Phenotypic heterogeneity of a compound heterozygous SUCLA2 mutation.

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)?

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]
Methylmalonic academia (UOA)	Yes	Yes	[Liu 2014]

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

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).