Categories: Nervous system phene

Possibly relevant human trait(s) and/or gene(s)s (MIM numbers): 607008 (gene) , 201450 (trait)

Links to MONDO diseases: No links.

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: Also known as medium-chain acyl-CoA dehydrogenase (MCAD) deficiency

Molecular basis: Christen et al. (2022) "sequenced the genome of the affected dog and compared the data to 923 control genomes of different dog breeds. The ACADM gene encoding MCAD was considered the top functional candidate gene. The genetic analysis revealed a single homozygous private protein-changing variant in ACADM in the affected dog. This variant, XM_038541645.1:c.444_445delinsGTTAATTCTCAATATTGTCTAAGAATTATG, introduces a premature stop codon and is predicted to result in truncation of ~63% of the wild type MCAD open reading frame, XP_038397573.1:p.(Thr150Ilefs*6)." Christen et al. (2022) confirmed that the C8/C10 acylcarnitine level in the blood of homozygous mutant dogs was 11-fold elevated and the C8/C12 level was 65-fold elevated compared to wt/wt or wt/mut dogs.

Genetic engineering: Unknown
Have human generated variants been created, e.g. through genetic engineering and gene editing

Clinical features: Christen et al. (2022): "A male neutered CKCS, born out of reportedly healthy parents, was presented at the age of 1.5 years, with an acute history of suspected complex focal seizures including prolonged lethargy, being less responsive and proprioceptive ataxia. These episodes initially occurred several times a week, lasting from 20 min to multiple hours during which the dog was mainly lethargic." The dog was started on anticonvulsant medication, which did not result in complete suppression of the seizures. After diagnosis of MCAD deficiency, "...the dog was prescribed a low-fat diet and a midnight snack consisting of carbohydrates. Prolonged periods of fasting and formulas that contained medium-chain triglycerides as primary source of fat were also advised to avoid. This management protocol correlated with a complete resolution of clinical signs for the following 6 months. The anticonvulsant medication was therefore reduced to subtherapeutic levels. However, this was reversed as the dose reduction resulted in an increase in seizure frequency." ... "At the time of writing, the dog has been stable for 9 months on 25 mg/kg levetiracetam three times a day, 3 mg/kg phenobarbital twice a day and a low-fat diet, with no further major seizures and a repeated normal neurological examination." Christen et al. (2022) noted that the clinical genotype-phenotype correlation remains unclear. While the ACADM variant causes the biochemical alteration in the blood acylcarnitine profiles, it is not fully clear whether the MCAD deficiency is also the (only) cause of the clinical signs of the studied patient. Christen et al. (2022) wrote: "MCAD deficiency in dogs seemingly does not clinically manifest as severe as in humans. However, our data show a clear increase in MCFAs in ACADM homozygous mutant dogs. This might point to an additional compensatory mechanism in the dog, which prevents or dampens the manifestation of clinical consequences of elevated MCFAs. In humans, phenotypic diversity ranging from sudden neonatal death to asymptomatic status has previously been reported. Human patients with complete loss of MCAD activity can also remain asymptomatic, suggesting that additional genetic or environmental factors may play a role in the phenotypic diversity. Additional genetic or environmental factors are also likely to modulate the phenotype in MCAD deficient dogs. The improvement of clinical signs upon changing to a low-fat diet in our index case indicates that the diet has a major influence on the clinical phenotype. At this time, we cannot exclude the possibility that additional genetic factors also modified the clinical phenotype. While our data conclusively demonstrate that the ACADM frameshift variant causes MCAD deficiency and the biochemical alterations in the lipid metabolism, it is not yet fully clear whether the MCAD deficiency alone is responsible for the clinical phenotype or whether additional environmental and/or genetic risk factors are required for the expression of clinical signs. The identification of the ACADM frameshift variant enables genetic testing for MCAD deficiency and will facilitate future prospective studies to clarify this important question."

Prevalence: Christen et al. (2022): "Targeted genotyping of the variant in 162 additional CKCS revealed a variant allele frequency of 23.5% and twelve additional homozygous mutant dogs."

Control: Christen et al. (2022): "Testing the CKCS breeding population for the identified ACADM variant is recommended to prevent the unintentional breeding of dogs with MCAD deficiency."

Breed: Cavalier King Charles Spaniel (Dog) (VBO_0200309).
Breeds in which the phene has been documented. For breeds in which a likely causal variant has been documented, see the variant table below

Associated gene: