The HDL2 Phenotype 21 HDL2 Clinical Presentation

The phenotype of HDL2 was initially described in eight members of the index family (Fig. 1) [11]. Segregation was consistent with autosomal dominant inheritance. The age of disease onset ranged from 26 to 48, with a non-significant trend toward younger onset in the later of the two generations evaluated. Dysarthria, rigidity, hyperreflexia, chorea or dystonia, weight loss, dementia, and psychiatric symptoms were detected in every case examined. Almost all cases had an action tremor, abnormal gait, and bradykinesia. Eye movements were relatively spared. Disease course was quite stereotyped, beginning with weight loss and a decline in coordination, with gradually progressive cognitive, psychiatric, and motor abnormalities. After about 10-15 years, affected individuals were profoundly demented, rigid, and essentially bed bound. As in other neurodegenerative diseases, death then followed from a combination of inanition and infection.

Walker and colleagues [26] described a similar family that only later was shown to have the HDL2 mutation. The proband, described late in his disease course, had

Fig. 1 Relative frequency of signs and symptoms of HDL2 in the index family. (Derived from Margolis et al. [11].)

mild chorea, was unable to speak or stand, and had lower extremity hyperreflexia (but overall decreased tone). One other family member had a similar phenotype, and another showed marked parkinsonism. In contrast, a member of a third pedigree was noted to have prominent chorea, abnormal eye movements, mild cognitive impairment and bradykinesia, and normal tone and reflexes [28]. A second case with this more classical Huntington's disease presentation has also been reported [20]. Overall, the clinical presentation of HD and HDL2 cannot be distinguished in a given individual, though a presentation characterized by prominent parkinsonism appears to be more common in HDL2 than in HD. Video clips of selected HDL2 cases have been published [27]. Unlike the autosomal recessive disorder chorea-acanthocytosis, muscle weakness, lip and tongue biting, and seizures are not part of the typical HDL2 clinical presentation [2]. There is also no evidence of the cardiac manifestations common in the X-linked McLeod syndrome, or the muscle and liver enzyme elevations common in either of these diseases.

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