Wallach's Interpretation of Diagnostic Tests: Pathways to Arriving at a Clinical Diagnosis (96 page)

Patients present with symptoms similar to Parkinson disease. Symptoms more specific to PSP include vertical supranuclear gaze palsy and unexplained falls due to postural instability. A genetic susceptibility has been suggested, but no genetic abnormality has been found to be causative. The diagnosis of PSP is made on clinical examination.

   Laboratory Findings

As in PD, laboratory and imaging studies are not definitive and should be performed to rule out treatable forms of disease (encephalitis, dopaminergic drug use, tumors, and Whipple disease). Blood, urine, and CSF are normal in PSP. Recent studies suggest that there may be biomarkers for PSP including a low homovanillic acid level in the CSF and decreased levels of tau protein.
^1,2
Pathologic evaluation of the brain at autopsy will identify globose neurofibrillary tangles within neurons and glia predominantly in the basal ganglia typical for PSP
³
and midbrain and cerebral cortical atrophy with hypopigmentation of the substantia nigra and locus ceruleus.
⁴
The abnormal filaments are composed of 4R tau.
^5,6

References

1.  Mendell JR, Engel WK, Chase TN. Modification by L-dopa of a case of progressive supranuclear palsy. With evidence of defective cerebral dopamine metabolism.
Lancet.
1970;1:593.

2.  Urakami K, Wada K, Arai H, et al. Diagnostic significance of tau protein in cerebrospinal fluid from patients with corticobasal degeneration or progressive supranuclear palsy.
J Neurol Sci.
2001;183:95.

3.  Williams DR, Lees AJ. Progressive supranuclear palsy: clinicopathological concepts and diagnostic challenges.
Lancet Neurol.
2009;8:270.

4.  Hauw JJ, Daniel SE, Dickson D, et al. Preliminary NINDS neuropathologic criteria for Steele- Richardson-Olszewski syndrome (progressive supranuclear palsy).
Neurology.
1994;44:2015.

5.  Kumar V, Abbas AK, Fausto N, et al.
Robbins and Code Trend Pathologic Basis of Disease
, 8th ed. Philadelphia, PA: Saunders Elsevier; 2004:1318.

6.  Takahashi M, Weidenheim KM, Dickson DW, et al. Morphological and biochemical correlations of abnormal tau filaments in progressive supranuclear palsy.
J Neuropathol Exp Neurol.
2002;61:33.

HUNTINGTON DISEASE

   Definition

Huntington disease (HD) is a neurodegenerative disease inherited as autosomal dominant and is caused by a repeat expansion in the huntingtin gene on chromosome 4p. The disease exhibits variable penetration rates in affected families but is fully penetrant when the repeat size is >38.
¹

   Clinical Presentation

Patients present with choreiform movements, psychiatric disorder, and dementia. The differentiation from other neurodegenerative dementias is made based on the preexistence of choreiform movements and/or psychiatric illness and from other movement disorders by the manner of abnormal movements.

   Laboratory Findings

The diagnosis of HD is based on a familial history, clinical assessment, and genetic testing. Genetic screening is also available for family members who wish to know their risk of disease. Testing for the CAG repeat length is now commercially available with good sensitivity and 100% specificity based on a cutoff of >38 repeats for HD.
²
Neuroimaging is no longer recommended.

References

1.  Richards RI. Dynamic mutations: a decade of unstable expanded repeats in human genetic disease.
Hum Mol Genet.
2001;10:2187.

2.  Kremer B, Goldberg P, Andrew SE, et al. A worldwide study of the Huntington’s disease mutation. The sensitivity and specificity of measuring CAG repeats.
N Engl J Med.
1994; 330:1401.

DYSTONIA

   Definition
Dystonia is a movement disorder with sustained muscle contractions. It may be hereditary or acquired.

   Clinical Presentation

Patients present with twisting repetitive movements and abnormal posture. Classification is by age of onset, anatomic distribution, and etiology. In primary dystonia, there are no neurologic symptoms in addition to the dystonic findings while in secondary dystonia, additional findings such as spasticity, ataxia, muscle weakness, ocular or cognitive impairment, or seizures may be present.
^1,2

A genetic etiology has been determined for dystonia with the two most common mutations the TOR1A gene in DYT1 dystonia and the THAP1 gene in DYT6 dystonia representing early-onset and late-onset dystonia, respectively.
^3,4
Doparesponsive dystonia presents in early childhood with focal dystonia and is frequently due to an autosomal dominant DYT5 dystonia caused by mutation in the GTP cyclohydrolase-1 gene.
⁵
Segawa syndrome, an autosomal recessive form, is due to a mutation in the tyrosine hydroxylase gene.
⁶

The diagnosis of dystonia is predominantly made on clinical examination with special attention to evaluation of the movement disorders.

   Laboratory Findings

Genetic testing for the DYT1 dystonia gene is available for early-onset dystonia, and in some areas, DYT5 dystonia genetic testing may be obtained. Other tests may help to exclude secondary dystonia these include neuroimaging with MRI or CT to evaluate the basal ganglia, CBC, electrolytes, renal and liver function tests, ANA, ceruloplasmin, serum copper and 24-hour urinary copper to rule out Wilson disease, and sedimentation rate.

References

1.  Geyer HL, Bressman SB. The diagnosis of dystonia.
Lancet Neurol.
2006;5:780.

2.  Phukan J, Albanese A, Gasser T, et al. Primary dystonia and dystonia-plus syndromes: clinical characteristics, diagnosis, and pathogenesis.
Lancet Neurol.
2011;10:1074.

3.  Bressman SB, Sabatti C, Raymond D, et al. The DYT1 phenotype and guidelines for diagnostic testing.
Neurology.
2000;54:1746.

4.  Fuchs T, Gavarini S, Saunders-Pullman R, et al. Mutations in the THAP1 gene are responsible for DYT6 primary torsion dystonia.
Nat Genet.
2009;41:286.