Neurology: Case of the Month

Check Your Diagnosis — Patient 41

Aliya Sarwar, M.D.; Dennis R. Mosier, M.D., Ph.D.

Diagnosis

Hallervorden-Spatz syndrome

Clinical Summary

This 13 year old boy experienced the onset of predominantly dystonic motor symptoms at age 5, with progression over time from task-specific, mild dystonias to more chronic and severe involvement of all limbs. Although he did not exhibit noticeable impairment of cognition, an older sister was severely affected, with progressive generalized dystonias and cognitive impairment. Although the family history suggests involvement of succeeding generations, the presence of parental consanguinity is consistent with the possibility of a recessively inherited disorder. On T2-weighted MRI, very low signal intensity was seen in the globus pallidus, red nucleus, and substantia nigra, consistent with increased iron deposition in these structures. This clinical presentation is highly suggestive of the Hallervorden-Spatz syndrome, also known as neurodegeneration with brain iron accumulation, type 1 (NBIA1).[1]

Variants of the Hallervorden-Spatz phenotype have been described. Some of these variant syndromes include additional features of optic atrophy or retinal degeneration (not documented in our patient's ophthalmologic examination, but records from other family members are incomplete). Another variant, the HARP syndrome (Hypobetalipoproteinemia, Acanthocytosis, Retinitis pigmentosa, Pallidal degeneration),[2-3] was not evident by ophthalmologic examination or by examination of the blood smear; we did not perform a lipoprotein analysis on this patient. A form of the syndrome with prominent parkinsonian features, associated with Lewy bodies on pathological examination, has also been described.[3]

To our knowledge, alopecia, which was noted in two affected family members, has not been described in association with Hallervorden-Spatz syndrome. However, since a clinically unaffected sibling of this patient also exhibited alopecia, the relationship of this feature to the neurologic findings is presently uncertain. A single kindred with presumed autosomal recessive inheritance of alopecia and progressive dystonia has been reported (OMIM #601164);[4] however, this kindred differed from the present case by the presentation of hypogonadism, facial and interosseous muscle atrophy, and MRI findings suggestive of white matter involvement.

Differential Diagnosis

Development of an extrapyramidal motor disorder in childhood should always suggest the possibility of Wilson's disease, a recessively inherited disorder linked to mutations in the ATP7B gene, a copper-transporting ATPase. Early treatment of Wilson's disease can result in complete or near-complete amelioration of associated liver and brain dysfunction. Although the typical presentation of Wilson's disease involves bulbar dysfunction, rigidity, and evidence of cerebellar as well as extrapyramidal dysfunction, dystonic presentations have been described. However, the normal copper and ceruloplasmin levels, the absence of liver enzyme abnormalities, and the lack of Kayser-Fleischer rings on ophthalmologic examination argue against a diagnosis of Wilson's disease in this patient. Dopa-responsive dystonia (DRD) should also be considered in the differential diagnosis of any child or adolescent patient presenting with a dystonic gait disorder, spastic diplegia, or juvenile parkinsonism. A therapeutic trial of low doses of levodopa is mandatory in such patients. An autosomal dominant form of DRD, linked in many families to mutations in GTP cyclohydrolase I,[5] frequently presents with marked diurnal fluctuation, which was not evident in this patient. An autosomal recessive form of DRD, linked in some families to mutations in the tyrosine hydroxylase gene, has also been described. In this patient, the relatively modest clinical response to levodopa, the existence of a family member with severe cognitive impairment (without documented response to levodopa), and the marked iron accumulation evident on MR imaging argue against a diagnosis of DRD. Juvenile-onset Huntington's disease must also be considered in any child presenting with a movement disorder. However, juvenile presentations of Huntington's disease, an autosomal dominant disorder, usually exhibit prominent limb rigidity, flexion hypertonia, and slurred speech, which were not evident in this patient. Emotional withdrawal, catatonic posturing, and seizures are also seen in many cases of juvenile Huntington's disease, although the choreoathetosis typical of adult cases is often absent or minimal. Prominent caudate atrophy is usually evident on imaging studies. Primary torsion dystonias, exemplified by the type associated with the DYT1 site on chromosome 9q34 (mutations identified in the torsinA gene), are typically dominantly inherited disorders; other inheritance patterns have been reported for the dystonia loci DYT2 and DYT3. In these syndromes, although hyperintensities on T2-weighted MRI suggestive of mild gliosis have been reported infrequently in the basal ganglia, prominent MRI findings, and particularly evidence of excessive iron accumulation, are absent.

Cases of glutaric acidemia, type I, which results from a deficiency of glutaryl-CoA dehydrogenase, may exhibit an early childhood onset of dystonia and choreoathetosis in the absence of hypoglycemic episodes. The best available imaging data[6] suggest that cortical atrophy occurs early in most cases, most prominently in the opercular region and anterior temporal lobes (93% of cases); macrocephaly and white matter involvement are frequent (~50%), and associated basal ganglia lesions exhibit high T2 signal and volume loss, rather than the T2 hypointensities suggestive of iron deposition. A pattern of opercular or anterior temporal atrophy in a child with progressive dystonia, even in the absence of other abnormalities, would thus strongly suggest the possibility of an organic acidemia. Iron deposition has not been observed in any of the other organic acidemias, although increased T2 signal may be observed in the basal ganglia of some patients with extrapyramidal presentations.[6] Atypical presentations of Lafora-body disease, which is usually dominated by myoclonus, seizures, and dementia, may be associated with a parkinsonian movement disorder, but should not be confused with the presentation of this patient. Prominent childhood-onset dystonia has been described in families with Leber's hereditary optic neuropathy (LHON).[7] In these patients, optic neuropathy, a family history of LHON, a maternal inheritance pattern, and/or patchy white matter changes on MRI may be clues to the existence of a mitochondrial disorder. Likewise, Leigh's disease may be associated with progressive rigidity and bilateral cavitation of the putamen, but should not be confused with the findings in this patient.

Discussion

Hallervorden-Spatz syndrome, or neurodegeneration with brain iron accumulation (type I), is an autosomal recessive disorder with childhood or early adolescent onset of extrapyramidal and corticospinal symptoms and signs, which progress slowly over many years. Late-onset cases (as old as age 68) have been described.[8] Symptoms frequently begin in the legs, as in this patient, but in some patients, a bulbar onset is evident, which may mimic the typical pattern of dysfunction seen in Wilson's disease. A general deterioration of cognitive function is frequent, but may lag behind the motor manifestations by many years. Restricted forms of the disease, as well as variability of clinical progression within families, may occur. The Hallervorden-Spatz syndrome has been described in families from a variety of ethnic backgrounds.

The MRI findings in patients with Hallervorden-Spatz syndrome are striking in the most extreme presentations,[9] with bilateral pallidal hypointensity on T2-weighted images (consistent with iron accumulation), and small medial zones of hyperintensity (corresponding with cavitary lesions on pathologic examination). This "eye of the tiger" sign, in the context of high clinical suspicion, is considered to be diagnostic for the Hallervorden-Spatz syndrome. However, early in the course of the disease, brain MRI may be normal, and some cases with prominent evidence of iron deposition do not exhibit significant medial hyperintensities. In Hallervorden-Spatz syndrome, iron accumulation typically occurs in the substantia nigra and the red nucleus as well as in the pallidum.

Neuropathologic examination of the brain in patients with Hallervorden-Spatz syndrome, in addition to the previously mentioned features with MRI correlates, has emphasized the presence of prominent axonal spheroids, which resemble those found in neuroaxonal dystrophy. In addition to these findings, neuronal loss and gliosis of the affected areas are observed. The significance of the prominent brain iron accumulation noted in Hallervorden-Spatz syndrome has been debated. Systemic disorders of iron overload, such as hemochromatosis, are not accompanied by significant brain dysfunction or iron accumulation in the basal ganglia. Iron chelation therapy has not resulted in clinical improvement in patients with Hallervorden-Spatz syndrome. Excessive iron accumulation in the basal ganglia is also evident in many cases of Parkinson's disease, as well as in other degenerative illnesses affecting the nigrostriatal system, leading to concern that the iron accumulation noted in Hallervorden-Spatz syndrome may be secondary to other processes. In support of this contention, increased iron deposition at distant sites in the basal ganglia has been documented following excitotoxic lesions of the striatum in animal models.[10] However, iron accumulation may be relatively modest in some disorders with pronounced striatal damage, suggesting that a primary predisposition to excessive brain iron accumulation could potentially exist in patients with Hallervorden-Spatz syndrome.

A causative gene for Hallervorden-Spatz syndrome has been linked to an interval flanked by markers D20S906 and D20S116 on chromosome 20p12.3-20p13.[11] In addition, there is evidence for multiple genetic loci associated with this syndrome.[11] The significant variability in clinical presentation of this disorder, even in patients from the same family, may suggest the presence of modifying genetic or environmental factors in the expression of the Hallervorden-Spatz syndrome.

Treatment of patients with Hallervorden-Spatz syndrome is largely symptomatic. Many patients, especially in the early stages of the disease, may respond modestly to levodopa treatment. Treatments for dystonia, including pharmacotherapy, focal injections of botulinum toxin, and surgical pallidotomy [12], may benefit some patients. Further progress is needed to understand the pathophysiology and to develop more effective treatments for patients with this disorder.

References

  1. Hallervorden J,Spatz H. Eigenartige Erkrankung im extrapyramidalen System mit besonderer Beteiligung des Globus pallidus und der Substantia nigra. Z Gesammte Neurolog Psychiatr. 1922;79:254-302.
    See also Online Mendelian Inheritance in Man (http://omim.org/entry/234200). It is noted that Dr. Hallervorden's troubling involvement in an active euthanasia program during World War II (summarized in Shevell M, Neurology. 1992;42:2214-9) has led to calls for the removal of Hallervorden's name from the eponym, or for replacement with the designation, neurodegeneration with brain iron accumulation, type 1 (NBIA1).
  2. Higgins JJ, Patterson MC, Papadopoulos NM, Brady RO, Pentchev PG, Barton NW. Hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome). Neurology. 1992;42(1):194-8.
    See also Orrell RW, Amrolia PJ, Heald A, Cleland PG, Owen JS, Morgan-Hughes JA, Harding AE, Marsden CD. Acanthocytosis, retinitis pigmentosa, and pallidal degeneration: a report of three patients, including the second reported case with hypoprebetalipoproteinemia (HARP syndrome). Neurology. 1995;45(3 Pt 1):487-92.
  3. Halliday W. The nosology of Hallervorden-spatz disease. J Neurol Sci. 1995;134 Suppl:84-91.
  4. Devriendt K, Legius E, Fryns JP. Progressive extrapyramidal disorder with primary hypogonadism and alopecia in sibs: a new syndrome? Am J Med Genet. 1996;62(1):54-7.
    See also Online Mendelian Inheritance in Man (http://omim.org/entry/241080).
  5. Ichinose H, Suzuki T, Inagaki H, Ohye T, Nagatsu T. Molecular genetics of dopa-responsive dystonia. Biol Chem. 1999;380(12):1355-64.
  6. Brismar J, Ozand PT. CT and MR of the brain in glutaric acidemia type I: a review of 59 published cases and a report of 5 new patients. AJNR Am J Neuroradiol. 1995;16(4):675-83. See also Brismar J, Ozand PT. CT and MR of the brain in the diagnosis of organic acidemias. Experiences from 107 patients. Brain Dev. 1994;16 Suppl:104-24.
    See also Shoffner JM, Brown MD, Stugard C, Jun AS, Pollock S, Haas RH, Kaufman A, Koontz D, Kim Y, Graham JR, et al. Leber's hereditary optic neuropathy plus dystonia is caused by a mitochondrial DNA point mutation. Ann Neurol. 1995;38(2):163-9.
  7. Jun AS, Brown MD, Wallace DC. A mitochondrial DNA mutation at nucleotide pair 14459 of the NADH dehydrogenase subunit 6 gene associated with maternally inherited Leber hereditary optic neuropathy and dystonia. Proc Natl Acad Sci USA. 1994;91(13):6206-10.
  8. Jankovic J, Kirkpatrick JB, Blomquist KA, Langlais PJ, Bird ED. Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism. Neurology. 1985;35(2):227-34.
  9. Savoiardo M, Halliday WC, Nardocci N, Strada L, D'Incerti L, Angelini L, Rumi V, Tesoro-Tess JD. Hallervorden-Spatz disease: MR and pathologic findings. AJNR Am J Neuroradiol. 1993;14(1):155-62.
    See also Brouwer OF, Laboyrie PM, Peters AC, Vielvoye GJ. Follow-up magnetic resonance imaging in Hallervorden-Spatz disease. Clin Neurol Neurosurg. 1992;94 Suppl:S57-60.
  10. Shoham S, Wertman E, Ebstein RP. Iron accumulation in the rat basal ganglia after excitatory amino acid injections--dissociation from neuronal loss. Exp Neurol. 1992;118(2):227-41.
    See also Sastry S, Arendash GW. Time-dependent changes in iron levels and associated neuronal loss within the substantia nigra following lesions within the neostriatum/globus pallidus complex. Neuroscience. 1995;67(3):649-66.
  11. Taylor TD, Litt M, Kramer P, Pandolfo M, Angelini L, Nardocci N, Davis S, Pineda M, Hattori H, Flett PJ, Cilio MR, Bertini E, Hayflick SJ. Homozygosity mapping of Hallervorden-Spatz syndrome to chromosome 20p12.3-p13. Nat Genet. 1996;14(4):479-81. Erratum in: Nat Genet 1997;16(1):109.
  12. Justesen CR, Penn RD, Kroin JS, Egel RT. Stereotactic pallidotomy in a child with Hallervorden-Spatz disease. Case report. J Neurosurg. 1999;90(3):551-4.

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