Infantile Onset Spinocerebellar Ataxia 2 (SCA2): A Clinical Report With Review of Previous Cases
TL;DR: A patient with infantile-onset spinocerebellar ataxia type 2 who inherited the disease from his father (47 CAG repeats) is described to help treating clinicians to suspect this disorder and to offer timely genetic counseling for a currently potentially untreatable disorder.
Abstract: Autosomal dominant cerebellar ataxia type I is a heterogeneous group of spinocerebellar ataxias with variable neurologic presentations, with age of onset varying from infancy to adulthood Autosomal dominant cerebellar ataxia type I is composed mainly of 3 prevalent spinocerebellar ataxia types with different pathogenic loci, specifically spinocerebellar ataxia 1 (6p24-p23), spinocerebellar ataxia 2 (12q241), and spinocerebellar ataxia 3 (14q321) The shared pathogenic mutational event is the expansion of the CAG repeat that results in polyglutamine extended stretches in the encoded proteins CAG repeat disorders generally show the phenomenon of anticipation, which is more often associated with paternal transmission In this report, we describe a patient with infantile-onset spinocerebellar ataxia type 2 (~320 CAG repeat) who inherited the disease from his father (47 CAG repeats) We have summarized the clinical, neuroimaging, electroencephalographic (EEG), and molecular data of previous cases and attempt to highlight the most consistent findings Our intent is to help treating clinicians to suspect this disorder and to offer timely genetic counseling for a currently potentially untreatable disorder
Citations
More filters
TL;DR: An 8-year-old girl, born of nonconsanguineous marriage, developed insidiousonset, progressive imbalance while walking from 2 years of age, and developed progressive incoordination of the hands causing difficulty in eating, writing, and daily activities.
Abstract: To the Editor: An 8-year-old girl, born of nonconsanguineous marriage, developed insidiousonset, progressive imbalance while walking from 2 years of age. Simultaneously, she also developed progressive incoordination of the hands causing difficulty in eating, writing, and daily activities. The symptoms heightened with activity and subsided with rest. There was no history of cognitive decline, behavioral problems or vision impairment. She had a positive family history of a similar illness. Multiple family members were affected (Fig. 1) and each subsequent generation was affected at an earlier age, suggesting an autosomaldominant inheritance with anticipation. She had a normal general physical examination. Her memory was intact, but she had a scanning speech. She had oculomotor apraxia, saccadic overshoot, normal fundi, generalized mild hypotonia, dysmetria, dysdiadochokinesia, and intention tremors. Gait examination revealed truncal and limb ataxia. Rest of the neurological and systemic examination was unremarkable. Examination of the parents was noncontributory. A clinical diagnosis of autosomal-dominant spinocerebellar ataxia (SCA) with variable penetrance and anticipation was considered. Magnetic resonance imaging of brain showed cerebellar atrophy with prominent folia (Fig. 2). Metabolic screen (including tandem mass spectroscopy/gas chromatography), lipid and immunoglobulin profile, serum a-feto-protein, nerve conduction study, and brainstem-evoked response audiometry were normal. Polymerase chain reaction–based fragment analysis revealed expanded (.35) CAG trinucleotide repeats in ATXN2 gene confirming the diagnosis of SCA type 2. Autosomal-dominant inheritance pattern with anticipation is the hallmark of SCA as in the index case. However, the mean age of the onset of SCA type 2 is commonly third to fourth decade, and onset in childhood is rare and atypical. Less than 20 cases of SCA type 2 in children have been reported worldwide, with the youngest case at 3 months of age.1 Although SCA type 2 has been reported as the most common cause of inherited ataxia in adults,2 it has been sparingly described in Indian children because of the variable phenotype; poor index of clinical suspicion; triplet expansion of reduced penetrant allele inherited from asymptomatic parent as in our index child; and lack of genetic testing.3 A good history elucidating the involved family members is crucial for clinical suspicion and needs confirmation by genetic testing. Children with SCA type 2 need regular follow-up as the full phenotypic spectrum may not be evident at presentation as in the index case and further neurological signs may evolve with time.
2 citations
TL;DR: The data of this study are relevant not only for clinical decision making but also for guidance in direction of genetic investigations, transancestral comparison of genotypes, and lastly provide insight for policy decision for the consideration of SCAs under rare disease category.
Abstract: Cerebellar ataxias (CAs) represent a group of autosomal dominant and recessive neurodegenerative disorders affecting cerebellum with or without spinal cord. Overall, CAs have preponderance for tandem nucleotide repeat expansions as an etiological factor (10 TREs explain nearly 30–40% of ataxia cohort globally). The experience of 10 years of common genetic ataxia subtypes for ≈5600 patients’ referrals (Pan‐India) received at a single center is shared herein. Frequencies (in %, n) of SCA types and FRDA in the sample cohort are observed as follows: SCA12 (8.6%, 490); SCA2 (8.5%, 482); SCA1 (4.8%, 272); SCA3 (2%, 113); SCA7 (0.5%, 28); SCA6 (0.1%, 05); SCA17 (0.1%, 05), and FRDA (2.2%, 127). A significant amount of variability in TRE lengths at each locus is observed, we noted presence of biallelic expansion, co‐occurrence of SCA‐subtypes, and the presence of premutable normal alleles. The frequency of mutated GAA‐FRDA allele in healthy controls is 1/158 (0.63%), thus an expected FRDA prevalence of 1:100 000 persons. The data of this study are relevant not only for clinical decision making but also for guidance in direction of genetic investigations, transancestral comparison of genotypes, and lastly provide insight for policy decision for the consideration of SCAs under rare disease category.
2 citations
TL;DR: A patient with neonatal-onset SCA2 that presented with choreic movements and dystonia with dystonic jerks, retinitis, seizures, and hypotonia as prominent clinical features instead of ataxia, resembling a global encephalopathy is described.
Abstract: Autosomal-dominant SCAs are a clinically, genetically, and pathologically heterogeneous group of degenerative disorders, mainly affecting the cerebellum and its connections. Although most commonly characterized by progressive cerebellar symptoms, a plethora of so-called nonataxia features may develop and become a diagnostic challenger. SCA2 is caused by an abnormal expansion of a CAG repeat in Ataxin-2 (ATXN2) gene, located on chromosome 12 (12q24.1). Normal CAG alleles range from 15 to 32 repeats. The disease usually presents with adult-onset progressive cerebellar ataxia, dysarthria, nystagmus, slow saccadic eye movements, and peripheral neuropathy. Childhood onset is uncommon and is frequently associated with larger triplet expansions (>100 repeats) and presents with multisystem involvement beyond the aforementioned neurologic symptoms, such as developmental delay, hypotonia, pigmentary retinopathy, seizures, dysphagia, and early death. Herein, we describe a patient with neonatal-onset SCA2 that presented with choreic movements and dystonia with dystonic jerks, retinitis, seizures, and hypotonia as prominent clinical features instead of ataxia, resembling a global encephalopathy.
2 citations
TL;DR: In methemoglobinemia, patients have higher metHb than the healthy population, and cyanosis is associated with severe progressive neurological disabilities, including mental retardation, microcephaly, and movement disorders.
Abstract: In methemoglobinemia, patients have higher metHb than the healthy population. It could be congenital, resulting from deficiency of enzymes which convert metHb back to Hb, or acquired as a result of various chemical agents. Two clinical types of recessive hereditary methemoglobinemia have been described. Type I is a benign form in which cyanosis is the sole clinical symptom. In type II, cyanosis is associated with severe progressive neurological disabilities, including mental retardation, microcephaly, and movement disorders [1].
TL;DR: In this article, the authors performed a bioinformatics review of published RNAseq polyQ expression data resulting from the presence of polyQ genes in search of neurodevelopmental expression patterns and comparison between diseases.
Abstract: Polyglutamine (PolyQ) diseases are neurodegenerative disorders caused by the CAG repeat expansion mutation in affected genes resulting in toxic proteins containing a long chain of glutamines. There are nine PolyQ diseases: Huntington’s disease (HD), spinocerebellar ataxias (types 1, 2, 3, 6, 7, and 17), dentatorubral-pallidoluysian atrophy (DRPLA), and spinal bulbar muscular atrophy (SBMA). In general, longer CAG expansions and longer glutamine tracts lead to earlier disease presentations in PolyQ patients. Rarely, cases of extremely long expansions are identified for PolyQ diseases, and they consistently lead to juvenile or sometimes very severe infantile-onset polyQ syndromes. In apparent contrast to the very long CAG tracts, shorter CAGs and PolyQs in proteins seems to be the evolutionary factor enhancing human cognition. Therefore, polyQ tracts in proteins can be modifiers of brain development and disease drivers, which contribute neurodevelopmental phenotypes in juvenile- and adult-onset PolyQ diseases. Therefore we performed a bioinformatics review of published RNAseq polyQ expression data resulting from the presence of polyQ genes in search of neurodevelopmental expression patterns and comparison between diseases. The expression data were collected from cell types reflecting stages of development such as iPSC, neuronal stem cell, neurons, but also the adult patients and models for PolyQ disease. Our comparative bioinformatic review highlighted several (neuro)developmental pathways and genes identified within PolyQ diseases and mouse models responsible for neural growth, synaptogenesis, and synaptic plasticity.
References
More filters
TL;DR: It is shown that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models.
Abstract: The causes of amyotrophic lateral sclerosis (ALS), a devastating human neurodegenerative disease, are poorly understood, although the protein TDP-43 has been suggested to have a critical role in disease pathogenesis. Here we show that ataxin 2 (ATXN2), a polyglutamine (polyQ) protein mutated in spinocerebellar ataxia type 2, is a potent modifier of TDP-43 toxicity in animal and cellular models. ATXN2 and TDP-43 associate in a complex that depends on RNA. In spinal cord neurons of ALS patients, ATXN2 is abnormally localized; likewise, TDP-43 shows mislocalization in spinocerebellar ataxia type 2. To assess the involvement of ATXN2 in ALS, we analysed the length of the polyQ repeat in the ATXN2 gene in 915 ALS patients. We found that intermediate-length polyQ expansions (27-33 glutamines) in ATXN2 were significantly associated with ALS. These data establish ATXN2 as a relatively common ALS susceptibility gene. Furthermore, these findings indicate that the TDP-43-ATXN2 interaction may be a promising target for therapeutic intervention in ALS and other TDP-43 proteinopathies.
1,117 citations
"Infantile Onset Spinocerebellar Ata..." refers background in this paper
...The intermediate-repeat CAG length (27-33 CAG/CAA) has been recently documented in association with amyotrophic lateral sclerosis.(4) The expansion length of >100 is associated with the juvenile onset of the spinocerebellar ataxia type 2 and presents with multisystem involvement beyond the aforementioned neurologic symptoms, such as developmental delay, hypotonia, retinal degeneration, infantile spasm, and epilepsy....
[...]
TL;DR: The steep inverse correlation between age of onset and CAG number suggests a higher sensitivity to polyglutamine length than in the other polyglUTamine expansion diseases.
Abstract: Two forms of the neurodegenerative disorder spinocerebellar ataxia are known to be caused by the expansion of a CAG (polyglutamine) trinucleotide repeat. By screening cDNA expression libraries, using an antibody specific for polyglutamine repeats, we identified six novel genes containing CAG stretches. One of them is mutated in patients with spinocerebellar ataxia linked to chromosome 12q (SCA2). This gene shows ubiquitous expression and encodes a protein of unknown function. Normal SCA2 alleles (17 to 29 CAG repeats) contain one to three CAAs in the repeat. Mutated alleles (37 to 50 repeats) appear particularly unstable, upon both paternal and maternal transmissions. The sequence of three of them revealed pure CAG stretches. The steep inverse correlation between age of onset and CAG number suggests a higher sensitivity to polyglutamine length than in the other polyglutamine expansion diseases.
859 citations
"Infantile Onset Spinocerebellar Ata..." refers background in this paper
...1).(1) Normal CAG alleles range from 15 to 32 repeats, with 22 repeats being the most common in healthy individuals....
[...]
...Minimal CAG repeat length in affected infants was 62, whereas all affected parents had 140 Journal of Child Neurology 29(1)...
[...]
...com Journal of Child Neurology 2014, Vol 29(1) 139-144 a The Author(s) 2013 Reprints and permission: sagepub....
[...]
166 citations
"Infantile Onset Spinocerebellar Ata..." refers background in this paper
...There have been reports of numerous families affected with spinocerebellar ataxia type 2 since the first report in the literature.(14) Infantile onset of spinocerebellar ataxia type 2 has been rarely reported in the literature....
[...]
TL;DR: Uninterrupted SCA2 repeat expansions found in families with autosomal dominant cerebellar ataxia result in somatic mosaicism and produce large hairpin RNAs, which may interact with double-stranded RNA-binding proteins.
Abstract: Background: Autosomal dominant parkinsonism (ADP) is caused in a large percentage of familial and sporadic cases by mutations in the LRRK2 gene, particularly G2019S. It is also caused by mutations in genes associated with autosomal dominant cerebellar ataxia (ADCA), notably CAG/CAA repeat expansions in SCA2 . Methods: We screened 164 families with ADP for expansions in the SCA2, 3 , and 17 genes and for the G2019S mutation in LRRK2 . The SCA2 CAG/CAA repeat expansion was sequenced to determine its structure. The phenotypes of patients with ADP caused by the SCA2 , LRRK2 , and unknown mutations were compared, as well as those of SCA2 patients with interrupted or uninterrupted expansions of the same size. Results: Three French ADP families had SCA2 mutations. The expansions ranged from 37 to 39 repeats and were interrupted and stable upon transmission. All patients (n = 9) had levodopa-responsive parkinsonism without cerebellar signs. They had significantly more symmetric signs and less rigidity than ADP caused by the G2019S mutation in LRRK2 or by unknown mutations. Interestingly, two sisters carrying both the SCA2 and the G2019S LRRK2 mutations had markedly earlier onset than their mother with only SCA2 . In contrast, similar-sized but uninterrupted repeats were associated with ADCA in which cerebellar ataxia was constant and associated only rarely with one or more mild parkinsonian signs. Conclusion: These results suggest that the configuration of the SCA2 CAG/CAA repeat expansions plays an important role in phenotype variability. Uninterrupted SCA2 repeat expansions found in families with autosomal dominant cerebellar ataxia result in somatic mosaicism and produce large hairpin RNAs, which may interact with double-stranded RNA-binding proteins. These characteristics are modified by interruption of the SCA2 repeat expansion as found in families with autosomal dominant parkinsonism.
126 citations
TL;DR: Testing for dominant ataxias should be included in the evaluation of infants with nonspecific progressive neurologic symptoms and retinitis pigmentosa, especially in cases with a positive family history for spinocerebellar ataxia.
Abstract: Autosomal dominant cerebellar ataxias are a heterogeneous group of neurodegenerative disorders that generally present in adulthood. Spinocerebellar ataxia type 2 typically presents with progressive cerebellar symptoms, slow ocular saccades, and peripheral neuropathy. The onset of symptoms is usually between 20 and 40 years. We describe an infant who presented with neonatal hypotonia, developmental delay, and dysphagia. Ocular findings of retinitis pigmentosa were noted at 10 months. Her father had mild spinocerebellar ataxia first noted at age 22 years. Molecular studies of the SCA2 gene showed a CAG expansion of 43 repeats in the father and an extreme CAG repeat expansion of more than 200 in the baby. Our report expands the known phenotype and genotype of SCA2. Testing for dominant ataxias should be included in the evaluation of infants with nonspecific progressive neurologic symptoms and retinitis pigmentosa, especially in cases with a positive family history for spinocerebellar ataxia.
99 citations
"Infantile Onset Spinocerebellar Ata..." refers background in this paper
...The expansion length of >100 is associated with the juvenile onset of the spinocerebellar ataxia type 2 and presents with multisystem involvement beyond the aforementioned neurologic symptoms, such as developmental delay, hypotonia, retinal degeneration, infantile spasm, and epilepsy.(5-12) In India, spinocerebellar ataxia type 2 represents the commonest subtype described,(13) and it is expected that in large, multigenerational families, phenotypic and genetic variability will be encountered....
[...]
...Infantile onset of spinocerebellar ataxia type 2 has been rarely reported in the literature.(5-12) Clinical presentation in the proband was of a neurodegenerative phenotype with onset in infancy....
[...]