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Dystonia

Focal-generalized

Focal-generalized

Focal-segmental

Focal-generalized

AD, autosomal dominant; Dy, dystonia; +, present; -, not present.

AD, autosomal dominant; Dy, dystonia; +, present; -, not present.

alcohol (DYT8 and DYT9), or anticonvulsant medications (DYT10). Parkinsonian features have been recognized in DYT3, DYT5, and DYT12. Clinical features of dystonia kindreds associated with parkinsonism are summarized in Table 6.

Clinical Description

DYT3, also known as X-linked dystonia-parkinsonism (XDP) or Lubag disease, was first identified in families residing on the Philippine island of Panay. The disease is inherited as an X-linked recessive trait with high penetrance and is thus transmitted to men by their mothers. Female carriers can manifest symptoms, although these are rare and much less severe than those in men. Onset is at a mean age of 35 yr but can range from age 12-60 yr.

The earliest feature in most DYT3 patients is mild parkinsonism. In particular, breakdown of rapid alternating movements and subtle body bradykinesia are often seen early. In some patients, an asymmetrical resting limb tremor similar to that in PD may in fact be misdiagnosed as PD. Other patients may have a coarse type of action and postural appendicular or axial tremor similar to essential tremor. With time, dystonia develops in the majority of patients. Those who develop segmental or multifocal dystonia within the first year of the disease, especially in combination with parkinsonism, usually have a more rapid progression. Patients with pure or predominant parkinsonism and either negative or late-onset dystonia have a more benign course. These parkinsonian patients may be levodopa-responsive. However, the dystonia can sometimes be exacerbated by levodopa.

When the family history cannot be adequately determined or when the maternal roots cannot be traced back to the Philippine island of Panay, some patients with XDP can be misdiagnosed as suffering from idiopathic torsion dystonia, essential tremor, PD, or other forms of parkinsonism-plus syndrome (34,35). Neuropathologic studies demonstrate a patchy or mosaic pattern of neuronal loss and gliosis in the striatum, with dorsal-to-ventral, rostral-to-caudal, and medial-to-lateral gradients (36). Furthermore, gliotic changes occur in the globus pallidus and substantia nigra pars reticularis.

DYT5 is a dopa-responsive dystonia also known as autosomal dominant progressive dystonia with marked diurnal fluctuation. This form of dystonia is caused by mutations in the guanosine triph-osphate cyclohydrolase I gene (GTPCHI) on chromosome 14q22.1-q22.2 (37). More than 70 mutations have been found in patients with DYT5. The age at onset is usually in the first decade and only occasionally in adulthood. Dystonia in DYT5 can be focal (frequently affecting a foot) or it can be generalized. Parkinsonian features include resting tremor, bradykinesia, rigidity, and postural insta bility. Parkinsonism usually occurs in adult-onset cases and at times can develop early in the course of the disease. The most characteristic features of DYT5 include marked diurnal fluctuation and excellent response to levodopa therapy. Some families with DYT5 can be difficult to distinguish from kindreds with autosomal recessive juvenile parkinsonism carrying the parkin mutation PARK2. There is considerable overlapping of clinical features between these two genetic conditions regarding age at onset, clinical signs and symptoms, and response to dopaminergic therapy. However, the pattern of inheritance is different: autosomal dominant in DYT5 and autosomal recessive in PARK2 families (38). Neuropathologic studies of DYT5 brains revealed no degenerative changes.

DYT12 has been described in only three families: two from the United States and one from Ireland (39,40). Linkage analyses of the three families revealed a disease locus on chromosome 19q13. The syndrome was termed "rapid-onset dystonia and parkinsonism" because of the acute development of symptoms within hours (or at most a few days). The dystonia usually affects bulbar and upper limb muscles, and the parkinsonian features include bradykinesia and postural instability. Resting tremor and rigidity are not seen. Response to levodopa and dopamine agonists is poor. Despite the initial rapid progression, the clinical course eventually levels off with no further deterioration. No brain pathologic changes were seen in one autopsied case of DYT12.

A family from Switzerland with levodopa-responsive dystonia (DYT14) has also been described (41). Linkage analysis showed a locus on chromosome 14q13 in close proximity to the GCH-1 gene. The patients from this family developed dystonia in both legs at a mean age of 3 yr. Later in the course of the disease, postural instability, frequent falls, and dystonia affecting the upper limbs were also observed. In one family member, a severe akinetic rigid syndrome developed at age 73 yr. Treatment with low-dose levodopa dramatically improved his symptoms. Neuropathologic studies revealed neuronal loss in the substantia nigra without Lewy bodies.

Case 2: (Video 2, see accompanying DVD) DYT3 (XDP/Lubag Disease)

The patient was a 39-yr-old right-handed Filipino man who was born and raised in the province of Iloilo on the Philippine island of Panay. At age 34, he noted a resting tremor of the right foot, difficulty in handwriting, and intermittent hyperextension of the neck. One year later, he experienced spontaneous jaw opening, slurring of speech, drooling, difficulty swallowing, and involuntary turning of the head to the left. By this time, he was forced to quit his profession as a dentist. By the third year of his disorder, the patient was already severely disabled and had lost 30 pounds because of difficulty in swallowing.

His medical history revealed no notable illness in the past. A review of the family history showed similar symptoms in an uncle (brother of his mother), whose symptoms started during his late 30s.

On examination 3 yr after onset (at age 37), the patient's dystonia was generalized in distribution and included inversion of the right foot at rest, dorsiflexion of the toes on raising the left foot (video 2, segment A), spontaneous jaw-opening, retrocollis and torticollis (with abundant phasic movements), hyperextension or arching of the back (video 2, segment B), and hyperextension and adduction of both arms on walking. As a sensory trick, the patient puts both hands in the occipital region in order to partially alleviate the retrocollis (video 2, segment C). He also had moderate parkinsonism in the form of hypophonic speech, reduced blinking, resting tremor of the right foot, diffuse rigidity, bradykinesia, breakdown of rapid alternating movements on finger/hand/foot tapping and hand opening/closing bilaterally, reduced arm swing, slowness in arising from a seated position, and retropul-sion (video 2, segment D).

He received bromocriptine, diphenhydramine, tetrabenazine, reserpine, baclofen, tizanidine, trihexyphenidyl, clonazepam, and haloperidol as monotherapy and in different combinations at maximally tolerated doses, with no change in his dystonia. Some improvement of the dystonia was achieved with trihexyphenidyl (10 mg/d) and clonazepam (2 mg/d). Levodopa (375 mg/d) slightly improved the resting tremor of the right foot but did not affect the bradykinesia. Levodopa was stopped after 3 mo because of subjective worsening of his cervical dystonia. Botulinum toxin type A

injections to the neck muscles gave the best, albeit temporary, relief of his cervical dystonia but caused considerable worsening of his dysphagia.

Familial Parkinsonism With Chorea (Huntington's Disease)

Huntington's disease (HD) is an adult-onset, progressive autosomal dominant neurodegenerative disorder caused by an abnormal expansion of CAG trinucleotide repeats in a gene on chromosome 4 coding for the huntingtin protein (42). In most cases of HD, the phenotype is characterized by hyper-kinetic movements (chorea), dementia, and personality disorder. However, phenotypic presentation and age at onset of symptoms in HD are variable and depend on the length of the CAG repeat expansion, with an inverse correlation between age at onset and the CAG repeat length (43). In addition, patients with early onset and larger CAG repeat sizes present more often with parkinsonism, dysto-nia, or eye movement abnormalities rather than chorea (44,45). Neuropathology in HD is characterized by a striking neuronal loss in the caudate and putamen, as well as a moderate neuronal loss in the thalamus and cerebral cortex (46).

Clinical Description

The clinical features seen in HD patients with parkinsonism, which include rigidity and bradykinesia, are summarized in Table 7 (47,48). In patients with classic HD, age at onset is between 35 and 44 yr, but in those with prominent parkinsonism, onset occurs at a substantially younger age (49,50). The parkinsonism in HD responds poorly to dopaminergic therapy. The akinetic rigid state is not associated with chorea, but rather with dementia and seizures. This form of HD is more rapidly progressive and is fatal within 10 yr.

A few cases of the akinetic rigid form of HD with later onset (age over 40 yr) have been reported. Levodopa therapy can be beneficial in these late-onset akinetic rigid forms of HD (51,52). In the terminal stages of the classic form of HD, rigidity and dystonia tend to replace chorea (53,54).

Familial Parkinsonism With Depression, Weight Loss, and Central Hypoventilation (Perry Syndrome)

In 1975, Perry et al. (55,56) described a family presenting with parkinsonism, depression, weight loss, and central hypoventilation. Subsequently, six other families with a similar phenotype were identified in North America, Europe, and Asia (57-62). The phenotype differs from other familial autosomal dominant or recessive parkinsonian syndromes linked to known mutations or loci. Molecular genetic study in these families is in progress, but the gene locus has not yet been identified. Neuro-pathologic findings include severe neuronal loss and gliosis in the substantia nigra with few or no Lewy bodies (57-61).

Clinical Presentation

The pattern of inheritance is autosomal dominant with high penetrance. Table 8 summarizes the clinical and pathologic features of seven kindreds described with this syndrome. The mean age at onset is 46 yr (range, 35-57). The phenotype consists of parkinsonism, weight loss, respiratory dysfunction, and depression. The parkinsonian features include a resting tremor, bradykinesia, and rigidity. Depression and severe weight loss are usually seen in the early stages of the disease. Affected individuals may die suddenly or die of respiratory failure (57,58,61). Suicide attempts also occur. The most consistent clinical signs include parkinsonism and hypoventilation. A good response to levodopa is seen in some but not all kindreds. The disease progression is relentless, leading to death in 2-8 yr.

Case 3: (Video 3, see accompanying DVD) Perry Syndrome (Fukuoka Family, Unknown Genetic Locus)

This 43-yr-old right-handed man (61) was referred by his employer to the company physician because of inability to perform his regular job duties. The examination performed at that time demon-

Table 7

Clinical Features Seen in Juvenile HD vs Adult-Onset HD Associated With Parkinsonism

Adult Form of HD

Feature Juvenile HD Associated with Parkinsonism

Average age

Adult Form of HD

Feature Juvenile HD Associated with Parkinsonism

Average age

at disease onset, yr

<20

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