Chorea, Ballism, and Athetosis

Introduction

Chorea consists of involuntary, continual, abrupt, rapid, brief, unsustained, and irregular movements that flow randomly from one body part to another. Patients can partially and temporarily suppress the chorea and frequently camouflage some of the choreiform movements by incorporating them into semipurposeful activities (parakinesia). The inability to maintain voluntary contraction (motor impersistence), such as manual grip (milkmaid grip) or tongue protrusion, is a characteristic feature of chorea and results in dropping of objects and clumsiness. Chorea should be differentiated from “pseudochoreoathetosis,” a movement disorder that is phenomenologically similar to chorea or athetosis (slow chorea) but results from loss of proprioception ( ). Muscle stretch reflexes in chorea are often “hung-up” and “pendular.” Affected patients typically have a peculiar, irregular, and dancelike gait. The pathophysiology of chorea is poorly understood, but in contrast to parkinsonism, dystonia, and other movement disorders, intracortical inhibition of the motor cortex is normal in chorea ( ). In addition, semiquantitative analysis of single-photon emission computed tomography (SPECT) in patients with hemichorea resulting from various causes suggests that there is an increase in activity in the contralateral thalamus, possibly because of disinhibition as a result of loss of normal pallidal inhibitory input ( ).

Chorea may be a manifestation of a primary neurologic genetic disorder, such as Huntington disease (HD) ( ), or it may occur as a neurologic complication of systemic, toxic, or other disorders ( ; ; ; ; ; ) ( Table 14.1 ; Fig. 14.1 ). Chorea may be seen in normal infants, but these movements usually disappear by age 8 months, and some of these movements may be purposeful ( ).

In this chapter we will briefly mention HD, but the focus will be on non-HD causes of chorea, because HD-like (HDL) phenotypes without the HD genotype are increasingly being described and must be recognized. Several neurodegenerative disorders, some with expanded trinucleotide repeats, have been reported as phenocopies of HD, including spinocerebellar ataxia (SCA), particularly SCA2 and SCA3 ( ), pure cerebello-olivary degeneration ( ), and dentatorubral-pallidoluysian atrophy (DRPLA) (see following section) ( ; ; ; ; ; ; ). In a study of 285 patients with clinical features consistent with those of HD, but who tested negative for HD by a DNA analysis, the following diagnoses were identified: five cases had HDL1 type 4 (HDL4), one had HDL1, one had HDL2, and one had Friedreich ataxia ( ).

Dentatorubral-pallidoluysian atrophy and Huntington disease–like disorders

DRPLA is an autosomal dominant neurodegenerative disorder that is particularly prevalent in Japan, but it also has been identified in Europe and in African American families (Haw River syndrome) ( ; ; ; ). Usually beginning in the fourth decade, the disorder may occur as an early-onset DRPLA (before 20 years of age) manifested by a variable combination of myoclonus, epilepsy, intellectual disability, or late-onset DRPLA (after 20 years of age), manifested by cerebellar ataxia, choreoathetosis, dystonia, rest and postural tremor, parkinsonism, and dementia ( Video 14.1 ).

Video 14.1 Dentatorubralpallidoluysian atrophy (DRPLA).

Unstable CAG expansion has been identified as the mutation in the DRPLA (or ATN1 ) gene on chromosome 12p13.31 ( ; ; ; ; ). The DRPLA gene codes for protein that has been identified as a phosphoprotein, c-Jun NH(2)-terminal kinase, one of the major factors involved in its phosphorylation. In DRPLA, this protein appears to be slowly phosphorylated; thus, it may delay a process that is essential in keeping neurons alive ( ). Similar to HD, there is an inverse correlation between the age at onset and the number of CAG repeats ( ). The early-onset type of DRPLA is associated with greater number of CAG repeats (62–79) compared with the late-onset type (54–67 repeats) ( ). Testing for the various gene mutations will undoubtedly lead to better recognition and appreciation of the spectrum of clinical and pathologic changes associated with these disorders. For example, a family with spastic paraplegia, truncal ataxia, and dysarthria, but without other clinical features of DRPLA, has been found to show homozygosity for an allele that carries intermediate CAG repeats in the DRPLA gene ( ). The DRPLA gene is expressed predominantly in neurons, but neurons that are vulnerable to degeneration in DRPLA do not selectively express the gene (Nishiyama et al., 1997).

Neuroimaging studies in patients with DRPLA often show evidence of cortical, brainstem, cerebellar atrophy, and widespread white matter changes ( ; ; ). Neuropathologic findings consist chiefly of degeneration of the dentatorubral system, globus pallidum externus (GPe), subthalamic nucleus, and, to a lesser extent, striatum, substantia nigra (SN), inferior olive, and thalamus ( ) and demyelination and reactive astrogliosis in the cerebral white matter ( ). Involvement of oligodendrocytes in autopsied brains and an increased number of affected glia, as well as larger expansions in CAG in these glia, in transgenic mice might explain the widespread demyelination ( ). Several pathologic reports have noted widespread deposition of lipofuscin. Similar to HD and other diseases associated with CAG repeat expansions, DRPLA also has been associated with the formation of perinuclear aggregates that can be prevented by the use of transglutaminase inhibitors such as cystamine and monodansyl cadaverine ( ). These intranuclear inclusions stain intensely with ubiquitin ( ). Subsequent studies have demonstrated accumulation of mutant atrophin-1 in the neuronal nuclei, rather than neuronal intranuclear inclusions, as the predominant pathologic feature in this neurodegenerative disorder ( ).

Other Huntington disease–like disorders

An autosomal dominant HDL neurodegenerative disorder, now classified as HDL1 and mapped to chromosome 20p ( ), is a familial prion disease with an expanded PrP. A 192-nucleotide insertion in the region of the prion protein gene (PRNP) encoding an octapeptide repeat in the prion protein, was found in a single family with HD phenotype, suggesting that PRNP mutations can result in HD phenocopies ( ).

Another disorder, termed HDL2, is characterized by onset in the fourth decade, involuntary movements such as chorea, dystonia, and other movement disorders (bradykinesia, rigidity, tremor); dysarthria; hyperreflexia; gait abnormality; psychiatric symptoms; weight loss; and dementia with progression from onset to death in about 20 years ( , ; ). The disorder appears to be present exclusively or predominantly in individuals of African origin. The neuroimaging and neuropathologic findings are very similar to those in HD, except that there appears to be more severe involvement of the occipital cortex ( ) and the intranuclear inclusions stain with 1C2 but not with antihuntingtin antibodies. Unlike the family linked to chromosome 20p, seizures are not present in the HDL2 family. All 10 affected family members had a CAG repeat expansion of 50 to 60 triplets. The gene was later mapped to chromosome 16q24.3 and was found to encode junctophilin-3, a protein of the junctional complex linking the plasma membrane and the endoplasmic reticulum ( ). Although acanthocytosis was emphasized by Walker and colleagues (2002; ) in their initial report and in 1 of 3 patients reported subsequently ( ), we have not been able to confirm the presence of acanthocytes in 1 member of the original family or in the other members when we carefully examined the peripheral smear.

The mutation associated with HDL2 has been identified as a CTG/CAG trinucleotide repeat expansion within the junctophilin-3 (JPH3) gene and loss of its protein product, Jph3, contributes to the pathogenesis of this autosomal dominant neurodegenerative disorder ( ). In the normal population, the repeat length ranges from 6 to 27 CTG triplets, whereas affected individuals have 41 to 58 triplets. One family, previously described as “autosomal dominant chorea-acanthocytosis with polyglutamine-containing neuronal inclusions” (see later) ( ) was subsequently found to have the triple nucleotide expansion of HDL2 ( ; ). The CTG repeat expansion at the HDL2 locus has been found to be responsible for 2% of patients with typical features of HD but without expanded CAG repeats in the IT15 gene and 0.2% of all HD families, again providing evidence that HD is clinically and genetically heterogeneous ( ). This group later analyzed 252 patients with an HDL phenotype, including 60 with typical HD, who had tested negative for pathologic expansion in the IT15 gene and found 2 patients who had an abnormal CTG expansion in the JPH3 gene and 2 other patients with abnormal CAG expansion in the gene coding for TATA-binding protein (TBP/SCA17), important in initiation of transcription ( ; ; ). SCA17, categorized as HDL4, has many clinical features that overlap with those of HD ( ; ). Thus, the frequency of mutation in either the JPH3 gene or TBP gene among patients with HDL phenotype is about 3%. Initially, the TBP expansion was found in the family with SCA17, characterized clinically by intellectual deterioration, cerebellar ataxia, epilepsy, and chorea. CUG repeat–containing RNA foci, resembling myotonic dystrophy type 1, were detected in neurons of HDL2 brains, suggesting that RNA toxicity may play a role in the pathogenesis of this neurodegenerative disorder ( ). HDL2 resembles HD clinically and pathologically more than any other disease ( ). In one study, 10 of 514 (2%) patients with HD phenocopy had C9orf72 expansion ( ). Thus, this mutation is one of the most common genetic causes of HDL disorders.

Although the majority of genetic forms of chorea are inherited in an autosomal dominant pattern, a novel autosomal recessive neurodegenerative HDL disorder has been described ( ). Beginning at 3 to 4 years of age and manifested by chorea, dystonia, ataxia, gait disorder, spasticity, seizures, mutism, intellectual impairment, and bilateral frontal and caudate atrophy, this neurodegenerative disorder has been linked to 4p15.3, different from the 4p16.3 HD locus, but confirmation of this finding is lacking. Although classified as HDL3, because of its autosomal recessive inheritance and clinical features atypical for HD, it should not be categorized as HDL. In fact the HDL terminology should be replaced with specific disorders in which genetic mutation has been identified.

Some cases of neuronal intranuclear inclusion disease, caused by expanded CAG repeats and characterized by the combination of parkinsonism, dystonia, chorea, and cognitive, lower motor neuron signs, and cognitive and behavioral abnormalities resulting in death by the third decade, also show intranuclear aggregates, similar to the other CAG disorders ( ).

Neuroacanthocytosis

After HD, neuroacanthocytosis is perhaps the most common form of hereditary chorea. Previously also referred to as chorea–acanthocytosis, it is now recognized that this multisystem, neurodegenerative disorder can be expressed by a wide variety of clinical and laboratory abnormalities, hence the term neuroacanthocytosis ( ; ; ; ;). The term neuroacanthocytosis was coined by Jankovic and colleagues ( ) to replace the old term Levine-Critchley syndrome choreoacanthocytosis to draw attention to the heterogeneous presentation with a variety of hyperkinetic (chorea, dystonia, tics) and hypokinetic (parkinsonism) movement disorders in addition to other neurologic deficits and abnormal laboratory findings. Symptoms usually begin in the third and fourth decades of life (range: 8–62 years) with lip and tongue biting followed by orolingual (eating) dystonia, motor and phonic tics, generalized chorea, stereotypies, and neck flexions (head drops), and trunk flexion and extension resembling a “rubber-man” ( ) ( Video 14.2 ). Besides neuroacanthocytosis, head drops are also characteristic of other movement disorders, including tics, stereotypies, choreas, myoclonus, hypotonic disorders, bobble head syndrome, ACDY5, Sandifer syndrome, and a variety of epileptic and sleep disorders ( ).

Video 14.2 Neuroacanthocytosis.

Other features of neuroacanthocytosis include cognitive and personality changes, seizures, dysphagia, dysarthria, vertical ophthalmoparesis, parkinsonism, amyotrophy, areflexia, evidence of axonal neuropathy, and elevated serum creatine kinase without evidence of myopathy. Hardie and colleagues (1991) reviewed the clinical, hematologic, and pathologic findings in 19 patients (10 males and 9 females) with a mean age of 32 years (range: 8–62 years) with more than 3% acanthocytes on peripheral blood smear. Of these patients, 12 with neuroacanthocytosis were familial and 7 were sporadic; 2 had the McLeod phenotype (see later). In their series, Hardie and colleagues (1991) found a variety of movement disorders, including chorea (58%), orofacial dyskinesia (53%), dystonia (47%), vocalizations (47%), tics (42%), and parkinsonism (34%). Although lip and tongue biting was observed in 16% of the patients, this is a characteristic feature of neuroacanthocytosis and, when present, strongly suggests the diagnosis. The use of a mouth guard has been reported to be effective in the treatment of oral self-mutilation associated with neuroacanthocytosis ( ). Besides movement disorders, other associated features included dysarthria (74%); absent or reduced reflexes (68%); dementia (63%); psychiatric problems such as depression, anxiety, and obsessive-compulsive disorder (OCD) (58%); dysphagia (47%); seizures (42%); muscle weakness and wasting (16%); and elevated creatine phosphokinase (CK) in 58%. Magnetic resonance volumetry and fluorodeoxyglucose positron emission tomography (PET) show striatal atrophy in patients with neuroacanthocytosis ( ). Longitudinal morphometric study in 13 patients with genetically or biochemically confirmed neuroacanthocytosis versus 25 matched controls showed not only reduction in size but also abnormality of shape of the head of caudate ( ).

Although autosomal dominant, X-linked recessive, and sporadic forms of neuroacanthocytosis have been reported, the majority of the reported families indicate autosomal recessive inheritance. A genome-wide scan for linkage in 11 families with autosomal recessive inheritance showed a linkage to a marker on chromosome 9q21, indicating a single locus for the disease ( ). Ueno and colleagues (2001) carried out a linkage-free analysis in the region of chromosome 9q21 in the Japanese population and identified a 260–base pair (bp) deletion in the expressed sequence tags (EST) region K1AA0986 in exons 60 and 61 that was homozygous in patients with neuroacanthocytosis and heterozygous in their parents. Further sequencing has identified a polyadenylation site with a protein with 3096 amino acid residues that has been named “Chorein” by the authors. This deletion is not found in normal Japanese and European populations ( ). In another study by Rampoldi and colleagues (2001) in European patients, a novel gene encoding a 3174-amino-acid protein on chromosome 9q21 with 73 exons was identified. They identified 16 mutations in the chorea acanthocytosis (ChAc) gene, later renamed VPS13A gene. These mutations were identified in various exons. They suggested that chorea acanthocytosis encodes an evolutionarily conserved protein that is involved in protein sorting ( ). Other single heterozygous mutations have been identified in this gene ( ). Molecular analysis by screening all 73 exons of the VPS13A gene showed marked genotype–phenotype heterogeneity ( ). The function of the protein product chorein is not yet fully understood, but it is probably involved in intracellular protein trafficking. Using antichorein antisera, the expression of chorein in peripheral red blood cells has been found to be absent or markedly reduced in patients with neuroacanthocytosis, but not with McLeod syndrome or HD ( ; ). Loss of chorein expression, measured by western blot analysis, has been found to be a reliable diagnostic test for neuroacanthocytosis.

Walker and colleagues (2002) described a family with chorea or parkinsonism and cognitive changes inherited in an autosomal dominant pattern. At autopsy, there was marked degeneration of the striatum and intranuclear inclusion bodies immunoreactive for ubiquitin, expanded polyglutamine CGG repeats, and torsinA. Interestingly, one of the patients had fragile X syndrome and two had expanded trinucleotide repeats at permutation range, previously associated with postural/kinetic tremor, parkinsonism, ataxia, and cognitive decline ( ). The family reported by Walker and colleagues (2002) turned out to have the trinucleotide repeat expansion associated with HDL2, but subsequent analysis of the family shed doubt on the presence of acanthocytes as a feature of the HDL2 syndrome ( ).

Identifications of novel mutations in the XK gene, responsible for McLeod syndrome are expanding its clinical phenotype ( ). Two patients from the original study by Rubio and colleagues (1997) were found to have the McLeod phenotype, an X-linked (Xp21) recessive form of acanthocytosis associated with depression, bipolar and personality disorder, and neurologic manifestations, including chorea, involuntary vocalizations, seizures, motor axonopathy, hemolysis, liver disease, and high creatine kinase levels ( ; , ; ). The phenotype of McLeod syndrome is similar to that of neuroacanthocytosis, but presentation is more variable, movement disorder may be minimal (chorea, dystonia, and parkinsonism), and there is no self-mutilation. Patients may also have variable psychiatric/cognitive symptoms, mild axonal neuropathy, myopathy, cardiomyopathy, and chronic granulomatous disease ( ).

Another genetic cause of a syndrome similar to neuroacanthocytosis is a rare mitochondrial disease resulting from mutations in the ELAC2 gene ( ). Clinical manifestations include cognitive decline, olfactory hallucinations, perioral chorea and distal chorea, dystonia, apraxia, bradykinesia, waddling gait, myopathy, hearing loss, diabetes, polyneuropathy, hypertrophic cardiomyopathy, and delayed psychomotor development. Death usually occurs during childhood.

Although 20 families have been described, the family history is usually negative. Neuroimaging in patients with neuroacanthocytosis typically reveals caudate and occasionally cerebellar atrophy with a rim of increased T2-intensity in the lateral putamen. Functional neuroimaging studies show evidence of downregulation of D2 dopamine receptors. In contrast to the autosomal recessive form of neuroacanthocytosis linked to mutations in VPS13A gene on chromosome 9, patients with McLeod syndrome usually do not exhibit lip-biting or dysphagia. This multisystem disorder is associated with low reactivity of Kell erythrocyte antigens (weak antigenicity of red cells) because of the absence of Kx 37-kDa, 444 AA, membrane protein that forms a complex with the Kell protein. The disorder is caused by different mutations in the XK gene encoding for the KX protein ( ; ; ). Mutations identified by various authors include frame shift mutations in exon 2 at codon 151, deletion at codon 90 in exon 2 and at codon 408 in exon 3, and splicing mutations in intron 2 of the XK gene ( ; ; ; ). Rarely, neuroacanthocytosis may be associated with abetaliproteinemia resulting from mutations in the microsomal triglyceride transfer protein ( ). In addition to acanthocytosis, the patients exhibit retinopathy; malabsorption, including that of vitamin E; low serum cholesterol levels; and abnormal serum lipoprotein electrophoresis. Aprebetalipoproteinemia can also cause movement disorders and acanthocytosis ( ).

An examination of wet blood or Wright-stained, fast-dry blood smear usually reveals over 15% of red blood cells as acanthocytes. In mild forms of acanthocytosis, scanning electron microscopy might be required to demonstrate the red blood cell abnormalities ( ). In a study of two patients with pathologically proven neuroacanthocytosis, Feinberg and colleagues (1991) noted that the yield in demonstrating acanthocytosis may be increased by using a coverslip because the contact with glass causes the fragile cells to undergo morphologic changes. Diluting the blood with normal saline, incubating the Wright-stained smear with ethylenediametetraacetic acid (EDTA), using a scanning electron microscope, and employing other techniques designed to increase “echinocytotic stress” are also helpful ( ; ). The characteristic acanthocytic appearance of red blood cells has been attributed to abnormalities in transmembrane glycoprotein band 3 that can be demonstrated on gel electrophoresis. It is not yet clear how the gene mutation leads to the abnormal morphology of the red cells.

By using high-performance liquid chromatography, fatty acids of erythrocyte membrane proteins were analyzed in six patients with neuroacanthocytosis ( ). In comparison with normal controls and patients with HD, erythrocytes of patients with neuroacanthocytosis showed a marked abnormality in the composition of covalently bound fatty acids: an increase in palmitic acid (C16:0) and a decrease in stearic acid (C18:0).

Brain MRI in patients with neuroacanthocytosis usually shows caudate and more generalized brain atrophy, but some cases also show extensive white matter abnormalities ( ). Caudate hypometabolism and atrophy have been demonstrated by PET studies and by neuroimaging. Similar to the findings in Parkinson disease (PD), PET scans in six patients with neuroacanthocytosis showed a reduction to 42% of normal in [ ¹⁸ F]dopa uptake in the posterior putamen; in contrast to PD, however, there was a marked reduction in the striatal [ ¹¹ C]raclopride (D2) receptor binding ( ).

Neuronal loss and gliosis were particularly prominent in the striatum and pallidum but may also affect the thalamus, SN, and anterior horns of the spinal cord ( ). The neuronal loss in the SN is most evident in the ventrolateral region, similar to that in PD, but the nigral neuronal loss is more widespread in neuroacanthocytosis ( ). The preservation of the cerebral cortex, cerebellum, subthalamic nucleus, pons, and medulla may serve to differentiate pathologically among neuroacanthocytosis, HD, and DRPLA. However, autopsy findings in brains of two brothers with neuroacanthocytosis manifested by parkinsonism without chorea showed no significant neuronal loss within the SN pars compacta (SNpc), but there was a low count of parvalbumin-positive interneurons in the cortex and striatum ( ). Brain biochemical analyses showed low substance P in the SN and striatum and increased levels of norepinephrine in the putamen and pallidum (De Yebenes et al., 1988).

Unfortunately, there is no effective treatment for neuroacanthocytosis, although chorea, stereotypy, dystonia, seizures, and other neurologic symptoms can be treated symptomatically, similar to other disorders. The associated parkinsonism rarely improves with dopaminergic therapy, probably because there is loss of postsynaptic dopamine receptors. We have seen some patients whose condition remained static for several years, followed by further progression and an eventual demise as a result of aspiration pneumonia or other complications of chronic illness.

Neurodegeneration with brain iron accumulation

A group of neurodegenerative disorders, formerly known as Hallervorden–Spatz disease, has received increasing attention as the genetic and pathogenic mechanisms of the various subtypes have become elucidated. The disease was first described in 1922 by Julius Hallervorden and Hugo Spatz, who later actively participated in Nazi euthanasia while working at the Kaiser Wilhelm Institute for Brain Research ( ; ). Because of their terrible past and shameless involvement with Nazi activities, this group of disorders has been renamed neurodegeneration with brain iron accumulation (NBIA) (Schneider, 2016; http://nbiacure.org ) ( Table 14.2 ). The prototype form of NBIA consists of an autosomal recessive disorder characterized by childhood-onset progressive rigidity, generalized dystonia, often associated with dystonic opisthotonus ( ) and oro-mandibular-lingual dystonia, choreoathetosis, spasticity, optic nerve atrophy, levodopa-responsive parkinsonism, and dementia ( ; ; ; ; ). Although chorea is not a typical feature of NBIA, “senile chorea” has been described in a patient with pathologically proven NBIA type 1 (NBIA-1) ( ).

The most classic NBIA, NBIA type 1 (NBIA-1) is the pantothenate kinase–associated neurodegeneration (PKAN). Linkage analyses initially localized the NBIA-1 gene on 20p12.3–p13; subsequently, 7-bp deletion and various missense mutations were identified in the coding sequence of the PANK2 gene, which codes for pantothenate kinase ( ; ). Pantothenate kinase is an essential mitochondrial regulatory enzyme in coenzyme A biosynthesis ( ). It has been postulated that as a result of phosphopantothenate deficiency, cysteine accumulates in the globus pallidus (GP) of brains of patients with NBIA-1. It undergoes rapid auto-oxidation in the presence of nonheme iron that normally accumulates in globus pallidus internus (GPi) and SN, generating free radicals that are locally neurotoxic ( ). Interestingly, atypical subjects were found to be compound heterozygotes for certain mutations for which classic subjects were homozygous. The disorder with the clinical phenotype of NBIA associated with mutations in the PANK2 gene is now referred to as PKAN ( ). On the basis of an analysis of 123 patients from 98 families with NBIA-1, Hayflick and colleagues (2003) found that “classic Hallervorden–Spatz syndrome” was associated with PANK2 mutation in all cases and that one third of “atypical” cases had the mutations within the PANK2 gene. Those who had the PANK2 mutation were more likely to have dysarthria and psychiatric symptoms, and all had the typical “eye of a tiger” abnormality on brain MRI with a specific pattern of hyperintensity within the hypointense GPi ( ; ).

Neuroacanthocytosis and NBIA may overlap in some clinical features. Although PKAN may be associated with acanthocytosis, another neuroacanthocytosis syndrome, linked to PKAN, is the hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration (HARP syndrome) ( ). This disorder is associated with dystonia, particularly involving the oromandibular region, rather than chorea and self-mutilation. Indeed, a homozygous nonsense mutation in exon 5 of the PANK2 gene that creates a stop codon at amino acid 371, found in the original HARP patient, establishes that HARP is part of the PKAN disease spectrum ( ; ).

The classification of NBIA is continuously being revised as our understanding of this group of disorders is improving. In addition to PKAN, other forms of NBIA include neuroferritinopathy, infantile neuroaxonal dystrophy, and aceruloplasminemia, and PLA2G6-associated neurodegeneration (PLAN), with mutations in the PLA2G6 gene, on chromosome 22q13.1 ( ; ; ; Schneider et al., 2012; ) (see Table 14.2 ). These disorders are chiefly manifested by childhood-onset axial hypotonia, spasticity, bulbar dysfunction, ataxia, dystonia, choreoathetosis, and MRI changes indicative of iron deposition in the GP and SN ( ). Previously diagnosed as infantile neuroaxonal dystrophy, now classified as NBIA-2, PLAN may also manifest as adult-onset, levodopa-responsive dystonia–parkinsonism without iron on brain imaging ( ; ; ). Another gene, FA2H, when mutated, has been found to cause not only leukodystrophy and hereditary spastic paraplegia, but also NBIA ( ). The FA2H -associated neurodegeneration (FAHN) is characterized by childhood-onset gait impairment, spastic paraparesis, ataxia, and dystonia ( ; ). FA2H is involved in lipid and ceramide metabolism. Another form of NBIA was highlighted by a report of 11 children with a biochemical profile suggestive of dopamine transporter (DAT) deficiency syndrome ( ). Manifesting in infancy, this disorder is usually characterized by severe parkinsonism–dystonia syndrome, but chorea, oculomotor deviations, and spasticity may also dominate the clinical phenotype. The cerebrospinal fluid (CSF) ratio of homovanillic acid to 5-hydroxyindoleacetic acid is usually increased. This autosomal recessive disorder has been attributed to homozygous or compound heterozygous SLC6A3 mutations and complete loss of DAT activity in the basal nuclei (indicated by abnormal DAT scan SPECT). Mutations in C19orf12, a gene that codes for mitochondrial membrane protein, hence the term mitochondrial membrane protein–associated neurodegeneration (MPAN), have been recently identified in patients with NBIA phenotype manifested by parkinsonism and levodopa-induced dyskinesias ( ). Although autosomal recessive inheritance has been reported, there is some evidence that an autosomal dominant mechanism also may play a role ( ).

Another NBIA associated with chorea and frequently misdiagnosed as HD is neuroferritinopathy, a progressive but potentially treatable disorder caused by mutations in the ferritin light chain gene (FTL1), located on 19q13.3–q13.4 ( ; ). Patients may be initially diagnosed as having idiopathic dystonia, PD, HD, or a variety of other disorders. In a study of a group of 41 genetically homogeneous subjects with the 460InsA mutation in FTL1, the mean age at onset was 39.4 ± 13.3 years (range: 13–63), beginning with chorea in 50%, focal lower limb dystonia in 42.5%, and parkinsonism in 7.5% ( ). The disease progressed over a 5- to 10-year period, eventually leading to aphonia, dysphagia, severe and often asymmetric motor disability, and finally dementia in the advanced stages. A characteristic action-specific facial dystonia was present in 65%. Serum ferritin levels were low in the majority of males and postmenopausal females, but may be normal, particularly in premenopausal females. Magnetic resonance imaging (MRI) typically shows gradient echo T2∗ hypointensity in red nuclei, SN, and GP brain imaging and was abnormal in all affected individuals and one presymptomatic carrier and T1 hyperintensity in the GP and posterior putamen. Chorea associated with neuroferritinopathy responds well to tetrabenazine (TBZ), a dopamine depletor ( ).

Another form of NBIA is the clinical syndrome previously called static encephalopathy of childhood with neurodegeneration in adulthood (SENDA), but as a result of identification of mutations in the X-chromosomal WDR45 gene encoding a beta-propeller protein, postulated to play a role in autophagy, the disorder is now referred to as BPAN ( ; ; ). Initially manifesting as global developmental delay with intellectual disability in infancy or early childhood, the patients (girls outnumber boys) then gradually become clumsy and develop spasticity and epilepsy and are often misdiagnosed as having cerebral palsy (CP). The second phase, which usually starts in adolescence and young adulthood, is manifested by progressive dystonia, cognitive decline, speech difficulties, and parkinsonism but no tremor. Patients initially respond to levodopa but often develop disabling motor fluctuations and dyskinesias and require deep brain stimulation (DBS) ( ). Because of sleep disturbances, hand stereotypies, and other abnormalities, many of these patients are initially diagnosed as having atypical Rett syndrome. In addition to iron accumulation in the SN, the pallidum may appear hypointense on gradient-echo or T2∗ sequences; T1-weighted signal hyperintensity with a central band of hypointensity in the SN seems to be a specific finding in BPAN. Although WDR45 is located on the X chromosome (most variants are nonsense mutations), affected individuals seem be sporadic cases with no family history of NBIA. Abnormal autophagy has been proposed as the mechanism of neurodegeneration in this disorder, although it is not clear how increased autophagy relates to iron accumulation.

One entity that should be added to the NBIA group of disorders is pallidonigroluysial atrophy (PNLA) ( ; ). In a series of 25 cases of pathologically proven PNLA cases the mean age at onset was 54.3 ± 14.3 years and average duration of disease was 7.9 ± 5.8 years ( ). In addition to gait or balance disturbance, often initially diagnosed as progressive supranuclear palsy, chorea was encountered in 20%; 36% had coexistent motor neuron disease. Besides extensive gliosis, many brains showed iron-positive pigments in the pallidonigroluysian system, and p62-positive glial inclusions without evidence of tauopathy.

Treatment of NBIA syndrome is challenging, but regression of symptoms after 6 months of iron chelation with deferiprone has been reported in some patients with NBIA ( ). Another approach, based on a mouse model of the disease (knockout exacerbated by ketogenic diet), suggests that treatment with pantethine, the dimeric form of pantothenic acid (vitamin B ₅ ), may be beneficial even in the human condition ( ). Potential therapeutics may involve strategies that reactivate pyruvate dehydrogenase due to its relationship with coenzyme A-dependent activation of mitochondrial acyl carrier protein ( ).

Essential chorea is a form of adult-onset, nonprogressive chorea without family history of chorea or other symptoms suggestive of HD and without evidence of striatal atrophy on neuroimaging studies. Sometimes referred to as senile chorea, essential chorea usually has its onset after age 60, and in contrast to HD, it is not associated with dementia or positive family history. Some cases of senile chorea, however, have been reported to have pathologic changes identical to those of HD; others have had predominant degeneration of the putamen rather than the caudate ( ). The CAG repeat length should, by definition, be normal, but Ruiz and colleagues (1997) found abnormal CAG expansion in three of six clinically diagnosed cases of senile chorea. Although the authors suggest that some patients with senile chorea have a sporadic form of HD, the term essential (or senile) chorea should be reserved for those patients with late-onset chorea without family history, without dementia, without psychiatric problems, and without CAG expansion. These criteria are necessary to separate senile or essential chorea from HD.