Week 3(1) - Pathophysiology and mechanisms underlying an inherited neurological disease- Spinocerebellar Ataxia.pdf
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Week 3(1) Inherited Neurological Disorders (HMG 44110A ) Pathophysiology and mechanisms underlying an inherited neurological disease: Inherited Ataxia ; Spinocerebellar Ataxia Dr. Merin Thomas [email protected]...
Week 3(1) Inherited Neurological Disorders (HMG 44110A ) Pathophysiology and mechanisms underlying an inherited neurological disease: Inherited Ataxia ; Spinocerebellar Ataxia Dr. Merin Thomas [email protected] Office hours : Monday & Wednesday, 3.00pm to 5.00pm Tuesday & Thursday 1.00pm to 3.00pm 1 Learning Objectives Ataxia - Types Inherited Ataxia – examples: FRDA, FXTAS, SCA Spinocerebellar Ataxia Etiology & Epidemiology Pathophysiology Family & Patient history, signs & symptoms Testing Management Prognosis Ataxia Ataxia is a neurological sign that manifests in a lack of coordination in the movement of different muscles in the body. It is a clinical finding and not a disease, which mainly presents abnormalities in gait, changes in speech, and abnormal eye movements such as nystagmus. It results from dysfunction of the brain areas, responsible for the coordination of movements, and, most commonly, the cerebellum. Introduction The three types of ataxia, according to the location, are cerebellar, sensory, and vestibular. Ataxia Vestibular Symptoms Cerebellar motor Symptoms Impaired walking Dizziness, Poor balance vertigo Clumsy hands Poor balance Slurred speech (falls) Stiffness and Visual slowness Introduction impairment Swallowing Blurred vision, difficulty double vision Ataxia Ataxia can also be subdivided into Sporadic (patients have no family history of ataxia and manifest in adulthood), Genetic (Hereditary) (caused by a defect in a gene and manifesting in childhood), and Acquired (due to structural or demyelinating conditions, toxicity, inflammatory or infections, and autoimmune conditions). Introduction Ataxia – Acquired/Sporadic This type of ataxia usually results from some type of environmental factor such as a brain injury, tumor or chemical exposure. For example, head trauma or stroke can cause ataxia. exposure to high levels of alcohol can lead to ataxia. A brain tumor can cause a person to become ataxic. Multiple System Atrophy (MSA) is a fairly common cause of adult-onset Introduction ataxia whose cause is unknown, and which is usually not inherited. Ataxia – Genetic/Inherited Hereditary ataxia is passed on in families and shows a clear inheritance pattern. Most types of hereditary ataxia are inherited: Autosomal dominant pattern Autosomal recessive pattern X-linked pattern In general, the hereditary ataxias are slowly progressive and are Introduction associated with atrophy of the cerebellum that can be seen on a brain scan. Ataxia – Genetic/Inherited AUTOSOMAL RECESSIVE PATTERN - Friedreich’s Ataxia Must inherit an abnormal gene from both parents Disease usually start before age 20 (Typical age of onset 10-15yrs). They are generally complex and disabling diseases. The most common type of ataxia with this pattern of inheritance The FXN gene is located at 9q21.11 The FXN gene provides instructions for making a protein called frataxin. This protein is found in cells throughout the body, with the highest Introduction levels in the heart, spinal cord, liver, pancreas, and skeletal muscles. Ataxia – Genetic/Inherited AUTOSOMAL RECESSIVE PATTERN - Friedreich’s Ataxia One region of the FXN gene contains a segment of DNA known as a GAA trinucleotide repeat. Normal individuals have 5 to 30 GAA repeat expansions, whereas affected individuals have from 70 to more than 1,000 GAA triplets. The length of the GAA trinucleotide repeat appears to be related to the age at which the symptoms of Friedreich ataxia appear, how severe they are, and how quickly they progress. Introduction Unlike the Autosomal dominant cerebellar ataxias (ADCAs) caused by CAG trinucleotide repeats, FRDA is not associated with anticipation. Ataxia – Genetic/Inherited AUTOSOMAL RECESSIVE PATTERN - Friedreich’s Ataxia Introduction Ataxia – Genetic/Inherited X-linked DOMINANT PATTERN - Fragile X–associated tremor/ataxia syndrome (FXTAS) Inherited degenerative disorder that affects aging persons, primarily men, and is associated with an array of neurological symptoms and medical conditions. It results from a premutation (50 to 200 CGG repeats) in the Fragile X mental retardation (FMR1) gene on the X chromosome. The symptoms of Fragile X syndrome are caused by an abnormality of the FMR1 gene on the X chromosome. Introduction The abnormality is an unstable triplet repeat expansion of CGG. A premutation is a situation in which there are an excess number of repeats in a gene that is at risk of increasing in length during reproduction, but which does not cause disease in the person with the Ataxia – Genetic/Inherited X-linked PATTERN - Fragile X–associated tremor/ataxia syndrome (FXTAS) Unaffected people have < 54 CGG repeats and people with Fragile X syndrome have > 200. People with 55 to 200 CGG repeats are considered to have a premutation because the increased number of repeats increases the likelihood that further mutation will result in > 200 repeats in a subsequent generation. Introduction People with the premutation are considered carriers. Risk of developing FXTAS increases with age. Ataxia – Genetic/Inherited X LINKED PATTERN - Fragile X–associated tremor/ataxia syndrome (FXTAS) Introduction Ataxia – Genetic/Inherited AUTOSOMAL DOMINANT PATTERN ADCAs are divided in two main groups: Spinocerebellar ataxias (SCAs) Episodic ataxias (EAs). The episodic ataxias are a group of autosomal-dominant diseases characterized by episodic attacks of ataxia with or without interictal neurologic symptoms (e.g., myokymia or cerebellar symptoms). Introduction 8 subtypes have been defined according to clinical and genetic characteristics EA1 and EA2, which are caused by mutations in KCNA1 and CACNA1A, account for the majority of EA Ataxia – Genetic/Inherited AUTOSOMAL DOMINANT PATTERN - Spinocerebellar Ataxia Spinocerebellar ataxia (SCA) is an inherited (autosomal dominant), progressive, neurodegenerative, and heterogeneous disease that mainly affects the cerebellum. SCA is a subset of hereditary cerebellar ataxia and is a rare disease. To date, more than 40 distinct genetic SCAs have been identified which are classified according to the genetic loci in order of identification. Introduction Ataxia – Genetic/Inherited AUTOSOMAL DOMINANT PATTERN - Spinocerebellar Ataxia SCA1 was the first SCA described, and then further subtypes were identified sequentially Well defined and common types are SCA1, SCA2, SCA3, and SCA6 which accounts for more than half of cases and other rare variants constitute the remaining cases Introduction Etiology Several types of spinocerebellar ataxia are associated with anticipation, in which there is a tendency of gradual expansion of CAG repeats in a consecutive generation. Normal alleles contain 15 to 50 repeats, whereas pathogenic alleles contain 71 to 1,300 repeats Etiology CAG repeat expansion occurs in SCA1, 2, 3, 6, 7, 12, and 17. SCA 8 - CTG*CAG' repeat expansion ; caused by a repeat expansion that sits within the overlapping genes ATXN8OS and ATXN8 Similarly, SCA 10 is caused by the expansion of ATTCT (pentanucleotide) SCA 31, 36, 37 involve amplification of TGGAA (pentanucleotide), GGCCTG (hexanucleotide), and ATTTC Introduction (pentanucleotide) respectively Epidemiology The global prevalence of spinocerebellar ataxia is 1 to 5 per 100000. SCA3 (25 to 50%) is most prevalent followed by descending prevalence SCA2 (13 to 18%), SCA6 (13-15%), and SCA7. The frequency of different types varies from region to region – limited data available Introduction Pathophysiology Though the exact pathogenesis of spinocerebellar ataxia is still not known many study series promulgated that common mechanisms of SCA are genetic mutations causing abnormal protein products, transcriptional dysregulation, dysfunction of autophagy, channelopathies, Introduction mitochondrial dysfunction, toxic RNA gain of function etc. Pathophysiology Six forms of SCA involve CAG repeat amplification encode glutamine, which gets assembled into ataxins that alters the protein configuration into beta-pleated structure and toxic gain of function with autosomal inheritance. Ataxins are misfolded proteins from the expansion of a polyglutamine (more than 40 glutamines), which is abnormally translocated and accumulated in nuclei that Introduction interact with other proteins and oligomerize forming intranuclear inclusions in Purkinje cells Pathophysiology The principal cell involved in degeneration are Purkinje cells, and other cells, such as granule cells, astrocytes, Golgi cells, and oligodendrocytes are not involved. Purkinje cells regulate fine movement and muscle coordination. So, the degeneration of Purkinje cells is highly associated with ataxia. Some studies support that reason behind the involvement and vulnerability of only Purkinje cells is due to its large cell body with abundant cytoplasm and granules, long and prominent dendrites Introduction with many extensions (arborization). Pathophysiology Proper functioning and energy supply by mitochondria are vital for survival, neuronal conduction, and development of the dendritic tree of active Purkinje cells. Mitochondrial dysfunction leads to the degeneration of Purkinje cells. Introduction Pathophysiology Introduction Pathophysiology Introduction Pathophysiology Channelopathies involving a mutation of voltage-gated calcium channel cause the release of calcium from calcium stores such as endoplasmic reticulum in SCA15, 16, and 29 and mitochondrial calcium influx in SCA28 which lead to enzyme activation and apoptosis of Purkinje cells. Loss of autophagy, another built-in proteolysis mechanism, and accumulation of misfolded long polyglutamine peptide may be the cause of neurodegeneration Introduction Family & Patient History Family history is vital and should not be missed Onset and duration of symptoms are variable; history of gradual onset and slow progression over the years The duration of such progressive disease is important since it takes years to manifest in full extent. Clinical features may vary significantly among individual members of a single-family. Introductionfeatures among the various There is a huge overlap of phenotypic spinocerebellar ataxia subtypes, even within family members or interfamilial cases. Family & Patient History Clinical manifestation is usually more severe and early onset in pediatric and adolescent phenotypes. Some studies concluded that the size of triplet repeat expansion affects the severity and onset of disease and has a direct relationship, i.e., larger the size of the triplet repeat, the more severe and early onset is the presentation. Certain signs and symptomsIntroduction differ according to the genetic differences and subtypes. Signs & Symptoms ; Patient History Many hereditary ataxias, including most of the more common SCAs, manifest significant central nervous system involvement beyond the cerebellum to the brainstem and spinal cord, hence the designation “spinocerebellar” ataxia. Signs & Symptoms ; Patient History For example, there can be brainstem motor neuron loss manifesting as tongue atrophy, facial weakness, temporalis muscle atrophy and fasciculations. Upper motor neuron involvement can lead to spasticity and hyperreflexia. Peripheral nerve involvement is common in some SCAs, causing both sensory and motor problems. Introduction In some SCAs, particularly earlier-onset forms, basal ganglionic involvement can cause generalized dystonia or bradykinesia. Testing / Evaluation Clinical manifestation and characterization are imperative before genetic analysis. But phenotypes of various SCA subtypes overlap, so, genotype has become the gold standard for diagnosis. In recent advances, more descriptions of phenotypic differentiation aids in sorting out variants. Introduction Testing / Evaluation – Genetic Testing Advances in molecular genetic analysis and testing expedite the definite early classification and diagnosis. There are distinct scenarios in which gene testing can be used by clinicians: 1.Diagnostic testing, 2.Predictive testing, 3.Prenatal testing, Introduction 4.Carrier testing, and 5.Risk factor assessment Testing / Evaluation – Genetic Testing Recognition of a specific mutated gene helps to test the same gene in other family members. In the setting of positive family history, genetic testing is the definitive way of identifying spinocerebellar ataxia subtypes. Polymerase chain reaction (PCR) of nucleotide repeats in different SCA gene loci helps to identify the specific gene and nucleotide repeats involved. Introduction In clinically suspected patients, genetic testing should be at first carried out in most common SCAs such as SCA1, 2, and 3 and then should proceed to other subtypes if the first series test is negative Testing / Evaluation – Genetic Testing Current commercially available genetic test “panels” include only the most common (SCA1, 2, 3, 6, and 7) and some less common (SCA 5, 8, 11, 10, 12, 13, 14 and 17), comprising 75% of the known SCA genes. Whereas a positive gene test for a specific SCA establishes the diagnosis, an entirely “negative” SCA gene test panel does not exclude a hereditary ataxia Introduction Testing / Evaluation – Neuroimaging Neuroimaging demonstrates the gross cerebellar atrophy most prominent in SCA2 and least in other subtypes, enlargement of ventricles, and atrophy of other parts of the brain as well. Some specific focal or regional atrophies appreciated in certain SCAs are Pontocerebellar atrophy with enlargement of the fourth ventricle in SCA3, Atrophy of vermis sparing brainstem in SCA5, Isolated cerebellar atrophy in SCA6, Introduction Atrophy of the cerebellar vermis and hemispheres in SCA8, and SCA10, cerebral atrophy in SCA12, etc. Testing / Evaluation – Neuroimaging Introduction CREDIT Wang et al./Cell Reports 2016 Genetic mutation causes ataxia in humans and dogs. (2016, June 16). EurekAlert! https://www.eurekalert.org/news-releases/603059 Management Spinocerebellar ataxia is a genetic disease that has no definitive cure. Treatment is mainly symptomatic to alleviate symptoms like seizures, tremors, depression, ataxia, and eye symptoms. Antiepileptic drugs for seizures, botulinum toxin injections for dystonia, beta-blockers, and primidone for tremors, antidepressants for depression, etc. can be utilized for symptomatic Introduction treatment. PROGNOSIS Although it takes a long time to appreciate the full range of the signs and symptoms, it is almost irreversible once it is evident. But the symptomatic treatment may improve the prognosis. Survival depends upon the length of CAG repeat expansion. Most patients require wheelchair support bye 10 to 15 years of disease onset, but physical therapy can delay the wheelchair requirement. Introduction REFERENCES Beart, P., Robinson, M., Rattray, M., & Maragakis, N. J. (2017). Neurodegenerative diseases: Pathology, Mechanisms, and Potential Therapeutic Targets. Springer. Wu, Z. (2017). Inherited neurological disorders: Diagnosis and Case Study. Springer. Hafiz S, De Jesus O. Ataxia. [Updated 2023 Aug 23]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan. Bhandari J, Thada PK, Samanta D. Spinocerebellar Ataxia. [Updated 2023 Sep 15]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan. Paulson, H. L. (2009). The spinocerebellar ataxias. Journal of Neuro-ophthalmology, 29(3), 227– 237. Spinocerebellar Ataxias including Machado-Joseph Disease. (n.d.-b). National Institute of Neurological Disorders and Stroke. Home - OMIM. (n.d.). https://www.omim.org/
