Journal of the Neurological Sciences 358 (2015) 530–531
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor A novel AFG3L2 mutation in a Somalian patient with spinocerebellar ataxia type 28 Keywords: Spinocerebellar ataxia SCA28 AFG3L2 African descent
1. Introduction Spinocerebellar ataxias (SCA) are a genetically heterogeneous, autosomal dominant group of neurological disorders consisting of slowly progressive gait and limb ataxia, imbalance, and dysarthria. Of the SCA subtypes identified, spinocerebellar ataxia type 28 (SCA28) is one of 11 subtypes not caused by repeat expansions [1]. SCA28 is due to heterozygous missense mutations in the ATPase family gene 3-like 2 (AFG3L2) gene with at least 13 mutations to date [2–4]. AFG3L2 is located on chromosome 18p11.22-q11.2, contains 17 exons, and codes for a subunit of m-AAA protease located on the inner mitochondrial membrane [2–6]. Recent genetic findings also include cases of a frameshift mutation, a heterozygous deletion, and a partial deletion of the AFG3L2 gene. Although more prevalent in early adulthood, age of onset for SCA28 may vary from 3 to 60. A recent study, however, has identified a frameshift mutation causing late-onset SCA28 at age 68 [7]. SCA28 symptoms primarily include slowly progressive gait and limb ataxia, dysarthria, and nystagmus. Ptosis, opthalmoparesis, and hyperreflexia of the lower limbs can also occur. To date, current literature has only reported cases in Caucasian populations. We present a new AFG3L2 mutation (G N A transition at 571, codon V191I) of SCA28 in the first known case of a patient of African descent and late age of onset. 2. Methods 2.1. Genetic analysis A complete genetic ataxia panel was performed by Athena Diagnostics (Worcester, MA). Abnormal sequence variants were confirmed with bidirectional sequencing of the PCR gene fragments (Please refer to the Athena website for further details). 2.2. Case report A 78 year old Somalian male experienced progressively worsening balance problems beginning in 2005. In 2011, he presented after development of an orthostatic tremor while standing, which restricted his ability to stand from a kneeling position during daily prayer. He also developed weakness in his legs bilaterally, as well as hesitant speech with
http://dx.doi.org/10.1016/j.jns.2015.10.003 0022-510X/© 2015 Elsevier B.V. All rights reserved.
difficulties finishing his sentences. He also experienced blurry vision and skewed double vision on leftward gaze. On examination, the patient spoke in an unsteady rhythm and had difficulty completing sentences due to ataxic dysarthria. Significant nystagmus was seen on horizontal gaze bilaterally. Tone and strength were unremarkable. There was an asymmetric, length-dependent large and small fiber neuropathy in the lower extremities. Reflexes were absent in the upper extremities, reduced at the patella, and absent at the ankles, with bilateral plantar flexor responses. Moderate dysmetria on finger-to-nose and heel-to-shin testing was noted bilaterally. Mild dysdiadochokinesia was also seen. The patient had a wide-based gait and was unable to walk in tandem. Brain MRI revealed severe global cerebellar atrophy and foci of increased T2 signal intensity in the left frontoparietal subcortical white matter (Fig. 1). A complete genetic analysis was performed for 20 genes of an ataxia panel. The following genes were found to be normal: APTX, DRPLA, FXN, MIRAS-POLG, SETX, SIL1, TTPA, and SCA 1-3, 5–8, 10, 12–14, and 17. An autosomal heterozygous missense mutation, occurring as a G N A transition at nucleotide position 571, codon V191I, was found for the AFG3L2 gene.
3. Discussion Most SCA28 mutations occur in exons 15 and 16 of the M41protease domain of the mitochondrial m-AAA metalloprotease complex [4]. The mutation leads to cytotoxicity from reactive oxygen species, thereby inhibiting oxidative phosphorylation in the Purkinje fibers. We report the first known case of an African patient with a novel missense (571:GN A) mutation in exon 4 of the AFG3L2 gene. To date, SCA28 has only been found in Caucasian patients, none of whom have the mutation described. While the presence of gait ataxia, dysarthria, and nystagmus is consistent with SCA28, the phenotype of our patient differs from the typical presentation. Our patient began manifesting symptoms at the age of 68, one of the latest ages of onset with only one other documented case of the same age and another at 70 [1,7]. He presented with markedly diminished reflexes, which contrasts from the hyperreflexia that is typically reported. He also had blurry vision and skewed double vision to the left, but did not present with ptosis. Previous studies have suggested that nystagmus is an initial manifestation while slow saccades, opthalmoparesis, and ptosis appear 20 years following initial diagnosis [3,5]. Therefore, the patient may develop ptosis in the future. Unfortunately, no family members were available to complete a full pedigree. Due to the incomplete family history, we are currently unable to determine whether future generations will manifest with similar symptoms or if the patient presents with a de novo mutation. Since no other family members or individuals of African descent with SCA28 have yet been identified, we can only speculate whether this is a case of a founder-effect mutation or a spontaneous AFG3L2 mutation. Should individuals with the same mutation be identified in the future,
Letter to the Editor
531
Fig. 1. Brain and brainstem MRI without contrast. Legend: (A) Sagittal T1 weighted and (B) axial T2 weighted magnetic resonance imaging demonstrate moderate atrophy of the cerebellum.
identifying a common haplotype and locating the origin of the chromosomal segment containing the mutation would point to a founder effect. Author contributions Ms. Qu, Ms. Wu, Dr. Zuzuárregui and Dr. Hohler contributed to drafting and revising the manuscript. Dr. Hohler was responsible for the study concept.
[5] C. Cagnoli, C. Mariotti, F. Taroni, M. Seri, A. Brussino, C. Michielotto, M. Grisoli, D. Di Bella, N. Migone, C. Gellera, S. Di Donato, A. Brusco, SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22-q11.2, Brain 129 (Pt 1) (2006) 235–242. [6] K.A. Myers, J. Warman Chardon, L. Huang, K.M. Boycott, Deletion of AFG3L2 associated with spinocerebellar ataxia type 28 in the context of multiple genomic anomalies, Am. J. Med. Genet. A 164A (12) (2014) 3209–3212. [7] Z. Musova, M. Kaiserova, E. Kriegova, R. Fillerova, P. Vasovcak, A. Santava, K. Mensikova, A. Zumrova, A. Krepelova, Z. Sedlacek, P. Kanovsky, A novel frameshift mutation in the AFG3L2 gene in a patient with spinocerebellar ataxia, Cerebellum 13 (3) (2014) 331–337.
Disclosures
Jane Qu⁎1 Connie K. Wu⁎1 Boston University School of Medicine, 72 E. Concord Street, Boston, MA 02118, United States Corresponding authors at: Boston University School of Medicine, 72 E. Concord St, C3, Boston, MA 02118, United States. E-mail addresses: [email protected] (J. Qu), [email protected] (C.K. Wu).
Ms. Qu reports no disclosures. Ms. Wu reports no disclosures. Dr. Zuzuárregui reports no disclosures. Dr. Hohler reports no disclosures. References
José Rafael P. Zuzuárregui Anna D. Hohler Boston University School of Medicine, Department of Neurology, 72 E. Concord St, C3, Boston, MA 02118, United States E-mail addresses: [email protected] (J.R.P. Zuzuárregui), [email protected] (A.D. Hohler).
[1] K. Smets, T. Feconinck, J. Baets, A. Sieben, J.-J. Martin, I. Smouts, S. Wang, F. Taroni, D. Di Bella, W. Van Hecke, P.M. Parizel, C. Jadoul, R. De Potter, F. Couvreur, E. Rugarli, P. De Jonghe, Partial deletion of AFG3L2 causing spinocerebellar ataxia type 28, Neurology 82 (23) (2014) 2092–2100. [2] Löbbe AM, Kang J-S, Hilker R, Hackstein H, Müller U, Nolte D. A novel missense mutation in AFG3L2 associated with late onset and slow progression of spinocerebellar ataxia type 28. J. Mol. Neurosci. 2014;52(4):493–496. [3] C. Mariotti, A. Brusco, D. Di Bella, C. Cagnoli, M. Seri, C. Gellera, S. Di Donato, F. Taroni, Spinocerebellar ataxia type 28: a novel autosomal dominant cerebellar ataxia characterized by slow progression and opthalmoparesis, Cerebellum 7 (2) (2008) 184–188. [4] Brussino A, Brusco, A, Dürr A. Spinocerebellar ataxia type 28. In: Pagon RA, Adam MP, et al. (eds) GeneReviews™ [Internet] 2011, updated 2013. University of Washington, Seattle. http://www.ncbi.nlm.nih.gov/books/NBK54582/.
29 July 2015
1
Co-first authors.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Letter to the Editor A novel AFG3L2 mutation in a Somalian patient with spinocerebellar ataxia type 28 Keywords: Spinocerebellar ataxia SCA28 AFG3L2 African descent
1. Introduction Spinocerebellar ataxias (SCA) are a genetically heterogeneous, autosomal dominant group of neurological disorders consisting of slowly progressive gait and limb ataxia, imbalance, and dysarthria. Of the SCA subtypes identified, spinocerebellar ataxia type 28 (SCA28) is one of 11 subtypes not caused by repeat expansions [1]. SCA28 is due to heterozygous missense mutations in the ATPase family gene 3-like 2 (AFG3L2) gene with at least 13 mutations to date [2–4]. AFG3L2 is located on chromosome 18p11.22-q11.2, contains 17 exons, and codes for a subunit of m-AAA protease located on the inner mitochondrial membrane [2–6]. Recent genetic findings also include cases of a frameshift mutation, a heterozygous deletion, and a partial deletion of the AFG3L2 gene. Although more prevalent in early adulthood, age of onset for SCA28 may vary from 3 to 60. A recent study, however, has identified a frameshift mutation causing late-onset SCA28 at age 68 [7]. SCA28 symptoms primarily include slowly progressive gait and limb ataxia, dysarthria, and nystagmus. Ptosis, opthalmoparesis, and hyperreflexia of the lower limbs can also occur. To date, current literature has only reported cases in Caucasian populations. We present a new AFG3L2 mutation (G N A transition at 571, codon V191I) of SCA28 in the first known case of a patient of African descent and late age of onset. 2. Methods 2.1. Genetic analysis A complete genetic ataxia panel was performed by Athena Diagnostics (Worcester, MA). Abnormal sequence variants were confirmed with bidirectional sequencing of the PCR gene fragments (Please refer to the Athena website for further details). 2.2. Case report A 78 year old Somalian male experienced progressively worsening balance problems beginning in 2005. In 2011, he presented after development of an orthostatic tremor while standing, which restricted his ability to stand from a kneeling position during daily prayer. He also developed weakness in his legs bilaterally, as well as hesitant speech with
http://dx.doi.org/10.1016/j.jns.2015.10.003 0022-510X/© 2015 Elsevier B.V. All rights reserved.
difficulties finishing his sentences. He also experienced blurry vision and skewed double vision on leftward gaze. On examination, the patient spoke in an unsteady rhythm and had difficulty completing sentences due to ataxic dysarthria. Significant nystagmus was seen on horizontal gaze bilaterally. Tone and strength were unremarkable. There was an asymmetric, length-dependent large and small fiber neuropathy in the lower extremities. Reflexes were absent in the upper extremities, reduced at the patella, and absent at the ankles, with bilateral plantar flexor responses. Moderate dysmetria on finger-to-nose and heel-to-shin testing was noted bilaterally. Mild dysdiadochokinesia was also seen. The patient had a wide-based gait and was unable to walk in tandem. Brain MRI revealed severe global cerebellar atrophy and foci of increased T2 signal intensity in the left frontoparietal subcortical white matter (Fig. 1). A complete genetic analysis was performed for 20 genes of an ataxia panel. The following genes were found to be normal: APTX, DRPLA, FXN, MIRAS-POLG, SETX, SIL1, TTPA, and SCA 1-3, 5–8, 10, 12–14, and 17. An autosomal heterozygous missense mutation, occurring as a G N A transition at nucleotide position 571, codon V191I, was found for the AFG3L2 gene.
3. Discussion Most SCA28 mutations occur in exons 15 and 16 of the M41protease domain of the mitochondrial m-AAA metalloprotease complex [4]. The mutation leads to cytotoxicity from reactive oxygen species, thereby inhibiting oxidative phosphorylation in the Purkinje fibers. We report the first known case of an African patient with a novel missense (571:GN A) mutation in exon 4 of the AFG3L2 gene. To date, SCA28 has only been found in Caucasian patients, none of whom have the mutation described. While the presence of gait ataxia, dysarthria, and nystagmus is consistent with SCA28, the phenotype of our patient differs from the typical presentation. Our patient began manifesting symptoms at the age of 68, one of the latest ages of onset with only one other documented case of the same age and another at 70 [1,7]. He presented with markedly diminished reflexes, which contrasts from the hyperreflexia that is typically reported. He also had blurry vision and skewed double vision to the left, but did not present with ptosis. Previous studies have suggested that nystagmus is an initial manifestation while slow saccades, opthalmoparesis, and ptosis appear 20 years following initial diagnosis [3,5]. Therefore, the patient may develop ptosis in the future. Unfortunately, no family members were available to complete a full pedigree. Due to the incomplete family history, we are currently unable to determine whether future generations will manifest with similar symptoms or if the patient presents with a de novo mutation. Since no other family members or individuals of African descent with SCA28 have yet been identified, we can only speculate whether this is a case of a founder-effect mutation or a spontaneous AFG3L2 mutation. Should individuals with the same mutation be identified in the future,
Letter to the Editor
531
Fig. 1. Brain and brainstem MRI without contrast. Legend: (A) Sagittal T1 weighted and (B) axial T2 weighted magnetic resonance imaging demonstrate moderate atrophy of the cerebellum.
identifying a common haplotype and locating the origin of the chromosomal segment containing the mutation would point to a founder effect. Author contributions Ms. Qu, Ms. Wu, Dr. Zuzuárregui and Dr. Hohler contributed to drafting and revising the manuscript. Dr. Hohler was responsible for the study concept.
[5] C. Cagnoli, C. Mariotti, F. Taroni, M. Seri, A. Brussino, C. Michielotto, M. Grisoli, D. Di Bella, N. Migone, C. Gellera, S. Di Donato, A. Brusco, SCA28, a novel form of autosomal dominant cerebellar ataxia on chromosome 18p11.22-q11.2, Brain 129 (Pt 1) (2006) 235–242. [6] K.A. Myers, J. Warman Chardon, L. Huang, K.M. Boycott, Deletion of AFG3L2 associated with spinocerebellar ataxia type 28 in the context of multiple genomic anomalies, Am. J. Med. Genet. A 164A (12) (2014) 3209–3212. [7] Z. Musova, M. Kaiserova, E. Kriegova, R. Fillerova, P. Vasovcak, A. Santava, K. Mensikova, A. Zumrova, A. Krepelova, Z. Sedlacek, P. Kanovsky, A novel frameshift mutation in the AFG3L2 gene in a patient with spinocerebellar ataxia, Cerebellum 13 (3) (2014) 331–337.
Disclosures
Jane Qu⁎1 Connie K. Wu⁎1 Boston University School of Medicine, 72 E. Concord Street, Boston, MA 02118, United States Corresponding authors at: Boston University School of Medicine, 72 E. Concord St, C3, Boston, MA 02118, United States. E-mail addresses: [email protected] (J. Qu), [email protected] (C.K. Wu).
Ms. Qu reports no disclosures. Ms. Wu reports no disclosures. Dr. Zuzuárregui reports no disclosures. Dr. Hohler reports no disclosures. References
José Rafael P. Zuzuárregui Anna D. Hohler Boston University School of Medicine, Department of Neurology, 72 E. Concord St, C3, Boston, MA 02118, United States E-mail addresses: [email protected] (J.R.P. Zuzuárregui), [email protected] (A.D. Hohler).
[1] K. Smets, T. Feconinck, J. Baets, A. Sieben, J.-J. Martin, I. Smouts, S. Wang, F. Taroni, D. Di Bella, W. Van Hecke, P.M. Parizel, C. Jadoul, R. De Potter, F. Couvreur, E. Rugarli, P. De Jonghe, Partial deletion of AFG3L2 causing spinocerebellar ataxia type 28, Neurology 82 (23) (2014) 2092–2100. [2] Löbbe AM, Kang J-S, Hilker R, Hackstein H, Müller U, Nolte D. A novel missense mutation in AFG3L2 associated with late onset and slow progression of spinocerebellar ataxia type 28. J. Mol. Neurosci. 2014;52(4):493–496. [3] C. Mariotti, A. Brusco, D. Di Bella, C. Cagnoli, M. Seri, C. Gellera, S. Di Donato, F. Taroni, Spinocerebellar ataxia type 28: a novel autosomal dominant cerebellar ataxia characterized by slow progression and opthalmoparesis, Cerebellum 7 (2) (2008) 184–188. [4] Brussino A, Brusco, A, Dürr A. Spinocerebellar ataxia type 28. In: Pagon RA, Adam MP, et al. (eds) GeneReviews™ [Internet] 2011, updated 2013. University of Washington, Seattle. http://www.ncbi.nlm.nih.gov/books/NBK54582/.
29 July 2015
1
Co-first authors.
