Mitochondrial complex III deficiency nuclear type 2 is an autosomal recessive severe neurodegenerative disorder that usually presents in childhood, but may show later onset. Affected individuals have motor disability, with ataxia, apraxia, dystonia, and dysarthria, associated with necrotic ... Mitochondrial complex III deficiency nuclear type 2 is an autosomal recessive severe neurodegenerative disorder that usually presents in childhood, but may show later onset. Affected individuals have motor disability, with ataxia, apraxia, dystonia, and dysarthria, associated with necrotic lesions throughout the brain. Most patients also have cognitive impairment and axonal neuropathy and become severely disabled later in life (summary by Ghezzi et al., 2011). For a discussion of genetic heterogeneity of mitochondrial complex III deficiency, see MC3DN1 (124000).
Ghezzi et al. (2011) reported 4 Italian patients with mitochondrial complex III deficiency. Two adult sibs from northeastern Italy had childhood onset of a slowly progressive neurodegenerative disorder. The sister presented at age 5 years with mild mental ... Ghezzi et al. (2011) reported 4 Italian patients with mitochondrial complex III deficiency. Two adult sibs from northeastern Italy had childhood onset of a slowly progressive neurodegenerative disorder. The sister presented at age 5 years with mild mental retardation and ataxic gait. These signs progressed over several years, and she developed hypodiadochokinesis, nystagmus, diplopia, dysphagia, and dysphonia. She also developed axonal motor degeneration as shown on EMG. By age 24, she was wheelchair-bound with tremor, dysmetria, dysarthria, hyperreflexia, and extensor plantar responses. Brain MRI showed progressive necrotic lesions in the caudate, olives, substantia nigra, and putamen. She also had cerebral atrophy and severe cerebellar atrophy. Magnetic resonance spectroscopy (MRS) showed a lactate peak in the putamina. Her 26-year-old brother presented at age 10 years with gait ataxia and poor school performance. He had a rapid downhill course characterized by progressive limb incoordination, dysarthria, dysphonia, hearing loss, nystagmus, dystonia, and severe cognitive regression. He became bedridden in a fluctuating comatose state. A third unrelated woman from the same region had a similar neurodegenerative disease course, with onset of ataxia and cognitive impairment at age 5 years; she eventually became bedridden in a fluctuating comatose state. Brain MRI showed progressive necrotic lesions in the brainstem, cerebellum, and cerebral peduncles. She had cerebellar atrophy and severe axonal degeneration of motor nerves. A fourth patient from southern Italy had normal psychomotor development until age 42 years, when he developed subacute, rapidly progressive neurologic failure resulting in death at age 45. Features included weakness with fasciculations, apraxia, dysarthria, bradykinesia, dystonia, paraparesis, and behavioral changes. He also had axonal degeneration of the peripheral motor nerves. Brain MRI showed diffuse cortical atrophy and necrotic lesions in the right caudate and putamina. Brain MRS showed an increased lactate peak. In all patients, muscle biopsies showed marked isolated complex III deficiency and impaired overall mitochondrial respiratory activity. There was also decreased TTC19 mRNA or protein in muscle tissue and/or fibroblasts.
Ghezzi et al. (2011) identified a homozygous truncating mutation in the TTC19 gene (613814.0001) in 2 sibs from northeastern Italy with mitochondrial complex III deficiency. A third unrelated patient from the same region had a similar disease course ... Ghezzi et al. (2011) identified a homozygous truncating mutation in the TTC19 gene (613814.0001) in 2 sibs from northeastern Italy with mitochondrial complex III deficiency. A third unrelated patient from the same region had a similar disease course and the same mutation. Haplotype analysis indicated a founder effect. Another man from southern Italy had a different homozygous mutation in the TTC19 gene (613814.0002). Immunofluorescence studies of patient tissues indicated a defect in the assembly of mitochondrial complex III.