Autosomal Recessive Forms of Chorea

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2.2.1 Pantothenate Kinase-Associated Neurodegeneration (PKAN)

Hallervorden and Spatz [54] first described five sisters with progressive dysarthria and dementia in 1922. Extrapyramidal symptoms dominate, particularly generalized dystonia with oromandibular involvement and parkinsonism, in addition to spasticity, behavioral changes followed by dementia, and pigmentary retinal degeneration, usually with onset in childhood [58]. However, chorea as the main feature has also been reported in a late adult-onset pathologically proven case [52].

Pathological examination of the original cases [54] revealed brown discoloration of the globus pallidus and substantia nigra, which is now known to be due to iron deposition most abundantly in the globus pallidus interna. The synonym "neurodegeneration with brain iron accumulation type 1" (NBIA-1) reflects these findings. Axonal spheroids, and gliosis of the pallidum and substantia nigra are also seen. MRI detects the pallidal abnormalities and the iron deposits. T2-weighted images show a central hyperintensity (probably representing fluid accumulation or edema) of the globus pallidus with a rim of signal hypointensity (iron deposition). This 'eye of the tiger' sign [121] is usually seen early in disease course [58] in the vast majority of cases. Acanthocytosis is found in about 8% of patients with PKAN.

PKAN is caused by mutation of the pantothenate kinase (PANK2) gene on chromosome 20p13-p12.3.

Recently, patients with a clinical picture similar to PKAN and iron deposition on MRI (in absence of the classic eye of the tiger sign) but without PANK2 mutations, were found to harbour mutations the PLA2G6 gene, encoding for a calcium-independent phospholipase A2, on chromosome 22q13 (Karak syndrome), a form of neuroaxonal dystrophy [58, 99].

2.2.2 Chorea-Acanthocytosis

Chorea-acanthocytosis is an autosomal recessive neurodegenerative disorder due to mutation of the VPS13A (CHAC) gene on chromosome 9q21 [114, 111]. Clinical features include chorea, dystonia with prominent orofacial involvement and self mutilation, tics, parkinsonism, eye movement abnormalities suggestive of brain stem involvement, seizures, subcortical dementia and psychiatric features with impairment of frontal lobe function [31, 51]. Myopathy and neuropathy are often present.

Blood tests reveal presence of acanthocytosis in the blood smear and elevated creatine kinase.

MRI demonstrates progressive caudate atrophy. Extensive neuronal loss and gliosis affecting the striatum, pallidum, and substantia nigra were found on postmortem examination [56]. Various aspects of chorea-acanthocytosis are discussed in detail elsewhere in this volume.

2.2.3 Wilson's Disease

Even though Wilson's disease most commonly presents with parkinsonian features and dystonia and tremor, chorea may be present and should therefore be considered [84].

2.2.4 Aceruloplasminemia

Deficiency of ceruloplasmin is due to inheritance of mutations in the gene for ceru-loplasmin and results in iron deposition in the cerebellum and basal ganglia [96, 143] and thus belongs to the NBIA spectrum. Typical presentation is with diabetes mellitus and retinal degeneration in the 20's. In middle age neurological signs appear, usually ataxia and spasticity. Movement disorders including dystonia, especially orofacial, parkinsonism and chorea may develop. Dementia may manifest in later years. Symptomatic heteroplasmic carriers have also been reported.

Ceruloplasmin functions as a ferroxidase, thus iron oxidation from Fe2+ to Fe3+ is impaired, and neurons are more vulnerable to oxidative stress. Neuropathologically, astrocytes and neurons laden with iron are found in the cerebellum, basal ganglia, and cortex [96, 143].

2.2.5 HDL3

A Saudi-Arabian family presenting with early onset mental deterioration, dysar-thria, extrapyramidal (dystonia) and pyramidal signs was reported as autosomal recessive variant of HD by Al-Tahan et al. [2] and Kambouris et al. [66]. Onset age was 3-4 years with extrapyramidal symptoms, ataxia, gait impairment, spasticity and intellectual decline. Brain imaging revealed progressive atrophy of the cau-dates bilaterally and the frontal cortex. HDL-3 was mapped to chromosome 4p15.3 [66], however, weakness of the evidence has been emphasized by Lesperance and Burmeister [81].

2.2.6 Friedreich Ataxia

Although progressive gait instability or general clumsiness, neuropathy and cardiomyopathy scoliosis are the classic presentation [38], chorea [55] and myoclonus [39] have also rarely been described. Friedreich ataxia, caused by expansion in the frataxin gene on chromosome 9, affects about 40,000 individuals in Europe and is very rare among black Africans.

2.2.7 Ataxia Telangiectasia

The wide range of clinical phenotypes in ataxia telangiectasia includes early-onset truncal ataxia, ocular motor apraxia, peripheral neuropathy, dysarthria and extrapyramidal features including facial hypomimia and dystonia. Chorea was present in the majority (68 of 70) of patients [140].

2.2.8 Ataxia with Ocular Motor Apraxia

The clinical spectrum of ataxia with ocular motor apraxia type 1 (AOA1), due to mutation in the aprataxin gene on chromosome 9p13.3 comprises oculomotor apraxia, axonal sensorimotor neuropathy, hypoalbuminaemia and hypercholestero-laemia. Choreic movements are frequent at onset (80%), but usually disappear in the course of the disease.

Similarly, AOA2 may present with a combination of eye signs (gaze nystagmus, strabismus, impaired smooth pursuit), ataxia, extrapyramidal features, including chorea, dystonia and tremor, dysphagia and neuropathy with onset in childhood or adolescence [77]. Findings of elevated cholesterol, creatine kinase, and alpha-fetoprotein support the diagnosis. In some populations AOA2 is the most common inherited cause of ataxia after Friedreich's ataxia. Similar to AOA1 the mutant protein may be involved in RNA repair [98].

2.2.9 Infantile Bilateral Striatal Necrosis

This condition causes chorea or dystonia in infants, and may be inherited in an autosomal recessive manner [8], but also appears to be due to mitochondrial mutations [32]. The diagnostic findings are of bilateral lesions in the striatum.

2.2.10 Other Inherited Metabolic Disorders

Movement disorders may be present as part of a constellation of neurological abnormalities in a number of inherited metabolic disorders. Autosomal recessive inheritance of mutations of critical synthetic enzymes is usually the etiology. Dystonia appears to be more common than chorea, possibly due to the co-existence of rigidity or spasticity, due to pyramidal tract involvement. Diagnosis is by assaying blood and urine for amino acids, by enzyme assays in lymphocytes, or genetic testing, as indicated.

Glutaric acidura typically presents with generalized dystonia and encephalopathy, and occasionally chorea [44, 105, 135]. On MRI dilation of the sylvian fissures can be seen and lesions of the putamen. Chorea, typically mild, can be seen in propionic academia, due to propionic-CoA carboxylase deficiency [122, 129]. Other aminoacidopathies in which chorea may occasionally be seen include 3-methylglutaconic academia [47], and succinic semialdehyde dehydrogenase deficiency.

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