Mitochondrial Complex Iii Deficiency, Nuclear Type 8

A number sign (#) is used with this entry because of evidence that mitochondrial complex III deficiency nuclear type 8 (MC3DN8) is caused by homozygous mutation in the LYRM7 gene (615831) on chromosome 5q23.

Description

Mitochondrial complex III deficiency, nuclear type 8, is an autosomal recessive disorder characterized by progressive neurodegeneration with onset in childhood. Affected individuals may have normal or delayed early development, and often have episodic acute neurologic decompensation and regression associated with febrile illnesses. The developmental regression results in variable intellectual disability and motor deficits, such as hypotonia, axial hypertonia, and spasticity; some patients may lose the ability to walk independently. Laboratory studies show increased serum lactate and isolated deficiency of mitochondrial complex III in skeletal muscle and fibroblasts. Brain imaging shows a characteristic pattern of multifocal small cystic lesions in the periventricular and deep cerebral white matter (summary by Dallabona et al., 2016).

For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).

Clinical Features

Invernizzi et al. (2013) reported a girl, born of consanguineous Moroccan parents, with a severe neuromuscular disorder resulting in death from respiratory failure at age 28 months. Her development was normal until age 20 months, when she began showing rapidly progressive weakness and reduced movement associated with anemia and lactic acidosis. During a febrile illness a month later she developed severe dyspnea with stridor and a fluctuating comatose state. Brain imaging revealed severe demyelinization and vacuolization of white matter as well as global atrophy with a thin corpus callosum. She survived the acute episode but had severe psychomotor regression, absence of head control, and severe spastic tetraparesis with reduced spontaneous movements. Biochemical assays of muscle tissue showed severe isolated mitochondrial complex III deficiency at about 20% of normal levels.

Dallabona et al. (2016) reported 7 patients, including 2 sibs, with MC3DN8. The first 4 patients, including the sibs, were ascertained from a cohort of 23 patients with defects of mitochondrial complex III, and 3 additional patients were ascertained from a large cohort of over 4,000 patients with an unclassified leukoencephalopathy who had a similar and distinct pattern of leukoencephalopathy on brain imaging. All patients had similar MRI findings, characterized by progressive changes with numerous small cavitations in the periventricular and deep cerebral white matter; the lesions often coalesced. Other imaging findings included abnormalities of the corpus callosum and white matter lesions in the cerebellar peduncles. The patients had onset of symptoms between 9 months and 14 years of age, although most presented in the first years of life. The disease course was characterized by subacute neurologic deterioration associated with a febrile infection in all except 1 patient. Patients had repeated episodes of subacute encephalopathy with psychomotor regression and irritability. Additional features were variable, but included hypotonia and failure to thrive in infancy, limb spasticity/dystonia, hyperreflexia, delayed psychomotor development, dysarthria, ophthalmoplegia, and nystagmus. Laboratory studies showed increased serum lactic acid and isolated complex III deficiency in muscle. However, 1 of the affected sibs was clinically asymptomatic at age 6 years, even though she had biochemical evidence of the disorder and borderline intelligence.

Inheritance

The transmission pattern of MC3DN8 in the family reported by Invernizzi et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In a female infant, born of consanguineous Moroccan parents, with MC3DN8, Invernizzi et al. (2013) identified a homozygous missense mutation in the LYRM7 gene (D25N; 615831.0001). Studies in yeast indicated that the mutation caused a temperature-sensitive respiratory growth defect.

In 7 patients, including 2 sibs with MC3DN8, Dallabona et al. (2016) identified 6 different homozygous mutations in the LYRM7 gene (see, e.g., 616831.0001-616831.0005). LYRM7 protein and/or decreased complex III were observed in available patient samples. Functional studies in yeast confirmed the pathogenicity of 2 novel mutations.