Journal of the Neurological Sciences 354 (2015) 118–121

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Letter to the Editor Infantile spinocerebellar ataxia type 7: Case report and a review of the literature Keywords: Spinocerebellar ataxia type 7 SCA7 Polyglutamine disorders

Dear Sirs, Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia associated with cone-rod and retinal dystrophy [1]. SCA7 is caused by a CAG repeat expansion (from 37 to 460 repeats) in the coding region of ATXN7 gene [1–3]. Expansion of the polyQ tract in the protein ataxin-7 leads to its accumulation in neuronal nuclear inclusions, and to selective neuronal and photoreceptor degeneration. Age at onset may be highly variable in SCA7, ranging from birth to 76 years, with a mean age at onset in the third to fourth decade of life according to the population [1,2]. A very severe, and rarely reported, infantile form may represent a diagnostic puzzle in which conventional molecular techniques may not reveal the large expansions of ATXN7. We describe a 2 year-old girl that was referred to our neurogenetics clinic due to milestones delay. She held her head steady at 4 months of age, sat unaided at 6 months, and was never able to walk independently. She uttered her first words at 1 year and 2 months of age. The child was born after an uneventful twin pregnancy through cesarean delivery at 37 weeks. At birth, her weight was 2600 g, length 46 cm and head circumference 33 cm. Her Apgar score was 9 at 5 min. She had a family history of SCA7. Her father started symptoms in the same year of her evaluation, when he was 37 year-old. She has an asymptomatic dizygotic twin sister, with normal milestones development and 3 other siblings that were asymptomatic (Fig. 1A). Her physical examination at 2 years and 1 month of age showed wide-based unsteady gait only possible with the support of another person, axial hypotonia, postural and cervical tremor, dysarthria, upper limb dysmetria, ankle clonus, and extensor plantar responses. At 2 years and 8 months of age, she was not able to stand even with support or to sit unaided, and presented an episode of aspiration pneumonia. Her physical examination showed aggravation of the reported signs. Fundoscopy, at 2 years and 10 months, was normal. At 3 years of age, her parents reported significant dysphagia associated with weight loss and recurrent episodes of aspiration pneumonia. At this time she also showed significant language regression and was only able to say single words utterances. In the following month, she was admitted at our hospital due to severe aspiration pneumonia, requiring intensive care unit support. She started with visual loss during the admission and also presented focal seizures, well controlled with phenytoin. She was discharged after 3 months of treatment to palliative homecare. At that time, she had weight recovery

http://dx.doi.org/10.1016/j.jns.2015.04.040 0022-510X/© 2015 Elsevier B.V. All rights reserved.

with nasoenteral feeding tube nutrition; however almost all her voluntary motor and cognitive functions were lost. She was not able to follow the examiner with her eyes and barely move herself. At homecare she needed 24 h bi-level positive airway pressure noninvasive ventilation and, after another episode of aspiration pneumonia (at age 3 years and 10 months), she is now dependent on continuous oxygen supplementation. She is still gaining weight (current weight on 75th percentile) with nasoenteral feeding tube nutrition and she is waiting for the placement of gastrostomy tube. At 3 years and 4 months of age, electroretinogram presented prolonged latencies of records bilaterally, and flash visual evoked potentials were absent. Electroencephalogram showed disorganized base rhythms with bursts of delta waves in anterior regions. Brain magnetic resonance imaging (MRI), at 1 year and 9 months of age, showed prominence of cerebellar folia and basis cisterns. When repeated, at 3 years and 4 months of age, diffuse volume reduction of the brain and progression of the brainstem and cerebellum atrophy were seen (Supplemental Fig. 1); together with mild T2 hyperintensity areas in periventricular and centrum semiovale white matter and in the topography of the transverse fibers of the pons. Determination of SCA7 allele sizes by conventional polymerase chain reaction (PCR) suggested a normal homozygous genotype of 10 CAG repeats (Fig. 1B). Next, triplet repeat primed PCR (TP-PCR) protocol was employed and revealed a massively expanded allele (Fig. 1C), which was further determined to be a tract of approximately 240 CAG repeats by agarose gel electrophoresis (Fig. 1D), confirming SCA7 diagnosis. The rarely documented infantile SCA7 phenotype is associated with massive CAG repeat expansions, generally on paternal disease transmission [1,2]. In the present report the expansion was associated with 36 years of anticipation. Table 1 summarizes the clinical, genetic, and molecular findings of the infantile onset SCA7 patients reported so far. Although infantile onset was rarely reported; juvenile disease (onset before 10 years of age) seems to be more frequent in SCA7 than in other SCAs, representing 15% of the total number of SCA7 patients in some series [4]. Infantile-onset SCA7 is remarkable for its widespread disease pathology that includes organ systems outside the central nervous system (CNS) [5–7]. Cerebellar and brain stem degeneration are so rapid in infantile forms that retinal degeneration and vision loss may not be evident; differently from adult-onset disease in which visual loss may precede, accompany, or follow the onset of ataxia. Ataxia may not be obvious in early infancy, but muscle wasting, weakness, and hypotonia are common. Other manifestations include structural cardiopathy, hepatomegaly, developmental delay, motor and cognitive regression, failure to thrive, abnormal renal function, and dysphagia (Table 1). Symptoms of infantile-onset SCA7 with no family history (due to dramatic anticipation) may be confused with acquired or other inherited diseases. The differential diagnosis may include autosomal recessive cerebellar ataxias, mitochondrial and lipid storage disorders, as well as neuronal ceroid lipofuscinosis [1]. Proper molecular techniques, as TP-PCR, should be applied whenever a large SCA7 repeat expansion is suspected to confirm the diagnosis.

Letter to the Editor Fig. 1. Patient's family pedigree and molecular diagnosis of massive SCA7 expansion. A: CAG repeats are indicated for all symptomatic members that underwent molecular diagnostic procedure. Age at onset is given in italic (years) bellow symbols. Proband is indicated with a black arrow. Squares indicate males and circle females; dark fill indicates affected individuals. Question marks indicate unknown diagnosis. B: Electrophoretic profile of SCA7 allele sizes by conventional PCR (green peaks). The negative control is a normal heterozygous individual with alleles corresponding to 11 and 12 CAG repeats, while the positive control is an adult-onset SCA7 individual presenting one expanded allele with 43 repeats (black arrow). In the patient, only one peak corresponding to 10 repeats is visible. C: Electrophoretic profile of SCA7 allele sizes by triple-primed PCR. In this technique, fragments of increasing length are iteratively amplified from the expanded allele, resulting in a ladder pattern of migration, identified in both a positive control and in the patient sample (black arrows). D: Agarose gel depicting the bands amplified by standard PCR. Lane 1: patient sample, presenting fragments of sizes correspondent to alleles with 10 and 240 CAG repeats (white arrow), respectively. Lane 2: adult-onset SCA7 positive control (10 and 43 CAG repeats); lane 3: healthy control, homozygous for the 10 CAG-repeats allele. MW: 1 kb DNA molecular weight marker.

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Letter to the Editor

Table 1 Clinical, genetics and molecular findings of infantile onset SCA7. Reference

Gender

AO

CAG exp

Parental gender

Parental AO

Parental CAGexp

Anticipation

Symptoms

Age at death

Benton et al. [8]

M

2m

306

M

45 y

43

45 y

• Hypotonia, microcephaly, cerebellar atrophy, ventricular dilation, delayed myelination, absent deep tendon reflexes, ankle clonus, normal fundoscopy examination, hypopharyngeal dysmotility with aspiration, absent cough reflex (5 m)

6m

M

b4 y

NI

M

45 y

43

N41 y

• NI

4y

F

Birth

460

M

35 y

49

35 y

• Acute respiratory distress (birth); • Hepatomegaly, delayed motor development, hypotonia, poor eye contact, retinitis pigmentosa (7 m)

8m

M

3m

325

M

35 y

49

35 y

• Failure to thrive, tachypnea, hepatomegaly, hypotonia, roving eye movements, retinitis pigmentosa; abnormal brainstem-evoked auditory potentials, absent responses on ERG, cerebellar atrophy (3 m)

5m

Jonasson et al. [9]

M

4y

NI

M

NI

45

NI

• Ataxia, visual impairment, dysarthria, dysphagia, muscle atrophy and cognitive impairment (4 y)

7y

M

1y

NI

F

NI

53

NI

• Ataxia and visual impairment (1 y)

2y

Ansorge et al. [10]

F

9m

180

M

ASa

39

NI

• Delayed motor development, limb tremor, dysphagia, failure to thrive (9 m) • Retinal pigmentary degeneration, nystagmus, hypotonia, brisk reflexes, marked cerebellar ataxia, cerebellar and brainstem atrophy (19 m)

2y5 m

Whitney et al. (2007)

M

5m

240

M

36 y

NI

35 y

• Failure to thrive, hypotonia (5 m) • Motor developmental delay; reduced deep tendon reflexes, poor oral control, possible pigment granularity on retina, abnormal renal function, cardiomegaly with congestive heart failure (7 m)

11 m

Trang et al. (2014)

M

11 mb

250b

F

20 y

45

19 y

• Delayed motor development (11 m). Regression of motor and cognitive skills, ataxia and tremor (16 m) • Atrophy of cerebellar hemispheres and vermis, focal segmental glomerulosclerosis (2 y, 6 m) • Esotropia, severe axial and peripheral hypotonia with significant head lag, absent deep tendon reflexes; extensor plantar responses (3 y)

3 y, 2 m

Donis et al. (2015)

F

1y

240

M

37 y

43

37 y

• Delayed motor development (1 y) • Mild cerebellar atrophy on MRI (1 y, 9 m) • Ataxic gait, axial hypotonia, postural and cervical tremor, upper limb dysmetria, ankle clonus, and extensor plantar responses (2 y, 1 m) • Marked dysphagia, weight loss, and recurrent pneumonias (3 y) • Focal seizures; visual loss with normal fundoscopy, but with prolonged latencies on electroretinogram and absent response on visual evoked potential; brain, brainstem and diffuse cerebellar atrophy on MRI (3 y, 4 m).

NA

van de Warrenburg et al. (2001)

AO: age of onset; F: female; M: male; m: months; MRI: magnetic resonance imaging; NI: not informed; NA: not applicable; y: years. a Asymptomatic. b Uncertain.

Supplementary data to this article can be found online at http://dx. doi.org/10.1016/j.jns.2015.04.040. Conflict of interest We have no disclosures. Study funding No targeted funding reported.

Authors' roles (1) Research project: A—conception, B—organization, C—execution (2) Manuscript: A—writing of the first draft, B—review and critique Karina Carvalho Donis: 1B, 1C, 2A, 2B Eduardo Preusser de Mattos: 1B, 1C, 2A, 2B André Anjos Silva: 1C, 2B Gabriel Vasata Furtado: 1C, 2B Maria Luiza Saraiva-Pereira: 1B, 2B Laura Bannach Jardim: 2B Jonas Alex Saute: 1A, 1B, 2A, 2B

Letter to the Editor

References [1] Garden GA, La Spada AR. Molecular pathogenesis and cellular pathology of spinocerebellar ataxia type 7 neurodegeneration. Cerebellum 2008;7:138–49. [2] Garden G. Spinocerebellar ataxia type 7. [updated 2012 Dec 20] , GeneReviews [online]; Aug 27 1998 [Available at http://www.ncbi.nlm.nih.gov/books/NBK1256. Accessed: January 12, 2015]. [3] Koob MD, Benzow KA, Bird TD, Day JW, Moseley ML, Ranum LP. Rapid cloning of expanded trinucleotide repeat sequences from genomic DNA. Nat Genet 1998;18: 72–5. [4] de Albuquerque MV, Pedroso JL, Braga Neto P, Barsottini OG. Phenotype variability and early onset ataxia symptoms in spinocerebellar ataxia type 7: comparison and correlation with other spinocerebellar ataxias. Arq Neuropsiquiatr 2015;73: 18–21. [5] van de Warrenburg BP, Frenken CW, Ausems MG, Kleefstra T, Sinke RJ, Knoers NV, et al. Striking anticipation in spinocerebellar ataxia type 7: the infantile phenotype. J Neurol 2001;248:911–4. [6] Whitney A, Lim M, Kanabar D, Lin JP. Massive SCA7 expansion detected in a 7month-old male with hypotonia, cardiomegaly, and renal compromise. Dev Med Child Neurol 2007;49:140–3. [7] Trang H, Stanley SY, Thorner P, Faghfoury H, Schulze A, Hawkins C, et al. Massive CAG repeat expansion and somatic instability in maternally transmitted infantile spinocerebellar ataxia type 7. JAMA Neurol 2015;72:219–23. [8] Benton CS, de Silva R, Rutledge SL, Bohlega S, Ashizawa T, Zoghbi HY. Molecular and clinical studies in SCA-7 define a broad clinical spectrum and the infantile phenotype. Neurology 1998;51:1081–6. [9] Jonasson J, Ström AL, Hart P, Brännström T, Forsgren L, Holmberg M. Expression of ataxin-7 in CNS and non-CNS tissue of normal and SCA7 individuals. Acta Neuropathol 2002;104:29–37. [10] Ansorge O, Giunti P, Michalik A, Van Broeckhoven C, Harding B, Wood N, et al. Ataxin-7 aggregation and ubiquitination in infantile SCA7 with 180 CAG repeats. Ann Neurol 2004;56:448–52.

Karina Carvalho Donis Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil Post Graduate Program in Children and Adolescent Health, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil Eduardo Preusser Mattos Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil

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André Anjos Silva Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil Gabriel Vasata Furtado Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil Maria Luiza Saraiva-Pereira Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil Department of Biochemistry, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil Laura Bannach Jardim Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil Post-Graduate Program in Genetics and Molecular Biology, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil Department of Internal Medicine, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil Jonas Alex Saute Medical Genetics Service, Hospital de Clínicas de Porto Alegre (HCPA), Porto Alegre, RS, Brazil Corresponding author at: Medical Genetics Service, Hospital de Clínicas de Porto Alegre, Rua Ramiro Barcelos 2350, Zip Code 90.035-903 Porto Alegre, Brazil. Tel.: +55 5133598011; fax: +55 513359 8010. E-mail address: [email protected]. 26 February 2015