A number sign (#) is used with this entry because of evidence that childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (DYTOABG) is caused by homozygous or compound heterozygous mutation in the MECR gene (608205) on chromosome 1p35.

Childhood-onset dystonia with optic atrophy and basal ganglia abnormalities (DYTOABG) is an autosomal recessive neurologic disorder characterized by onset of involuntary movements in the first decade of life. Optic atrophy develops around the same time or slightly later. Severity is variable, and some patients lose independent ambulation. Brain imaging shows abnormalities in the basal ganglia. Cognition appears to be unaffected (summary by Heimer et al., 2016).

Heimer et al. (2016) reported 7 patients from 5 unrelated families with onset of involuntary movements, mainly dystonia, between 15 months and 6.5 years of age. Some patients had mildly delayed motor development. Variable features included facial dystonia, lower limp spasticity with hyperreflexia, myoclonus, chorea, dyskinesias, dysarthria, and dysphagia. Most patients had difficulty walking, and some lost independent ambulation. Optic atrophy with decreased visual acuity developed in all but the youngest either immediately or within a few years of the appearance of dystonia. Some patients had abnormal eye movements, including nystagmus. Brain imaging showed hyperintense T2-weighted signal abnormalities in the basal ganglia, and some patients showed a lactate peak on MR spectroscopy. Although motor disability was progressive, there was a relative sparing of cognitive functions in most patients. None had seizures.

Liu et al. (2021) reported a 12-year-old boy who presented at age 7 years with unilateral limb dystonia, dysarthria, muscle weakness, and hypertonia. Brain MRI showed bilateral lesions in the globus pallidus and cerebral peduncles. EMG showed decreased compound muscle action potential, and an ophthalmologic examination was normal. After symptomatic treatment and administration of thiamine and biotin, the patient's symptoms improved, except for dystonia. During treatment with lipoic acid from the age of 10 years, he did not develop visual impairment or optic atrophy and he showed some improvement on brain MRI. There was no change in his dystonia.

The transmission pattern of DYTOABG in the families reported by Heimer et al. (2016) was consistent with autosomal recessive inheritance.

In a 12-year-old Chinese boy with DYTOABG who had treatment with lipoic acid from the age of 10 years, Liu et al. (2021) reported absence of visual impairment or optic atrophy and improvement in globus pallidus and cerebral peduncles abnormalities on brain MRI.

In 7 patients from 5 unrelated families with DYTOABG, Heimer et al. (2016) identified biallelic mutations in the MECR gene (608205.0001-608205.0006). The mutations, which were found either by whole-exome sequencing or direct sequencing of the MECR gene, were confirmed by Sanger sequencing and segregated with the disorder in the families. Patient fibroblasts from 4 families showed strongly reduced levels of MECR protein and about a 50% decrease in protein lipoylation compared to controls. Only some patient cells also showed mild and variable decreases in mitochondrial respiratory chain and electron transport system activities. Patient cells did not show changes in mitochondrial morphology compared to controls. Two of the variants failed to fully rescue a growth defect in yeast complementation assays, consistent with a loss-of-function effect. Heimer et al. (2016) concluded that DYTOABG is an inborn error of metabolism that is similar to some mitochondrial disorders by the involvement of organs with high energy demands and susceptibility to oxidative stress such as basal ganglia and optic nerve. However, it differs by the relative sparing of cognition and typical mitochondrial biomarkers. The authors noted the possibility of a therapeutic approach through dietary supplementation with lipoic acid.

In a 12-year-old boy with childhood-onset dystonia and basal ganglia but without optic atrophy, who was born to consanguineous Chinese parents (family G), Liu et al. (2021) identified a homozygous mutation in the MECR gene (D304Y; 608205.0007). The boy was treated with lipoic acid from age 10, which may explain the lack of optic atrophy. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents and an unaffected sib. MECR protein expression was reduced in patient fibroblasts. Molecular modeling suggested that the D304Y mutation resulted in disturbed protein stability.