Recent advances in non-Huntington's disease choreas.

INTRODUCTION: Chorea is primarily due to an imbalance of basal ganglia output pathways, often due to dysfunction or degeneration of the caudate nucleus and putamen, and can be due to many causes. METHODS: We reviewed the recent literature to identify newly-recognized causes of chorea, including auto-immune, metabolic, and genetic. We also focused upon developments in mechanisms relating to underlying pathophysiology of certain genetic choreas and advances in therapeutics. RESULTS: Novel autoantibodies continue to be identified as causes of chorea. Both COVID-19 infection and vaccination are reported to result rarely in chorea, although in some cases causality is not clearly established. Advances in genetic testing continue to find more causes of chorea, and to expand the phenotype of known genetic disorders. Deep brain stimulation can be successful in certain circumstances. CONCLUSION: Our understanding of mechanisms underlying this movement disorder continues to advance, however much remains to be elucidated.

Pseudo-ataxia due to Osteoid Osteoma.

Background: Ataxia is diagnosed by typical features on examination suggestive of a cerebellar etiology and can invoke extensive diagnostic testing. Osteoid osteomas (OOs) are benign bone tumors of the lower limbs that occasionally present with focal neurological signs. Case Report: A 3-year-old male presented with apparent progressive gait ataxia and non-specific leg pain. Initial imaging was unremarkable. However, 12 months later, a lesion was identified in the distal right femur, which was found to be an OO. The gait disorder and pain resolved after surgery. Discussion: This case highlights the challenges of diagnosing a gait disorder in young children.

The non-Huntington disease choreas: Five new things.

PURPOSE OF REVIEW: Chorea can be due to a wide variety of causes. In this review, I provide updates on several recently identified genetic and autoimmune causes of chorea, and review evidence supporting the use of deep brain stimulation in chorea. RECENT FINDINGS: New genes that may cause chorea include ADCY5 (encoding for adenylate cyclase 5) C9ORF72 (in addition to amyotrophic lateral sclerosis and frontotemporal dementia), and those responsible for the neurodegeneration with brain iron accumulation disorders. Novel autoantibodies are increasingly being identified as associated with a variety of neurologic syndromes, including chorea, in both paraneoplastic and non-paraneoplastic settings. Deep brain stimulation can be a useful intervention in patients with chorea who do not respond to oral medications, whether due to neurodegenerative or nondegenerative causes. SUMMARY: New causes of chorea continue to be identified. Correct diagnosis is essential for prognostication and treatment.

Short and long term outcome of bilateral pallidal stimulation in chorea-acanthocytosis.

BACKGROUND: Chorea-acanthocytosis (ChAc) is a neuroacanthocytosis syndrome presenting with severe movement disorders poorly responsive to drug therapy. Case reports suggest that bilateral deep brain stimulation (DBS) of the ventro-postero-lateral internal globus pallidus (GPi) may benefit these patients. To explore this issue, the present multicentre (n=12) retrospective study collected the short and long term outcome of 15 patients who underwent DBS. METHODS: Data were collected in a standardized way 2-6 months preoperatively, 1-5 months (early) and 6 months or more (late) after surgery at the last follow-up visit (mean follow-up: 29.5 months). RESULTS: Motor severity, assessed by the Unified Huntington's Disease Rating Scale-Motor Score, UHDRS-MS), was significantly reduced at both early and late post-surgery time points (mean improvement 54.3% and 44.1%, respectively). Functional capacity (UHDRS-Functional Capacity Score) was also significantly improved at both post-surgery time points (mean 75.5% and 73.3%, respectively), whereas incapacity (UHDRS-Independence Score) improvement reached significance at early post-surgery only (mean 37.3%). Long term significant improvement of motor symptom severity (≥ 20 % from baseline) was observed in 61.5 % of the patients. Chorea and dystonia improved, whereas effects on dysarthria and swallowing were variable. Parkinsonism did not improve. Linear regression analysis showed that preoperative motor severity predicted motor improvement at both post-surgery time points. The most serious adverse event was device infection and cerebral abscess, and one patient died suddenly of unclear cause, 4 years after surgery. CONCLUSION: This study shows that bilateral DBS of the GPi effectively reduces the severity of drug-resistant hyperkinetic movement disorders such as present in ChAc.

The Sac1 domain of SYNJ1 identified mutated in a family with early-onset progressive Parkinsonism with generalized seizures.

This study aimed to elucidate the genetic causes underlying early-onset Parkinsonism (EOP) in a consanguineous Iranian family. To attain this, homozygosity mapping and whole-exome sequencing were performed. As a result, a homozygous mutation (c.773G>A; p.Arg258Gln) lying within the NH2 -terminal Sac1-like inositol phosphatase domain of polyphosphoinositide phosphatase synaptojanin 1 (SYNJ1), which has been implicated in the regulation of endocytic traffic at synapses, was identified as the disease-segregating mutation. This mutation impaired the phosphatase activity of SYNJ1 against its Sac1 domain substrates in vitro. We concluded that the SYNJ1 mutation identified here is responsible for the EOP phenotype seen in our patients probably due to deficiencies in its phosphatase activity and consequent impairment of its synaptic functions. Our finding not only opens new avenues of investigation in the synaptic dysfunction mechanisms associated with Parkinsonism, but also suggests phosphoinositide metabolism as a novel therapeutic target for Parkinsonism.

Brain, blood, and iron: perspectives on the roles of erythrocytes and iron in neurodegeneration.

The terms "neuroacanthocytosis" (NA) and "neurodegeneration with brain iron accumulation" (NBIA) both refer to groups of genetically heterogeneous disorders, classified together due to similarities of their phenotypic or pathological findings. Even collectively, the disorders that comprise these sets are exceedingly rare and challenging to study. The NBIA disorders are defined by their appearance on brain magnetic resonance imaging, with iron deposition in the basal ganglia. Clinical features vary, but most include a movement disorder. New causative genes are being rapidly identified; however, the mechanisms by which mutations cause iron accumulation and neurodegeneration are not well understood. NA syndromes are also characterized by a progressive movement disorder, accompanied by cognitive and psychiatric features, resulting from mutations in a number of genes whose roles are also basically unknown. An overlapping feature of the two groups, NBIA and NA, is the occurrence of acanthocytes, spiky red cells with a poorly-understood membrane dysfunction. In this review we summarise recent developments in this field, specifically insights into cellular mechanisms and from animal models. Cell membrane research may shed light upon the significance of the erythrocyte abnormality, and upon possible connections between the two sets of disorders. Shared pathophysiologic mechanisms may lead to progress in the understanding of other types of neurodegeneration.

Update on the Non-Huntington's Disease Choreas with Comments on the Current Nomenclature.

CHOREA CAN BE CAUSED BY A MULTITUDE OF ETIOLOGIES: neurodegenerative, pharmacological, structural, metabolic, and others. In absence of other apparent causes, exclusion of Huntington's disease is often a first step in the diagnostic process. There are a number of neurodegenerative disorders whose genetic etiology has been identified in the past decade. Molecular diagnosis has enabled genetic identification of disorder subtypes which were previously grouped together, such as the neurodegeneration with brain iron accumulation disorders and the neuroacanthocytosis syndromes, as well as identification of phenotypic outliers for recognized disorders. Correct molecular diagnosis is essential for genetic counseling and, hopefully, ultimately genetic therapies. In addition, there has recently been recognition of other disorders which can mimic neurodegenerative disorders, including paraneoplastic and prion disorders. This article focuses upon recent developments in the field but is not intended to provide an exhaustive review of all causes of chorea, which is available elsewhere. I also discuss the nomenclature of these disorders which has become somewhat unwieldy, but may ultimately be refined by association with the causative gene.

Clinical and genetic analysis of 29 Brazilian patients with Huntington's disease-like phenotype / Análise clínica e genética em 29 pacientes Brasileiros com fenótipo doença de Huntington-símile

Huntington's disease (HD) is a neurodegenerative disorder characterized by chorea, behavioral disturbances and dementia, caused by a pathological expansion of the CAG trinucleotide in the HTT gene. Several patients have been recognized with the typical HD phenotype without the expected mutation. The objective of this study was to assess the occurrence of diseases such as Huntington's disease-like 2 (HDL2), spinocerebellar ataxia (SCA) 1, SCA2, SCA3, SCA7, dentatorubral-pallidoluysian atrophy (DRPLA) and chorea-acanthocytosis (ChAc) among 29 Brazilian patients with a HD-like phenotype. In the group analyzed, we found 3 patients with HDL2 and 2 patients with ChAc. The diagnosis was not reached in 79.3 percent of the patients. HDL2 was the main cause of the HD-like phenotype in the group analyzed, and is attributable to the African ancestry of this population. However, the etiology of the disease remains undetermined in the majority of the HD negative patients with HD-like phenotype.

A doença de Huntington (DH) é uma doença neurodegenerativa caracterizada por coréia, alterações comportamentais e demência, causada por uma expansão patológica do trinucleotídeo CAG no gene HTT. Vários pacientes têm sido descritos com o fenótipo típico para a DH porém sem a mutação esperada. O objetivo deste estudo foi avaliar a ocorrência de doenças como doença de Huntington-símile 2 (DHS-2), ataxias espinocerebelares tipo 1, 2, 3 e 17, atrofia dentatorubral-palidoluisiana e coreo-acantocitose (CAc) entre 29 pacientes brasileiros com fenótipo doença de Huntington-símile. No grupo analisado, encontramos 3 pacientes com DHS-2 e 2 pacientes com CAc. O diagnóstico permaneceu obscuro em 79,3 por cento dos pacientes. DHS-2 foi a principal causa do fenótipo DH-símile no grupo analisado, provavelmente devido a ancestralidade africana na população brasileira. Entretanto, a etiologia permaneceu indeterminada na maioria dos pacientes avaliados.

Insights into extensive deletions around the XK locus associated with McLeod phenotype and characterization of two novel cases.

The McLeod phenotype is derived from various forms of XK gene defects that result in the absence of XK protein, and is defined hematologically by the absence of Kx antigen, weakening of Kell system antigens, and red cell acanthocytosis. Individuals with the McLeod phenotype usually develop late-onset neuromuscular abnormalities known as the McLeod syndrome (MLS). MLS is an X-linked multi-system disorder caused by absence of XK alone, or when the disorder is caused by large deletions, it may be accompanied with Duchenne muscular dystrophy (DMD), chronic granulomatous disease (CYBB), retinitis pigmentosa (RPGR), and ornithine transcarbamylase deficiency (OTC). XK defects derived from a large deletion at the XK locus (Xp21.1) have not been characterized at the molecular level. In this study, the deletion breakpoints of two novel cases of McLeod phenotype with extensive deletions are reported. Case 1 has greater than 1.12 million base-pairs (mb) deletion around the XK locus with 7 genes affected. Case 2 has greater than 5.65 mb deletion from TCTE1L to DMD encompassing 20 genes. Phylogenetic analyses demonstrated that DMD, XK and CYBB have close paralogs, some of which may partially substitute for the functions of their counterparts. The loci around XK are highly conserved from fish to human; however, the disorders are probably specific to mammals, and may coincide with the translocation of the loci to the X chromosome after the speciation in birds. The non-synonymous to synonymous nucleotide substitution rate ratio (omega=dN/dS) in these genes was examined. CYBB and RPGR show evidence of positive selection, whereas DMD, XK and OTC are subject to selective constraint.

Neuroacanthocytosis: new developments in a neglected group of dementing disorders.

Neurological abnormalities associated with spiculated, "acanthocytic" red cells in blood have been summarized as neuroacanthocytosis. This is a heterogeneous group of conditions that can now be clearly subdivided on the basis of genetic discoveries. The core neuroacanthocytosis syndromes are autosomal recessive chorea-acanthocytosis (ChAc) and the X-linked McLeod syndrome (MLS). Huntington's disease-like 2 (HLD2) and pantothenate kinase associated neurodegeneration (PKAN) can now also be included. All of these share dyskinesias, cognitive deterioration and progressive neurodegeneration mainly of the basal ganglia, but they are sufficiently distinct to permit a specific working diagnosis on the basis of clinical, laboratory and imaging findings. In addition, the VPS13A (formerly called CHAC), XK, JPH3 and PANK2 genes, respectively, may be examined for mutations. Unfortunately, little is yet known about the normal and abnormal physiology of the protein products of these genes, but they appear to be involved in membrane function and intracellular protein sorting. Since no cures are yet available, development and study of disease models in experimental animals (mouse, C. elegans) is a priority for current research. From a clinical point of view, the common occurrence of cardiomyopathy in MLS, the transfusion hazards due to the McLeod Kell phenotype and the possibility of improving the violent trunk spasms and orofacial dyskinesias typical for ChAc (with subsequent lip or tongue mutilations and feeding dystonia) by deep brain surgery or stimulation should be considered in patient management.

Overexpression of torsinA in PC12 cells protects against toxicity.

Childhood-onset dystonia is an autosomal dominant movement disorder associated with a three base pair (GAG) deletion mutation in the DYT1 gene. This gene encodes a novel ATP-binding protein called torsinA, which in the central nervous system is expressed exclusively in neurons. Neither the function of torsinA nor its role in the pathophysiology of DYT1 dystonia is known. In order to better understand the cellular functions of torsinA, we established PC12 cell lines overexpressing wild-type or mutant torsinA and subjected them to various conditions deleterious to cell survival. Treatment of control PC12 cells with an inhibitor of proteasomal activity, an oxidizing agent, or trophic withdrawal, resulted in cell death, whereas PC12 cells that overexpressed torsinA were significantly protected against each of these treatments. Overexpression of mutant torsinA failed to protect cells against trophic withdrawal. These results suggest that torsinA may play a protective role in neurons against a variety of cellular insults.

Levodopa is toxic to dopamine neurons in an in vitro but not an in vivo model of oxidative stress.

Levodopa is the "gold standard" for the symptomatic treatment of Parkinson's disease (PD). There is a theoretical concern, however, that levodopa might accelerate the rate of nigral degeneration, because it undergoes oxidative metabolism and is toxic to cultured dopaminergic neurons. Most in vivo studies do not show evidence of levodopa toxicity; levodopa is not toxic to normal rodents, nonhuman primates, or humans and is not toxic to dopamine neurons in dopamine-lesioned rodents or nonhuman primates in most studies. However, the potential for levodopa to be toxic in vivo has not been tested under conditions of oxidative stress such as exist in PD. To assess whether levodopa is toxic under these circumstances, we have examined the effects of levodopa on dopamine neurons in mesencephalic cultures and rat pups in which glutathione synthesis has been inhibited by L-buthionine sulfoximine. Levodopa toxicity to cultured dopaminergic neurons was enhanced by glutathione depletion and diminished by antioxidants. In contrast, treatment of neonatal rats with levodopa, administered either alone or in combination with glutathione depletion, did not cause damage to the dopamine neurons of the substantia nigra or changes in striatal levels of dopamine and its metabolites. This study provides further evidence to support the notion that although levodopa can be toxic to dopamine neurons in vitro, it is not likely to be toxic to dopamine neurons in vivo and specifically in conditions such as PD.