ISSN 2398-2969      

Mitochondrial brain diseases

icanis
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 dogs (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. 
  • 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

  • Subacute necrotizing encephalomyelopathy in the Alaskan Husky: 
    • Mutation in the Thiamine Transporter 2 (SLC19A3) Gene. 
    • This gene controls the uptake of thiamine in the CNS via expression of the thiamine transporter protein THTR2. 
  • Leigh-like subacute necrotizing encephalopathy in Yorkshire terriers:
    • Mutation in the Thiamine Transporter 2 (SLC19A3) Gene. 
    • This gene controls the uptake of thiamine in the CNS via expression of the thiamine transporter protein THTR2. 
  • Shetland Sheepdog/Australian Cattle dog leukodystrophy: 3-4 weeks: 
    • A missense mutation in cytochrome b appears to be causal for this disease. 
    • Cytochrome b is an integral membrane protein. The substitution is hypothesized to reduce electron transfer and limit ATP production. 
  • Early onset epilepsy, mitochondrial dysfunction and neurodegeneration in Parson Russell terriers: 
    • An in-frame deletion in PITRM1 (pitrilysin metallopeptidase 1) encoding for a mitochondrial protease involved in mitochondrial targeting sequence processing and degradation. 
  • Canine spongiform leukoencephalomyelopathy in Border terriers: 

Timecourse

  • Subacute necrotizing encephalomyelopathy in the Alaskan Husky: eventually fatal although dogs can live for months to years before the signs progress. 
  • Leigh-like subacute necrotizing encephalopathy in Yorkshire terriers: eventually fatal although dogs can live for months to years before the signs progress. 
  • Shetland Sheepdog/Australian Cattle dog leukodystrophy: progressive leading to euthanasia. 
  • Early onset epilepsy, mitochondrial dysfunction and neurodegeneration in Parson Russell terriers: progressive leading to euthanasia. 
  • Hereditary polioencephalomyelopathy in Australian Cattle Dogs: progressive leading to euthanasia. 
  • Canine spongiform leukoencephalomyelopathy in Border terriers: non-progressive. 
  • Mitochondrial encephalopathy in Jack Russell terriers: progressive leading to euthanasia. 
  • Encephalomyelopathy with morphological abnormalities in mitochondria in an English Springer spaniel: progressive leading to euthanasia. 
  • Subacute necrotizing encephalopathy in American Staffordshire terriers. 
  • Polioencephalomyelopathy in a Shih Tzu: rapidly progressive leading to euthanasia. 
  • Polioencephalomyelopathy resembling Leigh’s disease in a crossbreed: rapidly progressive leading to euthanasia. 

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.
  • 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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