New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN

Abstract

Objective: To assess the frequency of mutations in C19orf12 in the greater neurodegeneration with brain iron accumulation (NBIA) population and further characterize the associated phenotype.

Methods: Samples from 161 individuals with idiopathic NBIA were screened, and C19orf12 mutations were identified in 23 subjects. Direct examinations were completed on 8 of these individuals, and medical records were reviewed on all 23. Histochemical and immunohistochemical studies were performed on brain tissue from one deceased subject.

Results: A variety of mutations were detected in this cohort, in addition to the Eastern European founder mutation described previously. The characteristic clinical features of mitochondrial membrane protein-associated neurodegeneration (MPAN) across all age groups include cognitive decline progressing to dementia, prominent neuropsychiatric abnormalities, and a motor neuronopathy. A distinctive pattern of brain iron accumulation is universal. Neuropathologic studies revealed neuronal loss, widespread iron deposits, and eosinophilic spheroidal structures in the basal ganglia. Lewy neurites were present in the globus pallidus, and Lewy bodies and neurites were widespread in other areas of the corpus striatum and midbrain structures.

Conclusions: MPAN is caused by mutations in C19orf12 leading to NBIA and prominent, widespread Lewy body pathology. The clinical phenotype is recognizable and distinctive, and joins pantothenate kinase-associated neurodegeneration and PLA2G6-associated neurodegeneration as one of the major forms of NBIA.

Figure 1. MRI findings in mitochondrial membrane protein-associated neurodegeneration

T2 fluid-attenuated inversion recovery images from 3 individuals (248, 437, 438, images A–C, respectively) with hyperintense streaking of the medial medullary lamina. Substantia nigra from the same individuals (D–F).

Figure 2. Histopathologic features of mitochondrial membrane protein-associated neurodegeneration

(A) Low-magnification (4×) view of hematoxylin & eosin stain of the globus pallidus, showing central pallor and widespread dark hemosiderin deposits. (B) At higher magnification (20×), the predominantly perivascular distribution of hemosiderin and the near complete loss of neurons in the globus pallidus are apparent; residual small nuclei are glial-derived. (C) Eosinophilic spheroidal structures as described in pantothenate kinase–associated neurodegeneration (PKAN) are readily apparent; some of these harbor residual nuclear outlines and lipofuscin pigment, indicating an origin in degenerating neurons (40×). (D) Perls stain (blue) for iron highlights densely stained hemosiderin deposits (white arrowhead) as well as more diffuse iron in the globus pallidus and increased iron associated with eosinophilic spheroids (black arrowhead, 20×). (E) Ubiquitin immunohistochemistry shows uniform, strong staining of spheroids (white arrowheads) as in PKAN (20×). (F) An immunostain for τ labels a subpopulation of spheroids (white arrowheads); occasional τ-positive neurites are in the background (20×). (G) TDP-43 immunostaining does not label any structures in the globus pallidus (white arrowhead); the brown signal is derived from hemosiderin deposits (20×). (H) Spheroids in the globus pallidus are not labeled with an antibody to α-synuclein (white arrowhead, 40×). Scale bars: 100 μm.

Figure 3. Histopathologic features of mitochondrial membrane protein-associated neurodegeneration

(A) Lewy neurites are abundant in relatively intact areas at the periphery of the globus pallidus (40×). (B) α-Synuclein immunohistochemistry of the putamen developed with Vector Red identifies Lewy bodies (white arrowhead) and neurites (20×), inset at higher magnification (60×). (C) Hematoxylin & eosin stain of the midbrain demonstrates sclerosis of the substantia nigra with only isolated residual neurons (10×); (D) many of these contain Lewy bodies (white arrowhead, 60×). (E) Perls stain (blue) of the midbrain shows only occasional areas of minute parenchymal iron deposits, predominantly in a perivascular distribution (40×). (F) α-Synuclein immunohistochemistry revealed abundant Lewy bodies in the neocortex (20×), inset at higher magnification (60×); (G) α-synuclein immunohistochemistry also highlighted Lewy neurites in a widespread distribution, including the cerebral cortex (depicted, 40×), basal ganglia, pons, and midbrain. (H) Neocortical Lewy bodies were ubiquitin positive, as in the case of sporadic Lewy body disease (20×). Scale bars: 100 μm.