Abstract

The spinocerebellar ataxia type 2 is a neurodegenerative disease with autosomal dominant inheritance; clinically characterized by progressive cerebellar ataxia, slow ocular saccades, nystagmus, ophthalmoplegia, dysarthria, dysphagia, cognitive deterioration, mild dementia, peripheral neuropathy. Infantile onset is a rare presentation that only has been reported in four instances in the literature. In the present work a boy aged 5 years 7 months was studied due to horizontal gaze-evoked nystagmus, without saccades, ataxic gait, dysarthria, dysphagia, dysmetria, generalized spasticity mainly pelvic, bilateral Babinsky. The mother aged 27 years-old presented progressive cerebellar ataxia, dysarthria, dysmetria, dysdiadochokinesis, limb ataxia and olivopontocerebellar atrophy. The molecular analysis was made by identifying the expansion repeats in tandem by long PCR to analyze the repeats in the ATXN2 gene. We found an extreme CAG expansion repeats of ~884 repeats in the child. We describe a Mexican child affected by SCA2 with an infantile onset, associated with a high number of CAG repeats previously no reported and anticipation phenomenon.

Keywords:
Ataxin-2 gene; anticipation phenomenon; autosomal dominant; spinocerebellar ataxia type 2; triplet expansion repeat

Spinocerebellar ataxia type 2 (SCA2) (MIM ID #183090) is an autosomal dominant disorder with progressive cerebellar ataxia, slow ocular and dysmetric vertical saccades, gaze-evoked nystagmus, supranuclear ophthalmoplegia, dysarthria, dysphagia, rigidity, spasticity, dysmetria and dysdiadochokinesis, bradykinesia, myoclonus, cognitive deterioration, mild dementia, dopamine-responsive parkinsonism, peripheral neuropathy and olivopontocerebellar atrophy (Choudhry et al., 2001Choudhry S, Mukerji M, Srivastava AK, Jain S and Brahmachari SK (2001) CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms. Hum Mol Genet 10:2437-2446.). SCA2 has a global prevalence of 1:35,000 individuals, is caused by (CAG)n abnormal long expansions in the ataxin-2 gene (ATXN2, 601517) (gene map locus 12q24.12), encoding a polyglutamine tract (polyQ) in the mutant protein which represent the large majority.

SCA2 is the most prevalent of the polyQ ataxias in Cuba, India, Mexico, and Southern Italy, and the second most prevalent worldwide, accounting for 15% of all cases (Antenora et al., 2017Antenora A, Rinaldi C, Roca A, Pane C, Lieto M, Saccá F, Peluso S, De Michele G and Filla A (2017) The multiple faces of spinocerebellar ataxia type 2. Ann Clin Transl Neurol 10:687-695.). An infantile onset is an uncommon occurrence presentation with only nine reports in the literature and is associated with extremely large CAG expansions (range 100–200 repeats). On the other hand, there are severe infantile cases with expansions between 50-70 repeats, sometimes is related with interruption CTG or CAA as occurs in adults with SCA2 and amyotrophic lateral sclerosis, which also leads to instability of ATXN2 mRNA (Choudhry et al., 2001Choudhry S, Mukerji M, Srivastava AK, Jain S and Brahmachari SK (2001) CAG repeat instability at SCA2 locus: anchoring CAA interruptions and linked single nucleotide polymorphisms. Hum Mol Genet 10:2437-2446.; Antenora et al., 2017Antenora A, Rinaldi C, Roca A, Pane C, Lieto M, Saccá F, Peluso S, De Michele G and Filla A (2017) The multiple faces of spinocerebellar ataxia type 2. Ann Clin Transl Neurol 10:687-695.), and meiotic instability a general feature of SCA2 without a familial history (Babovic et al., 1998Babovic VD, Snow K, Patterson MC and Michels VV (1998) Spinocerebellar ataxia type 2 (SCA 2) in an infant with extreme CAG repeat expansion. Am J Med Genet 79:383-387; Mao et al., 2002Mao R, Aylsworth AS, Potter N, Wilson WG, Breningstall G, Wick MJ, Babovic-Vuksanovic D, Nance M, Patterson MC, Gomez CM et al. (2002) Childhood-onset ataxia: testing for large CAG-repeats in SCA2 and SCA7. Am J Med Genet 110:338-345.; Moretti et al., 2004Moretti P, Blazo M, Garcia L, Armstrong D, Lewis RA, Roa B and Scaglia F (2004) Spinocerebellar ataxia type 2 (SCA2) presenting with ophthalmoplegia and developmental delay in infancy. Am J Med Genet A 124A:392-396.; Dirik et al., 2007Dirik E, Yis U, Basak N, Soydan E, Hüdaoglu O and Ozgönül F (2007) Spinocerebellar ataxia type 2 in a Turkish family. J Child Neurol 22:891-894.; Abdel and Zaki, 2008Abdel AA and Zaki MS (2008) Spinocerebellar ataxia type 2 (SCA2) in an an Egyptian family presenting with polyphagia and marked CAG expansion in infancy. J Neurol 55:413-419.; Paciorkowski et al., 2011Paciorkowski AR, Shafrir Y, Hrivnak J, Patterson MC, Tennison MB, Clark HB and Gomez CM (2011) Massive expansion of SCA2 with autonomic dysfunction, retinitis pigmentosa, and infantile spasms. Neurology 77:1055-1060.; Di Fabio et al., 2012Di Fabio R, Santorelli F, Bertini E, Balestri M, Cursi L, Tessa A, Pierelli F and Casali C (2012) Infantile childhood onset of spinocerebellar ataxia type 2. Cerebellum 11:526-530.; Vinther-Jensen et al., 2013Vinther-Jensen T, Ek J, Duno M, Skovby F, Hjermind LE, Nielsen JE and Nielsen TT (2013) Germline CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2. Eur J Hum Genet 21:626.; Singh et al., 2014Singh A, Faruq M, Mukerji M, Dwivedi MK, Pruthi S and Kapoor S (2014) Infantile onset spinocerebellar ataxia 2 (SCA2): a clinical report with review of previous cases. J Child Neurol 29:139–144.). However, cases with infantile SCA2 are explain by these features; there are childhood onset cases reported with mosaicism in germ cells such as spermatozoa with larger expanded alleles more than in peripheral blood cells (Moretti et al., 2004Moretti P, Blazo M, Garcia L, Armstrong D, Lewis RA, Roa B and Scaglia F (2004) Spinocerebellar ataxia type 2 (SCA2) presenting with ophthalmoplegia and developmental delay in infancy. Am J Med Genet A 124A:392-396.; Dirik et al., 2007Dirik E, Yis U, Basak N, Soydan E, Hüdaoglu O and Ozgönül F (2007) Spinocerebellar ataxia type 2 in a Turkish family. J Child Neurol 22:891-894.; Abdel and Zaki, 2008Abdel AA and Zaki MS (2008) Spinocerebellar ataxia type 2 (SCA2) in an an Egyptian family presenting with polyphagia and marked CAG expansion in infancy. J Neurol 55:413-419.; Vinther-Jensen et al., 2013Vinther-Jensen T, Ek J, Duno M, Skovby F, Hjermind LE, Nielsen JE and Nielsen TT (2013) Germline CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2. Eur J Hum Genet 21:626.).

The most frequent signs in infantile onset are developmental delay, visual impairment usually dependent on retinitis pigmentosa or optic atrophy, hypotonia, seizures with infantile spasms or myoclonic seizures, facial dysmorphism, dystonic features and early death (Tables 1 and 2) (Singh et al., 2014Singh A, Faruq M, Mukerji M, Dwivedi MK, Pruthi S and Kapoor S (2014) Infantile onset spinocerebellar ataxia 2 (SCA2): a clinical report with review of previous cases. J Child Neurol 29:139–144.; Antenora et al., 2017Antenora A, Rinaldi C, Roca A, Pane C, Lieto M, Saccá F, Peluso S, De Michele G and Filla A (2017) The multiple faces of spinocerebellar ataxia type 2. Ann Clin Transl Neurol 10:687-695.). Brain MRI scans showed extreme cerebellar and brainstem atrophy, but also different degrees of supratentorial atrophy, ventricular enlargement, and white matter signal abnormalities probably attributable to dysmyelination and/or delayed myelination (Singh et al., 2014Singh A, Faruq M, Mukerji M, Dwivedi MK, Pruthi S and Kapoor S (2014) Infantile onset spinocerebellar ataxia 2 (SCA2): a clinical report with review of previous cases. J Child Neurol 29:139–144.; Antenora et al., 2017Antenora A, Rinaldi C, Roca A, Pane C, Lieto M, Saccá F, Peluso S, De Michele G and Filla A (2017) The multiple faces of spinocerebellar ataxia type 2. Ann Clin Transl Neurol 10:687-695.). The aim of this report is to present the clinical findings and molecular studies in a Mexican child with familial SCA2 with extremely large CAG expansion repeats, and a literature review of clinical and molecular findings in early-onset cases with SCA2.

The clinical findings in the index case, a boy aged 5 yr 7 mo (Figure 1A), was the product of the first pregnancy complicated by hyperemesis during the first trimester, delivery was by cesarean section due to macrosomia. Since birth the patient presented feeding difficulties due to dysphagia that persists at this time; at 3 months of age nystagmus was present. Psychomotor development, at 12 months he began to walk with evident ataxic gait. When he started speaking at 2-3 years of age, he presented dysarthria, at this moment he has progression of all the symptomatology, poor coordination, walking difficulty, incontinence (he never had sphincter control) and he continues with dysphagia. At physical examination he presented horizontal gaze-evoked nystagmus, without saccades, ataxic gait, dysarthria, dysphagia, dysmetria, generalized spasticity mainly pelvic, bilateral Babinsky. CT brain scan revealed mild pontine atrophy, moderate cerebellar atrophy (Table 2) (Figure 1B,C).

Figure 1
A. Pedigree, arrow: the propositus. B-C., Propositus' CT brain scan showing mild pontine atrophy and moderate cerebellar atrophy.

Family data: Mother aged 27 years similarly affected, clinical symptomatology began at 7 years of age with walking and speech difficulties. At 10 years of age she started with seizures, controlled for 5 years. Currently presents ataxia, dysarthria, dysmetria, dysdiadochokinesia, ataxic gait with olivopontocerebellar atrophy. Father aged 30-year-old neurologically healthy. Two maternal aunts of 30 and 23 years and the maternal grandmother (age of onset 40 yr), were similarly affected. Mother with molecular analysis positive to SCA2 with a genotype 22/49 CAG expansion repeats and father with normal range or expansion repeats.

Genomic DNA was extracted from peripheral blood leukocytes using the Gene Catcher Kit (Invitrogen) of the index case. The analysis of the ataxin-2 gene was performed by long PCR using a pair of oligonucleotides flanking the repeated CAGs. The sequence of the oligonucleotides was as follows: FWP1 5′-GGGCCCCTCACCATGTCG-3′; and RWP 5′-CGGGCTTGCGGACATTGG-3′ (Sigma Aldrich). PCR was carried out in a total volume of 10 μl containing 100 ng of human DNA, 0.4 μM of each oligonucleotide, 200 μM of each dNTP; 0.6 μl of the 10x reaction buffer (Roche Diagnostics GmbH), 2 mM MgCl2 (Roche Diagnostics), 0.5 U of the enzyme Taq DNA polymerase (Roche Diagnostics GmbH) and 10% DMSO (Sigma-Aldrich) (Magaña et al., 2008Magaña JJ, Vergara MD, Sierra-Martínez M, García-Jiménez E, Rodríguez-Antonio F, del Rocío Gómez M, Valdés-Flores M and Cisneros B (2008) Molecular analysis of the CAG repeat among patients with Type-2 spinocerebellar ataxia in the Mexican population. Gac Med Mex 144:413-418.; Flores-Alvarado et al., 2016Flores-Alvarado LJ, Dávalos-Rodríguez NO, García-Cruz D, Madrigal-Ruiz PM, Ruiz-Mejía R, Aguilar-Aldrete ME and Ramirez-Garcia SA (2016) (CAG)n polymorphism of the ATXN2 gene, a new marker of susceptibility for type 2 diabetes mellitus. Rev Panam Salud Publica 40:318-324.). The amplification program consisted of 28 cycles, including denaturation at 96 °C for 60 s, hybridization at 59 °C for 30 s and polymerization at 72 °C for 60 s (Magaña et al., 2008Magaña JJ, Vergara MD, Sierra-Martínez M, García-Jiménez E, Rodríguez-Antonio F, del Rocío Gómez M, Valdés-Flores M and Cisneros B (2008) Molecular analysis of the CAG repeat among patients with Type-2 spinocerebellar ataxia in the Mexican population. Gac Med Mex 144:413-418.; Flores-Alvarado et al., 2016Flores-Alvarado LJ, Dávalos-Rodríguez NO, García-Cruz D, Madrigal-Ruiz PM, Ruiz-Mejía R, Aguilar-Aldrete ME and Ramirez-Garcia SA (2016) (CAG)n polymorphism of the ATXN2 gene, a new marker of susceptibility for type 2 diabetes mellitus. Rev Panam Salud Publica 40:318-324.).

The PCR product was mixed with deionized formamide and denatured in water bath for seven minutes. Then it was placed on ice frappe for five minutes, and subjected by electrophoresis on 10% polyacrylamide gels (PAGE, 29:1). From the PCR products, were made a dilution 1:5 to apply 5 mL in the respective lane. PAGE gel was run at 150 volts, during 6.25 hours (Magaña et al., 2008Magaña JJ, Vergara MD, Sierra-Martínez M, García-Jiménez E, Rodríguez-Antonio F, del Rocío Gómez M, Valdés-Flores M and Cisneros B (2008) Molecular analysis of the CAG repeat among patients with Type-2 spinocerebellar ataxia in the Mexican population. Gac Med Mex 144:413-418.); and subsequently stained with a solution containing; 0.1 g silver nitrate, 0.5 mL of acetic acid and 10 mL of ethanol graduated at 100 mL (12). The development solution used in the PAGE gels contained 3% sodium hydroxide with 270 μL of 37% formaldehyde graduated to 100 ml (Flores-Alvarado et al., 2016Flores-Alvarado LJ, Dávalos-Rodríguez NO, García-Cruz D, Madrigal-Ruiz PM, Ruiz-Mejía R, Aguilar-Aldrete ME and Ramirez-Garcia SA (2016) (CAG)n polymorphism of the ATXN2 gene, a new marker of susceptibility for type 2 diabetes mellitus. Rev Panam Salud Publica 40:318-324.).

The amplified fragment of 130 bp corresponds to a normal allele of 22 CAG repeats. The normal range is between 13-31 CAG repeats and in affected cases greater than 32 repeats (Guzmán-López et al., 2018Guzmán-López R, García-Cruz D, Magallanes-Ordoñez JJ, Siliceo-Murrieta J, Dávalos-Rodríguez N, Ruiz-Mejía R, Madrigal-Ruiz PM, Cruz-Bastida JM, Cruz-Bastida JS, Duque-Bautista H et al. (2018) Childhood obesity, insulin resistance and the polymorphism (CAG)n of the ATXN2 gene. Rev Med MD 9:134-139.). In the PCR-PAGE denaturing assay (Figure 2) the first lane is a molecular weight marker of 100 bp, the second lane is the white control PCR which appears white, without amplified product, in lanes 4 and 6 is the sample 124 with a DNA dilution of 1:5, there is a band of 130 bp and another band at 2 kb that was calculated as 2,652 bp which generates the genotype 22/~884 repeats; in lanes 3 and 7 is the sample 125 with a DNA dilution of 1:5, a band of 130 bp is observed and in lane 5 there is a negative control sample for the trinucleotide expansion repeat. Thus, with these considerations, the index case presented a normal allele of 22 CAG repeats, and an allelic variant of ~884 CAG expansion repeats (2,652 bp), being carrier of the genotype 22/~884. This result was corroborated by the RED (Repeat Expansion Detection) method in the IDIBELL Center of Molecular Diagnosis; showing a higher penetrance allele of 2600 bp.

Figure 2
PAGE gel showing in the 4^th and 6^th lanes the extreme CAG repeats expansion ~884.

The present case is the first report of an index case with autosomal dominant SCA2 of neonatal presentation due to massive expansion of more than 884 CAG repeats in exon 1 of ATXN2. Massive expansions in the SCA2 are considered above one hundred repeats, longer are associated with an early onset age, and also are related with severe clinical findings (Antenora et al., 2017Antenora A, Rinaldi C, Roca A, Pane C, Lieto M, Saccá F, Peluso S, De Michele G and Filla A (2017) The multiple faces of spinocerebellar ataxia type 2. Ann Clin Transl Neurol 10:687-695.). Certainly, the present case started with symptoms since birth and severe neurological deterioration and a genotype with a longer allele, compared with other neonatal cases (Babovic et al., 1998Babovic VD, Snow K, Patterson MC and Michels VV (1998) Spinocerebellar ataxia type 2 (SCA 2) in an infant with extreme CAG repeat expansion. Am J Med Genet 79:383-387; Dirik et al., 2007Dirik E, Yis U, Basak N, Soydan E, Hüdaoglu O and Ozgönül F (2007) Spinocerebellar ataxia type 2 in a Turkish family. J Child Neurol 22:891-894.).

So, the range in 19 reported cases with SCA2 with age of onset in childhood was 0-48 months, which were carriers of the heterozygous genotype (22/X), in which X corresponds to an allele with abnormal expansion repeats with an average range of 62-841 repeats (Table 1) (Babovic et al., 1998Babovic VD, Snow K, Patterson MC and Michels VV (1998) Spinocerebellar ataxia type 2 (SCA 2) in an infant with extreme CAG repeat expansion. Am J Med Genet 79:383-387; Mao et al., 2002Mao R, Aylsworth AS, Potter N, Wilson WG, Breningstall G, Wick MJ, Babovic-Vuksanovic D, Nance M, Patterson MC, Gomez CM et al. (2002) Childhood-onset ataxia: testing for large CAG-repeats in SCA2 and SCA7. Am J Med Genet 110:338-345.; Moretti et al., 2004Moretti P, Blazo M, Garcia L, Armstrong D, Lewis RA, Roa B and Scaglia F (2004) Spinocerebellar ataxia type 2 (SCA2) presenting with ophthalmoplegia and developmental delay in infancy. Am J Med Genet A 124A:392-396.; Dirik et al., 2007Dirik E, Yis U, Basak N, Soydan E, Hüdaoglu O and Ozgönül F (2007) Spinocerebellar ataxia type 2 in a Turkish family. J Child Neurol 22:891-894.; Abdel and Zaki, 2008Abdel AA and Zaki MS (2008) Spinocerebellar ataxia type 2 (SCA2) in an an Egyptian family presenting with polyphagia and marked CAG expansion in infancy. J Neurol 55:413-419.; Paciorkowski et al., 2011Paciorkowski AR, Shafrir Y, Hrivnak J, Patterson MC, Tennison MB, Clark HB and Gomez CM (2011) Massive expansion of SCA2 with autonomic dysfunction, retinitis pigmentosa, and infantile spasms. Neurology 77:1055-1060.; Di Fabio et al., 2012Di Fabio R, Santorelli F, Bertini E, Balestri M, Cursi L, Tessa A, Pierelli F and Casali C (2012) Infantile childhood onset of spinocerebellar ataxia type 2. Cerebellum 11:526-530.; Vinther-Jensen et al., 2013Vinther-Jensen T, Ek J, Duno M, Skovby F, Hjermind LE, Nielsen JE and Nielsen TT (2013) Germline CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2. Eur J Hum Genet 21:626.; Avelino et al., 2014Avelino MA, Pedroso L, Orlacchio A, Barsottini OGP and Masruha MR (2014) Neonatal SCA2 presenting with choreic movements and dystonia with dystonic jerk, retinitis, seizures and hypotonia. Mov Disord Clin Pract 1:252-254.; Singh et al., 2014Singh A, Faruq M, Mukerji M, Dwivedi MK, Pruthi S and Kapoor S (2014) Infantile onset spinocerebellar ataxia 2 (SCA2): a clinical report with review of previous cases. J Child Neurol 29:139–144.).

Abnormal expansions in many trinucleotide expansion diseases are related with the anticipation phenomenon, resulting into longer mutant alleles of maternal origin. However, in infantile SCA2 with massive expansion, most of the reported cases with paternal origin contribute with a greater effect to the anticipation phenomenon (Table 1). On the other hand, there are three reported cases and the present one, with a maternal origin associated with a massive expansion (Mao et al., 2002Mao R, Aylsworth AS, Potter N, Wilson WG, Breningstall G, Wick MJ, Babovic-Vuksanovic D, Nance M, Patterson MC, Gomez CM et al. (2002) Childhood-onset ataxia: testing for large CAG-repeats in SCA2 and SCA7. Am J Med Genet 110:338-345.; Paciorkowski et al., 2011Paciorkowski AR, Shafrir Y, Hrivnak J, Patterson MC, Tennison MB, Clark HB and Gomez CM (2011) Massive expansion of SCA2 with autonomic dysfunction, retinitis pigmentosa, and infantile spasms. Neurology 77:1055-1060.; Trang et al., 2015Trang H, Stanley SY, Thorner P, Faghfoury H, Schulze A, Hawkins C, Pearson CE and Yoon G (2015) Massive CAG repeat expansion and somatic instability in maternally transmitted infantile spinocerebellar ataxia type 7. JAMA Neurol 72:219-23.).

There are two clinical prognostic severity markers in SCA2, which are saccades and dysphagia (Wadia et al., 1998Wadia N, Pang J, Desai J, Mankodi A, Desai M and Chamberlain S (1998) A clinicogenetic analysis of six Indian spinocerebellar ataxia (SCA2) pedigrees. The significance of slow saccades in diagnosis. Brain 121:2341-2355.). Dysphagia was reported in five cases with massive repeats, greater than 200 repeats (Babovic et al., 1998Babovic VD, Snow K, Patterson MC and Michels VV (1998) Spinocerebellar ataxia type 2 (SCA 2) in an infant with extreme CAG repeat expansion. Am J Med Genet 79:383-387; Mao et al., 2002Mao R, Aylsworth AS, Potter N, Wilson WG, Breningstall G, Wick MJ, Babovic-Vuksanovic D, Nance M, Patterson MC, Gomez CM et al. (2002) Childhood-onset ataxia: testing for large CAG-repeats in SCA2 and SCA7. Am J Med Genet 110:338-345.; Abdel and Zaki, 2008Abdel AA and Zaki MS (2008) Spinocerebellar ataxia type 2 (SCA2) in an an Egyptian family presenting with polyphagia and marked CAG expansion in infancy. J Neurol 55:413-419.; Avelino et al., 2014Avelino MA, Pedroso L, Orlacchio A, Barsottini OGP and Masruha MR (2014) Neonatal SCA2 presenting with choreic movements and dystonia with dystonic jerk, retinitis, seizures and hypotonia. Mov Disord Clin Pract 1:252-254.). The present case presented dysphagia since birth.

Abnormalities in the electroencephalogram were frequent in infantile SCA2 cases reports, but the present case did not present abnormal patterns in the electroencephalogram or epilepsy with tonic seizures or myoclonic seizures (Mao et al., 2002Mao R, Aylsworth AS, Potter N, Wilson WG, Breningstall G, Wick MJ, Babovic-Vuksanovic D, Nance M, Patterson MC, Gomez CM et al. (2002) Childhood-onset ataxia: testing for large CAG-repeats in SCA2 and SCA7. Am J Med Genet 110:338-345.; Paciorkowski et al., 2011Paciorkowski AR, Shafrir Y, Hrivnak J, Patterson MC, Tennison MB, Clark HB and Gomez CM (2011) Massive expansion of SCA2 with autonomic dysfunction, retinitis pigmentosa, and infantile spasms. Neurology 77:1055-1060.; Vinther-Jensen et al., 2013Vinther-Jensen T, Ek J, Duno M, Skovby F, Hjermind LE, Nielsen JE and Nielsen TT (2013) Germline CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2. Eur J Hum Genet 21:626.; Singh et al., 2014Singh A, Faruq M, Mukerji M, Dwivedi MK, Pruthi S and Kapoor S (2014) Infantile onset spinocerebellar ataxia 2 (SCA2): a clinical report with review of previous cases. J Child Neurol 29:139–144.). While cerebellar and brainstem atrophy were related with massive CAG expansions (> 200) in the ATXN2 gene (Babovic et al., 1998Babovic VD, Snow K, Patterson MC and Michels VV (1998) Spinocerebellar ataxia type 2 (SCA 2) in an infant with extreme CAG repeat expansion. Am J Med Genet 79:383-387; Mao et al., 2002Mao R, Aylsworth AS, Potter N, Wilson WG, Breningstall G, Wick MJ, Babovic-Vuksanovic D, Nance M, Patterson MC, Gomez CM et al. (2002) Childhood-onset ataxia: testing for large CAG-repeats in SCA2 and SCA7. Am J Med Genet 110:338-345.; Moretti et al., 2004Moretti P, Blazo M, Garcia L, Armstrong D, Lewis RA, Roa B and Scaglia F (2004) Spinocerebellar ataxia type 2 (SCA2) presenting with ophthalmoplegia and developmental delay in infancy. Am J Med Genet A 124A:392-396.; Dirik et al., 2007Dirik E, Yis U, Basak N, Soydan E, Hüdaoglu O and Ozgönül F (2007) Spinocerebellar ataxia type 2 in a Turkish family. J Child Neurol 22:891-894.; Paciorkowski et al., 2011Paciorkowski AR, Shafrir Y, Hrivnak J, Patterson MC, Tennison MB, Clark HB and Gomez CM (2011) Massive expansion of SCA2 with autonomic dysfunction, retinitis pigmentosa, and infantile spasms. Neurology 77:1055-1060.; Magaña et al., 2008Magaña JJ, Vergara MD, Sierra-Martínez M, García-Jiménez E, Rodríguez-Antonio F, del Rocío Gómez M, Valdés-Flores M and Cisneros B (2008) Molecular analysis of the CAG repeat among patients with Type-2 spinocerebellar ataxia in the Mexican population. Gac Med Mex 144:413-418.; Vinther-Jensen et al., 2013Vinther-Jensen T, Ek J, Duno M, Skovby F, Hjermind LE, Nielsen JE and Nielsen TT (2013) Germline CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2. Eur J Hum Genet 21:626.; Singh et al., 2014Singh A, Faruq M, Mukerji M, Dwivedi MK, Pruthi S and Kapoor S (2014) Infantile onset spinocerebellar ataxia 2 (SCA2): a clinical report with review of previous cases. J Child Neurol 29:139–144.; Avelino et al., 2014Avelino MA, Pedroso L, Orlacchio A, Barsottini OGP and Masruha MR (2014) Neonatal SCA2 presenting with choreic movements and dystonia with dystonic jerk, retinitis, seizures and hypotonia. Mov Disord Clin Pract 1:252-254.). A case whose brain at 5 years 10 months showed diffuse T2 white matter signal abnormalities, with cavitations of the parieto-occipital lobes and cortical and cerebellar volume loss, was found carrier of a genotype 22/~750 (Paciorkowski et al., 2011Paciorkowski AR, Shafrir Y, Hrivnak J, Patterson MC, Tennison MB, Clark HB and Gomez CM (2011) Massive expansion of SCA2 with autonomic dysfunction, retinitis pigmentosa, and infantile spasms. Neurology 77:1055-1060.). In the present case the CT brain scan revealed mild pontine atrophy, moderate cerebellar atrophy, with longer repeats 22/~841. This indicates that the severity of the damage to the brain structures not only depend of the ATXN2 VNTR expansion, but may influence other genes in which ATXN2 forms a network, that corresponds to a new frontier of research in SCA2.

The present case presented gaze-evoked nystagmus without retinitis pigmentosa common in childhood SCA2 due to long CAG repeats in ATXN2 gene (see Table 2), greater than one hundred repeats (Babovic et al., 1998Babovic VD, Snow K, Patterson MC and Michels VV (1998) Spinocerebellar ataxia type 2 (SCA 2) in an infant with extreme CAG repeat expansion. Am J Med Genet 79:383-387; Mao et al., 2002Mao R, Aylsworth AS, Potter N, Wilson WG, Breningstall G, Wick MJ, Babovic-Vuksanovic D, Nance M, Patterson MC, Gomez CM et al. (2002) Childhood-onset ataxia: testing for large CAG-repeats in SCA2 and SCA7. Am J Med Genet 110:338-345.; Paciorkowski et al., 2011Paciorkowski AR, Shafrir Y, Hrivnak J, Patterson MC, Tennison MB, Clark HB and Gomez CM (2011) Massive expansion of SCA2 with autonomic dysfunction, retinitis pigmentosa, and infantile spasms. Neurology 77:1055-1060.; Di Fabio et al., 2012Di Fabio R, Santorelli F, Bertini E, Balestri M, Cursi L, Tessa A, Pierelli F and Casali C (2012) Infantile childhood onset of spinocerebellar ataxia type 2. Cerebellum 11:526-530.; Vinther-Jensen et al., 2013Vinther-Jensen T, Ek J, Duno M, Skovby F, Hjermind LE, Nielsen JE and Nielsen TT (2013) Germline CAG repeat instability causes extreme CAG repeat expansion with infantile-onset spinocerebellar ataxia type 2. Eur J Hum Genet 21:626.; Avelino et al., 2014Avelino MA, Pedroso L, Orlacchio A, Barsottini OGP and Masruha MR (2014) Neonatal SCA2 presenting with choreic movements and dystonia with dystonic jerk, retinitis, seizures and hypotonia. Mov Disord Clin Pract 1:252-254.; Singh et al., 2014Singh A, Faruq M, Mukerji M, Dwivedi MK, Pruthi S and Kapoor S (2014) Infantile onset spinocerebellar ataxia 2 (SCA2): a clinical report with review of previous cases. J Child Neurol 29:139–144.). In the literature has been reported massive expansion repeats (more than 750 repeats) in SCA2 with autonomic dysfunction, retinitis pigmentosa, and infantile spasms; the difference in the present case without retinitis pigmentosa, not only be explained by the age of onset, but also by the same molecular and allelic heterogeneity of retinitis, which is polygenic with different inheritance patterns (Fahim et al., 2018Fahim AT, Daiger SP and Weleber RG, Nonsyndromic Retinitis Pigmentosa, Overview, https://www.ncbi.nlm.nih.gov/books/NBK1417/.
https://www.ncbi.nlm.nih.gov/books/NBK14... ).

In patients with infantile SCA2, some craniofacial alterations were found, such as microcephaly in four cases and one case showed facial dysmorphism (Paciorkowski et al., 2011Paciorkowski AR, Shafrir Y, Hrivnak J, Patterson MC, Tennison MB, Clark HB and Gomez CM (2011) Massive expansion of SCA2 with autonomic dysfunction, retinitis pigmentosa, and infantile spasms. Neurology 77:1055-1060.). These findings were not relevant in the present case, but it would be worthwhile to analyze them clinically in detail, because there is a possibility that they are not syndromic but may be related to an ATXN2 effect on cranial morphogenesis.

Peripheral nerve affection, polyphagia and obesity were striking manifestations in the middle stage of the disease, as well as generalized edema and proteinuria, and minimal change glomerulonephritis that were found in an isolated patient. This might support a previously suggested relationship between the ataxin-2 gene and body weight and insulin resistance, which is modulated by ataxin-2 by the pathway of insulin by GRB2 and SRC (Flores-Alvarado et al., 2016Flores-Alvarado LJ, Dávalos-Rodríguez NO, García-Cruz D, Madrigal-Ruiz PM, Ruiz-Mejía R, Aguilar-Aldrete ME and Ramirez-Garcia SA (2016) (CAG)n polymorphism of the ATXN2 gene, a new marker of susceptibility for type 2 diabetes mellitus. Rev Panam Salud Publica 40:318-324.; Guzmán-López et al., 2018Guzmán-López R, García-Cruz D, Magallanes-Ordoñez JJ, Siliceo-Murrieta J, Dávalos-Rodríguez N, Ruiz-Mejía R, Madrigal-Ruiz PM, Cruz-Bastida JM, Cruz-Bastida JS, Duque-Bautista H et al. (2018) Childhood obesity, insulin resistance and the polymorphism (CAG)n of the ATXN2 gene. Rev Med MD 9:134-139.; Ramirez-Garcia et al., 2019Ramirez-Garcia SA, Sánchez-Corona J, Ortega-Pacheco D, Ramírez-Bohórquez E and García-Cruz D (2019) Ataxina-2, nuevo blanco en enfermedades genéticas complejas. Gac Med Mex 155:58-62.). The two carriers of these phenotypic findings had an expanded alleles range between 90 and less than 130 CAG repeats, which corroborates the participation of ataxin-2 gene in the development of metabolic syndrome traits (Flores-Alvarado et al., 2016Flores-Alvarado LJ, Dávalos-Rodríguez NO, García-Cruz D, Madrigal-Ruiz PM, Ruiz-Mejía R, Aguilar-Aldrete ME and Ramirez-Garcia SA (2016) (CAG)n polymorphism of the ATXN2 gene, a new marker of susceptibility for type 2 diabetes mellitus. Rev Panam Salud Publica 40:318-324.; Ramirez-Garcia et al., 2019Ramirez-Garcia SA, Sánchez-Corona J, Ortega-Pacheco D, Ramírez-Bohórquez E and García-Cruz D (2019) Ataxina-2, nuevo blanco en enfermedades genéticas complejas. Gac Med Mex 155:58-62.). However, our tester has the highest repeating range in the literature, and has not developed any of these findings, which suggests that there are other genes that can modify the SCA2 phenotype, especially in the case of children (Ramírez-Garcia et al., 2011Ramírez-Garcia SA, Volpini V, Castañeda-Cisneros G, Sánchez-Corona J, Morán-Moguel MC, Gutierrez- Rubio S and Garcia-Cruz D (2011) Expansión del repetido (CAG)n del gen ATXN2 en pacientes del Noroccidente de Mexico con ataxia espinocerebelosa y la evidencia de cinco genes modificadores. Rev Arch Cien 3:28.; Trang et al., 2015Trang H, Stanley SY, Thorner P, Faghfoury H, Schulze A, Hawkins C, Pearson CE and Yoon G (2015) Massive CAG repeat expansion and somatic instability in maternally transmitted infantile spinocerebellar ataxia type 7. JAMA Neurol 72:219-23.).

In conclusion, the present report describes a child with infantile SCA2 with a massive expansion of CAG trinucleotides of the ATXN2 gene reported up to date in the literature, which resulted in a very early onset of clinical findings, since birth, and whose phenotype mainly corresponds to the severe affection of the central and peripheral nervous system. Also, this is the first childhood case in a Mexican and Latin-American population. The review of the literature of 18 cases of infantile SCA2 and the comparison with the present case shows a great clinical and molecular heterogeneity, which does not always correlate with the greater number of CAG repeats of the ATXN2 gene. The most frequent clinical signs were hypsarrhythmia, hypotonia, pigmentosa retinitis, cerebellar atrophy, as well as middle brain and lengthening of the ventricular system. The range of CAG repeats ranged between 69-884 repeats; however, longer repeats have more severe phenotypes.

Acknowledgments

This research was supported by Grants PROCOFIN- SEP-PRODEP and Marcagen S.A. de C.V. For the professional editing of English language by Brieden Coy Marriot BA, chief of the language center of Sierra Sur University. We would like to thank Hector V. Ortega MD, Adjunct Professor of Neurosurgery research, Adjunct Professor of Biomedical Engineering, Thomas Jefferson University, for scientific advice.

Conflict of Interest

The authors declare that there is no conflict of interest.

Author Contributions

JSC wrote the manuscript, conceived and designed the study, SARG conducted experiments, wrote the manuscript, GCS analyzed data and was responsible of the management clinical of the patient, SAGR conducted experiments, VV conducted experiments, DMSG analyzed data, JEGO analyzed data, and DGC conceived and designed the study and wrote the manuscript. All authors read and approved the final version.

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