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

Abstract

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). 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 proteinassociated 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.

MRI of neurodegeneration with brain iron accumulation

“…Whether this aspect is specific to MPAN remains to be determined. Additional T1 hyperintensity [9], SWI hypointensity [43,44]…”

Cerebral Iron Deposition in Neurodegeneration

“…Aging ↑ serum ferritin [53] ↑ Fe in red nucleus, putamen, substantia nigra, dentate nucleus, globus pallidus, caudate nucleus, subthalamic nucleus, cortex [7] Fe remains stable in oligodendroglia; Fe accumulates in astrocytes and dystrophic microglia in cortex and deep gray matter [12] Fe bound to ferritin in cytoplasm of microglia and astrocytes and to neuromelanin in neurons [12,28] AceruloplasMinemia ↑ Fe in liver, pancreas, retina ↑ serum ferritin, ↓ transferrin saturation [54,55] ↑ Fe in putamen, caudate, lateral, habenular, and pulvinar thalamic nuclei, red nucleus, dentate nucleus, inner cortical layers, hippocampus, mammillary bodies, superior and inferior colliculi [56,57] ↑ Fe in astrocytes, neurons [58][59][60] Fe stored in ferritin/ hemosiderin in lysosomal dense bodies and cytoplasmic inclusions [61,62] Hereditary Ferritinopathy ↑ Fe in liver, kidney, skin, muscle ↓ serum ferritin [63][64][65] ↑ Fe in globus pallidus, substantia nigra, dentate nucleus, putamen, thalamus, caudate, deep cortical layers [66][67][68] ↑ Fe in nuclei and cytoplasm of microglia, oligodendroglia, neurons, and also extracellularly [64,69] Fe stored in inclusion bodies consisting of abnormal ferritin aggregates [69,70] Pantothenate Kinase-Associated Neurodegeneration -↑ Fe in globus pallidus, substantia nigra [71][72][73][74] ↑ Fe in astrocytes, neurons, perivascular macrophages, iron dust in neuropil [75,76] Fe stored in cytoplasmic inclusions co-localized with ferritin [75] Mitochondrial Membrane Protein-Associated Neurodegeneration -↑ Fe in globus pallidus, substantia nigra, putamen, caudate [77,78] ↑ Fe in perivascular macrophages, astrocytes, neurons…”

“…MPAN (OMIM #614298) typically manifests with progressive spastic paraparesis, psychiatric disturbances, and slow cognitive decline, variably accompanied by motor neuropathy, dystonia, parkinsonism, and visual symptoms [192]. Abnormal Fe deposits are consistently located in globus pallidus and SN while late-onset cases show Fe accumulation also in the putamen and caudate [78], which has been confirmed also in younger MPAN patients by R2* mapping at 7T MRI (Table 1) [77]. Microscopically, iron deposits are found in perivascular macrophages, astrocytes, and neurons [79,80].…”

Neurodegeneration with Brain Iron Accumulation and a Brief Report of the Disease in Iran

“…Respectively, there were 23, 5, 3, 1, 3, 3, and one family with PKAN, MPAN, PLAN, JABELS, BPAN, Kufor-Rakeb and WSSs in Iran (Figure 4). 74,[91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108][109] Like the other countries, the most common form of NBIA was PKAN accounting for more than half of the cases (59%) (Figure 4). A high percentage of the PKAN may be due to the easy diagnostics procedures; the specific pattern on MRI, which is the "eye of tiger" sign.…”