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| CASE REPORT |
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| Year : 2019 | Volume
: 67
| Issue : 5 | Page : 1341-1343 |
A Novel Mutation in Neurodegeneration with Brain Iron Accumulation - A Case Report
Sundarachary Nagarjunakonda, Rajeswari Daggumati, Veeramma Uppala, Ramakrishna Gajula, Sridhar Amalakanti
Department of Neurology, Government General Hospital, Guntur Medical College, Guntur, Andhra Pradesh, India
| Date of Web Publication | 19-Nov-2019 |
Correspondence Address:
Dr. Rajeswari Daggumati
Department of Neurology, Government General Hospital, Guntur Medical College, Guntur - 522 001, Andhra Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/0028-3886.271257
Neurodegeneration with brain iron accumulation (NBIA), previously called Hallervorden Spatz disease, is a group of disorders which share the hallmark of iron deposition in the brain. They are collectively characterized by extrapyramidal movement disorders, particularly those of parkinsonism, dystonia, cognitive regression, neuropsychiatric abnormalities, pyramidal features, optic atrophy, and retinal abnormalities. There is aberrant brain iron metabolism, with large amounts of iron deposited in the globus pallidus and the substantia nigra pars reticulata. NBIA displays a marked genetic heterogeneity, and 10 genes have been associated with different NBIA subtypes at present. We present a 12-year-old boy with a one and a half-year history of a slow, progressive gait disturbance. An MRI of his brain revealed T2, FLAIR bilateral symmetrical hypointensities in globus pallidus and substantia nigra s/o NBIA. His genetic analysis revealed a novel homozygous missense variation in exon 2 of the C19orf12 gene (chr19:30199203; A>C) that results in the amino acid substitution of valine for phenylalanine at codon 51 (p.F51V; ENST00000392278). This is consistent with the MPAN (mitochondrial membrane protein-associated neurodegeneration) subtype.
Keywords: Brain iron metabolism, Hallervorden Spatz disease, mitochondrial membrane protein-associated neurodegeneration, neurodegeneration, pantothenate kinase-associated neurodegeneration (PKAN)
Key Message: Along with pantothenate kinase-associated neurodegeneration, MPAN should also be considered in the differential diagnosis of "eye of the tiger" sign. Lack of typical clinical phenotype should not preclude the diagnosis of MPAN.
How to cite this article:
Nagarjunakonda S, Daggumati R, Uppala V, Gajula R, Amalakanti S. A Novel Mutation in Neurodegeneration with Brain Iron Accumulation - A Case Report. Neurol India 2019;67:1341-3 |
How to cite this URL:
Nagarjunakonda S, Daggumati R, Uppala V, Gajula R, Amalakanti S. A Novel Mutation in Neurodegeneration with Brain Iron Accumulation - A Case Report. Neurol India [serial online] 2019 [cited 2023 Mar 21];67:1341-3. Available from: https://www.neurologyindia.com/text.asp?2019/67/5/1341/271257 |
Neurodegeneration with brain iron accumulation (NBIA) consists of a group of inherited heterogenous neurodegenerative disorders. Prevalence data is incomplete, but all forms of NBIA are considered to be “ultra-rare” with less than 1/1000000 affected.[1] Advances in sequencing technologies have greatly facilitated rapid gene discovery and have improved our understanding of the disease processes. Ten NBIA genes have been identified to date.[1] Mutations within C19orf12 have recently been identified in patients with NBIA. This gene C19orf12 codes for a mitochondrial membrane protein.[2] The corresponding phenotype was named mitochondrial membrane protein-associated neurodegeneration (MPAN, NBIA 4, MIM# 614298) which has an autosomal recessive inheritance.[3] We present a typical case of MPAN with a novel mutation of C19orf12 gene.
| » Case Report | |  |
A 12-year-old previously healthy boy, born of consanguineous parentage, was brought with the complaints of difficulty in walking from when he was 10 years of age. There were no adverse antenatal or perinatal events present. He was first noticed to have frequent falls, difficulty walking on uneven surfaces, difficulty in ascending and descending stairs without support. He developed stiffness of both his lower limbs and tended to walk on his toes. There was no history of cognitive decline, personality or behavioral disturbance, visual or hearing disturbance, involuntary movements or seizures. Two second cousins in the family were diagnosed with NBIA.
On examination, the patient had equinus deformity of both feet, spasticity of both lower limbs with exaggerated DTRs, bilateral ankle clonus and spastic gait. An MRI scan of the brain [Figure 1] revealed bilateral symmetrical T2, FLAIR hypointensities in the globus pallidi, and substantia nigra. Signals from the brainstem and cerebellum were normal. Nerve conduction study were normal. Complete blood picture and peripheral smear was normal. Serum copper and ceruloplasmin, 24-hr urinary copper, serum iron, and ferritin were normal. Screening for inborn errors of metabolism including serum lactate and urine for amino acids and organic acids. No abnormality was detected. Ophthalmological assessment was normal. | Figure 1: MRI brain T2 axial and FLAIR (a and b) imaging of index case showing bilateral symmetric hypo intensity of globus pallidi (black arrows), faint hyper intensity is seen along the medial medullary lamina (white arrows)
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Multigene panel testing for PANK2 and NBIA associated genes was sought. Exome sequencing analysis revealed a homozygous missense variation in exon 2 of the C19orf12 gene (chr19:30199203; A>C) that results in the amino acid substitution of valine for phenylalanine at codon 51 (p.F51V. This is consistent with the MPAN (mitochondrial membrane protein-associated neurodegeneration) subtype. This is a novel variant but predicted to be pathogenic by mutation prediction.
Symptomatic therapy with Baclofen and physiotherapy was initiated. Genetic counseling of his parents was performed. A confirmation of carrier status in parents was recommended. The autosomal recessive pattern of inheritance, absence of curative therapy, progressive nature of disease and prognosis were explained to the parents.
| » Discussion | | |
Our patient with NBIA has a novel gene mutation but with a lack of the characteristic features of MPAN such as cognitive decline, optic atrophy and neuropathy. According to Hardig et al. 2013, 67 MPAN patients have been described in the literature.[4] A compilation of all these cases shows that MPAN leads to a distinctive phenotype with optic atrophy and motor axonal neuropathy (lower motor neuron signs) as the most distinctive features.
Twenty-eight different mutations have been described in C19orf12 in 55 published families (67 cases) including frameshift mutations, missense mutations, nonsense mutations, and splice-site mutations.[4] Gagliardi et al. (2015) further described six novel mutations after the screening of C19orf12 in five unrelated NBIA families.[5]
This case report reveals a novel homozygous missense variation in exon 2 of the C19orf12 gene (chr19:30199203; A>C) that results in the amino acid substitution of valine for phenylalanine at codon 51 (p.F51V; ENST00000392278). This variant is predicted to be possibly damaging by PolyPhen and damaging LRT and Mutation Tester. This mutation has not been previously reported.
Pallidal and nigral iron accumulation is observed on the brain MRI scan on the T2 and GRE sequences, variably accompanied by hyperintense streaking of the globus pallidus in the region of the medial medullary lamina.[1] This may be interpreted as an “eye of the tiger”, leading to an erroneous diagnosis of PKAN. Cortical and cerebellar atrophy may be seen in advanced stages of the disease.[5] The MRI scan of the brain in our patient had shown hyperintense streaking in the region of the medial medullary lamina and surrounding hypointensity suggesting the “eye of tiger sign” mimic.[2] This MRI finding has been described in a series of patients with MPAN.[4] The “eye of tiger sign” seen in PKAN is typically larger, more hyperintense and is not confined to the medial medullary lamina, thus differentiating the PKAN from MPAN.[6] Considering the high proportion and the small size of the gene with only three exons, C19orf12 should always be analyzed in NBIA patients.
Although not pathognomonic for PKAN, the “eye of the tiger sign” is still very distinctive for PKAN, but MPAN should also 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.
| » References | | |
| 1. | Salomão RPA, Pedroso JL, Gama MTD, Dutra LA, Maciel RH, Godeiro-Junior C, et al. A diagnostic approach for neurodegeneration with brain iron accumulation: Clinical features, genetics and brain imaging. Arq Neuropsiquiatr 2016;74:587-96.  |
| 2. | Hogarth P. Neurodegeneration with brain iron accumulation: Diagnosis and management. J Mov Disord 2015;8:1-13. |
| 3. | Gagliardi M, Annesi G, Lesca G, Broussolle E, Iannello G, Vaiti V, et al. C19orf12 gene mutations in patients with neurodegeneration with brain iron accumulation. Parkinsonism Relat Disord 2015;21:813-6. |
| 4. | Hartig MB, Iuso A, Haack T, Kmiec T, Jurkiewicz E, Heim K, et al. Absence of an orphan mitochondrial protein, c19orf12, causes a distinct clinical subtype of neurodegeneration with brain iron accumulation. Am J Hum Genet 2011;89:543-50. |
| 5. | Hogarth P, Gregory A, Kruer MC, Sanford L, Wagoner W, Natowicz MR, et al. New NBIA subtype: Genetic, clinical, pathologic, and radiographic features of MPAN. Neurology 2013;80:268-75. |
| 6. | Yoganathan S, Sudhakar SV, Thomas M, Dutta AK, Danda S. “Eye of tiger sign” mimic in an adolescent boy with mitochondrial membrane protein associated neurodegeneration (MPAN). Brain Dev 2016;38:516-9. |
[Figure 1]
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C19orf12 mutation causing mitochondrial membrane-protein Associated Neurodegeneration masquerading as spastic paraplegia |
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