Categories: Nervous system phene , Homeostasis / metabolism phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 614785 (gene) , 617086 (trait)

Links to relevant human diseases in MONDO:

• MONDO:0014905: encephalopathy due to defective mitochondrial and peroxisomal fission 2

Mendelian trait/disorder: yes

Mode of inheritance: Autosomal recessive

Disease-related: 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."
Suiter et al. (2024) report a 9-month-old male Bullmastiff cross dog with progressive proprioceptive ataxia and behaviour changes that was homozygous for the known MFF frameshift variant. Diagnostic imaging and histopathological findings in this dog differed from previously reported cases, "suggesting a different selective regional vulnerability of the neurons."

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

Breed: Bull Mastiff (Dog) (VBO_0200253).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene: