Dr Suvojit Bhowmik DM1 Dr Ashok Kumar Kayal, Professor1 Dr.(Prof) Shyamal Kumar Das, DM2
Department(s) and institution(s):
1. Department of Neurology, Gauhati Medical College and Hospital, Guwahati, Assam, India
2. Department of Neurology, Bangur Institute of Neurosciences, Kolkata, West-e,
Name: Dr. Suvorit Bhowmick
Address: Department of Neurology, Gauhati Medical College and Hospital, Bhangagarh, Guwahati – 781032.
Ataxia is a clinical syndrome of imbalance and incoordination due to pathology in the cerebellum, spinocerebellar pathways, pontocerebellar pathways or afferent proprioceptive inputs (sensory ataxia).1 This overview focuses on cerebellar ataxias, with emphasis on Indian research.
In the 1950s, Greenfield attempted a clinicopathological classification of ataxic disorders, such as olivopontocerebellar atrophy, cerebellar cortical atrophy and spinocerebellar degeneration. Anita Harding recognized pitfalls in the classification, wherein hereditary disorder in a single family often had to be assigned to different categories. Her classification of ataxia in the 1980s, based on clinical criteria, renewed the interest of neurologists in ataxia and paved way for molecular techniques to identify numerous gene loci responsible for ataxia syndromes. Currently, ataxias can be divided into three major groups: hereditary ataxias, non-hereditary degenerative ataxias and acquired ataxias (Table 1).2 Autosomal recessive inheritance is likely in patients with early onset ataxia (before the age of 25 years) and healthy parents. A familial disorder affecting successive generations is suggestive of autosomal dominant ataxia. Reaching a diagnosis becomes quite challenging in adult onset sporadic ataxia wherein the entire spectrum of non-genetic and genetic causes needs consideration.3
Sporadic cerebellar ataxias
Acute onset cerebellar ataxia is a diagnostic and therapeutic emergency, when one must consider cerebellar stroke, cerebellar abscess, meningitis, vitamin B1 deficiency and drug intoxication. When cerebellar ataxia has subacute to chronic onset and is progressive, the differential diagnosis includes cerebellar tumor, paraneoplastic syndrome, Creutzfeldt–Jakob disease, Whipple’s disease, celiac disease, autoimmune thyroiditis, ataxia associated with autoantibodies to glutamic acid decarboxylase, and neurodegenerative diseases like multiple system atrophy.4
Autosomal recessive cerebellar ataxias (ARCAs)
Friedreich’s ataxia (FRDA) is characterized by early-onset progressive gait and limb ataxia, dysarthria, ocular fixation instability, loss of vibration and proprioceptive sense, areflexia and pyramidal signs. Other manifestations include cardiomyopathy, diabetes mellitus, scoliosis and pes cavus. Progressive cerebellar atrophy does not occur.5 In most of the patients, there is triplet GAA expansion within the first intron of the frataxin gene found on chromosome 9q13.6 FRDA is found in individuals of European, North African, Middle Eastern or Indian origin.7 Its prevalence and carrier frequency in the Caucasians are about 1 per 50,000 and 1 per 85 respectively. Linkage disequilibrium studies have found a common haplotype with the expanded alleles and normal alleles having a higher number of GAA repeats (large normal [LN] alleles).8 While LN alleles account for 17% of the normal alleles in Caucasians, their frequency in India is lower (6%).8,9 A study from East India identified the same common founder haplotype (ATCC) reported worldwide for FRDA patients. In addition, a new haplotype (ACCT) was identified, probably of Indian origin. It has been postulated that FRDA mutation in North India arose from a pre-existing pool of pre-mutation alleles introduced through European migration and in South India through admixture of populations.10 Recent studies from India have explored mitochondrial genome variation and potential role of circulating cell-free nuclear DNA and mitochondrial DNA in blood plasma as biomarkers in patients of FRDA.11,12
ARCAs which can mimic FRDA are ataxia with vitamin E deficiency (AVED), abetalipoproteinemia and Refsum’s disease.13 In addition to ataxia, there may be retinitis pigmentosa and cardiomyopathy in AVED. Most of the patients are from North Africa, Europe, North America and Japan.14 The neurological manifestations of abetalipoproteinemia are similar toataxia with vitamin E deficiency ( AVED) . There is also lipid malabsorption, hypocholesterolaemia and acanthocytosis. It is a rare disorder with a frequency of less than 1/100,000.15 The clinical features of Refsum’s disease include ataxia, peripheral polyneuropathy, sensorineural deafness, retinitis pigmentosa, anosmia, skeletal abnormalities, ichthyosis, renal failure, cardiac myopathy and arrhythmias.16 Patients of AVED and abetalipoproteinemia have been reported from India, albeit without genetic confirmation.17,18
Some ARCAs can be distinguished from FRDA by the presence of cerebellar atrophy on neuroimaging.13 Late onset Tay-Sachs disease (juvenile onset or adult onset forms) is characterized by ataxia, areflexia, proximal muscle weakness, muscle atrophy, fasciculations, psychiatric and behavioral problems. There can be spasticity, seizures and dementia in the juvenile onset form. The disease is common in Ashkenazi Jews.19 Clinical manifestations of cerebrotendinous xanthomatosis (CXT) include ataxia, peripheral neuropathy, pyramidal signs, extrapyramidal signs, seizures, psychiatric problems, dementia, cataracts, tendon xanthomas, early atherosclerosis, osteoporosis and diarrhea. While the disease has predilection for Jews of Moroccan origin, several cases have been reported from India.20,21 Mitochondrial recessive ataxia syndrome (MIRAS) is a common cause of ataxia in Finland. There can be additional peripheral neuropathy, myoclonus, epilepsy, psychiatric features, myopathy and ophthalmoplegia.22 Spinocerebellar ataxia with axonal neuropathy, characterized by ataxia, peripheral axonal sensorimotor neuropathy, distal amyotrophy and pes cavus, is found in Saudi Arabia.23
ARCAs which have earlier age of onset than FRDA and prominent cerebellar atrophy on neuroimaging include Ataxia telangiectasia (AT), AT-like disorder, ataxia with oculomotor apraxia (AOA), type 1 and type 2, autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), infantile-onset spinocerebellar ataxia (IOSCA), Cayman ataxia (CA) and Marinesco-Sjögren’s syndrome (MSS).13 AT is reported from all over the world. Clinical features include ataxia, oculomotor abnormalities, extrapyramidal features, mucocutaneous telangiectasia, recurrent sinopulmonary infections, radiosensitivity and predisposition to cancers.13,24 AOA type 1 is the most common ARCA in Japan and is also reported from Europe and North Africa.25 AOA type 2 is probably the second most common autosomal recessive ataxia after FRDA in Europe.26 ARSACS is found in Northeast Canada, Europe, Eurasia, North Africa and Japan.13 IOACS is seen in Finland.27 CA is found in Grand Cayman Island in the Caribbean. With the exception of AT and ARSACS, these disorders have not been reported from India.28,29 A study from National Institute of Mental Health and Neurosciences, Bengaluru is probably the largest study on AT from India. In their cohort of 100 patients, findings other than ataxia and telangiectasia included impaired pursuit and slow saccades (60%), ocular apraxia (84%), nystagmus (23%), extrapyramidal signs (31%) and hyporeflexia (61%). Low immunoglobulin levels were found in 15/28 (53.6%) and elevated alpha fetoprotein levels in 39/47(83.0%) patients.30
Autosomal dominant cerebellar ataxias (ADCAs)
Spinocerebellar ataxias (SCAs) comprise a large group of heterogeneous neurodegenerative disorders inherited in an autosomal dominant fashion. To date, 40 SCAs have been described.31 The most common ones are due to CAG repeat expansions in the coding regions of the respective genes (SCAs 1, 2, 3, 6, 7 and 17). Geographic distribution and important clinical features of some SCAs are listed in Tables 2 and 3 respectively. In most cases, symptoms appear in the third to fifth decade. Neuroimaging studies show cerebellar atrophy with variable brainstem, supratentorial and spinal cord involvement. Cerebellar atrophy is more progressive in SCAs due to repeat expansions than due to point mutations. The phenomenon of anticipation occurs due to progressive repeat expansion at every parent-child transmission. Occasionally anticipation is so extreme in SCA7 and SCA2 that infantile cases occur in apparently asymptomatic parents. SCAs 8, 10, 12, 31 and 36 are due to non-coding repeat expansions, which have lesser tendencies for anticipation. SCA8 is linked to an expanded CTG repeat. The remaining SCAs are due to point mutations or deletions in the respective genes. ADCAs not in the SCA classification are dentatorubral-pallidoluysian atrophy (DRPLA), neuroferritinopathy, prion diseases, Alexander disease and adult-onset leukodystrophies.32
Much research on ataxia in India has been on SCAs, pioneered by Noshir Hormusjee Wadia. In 1971, Wadia and Swami described nine Indian families with a form of spinocerebellar degeneration different from the previously described hereditary ataxias of the West. The key distinguishing features were slow saccades and peripheral neuropathy.33 Neuroimaging showed olivopontocerebellar atrophy. It was subsequently classified as SCA2.34 Slow saccades have also been found, less commonly, in other SCAs.35 The major studies on SCAs from different regions of India are shown in Figure 1.34-46
SCA1, SCA2 and SCA3 have been found in many regions of India, although SCA1 is more common in South India and SCA3 in the Bengalis of East India.37,39,40 A study from East India found that the frequency of LN alleles at SCA2 locus in Indian population was intermediate between the Caucasians and the Japanese.36
SCA6 was thought to be uncommon India. However, a recent study from East India found its frequency to be 13.3% in patients with possible SCAs.35,47
The frequency of SCA7 in India is low. Based on CAG repeat analysis in healthy individuals, a study from North India found that the ethnic population of IE-N-LP2 (from the Indian Genetic Consortium) is predisposed to SCA7.45 However, SCA7 has also been reported in a in a girl of ethnic tribe from Northeast India and in a family from South India.48,49 There are possibly multiple founders of the disease because a common haplotype is not shared by different SCA7 families across the world, there are possibly multiple founders of the disease.50
SCA12 was first reported in an American family of German descent.51 The rest of the reported families are of Indian descent, majority of which belong to the Agarwal community. A common haplotype was found associated with majority of expanded chromosomes in affected families, suggesting a founder effect. This haplotype was different from the American family.44
SCA17 has been reported in three families of Indian descent.52,53
Fragile X-associated Tremor/Ataxia syndrome (FXTAS) is a clinically heterogeneous disorder characterized predominantly by tremor, followed by late onset gait ataxia, autonomic dysfunction and/or cognitive impairment.54 A recent study from North India found three cases of FXTAS amongst 109 patients of late onset cerebellar ataxia and/or tremor.55
Episodic ataxias (EAs)
EAs are autosomal dominant ataxias characterized by intermittent attacks of ataxia accompanied variably by dysarthria, vertigo and nystagmus.56 Seven subtypes have been described, which can be distinguished clinically by the duration of ataxia and associated manifestations.57 There have been few case reports from India, one of them being a genetically confirmed case of EA2.58, 59, 60
Ataxia can be the presentation of myriad diseases. Therefore, localization and classification are important to facilitate diagnosis. The investigations need to focus on the treatable causes of ataxia (AVED, abetalipoproteinemia, Refsum’s disease, CXT, Niemann-Pick type C, ARCA type 2 due to coenzyme Q10 deficiency).4 Family history is important to identify hereditary ataxias, as the affected patients will need genetic counseling. One must be careful in diagnosis, as hereditary ataxias may have sporadic presentation.
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