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bnM. basal nucleus of Meynert; D. depression; HV. hypoventilation; LB. Lewy body; NA. not available; P. parkinsonism; Resp.. response; SN. substantia nigra; WL. weight loss; +. present; -. not present.

Familial Parkinsonism Owing to a Defect in Copper Metabolism (Wilson's Disease)

Wilson's disease (WD) is an autosomal recessive disorder in which copper metabolism is impaired. The causative "WD gene," known as ATP7B, is located on chromosome 13q14-q21 and is involved in the copper-transporting P-type adenosine triphosphatase interaction between copper and ceruloplas-min (63-65). More than 200 mutations have been found in this gene, and WD occurs worldwide. It is a progressive disorder with a variable age at onset, ranging from 7 to 58 yr. The initial symptoms can be hepatic, behavioral, or neurological (66). Most patients exhibit intracorneal pigmentation (KayserFleischer ring) at the initial presentation (67). Neurological symptoms include various combinations of resting tremor, intention tremor, dysarthria, unsteady gait, dystonia, bradykinesia, and rigidity (68). On neuropathologic examination, the most striking changes, consisting of pigmentation and spongy degeneration, are seen in the basal ganglia. Microscopically, the basal ganglia exhibit neuronal loss as well as abundant protoplasmic astrocytes, including giant cells called "Alzheimer cells" (69).

Clinical Presentation

Tremor and rigidity are the most common parkinsonian manifestations of WD (70). Throughout the course of the illness, the tremor may be unilateral and present only at rest, and it may be indistinguishable from PD tremor. In the advanced stages of WD, some patients develop a "wing-beating" type of tremor. Rigidity is frequently present, together with dystonia. A fixed open mouth and drooling are common. If no treatment is administered, the disease is relentlessly progressive (68).

Familial Parkinsonism With Iron Metabolism Deficiency (Neurodegeneration With Brain Iron Accumulation, Hallervorden-Spatz Syndrome)

Neurodegeneration with brain iron accumulation (NBIA) is a heterogeneous group of disorders with sporadic and familial forms. This syndrome was previously known as Hallervorden-Spatz disease. It typically begins in childhood with extrapyramidal features, including chorea, rigidity, and dystonia. In addition, pyramidal signs, progressive dementia, and, less commonly, retinitis pigmentosa and seizures are also seen (71,72). Some familial cases present with late-onset parkinsonism that can occasionally be responsive to levodopa (73,74).

The molecular genetic study of an Amish family with NBIA demonstrated linkage to a locus on chromosome 20p12.3-p13 (75). More recently, a mutation in the coding sequence of a pantothenate kinase gene called PANK2 was found in this family (76). Additional missense and null mutations have been identified in other familial forms of NBIA (77). The term "PKAN" (pantothenate kinase-associated neurodegeneration) means a defect of the gene PANK2 leading to a deficiency of the enzyme pantothenate kinase. Interestingly, missense mutations in PANK2 were identified in individuals with atypical PKAN. There are also families with NBIA with no linkage to the PANK2 locus (77-79), suggesting the existence of another chromosomal locus for this disorder. Clinical features similar to NBIA were seen in families with neuroferritinopathy who had mutations in the ferritin light chain (78) and in families with aceruloplasminemia who had mutations in the gene encoding for ceruloplasmin (79). A striking rust-brown pigmentation is seen in the globus pallidus and substantia nigra pars reticulata (80). In these structures, many axonal spheroids are seen. The presence of Lewy bodies and neurofibrillary tangles was also reported in NBIA (81,82).

Clinical Presentation

NBIA is characterized by extrapyramidal features, including rigidity and dystonia. Age at onset in familial forms is usually in the first or second decade. However, a later onset has also been reported (73,74). Rigidity usually starts first in the lower extremities but later affects the upper extremities as well. Involuntary choreoathetoid movements sometimes precede or accompany rigidity. Orobuccolingual rigidity may be a presenting feature and can lead to difficulties in articulation and swallowing. Pyramidal tract involvement is common. Cognitive dysfunction and epilepsy occur rarely (71).

Familial Parkinsonism With Mitochondrial Abnormality

Increasingly, mitochondrial dysfunction (particularly of complex I) has been recognized to play an important role in the pathogenesis of PD. Complex I activity is decreased in the substantia nigra of PD patients compared to normal controls (83). Similarly, cytoplasmic hybrid (cybrid) cell lines expressing mitochondrial DNA (mtDNA) from the platelets of PD patients have impaired complex I activity compared to platelets of normal controls (84,85). 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or rotenone may produce PD in animal models by inhibiting complex I mitochondrial activity. These data suggest that mitochondrial dysfunction plays an important role in the pathogenesis of PD. In addition, mtDNA dysfunction has been identified in two large PD families with a maternal mode of inheritance (86,87).

Clinical Description

In the first family with maternally inherited PD, in which three generations were studied, cybrid cell line cultures demonstrated decreased complex I activity (86). The average age at onset was 42 yr (range, 41-79 yr). The phenotype resembled "classic" PD, with a resting tremor, bradykinesia, and rigidity. A good response to levodopa was observed. So far, no specific mutation has been identified in this family. The second family had a mixed phenotype resembling adult-onset multisystem degeneration. The clinical features included levodopa-responsive parkinsonism, dementia, dysto-nia, extraocular movement abnormalities, and pyramidal signs. A missense mtDNA mutation in the gene for the nicotinamide dehydrogenase 4 (ND4) subunit of complex I was identified in this family (87). One case was autopsied, showing loss of pigmented neurons in the substantia nigra and absence of Lewy bodies.

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