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. Author manuscript; available in PMC: 2017 Nov 1.
Published in final edited form as: Neurocase. 2016 Nov 1;22(5):476–483. doi: 10.1080/13554794.2016.1247458

Clinical and imaging characteristics of late onset mitochondrial membrane protein-associated neurodegeneration (MPAN)

Ethan Gore a, Brian S Appleby b, Mark L Cohen c, Suzanne D DeBrosse d, James B Leverenz e, Bruce L Miller f, Sandra L Siedlak g, Xiongwei Zhu g, Alan J Lerner a
PMCID: PMC5568540  NIHMSID: NIHMS881299  PMID: 27801611

Abstract

Young onset dementias present significant diagnostic challenges. We present the case of a 35-year-old Kuwaiti man with social withdrawal, drowsiness, irritability, anxiety, aphasia, memory loss, hypereflexia, and Parkinsonism. Brain MRI showed bilateral symmetric gradient echo hypointensities in the globi pallidi and substantiae nigrae. Left cortical hypometabolism was seen on brain fluorodeoxyglucose positron emission tomography. A cortical brain biopsy revealed a high Lewy body burden. Genetic testing revealed a homozygous p.T11M mutation in the C19orf12 gene consistent with mitochondrial membrane protein-associated neurodegeneration. This is the oldest onset age of MPAN reported.

Keywords: Mitochondrial membrane, protein-associated, neurodegeneration (MPAN), neurodegeneration with brain iron accumulation (NBIA), Lewy body, Parkinsonism, whole exome sequencing

Introduction

Recent advances in imaging and genomic analysis have allowed the definitive diagnosis of hereditary causes of dementia prior to autopsy. We present the case of a young man, born to consanguineous parents, who developed dementia with pyramidal and extrapyramidal signs associated with symmetric gradient echo (GRE) hypointensities of the globi pallidi on magnetic resonance imaging (MRI). Whole exome sequencing revealed a homozygous mutation in C19orf12 causing the oldest known onset of mitochondrial membrane protein associated neurodegeneration (MPAN). Like the other two MPAN pathology reports, this patient’s brain biopsy revealed a high Lewy body burden. In this paper, we review the clinical, genetic, and histological characteristics of MPAN.

Case

A 35-year-old Kuwaiti police officer presented to a clinic in Kuwait for a change in behavior in early 2014. Over the prior 2 months, he had developed “nonsense talking” characterized by semantic paraphasias with preserved fluency, blunted affect, social withdrawal, memory problems, and drowsiness. He complained of a new mild tremor in his hands when nervous. There was no history of head trauma. His parents were consanguineous (see Figure 1). Three of his six siblings had intellectual disability and dysmorphic features. Exam at that time showed an Arabic Mini Mental Status Exam score of 23/30, and the remainder of the exam was normal except for mild hypereflexia.

Figure 1.

Figure 1

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Pedigree provided by the patient’s uncle demonstrating the consanguinity of the patient’s (proband’s) parents.

The proband, a homozygote for the C19orf12 mutation, is depicted by a black square at the bottom. Heterozygotes are half shaded.

His Vitamin B12 level was 185 ng/L (abnormal < 150 ng/L). The following laboratory studies were unremarkable: comprehensive metabolic panel, thyroid-stimulating hormone, erythrocyte sedimentation rate, antinuclear antibody, C-reactive protein, urinalysis, ammonia, copper, ceruloplasmin, heavy metals, coagulation studies, anti-thyroglobulin antibody, antithyroperoxidase antibody, paraneoplastic panel, serum lactate, and plasma amino acids. His routine CSF studies were normal, and there were no oligoclonal bands. MRI of the brain is shown in Figure 2. Fluorodeoxyglucose positron emission tomography (FDG-PET) showed hypometabolism in left parietal, temporal, anterior occipital, and left caudate nucleus (see Figure 3). A left frontal cortical brain biopsy performed to rule out vasculitis showed no evidence of vasculitis but did reveal many intracytoplasmic neuronal spheroids and a few similar appearing extraneuronal spheroids. These inclusions were labeled by p62 and alpha-synuclein immunohistochemistry stains confirming their identity as Lewy bodies. The biopsied tissue from the dura mater, leptomeninges, and subcortex was normal (see Figure 4). CT of the brain after the biopsy is shown in Figure 5.

Figure 2.

Figure 2

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Top left: 3T MRI T1 coronal image with contrast showing bifrontal parenchymal volume loss, asymmetric parenchymal volume loss of the temporal lobes, and hypointensity of the globi pallidi. Top right: 3T MRI FLAIR axial image showing hypointensity of the globi pallidi and putamina, mild periventricular white matter hyperintensities, and left greater than right temporoparietal parenchymal volume loss. Bottom left: 3T MRI susceptibility weighted image (SWI) showing hypointensity of the globi pallidi, caudate heads, and putamina and relatively hyperintense streaking of the medullary laminae. Bottom right: 3T MRI SWI showing hypointensity of the substantiae nigrae as well as the globi pallidi, caudate heads, and putamina.

Figure 3.

Figure 3

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Top: FDG-PET axial image showing relative hypoperfusion of the left temporal, parietal, occipital, and insular frontal cortices. Bottom: FDG-PET coronal image showing relative hypoperfusion of the left frontal and temporal cortices.

Figure 4.

Figure 4

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Top left: Hematoxylin and eosin stain of cortex showing spherical neuronal intracytoplasmic inclusions resembling Lewy bodies in the top circle and similar extra-neuronal inclusions in the bottom circle. Top right: Hematoxylin and eosin stain of cortex with a higher magnification view of the extra-neuronal inclusions that resemble extra-neuronal Lewy bodies. Bottom left: Alpha synuclein immunohistochemistry staining of the intracytoplasmic inclusions. Bottom right: Ubiquitin-binding protein p62 immunohistochemistry staining of the intracytoplasmic inclusions.

Figure 5.

Figure 5

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CT axial image showing bilateral hyperdensities in the globi pallidi and pneumocephaly from a left frontal brain biopsy.

Eleven months after onset, his speech had gradually worsened so that he could only speak a few words, and he had developed slow movement, imbalance, festination, acalculia, poor memory, anxiety, and irritability. He was sleeping up to 14 h/day. On examination, he was well dressed and nourished with good eye contact. His mood was described as “Okay,” and his affect was full range. His Arabic Montreal Cognitive Assessment score was 8/30 demonstrating a predominantly receptive aphasia with relatively preserved repetition. He had no spontaneous speech, and his verbal responses were brief. He had clonus of the ankles, brisk deep tendon reflexes, and a positive glabellar sign. He had bradykinesia and decreased arm swing worse on the left side and a mild bilateral resting tremor.

Genetic testing was performed, and whole exome sequencing at GeneDx laboratory (Gaithersburg, MD) revealed a homozygous p.T11M mutation in C19orf12 consistent with mitochondrial MPAN, a form of neurodegeneration with brain iron accumulation (NBIA) (Accession numbers: NM_001031726.2 and NM_031448.3).

Deferiprone, an iron chelator, was experimentally prescribed but not tolerated due to gastrointestinal side effects (Aoun & Tiranti, 2015; Cossu et al., 2014). Over his second year of illness, the patient developed frequent visual hallucinations, rapid eye movement sleep behavior disorder, urinary and bowel incontinence, staring spells lasting up to 15 min, inappropriate laughter and crying, and apraxia. As of March 2016, he was able to walk without assistance, but he needed help preparing meals and around the clock supervision due to frequent wandering.

Discussion

The first symptoms of this patient’s neurological disorder were tremor, slow gait, social withdrawal, transcortical sensory aphasia, poor concentration, and drowsiness. This constellation of symptoms raises concern for a bilateral cortical, subcortical, basal ganglia, thalamic, and upper brainstem dysfunction worse on the left side. The differential diagnosis for such a presentation is broad and includes Wilson’s disease, Huntington’s disease, Huntington’s disease-like 2, young onset Parkinson’s disease, neuroacanthocytosis, and other NBIAs (see Table 1) (Freeman et al., 2007; Gregory & Hayflick, 2014; Gregory et al., 2008; Hayflick, 2014; Karkheiran, Shahidi, Walker, & Paisan-Ruiz, 2015; Keogh, Jonas, Coulthard, Chinnery, & Burn, 2012; Kurian & Hayflick, 2013; Lehn, Boyle, Brown, Airey, & Mellick, 2012; Levine, Estes, & Looney, 1968; Mahoney, Selway, & Lin, 2011; Margolis et al., 2001; Margolis, 2012; McNeill, Pandolfo, Kuhn, Shang, & Miyajima, 2008; Schneider & Bhatia, 2012; Schneider & Bhatia, 2012; Schrag, Ben-Shlomo, Brown, Marsden, & Quinn, 1998; Stevenson & Hardie, 2001; Williams, Hadeed, al-Din, Wreikat, & Lees, 2005; Yonekawa, Okabe, Asamoto, & Ohta, 1999).

Table 1.

Information on the 10 known types of NBIA (Al-Semari & Bohlega, 2007; Dusi et al., 2014; Gregory & Hayflick, 2014; Haack et al., 2012; Kurian & Hayflick, 2013; Schneider & Bhatia, 2012).

NBIA type Mutation Onset Symptoms Pearls
PKAN PANK2 Early – 3 years old
Atypical teens and 20s		 Early-spastic paraparesis, dystonia, rigidity, pigmentary retinopathy, step-wise decline to inability to walk over 10–15 years
Atypical-dysarthria, palilalia, slower progression		 35–50% of NBIA
Eye of the tiger
Phospholipase A2 group VI associated neurodegeneration (PLAN) (PARK14) PLA2G6 Infantile – <3 years
Atypical teens
PRDP – age 4–30		 Infantile-ataxia, spastic tetraparesis, death by age 10
Atypical-ataxia, social communication deficits, impulsivity, dystonia
PRDP – dysarthria, dystonia, Parkinsonism, dopamine-induced dyskinesia		 20% of NBIA
Cerebellar parenchymal volume loss and gliosis and secondary thinning of the posterior corpus callosum
Claval hypertrophy
Only half have elevated brain iron on MRI
MPAN C19orf12 3–35 years old (mean of 10) Spasticity > dystonia, optic parenchymal volume loss, Parkinsonism, nearly universal progression to dementia, early urinary incontinence, motor axonal peripheral neuropathy T2 hyperintense streaking of medullary lamina in some
FAHN FA2H Childhood or adolescence Spasticity, dystonia, optic parenchymal volume loss, supranuclear gaze palsy Associated with leukodystrophy
Kufor–Rakeb syndrome (PARK9) ATPase type 13A2 Usually adolescence but into 30s Pyramidal signs, levodopa responsive Parkinsonism with early dopamine-induced dyskinesia Not all have elevated brain iron visible on MRI
BPAN WDR45 Early childhood Global delay in early childhood with development of Parkinsonism, dystonia, and dementia in adulthood X-linked dominant
CoPAN CoASY 2–3 years old Toe walking and by grade school dystonia; by age 20, tics, dementia, and inability to walk, motor neuropathy CoASY catalyzes the final two of three steps in the synthesis of coenzyme A from pantothenate (PANK2 catalyzes the first)
Neuroferritinopathy FTL1 Adulthood (mean of 39) Asymmetric chorea or dystonia, low ferritin Autosomal dominant
Cortical iron on susceptibility weighted MRI
Aceruloplasminemia Ceruloplasmin 16–71 (mean of 51) Dementia, retinal degeneration, diabetes, iron deficiency anemia, ceruloplasmin undetectable Iron seen in the basal ganglia, thalamus, cerebellum, cortex, pancreas, and liver
Woodhouse–Sakati syndrome DCAF17 Evident at puberty Alopecia, hypogonadism (small testes or streak ovaries), sensorineural deafness, low insulin-like growth factor 1, chorea, dystonia, scoliosis White matter changes
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PKAN: Pantothenate kinase-associated neurodegeneration; PANK: pantothenate kinase; PLA2G6: phospholipase A2 group VI; PRDP: PLA2G6-related dystonia-Parkinsonism; MPAN: mitochondrial membrane protein associated neurodegeneration; C19orf12: chromosome 19 open reading frame 12; FAHN: fatty acid hydroxylase-associated neurodegeneration; FA2H: fatty acid 2 hydroxylase; BPAN: beta propeller associated neurodegeneration; WDR45: WD repeat 45; CoPAN: coenzyme A synthase protein associated neurodegeneration; CoASY: coenzyme A synthase; FTL: ferritin light chain; DCAF: DDB1- and CUL4-associated factor.

NBIA is a group of disorders caused by mutations in 10 known genes (Gregory & Hayflick, 2014). The prevalence of NBIA is less than one per million people in the United States. The most common NBIA disorders are pantothenate kinase-associated neurodegeneration (PKAN) due to mutations in pantothenate kinase 2 (PANK2) followed by phospholipase A2 group VI (PLA2G6)-associated neurodegeneration (PLAN) due to mutations in PLA2G6 which together comprise over half the cases. The third most common NBIA disorder is mitochondrial MPAN which is caused by mutations in C19orf12 and accounts for 5–30% of NBIA cases (Gagliardi et al., 2015; Hartig, Prokisch, Meitinger, & Klopstock, 2013; Hogarth et al., 2013). A C19orf12 mutation associated with brain iron accumulation was first described in 2011 in three members of a Polish family who had NBIA but no PANK2 mutation. Targeted genetic sequencing of 23 other Polish NBIA patients without PANK2 mutations revealed C19orf12 mutations in 11 of them (Hartig et al., 2011). To date, fewer than 100 cases of MPAN have been described.

MPAN is an autosomal recessively inherited disease caused by mutations in C19orf12, which encodes a protein of unknown function found throughout the body, especially expressed in the brain, blood cells, and adipocytes (Colombelli, Aoun, & Tiranti, 2015). The protein has been localized to mitochondria, endoplasmic reticula, and mitochondrial-associated membranes, and its long hydrophobic domain and glycine zipper motifs suggest that it may be a transmembrane protein (Venco et al., 2015). Mutations in C19orf12 result in a higher percentage of the protein outside the mitochondria perhaps due to inability to fit into membranes. The gene is co-regulated with genes involved in fatty acid biogenesis and in degradation of branched chain amino acids. These processes are both related to coenzyme A metabolism which is dysfunctional in other types of NBIA (Levi & Finazzi, 2014; Meyer, Kurian, & Hayflick, 2015)). In contrast to the better understood pathophysiologies of aceruloplasminemia and neuroferritinopathy, it is unclear specifically why brain iron accumulation and brain dysfunction occur in people with MPAN.

The mean age at onset of MPAN is 10 years of age, and cases have been reported between 3 and 30 years of age (Gregory et al., 2014). Usually, the first signs are gait changes that progress to spastic paraparesis and dystonia which may be limited to the hands and feet. In seven patients reported, the average age of wheelchair requirement was 21.7 years of age (Hartig et al., 2013).

This patient’s disease broadens the spectrum of MPAN as it is the oldest onset of the disease at 35 years of age. Other p. T11M C19orf12 mutations have also been associated with older than average onset (Dezfouli et al., 2013). The T11M mutation is a missense mutation that has been reported in at least eight families. C19orf12 encodes a long and a short isoform that differ by 11 amino acids based on 2 alternative first exons. The vast majority of the C19orf12 mutations affect both isoforms. The T11M mutation only affects the long isoform which implicates its involvement in the pathogenesis of MPAN. In six patients from five families with homozygous p. T11M mutations, the average onset age was 25 years of age, ranging from 21 to 28. Chimpanzees and chickens are the only other known species with two isoforms of C19orf12, raising the possibility of an animal model of MPAN. Other species evaluated only have a short isoform.

Neuropsychiatric symptoms are common at onset and include labile mood, depression, anxiety, hallucinations, perseveration, inattention, and hyperactivity. In children, it may present as attention deficit hyperactivity disorder congener. Dysarthria from oromandibular dystonia is very common and often presents early in the disease. Dysphagia occurs in about half of people with MPAN. Parkinsonism is seen in about half of cases, and its response to dopaminergic agents is variable and without dyskinesia. Optic atrophy is reported in over 70% of MPAN patients and is more prominent in young onset cases, whereas Parkinsonism is more prominent with older onset (Kleffner et al., 2015). Four of 23 patients with MPAN first sought medical care due to vision loss related to optic atrophy.

Two clinical symptoms distinguishing MPAN from other NBIA disorders are early incontinence and motor axonal polyneuropathy. Eleven of 17 people with C19orf12 mutations developed urinary incontinence, often prior to severe walking or cognitive problems. Nine of 13 MPAN patients who underwent electrophysiological testing showed evidence of motor axonal neuropathy which can be severe. MPAN patients with a positive Babinski sign and hyporeflexia and distal atrophy have been described (Deschauer et al., 2012; Dogu et al., 2013). Skin biopsy in two MPAN patients revealed axonal spheroids. This patient developed incontinence within 2 years and early in the clinical course had hypereflexia. He did not undergo a nerve conduction study. MPAN progresses over 1 year to a few decades, nearly universally causes dementia, and is uniformly fatal. There are no specific treatments; a few clinical trials have used iron chelators in patients with NBIA but no patients with MPAN were included (Cossu et al., 2014; Zorzi et al., 2011).

Lactate dehydrogenase may be high in MPAN, but otherwise routine laboratory testing is unremarkable (Schulte et al., 2013). Brain MRI in MPAN typically shows T2 hypointensity of the globi pallidi and substantiae nigrae with generalized atrophy that depends on the stage of the illness. The T2 hypointensity is due to susceptibility effects related to increased paramagnetic iron accumulation and is, therefore, seen best using susceptibility weighted sequences like GRE. On T2-weighted images, some MPAN patients have hyperintense streaking that highlights the entire length of the medullary lamina between the internal and external segments of the globus pallidus (Amaral et al., 2015). This streaking may occur due to inflammation, or simply sparing from iron accumulation. This may appear similar to the “eye of the tiger” sign usually seen in PKAN as a rounded, drop-like T2 hyperintensity at the anterior end of the medullary lamina over a background of hypointense globi pallidi (Hayflick, Hartman, Coryell, Gitschier, & Rowley, 2006; Skowronska, Kmiec, Kurkowska-Jastrzębska, & Czlonkowska, 2015).

Prior research is unclear about when brain iron accumulation occurs and whether or not increased brain iron accumulation always eventually occurs with C19orf12 mutations. Two Malian sisters, ages 7 and 12, developed progressive spastic paraparesis and peripheral neuropathy and were found to have C19orf12 mutations but no extrapyramidal symptoms, cognitive deficits, or optic atrophy even 5 years later. In 2010, before the first description of MPAN, their syndrome was called hereditary spastic paraplegia type 43 (Landoure et al., 2013). A brain MRI in one of the siblings showed no basal ganglia hypointensity. Two Brazilian siblings, ages 14 and 15, with the same genotype who also presented with progressive spastic paraparesis were found to have iron deposition on MRI and optic atrophy, and one had cognitive deficits, but neither had extrapyramidal symptoms. Observation and analysis of these cases may provide insight into how brain damage occurs in MPAN.

No standardized formula exists to distinguish between physiologic and pathologic brain iron accumulation. Brain iron increases with age, and T2 hypointensity from iron becomes more prominent with increasing magnetic field strength (Aoki et al., 1989; Schenck, 1995; Schneider et al., 2013). In a young symptomatic patient with basal ganglia hypointensities on T2 and especially SWI, we felt that NBIA-genetic testing was appropriate (International Huntington Association and the World Federation of Neurology Research Group on Huntington’s Chorea, 1994; Points to Consider in the Clinical Application; Rabbani, Tekin, & Mahdieh, 2014).

In MPAN, the globus pallidus usually appears normal or sometimes slightly hyperintense on T1 images. This may be due to an iron-related discrepancy between the paramagnetic effect on T1 and T2 shortening as has been described with manganese. In our patient’s case, the globus pallidus was hypointense on T1 images, which is unreported. Because the globus pallidus in this case appears hypointense on T2 and SWI sequences as expected, we believe that the globus pallidus T1 hypointensity is due to iron-related susceptibility artifact that is stronger with a 3T magnet than the prior brain MRIs of patients with MPAN obtained with 1.5T magnets. Brain iron deposition can cause a uniform T1 hypointensity less prominent than that on T2 (Hegde, Mohan, Lath, & Lim, 2011; del C. Valdés Hernández et al., 2014; del C. Valdés Hernández, Maconick, Tan, & Wardlaw, 2012).

Another feature of this MRI that is atypical in MPAN is the hypointensity of the caudate and putamen on FLAIR and SWI. Hypointensity of the dorsal striatum has been reported in MPAN but not to the degree seen here (Dogu et al., 2013; Goldman et al., 2013; Hartig et al., 2013). Because the striatal-imaging characteristics are similar to those in the globus pallidus, we believe the striatal signal changes are due to iron deposition. Histological evidence of elevated iron in the caudate and putamen specifically in MPAN has not been reported. The hypointensities may appear more dramatic in this case due to a higher magnetic field strength or due to greater iron deposition. Striatal involvement has been shown in other patients with homozygous T11M mutations and in a younger patient with a different mutation (Dogu et al., 2013; Goldman et al., 2013; Hartig et al., 2013). Based on the small number of cases with caudate and putamen changes, we do not believe the presence or degree of MRI hypointensity of the caudate and putamen to be predictive of a particular MPAN mutation type.

This patient’s MRI shows a higher degree of asymmetric parenchymal volume loss than other reported MRIs in MPAN. It is corroborated by asymmetric metabolism on FDG-PET imaging. Our case is the first to report FDG-PET in MPAN, and it is unknown whether or not metabolic asymmetry should be considered typical of MPAN. The cortical hypometabolism shown in Figure 3 correlates well with this patient’s clinical presentation, but surprisingly the basal ganglia metabolism was relatively spared.

Microscopic examination of two MPAN brains revealed iron in the basal ganglia, especially the globus pallidus, with iron deposition in neurons, astrocytes, and perivascular macrophages. In those cases, extremely high concentrations of Lewy bodies were found in the cortex, hippocampus, brainstem, spinal cord, and basal ganglia, especially the globus pallidus. In the substantia nigra, Lewy bodies and Lewy neurites were accompanied by nearly complete axonal loss. Axonal spheroids and hyperphosphorylated tau-containing inclusions were also seen in the brain. Ultrastructural studies of the Lewy bodies are ongoing but beyond the scope of this paper.

The biopsy in this case is the third reported histological examination of brain tissue from a patient with MPAN. Like the other two, it revealed very high concentrations of cortical Lewy bodies. Similar to other patients with alpha-synucleinopathies, this patient developed frequent well-formed visual hallucinations, staring spells lasting up to 15 min, rapid eye movement sleep behavior disorder, and incontinence. Although the cause of alpha-synucleinopathies remains unclear, growing evidence implicates mitochondrial dysfunction. With more confidence that MPAN is an alpha-synucleinopathy, the already established link between alpha-synucleinopathies and mitochondrial dysfunction becomes stronger. Thinking of MPAN as an alpha-synucleinopathy may help to untangle the complex association between the alpha synucleinopathies and brain iron deposition.

In conclusion, MPAN should be considered with the onset of behavioral and cognitive deficits, extrapyramidal symptoms, and pyramidal signs even in patients presenting in the fourth decade of life. At 35 years of age, this is the oldest onset of MPAN reported, corroborating the link between p.T11M C19orf12 mutations and an older age of clinical disease onset in MPAN. This is the first report of a brain FDG-PET scan in a patient with MPAN, and it reveals asymmetric hypometabolism. Along with PD, dementia with Lewy bodies, multiple system atrophy, pure autonomic failure, some amyloidoses, some tauopathies, and PLAN, MPAN should be considered to be an alpha-synucleinopathy (Gregory et al., 2008; Jellinger, 2003; Li et al., 2013). Hopefully, the recognition and analysis of future cases of MPAN will help reveal the function of the C19orf12 gene product and clarify the pathogenesis of other alpha-synucleinopathies and NBIAs.

Acknowledgments

We thank the patient and his family for their contribution to this work.

Footnotes

Disclosure statement

The authors have no financial or nonfinancial relationships to disclose.

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