Mitochondrial Complex Iii Deficiency, Nuclear Type 2

A number sign (#) is used with this entry because mitochondrial complex III deficiency nuclear type 2 (MC3DN2) is caused by homozygous or compound heterozygous mutation in the nuclear-encoded TTC19 gene (613814) on chromosome 17p12.

Description

Mitochondrial complex III deficiency nuclear type 2 is an autosomal recessive severe neurodegenerative disorder that usually presents in childhood, but may show later onset, even in adulthood. 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). The disorder may present clinically as spinocerebellar ataxia or Leigh syndrome, or with psychiatric disturbances (Morino et al., 2014; Atwal, 2014; Nogueira et al., 2013).

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

Clinical Features

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.

Nogueira et al. (2013) reported 4 Portuguese sibs, born of parents who were likely related, with a complex neurodegenerative disease associated with significant psychiatric features. The age at onset varied between 12 and 34 years, but followed a relentlessly progressive course in each patient, resulting in death in 2 patients between ages 30 and 49 years. All presented with psychiatric signs, such as compulsive lying, obsessive-compulsive behavior, aggression, avoidance, and hallucinations; 1 patient also had gait ataxia at onset. All developed gait ataxia, dysarthria, dysmetria, and muscle weakness, consistent with cerebellar disease, as well as pyramidal signs and spastic paraparesis later in the disease course. Some patients had extrapyramidal signs. The psychiatric features progressed to include major depression, psychosis, and extremely poor social interactions. Brain MRI showed olivopontocerebellar atrophy and abnormal signals in the putamen, caudate, and brainstem on T2-weighted imaging. Cortical brain atrophy appeared at a later stage. Two patients had electrophysiologic evidence of an axonal neuropathy. Muscle biopsy in all patients showed a marked reduction of mitochondrial complex III activity to about 33% of control values, and muscle biopsy of 1 patient showed decreased mtDNA copy number (about 45% of controls). Skin fibroblasts showed normal ATP production, but increased levels of reactive oxygen species (ROS).

Atwal (2014) reported a 4-year-old Hispanic boy with MC3DN2 who was noted to have global developmental delay at age 7-8 months, followed by language regression at age 13 months. Brain MRI showed T2-weighted signals in the putamen, caudate, and brainstem, consistent with a diagnosis of Leigh syndrome. Muscle biopsy showed decreased activity of complexes I+III (79%), II (52%), II+III (36%), and IV (46%) of the mitochondrial respiratory chain.

Morino et al. (2014) reported a 37-year-old Japanese woman, born of consanguineous parents, who presented clinically with adult-onset spinocerebellar ataxia. The patient first developed dysarthria at age 31 years. She then showed hyperreflexia, ataxic gait, truncal ataxia, horizontal nystagmus, and intellectual impairment, and she began to use a wheelchair at age 34. She also had pes cavus. Brain MRI showed cerebellar atrophy and T2-weighted hyperintensities in the inferior olives at age 33. Blood lactate was normal at age 35, but increased at age 37, suggesting mitochondrial dysfunction. Morino et al. (2014) noted that the phenotype in this patient was mild compared to other reported patients.

Inheritance

The transmission pattern of MC3DN2 in the families reported by Ghezzi et al. (2011) was consistent with autosomal recessive inheritance.

Molecular Genetics

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 truncating mutation in the TTC19 gene (613814.0002). Immunofluorescence studies of patient tissues indicated a defect in the assembly of mitochondrial complex III.

In 4 Portuguese sibs with progressive autosomal recessive cerebellar ataxia and severe psychiatric manifestations combined with decreased mitochondrial complex III activity in muscle, Nogueira et al. (2013) identified a homozygous truncating mutation in the TTC19 gene (613814.0003).

In a 4-year-old Hispanic boy with MC3DN2 presenting as Leigh syndrome, Atwal (2014) identified compound heterozygosity for 2 truncating mutations in the TTC19 gene (613814.0004 and 613814.0005). The mutation was found upon submission of the patient's DNA for a Leigh syndrome diagnostic panel.

In a 37-year-old Japanese woman, born of consanguineous parents, with adult-onset MC3DN2 manifest clinically as spinocerebellar ataxia (SCA), Morino et al. (2014) identified a homozygous truncating mutation in the TTC19 gene (613814.0006). The mutation was found by exome sequencing.