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Spinocerebellar ataxia type 3 (SCA3)

Spinocerebellar ataxia type 3 (SCA3)



Overview              

Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is a rare, inherited genetic disorder that causes progressive loss of balance, coordination, and movement control

Symptoms

Ataxia: Unsteady gait, stumbling, and poor hand-eye coordination.

Spasticity and Rigidity: Tight, stiff muscles and slow movement.

Dystonia: Uncontrolled muscle tensing that leads to unusual postures or twisting.

Tremors: Shaking when attempting fine motor tasks or using the hands.

Bulging Eyes: A distinct "staring" or wide-eyed appearance (eyelid retraction).

Double Vision: Difficulty moving the eyes normally, slow eye movements, or impaired gaze (ophthalmoplegia).

Dysarthria: Slow, slurred, or unclear speech.

Dysphagia: Trouble swallowing, which can increase the risk of choking

Peripheral Neuropathy: Numbness, tingling, cramps, or burning pain in the hands and feet.

Sleep Disorders: Restless legs syndrome or REM sleep behavior disorder.

Causes

CAG Trinucleotide Expansion: The condition occurs due to an unstable expansion of a cytosine-adenine-guanidine (CAG) repeat sequence within the coding region of the ATXN3 gene.

Repeat Lengths: Healthy individuals typically have 10 to 44 CAG repeats, whereas people with SCA3 have an abnormal expansion ranging from about 52 to 91 repeats.

Polyglutamine Tract: This expanded CAG triplet codes for an elongated string of the amino acid glutamine (a polyglutamine or polyQ stretch) in the resulting ataxin-3 protein.

Protein Misfolding & Aggregation: The abnormal, elongated ataxin-3 protein misfolds and forms toxic clumps (aggregates) inside the nuclei of neurons.Neuronal Degeneration:

Autosomal Dominant: SCA3 is inherited in an autosomal dominant manner, meaning a single copy of the altered gene from one parent is enough to cause the disease.

Parental Risk: An affected parent has a 50% chance of passing the mutated gene to each child.

Anticipation: The repeat size tends to expand further when passed down from one generation to the next, often leading to earlier onset or more severe symptoms in offspring.

Diagnosis

Clinical Evaluation: Doctors review family medical history and assess symptoms like balance loss (ataxia), poor hand coordination, speech issues (dysarthria), and abnormal eye movements.

Neuroimaging: An MRI or CT scan of the brain may be performed to check for cerebellar and brainstem shrinkage (atrophy), supporting the clinical findings.

Molecular Genetic Testing: A blood test analyzes DNA for a pathological expansion of CAG repeats in the ATXN3 gene. Normal alleles typically have up to 44 repeats, whereas a full disease-causing expansion generally exceeds 56 repeats.

Treatment

Therapies: Physical and occupational therapy help maintain mobility, improve coordination, and prevent falls. Speech therapy assists with swallowing difficulties (dysphagia) and slurred speech (dysarthria).

Assistive Devices: Canes, walkers, and wheelchairs help preserve independence and mobility.

Medications: Pharmacologic options can help manage specific symptoms like spasticity, tremors, dystonia, pain, and sleep or mood disorders.

Multidisciplinary Team: Care is best managed by a team that may include a neurologist, physical therapist, occupational therapist, and speech-language pathologist

Antisense Oligonucleotide (ASO) Therapy: Companies like Cure Rare Disease are developing ASOs designed to bind to messenger RNA and reduce levels of the toxic Ataxin-3 protein.

Investigational Drugs: Clinical trials, such as studies evaluating intravenous trehalose (SLS-005), are exploring ways to help cells clear abnormal protein aggregates.

Cell and Stimulation Therapies: Early research is investigating the safety of non-invasive brain stimulation like transcranial alternating current stimulation (tACS) and donor stem cell therapies (such as Stemchymal).

Type of Doctor Department : A neurologist

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