The Differences/Comorbidity Between Ataxia & Dyspraxia, My Testing, My Potential Causal Genetic Variants
This is a blog post about explaining the differences between Ataxia and Dyspraxia and their comorbidity. I have both Ataxia and Dyspraxia. I thought that all of my coordination/motor movement problems were in connection to Dyspraxia, but they are also in connection to Ataxia.
I go over Ataxia and Dyspraxia.
I go over my test results with explanations.
I go over my ultra rare high impact potential disease-causing variants that could be connected to my Ataxia and show genetic overlap with Dyspraxia.
I also go over how they can affect the cerebellar system.
I am a 53 year old man with Ataxia, Dyspraxia, Dyslexia, ADHD.
https://neurodivergence.blogspot.com/
I first learned about Dyspraxia back in 2003. I read a list of the problems, and I realized that I am Dyspraxic.
I showed my mother a list, and I asked her does this look familiar. She looked at them, and she immediately told me "These fit you to a T."
My mother had told me that I was tested by neurologists because of concerns about speech, coordination, balance problems before I was 3 years old. They didn't find any brain damage.
I had early intevention therapies that include auditory therapy, speech therapy, phonics training, and motor skills therapy which made my Ataxic, Dyspraxic, Dyslexic symptoms mild and subtle. I went from being somebody that resembled a person with an intellectual handicap and/or severe autism to somebody that resembled a person with mild autism and/or just somebody that is an "oddball". My poor short memory has given impression to some that I am stupid. This led to being very anxious and self conscious on a regular basis.
I started off as a regular student in kindergarten, but I was misplaced with intellectually handicapped children in 1st grade. When I was around 6 years old, my mother had her Fallopian Tubes because she believed that I needed a lot of attention and care. By the end of the 1st grade, I was found to have above average intelligence. Throughout 1st grade, I had intensive speech therapy and had learned to think in words. I am primarily a visual/picture thinker and lacked understanding of words in early childhood. I was placed in a more appropriate special education class in 2nd grade, and I was partially mainstreamed before the end of the 2nd grade. A fellow student and I went to regular classroom for science throughout my time in 2nd grade. I was called the R-word on a regular basis by regular school children which often led to me retaliating. Because of concerns of immaturity, my mother chose to have me held back in 2nd grade even though she was told that I could skip a grade. I was in regular classroom for most of the time and spent time. I was completely a regular student from 3rd grade to 12th grade.
Because of my experiences as one that had special education, I always knew that I was not a normal person which led to growing up with much insecurity. I lived in the "closet" as I tried to fit in with normal people without telling them my special education past. Unfortunately, I always came off as abnormal and stupid resulting in being teased and bullied throughout my life that included school and work. I also ended up with psychiatric misdiagnoses. The navy doctors and mental health professionals didn't understand what was really going on with me. I didn't understand myself at the time as I was having pervasive feelings of inadequacy.
the problems caused by Dyspraxia:
according to Madeleine Portwood's book Understanding Developmental Dyspraxia
I have the book. I even typed up the book's questionnaries in the book for my mother to answer and sign to give to Dr. Harold Levinson for insight into my problems to help with testing in 2005.
Clumsiness
Poor Posture
Walking awkwardly
Confused about which hand to use
Difficulties throwing or catching a ball
Sensitivity to touch
Find some clothes uncomfortable
Poor short-term memory, they often forget tasks learned the previous day
Poor body awareness
Reading and writing difficulties
Cannot hold a pen or pencil properly
Poor sense of direction
Cannot hop, skip, or ride a bike
Slow to learn to dress or feed themselves
Cannot answer simple questions even though they know the answers
Speech problems, slow to learn to speak or speech may be incoherent
Impatience
Intolerance to having hair or teeth brushed, or nails and hair cut
Plasters are uncomfortable to wear
I bought and read books by Dr. Harold N. Levinson who recognized the co-morbidity that Dyslexia, Dyspraxia, ADHD, and other neurodivergent conditions have with each other and that they are caused by Cerebellar Vestibular Dysfunction. In 2005, I went to his New York clinic and got testing done which led to a diagnosis of Cerebellar-Vestibular Dysfunction.
In 2006, I was examined by Veteran Affairs neurologists. They had confirmed my Dyslexia and Dyspraxia. They also noted that I had symptoms of Ataxia which I didn't understand until recently. I thought all of my coordination problems were from Dyspraxia. Ataxia is listed in my Veteran Affairs Problems List.
Ataxia
Ataxia is a neurological condition characterized by a lack of voluntary coordination of muscle movements. It results from dysfunction in the parts of the nervous system that control movement, primarily the cerebellum.
Dyspraxia
Dyspraxia (also known as Developmental Coordination Disorder or DCD) is a developmental disorder that affects motor coordination. It is characterized by difficulties in the planning and execution of coordinated movements.
Differences between Ataxia and Dyspraxia
Ataxia typically relates to cerebellar dysfunction and presents with significant balance and coordination problems, while dyspraxia involves motor planning deficiencies and variable performance in executing movements.
Differences between Ataxia's cause and Dyspraxia's cause
Ataxia is primarily caused by neurological damage due to diseases, genetics, or external factors, specifically affecting coordination and balance.
Dyspraxia arises from developmental issues with planning and executing movements, linked to atypical brain growth, prenatal events, and sometimes genetic factors. It does not typically involve direct neurological damage.
Dyspraxia has a much higher prevalence in the general population compared to Ataxia. Dyspraxia is commonly identified in children, impacting a significant percentage of the child population, while ataxia, especially hereditary forms, tends to be much rarer and affects relatively few individuals overall.
Ataxia - Rough estimates suggest that ataxia affects 0.026% of children. The figure could vary depending on the specific form of ataxia and regional differences in diagnosis and reporting. Rare types of inherited ataxias (like Friedreich's ataxia or Spinocerebellar ataxias) are less common, often affecting fewer than 0.001% of people. The incidence of ataxia due to acquired conditions (e.g., stroke, multiple sclerosis, alcohol use, or viral infections) can vary significantly depending on the underlying cause.
Differences between Ataxic testing and Dyspraxic testing
The testing processes for ataxia and dyspraxia are fundamentally different due to their distinct nature and underlying causes. Ataxic testing focuses on neurological evaluation and identifying structural issues, while dyspraxic testing emphasizes motor skills and functional capabilities, particularly in developmental contexts.
Differences between Ataxic treatment and the Dyspraxic treatment
Ataxia and dyspraxia involve challenges with coordination and movement, treatment strategies differ significantly based on the nature of each condition. Ataxia treatment often focuses on symptom control and rehabilitation based on the underlying cause, while dyspraxia treatment emphasizes skill development and adaptations to improve functioning in daily activities.
Differences between Ataxic balance and coordination issues and Dyspraxic balance and coordination issues
Ataxia and dyspraxia present with distinct balance and coordination challenges due to their differing neurological origins. Ataxia is primarily characterized by severe coordination and balance problems, often leading to instability and fall risk. Conversely, dyspraxia involves issues with motor planning, resulting in clumsiness and difficulty performing coordinated movements, though balance may be more intact in static situations.
Differences between Ataxic motor planning and execution issues and Dyspraxic motor planning and execution issues
Ataxia and dyspraxia exhibit distinct motor planning and execution issues due to their different neurological bases. Ataxia is characterized by impaired coordination and balance, primarily affecting movement execution. In contrast, dyspraxia involves significant challenges with the planning and sequencing of movements, even when motor abilities may be intact.
Differences between Ataxic visual issues and Dyspraxic visual issues
The visual issues associated with ataxia primarily stem from oculomotor dysfunction and difficulties in visual-motor coordination that impact movement and balance. In contrast, dyspraxia involves more pronounced challenges with visual-spatial processing, eye-hand coordination, and perceptual skills.
Differences between Ataxic speech issues and Dyspraxic speech issues
While both ataxia and dyspraxia can result in speech issues, they manifest in different ways due to their distinct neurological bases. Ataxia typically leads to dysarthria with slurred speech and irregular prosody, while dyspraxia manifests as verbal dyspraxia, characterized by challenges with the planning and execution of speech sounds.
Comorbidity
Ataxia-Dyspraxia comorbidity is a recognized concept, though it is not a formally categorized condition. It is is often associated with underlying neurological or genetic conditions that impact motor skills and brain development.
The exact percentage of individuals with both ataxia and dyspraxia is not well-documented due to limited research on their direct comorbidity. However, overlapping motor and coordination challenges between these conditions suggest they may co-occur in rare cases, especially in individuals with neurodevelopmental disorders or certain genetic syndromes.
Both conditions involve dysfunction in brain regions associated with motor control, particularly the cerebellum and motor planning areas.
Ataxia and Dyspraxia both impair balance, coordination, and fine motor skills, which can manifest similarly, making differential diagnosis complex.
Certain genetic syndromes (e.g., mitochondrial disorders, cerebellar malformations) may present with features of both Ataxia and Dyspraxia.
Dyspraxia often co-occurs with attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD), which can also be seen in ataxia due to shared developmental pathways.
I had testing done at Dr. Harold Levinson's clinic.
His findings highlight significant coordination and balance difficulties based on the results of neurological testing, electronystagmography, and posturography. Here's a breakdown of the key findings:
Neurological Testing
1. Romberg Instability refers to an inability to stand still with either both feet together or on one foot, most commonly abnormal with the eyes closed.
eyes closed - dysfunction
right foot - dysfunction
left foot - dysfunction
Instability with eyes closed on both the right and left foot suggests sensory or proprioceptive dysfunction.
2. Dysdiadochokinesis indicates a difficulty with rapid alternating movements, tested by rotating hands and forearms repeatedly with the arms extended.
bilateral - dysfunction
3. Finger-to-Nose Testing tests the visuo-spatial perception and proprioceptive feedback considered to be controlled by the Cerebellum.
eyes closed - dysfunction
Problems with this test suggest proprioceptive deficits or impaired motor planning.
4. Tandem Instability refers to a difficulty in heel-to-toe successive walking.
placement - dysfunction
5. Speech
mild articulation problems, slow speech, auditory input problems which indicate underlying neurological issues affecting motor control of speech and auditory processing
Electronystagmography (ENG) is a standardized neurophysiological test in which eye movements are induced and measured under various testing conditions. Fine and reflexive eye movements are controlled by the cerebellum and the vestibular system. As a result, the ENG can help determine whether or not an inner-ear abnormality exists.
1. Rotational Test: This test measures vestibular response to rotation. The patient is rotated which induces a rapid, rhthymic response. If the nystagmus is dysrhythmic, hypo, or hyper, this is considered to be an abormal response.
Abnormal
dysthrythmic on clockwise
dysthyrhmic on counter clockwise
Abnormal dysrhythmic eye movements in both clockwise and counterclockwise directions suggest vestibular or central nervous system impairments.
2. Saccade Test: In this test, a dot removes randomly on the screen and the patient must "chase" it with his/her eyes. A saccade is a quick, jerky eye movement which positions a visual target on the retina. The cerebellum plays a role in associating the functions of various brain stem structures related to generating saccades.
Abnormal indicating deficits in ocular motor control, likely related to cerebellar or brainstem pathways.
3. Pursuit Test: In this test, the dot cycles back and forth across the screen and measures the patient's ability to make smooth eye movements. Smooth pursuit eye movements continuously follow a moving target with a high acuity retinal region. An inability to produce smooth pursuit movements is known to result from cerebellar dysfunction.
Abnormal
4. Optokinetic Test: In this test, a series of dots move off the screen causing the patient to rapidly refix his/her gaze, testing the ocular tracking reflex. Optokinetic testing involves continous drifting and rapidly resetting eye movements.
Abnormal indicating difficulties with visually induced reflexive eye movements, further pointing to vestibular and central processing dysfunctions.
Posturography - Many of the symptoms of in an inner ear disorder (e.g. imbalance, dizziness, motion sickness, etc.) can result from other illnesses as well (i.e. extreme stress and anxiety, dysfunction of cerebral and other related Central Nervous System structures). Posturography aids in this differentiation since a vestibular dysfunction produces a specific, quantifiable frequency and pattern of movement which is distinct from that caused by other disorders.
Posturography testing asseses overall balance function (sensory integration) , vision dependence, proprioception (internal senses) dependence, symmetry of weight bearing, lateral sway, and overall assessment of vestibular deficit.
1. Sway Frequency - This helps determine the location of a balance impairment. A low (F-1) frequency is considered normal movement. A dominant F2-F4 is indicative of a vestibular problem. A higher frequency (F5-F6) is thought to result from a more cerebellar problem, and above F7 is considered to be a motor cortex abnormality.
F2 - F4 - abnormal indicating a vestibular problem
F5 - F6 - borderline indicating a mild cerebellar problem
F7 - F8 - borderline indicating a mild motor cortex abnormality
2. Weight Distribution - The bearing of one's weight in an abnormal and dysmetric fashion (i.e. to put more weight on the heels or left foot, per se) can indicate either a cerebellar determined muscle imbalance or a vestibular imbalance.
Mildly abnormal which suggest imbalances in weight-bearing capacity.
3. Stability - This is a measure of the overall level of instability which is compared to normal subjects in a determination of postural control.
Mildly abnormal which points to subtle difficulties in maintaining upright posture.
4. Lateral Sway - A large degree of lateral sway is seen in intoxicated subjects and results from vestibular impairment. This is also true for the non-intoxicated patient suffering from a vestibular problem.
Mildy abnormal which indicates potential vestibular or proprioceptive integration issues.
The findings collectively point towards vestibular dysfunction and cerebellar involvement, with potential sensory integration issues impacting balance and coordination.
https://www.facebook.com/photo/?fbid=10151646370785901&set=a.10151646363485901
https://www.facebook.com/photo/?fbid=10151646371040901&set=a.10151646363485901
Veteran Affairs neurological testing
Mental function:
EOM (Extraocular Movements) full, but impaired saccades
suggests neural pathways implicated in saccadic eye movements may be dysfunctional.
Abnormal cerebellar system:
Nystagmus opticokinetic with slowed saccades but symmetric horizontally and vertically, difficulty initiating saccades to command and to read.
The presence of nystagmus during optokinetic testing indicates instability in, or dysfunction of, the vestibular or cerebellar systems. The slowed saccades, particularly during visually guided tasks, suggest cerebellar control deficits.
The presence of symmetric nystagmus horizontally and vertically implies that there may not be a lateralized lesion affecting the cerebellum or other areas controlling eye movements.
The challenges in initiating saccades may also point to impaired cognitive processes related to visual attention and executive function, which can be linked to cerebellar and cortical interactions.
Dysdiadokokinesia present symmetrically all 4 extremities
indicates a struggle with rapid alternating movements, which can reflect cerebellar dysfunction impacting coordination and motor control.
Ataxia, on target finger-nose, but dysmetria with moving target showing again slowed saccadic eye movements
suggest significant proprioceptive and motor planning disturbances. This reinforces the likelihood of cerebellar dysfunction impacting both coordination and motor execution.
Reflexes:
Gait with mild ataxia
indicates an unstable or unsteady walking pattern, often a hallmark of cerebellar dysfunction. This could compromise the patient's mobility, risk of falls, and overall functional independence.
Conclusion:
The constellation of findings from the neurological assessment points towards significant cerebellar dysfunction that impacts various areas including coordination, balance, and eye movement control.
https://www.facebook.com/photo/?fbid=10151646379265901&set=a.10151646363485901
https://www.facebook.com/photo/?fbid=10151646379615901&set=a.10151646363485901
Veteran Affairs neuropsychologist noted my speech was mildly dysarthric.
Dysarthria is a motor speech disorder resulting from neurological injury that affects the muscles used in speech production. It can manifest as slurred, slow, or difficult speech; changes in voice quality (such as a soft or nasal voice); and difficulty with articulation and pronunciation.
https://www.facebook.com/photo/?fbid=10151646385810901&set=a.10151646363485901
My Veteran Affairs Problems List in regards to coordination
Ataxia (ICD-9-CM 781.3)
Deficiencies of saccadic eye movements (ICD-9-CM 379.57)
With Ataxia being a very rare neurological condition, I focused on just my ultra rare potential disease-causing high impact variants. I have three potential disease-causing high impact ultra rare variants in genes that have high expression in the cerebellar system as well as the overall nervous system. They also have Ataxia as a human phenotype according to MayaanLab and/or Genecards.
One is a Splice Acceptor TMEM63A variant that my mother has, and so I inherited it from her.
The other two are Stop Gained (aka Nonsense) vairants that my mother doesn't have, but I know if it is inherited from my deceased father. Therefore, I don't don't know if either variant is a de novo variant which is a genetic variant that occurs for the first time in an individual and is not inherited from either parent. It arises spontaneously, often during the formation of eggs or sperm or in early embryonic development.
Both Stop Gained variants are nonsense-mediated decay (NMD)-escaping variant which are genetic variants that create a premature stop codon, but the faulty mRNA is not destroyed by the cell's quality control system (NMD). Instead, the mRNA is used to make a truncated protein which can sometimes be harmful or interfere with normal cellular functions. It is a variant that "escapes" the system designed to stop defective protein production, allowing potentially harmful proteins to be made.
Therefore, NMD-escaping Stop Gained variants have a potential to be more harmful than Stop Gained variants that don't escape nonsense-mediated decay.
A splice acceptor variant is a type of genetic mutation that occurs at the splice acceptor site of a gene. The splice acceptor site is located at the 3' end of an intron, just before the start of an exon. This site is crucial for the proper splicing of pre-mRNA during the process of converting it into mature mRNA.
When a splice acceptor variant occurs, it can disrupt the normal splicing process, leading to the inclusion or exclusion of exons, or the use of cryptic splice sites. This can result in the production of abnormal proteins, which may contribute to various genetic disorders
rs966645435 1-225867164-C-G
TMEM63A Splice Acceptor variant
18 out of 1,614,038 (0.001115%) GnomAD
16 out of 490,776 (0.0033%) AllOfUs
6 out of 264, 690 (0.0023%) TOPMED
found in a total of 40 people
my mother has the variant, and so I inherited it from her
CADD score: 28.7
https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA38540925
https://neurodivergence.blogspot.com/2024/03/my-rare-single-nucleotide-variants-that.html
TMEM63A (Transmembrane Protein 63A) is a gene that encodes a mechanosensitive ion channel involved in detecting mechanical stimuli such as stretch or pressure. It plays a critical role in maintaining osmoregulation and ionic homeostasis, ensuring cells adapt to changes in mechanical and osmotic environments.
Key Functions:
Mechanosensation: Converts mechanical forces into cellular signals.
Osmoregulation: Regulates ion flow to maintain cellular ionic balance during osmotic stress.
Cellular Adaptation: Supports cellular responses to mechanical and environmental changes.
Role in Biological Systems:
Found in multiple tissues, including the nervous system, where it supports mechanotransduction and neuronal signaling.
Contributes to functions in sensory systems such as touch, balance, and proprioception.
Clinical Significance:
Variants or disruptions in TMEM63A can impair its function, leading to neurological or sensory deficits, and it may play a role in conditions affecting ion homeostasis or mechanosensation.
A splice acceptor variant in TMEM63A disrupts the normal splicing of its mRNA, potentially leading to a truncated or misfolded TMEM63A protein. TMEM63A encodes a mechanosensitive ion channel critical for maintaining ionic balance, mechanotransduction, and cellular osmoregulation. The effects of this variant on the nervous system, cerebellar system, and vestibular system stem from its disruption of these essential processes.
Nervous System:
Protein Role: TMEM63A helps neurons respond to mechanical stimuli and maintain ionic balance, crucial for neuronal excitability and signaling.
Effects: A dysfunctional TMEM63A protein impairs mechanosensation and ion homeostasis, leading to sensory deficits, disrupted neuronal communication, and increased risk for neurodevelopmental disorders and neurodegeneration.
Cerebellar System:
Protein Role: TMEM63A contributes to the function of Purkinje cells and other cerebellar neurons by regulating osmoregulation and mechanotransduction, necessary for motor coordination and learning.
Effects: Impaired TMEM63A activity can disrupt cerebellar neuron signaling, leading to ataxia, motor coordination deficits, and cognitive impairments linked to cerebellar dysfunction.
Vestibular System:
Protein Role: TMEM63A is involved in mechanosensory functions of vestibular hair cells, which detect head movements and gravitational forces to maintain balance.
Effects: A splice acceptor variant can impair the function of hair cells and vestibular neurons, leading to balance disorders, vertigo, and spatial disorientation due to disrupted mechanotransduction and ionic imbalances.
Summary:
A splice acceptor variant in TMEM63A alters the structure or function of the TMEM63A protein, a critical mechanosensitive ion channel. This disruption affects neuronal signaling, mechanotransduction, and ionic regulation, leading to sensory deficits, ataxia, and balance disorders across the nervous, cerebellar, and vestibular systems.
A stop gained variant, also known as a nonsense mutation, is a type of genetic mutation where a change in the DNA sequence introduces a premature stop codon within a gene. This results in the early termination of protein synthesis, leading to a truncated and usually nonfunctional protein.
These truncated proteins can have significant impacts on cellular function and are often associated with various genetic disorders and diseases
novel 12-106067419-T-A
NUAK1 Stop Gained NMD-escaping variant
not found in any population
my mother doesn't have the variant, but I don't know if I inherited from my deceased father
therefore, I don't know if it's de novo
CADD score: 38
https://neurodivergence.blogspot.com/2024/10/gene-inspector-pro-and-variants-that-i.html
NUAK1 (NUAK Family Kinase 1) is a serine/threonine kinase belonging to the AMPK-related kinase family, involved in various cellular processes essential for growth, stress response, and development.
Key Functions:
Cytoskeletal Regulation: Modulates actin and microtubule dynamics, critical for cell structure and motility.
Neuronal Development: Facilitates neuronal migration, axon elongation, and proper brain development.
Stress Response: Plays a role in cellular adaptation to metabolic and oxidative stress.
Role in Biological Systems:
Nervous System: Supports neuronal connectivity, synaptic development, and brain architecture.
Cerebellar System: Involved in motor coordination through regulation of neuronal positioning and signaling.
Cellular Maintenance: Regulates cell adhesion, division, and survival under stress conditions.
Clinical Significance:
Mutations or dysregulation of NUAK1 have been linked to neurodevelopmental disorders, neurodegenerative diseases (e.g., Alzheimer’s and Parkinson’s), and cancers due to its role in cell survival and cytoskeletal integrity.
Summary: NUAK1 is a kinase essential for neuronal development, cytoskeletal regulation, and cellular stress response, making it a key player in maintaining brain structure and function.
An NMD-escaping stop-gained variant in NUAK1 leads to the production of a truncated NUAK1 protein, which lacks functional domains necessary for its role as a serine/threonine kinase. NUAK1 is critical for regulating cytoskeletal dynamics, neuronal migration, axonal growth, and synaptic function. The variant's effects on the nervous system, cerebellar system, and vestibular system stem from this loss of functionality.
Nervous System:
Protein Role: NUAK1 regulates cytoskeletal organization and intracellular signaling pathways crucial for neuronal development and function.
Effects: Impaired neuronal migration, axonal transport, and synaptic communication lead to neurodevelopmental disorders (e.g., autism, intellectual disabilities) and neurodegenerative diseases (e.g., Parkinson’s, Alzheimer’s).
Cerebellar System:
Protein Role: NUAK1 supports Purkinje and granule cell migration, axon-dendrite connectivity, and synaptic plasticity in the cerebellum.
Effects: Truncated NUAK1 disrupts cerebellar circuit formation and maintenance, causing ataxia, motor coordination deficits, and cognitive or emotional impairments.
Vestibular System:
Protein Role: NUAK1 is involved in mechanotransduction, vestibular neuron migration, and the structural integrity of vestibular hair cells.
Effects: The dysfunctional protein impairs balance signal processing, leading to vertigo, unsteady gait, and spatial disorientation.
Summary:
The truncated NUAK1 protein, produced due to an NMD-escaping stop-gained variant, disrupts critical pathways across the nervous, cerebellar, and vestibular systems. Its failure to regulate cytoskeletal organization, neuronal migration, and synaptic functions leads to motor, sensory, and cognitive impairments, with manifestations like ataxia, balance disorders, and neurodevelopmental or neurodegenerative conditions.
rs867998099 17-2379146-C-T
SGSM2 Stop Gained NMD-Escaping variant
3 out of 1,614,054 (0.0001859%) GnomAD
2 out of 490,784 (0.0004%) AllofUs
2 out of 264,690 (0.0008%) TOPMED
1 out of 16,760 (00.006%) 8.3KJPN
found in a total of 8 people
my mother doesn't have the variant, but I don't know if I inherited it from my deceased father
therefore, I don't know if it's de novo
CADD score: 40
https://reg.clinicalgenome.org/redmine/projects/registry/genboree_registry/by_caid?caid=CA286906028
https://neurodivergence.blogspot.com/2024/03/my-rare-single-nucleotide-variants-that.html
SGSM2 (Small G Protein Signaling Modulator 2) is a protein involved in regulating small GTPases (e.g., Rab and Ras family proteins), which are essential for intracellular signaling, vesicle trafficking, and cytoskeletal dynamics.
Key Functions:
Small GTPase Regulation: Modulates signaling pathways that control cell communication and transport.
Vesicular Trafficking: Facilitates the movement of vesicles within cells, crucial for neurotransmitter release and synaptic function.
Cytoskeletal Organization: Maintains cellular structure and aids in processes like neuronal migration and axonal transport.
Role in Biological Systems:
Nervous System: Supports synaptic communication, neuronal growth, and intracellular transport.
Cerebellar System: Assists in the development and maintenance of cerebellar neurons for motor coordination.
Vestibular System: Contributes to balance and mechanotransduction by supporting vesicle trafficking and signaling in sensory cells.
Clinical Significance:
Mutations in SGSM2, such as NMD-escaping stop-gained variants, can impair its function, leading to disrupted intracellular signaling, synaptic deficits, and potential links to neurodevelopmental disorders, neurodegeneration, and balance-related conditions.
Summary: SGSM2 is a crucial regulator of intracellular trafficking and cytoskeletal organization, playing a vital role in neuronal communication, growth, and sensory functions. Its dysfunction can result in neurological and sensory impairments.
An NMD-escaping stop-gained variant in SGSM2 results in the production of a truncated SGSM2 protein, which loses its ability to regulate small GTPases (e.g., Rab and Ras proteins). SGSM2 plays a critical role in vesicle trafficking, cytoskeletal organization, and intracellular signaling, which are essential for neuronal and sensory system functionality. The variant's effects on the nervous system, cerebellar system, and vestibular system stem from the disruption of these processes.
Nervous System:
Protein Role: SGSM2 supports small GTPase activity to maintain vesicle trafficking, neurotransmitter release, and axonal transport in neurons.
Effects: The truncated SGSM2 protein disrupts synaptic communication, neuronal migration, and axonal integrity, leading to neurodevelopmental disorders (e.g., autism, intellectual disabilities) and neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s).
Cerebellar System:
Protein Role: SGSM2 regulates vesicle transport and cytoskeletal stability in Purkinje cells and granule cells, which are essential for motor coordination and learning.
Effects: Dysfunctional SGSM2 impairs cerebellar neuron migration and synaptic plasticity, causing ataxia, motor deficits, and cognitive or emotional impairments associated with cerebellar dysfunction.
Vestibular System:
Protein Role: SGSM2 ensures proper trafficking and cytoskeletal support in vestibular hair cells and neurons, facilitating mechanotransduction and balance signal processing.
Effects: The truncated protein disrupts hair cell function and neuronal signaling, leading to vertigo, unsteady gait, and spatial disorientation due to impaired balance mechanisms.
Summary:
The truncated SGSM2 protein, caused by an NMD-escaping stop-gained variant, disrupts small GTPase regulation critical for vesicle trafficking, cytoskeletal integrity, and signal transduction. This leads to widespread effects across the nervous, cerebellar, and vestibular systems, manifesting as coordination issues, balance disorders, and neurodevelopmental or neurodegenerative conditions.
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