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Phenotypic heterogeneity of a compound heterozygous SUCLA2 mutation
Molecular Genetics and Metabolism Reports 10 (2017) 31–32
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism Reports journal homepage: www.elsevier.com/locate/ymgmr
Correspondence Phenotypic heterogeneity of a compound heterozygous SUCLA2 mutation
Table 1 Phenotypic manifestations of SUCLA2 mutations in the present and previous studies. Phenotype
Keywords: mtDNA M.9155ANG Deafness Diabetes Gene Mitochondrial disorder Stroke-like episode
Letter to the Editor With interest we read the article by Huang et al. about two siblings carrying both the same compound heterozygous SUCLA2 mutation, which manifested phenotypically with a progressive multisystem syndrome, resulting in severe disability (patient-1) or death (patient-2) [1]. We have the following comments and concerns. Patient-1 was treated with dichloroacetate (DCA) over at least 4y. DCA is well-known for its neurotoxicity in MELAS patients, resulting in severe polyneuropathy [2]. To which degree was the continuous deterioration of the phenotype attributable to the mitochondrion-toxic effect of DCA? Was polyneuropathy by age 1y attributed to the SUCLA2 mutation or interpreted as side effect of DCA? Was polyneuropathy a complication of diabetes? Ketogenic diet has been shown to be highly beneficial for epilepsy, migraine, autism, or myopathy in single patients with a mitochondrial disorder (MID) [3]. Ketogenic diet may even improve cerebral lesions on MRI in Leigh syndrome [4]. Why was a ketogenic diet not applied to patient-1 but only to patient-2? Was ketogenic diet in patient-2 beneficial? Patient-1 had normal cerebral MRI at age 3m and callosal thinning at age 7m. Why was no further MRI carried out during the next 13y despite obvious progression of cerebral involvement (Table 1)? Were bone fractures in both patients spontaneous or traumatic? Was a densitometry carried out? Which were the calcium, phosphate, and hormone levels in both patients? Was multiple hormone deficiency attributed to hypopituitarism? Was there a pituitary adenoma? MID patients frequently develop cardiac disease, which may be subclinical at onset [5]. Which were the results of long-term ECG and echocardiography when actively searching for cardiac involvement? Overall, this interesting study could be strengthened by reporting why DCA was given for 4y (patient-1), why no ketogenic diet was tried (patient-1), if there was a pituitary adenoma, and how cerebral involvement progressed on MRI (patient-1).
CNS involvement Encephalopathy Dystonia Spasticity Choreoathetosis Migraine Developmental delay Irritability Hypotonia Perturbed sleep/wake cycle Dysarthria/anarthria Basal ganglia involvement Epilepsy Corpus callosum thinning Low-lying conus medullaris Leigh-like MRI Ocular involvement Blindness (optic atrophy) Otologic involvement Hearing loss Gastrointestinal involvement Cyclic vomiting Constipation Gastroparesis Gastro-intestinal dysmotility Cecal volvulus GERD Poor feeding Gallstones Endocrine involvement Diabetes Short stature Hypogonadism Osteoporosis (spontaneous fractures) Hyperhidrosis Peripheral nerve involvement Polyneuropathy Muscle involvement Myopathy Ptosis Facial weakness Ophthalmoparesis Bone marrow involvement Anemia Thrombocytopenia Pulmonary involvement Chronic reactive airway disease Others Cardiomyopathy Sacral dimple Immunodeficiency Dysmorphism Fanconi syndrome Lactic acidosis
Patient 1
Patient 2
Previously reported
Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes No Yes No No
Yes Yes Yes No No Yes No Yes Yes Yes No No No Yes Yes
[Lamperti 2012] [Carrozza 2016] [Carrozza 2016] [Ostergaard 2007] No [Carrozza 2016] [Lamperti 2012] [Carrozza 2016] No [Lamperti 2012] [Carrozzo 2016, Liu 2014] [Carrozza 2016] No No [Wortmann 2009]
No
Yes
No
Yes
Yes
[Morawa 2009, Carrozza 2016]
Yes No No No No Yes Yes No
Yes Yes Yes Yes Yes Yes Yes Yes
[Carrozza 2016] No No [Lamperti 2012] No [Carrozza 2016] [Carrozza 2016] No
Yes Yes Yes Yes
No Yes No Yes
No [Carrozza 2016] No No
No
No
[Carrozza 2016, Ostergaard 2007]
Yes
Yes
[Carrozza 2007]
Yes Yes Yes Yes
Yes Yes Yes Yes
[Carrozza 2016] [Carrozza 2016] [Liu 2014] [Carrozzas 2016]
No No
Yes Yes
No No
Yes
No
[Carrozzas 2016]
No No No No No Yes
No Yes Yes No No Yes
[Carrozzo 2007] No [Carrozza 2016] [Carrozza 2016] [Carrozza 2007] [Liu 2014]
http://dx.doi.org/10.1016/j.ymgmr.2016.12.007 2214-4269/© 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
32
Correspondence
Table 1 (continued) Phenotype Methylmalonic academia (UOA)
Patient 1
Patient 2
Previously reported
Yes
Yes
[Liu 2014]
GERD: gastro-enterological reflux disease, UOA: urine organic acids.
References [1] X. Huang, J.K. Bedoyan, D. Demirbas, D.J. Harris, A. Miron, S. Edelheit, G. Grahame, S.D. DeBrosse, L.J. Wong, C.L. Hoppel, D.S. Kerr, I. Anselm, G.T. Berry, Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion, Mol. Genet. Metab. (2016) http://dx.doi.org/10.1016/j.ymgme.2016.11.005 (pii: S10967192(16)30314-6, Nov 12). [2] P. Kaufmann, K. Engelstad, Y. Wei, S. Jhung, M.C. Sano, D.C. Shungu, W.S. Millar, X. Hong, C.L. Gooch, X. Mao, J.M. Pascual, M. Hirano, P.W. Stacpoole, S. DiMauro, D.C. De Vivo, Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial, Neurology 66 (2006) 324–330. [3] C. Steriade, D.M. Andrade, H. Faghfoury, M.A. Tarnopolsky, P. Tai, Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) may respond to adjunctive ketogenic diet, Pediatr. Neurol. 50 (2014) 498–502.
[4] F.A. Wijburg, P.G. Barth, L.A. Bindoff, M.A. Birch-Machin, J.F. van der Blij, W. Ruitenbeek, D.M. Turnbull, R.B. Schutgens, Leigh syndrome associated with a deficiency of the pyruvate dehydrogenase complex: results of treatment with a ketogenic diet, Neuropediatrics 23 (1992) 147–152. [5] J. Finsterer, S. Kothari, Cardiac manifestations of primary mitochondrial disorders, Int. J. Cardiol. 177 (2014) 754–763.
Josef Finsterer Krankenanstalt Rudolfstiftung, Vienna, Austria Corresponding author at: Postfach 20, 1180 Vienna, Austria. E-mail address: fifi[email protected] Sinda Zarrouk-Mahjoub University of Tunis El Manar, Genomics Platform, Pasteur Institute of Tunis, Tunisia 18 December 2016 Available online xxxx
Contents lists available at ScienceDirect
Molecular Genetics and Metabolism Reports journal homepage: www.elsevier.com/locate/ymgmr
Correspondence Phenotypic heterogeneity of a compound heterozygous SUCLA2 mutation
Table 1 Phenotypic manifestations of SUCLA2 mutations in the present and previous studies. Phenotype
Keywords: mtDNA M.9155ANG Deafness Diabetes Gene Mitochondrial disorder Stroke-like episode
Letter to the Editor With interest we read the article by Huang et al. about two siblings carrying both the same compound heterozygous SUCLA2 mutation, which manifested phenotypically with a progressive multisystem syndrome, resulting in severe disability (patient-1) or death (patient-2) [1]. We have the following comments and concerns. Patient-1 was treated with dichloroacetate (DCA) over at least 4y. DCA is well-known for its neurotoxicity in MELAS patients, resulting in severe polyneuropathy [2]. To which degree was the continuous deterioration of the phenotype attributable to the mitochondrion-toxic effect of DCA? Was polyneuropathy by age 1y attributed to the SUCLA2 mutation or interpreted as side effect of DCA? Was polyneuropathy a complication of diabetes? Ketogenic diet has been shown to be highly beneficial for epilepsy, migraine, autism, or myopathy in single patients with a mitochondrial disorder (MID) [3]. Ketogenic diet may even improve cerebral lesions on MRI in Leigh syndrome [4]. Why was a ketogenic diet not applied to patient-1 but only to patient-2? Was ketogenic diet in patient-2 beneficial? Patient-1 had normal cerebral MRI at age 3m and callosal thinning at age 7m. Why was no further MRI carried out during the next 13y despite obvious progression of cerebral involvement (Table 1)? Were bone fractures in both patients spontaneous or traumatic? Was a densitometry carried out? Which were the calcium, phosphate, and hormone levels in both patients? Was multiple hormone deficiency attributed to hypopituitarism? Was there a pituitary adenoma? MID patients frequently develop cardiac disease, which may be subclinical at onset [5]. Which were the results of long-term ECG and echocardiography when actively searching for cardiac involvement? Overall, this interesting study could be strengthened by reporting why DCA was given for 4y (patient-1), why no ketogenic diet was tried (patient-1), if there was a pituitary adenoma, and how cerebral involvement progressed on MRI (patient-1).
CNS involvement Encephalopathy Dystonia Spasticity Choreoathetosis Migraine Developmental delay Irritability Hypotonia Perturbed sleep/wake cycle Dysarthria/anarthria Basal ganglia involvement Epilepsy Corpus callosum thinning Low-lying conus medullaris Leigh-like MRI Ocular involvement Blindness (optic atrophy) Otologic involvement Hearing loss Gastrointestinal involvement Cyclic vomiting Constipation Gastroparesis Gastro-intestinal dysmotility Cecal volvulus GERD Poor feeding Gallstones Endocrine involvement Diabetes Short stature Hypogonadism Osteoporosis (spontaneous fractures) Hyperhidrosis Peripheral nerve involvement Polyneuropathy Muscle involvement Myopathy Ptosis Facial weakness Ophthalmoparesis Bone marrow involvement Anemia Thrombocytopenia Pulmonary involvement Chronic reactive airway disease Others Cardiomyopathy Sacral dimple Immunodeficiency Dysmorphism Fanconi syndrome Lactic acidosis
Patient 1
Patient 2
Previously reported
Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes No Yes No No
Yes Yes Yes No No Yes No Yes Yes Yes No No No Yes Yes
[Lamperti 2012] [Carrozza 2016] [Carrozza 2016] [Ostergaard 2007] No [Carrozza 2016] [Lamperti 2012] [Carrozza 2016] No [Lamperti 2012] [Carrozzo 2016, Liu 2014] [Carrozza 2016] No No [Wortmann 2009]
No
Yes
No
Yes
Yes
[Morawa 2009, Carrozza 2016]
Yes No No No No Yes Yes No
Yes Yes Yes Yes Yes Yes Yes Yes
[Carrozza 2016] No No [Lamperti 2012] No [Carrozza 2016] [Carrozza 2016] No
Yes Yes Yes Yes
No Yes No Yes
No [Carrozza 2016] No No
No
No
[Carrozza 2016, Ostergaard 2007]
Yes
Yes
[Carrozza 2007]
Yes Yes Yes Yes
Yes Yes Yes Yes
[Carrozza 2016] [Carrozza 2016] [Liu 2014] [Carrozzas 2016]
No No
Yes Yes
No No
Yes
No
[Carrozzas 2016]
No No No No No Yes
No Yes Yes No No Yes
[Carrozzo 2007] No [Carrozza 2016] [Carrozza 2016] [Carrozza 2007] [Liu 2014]
http://dx.doi.org/10.1016/j.ymgmr.2016.12.007 2214-4269/© 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
32
Correspondence
Table 1 (continued) Phenotype Methylmalonic academia (UOA)
Patient 1
Patient 2
Previously reported
Yes
Yes
[Liu 2014]
GERD: gastro-enterological reflux disease, UOA: urine organic acids.
References [1] X. Huang, J.K. Bedoyan, D. Demirbas, D.J. Harris, A. Miron, S. Edelheit, G. Grahame, S.D. DeBrosse, L.J. Wong, C.L. Hoppel, D.S. Kerr, I. Anselm, G.T. Berry, Succinyl-CoA synthetase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondrial oxidative enzymes in skeletal muscle without mitochondrial DNA depletion, Mol. Genet. Metab. (2016) http://dx.doi.org/10.1016/j.ymgme.2016.11.005 (pii: S10967192(16)30314-6, Nov 12). [2] P. Kaufmann, K. Engelstad, Y. Wei, S. Jhung, M.C. Sano, D.C. Shungu, W.S. Millar, X. Hong, C.L. Gooch, X. Mao, J.M. Pascual, M. Hirano, P.W. Stacpoole, S. DiMauro, D.C. De Vivo, Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial, Neurology 66 (2006) 324–330. [3] C. Steriade, D.M. Andrade, H. Faghfoury, M.A. Tarnopolsky, P. Tai, Mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS) may respond to adjunctive ketogenic diet, Pediatr. Neurol. 50 (2014) 498–502.
[4] F.A. Wijburg, P.G. Barth, L.A. Bindoff, M.A. Birch-Machin, J.F. van der Blij, W. Ruitenbeek, D.M. Turnbull, R.B. Schutgens, Leigh syndrome associated with a deficiency of the pyruvate dehydrogenase complex: results of treatment with a ketogenic diet, Neuropediatrics 23 (1992) 147–152. [5] J. Finsterer, S. Kothari, Cardiac manifestations of primary mitochondrial disorders, Int. J. Cardiol. 177 (2014) 754–763.
Josef Finsterer Krankenanstalt Rudolfstiftung, Vienna, Austria Corresponding author at: Postfach 20, 1180 Vienna, Austria. E-mail address: fifi[email protected] Sinda Zarrouk-Mahjoub University of Tunis El Manar, Genomics Platform, Pasteur Institute of Tunis, Tunisia 18 December 2016 Available online xxxx