 2 of the corroborative findings should be present. None of the exclusionary factors should be present.
- Obligate features
- Onset during the first 2 decades of life
- Progression of signs and symptoms
- Evidence of extrapyramidal dysfunction including one or more of the following: dystonia, rigidity, choreoathetosis
- Corroborative features
- Corticospinal tract involvement
- Progressive intellectual impairment
- Retinitis pigmentosa and/or optic atrophy
- Seizures
- Positive family history consistent with autosomal recessive inheritance
- Hypointense areas on MRI involving the basal ganglia
- Abnormal cytosomes in circulating lymphocytes and/or sea-blue histiocytes in bone marrow
- Exclusionary features
- Abnormal ceruloplasmin levels and/or abnormalities in copper metabolism
- Presence of overt neuronal ceroid lipofuscinosis as demonstrated by severe visual impairment and/or seizures that are difficult to control
- Predominant epileptic symptoms
- Severe retinal degeneration or visual impairment preceding other symptoms
- Presence of familial history of Huntington chorea and/or other autosomal dominantly inherited neuromovement disorders
- Presence of caudate atrophy on imaging studies
- Deficiency of hexosaminidase A
- Deficiency of ganglioside monosialic acid-1 (GM1)-galactosidase
- Nonprogressive course
- Absence of extrapyramidal signs
- Obligate features
Causes
No single risk factor is known to predispose individuals to HSD. The role of genetic factors has been proposed on the basis of known familial cases. By homozygosity mapping, a gene for the disease has been localized to band 20p12.3-13, raising the possibility of a future genetic test for the disease (Taylor, 1996).
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References
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Further Reading
Keywords
HSD, neurodegeneration with brain iron accumulation type 1, NBIA-1, late infantile neuroaxonal dystrophy, Hallervorden-Spatz disease, progressive extrapyramidal dysfunction, dementia, PANK2 gene, Hallervorden-Spatz syndrome
