ISSN 2398-2950      

Mitochondrial brain diseases

ffelis
Contributor(s):

Mark Lowrie

Laurent Garosi


Introduction

  • Mitochondria are maternally-inherited cellular organelles located in the cytoplasm of most eukaryotic cells, with the significant exception of erythrocytes. 
  • Also known as the ‘powerhouse’ of the cell as important in energy production. 
  • Mitochondrial diseases are a type of metabolic disorder, involving the respiratory chain which is controlled by both the mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). 
  • Tissues with high metabolic demand such as brain, heart, and muscle are more prone to develop dysfunction. 
  • Clinical suspicion of a mitochondrial disease can be raised when in the presence of a progressive history of neurological dysfunction, most commonly in young cats (under 2 years of age) particularly in the face of a multisystemic disorder. 
  • A number of different mitochondrial diseases have been identified in dogs, many with the genetic mutation identified. Only one has been reported in a cat. 
  • Signs: multifocal neurological signs typically in young animals <2 years. 
  • Cause: mutations in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Usually autosomal recessive mode of inheritance. 
  • Signs: chronic, progressive neurological signs - ataxia, intention tremor, progressive para/tetraparesis, hypermetria, cranial nerve abnormalities, seizures and vestibular signs. 
  • Diagnosis: some genetic tests now available for some of these conditions. For the others, no definitive tests available; CSF and CNS imaging (CT, MRI) can be helpful to rule out other disorders; diagnosis typically made with histopathological evaluation at necropsy; organic acid, amino acid and metabolic pathway testing may be considered on CSF.
  • Treatment: none. 
  • Prognosis: guarded-poor. 

Pathogenesis

Etiology

  • Inherited genetic mutations in mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) coding for mitochondrial components, as well as de novo mutations within the individual. 
  • In addition to genetic causes, environmental factors could also play a role in the onset and development of other non-classic mitochondrial disorders. 
  • Furthermore, clinical presentation varies due to heteroplasmy, term describing the presence of mutated and wild-type mtDNA genomes within an individual cell. 
  • Signs of dysfunction typically involve multiple organ systems, however tissues metabolically more active and with high energy requirements such as the nervous system, heart and skeletal muscle are commonly affected. 

Predisposing factors

Specific

  • Genetic investigations in the affected cat revealed 2 polymorphisms within the tRNA-Leu(UUR) gene of mitochondrial DNA. One was affecting the Ac Stem loop in the secondary leaf structure of mitochondrial tRNA-Leu, which often is a pathogenic hotspot in humans for mitochondrial encephalopathy. 

Timecourse

  • Clinical signs worsened over 6 months and then euthanasia was performed. 

Diagnosis

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Treatment

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Prevention

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Outcomes

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Further Reading

Publications

Refereed Papers

  • Recent references from PubMed and VetMedResource.
  • Dell’Era E, Polidori M, Bernardini M et al (2021) Selective symmetrical necrotizing encephalopathy secondary to primary mitochondrial disorder in a cat. J Vet Intern Med 35, 2401-2408 PubMed
  • Hytönen M K, Sarviaho R, Jackson C B, Syrjä P, Jokinen T, Matiasek K, Rosati M, Dallabona C, Baruffini E, Quintero I, Arumilli M, Monteuuis G, Donner J, Anttila M, Suomalainen A, Bindoff L A, Lohi H (2021) In-frame deletion in canine PITRM1 is associated with a severe early-onset epilepsy, mitochondrial dysfunction and neurodegeneration. Hum Genet DOI: 10.1007/s00439-021-02279-y PubMed
  • Drögemüller M, Letko A, Matiasek K, Jagannathan V, Corlazzoli D, Rosati M, Jurina K, Medl S, Gödde T, Rupp S, Fischer A (2020) SLC19A3 Loss-of-Function Variant in Yorkshire Terriers with Leigh-Like Subacute Necrotizing Encephalopathy. Genes 11(10), 1215 PubMed.
  • Gutierrez-Quintana R, McLaughlin M, Grau Roma L, Hammond G, Gray A, Lowrie M (2019) Spongiform leucoencephalomyelopathy in border terriers: clinical, electrophysiological and imaging features. Vet Rec 185(12), 375 PubMed
  • Chai O, Milgram J, Shamir M H, Brenner O (2015) Polioencephalomyelopathy in a mixed breed dog resembling Leigh’s disease. Can Vet J 56(1), 59 PubMed
  • Vernau K, Napoli E, Wong S, Ross‐Inta C, Cameron J, Bannasch D, Bollen A, Dickinson P, Giulivi C (2015) Thiamine Deficiency‐Mediated Brain Mitochondrial Pathology in Alaskan Huskies with Mutation in SLC19A3. 1. Brain Pathol 25(4), 441-453 PubMed
  • Collins D, Angles J M, Christodoulou J, Spielman D, Lindsay S A, Boyd J, Krockenberger M B (2013) Severe subacute necrotizing encephalopathy (Leigh-like syndrome) in American Staffordshire bull terrier dogs. J Comp Pathol 148(4), 345-353 PubMed.
  • Vernau K M, Runstadler J A, Brown E A  et al (2013) Genome-wide association analysis identifies a mutation in the thiamine transporter 2 (SLC19A3) gene associated with Alaskan Husky encephalopathy. PloS One 8(3), e57195 PubMed
  • Martin‐Vaquero P, Da Costa R C, Simmons J K, Beamer G L, Jäderlund K H, Oglesbee M J (2012) A novel spongiform leukoencephalomyelopathy in Border Terrier puppies. J Vet Int Med 26(2), 402-406 PubMed.
  • Baiker K, Hofmann S, Fischer A, Gödde T, Medl S, Schmahl W, Bauer M F, Matiasek K (2009) Leigh-like subacute necrotising encephalopathy in Yorkshire Terriers: neuropathological characterisation, respiratory chain activities and mitochondrial DNA. Acta Neuropathol 118, 697-709 PubMed
  • Kent M, Platt S R, Rech R R, Neravanda D, Uhl E W, Schatzberg S J (2009) Clinicopathologic and magnetic resonance imaging characteristics associated with polioencephalomyelopathy in a Shih Tzu. JAVMA 235(5), 551-557 PubMed
  • Li F Y, Cuddon P A, Song J, Wood S L, Patterson J S, Shelton G D, Duncan I D (2006) Canine spongiform leukoencephalomyelopathy is associated with a missense mutation in cytochrome b. Neurobiol Dis 21(1), 35-42 PubMed.
  • Gruber A D, Wessmann A, Vandevelde M, Summers B A, Tipold A (2002) Mitochondriopathy with regional encephalic mineralization in a Jack Russell Terrier. Vet Pathol 39(6), 732-736 PubMed.
  • Wood S L, Patterson J S (2001) Shetland Sheepdog leukodystrophy. J Vet Intern Med 15, 486-493 PubMed.
  • Brenner O, Wakshlag J J, Summers B A, de Lahunta A (2000) Alaskan Husky encephalopathy – a canine neurodegenerative disorder resembling subacute necrotizing encephalomyelopathy (Leigh syndrome). Acta Neuropathol 100, 50-62 PubMed
  • Harkin K R, Goggin J M, DeBey B M et al (1999) Magnetic resonance imaging of the brain of a dog with hereditary polioencephalomyelopathy. JAVMA 214, 1342-1334 PubMed.
  • Wakshlag J J, de Lahunta A, Robinson T et al (1999) Subacute necrotising encephalopathy in an Alaskan Husky. J Small Anim Pract 40, 585-589 PubMed
  • Brenner O, de Lahunta A, Cummings J F et al (1997) A canine encephalomyelopathy with morphological abnormalities in mitochondria. Acta Neuropathol (Berl) 94, 390-397 PubMed.  
  • Brenner O, de Lahunta A, Summers B A et al (1997) Hereditary polioencephalomyelopathy of the Australian Cattle dog. Acta Neuropathol (Berl) 94, 54-66 PubMed

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