Late‐Onset Mitochondrial Membrane Protein–Associated Neurodegeneration With Extensive Brain Iron Deposition

A 38‐year‐old female, born to a consanguineous marriage, with a 2‐year history of neuropsychiatric symptoms and mental decline, referred to our center for further assessments. On admission, she was bedridden and unable to talk and obey orders. She had severe rigidity and spasticity of extremities with brisk muscle stretch reflexes and bilateral Babinskie sign. She also had jerky movements of the limbs, consistent with myoclonus. Ophthalmological examination revealed neither optic atrophy nor retinopathy.

MRI of the brain showed symmetric and extensive iron deposition in bilateral caudates, putamens, globus pallidi (GP), and SN (Fig. 1).

Figure 1.

Susceptibility‐weighted imaging sequences showing iron deposition in the SN (A), putamens, GP, and caudate nuclei (B,C). Inferior row, same sequences in 1 of our patients with classic MPAN with a homozygous mutation in C19orf12 gene (NM_001031726.3: c.194G>T (p.Gly65Val) showing iron deposition just in the SN and globus pallidus. She is 22 years old now, and her disease started at the age of 8 with progressive visual loss followed by gait disturbance. The MRI was done at the age 12 (D–F).

Whole‐exome sequencing revealed a homozygous mutation in the C19orf12 gene (NM_001031726.3: c.32C>T (p.Thr11Met), indicative of a diagnosis of mitochondrial membrane protein–associated neurodegeneration (MPAN). MPAN is a subtype of neurodegeneration with brain iron accumulation syndromes caused by mutation in the C19orf12 gene. Clinically, MPAN presents with progressive spasticity, dystonia‐parkinsonism, optic atrophy, motor neuronopathy, and neuropsychiatric and cognitive symptoms.1 Although iron deposition in the SN and GP are typical of MPAN, there is one other case report of MPAN with iron deposition in the putamen and caudate nuclei.2

This case is 1 of 2 cases with the oldest onset age reported so far in MPAN and suggests that p.Thr11Met mutation in the C19orf12 gene may cause a late‐onset form of the disease with a rapidly progressive course and extensive iron deposition in the brain.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Manuscript: A. Writing of the First Draft, B. Review and Critique.

A.A.: 1B, 1C

M.M.: 2A

R.H.: 1C

A.D.: 1C

A.F.: 2B

A.E.L.: 2B

M.R.: 1A, 1B, 2A

Disclosures

Ethical Compliance Statement

The authors confirm that the approval of an institutional review board was not required for this work. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. The patient's sister signed informed consent for publishing her information.

Funding Sources and Conflicts of Interest

The authors acknowledge the University of Social Welfare and Rehabilitation Sciences (USWR) and National Institute for Medical Research Development (NIMAD) for funding the research. The authors report no conflicts of interest.

Financial Disclosures for previous 12 months

Alfonso Fasano receives consultancy fees from: AbbVie, Medtronic, Boston Scientific, Sunovion, Chiesi farmaceutici, UCB, and Ipsen; receives honoraria from AbbVie, Medtronic, Boston Scientific, Sunovion, Chiesi farmaceutici, UCB, and Ipsen; receives grant support from University of Toronto, Weston Foundation, AbbVie, Medtronic, and Boston Scientific; and sits on advisory boards for AbbVie, Boston Scientific, and Ipsen.