OMIA 002551-9615 : Mitochondrial fission encephalopathy in Canis lupus familiaris

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 614785 (gene) , 617086 (trait)

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal Recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2022

Species-specific name: Mitochondrial fission encephalopathy; familial cerebellar ataxia with hydrocephalus

Species-specific symbol: MFE

History: The first report of this disease in the scientific literature was provided by Carmichael et al. (1983).

Inheritance: As reported by Cristen et al. (2022), evidence for autosomal recessive inheritance of this disorder in Bullmastiffs was provided by Carmichael et al. (1983).

Cristen et al. (2022) reported that "Genotypes [at the MFF locus] in a cohort of four affected and 70 unaffected Bullmastiffs showed perfect [autosomal recessive] segregation with the disease phenotype. . . . All four available cases were homozygous mutant, one obligate carrier was heterozygous and none of the 70 unaffected dogs were homozygous for the mutant allele."

Molecular basis: Cristen et al. (2022) reported that comparison of the whole-genome sequence of an affected Bullmastiff "with 782 control genomes of dogs from diverse breeds . . . revealed a private homozygous frameshift variant in the MFF gene in the affected dog, XM_038574000.1: c.471_475delinsCGCTCT, that is predicted to truncate 55% of the wild type MFF open reading frame, XP_038429928.1: p.(Glu158Alafs*14). Human patients with pathogenic MFF variants suffer from ‘encephalopathy due to defective mitochondrial and peroxisomal fission 2' ".

Clinical features: Carmichael et al. (1983) provided the first clinical and pathological description of the disease. The most striking findings were ataxia, visual impairment and changes in behaviour. Cristen et al. (2022) "investigated two young Bullmastiffs showing similar clinical signs. They developed progressive gait and behavioural abnormalities with an onset at around 6 months of age. Neurological assessment was consistent with a multifocal brain disease. Magnetic resonance imaging of the brain showed intra-axial bilateral symmetrical focal lesions localised to the cerebellar nuclei. Based on the juvenile age, nature of neurological deficits and imaging findings, an inherited disorder of the brain was suspected."

Pathology: Carmichael et al. (1983) reported "Macroscopically there was a moderate to severe internal hydrocephalus with dilation of all ventricles and the cerebral aqueduct. In addition a yellow/brown discoloration of the cerebellar nuclei was noted. The salient microscopic abnormality, a spongy vacuolar change with gliosis, was present in three deep cerebellar nuclei ... and a small localised area in the base of the inferior colliculus. ... Gliosis was present with an increase in both microglia and astrocytes, many of which were hypertrophied. Axonal spheroids were frequently observed within the lesions. ... The lesions were all bilaterally symmetrical."

Carmichael (1987) documented changes in the morphology of mitochondria of affected dogs by electron microscopy: "Mitochondria were increased in number and many bizarre forms were present."

Prevalence: Cristen et al. (2022) reported that "The carrier frequency in the unrelated control cohort [of Bullmastiffs] was 12/65 (18%)".

Breed: Bull Mastiff.

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
MFF mitochondrial fission factor Canis lupus familiaris 25 NC_051829.1 (40359046..40389383) MFF Homologene, Ensembl, NCBI gene

Variants

By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Inferred EVA rsID Year Published PubMed ID(s) Acknowledgements
1489 Bull Mastiff Mitochondrial fission encephalopathy MFF delins, small (<=20) Naturally occurring variant UU_Cfam_GSD_1.0 25 g.40322999_40323003delinsCGCTCT c.471_475delinsCGCTCT p.(E158Afs*14) XM_038574000.1; XP_038429928.1 2022 36085405

References


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.
2022 Christen, M., Gutierrez-Quintana, R., Vandenberghe, H., Kaczmarska, A., Penderis, J., José-López, R., Rupp, A., Griffiths, I.R., Jagannathan, V., Leeb, T. :
Mitochondrial fission factor (MFF) frameshift variant in Bullmastiffs with mitochondrial fission encephalopathy. Anim Genet :, 2022. Pubmed reference: 36085405. DOI: 10.1111/age.13263.
2001 Johnson, R.P., Neer, T.M., Partington, B.P., Cho, D.Y., Partington, C.R. :
Familial cerebellar ataxia with hydrocephalus in bull mastiffs. Vet Radiol Ultrasound 42:246-9, 2001. Pubmed reference: 11405268. DOI: 10.1111/j.1740-8261.2001.tb00934.x.
1987 Carmichael, S. :
Familial cerebellar ataxia in the Bull Mastiff. Master thesis, University of Glasgow Veterinary School :https://theses.gla.ac.uk/77525/1/10995573.pdf, 1987.
1983 Carmichael, S., Griffiths, I.R., Harvey, M.J. :
Familial cerebellar ataxia with hydrocephalus in bull mastiffs. Vet Rec 112:354-8, 1983. Pubmed reference: 6857976. DOI: 10.1136/vr.112.15.354.

Edit History


  • Created by Tosso Leeb on 30 Apr 2022
  • Changed by Tosso Leeb on 16 May 2022
  • Changed by Frank Nicholas on 13 Sep 2022
  • Changed by Tosso Leeb on 19 Sep 2022