Primers on Dystonia

Primers on Dystonia

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Where can I get a good biochemical overview of dystonia? I will be working in a research lab that focuses on dystonia and I would like to not be clueless.

A good article on the pathophsiology is,

The pathophysiological basis of dystonias, Nature Reviews Neuroscience 9, 222-234 (March 2008)

For a review of the treatment,

Treatment of dystonia, lancet neurology, Volume 5, Issue 10, October 2006, Pages 864-872.

A comprehensive textbook on movement disorders in general is The oxford textbook of movement disorders


Dystonia is characterized by involuntary muscle contractions. Its many forms are genetically, phenotypically and etiologically diverse and it is unknown whether their pathogenesis converges on shared pathways. Mutations in THAP1 [THAP (Thanatos-associated protein) domain containing, apoptosis associated protein 1], a ubiquitously expressed transcription factor with DNA binding and protein-interaction domains, cause dystonia, DYT6. There is a unique, neuronal 50-kDa Thap1-like immunoreactive species, and Thap1 levels are auto-regulated on the mRNA level. However, THAP1 downstream targets in neurons, and the mechanism via which it causes dystonia are largely unknown. We used RNA-Seq to assay the in vivo effect of a heterozygote Thap1 C54Y or ΔExon2 allele on the gene transcription signatures in neonatal mouse striatum and cerebellum. Enriched pathways and gene ontology terms include eIF2α Signaling, Mitochondrial Dysfunction, Neuron Projection Development, Axonal Guidance Signaling, and Synaptic LongTerm Depression, which are dysregulated in a genotype and tissue-dependent manner. Electrophysiological and neurite outgrowth assays were consistent with those enrichments, and the plasticity defects were partially corrected by salubrinal. Notably, several of these pathways were recently implicated in other forms of inherited dystonia, including DYT1. We conclude that dysfunction of these pathways may represent a point of convergence in the pathophysiology of several forms of inherited dystonia.

Biological basis

• Dystonia is thought to be caused by dopamine dysregulation, loss of inhibition, abnormal neuroplasticity, and abnormal sensory processing.

• Classically thought of as a basal ganglia disorder, dystonia is now thought to be dysfunction of a larger network, including the basal ganglia, thalamus, brainstem, cerebellum, and cortex.

• There is an ever-growing list of genetic causes of dystonia many genetic causes feature other coexistent movement disorders in their phenotype.

Etiology and pathogenesis

Isolated dystonia is most commonly caused by an autosomal dominant gene mutation ( 11 ). With the development of new sequencing technologies, there is acceleration in the discovery of genes contributing to isolated dystonia ( 23 80 10 11 ). The underlying pathogenesis of dystonia has been proposed to include loss of inhibition, disruption of sensory processing, and abnormal neuroplasticity. Classically associated with dysfunction of the basal ganglia, accumulating evidence suggests a complex network including the cerebellum, brainstem, basal ganglia, thalamus, and sensorimotor cortices.

Genetics. The first gene identified for isolated dystonia was DYT1 associated with early-onset isolated dystonia in Ashkenazi Jewish families, and in 1 large non-Jewish family. This gene has been mapped to chromosome 9q32-34 ( 107 ). The gene is inherited in an autosomal dominant fashion with a penetrance of 30% to 40%. The estimated range of prevalence of the most common pathogenic variant that causes DYT1 is approximately 17.6 to 26.1 carriers per 100,000 individuals ( 110 ).

There is genetic heterogeneity, but linkage analysis indicated the existence of a locus for idiopathic torsion dystonia at 9q34 in both Jewish and non-Jewish kindreds ( 150 ). In patients without a family history of dystonia, the frequency of detecting a DYT1 gene mutation is less than 5% ( 17 ) and 6% ( 85 ), respectively. DYT1 dystonia is the most common cause of early-onset isolated dystonia and is more common in the Ashkenazi Jewish population due to a founder mutation ( 122 ). Subjects with the DYT1 gene mutation typically present with childhood-onset dystonia that begins in a limb and generalizes, but phenotypic expression can vary from asymptomatic to focal, segmental, multifocal, and generalized dystonia with childhood or late adult-onset ( 102 ).

DYT1 mutations have been observed in several ethnic groups. A review of the published literature of the clinical studies of DYT1 dystonia described the phenotype in 3 groups: Ashkenazi Jewish, non-Jewish Western, and Asian (Lee at al 2012). The Asian patients were differentiated from Western patients by more frequent axial onset, more common segmental dystonia, and no cranial involvement at onset. Non-Jewish Western patients had more frequent leg involvement at onset compared to other ethnic groups.

The DYT1 gene encodes a 332-amino acid protein called torsinA ( 105 44 ). There is a glycosaminoglycan deletion at position 946, which encodes for glutamic acid ( 69 ), and deletion of a glutamate residue from this protein is considered to be responsible for this form of dystonia ( 06 ). TorsinA is widely expressed in the human central nervous system ( 70 ) and is closely related to the heat shock protein family ( 106 ). Torsins belong to the AAA+ superfamily of adenosine triphosphatases. TorsinA is found in the endoplasmic reticulum and nuclear envelope, and it is related to membrane trafficking, lipid metabolism, and quality control and folding of proteins ( 43 ). Additionally, torsinA interacts with SNARE complex and interferes with vesicle docking and fusion ( 22 ).

The second gene identified in isolated dystonia, DYT6, has been mapped to chromosome 8p21-q22 in Amish-Mennonites with focal onset in the cranial, cervical, or upper limb muscles ( 126 ). DYT6 involves mutations in THAP1, encoding for a nuclear pro-apoptotic protein, which is also involved in transcriptional regulation ( 39 ). Patients with this mutation predominantly present with craniocervical and laryngeal dystonia and may have generalized dystonia ( 47 ). In a review of 130 patients with THAP1 mutations, the onset of the dystonia tended to be in the 20s and 30s, affecting arm and neck ( 74 ). Progression to generalized dystonia happened in 43.1% of the patients.

Combined linkage and whole-exome sequencing of a large Caucasian pedigree from the United States with adult-onset primary cervical dystonia identified an exonic splicing enhancer mutation in exon 7 of CIZ1 on chromosome 9q34.11 ( 153 ). CIZ1 encodes Cip1-interacting zinc finger protein 1, a DNA replication factor. CIZ1 has been identified as DYT23. However, subsequent studies did not identify additional causative mutation ( 81 ).

Mutations in the gene ANO3 have been identified in a moderately sized UK kindred with autosomal dominant craniocervical dystonia ( 24 ). Another study of 10 patients from 3 families demonstrated a variable age at onset ranging from childhood to the forties ( 134 ). The most common site of onset was cranial dystonia, followed by spasmodic dysphonia. All carriers had tremor of the arms, and 2 patients had myoclonus. A family from Flemish origin had blepharospasm, cervical dystonia, and tremor compatible with essential tremor ( 91 ). ANO3 codes for a Ca2+-gated chloride channel located in the striatum. Mutations in ANO3 have been designated as the DYT24 locus.

Exome sequencing in 2 families with isolated dystonia identified a causative gene, GNAL, located on chromosome 18p ( 40 ). Further screening in 39 families identified 6 additional mutations in GNAL. All carriers were Caucasian of mixed European ancestry. The average age at onset was 31.1 years, with 82% of cases having cervical onset and most progressing to other sites, especially cranial and speech involvement. Arm involvement was only seen in 32% of cases, distinguishing this phenotype from that of THAP1. GNAL mutations have been identified in other populations, including an African-American pedigree ( 144 ), and a pathogenic mutation in a Japanese patient ( 72 ). GNAL encodes guanine nucleotide-binding protein subunit alpha [Ga(olf)], which is expressed in the striatum and cerebellar Purkinje cells and is involved in D1 receptor functioning. Mutations in GNAL have been designated as the DYT25 locus.

Mutations in TUBB4 (tubulin beta-4) have been found to be associated with familial autosomal dominant spasmodic dysphonia, so-called “whispering dysphonia” designated as DYT4 ( 52 83 ). The phenotype is characterized by spasmodic dysphonia, lower facial atrophy, thin body habitus, and a dystonic “hobby horse” gait. Isolated limb dystonia can be the initial presentation of Parkin-related disease ( 31 ). In the retrospective analysis of a cohort with 44 patients with Parkin mutation, 8 patients presented initially with dystonia in the lower extremity, which preceded the onset of parkinsonism by 5.0 ±6.4 years (range 1-16).

Mutations in COL6A3 (collagen type VI, alpha-3 chain), already known to cause Ulrich congenital myopathy and Bethlem myopathy, have also been described to cause young-onset isolated dystonia in an autosomal recessive pattern now designated DYT27 ( 67 ). Long known to have a role in the extracellular matrix that is widely expressed throughout the body, the molecular roles of collagens in the CNS are not limited to structural adhesion activities but comprise a wide range of cellular processes, including neural circuit formation and maintenance ( 55 ). It was originally described in 5 cases of 3 German families as isolated dystonia that would begin in childhood or early adulthood, initially involve the neck or the hand as writer’s cramp, and slowly progress to segmental or generalized dystonia with relatively preserved lower limb function ( 67 ). All 5 cases in the original cohort were found to have mutations near the C-terminal tail, particularly in exon 41, whereas mutations leading to myopathies were clustered in the N-terminal and triple-helical segments ( 156 ). One case of dystonia associated with COL6A3 described mutations in exons 10 and 11 ( 108 ). This is a rare cause of isolated dystonia, with only 7 cases published as of 2020 ( 82 108 ).

Haploinsufficiency of KMT2B (lysine methyltransferase 2B) has been described as a common cause of young-onset dystonia and is now designated as DYT28 ( 155 ). The clinical phenotype is similar to TOR1A dystonia (DYT1) onset is typically in the first decade of life, and symptoms begin in the lower limbs and then generalize. In addition to this, about half of KMT2B patients have intellectual disability and often express abnormal facial features such as an elongated face and bulbous nose ( 157 ). Lysine-specific methyltransferase 2B plays a role in epigenetic regulation and is highly expressed in areas in the brain responsible for movement, such as the cerebellum ( 90 ). Dosage reduction of KMT2B in mouse neurons leads to impaired transcription of genes known to be implicated in dystonia ( 68 ). Most mutations in KMT2B are de novo only 3 cases of clear autosomal dominant transition have been described as of 2019 ( 157 ). The prevalence of KMT2B dystonia is estimated to be between 10% to 20% of young-onset dystonia cases. Genetic testing for KMT2B is recommended if initial testing for TOR1A is negative ( 157 ).

Dopa-responsive dystonia is 1 of the dystonia-plus syndromes, characterized by dystonia and parkinsonism ( 130 ). This condition is characterized by onset in the first decade of life, initially affecting the legs, causing difficulty walking. Symptoms have diurnal fluctuation with marked improvement with levodopa. The most common cause of dopa-responsive dystonia is an autosomal dominant inherited mutation of guanosine triphosphate cyclohydrolase 1 ( 57 ). This disorder is discussed in further detail separately (see Dopa-responsive dystonia).

X-linked dystonia parkinsonism, also known as DYT3 or “Lubag” is an adult-onset progressive disorder characterized by dystonia and parkinsonism that was first described in 1975 in Filipino men from the Panay islands ( 75 ). This disorder classically presents at around age 40 with focal dystonia, most commonly in the legs or oromandibular region, and subsequently generalizes. Parkinsonism typically presents later with rest tremor, bradykinesia, and shuffling gait and is the predominant symptom after 10 years of disease ( 76 ). X-linked dystonia parkinsonism has been associated with 2 genes, the DYT3 gene and TAF1 (TATA binding protein-associated factor-1) ( 123 ) .There is no male-to-male transmission, and women are mostly carriers, although a few affected females have been described ( 76 ).

Myoclonus-dystonia is characterized by myoclonic jerks and dystonia and can be inherited in an autosomal dominant fashion. The disorder presents in childhood, with an earlier onset in girls than in boys. Classically, the predominant phenomenology is myoclonus of the trunk and arms that is alcohol-responsive. Dystonia is relatively mild and may present as cervical dystonia or writer’s cramp. Psychiatric disorders have been described including depression, anxiety, and obsessive-compulsive disorder. A report of genetically confirmed myoclonus-dystonia patients found 3 patterns of motor symptoms early childhood-onset upper body myoclonus and dystonia, early childhood-onset lower limb dystonia progressing to more pronounced myoclonus and upper limb involvement, and later childhood-onset with upper body myoclonus and dystonia with cervical involvement ( 112 ). Mutations in the gene for epsilon-sarcoglycan have been associated with myoclonus dystonia ( 158 ) and have been designated as DYT11.

Dystonia may be associated with parkinsonism in the syndrome “rapid-onset dystonia-parkinsonism,” designated as DYT12 ( 16 ). This autosomal dominant disorder is characterized by rapid development of focal, segmental, or unilateral dystonia, often over a period of hours or days, involving primarily the cranial structures and upper limbs in a rostrocaudal progression. It is often associated with bulbar symptoms (particularly dysarthria and dysphagia), bradykinesia, postural instability, other parkinsonian features, depression, social phobias, and seizures. The progression is relatively slow, and some patients stabilize over period of months or year and may have a “second onset” with abrupt worsening. Rapid-onset dystonia-parkinsonism has been found to be caused by mutations in the Na+/K+ -ATPase alpha3 gene ATP1A3 on 19q13 ( 16 ) and has been designated as DYT12. Another gene, PRKRA, called DYT16, was identified in a family with autosomal pattern of dystonia with parkinsonism ( 117 ). The phenotype included early-onset generalized dystonia with laryngeal dystonia, oromandibular dystonia, dysphagia, and retrocollis. Parkinsonism does not improve with levodopa.

In 2020, an analysis of all known monogenic genes causing idiopathic dystonia and all known mutations identified as risk variants for neuropsychiatric symptoms, such as anxiety, depression, obsessive-compulsive disorder, and schizophrenia, has suggested that these 2 processes share underlying dysfunction in molecular pathways and may be why neuropsychiatric symptoms are seen so often in dystonia patients ( 89 ).

The identification of genes is crucial for future targeted therapies. However, given the variability in the phenotypes, it can be challenging to test gene-by-gene. Whole exome sequencing seems to be a promising tool to be used. In a study of 16 families with early-onset generalized dystonia patients, whole exome sequencing identified known pathogenic genes in 37.5% of families ( 154 ).

Functional anatomy of basal ganglia. Although dystonia can arise from many areas of the brain, abnormalities in the basal ganglia have been identified in most cases (Feiwall et al 1999 114 ). The basal ganglia include striatum (caudate, putamen, nucleus accumbens, and olfactory tubercle), globus pallidus (interna, externa, and ventral pallidum), subthalamic nucleus, and substantia nigra (substantia nigra pars compacta and pars reticulate). Most of the input to the basal ganglia is received by the striatum from the cortex whereas GPi and SNpr are the main output nuclei of the basal ganglia. The output is inhibitory on to thalamus. The thalamus then projects on the cortex in an excitatory fashion. There is topographical organization in the basal ganglia, meaning that parts of GPi, for instance, affect specific muscles, much like a homunculus.

The basal ganglia has traditionally been considered to have a direct (cortex -> striatum -> GPi/SNr -> thalamus), indirect (cortex -> striatum -> GPe -> GPi/SNr -> thalamus and also cortex -> striatum -> GPe -> STN -> GPi/SNr -> thalamus), and hyperdirect (cortex -> STN -> GPi/SNr -> thalamus) pathways.

Substantia nigra pars compacta plays a modulatory role in the basal ganglia circuitry by providing dopamine influences on the striatum. There are D1- and D2-like receptors. The D1-like receptors facilitate the striatal output to GPi/SNpr (the direct pathway), whereas the D2-like receptors inhibit the striatal output to GPe (the indirect pathway).

The functional interplay between the basal ganglia pathways can be studied by considering the following points ( 92 ).

1. There is a tonically active basal ganglia output that is inhibitory to the thalamus and then to the motor pattern generators. This acts like a parking brake in a stationary car.

2. The hyperdirect pathway receives input primarily from the frontal lobe, whereas the direct pathway receives input from wide areas of the cortex.

3. The hyperdirect pathway is faster acting, whereas the direct pathway is slower.

4. The hyperdirect pathway is divergent, whereas the direct pathway is convergent. Divergence of the hyperdirect pathway means that the output from the subthalamic nucleus spreads to the areas of GPi/SNr that influence almost all of the body. Conversely, the output from the striatum on to the GPi/STN is more focused and, hence, convergent.

5. The hyperdirect pathway is weaker, whereas the direct pathway is stronger.

Assuming these points, one can imagine how a movement is initiated by the cortex by activating select (groups of) muscles as well as how the basal ganglia limit its spread to unwanted muscles.

When the cortex wants to initiate a movement, the frontal lobe, via the fast hyperdirect pathway, first provides a widespread excitation of the GPi/SNpr, which inhibits the thalamus/cortex and, thus, provides widespread inhibition. Shortly thereafter, the direct pathway (which is slower but more convergent and more powerful than the hyperdirect pathway) provides inhibition to a focused area of GPi/SNpr, which then releases its inhibitory effect on the thalamus (like releasing the brakes) and facilitates movement. The indirect pathway, which is slower, provides a more widespread inhibition and further focusing of the movement.

Primers on Dystonia - Biology

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A novel mutation in SLC39A14 causing hypermanganesemia associated with infantile onset dystonia

Mohammed Faruq, Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Mall Road, New Delhi, 110007 India.

Department of Pediatrics, Maulana Azad Medical College, New Delhi, India

Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India

Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India

Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India

Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India

Child Development Centre, Department of Paediatrics Maulana Azad Medical College, New Delhi, India

Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India

Department of Radiodiagnosis, Maulana Azad Medical College, New Delhi, India

Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, New Delhi, India

Mohammed Faruq, Genomics and Molecular Medicine, CSIR-Institute of Genomics and Integrative Biology, Mall Road, New Delhi, 110007 India.



Mutations in SLC39A14 cause a recessive disorder of manganese (Mn) metabolism that manifests as childhood onset progressive neurodegeneration characterized by parkinsonism and dystonia.


The present study genetically investigated a case of hypermanganesemia. We describe a family where an affected child with a history of progressive neurodegeneration showed symptoms of dystonia with increased levels of blood Mn and altered signal intensities in globus pallidus and dentate nucleus. Whole exome sequencing was conducted to genetically investigate the pathology in the child, which allowed us to identify a novel homozygous causal mutation in SLC39A14.


Insilico modeling of the novel homozygous causal mutation in SLC39A14 predicted that it was deleterious, affecting Mn binding and transportation of metal by transmembrane instability of the protein structure. The clinical features of other reported mutations in SLC39A14 were also reviewed and the clinical spectrum in our case conforms to the described neurological abnormalities.


We conclude that the mutation identified in SLC39A14 in our case is a novel variation linked to recessive disorders of hypermaganesemia and dystonia.


We demonstrated that BTBR mice exhibited severe infancy-onset dystonia-like behaviors with significant impairments in motor coordination and motor learning, which were also observed in patients with ASD. These motor dysfunctions were highly linked to the abnormal development of the cerebellum. The emerging of dystonia-like behavior in BTBR mice coincided with an increasing proliferation of GCPs, which gave rise to enlargement of the EGL in cerebella and enhanced foliation. Besides, Purkinje neurons in BTBR mice were found to have somatic hypotrophy, with increased dendritic spine formation but suppressed spine maturation. TRPC was suggested to be responsible for the impaired neurodevelopment and further motor dysfunction. Our observations demonstrated that disturbed cerebellar neurogenesis occurred during the comorbidities of ASD and movement disorders, and attention should be paid to the key role played by TRPC protein family for further study and future approaches of therapy.

Motor dysfunction represents a heterogeneous array of non-diagnostic symptoms in ASD. In this study, we identified dystonia-like behavior, such as hyperflexion, clasping and twisting, eliciting by tail suspension in BTBR mice. The abnormal hindlimb clasping or twisting in BTBR mice also caused a defect to hang from a wire grid. Additionally, impaired fine motor skills in ASD patients are highly linked with social symptomatology (LeBarton and Iverson, 2013). In agreement with these findings, we report here that BTBR mice exhibited skilled walking pattern deficits using the regularly and irregularly spaced horizontal ladder test. The rotarod task is often regarded as a test of cerebellar coordination and motor ability. WT mice showed better performance on the rotarod task across the consecutive learning test, while BTBR mice exhibited slower learning which might due to the inattention.

Postmortem and functional imaging studies widely identified the cerebellum as one of the most important brain regions associated with motor deficits in ASD patients (Wang et al., 2014 Hampson and Blatt, 2015). The onset of motor deficits in BTBR mice coincided with the critical period of cerebellar development, suggesting abnormalities in the cerebellum as the neural substrate of motor impairments. Haijie Yang reported an increase in cerebellar foliation and larger gross brain volume of BTBR mice (Yang et al., 2015). In agreement with this finding, we found that increased cerebellar size and IGL area were obvious compared to the WT mice, with microscopic enhanced foliation. The phenotype was meaningful, for that folia in the cerebellum serve as a broad platform for organizing cerebellar circuits and be critical in sensory-motor tasks (Sudarov and Joyner, 2007). Welker suggested it as the fundamental unit of sensorimotor integration (Welker, 1990), and disturbed foliation was involved in defects of motor coordination (Le Roy-Duflos, 2001 Chen et al., 2005). Inward accumulation of proliferated GCPs is a pivotal driving force in the cerebellar foliation, and the existing mouse model of disturbed foliation demonstrated an aberrant proliferation of GCPs (Corrales et al., 2006 Wefers et al., 2017). The present study detected increased GCP proliferation and IGL expansion in the BTBR mouse cerebellum. Impaired radial migration was also observed in rodents with increased foliation (Hosaka et al., 2012 Ryan et al., 2017), and a dramatic increase in foliation was credited with a prolonged period of migration of GCPs in human cerebella (Sillitoe and Joyner, 2007). However, Bergmann glia guided migration was not altered in BTBR mice from early postnatal days to adulthood. Thus, the extra lobes of cerebella in BTBR mice are likely arose from over-produced GCPs.

Other reports suggest that PCs also participate in cerebellar foliation (Altman, 1997 Sudarov and Joyner, 2007). PCs anchor the outline of the cortex via axonal projections to the underlying WM at positions that define the base of the fissures. Cerebella of BTBR mouse displayed hypotrophic Purkinje neurons at an early developmental period. The abnormal development of granule cells could ultimately regulate the growth of PCs (Salinas et al., 1994 Shimada et al., 1998 Sadakata et al., 2004), and we inferred that the disrupted patterning of Purkinje cells may be secondary to abnormal GC development. We cannot ignore the fact that PCs are the sole efferent neurons in cerebellum which connect to the outer brain and participate in more complicated neural activity. Abnormal PC development determined the dysfunction of cerebella. Parallel fibers extended by granule neurons in the EGL traveled up and stretched to both sides, being parallel to the pial surface in the ML to connect the Purkinje dendrite. Considering the multiplying granule neurons and invariable even decreased PCs, superabundant incoming of information to an individual PC was predictable. Moreover, the synaptic structure identified by dendritic spines in Purkinje neurons was significantly affected because much more spines existed in a lower matured proportion. Synapses were likely overproduced, but the maturation was suppressed. Immature spines commonly aid in the initiation of synaptic contact (Dunaevsky et al., 1999), and mature spines containing an abundance of neurotransmitter receptors are truly to support synaptic activity (Matsuzaki et al., 2001 Nimchinsky et al., 2002). Abnormal spine formation and maturation would impact the neural circuit and disturb the allomeric function of the brain. Additionally, increasing afferent signal to PCs would inevitably break the physiological balance in transduction, which indicates the critical role played by disturbed information transfer in cerebellar dysfunction.

TRPC is a non-selective cation channel that dominantly modulates the Ca 2+ entry pathway and the release of intracellular Ca 2+ (Dietrich and Gudermann, 2007). TRPC3, 4 and 6 belong to the TRPC protein family are particularly expressed in cerebella during the first 6 weeks after birth, at the critical neurogenesis period of the cerebellum, to regulate cerebellar development (Huang et al., 2007).TRPC3 expression reflects development of the Purkinje cells and TRPC4 expression is restricted to granule neurons and their precursor. TRPC6 plays an essential role in G2/M phase transition (Shi et al., 2009), and inhibition or activation of TRPC6 expression suppresses or accelerates cell growth (Cai et al., 2009 Shi et al., 2009), respectively. Moreover, TRPC6 participates in the development of dendritic spines and regulates the formation of excitatory synapses in the hippocampus (Zhou et al., 2008), and inhibition of TRPC6 reduces dendritic arborization and spine density (Tai et al., 2008). The results of RNA-seq analysis indicated that TRPC family might be an important regulator involved in the abnormality of cerebellar development of BTBR mice. Moreover, other studies suggest the relationship between TRPC and ASD. Wei Li found that TRPC signaling was impaired in hippocampal neurons of Mecp2 mutant mice, another ASD mouse model, which led to activity-dependent BDNF release disturbances that further accounted for sensory and motor abnormalities (Li et al., 2012). Later, Griesi-Oliveira K demonstrated a reduction or haploinsufficiency of the TRPC6 gene in ASD individuals, which led to impaired neuronal development, morphology, and function (Griesi-Oliveira et al., 2015). These findings imply TRPC genes could be novel predisposing genes for ASD to elucidate the underlying pathophysiology mechanism.

Future developments

High-throughput sequencing, with its rapidly decreasing costs and increasing applications, is replacing many other research technologies. For example, gene expression studies are slowly moving from expression array technologies to RNA sequencing for the higher resolution, lower biases and ability to discover novel transcripts and mutations. With the availability of deeply sequenced RNA-seq data sets and high-resolution variation information, it has been possible to delineate allele-specific binding of transcription factors and allele-specific binding based on the maternal- versus paternal-derived alleles ( Rozowsky et al, 2011 ). As more personal genomes become available, the functional elements can be mapped specifically to the individual's own genetic information. Cytogenetics is being replaced by paired-end sequencing to identify genomic rearrangements and copy number variants at a much higher resolution and throughput.

Nonetheless, significant challenges remain with NGS. These include data processing and storage. In 5 years’ time, we are likely to have sequenced more than a million human genomes. Where and how these data will be stored will be a big problem. Another significant challenge is genome interpretation. This includes not only the analysis of genomes for functional elements but the understanding of the significance of variants in individual genomes on human phenotypes and disease. All these add to the still-impractical costs of vast sequencing applications in the clinic. Although sequencing costs have dipped tremendously in recent years, further decrease in costs have to occur before more ambitious applications, such as whole-genome sequencing and longitudinal monitoring, can have a chance in the clinic.

Cost–benefit analyses of sequencing applications in the clinic have to be conducted before actual medical application. Comparison with currently available techniques needs to be done, and a decision made to whether such screens should be made routine or only under exceptional cases. The benefits of sequencing applications in the medical clinic definitely look promising, but much remains to be done in ironing out minute details to make it practical and applicable.

With many people's genomes sequenced, security also becomes an important factor. How will these information be stored, and who will have access to them? Will the individuals know every detail of their genome, or only those pertinent to disease diagnosis or treatment? How can we prevent the possible emergence of ‘genetic discrimination’? Ethical issues will definitely emerge with the commonalization of personal genomes, and these issues need to be resolved before we arrive there.

Our current knowledge and understanding of the human genome still lies largely in the coding regions of the genome. SNPs and SVs that are discovered in non-coding regions are generally dismissed as ‘less important’ and ‘not causal’. Although this approach allows us to prioritize and focus resources on the more probable damaging mutations, the effects of non-coding regions in regulation and human disease are becoming more evident. Based on the wealth of non-genic functional regulatory regions obtained from the ENCODE project, RegulomeDB has been developed as a resource for integrating and cross-validating polymorphisms to the regulatory regions ( Boyle et al, 2012 ). Disease-associated SNPs obtained from GWAS studies might point to gene deserts, but could essentially lie in regulatory sites of downstream genes. Often, the SNP that is in linkage disequilibrium with the reported SNP might be more informative ( Boyle et al, 2012 ). It is necessary, in the future, to develop ways to map sequencing data onto currently difficult-to-map regions, such as highly repetitive and low-expressed regions. Sequencing technology is rapidly improving, but the analytical capabilities to understand everything that is being generated by the sequencers is lagging far behind. We need to advance the computational technologies as we progress towards the systemic use of high-throughput sequencing in research and medicine.

Botulinum Toxin for Treatment of Dystonia, Sialorrhea (Drooling), and Tremor in Parkinson’s

Introduction: I have a new friend with Parkinson’s. He has always been very active and genuinely enjoys playing golf. However, he has a hard time controlling dystonia, which has hindered much of his daily exercise. This got me thinking, and it leads me to the topic of this blog post. The goal is to describe how botulinum toxin works, allowing someone with Parkinson’s and bothersome dystonia some regular relief. Botulinum toxin is also used to treat excessive drooling (sialorrhea) and even the Parkinson’s tremor in some clinical studies.

“If you want to live a happy life, tie it to a goal, not to people or objects.” Albert Einstein

A Primer on Botulinum Toxin: Botulinum toxin, abbreviated as BTX or BoNT, is derived from the anaerobic bacteria, Clostridium botulinum. Anaerobic? This refers to an organism that is capable of living and existing in the absence of free oxygen. Humans are aerobic organisms we definitely need oxygen to survive. There are seven neurotoxins from BTX, designated A, B, C (C1, C2), D, E, F, and G. The most widely used BTX is Botox® (OnabotulinumtoxinA).The BTX substance is a protease, a protein that cleaves or chews-up other proteins. BTX is a two-chain (heavy and light) zinc-containing metalloprotease. The heavy chain gives the cholinergic specificity (help direct binding to presynaptic receptors), the light chain has the proteolytic activity.

BTX mode of action is binding presynaptically to high-affinity sites on nerve terminals, which ultimately stops the release of acetylcholine, causing paralysis of the neuromuscular effect. The mechanism that has been worked out for BTX is as follows: (i) the light chain BTX recognizes and cleaves SNARE proteins (SNAP-25, Syntaxin, Synaptobevin), (ii) typically, these SNARE proteins form a complex with neurotransmitters and are contained in vesicles, (iii) cleaved SNARE proteins do not complex with acetylcholine (iv) the fusion of membranes does not occur (v) acetylcholine is not released into the muscle cell thus, paralyzing the cell. (vi) Over time, the neuromuscular junction regenerates as the activity (life-time) of BTX diminishes. The drawing below explains the process of how BTX works.

“Success is not the key to happiness. Happiness is the key to success. If you love what you are doing, you will be successful.” Albert Schweitzer

Therapeutic Uses and Cosmetic Purposes for BTX:Keeping in mind that BTX is one of the most poisonous biological substances known, it has found wide use in both the medical world and in the setting of cosmetic treatment. By blocking the release of acetylcholine in the neuromuscular junction, BTX causes temporary paralysis of the muscle. Depending on where the BTX has been injected, this temporary paralysis can last 3-6 months. BTX injection has been used for treating several medical conditions, including: strabismus (abnormal alignment of the eyes such as someone with squinting eyes), focal dystonias (involuntary spasms in small muscles in the body), hemifacial spasm [frequent involuntary contractions (spasms) of the muscles on one side (Hemi-) of the face (facial)], migraine headaches, hypersalivation, and hyperhidrosis (abnormally excessive sweating). This is but a brief list of some of the various conditions treated with BTX. In the world of cosmetics, BTX has found a lot of use in reducing facial wrinkles, lines, and creases.

The FDA in the USA has approved the following BTX products and for the following uses (derived and compiled from “Manufacture of Commercial Botulinum Neurotoxins for Human Treatment” by E.A. Johnson and neuromuscular-blockers-botulinum-toxins from Medscape):
OnabotulinumtoxinA (Botox®, Botox Cosmetic®),
Botox® – Cervical dystonia, severe primary axillary hyperhidrosis, strabismus, blepharospasm, neurogenic detrusor overactivity, chronic migraine, upper limb spasticity
Botox Cosmetic® – Moderate to severe glabellar lines, moderate to severe lateral canthal lines, known as crow’s feet
AbobotulinumtoxinA (Dysport®) – Upper and lower limb spasticity, cervical dystonia, and moderate-to-severe glabellar lines in adults it is also indicated for lower limb spasticity in children aged 2 years or older
IncobotulinumtoxinA (Xeomin®) – Upper limb spasticity, cervical dystonia, blepharospasm, moderate to severe glabellar lines, chronic sialorrhea
-PrabotulinumtoxinA (Jeuveau®) – Moderate-to-severe glabellar lines
-RimabotulinumtoxinB (Myobloc®) – Cervical dystonia

Given at the end of the post are some references/literature for anyone interested in the original study/review.

“The happiness of your life depends upon the quality of your thoughts.” Marcus Aurelius

BTX for Treating Dystonia in Parkinson’s:Dystonia is an abnormal muscle tone that leads to muscular spasm and abnormal posture. Dystonia usually occurs due to either neurological disease or a side effect of drug therapy. Carbidopa/Levodopa treatment can have a variable response to dystonia, improving it, or making it worse in some people-with-Parkinson’s (PwP).

Dystonia on its own is a movement disorder, and it occupies the number three slot in terms of the number of cases of movement disorders. Dystonia is a frequent component of Parkinson’s. It is estimated that between 50-60% of PwP have some first-hand experience with dystonia.

BTX has been shown in several clinical studies to improve painful foot dystonia. Typically, BTX was injected into two muscles based on the resulting shape of the toes/foot. However, other studies were met with less success. One can imagine this variable-type of response is due to the location of the affected muscle(s) in hand or foot and the precise anatomic location chosen for injection of the BTX into the muscle. The figure below highlights some of the aspects of dystonia in Parkinson’s and many possible muscles available for injecting and directing the BTX to remove the affected muscle’s pain and frustration.

“The most important thing is to enjoy your life – to be happy – it’s all that matters.” Audrey Hepburn

BTX for Treating Sialorrhea (Drooling) in Parkinson’s: Drooling or excess saliva is commonly found in Parkinson’s. It is thought that the PwP with sialorrhea does not have increased production of saliva, but it is due to a dysfunction of salivary function or clearance (e.g., one does not swallow enough to clear out the saliva). Reducing the amount of saliva produced by temporarily halting its release from the salivary gland by BTX treatment could provide relief from the ‘burden’ of getting rid of excess. Drooling in Parkinson’s is quite common, occurring >70% in PwP.

There have been several clinical trials done with BTX to control drooling in PwP, and they have all met with some success (when compared to controls). Evidently, most studies have focused on the parotid gland to target neuromuscular junctions with BTX to temporarily paralyze these muscles to reduce the overall burden for saliva. Given below in the figure are examples of anatomic components in the mouth that are likely targets for BTX treatment to control sialorrhea in Parkinson’s.

“Happiness is not a goal it is a by-product.” Eleanor Roosevelt

BTX for Treating Tremor in Parkinson’s: The Parkinson’s tremor is one of the disorder’s “Cardinal features”, but not everyone has this tremor. The Parkinson’s tremor in some PwP can be well-controlled with Carbidopa/Levodopa, but it does not work nearly as well in others. Thus, it’s more of a nuisance for most people, but with time people will explore deep brain stimulation surgery, for example, the potential use of BTX.

There have been many different clinical trials using BTX to safely treat the hand tremor in Parkinson’s. Typically, based on the numbers of patients, this is merged with others with essential tremor. In one of the earlier studies from 1991, using 51 patients, injecting BTX into the forearm extensor and flexor muscles. The study showed some improvement in the tremor group compared to controls. The only negative result noted was occasional focal muscle weakness.

In a different clinical study to evaluate BTX and Parkinson’s tremor, the BTX injection was guided using electromyographic (EMG) technology to optimize the toxin’s effect on muscle. In trying to summarize the results published, it would appear that BTX in tremor is much more complicated to achieving success due to a large number of muscle injection sites that are typically required. By contrast, the fewer muscles involved in dystonia have shown that BTX has been much more successful. Shown below are the numerous muscles in the forearm and hand, which suggest that achieving success with BTX to manage tremor can be a difficult process.

“The secret of happiness is not in doing what one likes, but in liking what one does.” James M. Barrie

BTX and Treating Parkinson’s:In this blog post, I have tried to summarize the use of BTX in treating various symptoms of Parkinson’s. During my education, it became apparent that BTX may have some real application in certain parts of Parkinson’s, but not all aspects of this disorder. Remembering that I am a scientist, not a clinician, and I’m not recommending anyone try any of these techniques clinically without first consulting your neurologist and your family. However, these are interesting scientific observations. BTX is found wide application in medicine, attending many different sorts of problems in patients, met with much success. I have only mentioned a few of the applications of BTX and Parkinson’s, primarily because the process is precisely the same using small amounts of BTX are injected into neuromuscular junctions. Cited below are 12 different journal articles some are review articles. Some are primary clinical trial studies and will give you much more depth and detail into the use of BTX in Parkinson’s.

“Be so happy that when others look at you, they become happy too.” Harbhajan Singh Yogi

References for Botulinum Toxin and Parkinson’s disease:

  1. Mills, R., Bahroo, L. and Pagan, F., 2015. An update on the use of botulinum toxin therapy in Parkinson’s disease. Current neurology and neuroscience reports, 15(1), p.511.
  2. Dogu, O., Apaydin, D., Sevim, S., Talas, D.U. and Aral, M., 2004. Ultrasound-guided versus ‘blind’intraparotid injections of botulinum toxin-A for the treatment of sialorrhoea in patients with Parkinson’s disease. Clinical neurology and neurosurgery, 106(2), pp.93-96.
  3. Sheffield, J.K. and Jankovic, J., 2007. Botulinum toxin in the treatment of tremors, dystonias, sialorrhea and other symptoms associated with Parkinson’s disease. Expert Review of Neurotherapeutics, 7(6), pp.637-647.
  4. Ruiz-Roca, J.A., Pons-Fuster, E. and Lopez-Jornet, P., 2019. Effectiveness of the botulinum toxin for treating sialorrhea in patients with Parkinson’s disease: a systematic review. Journal of Clinical Medicine, 8(3), p.317.
  5. Cardoso, F., 2018. Botulinum toxin in parkinsonism: The when, how, and which for botulinum toxin injections. Toxicon, 147, pp.107-110
  6. Pacchetti, C., Albani, G., Martignoni, E., Godi, L., Alfonsi, E. and Nappi, G., 1995. “Off” painful dystonia in Parkinson’s disease treated with botulinum toxin. Movement disorders: official journal of the Movement Disorder Society, 10(3), pp.333-336.
  7. Jankovic, J., 2009. Disease-oriented approach to botulinum toxin use. Toxicon, 54(5), pp.614-623.
  8. Shetty, A.S., Bhatia, K.P. and Lang, A.E., 2019. Dystonia and Parkinson’s disease: What is the relationship?. Neurobiology of disease, 132Niemann, N. and Jankovic, J., 2018. Botulinum toxin for the treatment of hand tremor. Toxins, 10(7), p.299.
  9. Gupta, A.D. and Visvanathan, R., 2016. Botulinum toxin for foot dystonia in patients with Parkinson’s disease having deep brain stimulation: a case series and a pilot study. Journal of Rehabilitation Medicine, 48(6), pp.559-563.
  10. Samotus, O., Lee, J. and Jog, M., 2020. Standardized algorithm for muscle selection anddosing of botulinum toxin for Parkinson tremor using kinematic analysis. Therapeutic advances in neurological disorders, 13, p.1756286420954083.
  11. Wree, A., Hawlitschka, A., Holzmann, C., Witt, M., Kurth, J., Lindner, T., Mann, T. and Antipova, V., 2020. Interlinking potential therapy with botulinum neurotoxin-A and Parkinson’s disease. In Diagnosis and Management in Parkinson’s Disease (pp. 665-681). Academic Press.
  12. Lagalla, G., Millevolte, M., Capecci, M., Provinciali, L. and Ceravolo, M.G., 2006. Botulinum toxin type A for drooling in Parkinson’s disease: a double‐blind, randomized, placebo‐controlled study. Movement disorders: official journal of the Movement Disorder Society, 21(5), pp.704-707.

“Learn to enjoy every minute of your life. Be happy now. Don’t wait for something outside of yourself to make you happy in the future. Think how really precious is the time you have to spend, whether it’s at work or with your family. Every minute should be enjoyed and savored.” Earl Nightingale


This sporadic case, with SCA 3 gene mutation, presented with the combined syndrome of painful, disabling foot dystonia, peripheral neuropathy, and minimal cerebellar dysfunction. Interestingly, there was a dramatic improvement of the dystonia with levodopa treatment in the absence of florid symptoms or signs of parkinsonian phenotype. To the best of our knowledge, a meaningful response of dystonia in SCA 3 to levodopa has not previously been reported. In a family of African origin presenting with a parkinsonian phenotype of SCA 3, one of the subjects, a 51 year old woman (No 3018), was noted to have left foot dystonia, especially in the morning. 3 However, her response to levodopa treatment was not known. In a Ghanaian patient with Machado-Joseph disease, the manifestation of dopamine agonist responsive parkinsonian phenotype was associated with levodopa induced motor fluctuation (in the form of freezing and wearing off phenomenon), while dystonia was not the predominant feature. 4 Severe generalised dystonia was the presenting feature in a German patient reported by Munchau et al. 1 Like the case reported here, he was heterozygous for SCA 3 gene mutation, but showed only a mild improvement of his dystonia after starting levodopa. The response lasted for two weeks only, unlike the significant benefit seen for two years in our patient. In a study by Jardim and colleagues, dystonia in SCA 3 was correlated with a higher mean CAG repeat length, varying from 69 to 85. 9 Shinotoh et al observed dysfunction of the nigrostriatal dopaminergic system in a patient with Machado-Joseph disease with moderate dystonia, using 6 fluoro-L-dopa positron emission tomography. 10

Learning points

SCA 3 is characterised by wide range of clinical manifestations, including four subphenotypes.

SCA 3 can present as levodopa responsive dystonia phenotype.

Awareness of the atypical presentations of SCA3 has diagnostic and therapeutic relevance.

There are a few clinical syndromes characterised by dystonia that are responsive to levodopa (box 1).

Box 1: Syndromes characterised by levodopa responsive dystonia

Autosomal dominant: guanosine triphosphate cyclohydrolase 1 deficiency.

Autosomal recessive: tyrosine hydroxylase deficiency.

Familial Parkinson’s disease:

Advanced idiopathic Parkinson’s disease:

Spinocerebellar ataxia type 3:

The onset of dystonia in the fourth decade, the absence of diurnal fluctuation and sleep benefit distinguish the present case from dopa responsive dystonia. In some patients “off” dystonia is actually the presenting sign of Parkinson’s disease, with foot posturing on awakening being the most common symptom. 11 This dystonia can create significant distress for patients and respond to dopaminergic agents. The dystonia in our patient, though lacking the parkinsonian phenotype, mimicked the features encountered in “off” dystonia of advanced Parkinson’s disease. Before the availability of genetic tests for autosomal dominant cerebellar ataxia, the phenotypic classification required the presence of ataxia as an initial or predominant clinical feature. However recent reports indicate the occurrence of movement disorders as the predominant or presenting feature, overshadowing ataxia in SCA 3 (table 1). In such a scenario, ordering the appropriate genetic test remains a diagnostic challenge. When encountered in standard neurological practice, these patients would receive a diagnosis of Parkinson’s disease, multisystem atrophy, and primary dystonia respectively. Awareness of these atypical clinical presentations and observation of intrafamilial phenotypic variability among members of the same family may help diagnose the appropriate genetic disorder. This also has significant relevance during genetic counselling.

Extrapyramidal presentation of SCA 3

In the light of SCA 3/Machado-Joseph disease presenting as levodopa responsive parkinsonian and dystonic phenotypes (as evident in our case), a therapeutic trial of levodopa may be considered for dystonia (even in the absence of parkinsonian feature), at least in the initial stage of the disease. In the near future, further genetic and functional neuroimaging studies may throw more light on the diverse clinical manifestations of this degenerative disorder and provide the scientific basis for anticipating levodopa responsiveness of the extrapyramidal features.

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