Novel MECR Mutation in Childhood-Onset Dystonia, Optic Atrophy, and Basal Ganglia Signal Abnormalities

Childhood-onset dystonia, optic atrophy, and basal ganglia signal abnormalities (DYTOABG) is a rare mitochondrial fatty acid synthesis (mtFAS) defect and is caused by MECR gene mutations. Here, we report a patient who was diagnosed with DYTOABG and detected compound heterozygous mutations (c.772C > T/p.Arg258Trp and c.1009C > T/ p.Arg337Ter) in the MECR (NM_016011.4) gene using whole exome sequencing (WES).

A 5-year-old female child, born out of nonconsanguineous marriage, was presented to the genetic department with dystonia. She was born at 35th weeks of gestation by caesarean section due to preeclampsia following an uneventful pregnancy with normal birth measurements and had no dysmorphic feature. She was the second child of her family and the fifth pregnancy of her mother. Her parents and elder brother were healthy and none of them presented with any neurological disease. Three fetuses of the parents were exposed to unexplained spontaneous abortions. According to the proband's mother, the disease started with a gait disturbance at 3.5 years of age and the patient had frequent falls. Cranial magnetic resonance imaging (MRI) was performed on the patient and the basal ganglia signal abnormalities were observed at 4 years of age ([Fig. 1A]). The patient was hospitalized with a severe respiratory tract infection and connected to a mechanical ventilator due to respiratory failure at 5 years of age. Cerebral and cerebellar atrophy were observed in addition to the detected basal ganglion signal abnormalities of the patient at the same time in the cranial MRI ([Fig. 1B]). Also, epilepsy and dystonia started during this period. Bilateral optic atrophy was detected in an eye examination at 5.5 years of age. The laboratory tests for inborn error of metabolism in the blood and urine of the patient were normal. The patient's muscle histopathologic examination that was performed by staining muscle samples for respiratory chain enzymes and ragged red fibers was normal. There was no histological argument for mitochondrial disorders.

Fig. 1 T2 axial magnetic resonance images of the patient and results of DNA sequencing. (A) Hyperintense signal in the putamen and globus pallidus. (B) Hyperintense signal and cystic changes in the putamen (indicated by black arrow), caudate nucleus and globus pallidus in addition to generalized mildly cerebral atrophy. (C) Sequencing of DNA extracted of peripheral leucocytes identified compound heterozygous germline mutations; c.772C > T/p.Arg258Trp and c.1009C > T/p.Arg337Ter (indicated by red frames). a, patient; b, father; c, mother; d, brother.

She was diagnosed with DYTOABG using next-generation sequencing (NGS) combined with Sanger's sequencing for the definite diagnosis. We detected compound heterozygous variations (c.772C > T/p.Arg258Trp and c.1009C > T/ p.Arg337Ter) in the MECR gene and these two variations were not found together in other healthy family members ([Fig. 1C]). The variant c.772C > T has been previously reported in the literature but the other variant c.1009C > T has not been previously reported in the Human Gene Mutation Database (HGMD; http://www.hgmd.cf.ac.uk/ac/index.php ) and according to The American College of Medical Genetics and Genomics (ACMG) criteria, it is classified as pathogenic.

To our knowledge, seven patients from five unrelated families diagnosed with DYTOABG have been reported, and six different mutations have been detected associated with the disease in the literature. The clinical and radiological features of our patient were similar to these patients.[1]

In summary, our patient, who has a novel mutation (MECR; c.1009C > T; p.Arg337Ter), is the eighth case reported in the literature with DYTOABG.

• Reference

• 1 Heimer G, Kerätär JM, Riley LG. , et al; University of Washington Center for Mendelian Genomics. MECR mutations cause childhood-onset dystonia and optic atrophy, a mitochondrial fatty acid synthesis disorder. Am J Hum Genet 2016; 99 (06) 1229-1244