Dysarthria, Ataxia, and Dystonia Associated with COX20 (FAM36A) Gene Mutation: A Case Report of a Turkish Child.

Sir,

Cytochrome c oxidase 20 (COX20) encodes a protein with a role in the assembly and stability of mitochondrial complex IV. Complex IV is the final component of the respiratory chain and is responsible for the reduction of molecular oxygen and oxidation of cytochrome C.[1] Several disorders have been reported encephalopathies, myopathies, and liver disease to Leigh's syndrome, and metabolic acidosis that associated with mutations of both nuclear and mitochondrial complex IV in the literature.[234]

COX20 is important for complex IV function. In COX20 deficient mitochondria, respiratory chain assembly intermediates are accumulated and showed reduced respiratory capacity. This dysfunction was because of the role of COX20 in the maturation of the COX2 protein and COX2's integration into the complex IV holocomplex.[5]

To date, only a few patients with COX20 deficiency have been described in the literature.[2346] Here, we report a Turkish child with COX20 deficiency, who presented with hypotonia, ataxia, dysarthria, and dystonia.

An 11-year-old boy presented with progressive walking difficulty and slurred speech. He had infantile hypotonia, and early milestones were delayed. He started to walk at 24 months of age and developed progressive ataxia at 2, 5 years. At 5 years, he developed slurred dysarthric speech. His gait and speech progressively worsened. He had dystonia in the upper extremities from the age of 10 years. The parents were consanguineous, and there was no family history of neurologic diseases. He was born at term and had no neonatal problems. He had two elder siblings who were healthy. Pedigree was shown in [Figure 1]. On neurological examination in our hospital, he had dysarthria, bilateral dysmetria, intention tremor, dysdiadochokinesia, and gait ataxia. He also had dystonic posturing of both hands-on walking. Muscle tone had increased and deep tendon reflexes were brisk in all extremities. Babinski sign was negative bilaterally. His cognitive function and ophthalmologic evaluation were normal. The etiology of ataxia was investigated. The results of complete blood counting, uric acid, folic acid, vitamin B12, alpha-fetoprotein, and ceruplasmin were in the normal range. His liver, renal, and thyroid function tests were normal. Urine organic acids, plasma amino acids, and lactate levels were also normal. Cerebral magnetic resonance imaging (MRI) showed cerebellar atrophy [Figure 2], and spinal cord imaging was normal. Nerve conduction studies were also normal. Genetic tests for ataxia (ATXN1, ATXN2, MJD1, CANA1, ATXN7, ATXN8OS, ATXN10, FRDA1, and TBP genes) revealed no pathogenic variant. Clinical exome sequencing analysis was performed in the patient using TruSight One kits (Illumina Inc., San Diego, CA, USA). The bioinformatics analysis was performed at the Genetics Diagnosis Center. Annotations included according to the reference databases from ExAC (Exome Aggregation Consortium), 1000 Genomes Project, ClinVar pathogenicity annotations, and OMIM (Online Mendelian Inheritance in Man) disorders. As a result of the clinical exome analysis, a homozygous mutation at the COX20 gene (c. 190A > C; pT64P) was identified, which is related to his clinical findings.

Figure 1

Pedigree of the patient

Figure 2

Cerebral magnetic resonance imaging showed cerebellar atrophy

COX20 is an assembly factor encoded by nuclear DNA, which is important for mitochondrial complex IV function. COX biosynthesis proceeds from COX1. Inner membrane protein COX20 is very important for COX2 maturation. COX20 acts as a chaperone that binds the newly synthesized COX2 molecule. COX20 mutations were thought to alter COX20 assembly and maturation by altering the structural stability of the COX20 protein.[78]

COX20 deficiency is a rare recessive disorder with early-onset hypotonia, ataxia, areflexia, dystonia, dysarthria, and sensory neuropathy. In the literature, a few cases have been reported with COX20 deficiency.[234] The first three affected children reported with COX20 deficiency were from Turkish families from two separate relatives and all were homozygous for the same pathogenic mutation (c.154A>C; pT52p). The first patient was reported by Szklarczyk et al.[6] This patient had microcephaly in addition to hypotonia, dystonia, dysarthria, ataxia, and sensory neuropathy. In addition, mildly elevated serum and CSF lactate levels and normal MRI findings were also present. The other two patients were reported by Doss et al.[4] Two affected siblings had childhood-onset cerebellar ataxia, dystonia, and sensory axonal neuropathy. In the brother, dystonic features were most pronounced in the legs, while his sister developed torticollis. Otero et al.[3] reported four patients with features that include childhood hypotonia, areflexia, ataxia, dysarthria, dystonia, and sensory neuropathy. Three of 4 patients had neuropathy, and none had cerebellar atrophy. They identified the same novel compound heterozygous mutation (c. 157 + 3G > C, c. 41A >G) in COX20 gene. The family of these four patients were nonconsanguineous. In another study, Xu et al.[2] described two patients from a nonconsanguineous family exhibiting autosomal recessive sensory-dominant axonal neuropathy and static encephalopathy. The genetic analysis revealed that both patients harbored compound heterozygous mutations (p. Lys14Arg and p. Trp74Cys) of COX20 gene. The family of these patients was not related. Our patient had early-onset hypotonia, ataxia, dysarthria, and dystonia but no sensory neuropathy. He had mild cerebellar atrophy in cerebral MRI. His parents were relatives. Table 1 presents the analysis of the cases of COX20 deficiency from the literature and our patient.

Table 1

The analysis of cases of COX20 deficiency from the literature and our patient

	Age/ Sex	Ambulation	Speech impairment	Ocular findings	Cognitive impairment	MRI findings	Neuropathy	Mutation
Szklarczyk et al.[6]	10/M	+	+	Normal	NR	Normal	NR	c. 154A>C; p.Thr52Pro
Doss et al.[4]	25/M	-	+	Normal	-	cerebellar atrophy	+	c. 154A>C; p.Thr52Pro
	32/F	+	+	Normal	-	cerebellar atrophy	+	c. 154A>C; p.Thr52Pro
Otero et al.[3]	13/F	-	+	Normal	-	Normal	+	c. 41A>G, c. 157+3G>C
	32/F	-	+	Normal	-	Normal	+
	38/M	-	+	Normal	+	Normal	-
	70/M	-	+	Normal	+	Normal	-
Hu et al.[2]	19/M	+	+	NR	+	Normal	+	p.Lys14Arg, p.Trp74Cys
	16/M	-	+	NR	+	Normal	+
Our pateint	11/M	+	+	Normal	-	cerebellar atrophy	-	c. 190A>C; pT64P

NR: not reported

In conclusion, we detected mutation in COX20 gene to early-onset hypotonia, ataxia, dystonia, and speech disorder that is characterized by reduced complex IV activity. COX20 deficiency should be in the differential diagnosis of early-onset hypotonia, ataxia, speech disorder, and dystonia.

Declaration of patient consent

Informed consent was obtained from the parents of the child included in the study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.