Objective: To illustrate a rare Turkish patient with homozygous C19ORF12 mutation and discuss limitations regarding the current terminology and classification.

Background: Neurodegeneration with brain iron accumulation (NBIA) is a group of disorders with genetic heterogeneity characterized by iron accumulation in the basal nuclei. Membrane protein-associated neurodegeneration (MPAN) is the third most common subtype of NBIA, and it is caused by mutations of the C19ORF12 gene encoding a transmembrane mitochondrial protein.

Method: We evaluated a 24-year-old male patient who presented with progressive gait difficulty and slurring of speech since 12 years old. His mother and father were first-degree relatives and his only sibling, the older brother, had been exitus following a similar course of the disease at the age of 26 years old.  The neurological exam of the patient showed paraparesis, lower extremity spasticity, and mild cerebellar signs, Extrapyramidal examinations revealed lower extremity dystonia. Detailed laboratory investigations and whole-genome exome sequencing have been performed. The diagnosis of the patient has been discussed in the context of related literature.

Results: Fundus examination revealed bilateral temporally accentuated atrophy of the optic nerve and glittering pigmentation of the macula. Electrophysiological investigations revealed findings compatible with motor neuron disease. The cranial MRI showed iron deposition in bilateral basal ganglia and hypointense signals in bilateral substantia nigra, suggestive of an underlying neuron brain iron accumulation disease. The whole-genome exome sequencing revealed homozygote genomic changes of the c.210dupG (p. Leu71fs*12)] in the C19orf12 gene (NM_001031726.3). The Sanger sequencing analyses (3^rd exon) also confirmed the mutation.

Conclusion: The mutations of the orphan gene C19ORF12 lead to various phenotypes including MPAN, Behr syndrome, HSP type 43, and juvenile-onset ALS. The clinical presentation of our patient includes features resembling all the other clinical entities associated with the C19ORF12 gene mutation. Via the presentation of our patient, we remark on the limitation of distinguishing these presentations as distinct entities and suggest the use of the terminology of ‘C19ORF12-related disorder’ which emphasizes the responsible genetic locus and pathophysiological mechanisms.

« Back to 2023 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/detailed-illustration-of-a-turkish-patient-with-homozygous-c19orf12-mutation/