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Metabolic Brain Disease

, Volume 33, Issue 4, pp 987–988 | Cite as

Cerebellar atrophy is common among mitochondrial disorders

  • Josef Finsterer
  • Sinda Zarrouk-Mahjoub
Commentary
  • 331 Downloads

We read with interest the article by Inbar-Feigenberg about two siblings carrying the same POLG1 mutations inherited from their consanguineous parents. Both siblings presented with cerebellar atrophy (Inbar-Feigenberg et al. 2018). We have the following comments and concerns.

Cerebellar atrophy is a common CNS manifestation of mitochondrial disorders (MIDs) and has been reported in specific and non-specific MIDs. Specific MIDs associated with cerebellar atrophy include MELAS, MERRF, Leigh syndrome, MIDD, NARP, CPEO and CPEO plus, KSS, LHON, IOSCA, PCH6, ADOA, and DIDMOAD (Table 1). In non-specific MIDs cerebellar atrophy was reported in patients carrying mutations in the RARS2, SLC25A46, CoQ10, and EXOSC3 genes respectively (Bindu et al. 2015). Mutations in the POLG1 gene have been also repeatedly reported in association with cerebellar atrophy (Mehta et al. 2011). Cerebellar atrophy may go along with or without clinical manifestations.
Table 1

Specific and non-specific MIDs manifesting with cerebellar atrophy

MID

Mutation

Reference

MELAS

m.3243A>G

(Tsujikawa et al. 2015)

MERRF

m.8344A>G

(Ito et al. 2008)

Leigh syndrome

m.8993T>G

(Haginoya et al. 2016)

MIDD

m.3243A>G

(Fromont et al. 2009)

NARP

m.8993T>C

(Mitani et al. 2000)

CPEO

mtDNAdel

(Heidenreich et al. 2006)

CPEO plus

m.960delC

(Lv et al. 2017)

KSS^

mtDNAdel

(Müller et al. 2003)

LHON

m.11778G>A

(Nakaso et al. 2012)

 

m.3394T>C

 

IOSCA

nm

(Koskinen et al. 1995)

PCH6

RARS2

(Lühl et al. 2016)

ADOA

OPA1

(Roubertie 2015)

DIDMOAD

nm

(Hershey et al. 2012)

Nonspecific

RARS2

(Ngoh et al. 2016)

Nonspecific

SLC25A46

(Nguyen et al. 2017)

Nonspecific

CoQ10

(Chung et al. 2017)

Nonspecific

EXOSC3

(Schottmann et al. 2017)

Nm not mentioned

The authors mention a stroke-like lesion (SLL), the morphological equivalent of a stroke-like episode (SLE) in the cerebellum of patients carrying POLG1 mutations (Inbar-Feigenberg et al. 2018). However, SLLs typically occur supratentorially and are characterised by DWI and ADC hyperintensities. When searching Pubmed for cerebellar SLLs, no hit could be achieved. Thus, it would be interesting to know if the authors have ever observed a cerebellar SLL in their MID cohort. Which were the clinical manifestations of the cerebellar SLE, were NO-precursors given, did they exhibit a beneficial effect on the clinical manifestations, and which was the outcome?

Since POLG1 mutations usually manifest as multisystem disease, we should be informed about the entire phenotype of the two siblings. Particularly we would like to know which organs other than the brain were affected, which pattern of organ involvement was observed during the course, and if there was phenotypic heterogeneity between the two siblings. POLG1 mutations may additionally manifest in the ears as hypoacusis, in the skeletal muscle, peripheral nerves, eyes, gastrointestinal tract, endocrine organs, and the skin (Finsterer and Scorza 2018).

Did each of the consanguineous parents carry the mutation? Were other first-degree family members clinically affected? What about the grandparents of these siblings?

Were blood test ever carried out in sibling-1? Was parathormone normal? Was there pituitary insufficiency? Was there growth hormone deficiency? Were the parents phenotypically striking?

Which was the cause of death in sibling-1 after delivery? It is mentioned that there were intrauterine seizures (Inbar-Feigenberg et al. 2018). Did sibling-1 also present with seizures during the short period of his postnatal life? Did sibling-1 die from intractable seizures, central respiratory insufficiency, or from cardiac or pulmonary compromise? Was fetal ECG and echocardiography normal? Was an EEG recorded?

In summary, it is not unusual that patients carrying POLG1 mutations manifest with cerebellar atrophy. Cerebellar atrophy occurs also frequently in MIDs due to mutations in genes other than POLG1. The genetic status of the parents should be provided and the entire clinical presentation of the two siblings should be reported in detail.

Notes

Author’s contribution

JF: design, literature search, discussion, first draft, SZ-M: literature search, discussion, critical comments.

Compliance with ethical standards

Conflicts of interest

There are no conflicts of interest.

References

  1. Bindu PS, Arvinda H, Taly AB, Govindaraju C, Sonam K, Chiplunkar S, Kumar R, Gayathri N, Bharath Mm S, Nagappa M, Sinha S, Khan NA, Govindaraj P, Nunia V, Paramasivam A, Thangaraj K (2015) Magnetic resonance imaging correlates of genetically characterized patients with mitochondrial disorders: A study from south India. Mitochondrion 25:6–16CrossRefPubMedGoogle Scholar
  2. Finsterer J, Scorza FA (2018) Phenotypic spectrum of POLG1 mutations. Neurol Sci 39:571–573CrossRefPubMedGoogle Scholar
  3. Inbar-Feigenberg M, Blaser S, Hawkins C, Shannon P, Hewson S, Chitayat D (2018) Mitochondrial POLG related disorder presenting prenatally with fetal cerebellar growth arrest. Metab Brain Dis.  https://doi.org/10.1007/s11011-018-0218-2
  4. Mehta AR, Fox SH, Tarnopolsky M, Yoon G (2011) Mitochondrial mimicry of multiple system atrophy of the cerebellar subtype. Mov Disord 26:753–755CrossRefPubMedGoogle Scholar
  5. Tsujikawa K, Senda J, Yasui K, Hasegawa Y, Hoshiyama M, Katsuno M, Sobue G (2016) Distinctive distribution of brain volume reductions in MELAS and mitochondrial DNA A3243G mutation carriers: A voxel-based morphometric study. Mitochondrion 30:229–235CrossRefPubMedGoogle Scholar
  6. Ito S, Shirai W, Asahina M, Hattori T (2008) Clinical and brain MR imaging features focusing on the brain stem and cerebellum in patients with myoclonic epilepsy with ragged-red fibers due to mitochondrial A8344G mutation. AJNR Am J Neuroradiol 29:392–395CrossRefPubMedGoogle Scholar
  7. Haginoya K, Kaneta T, Togashi N, Hino-Fukuyo N, Kobayashi T, Uematsu M, Kitamura T, Inui T, Okubo Y, Takezawa Y, Anzai M, Endo W, Miyake N, Saitsu H, Matsumoto N, Kure S (2016) FDG-PET study of patients with Leigh syndrome. J Neurol Sci 362:309–313CrossRefPubMedGoogle Scholar
  8. Fromont I, Nicoli F, Valéro R, Felician O, Lebail B, Lefur Y, Mancini J, Paquis-Flucklinger V, Cozzone PJ, Vialettes B (2009) Brain anomalies in maternally inherited diabetes and deafness syndrome. J Neurol 256:1696–1704CrossRefPubMedGoogle Scholar
  9. Mitani M, Jinnai K, Takahashi K, Koide R, Tsuji S (2000) A case of NARP (neurogenic muscle weakness, ataxia, and retinitis pigmentosa) with a T-to-C point mutation at nt 8993 of mitochondrial DNA. Rinsho Shinkeigaku 40:600–604 PubMedGoogle Scholar
  10. Heidenreich JO, Klopstock T, Schirmer T, Saemann P, Mueller-Felber W, Auer DP (2006) Chronic progressive external ophthalmoplegia: MR spectroscopy and MR diffusion studies in the brain. AJR Am J Roentgenol 187:820–824CrossRefPubMedGoogle Scholar
  11. Lv ZY, Xu XM, Cao XF, Wang Q, Sun DF, Tian WJ, Yang Y, Wang YZ, Hao YL (2017) Mitochondrial mutations in 12S rRNA and 16S rRNA presenting as chronic progressive external ophthalmoplegia (CPEO) plus: A case report. Medicine (Baltimore) 96(48):e8869.  https://doi.org/10.1097/MD.0000000000008869 CrossRefGoogle Scholar
  12. Müller W, Mennel HD, Bewermeyer K, Bewermeyer H (2003) Is there a final common pathway in mitochondrial encephalomyopathies? Considerations based on an autopsy case of Kearns-Sayre syndrome. Clin Neuropathol 22:240–245PubMedGoogle Scholar
  13. Nakaso K, Adachi Y, Fusayasu E, Doi K, Imamura K, Yasui K, Nakashima K (2012) Leber's Hereditary Optic Neuropathy with Olivocerebellar Degeneration due to G11778A and T3394C Mutations in the Mitochondrial DNA. J Clin Neurol 8:230–234CrossRefPubMedPubMedCentralGoogle Scholar
  14. Koskinen T, Valanne L, Ketonen LM, Pihko H (1995) Infantile-onset spinocerebellar ataxia: MR and CT findings. AJNR Am J Neuroradiol 16:1427–1433PubMedGoogle Scholar
  15. Lühl S, Bode H, Schlötzer W, Bartsakoulia M, Horvath R, Abicht A, Stenzel M, Kirschner J, Grünert SC (2016) Novel homozygous RARS2 mutation in two siblings without pontocerebellar hypoplasia - further expansion of the phenotypic spectrum. Orphanet J Rare Dis 11:140CrossRefPubMedPubMedCentralGoogle Scholar
  16. Roubertie A, Leboucq N, Picot MC, Nogue E, Brunel H, Le Bars E, Manes G, Angebault Prouteau C, Blanchet C, Mondain M, Chevassus H, Amati-Bonneau P, Sarzi E, Pagès M, Villain M, Meunier I, Lenaers G, Hamel CP (2015) Neuroradiological findings expand the phenotype of OPA1-related mitochondrial dysfunction. J Neurol Sci 349:154–160CrossRefPubMedGoogle Scholar
  17. Hershey T, Lugar HM, Shimony JS, Rutlin J, Koller JM, Perantie DC, Paciorkowski AR, Eisenstein SA, Permutt MA, Washington University Wolfram Study Group (2012) Early brain vulnerability in Wolfram syndrome. PLoS One 7(7):e40604.  https://doi.org/10.1371/journal.pone.0040604
  18. Ngoh A, Bras J, Guerreiro R, Meyer E, McTague A, Dawson E, Mankad K, Gunny R, Clayton P, Mills PB, Thornton R, Lai M, Forsyth R, Kurian MA (2016) RARS2 mutations in a sibship with infantile spasms. Epilepsia 57:e97–e102CrossRefPubMedPubMedCentralGoogle Scholar
  19. Nguyen M, Boesten I, Hellebrekers DM, Mulder-den Hartog NM, de Coo IF, Smeets HJ, Gerards M (2017) Novel pathogenic SLC25A46 splice-site mutation causes an optic atrophy spectrum disorder. Clin Genet 91:121–125CrossRefPubMedGoogle Scholar
  20. Chung WK, Martin K, Jalas C, Braddock SR, Juusola J, Monaghan KG, Warner B, Franks S, Yudkoff M, Lulis L, Rhodes RH, Prasad V, Torti E, Cho MT, Shinawi M (2015) Mutations in COQ4, an essential component of coenzyme Q biosynthesis, cause lethal neonatal mitochondrial encephalomyopathy. J Med Genet 52:627–635CrossRefPubMedGoogle Scholar
  21. Schottmann G, Picker-Minh S, Schwarz JM, Gill E, Rodenburg RJT, Stenzel W, Kaindl AM, Schuelke M (2017) Recessive mutation in EXOSC3 associates with mitochondrial dysfunction and pontocerebellar hypoplasia. Mitochondrion 37:46–54CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Krankenanstalt RudolfstiftungViennaAustria
  2. 2.Pasteur Institute of TunisUniversity of Tunis El Manar and Genomics PlatformTunisTunisia

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