Spinocerebellar ataxia type 2 (SCA2) is a rare autosomal dominant disorder caused by a (CAG)n trinucleotide expansion in a gene ATXN2. It usually debuts at the age of 40, and symptoms include difficulty articulating speech, dysmetria, ataxia, supranuclear ophthalmoplegia, slow saccadic eye movements, peripheral neuropathy (decreased sense of vibration, decreased/absent ankle and knee jerks). Perioral spasm, tremor of the head, and cramps are another common feature of this disorder. One quarter of the patients can have pyramidal signs such as Babinski sign and increased muscle tone. Average life expectancy is 11 years.
This disorder is common in India and Cuba, especially in province of Holguin with incidence of 4 of every 10,000.
Symptoms
SCA2 usually has 3 stages: asymptomatic, prodrome, and ataxic stage. In some cases, patients can experience parkinsonism as sole symptom of this disorder, and some patients can develop amyotrophic lateral sclerosis (ALS) in case of intermediate CAG expansions.
SCA2 stages and infantile-/juvenile-onset
Asymptomatic and prodrome stage In asymptomatic stage, patients don't develop any signs of this disorder, but in prodrome, patients usually develop sleep issues, muscle cramps, defects in sway control, dysautonomia, olfactory disorder, exaggerated reflexes, positive Babinski sign, sensory issues, and slowing of saccades; it can precede ataxic stage up to 15 years. Also, volume loss in pons, and specific frontal and parietal parts on MRI can be seen.
Ataxic stage In this stage patients experience slowing of saccades, truncal ataxia, dysmetria, dysdiachokinesia, dysarthria, postural instability, and occasionally decreased muscle tone. As this disorder progresses, fasciculation of arm and mouth, ophthalmoparesis, dysphagia, sphincter function disruption, myoclonus, dystonia, neuronopathy, chorea, and dementia can be seen.
Purkinje cells show poor branching and torpedo-like malformation of axons. Parallel fibers are scant, and Purkinje cells and granule cells are decreased in number. MRI shows atrophy of the white matter of the cerebellum, middle cerebellar peduncle, corticospinal tract, and pons. Later, atrophy spreads to cerebellar grey matter and cerebro-cerebellar tract. In severe stages, there is a severe degeneration of the corpus striatum, cortex, and thalamus.
Infantile-onset and juvenile-onset In infantile-onset SCA2 begins at an age of 0–1. Patients first experience developmental delays with hypotonia which then progresses into rapid developmental regression with epilepsy, and gaze aversion; patients usually die at the age of 0.5–3 years.
Juvenile-onset SCA2 debuts at the age of 2–15. Patients experience cerebellar tremor and ataxia at first, which then progresses into regression, oculomotor disease, and involvement of extrapyramidal and peripheral nervous system; patients usually die at the age of 26 to more than 50 years.
Parkinsonism Parkinsonism is a term for motor symptoms, which include hypokinesia, tremors, and rigidity. In some occasions patients develop parkinsonism which has good response to levedopa, some patients might additionally develop ataxia.
ALS ALS is neurodegenerative condition which causes death of motor neurons. Intermediate expansion (30-33 repeats) of CAG in ATXN2 allele can cause increased risk of ALS, although some patients can develop SCA2 and ALS at the same time.
Diagnosis Suspicion of SCA2 can be made by its symptoms (such as slowing of saccade, ataxia), and by family history; diagnosis can be confirmed by genetic testing of CAG expansion in ATXN2 gene.
Polymerase chain reaction (PCR) can be used to detect CAG expansion less than 100, but southern blotting (a laboratory technique to study DNA) can used to detect expansions more than 100.
Cause SCA2 is caused by (CAG)n nucleotides expansion in a gene ATXN2. Normally, ATXN2 contains less than 31 repeats, although 30-33 repeats can increase risk of ALS. Patients usually have from 33 to more than 200 CAG repeats; occasionally homozygous 31 repeats can cause SCA2. Anticipation (a phenomnon when symptoms get worse each generation) can be seen in this disorder; usually fathers pass more CAG repeats. Interruption by (CAA)n repeats can confer stability to expansion. +Repeats associated with SCA2Age of onsetRepeat sizeNormal alleleLess than 31 CAGALS-predisposing allele 30-33 CAGReduced penetrance34-35 CAGFull penetrance37-202 CAG
Pathophysiology
Ataxin-2 is a protein which contains 1312 amino acids; polyglutamine stretch is located near the N-terminus in the coding region of exon 1. CAG (CAA nucleotides too) nucleotides expansion causes stretching of the polyglutamine tract, which in turn might make the ataxin-2 protein aggregate and form inclusion bodies in neurons; these inclusion bodies contain other proteins, such as ataxin-1, ataxin-3. These mutated proteins cause disruption of endoplasmic reticulum membrane by BAX insertion, which in turn activates caspase-7 and might lead to apoptosis. Also, superoxide dismutase levels are elevated, while catalase levels are decreased, which causes oxidative stress and mitochondrial dysfunction.
Dysfunction of autophagy Autophagy is a process when a part of cytoplasm gets engulfed and forms autophagosome, and consequent fusion with lysosome causes degradation of its content. In SCA2 this process is hampered, which is evident by accumulation of p62/SQSTM1 and LC3-II (both of them are autophagy markers).
RNA toxicity ATXN2 locus encodes 2 transcripts, one of them is ATXN2-AS. ATXN2-AS has CUG repeats which are toxic; CUG repeats bind to MBNL1 protein and causes APP and NMDA-R1 missplicing. ATXN2 sense transcripts cause aberrant interaction with TBL3, which causes hampering in rRNA maturation and contributes to apoptosis of neurons.
Issues in calcium homeostasis A2BP1 normally binds to ATXN2 C-terminus, which in turn target exon 5 of GLUN1, but in SCA2 A2BP1 cannot bind to mutated ATXN2, which in turn causes missplicing and can trigger excitotoxicity (by increased levels of calcium ions) which causes apoptosis. Also, SCA2-induced pluripotent cells show altered expression of other glutamate receptor subinit genes (such as GRM3 and GRIA4) which again can cause exciotoxicity. Mutated ataxin-2 binds to inositol 1,4,5-trisphosphate receptor in the ER membrane, and causes release of calcium into the cytoplasm; there is an alteration in the expression of the calcium channels and transporters, genes related to IP3 metabolism and calmodulin dependent kinases. There is an upregulation of SAM68 protein which causes NRXN1 mRNA to be spiliced to specific isoforms which alters connections between Purkinje and granule cells.
Alteration of stress granule dynamics Ataxin-2 is a part of stress granules and interacts with TDP-43 and STAU1; mutated ataxin-2 causes mislocalisation of TDP-43 and there is an overabundance of STAU1; STAU impairs the assembly of stress granules.
Treatment This disorder doesn't have a cure, but supportive care is possible. Pharmacological treatments, such as high-doses of vitamin B, magnesium, mexiletine, quinine might alleviate muscle cramps; anticholinergics and dopaminergics are effective in management of dystonia, hypokinesia, and tremor. Postural tremor can be treated using DBS. Physiotherapy can be used to ease symptoms.
Research
In 2011, researchers showed that zinc supplementation decreased symptoms of ataxia, dysdiadochocinesia, and slowed saccade. In 2014, researchers showed that lithium didn't show change of symptoms and brain volume, but it showed decreased points in Beck depression inventory test. Later, in 2022, researchers showed that riluzole didn't show any effects in patients with SCA2.
In 2017, researchers used ASOs in mice model of SCA2 which showed positive results, specifically it decreased levels of ataxin-2 and improved motor function.
History Wadia and Swami reported 9 Indian families with SCA2 in 1971. In 1993, Gispert and colleagues mapped SCA2 to long arm of chromosome 12, and later ATXN2 was discovered by Pulst and collagues.
In 2010, Elden and colleagues showed that intermediate CAG expansion in ATXN2 increased risk for ALS.
References