Case Report
1 Medical student of the Iguaçu University, Nova Iguaçu, Rio de Janeiro, Brazil
2 Physician, Neurologist, Adjunct Professor of Medicine at Universidade Iguaçu, Nova Iguaçu, Rio de Janeiro, Brazil
3 Department of Neurology of Hospital Geral de Nova Iguaçu, Adjunct Professor of Medicine at Iguaçu University-UNIG/Nova Iguaçu, RJ, Brazil
Address correspondence to:
Antônio Marcos da Silva Catarino
Rua Galvão Peixoto 70, Room 811, CEP 24 2230-100, Icaraí, Niterói-RJ,
Brazil
Message to Corresponding Author
Article ID: 101470Z01RL2024
Introduction: Spinocerebellar ataxia type 7 is part of a rare group of neurodegenerative diseases, characterized by lesions in the brainstem, cerebellum, spinal cord, and retina, manifesting as motor disturbances associated with signs of pyramidal involvement and amaurosis. The dysfunction is caused by autosomal dominant genetic alterations, with disease severity and the age of symptom onset being directly linked to the patient’s genetic expression.
Case Report: We present the case of a 24-year-old woman, previously healthy, who denied smoking, drinking alcohol, or taking any other drugs. She reported that approximately nine months, she had experienced a decline in dexterity for tasks requiring fine motor skills. She also exhibited impaired gait, frequent falls, and difficulties in performing basic activities of daily living (ADLs). On neurological examination, she presented with an ataxic and staggering gait, tremor during movement, dysmetria, dysdiadochokinesia, movement decomposition, dysarthria (scanning speech), dysphagia, dystasia, dysbasia, and nystagmus, all of which are indicative of cerebellar impairment. A genetic panel revealed the presence of 44 cytosine-adenine-guanine nucleotide repeat expansions on allele 2 of the ATXN7 gene, confirming the diagnosis of spinocerebellar ataxia type 7.
Conclusion: In this case report, the diagnosis of spinocerebellar ataxia was established through a comprehensive assessment of the patient’s clinical history, neurological examination, imaging studies, and genetic profiling, all of which are essential for reaching a definitive diagnosis. The prognosis for this disease varies due to ongoing research into its pathophysiology. Furthermore, discussions within the scientific community regarding potential cures for this condition continue.
Keywords: Ataxias, Cerebellar degeneration, Spinocerebellar ataxia type 7
Spinocerebellar ataxias (SCAs) constitute a group of diverse neurodegenerative ataxic disorders affecting the cerebellum, brainstem, and spinal cord [1]. They arise from autosomal dominant genetic mutations [2]. The classification of these ataxias has evolved over time and was initially divided into three groups: type 1 (ADCA-I), type 2 (ADCA-II), and type 3 (ADCA-III). With the advancement of biotechnologies, positional genetic cloning techniques have been employed to identify the genes that are responsible for the mutations found in SCAs. Consequently, ADCA-II was then renamed spinocerebellar ataxia type 7 (SCA-7) [1].
The genetic origin of the disease is based on expanded repeats [3] of the cytosine-adenine-guanine (CAG) trinucleotide in the coding region of the ATXN7 gene, responsible for encoding the ataxin-7 protein. These repetitions lead to an uninterrupted series of glutamine residues, resulting in an abnormal polyglutamine (polyQ) tract and, consequently, the accumulation of the synthesized protein [4],[5]. The clinical phenotype is dependent on the number of nitrogen base repeats, with higher expression leading to a faster disease progression and earlier symptom onset [1],[4]. The resulting disorder, stemming from the degeneration of neurons in the brainstem and cerebellum, clinically presents as progressive cerebellar ataxia with signs of pyramidal tract involvement [6]. Additionally, ophthalmoplegia and progressive amaurosis are observed due to cone and rod dystrophy in the macular region of the retina [7]. Spinocerebellar ataxia type 7 is a rare disorder, with a prevalence of 0.3 to 2 per 100,000 individuals [4], showing a higher incidence in Finland, Sweden, Scandinavia, the United States, and China [3],[4]. Among genetically confirmed diseases, SCA-7 represents approximately 1–11.7% of cases, with diagnostic confirmation often hindered by limited access to genetic screening, which is crucial given the various potential differential diagnoses [7]. In light of the above, the objective of this study is to present a case report of SCA-7 and provide a genetic foundation related to the disease, along with its implications not only for the patient but also for those within their hereditary lineage.
NM, 24-years-old, woman, teacher, with no comorbidities. She denied using illicit and legal substances, such as cigarettes and alcohol. It was reported that approximately nine months ago, she started a decline in dexterity for tasks that requires fine motor skills and walking impairments. Initially, the issue was treated as a possible psychiatric condition. In February, she looked for assistance from the Neurology department due to frequent falls and difficulties/incapacities in basic and instrumental activities of daily living. Family History: Although she had no direct contact with her father, she mentioned that he had difficulties walking, appearing intoxicated. On inspection, proptosis was observed. During the neurological examination, she exhibited a staggering ataxic gait, tremors during movement, dysmetria, dysdiadochokinesia, movement decomposition, scanning speech (dysarthria), dysphagia, dystasia, dysbasia, and nystagmus. All of these findings are indicative of cerebellar impairment. However, she did not present muscle weakness or sensory deficits suggestive of space occupying lesions in cord. Cranial magnetic resonance imaging (MRI): Atrophy of the posterior fossa structures (cerebellum and pons) was observed, along with tapering of the upper and middle cerebellar peduncles. There was a reduction in the thickness of the pons (Figure 1 and Figure 2). Additionally, there was marginal widening of the cingulate gyrus sulcus, reflecting a reduction in bilateral parietal cortical thickness (Figure 3). Genetic Panel: Molecular testing identified an ATXN7 allele with approximately 44 CAG repeats (Figure 4). This expansion is responsible for the SCA7 form of spinocerebellar ataxia.
Spinocerebellar ataxia type 7 (SCA7) is a rare, late-onset, and slowly progressive autosomal dominant neurodegenerative disease. It is caused by an expanded CAG (CAGexp) repeat in the ATXN7 gene located on chromosome 3, resulting in the insertion of an elongated polyglutamine (polyQ) protein ataxin-7 [8]. Affected individuals typically have an allele with 36 to 460 CAG repeats [9]. As a differential diagnosis, the most common are other types of ACS, such as SCA1, SCA2, SCA3, ischemic vascular accident (CVA) in the cerebellum or brain stem, hemorrhage in the brain, multiple sclerosis, and Wernicke–Korsakoff syndrome [10]. In the case presented, the patient has 44 CAG repeats, which confirms the diagnosis of SCA7. The diagnosis is typically confirmed through the ATXN7/SCA7 gene expansion test. As a result, individuals with SCA7 develop alterations that affect the functioning of cerebellar, spinal cord, and retinal cells [11]. Symptoms of SCA7 typically emerge in early adulthood, around the ages of 20–30 [12]. In this case, the patient is 24 years old, which falls within the expected age range. The age at diagnosis and symptom onset is crucial in SCA7 patients, as younger onset is associated with faster disease progression [13]. Clinical manifestations are characterized by pyramidal tract signs, ophthalmoplegia, Parkinsonism, slow saccadic eye movements, and muscle weakness [3]. The patient exhibits alterations in proprioception, gait, eye motility, and visual acuity, manifesting nystagmus and exophthalmos. In MRI, it is possible to observe brainstem atrophy in SCA7 patients, suggesting that the pons is the most affected structure in the central nervous system, preceding the involvement of the cerebellum and supratentorial regions [14]. This is consistent with the imaging findings in the patient, showing atrophy of brainstem structures. Being history, checking if grandparents, parents, and siblings, if any, exhibit any features, signs, or symptoms of the disease. Moreover, genetic testing for spinocerebellar ataxias should ideally be performed in all family members to facilitate screening and early diagnosis. There is currently no specific treatment for this disease; however, gene silencing studies are underway to prevent the development of SCA7. Allele-specific silencing of the polyglutamine mutation in SCA7 models is being explored in research [2]. The prognosis of the disease involves the loss of vision due to the degeneration of photoreceptor cones and motor impairments, such as dysphagia and dysarthria [5].
Based on the patient’s genetic panel combined with the clinical history of frequent falls, neurological examination showing ataxic gait, movement tremor, dysmetria, dysdiadochokinesia, nystagmus, and the imaging findings of pontine atrophy, the diagnosis of spinocerebellar ataxia type 7 has been confirmed. The prognosis varies, but improvement in the condition is unlikely. The mechanisms of this disease are not well understood, and there is a low probability of significant interventions that can improve the prognosis. Despite robust therapeutic evidence, there is no cure for this condition, only treatment aimed at managing some of the symptoms.
1.
Del-Favero J, Krols L, Michalik A, et al. Molecular genetic analysis of autosomal dominant cerebellar ataxia with retinal degeneration (ADCA type II) caused by CAG triplet repeat expansion. Hum Mol Genet 1998;7(2):177–86. [CrossRef] [Pubmed]
2.
Sullivan R, Yau WY, O'Connor E, Houlden H. Spinocerebellar ataxia: An update. J Neurol 2019;266(2):533–44. [CrossRef] [Pubmed]
3.
Zeigelboim BS, Dumke C, Klagenberg KF, Mengelberg H. Spinocerebellar ataxia type 7. [Article in Portuguese]. J Soc Bras Fonoaudiol 2011;23(2):183–6. [CrossRef] [Pubmed]
4.
Martin JJ. Spinocerebellar ataxia type 7. Handb Clin Neurol 2012;103:475–91. [CrossRef] [Pubmed]
5.
Niewiadomska-Cimicka A, Trottier Y. Molecular targets and therapeutic strategies in spinocerebellar ataxia type 7. Neurotherapeutics 2019;16(4):1074–96. [CrossRef] [Pubmed]
6.
Hernandez-Castillo CR, Diaz R, Rezende TJR, et al. Cervical spinal cord degeneration in spinocerebellar ataxia type 7. AJNR Am J Neuroradiol 2021;42(9):1735–9. [CrossRef] [Pubmed]
7.
Ahn JK, Seo JM, Chung H, Yu HG. Anatomical and functional characteristics in atrophic maculopathy associated with spinocerebellar ataxia type 7. Am J Ophthalmol 2005;139(5):923–5. [CrossRef] [Pubmed]
8.
La Spada AR. Spinocerebellar Ataxia Type 7. In: Adam MP, Feldman J, Mirzaa GM, et al. editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1993–2024. [Pubmed]
9.
Kreuz FR, Grünewald T, Müller A, Reichmann H, Zühlke C. Spinocerebellar ataxia type 7: Frequency of CAG repeat length in a German family. J Neurol 1999;246(11):1105–6. [CrossRef] [Pubmed]
10.
In: BMJ Best Practice [Internet]. Assessment of ataxia: BMJ Publishing Group; Jan 25, 2024. Available from: BMJ Best Practice. [Available at: https://bestpractice.bmj.com/topics/en-gb/1097]
11.
Horton LC, Frosch MP, Vangel MG, Weigel-DiFranco C, Berson EL, Schmahmann JD. Spinocerebellar ataxia type 7: Clinical course, phenotype-genotype correlations, and neuropathology. Cerebellum 2013;12(2):176–93. [CrossRef] [Pubmed]
12.
Gousse G, Patural H, Touraine R, et al. Lethal form of spinocerebellar ataxia type 7 with early onset in childhood. Arch Pediatr 2018;25(1):42–4. [CrossRef] [Pubmed]
13.
14.
Linhares S da C. Ataxia espinocerebelar do tipo 7: Estudo genético-molecular, origem ancestral e caracterização fenotípica do envolvimento do SNC através de imagens por ressonância magnética nuclear. 2007. Tese (Doutorado) – Universidade de São Paulo, Ribeirão Preto, 2007. [Available at: https://repositorio.usp.br/item/001647821]
Roberto Monteiro Leitão - Conception of the work, Design of the work, Analysis of data, Drafting the work, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Marco Orsini - Conception of the work, Design of the work, Analysis of data, Drafting the work, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Mariana Pontes do Nascimento Mateus - Conception of the work, Design of the work, Analysis of data, Drafting the work, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Renan Falconi - Conception of the work, Design of the work, Acquisition of data, Analysis of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Antônio Marcos da Silva Catarino - Conception of the work, Design of the work, Acquisition of data, Analysis of data, Drafting the work, Revising the work critically for important intellectual content, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Gilberto Canedo Martins Jr - Conception of the work, Design of the work, Drafting the work, Final approval of the version to be published, Agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Guarantor of SubmissionThe corresponding author is the guarantor of submission.
Source of SupportNone
Consent StatementWritten informed consent was obtained from the patient for publication of this article.
Data AvailabilityAll relevant data are within the paper and its Supporting Information files.
Conflict of InterestAuthors declare no conflict of interest.
Copyright© 2024 Roberto Monteiro Leitão et al. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information.