Phenotypic heterogeneity of a compound heterozygous SUCLA2 mutation

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Phenotypic heterogeneity of a compound heterozygous SUCLA2 mutation

J. Finsterer, S. Zarrouk-Mahjoub

To cite this version:

J. Finsterer, S. Zarrouk-Mahjoub. Phenotypic heterogeneity of a compound heterozygous SU- CLA2 mutation. Molecular Genetics and Metabolism Reports, Elsevier, 2017, 10, pp.31-32.

�10.1016/j.ymgmr.2016.12.007�. �hal-01565821�

Correspondence

Phenotypic heterogeneity of a compound heterozygousSUCLA2mutation

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 de-

terioration of the phenotype attributable to the mitochondrion-toxic ef- fect 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 bene

fi

cial 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 bene

fi

cial?

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, phos- phate, and hormone levels in both patients? Was multiple hormone de

fi

ciency 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 in- volvement progressed on MRI (patient-1).

Molecular Genetics and Metabolism Reports 10 (2017) 31–32

Table 1

Phenotypic manifestations of SUCLA2 mutations in the present and previous studies.

Phenotype Patient

1

Patient 2

Previously reported

CNS involvement

Encephalopathy Yes Yes [Lamperti 2012]

Dystonia Yes Yes [Carrozza 2016]

Spasticity Yes Yes [Carrozza 2016]

Choreoathetosis Yes No [Ostergaard 2007]

Migraine Yes No No

Developmental delay Yes Yes [Carrozza 2016]

Irritability Yes No [Lamperti 2012]

Hypotonia Yes Yes [Carrozza 2016]

Perturbed sleep/wake cycle No Yes No

Dysarthria/anarthria Yes Yes [Lamperti 2012]

Basal ganglia involvement Yes No [Carrozzo 2016, Liu 2014]

Epilepsy No No [Carrozza 2016]

Corpus callosum thinning Yes No No Low-lying conus medullaris No Yes No

Leigh-like MRI No Yes [Wortmann 2009]

Ocular involvement

Blindness (optic atrophy) No Yes No Otologic involvement

Hearing loss Yes Yes [Morawa 2009, Carrozza

2016]

Gastrointestinal involvement

Cyclic vomiting Yes Yes [Carrozza 2016]

Constipation No Yes No

Gastroparesis No Yes No

Gastro-intestinal dysmotility No Yes [Lamperti 2012]

Cecal volvulus No Yes No

GERD Yes Yes [Carrozza 2016]

Poor feeding Yes Yes [Carrozza 2016]

Gallstones No Yes No

Endocrine involvement

Diabetes Yes No No

Short stature Yes Yes [Carrozza 2016]

Hypogonadism Yes No No

Osteoporosis (spontaneous fractures)

Yes Yes No

Hyperhidrosis No No [Carrozza 2016, Ostergaard

2007]

Peripheral nerve involvement

Polyneuropathy Yes Yes [Carrozza 2007]

Muscle involvement

Myopathy Yes Yes [Carrozza 2016]

Ptosis Yes Yes [Carrozza 2016]

Facial weakness Yes Yes [Liu 2014]

Ophthalmoparesis Yes Yes [Carrozzas 2016]

Bone marrow involvement

Anemia No Yes No

Thrombocytopenia No Yes No

Pulmonary involvement Chronic reactive airway disease

Yes No [Carrozzas 2016]

Others

Cardiomyopathy No No [Carrozzo 2007]

Sacral dimple No Yes No

Immunodeficiency No Yes [Carrozza 2016]

Dysmorphism No No [Carrozza 2016]

Fanconi syndrome No No [Carrozza 2007]

Lactic acidosis Yes Yes [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/).

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Molecular Genetics and Metabolism Reports

j o u r n a l h o m e p a g e :w w w . e l s e v i e r . c o m / l o c a t e / y m g m r

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 synthe- tase (SUCLA2) deficiency in two siblings with impaired activity of other mitochondri- al 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: S1096- 7192(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, con- trolled clinical trial, Neurology 66 (2006) 324–330.

[3]C. Steriade, D.M. Andrade, H. Faghfoury, M.A. Tarnopolsky, P. Tai, Mitochondrial en- cephalopathy 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 defi- ciency 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:

fifigs1@yahoo.de

Sinda Zarrouk-Mahjoub University of Tunis El Manar, Genomics Platform, Pasteur Institute of Tunis, Tunisia 18 December 2016

Table 1(continued)

Phenotype Patient

1

Patient 2

Previously reported

Methylmalonic academia (UOA)

Yes Yes [Liu 2014]

GERD: gastro-enterological reflux disease, UOA: urine organic acids.

32 Correspondence