Neuro-acanthocytosis is a genetically and phenotypically heterogeneous group of disorders that includes chorea-acanthocytosis and McLeod syndrome [2]. Chorea-acanthocytosis is a rare autosomal recessive disorder caused by mutations in the VPS13A gene on chromosome 9q21, which encodes the protein chorein. The disease typically presents in adulthood, with a mean age of 30 years, and rarely before the age of 20 or after the age of 50 years. Chorea acanthocytosis is relentlessly progressive, and sufferers may develop significant disability within a few years [3].

Affected individuals develop a mixed movement disorder, typically involving chorea and dystonia, and occasionally Parkinsonism later in the course of the disease, in addition to other neurological features such as seizures, neuropathy, and myopathy [2, 4]. The chorea in chorea-acanthocytosis is generalized, affecting the limbs, face, and trunk, and often interferes with ambulation, causing frequent falls. Co-existing dystonia is often present. There may be prominent oral involvement, and the presence of feeding-related tongue dystonia or self-mutilatory mouth movements, often appearing early in the course of the disease, provide a useful clue to the diagnosis [5]. Head drop and axial extension have also been reported to be characteristic features in advanced disease [6]. Cognitive and behavioral disturbances are seen in the majority of affected individuals [2] and neuropsychiatric symptoms may precede the onset of the movement disorder [7].

McLeod neuro-acanthocytosis syndrome is an X-linked recessive disorder , caused by mutations in the XK gene located at Xp21.1, which encodes an antigen of the Kell blood group [7]. Affected males manifest a progressive chorea syndrome, in addition to cognitive and behavioral disturbances. Reports of heterozygous females manifesting chorea and cognitive disturbance have also been identified [2]. Similar to chorea-acanthocytosis, seizures and subclinical neuromuscular disease are also present. The chorea is generalized and often interferes with ambulation with frequent falls. Hematologically, the McLeod blood group phenotype is characterized by absent expression of the Kx erythrocyte antigen and reduced expression of the Kell blood group antigen, leading to acanthocytosis and compensated hemolysis. In contrast to those with chorea-acanthocytosis, affected individuals may also develop dilated cardiomyopathy and arrhythmias , with a risk of sudden cardiac death.

Wilson’s disease is an autosomal recessive disorder caused by mutations in the ATP7B gene on chromosome 13q14.3, which encodes for a copper transporting P-type transmembrane ATPase [8]. The age at onset ranges from early childhood to the sixth decade of life, with a mean age of onset between 15 and 21 years. The majority of affected individuals are dysarthric, with varying spastic, ataxic, hypokinetic, and dystonic components to their speech. Neurological Wilson’s disease may present with dystonia, tremor or parkinsonism, or a combination of movement disorders. Chorea has been reported in 6–16% of cases, and tends to accompany other neurological manifestations.

Benign hereditary chorea (BHC ) is classically caused by autosomal dominant mutations in the NKX2.1 (TITF1) gene, located on the long arm of chromosome 14 [9]. There is a slight female preponderance, with a male to female ratio of 0.70 [10]. Usually, affected individuals develop generalized chorea with onset during early childhood, with a median age of 2.5–3 years, although onset from infancy to late childhood and adolescence has also been described [11]. Chorea is worsened with stress, and improves during sleep. There is often a history of decreased muscle in the first year of life, in addition to delayed motor milestones, particularly with walking. The chorea tends to improve up until puberty or early adulthood, before stabilizing during adulthood [10]. Infrequently, there may be a complete resolution of chorea. Associated movement disorders have also been described, including myoclonus, dystonia, tics, and drop attacks. In some cases, as chorea improves with age, myoclonus becomes the main disabling symptom in adulthood. Dysarthria has also been reported [12]. Nonmotor features are additionally associated with BHC, and include learning difficulties, which were observed in 20 out of 28 individuals in one series [10], and attention deficit hyperactivity disorder (ADHD) . Cerebral imaging in BHC is typically normal.

The mutation in ADCY5, the gene described in 2001 and linked to familial dyskinesia with facial myokymia, has been reported in patients with a phenotype of BHC. In general, patients present with hyperkinetic movements, mainly chorea and dystonia, but also other forms of dyskinesia. Quite often, they have preserved cognition and no other major neurological features. In contrast to BHC cases secondary to NKX2-1 mutations , patients with ADCY5 mutation may show significant progression of symptoms until adulthood. Facial myokymia, cardiac heart failure, more prominent dystonic posturing, and even cognitive decline may occur in ADCY5-related disorder [13].

C9orf72 disease is an autosomal dominant condition caused by an expanded hexanucleotide repeat in the C9orf72 gene. This was originally described in a Finnish and a European cohort [14] and in a family of Irish descent [15] with familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). This is considered the most common genetic cause of FTLD-ALSC9orf72 disease is an autosomal dominant condition caused by an expanded hexanucleotide repeat in the C9orf72 gene. This was originally described in a Finnish and European cohort [14] and a family of Irish descent [15] with familial frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). This is considered the most common genetic cause of FTLD-ALS.

In a large Huntington’s disease (HD) phenocopy cohort [16], the mean age of onset was 42.7 years. Affected individuals manifested chorea, dystonia, myoclonus, tremor, and parkinsonism. Upper motor neuron signs were also present in some affected individuals. Executive dysfunction was common, and psychiatric and behavioral problems tended to occur early. No clear differences in the size of the expanded hexanucleotide repeat have been identified to account for the varied phenotypic presentations of C9orf72 disease. Incomplete penetrance has been described and generalized atrophy may be observed on MRI.