A number sign (#) is used with this entry because mitochondrial complex III deficiency nuclear type 1 (MC3DN1) is caused by homozygous or compound heterozygous mutation in the nuclear-encoded BCS1L gene (603647) on chromosome 2q35.

Autosomal recessive mitochondrial complex III deficiency is a severe multisystem disorder with onset at birth of lactic acidosis, hypotonia, hypoglycemia, failure to thrive, encephalopathy, and delayed psychomotor development. Visceral involvement, including hepatopathy and renal tubulopathy, may also occur. Many patients die in early childhood, but some may show longer survival (de Lonlay et al., 2001; De Meirleir et al., 2003).

Genetic Heterogeneity of Mitochondrial Complex III Deficiency

Mitochondrial complex III deficiency can be caused by mutation in several different nuclear-encoded genes. See MC3DN2 (615157), caused by mutation in the TTC19 gene (613814) on chromosome 17p12; MC3DN3 (615158), caused by mutation in the UQCRB gene (191330) on chromosome 8q; MC3DN4 (615159), caused by mutation in the UQCRQ gene (612080) on chromosome 5q31; MC3DN5 (615160), caused by mutation in the UQCRC2 gene (191329) on chromosome 16p12; MC3DN6 (615453), caused by mutation in the CYC1 gene (123980) on chromosome 8q24; MC3DN7 (615824), caused by mutation in the UQCC2 gene (614461) on chromosome 6p21; MC3DN8 (615838), caused by mutation in the LYRM7 gene (615831) on chromosome 5q23; MC3DN9 (616111), caused by mutation in the UQCC3 gene (616097) on chromosome 11q12; and MC3DN10 (618775), caused by mutation in the UQCRFS1 gene (191327) on chromosome 19q12.

See also MTYCB (516020) for a discussion of a milder phenotype associated with isolated mitochondrial complex III deficiency and mutations in a mitochondrial-encoded gene.

De Lonlay et al. (2001) reported 6 patients from 4 unrelated Turkish families with complex III deficiency who presented with neonatal proximal tubulopathy, hepatic involvement, and encephalopathy. The first patient was a girl born to consanguineous parents after a normal pregnancy and delivery. Immediately after birth she presented feeding difficulties with vomiting and gastric hemorrhage. She developed liver failure, lactic acidosis, and tubulointerstitial nephritis, as well as severe encephalopathy with microcephaly, deafness, and blindness, and died at age 3 months. Her sister was born after an uneventful pregnancy and delivery but developed lactic acidosis immediately after birth. Subsequently, she developed severe encephalopathy and hepatic dysfunction with mild cholestasis, elevated liver enzymes, and tubulopathy. At 2 years of age, brain MRI showed atrophy and large reduction in white matter. Complex III deficiency was demonstrated in muscle from this patient and in the liver of an aborted fetus in this family. A boy, born to consanguineous parents who were unrelated to the first family, was small for gestational age and developed a de Toni-Debre-Fanconi syndrome immediately after birth. He was hypotonic with brisk tendon reflexes and had a metabolic acidosis with a plasma lactate level of 8 mmol/l. He had mildly elevated liver enzymes as well as mildly elevated CPK. Krebs cycle intermediates accumulated in his urine. Cerebral ultrasound showed scattered brainstem lesions compatible with a diagnosis of Leigh syndrome (256000). The patient's neurologic condition rapidly worsened and he died at 6 months of age. In another unrelated family, a girl was born to consanguineous parents after a postterm pregnancy. She was small for gestational age, and developed severe metabolic acidosis with a plasma lactate level of 22 mmol/l. Tests showed elevated liver enzyme levels, and Krebs cycle intermediates were found in her urine. She developed proximal tubulopathy, and renal ultrasound showed hyperechogenic kidneys. At 1 year of age, she had acute episodes of ventilation abnormalities, and died from central ventilatory failure at 2 years of age. Cerebral MRI showed lesions scattered from the basal ganglia to the brainstem compatible with a diagnosis of Leigh syndrome. The last patient was a boy born to nonconsanguineous parents unrelated to all other families after an uneventful pregnancy and delivery. He developed metabolic acidosis immediately after birth and presented with elevated liver enzyme levels, hypoglycemia, and urinary accumulation of Krebs cycle intermediates. He experienced acute myoglobinuria at 1 month of age. Psychomotor development was normal at 5 months of age, after which the patient was lost to follow-up.

Fernandez-Vizarra et al. (2007) reported 2 unrelated girls with complex III deficiency who presented with an encephalopathic phenotype. In the first months of life, the first child, born of unrelated Italian parents, showed failure to thrive, muscle hypotonia, severe psychomotor delay, and seizures. By 1 year of age she had severe spastic quadriparesis with muscle wasting, no postural control, and persistent lactic acidosis. She died at age 4 years. The second girl, born of unrelated Moroccan parents, showed normal development until age 9 months, when she presented with acute psychomotor regression, muscle hypotonia, and failure to thrive. Symptoms progressed to spastic quadriparesis and severe mental impairment. Blood lactate was increased in both girls. Brain MRI in both patients showed cerebral atrophy and abnormal signals in the thalami, basal ganglia, and periventricular white matter. Although neither patient had other organ involvement, including heart, liver, and kidneys, both had brittle hair.

Blazquez et al. (2009) reported a 4-year-old Spanish boy with complex III deficiency due to a homozygous BCS1L mutation. He presented at 6 months of age with psychomotor retardation, failure to thrive, hypotonia, lactic acidosis, and hepatic dysfunction. Physical examination showed unstable head support, poor eye fixation, coarse facies, and epicanthus. There was hypertrichosis of the frontal head zone and limbs, and excessive fat distribution in the upper back, neck, hands and feet, with almost no fat on the limbs. Respiratory chain activity in muscle and fibroblasts showed an isolated complex III defect (58% of normal in muscle, 93% in fibroblasts). At age 4 years, he still showed psychomotor retardation, had developed mild sensorineural hearing loss, and persistent lactic acidemia, but renal function, hair, and iron metabolism were normal. Brain MRI was normal.

Clinical Variability

De Meirleir et al. (2003) reported 2 Spanish sibs with fatal infantile complex III deficiency caused by compound heterozygosity for mutation in the BCS1L gene (R45C, 603647.0006; R56X, 603647.0007). Both had severe metabolic acidosis noted shortly after birth, as well as difficulty regulating blood sugar levels. Both had severe liver dysfunction and a renal tubulopathy. One died at age 3 weeks of lactic acidosis. The second infant also developed obvious neurologic involvement, with delayed myelination, axial hypotonia, and developmental delay. He died at age 3 months. Postmortem liver examination of both infants showed liver fibrosis, severe cholestasis, and hepatosiderosis with accumulation of iron in aggregates of macrophages and in Kupffer cells. Mitochondria appeared enlarged with few or no cristae and a fluffy matrix. De Meirleir et al. (2003) suggested that the iron accumulation could be explained by the lack of incorporation of iron in the iron-sulfur cluster of complex III.

Ramos-Arroyo et al. (2009) reported another Spanish infant with the R45C and R56X mutations. She presented with neonatal severe hypotonia, food intolerance, and vomiting. She soon developed a proximal renal tubulopathy with glucosuria, phosphaturia, and aminoaciduria, metabolic lactic acidosis, and hepatic involvement. Bilateral cataracts were also noted. At age 4 months, she showed nystagmus, hypertonia, microcephaly, developmental delay, and failure to thrive. Her neurologic condition and metabolic acidosis worsened rapidly, and she died at 6 months of age. Biochemical studies of muscle tissue showed impaired activity of mitochondrial complex III. Ramos-Arroyo et al. (2009) noted that this child did not have evidence of altered iron metabolism, as had been observed in the patients reported by De Meirleir et al. (2003), and as has been observed in patients with the allelic disorder GRACILE syndrome (603358). Ramos-Arroyo et al. (2009) postulated that phenotypic variability even in individuals with the same BCS1L genotype may reflect tissue-specific expression of the mutant gene.

Moran et al. (2010) described cellular studies of 6 patients, including 2 sibs, with mitochondrial complex III deficiency due to mutations in the BCS1L gene. Four of the patients had previously been reported by De Meirleir et al. (2003), Blazquez et al. (2009), and Gil-Borlado et al. (2009). Two of the patients were reported for the first time: 1 with early death at age 7 months and another with a slightly attenuated phenotype who was alive at age 5 years. Cultured fibroblasts from the patients showed variable deficiency of complex III activity, which correlated with the phenotypic severity. The 2 least severely affected individuals had low-normal levels of complex III activity and expression. Other complex activities were variably affected in all patients. Fibroblasts from all patients showed defective growth in glucose medium, with greater relative growth in the less severely affected patients. Western blot analysis detected accumulation of mutant BCS1L in the cytoplasm of patients fibroblasts, suggesting impaired mitochondrial import of the mutant protein, and reduced levels of intramitochondrial fully-assembled BCS1L complexes compared to wildtype cells. The more severely affected patients also showed evidence of increased reactive oxygen species and apoptosis compared to the lesser affected patients. Mitochondrial structure abnormalities were also observed.

In 6 patients with complex III deficiency, de Lonlay et al. (2001) identified biallelic mutations in the BCS1L gene (603647.0001-603647.0004). Complementation studies in yeast confirmed the deleterious effect of the mutations in these patients. De Lonlay et al. (2001) concluded that mutation of BCS1L seems to be a frequent cause of complex III deficiency, as one-third of their Turkish patients with complex III deficiency had BCS1L mutations.

In 2 unrelated girls with complex III deficiency manifest as encephalopathy, Fernandez-Vizarra et al. (2007) identified compound heterozygous mutations in the BCS1L gene (see, e.g., R184C; 603647.0009 and R183C; 603647.0012). Studies in yeast showed that the mutations significantly reduced mitochondrial cytochrome content and respiratory activity, as well resulted in decreased levels of fully assembled complex III.

Blazquez et al. (2009) reported a 4-year-old Spanish boy with complex III deficiency caused by a homozygous mutation in the BCS1L gene (T50A; 603647.0011).