We present a patient with progressive spastic ataxia, with dystonia and anarthria undiagnosed until detailed genetic analysis revealed an MPAN mutation. Highlighting the worldwide MPAN distribution, a 30 year history of absent diagnosis and the impact and cost saving of an early but detailed genetic analysis in complex progressive movement disorders, particularly the anarthric NBIA group

Fedotova, E

Houlden, H

Illarioshkin, SN

Klyushnikov, S

Schottlaender, LV

Selikhova, M

Wiethoff, S

UCL Discovery

Selikhova et al  Short report with video                                          *Video as part of the manuscript   An MPAN case from Russia. 30 years of the natural history. M. Selikhova,³ E.Fedotova,¹ S.Wiethoff, ² L.V. Schottlaender, ² S. Klyushnikov¹, S.N. Illarioshkin¹ and H. Houlden ² ¹Research Centre of Neurology, Department of Neurogenetics, Moscow, Russia   ²Institute of Neurology, Department of Molecular neurosciences, UCL, United Kingdom ³Reta Lila Weston Institute, UCL, United Kingdom  Address for correspondence: Prof Henry Houlden – a corresponding author. London, WC1N 1PJ, United Kingdom. Telephone: +44-20-7679 4246  Fax:            +44-20-7278 4993 Email: h.houlden@ucl.ac.uk   Short Abstract We present a patient with progressive spastic ataxia, with dystonia and anarthria undiagnosed until detailed genetic analysis revealed an MPAN mutation. Highlighting the worldwide MPAN distribution, a 30 year history of absent diagnosis and the impact and cost saving of an early but detailed genetic analysis in complex progressive movement disorders, particularly the anarthric NBIA group.          Selikhova et al  Short report with video   Main text A 38-year-old right-handed patient from Yakutia, Russia presented to the Moscow Research Centre of Neurology with a 30-year history of a disabling neurological disorder without clear diagnosis.  The patient was born at term from non–consanguineous parents, their 4th uncomplicated pregnancy. There is no history of neurological disorders in her family. She had mild learning difficulties. Otherwise, early milestones and development were normal. At the age of ten, she developed stumbled gait and falls. At the age of fifteen, her examination revealed a spastic gait, symmetrical leg weakness, bilateral optic atrophy without significant visual impairment, normal CSF and an overall diagnosis of probable hereditary spastic paraparesis (HSP). By the age of twenty, she became ataxic, dysarthric and lost ambulance. By the age of 25, she developed additional clumsiness in the hands, anterocollis and urinary urgency and at 35 seizures. On our examination at 35 years of age she was anarthric, oromandibular dyskinesia, mild dysphagia, restriction of eye movements to the left side, dystonic smile, dystonic hand-posturing, laterocollis, moderate weakness in the upper limbs. There was paraplegia in the lower limbs with foot drop, pes cavus and hammer toes. Muscle tone and tendon reflexes were reduced throughout but a positive Hoffman, ankle clonus and Babinski sign elicited bilaterally (video). She had moderate cognitive impairment. General examination was normal and routine blood tests, copper study were normal. EMG and NCS revealed severe axonal motor polyneuropathy. MRI brain showed mild cerebellar atrophy and a marked hypodensity on T2 and SW1 imaging in the basal ganglia, particularly in the globus pallidum (GP) and substantia nigra (SN), suggestive of pathological iron accumulation (Figure 1a). Pantothenate kinase2 (PANK-2) genetics were negative. Further DNA analysis was performed at the Institute of Neurology, London. Selikhova et al  Short report with video    Genetical results  TruSight One sequencing panel (Illumina, TruSight One) was performed which focuses on exonic regions harboring disease-causing mutations based on information in the Human Gene Mutation Database (HGMD Professional), the Online Mendelian Inheritance in Man (OMIM) catalog, GeneTests.org, Illumina TruSight panels, and other commercially available sequencing panels. This sequencing panel analyses over 4000 genes per run. Analysis revealed the previously published homozygous 11 basepair deletion c.204_214del11- (p.Gly69ArgfsX10) in C19orf12 (NM_001031726.2) which was subsequently confirmed by Sanger sequencing (Figure 2) [1], thereby establishing the genetic diagnosis of mitochondrial membrane protein-associated neurodegeneration (MPAN) with autosomal recessive inheritance.   Discussion This genetically proven case of MPAN from Russia provides a rare opportunity to observe a 30-year natural history of a relatively new form of neurodegeneration with brain iron accumulation (NBIA). Insidious onset of progressive spastic paraparesis in the 2nd decade of life, initially mimicking HSP. However, optic atrophy is exceptionally rare in HSP. By contrast, it affects 74% MPAN cases [2]. A subsequent development of ataxia and neuropathy justified screening for mitochondrial and metabolic diseases, whereas normal white matter appearance on MRI with an excessive iron accumulation in basal ganglia narrowed the diagnostic search as did the relatively early development of anarthria, a red flag for NBIA. By contrast to Pantothenate-kinase associated neurodegeneration (PKAN), the “eye of tiger” is absent in MPAN, a marked MR T2 hypodensity in GP appears late and is not disease specific. (Picture 1) [3,4]  Selikhova et al  Short report with video   MPAN accounts for 80% of Polish and most Iranian NBIA cases without PANK-2 mutation and is prevalent in 5% of NBIA in other ethnicities. [5,6] The phenotype in our case was closely resemble MPAN cases from the Polish cohort, described by Hartig et al (2011). Later disease onset from a spastic gait, absence of tiptoe walking and slower progression were against the diagnosis of PKAN. Early significant axonal neuropathy is more common to MPAN, than for fatty acid 2-hydroxylase (FA2H) mutation and juvenile Phospholipase A2 associated neurodegeneration. [7,8] LD resistant orolingual – mandibular dystonia, hands and feet dystonia with choreoatetosis, torticollis contributed to the diagnosis of NBIA but developed 25 years later, when the patient loss of ability to stand and speak. LD responsive Parkinsonism and behavioural disorder are reported in MPAN cases but were absent in our patient. [1] The identified mutation in C19orf12 leads to a frameshift with premature stop codon and is predicted to cause truncation of more than 50% of the mitochondrial membrane protein, located in the brain cells, adipocytes and blood cells [9]. The loss of the protein disrupts the co-regulation with genes involved in fatty acid metabolism [10]. The role of this mutation in the clinical and pathological identity of the disease remains to be identified.   The limited pathological studies in MPAN have revealed axonal spheroids and iron containing deposits in the GP and SN. Lewy bodies pathology also can appear in the cortex, brainstem and spinal cord [6]. Our report represents the first MPAN case reported from Russia, which has been genetically diagnosed in the UK and highlights the worldwide distribution and heterogeneity of NBIA.  Acknowledgement: we are very grateful to the mother and sister of our patient, who kindly agreed to share the clinical history with the medical journal.  Selikhova et al  Short report with video    AUTHOR ROLES 1. Research project: A. Conception, B. Organization, C. Execution. 2. Statistical analysis: A. Design, B. Execution, C. Review and critique. 3. Manuscript: A. Writing of the first draft, B. Review and critique. M. Selikhova  1BC, 3A E. Fedotova 1BC, 3B   S.Wiethoff 1C, 3B   L.V. Schottlaender 1C, 3B  S. Klyushnikov 1B,3B  S.N. Illarioshkin 1A,3B  H. Houlden 1AB,3B Full Financial Disclosures of all Authors for the Past Year (not related to the research covered in this article). Selikhova M Stock Ownership in medically-related fields: none Consultancies: none Advisory Boards: none  Partnerships: none Honoraria: none Grants: none Intellectual Property Rights: none Expert Testimony: none Employment:  University College London     Contracts: none Royalties: none Other: none    Reference 1. Hartig MB, Iuso A, Haack T, et al. Absence of an orphan mitochondrial protein (C19orf12) causes a distinct clinical subtype of neurodegeneration with brain iron accumulation (NBIA). Am J Hum Genet 2011;89:543–550. PMC3188837 2. Illarioshkin S.N.,  Rudenskaya G.E, Ivanova-Smolenskaya I.A. et al. Hereditary ataxias and Paralegias. 2006. M. MEDpress-inform.- 416p  3. Horvath R, Holinski-Feder E, Neeve VCM, et al. A new phenotype of brain iron accumulation with dystonia, optic atrophy, and peripheral neuropathy. Mov Disord 2012;27:789–793. 4. Hayflick SJ, Hartman  M, Coryell J., at al. Brain MRI in neurodegeneration with brain iron accumulation with and without PANK2 mutations. Am. J. Neuroradiol., 2006, 27, 1230-3. Selikhova et al  Short report with video   5. Dezfouli M., Alavi A., Rohani M. et al. PANK2 and C19orf12 mutations are common causes of neurodegeneration with brain iron accumulation. Mov Disord 2013; 28: 228—232. 6. Hogarth P, Gregory A, Kruer MC et al. New NBIA subtype: genetic, clinical, pathologic, and radiographic features of MPAN. Neurology. 2013 Jan 15;80(3):268-75. doi: 10.1212/WNL.0b013e31827e07be.   7. Kruer MC, Paisan-Ruiz C, Boddaert, N. et al. Defective FA2H leads to a novel form of neurodegeneration with brain iron accumulation (NBIA). Ann.Neurol., 2010, 68, 611-8. 8. Kurian MA,  Morgan NV, MacPherson  L., et al. Phenotypic spectrum of neurodegeneration associated with mutations in the PLA2G6 gene (PLAN). Neurology, 2008, 70, 1623-9. 9. Zakharova EY, Rudenskaya GE. A new form of hereditary neurodegeneration with brain iron accumulation: clinical and molecular-genetic characteristics. Zh Nevrol Psikhiatr Im S S Korsakova. 2014;114(1):4-12. [Article in Russian] 10. Schulte E.C,  Claussen M.C., Jochim A.et al. Mitochondrial Membrane Protein Associated Neurodegenration: A Novel Variant of Neurodegeneration With Brain Iron Accumulation. Movement Disorders, Vol. 28, No. 2, 2013  Fig 1. Imaging of MPAN (upper row) and PKAN (lower row)    Fig. 2 . the Sanger-Sequencing  Sanger and TruSight-for the patient with MPAN. Selikhova et al  Short report with video    

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A 30-year history of MPAN case from Russia

https://discovery.ucl.ac.uk/id/eprint/10087805/

A 30-year history of MPAN case from Russia

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