Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN)

Dear Editor, Neurodegeneration with brain iron accumulation is a group of inherited disorders characterized by cognitive dysfunction and extrapyramidal and pyramidal signs with iron accumulation at the basal ganglia. Identifying single neurodegeneration with brain iron accumulation (NBIA) subtype is challenging due to clinical and genetic heterogeneity. Mitochondrial membrane protein-associated neurodegeneration, the third most common NBIA subtype, is a rare autosomal recessive disease caused by C19orf12 mutation.[1] We herein report two cases of MPAN, one with atypical and the other with typical presentation. CASE 1 A 16-year-old male born of nonconsanguineous parentage, second in birth order, and with normal birth and developmental history presented with difficulty in walking with stiffness and dragging of left foot and frequent tripping episodes for 4 years. He had dysarthria and reduced scholastic performance for 2 years. On examination, he had cognitive impairment with a Montreal cognitive assessment score (MOCA) of 20/30, spastic dysarthria, hypometric saccades (horizontal > vertical), spastic paraparesis with brisk reflexes, extensor plantar bilaterally, and spastic gait with the normal sensory and cerebellar examination. As he presented with predominant spastic paraparesis with spastic dysarthria and cognitive impairment Complicated Hereditary spastic paraplegia (HSP) was considered as a possible diagnosis. Nerve conduction velocities showed normal latencies and velocities. MRI brain showed symmetrical T2/Flair hypointensities in bilateral globus pallidi, substantia nigra, and with faint hyperintensity along medial medullary lamina suggestive of MPAN [Figure 1a]. Whole exome sequencing with Next generation sequencing showed homozygous mutation in exon 2 of C19orf12 (c. 151T > G) confirming the diagnosis of MPAN.Figure 1: (a) T2 MRI axial images showing bilateral symmetrical hypointensities in subtantia nigra, global pallidi with hyperintensity along with Medial medullary lamina. (b) MRI Flair axial images showing hypointensity in substantia nigra and globus pallidiCASE 2 A 23-year-old female born of consanguineous parentage presented with abnormal posturing of all limbs for 12 years. Initially, the dystonic posturing started in the right foot followed by the left foot while walking which progressed to involve the trunk and upper limbs over the next 4 years, and she regressed to crawling. She had a cognitive decline and in the last 6 years, she developed behavioral abnormalities, initially aggressiveness followed by apathetic behavior over the next 2 years. There was no family history. On examination, MOCA was 8/30, and fundus showed bilateral optic atrophy with visual acuity of 6/60; she had hypotonic speech, bilateral brisk reflexes, extensor plantars, and dystonia of four limbs. MRI brain showed hypointensity in bilateral globus pallidi and substantia nigra [Figure 1b]. Genetic analysis showed novel homozygous mutation in C19orf12 (c98T>A PL33Q) suggestive of MPAN. The phenotype of MPAN includes optic atrophy, pyramidal signs (spasticity), extrapyramidal signs, cognitive decline, neuropsychiatric abnormalities, and motor axonal neuropathy.[2] Hartig et al. in their review described 67 patients with MPAN and described the most common symptoms and signs as upper motor signs in 87.9%, dysarthria in 82.3%, optic atrophy in 75.0%, dystonia in 66.7%, cognitive decline in 85.9%, psychiatric abnormalities in 64.3%, lower motor neuron signs in 56.3%, dysphagia in 55.6%, and parkinsonism in 44.6%.[3] They found that optic atrophy and lower motor neuron signs (motor axonal neuropathy) are the most distinguishing features of MPAN. Case 2 had a typical MPAN presentation with dystonia, optic atrophy, and dementia, but Case 1 presented with spastic paraplegia without typical features such as optic atrophy, dystonia, parkinsonism, and neuropathy. This HSP-like presentation is very rare, with only a few cases reported in the literature. Meilleur et al.[4] reported two sisters with childhood-onset spastic paraplegia and two children from Brazil.[5] From India, Ramesh et al.[6] and Sundarachary Nagarjunakonda et al.[7] described similar presentation of MPAN (HSP-like presentation) with similar mutation of C19orf12 resulting in the substitution of valine for phenylalanine (c.151T>G). All three cases (including ours) from India had similar presentation with similar genetic mutation which can be considered for genotype-phenotype correlation for Indian patients [Table 1].Table 1: Various reports of HSP-like presentation of MPAN reported from IndiaImaging features of MPAN are iron accumulation in globus pallidus and substantia nigra, and there can be hyperintense streaking of media medullary lamina.[89] MRI in Case 2 showed iron deposition and medial medullary lamina streak typical for MPAN and Case 1 showed hypointensity in bilateral globus pallidi and substantia nigra. Although there was a variation in clinical features, imaging was similar in both patients. Different mutations in the MPAN gene may result in different phenotypes. Although HSP-like presentation is rare for MPAN, for those presenting with spastic paraplegia, MPAN should be considered in the differential diagnosis. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

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