Novel TTC19 mutation in a family with severe psychiatric manifestations and complex III deficiency

Abstract

Complex III of the mitochondrial respiratory chain (CIII) catalyzes transfer of electrons from reduced coenzyme Q to cytochrome c. Low biochemical activity of CIII is not a frequent etiology in disorders of oxidative metabolism and is genetically heterogeneous. Recently, mutations in the human tetratricopeptide 19 gene (TTC19) have been involved in the etiology of CIII deficiency through impaired assembly of the holocomplex. We investigated a consanguineous Portuguese family where four siblings had reduced enzymatic activity of CIII in muscle and harbored a novel homozygous mutation in TTC19. The clinical phenotype in the four sibs was consistent with severe olivo–ponto–cerebellar atrophy, although their age at onset differed slightly. Interestingly, three patients also presented progressive psychosis. The mutation resulted in almost complete absence of TTC19 protein, defective assembly of CIII in muscle, and enhanced production of reactive oxygen species in cultured skin fibroblasts. Our findings add to the array of mutations in TTC19, corroborate the notion of genotype/phenotype variability in mitochondrial encephalomyopathies even within a single family, and indicate that psychiatric manifestations are a further presentation of low CIII.

Appendix—clinical data in patients harboring a new mutation in TTC19

Case II-04 was a 33-year-old man who had displayed obsessive–compulsive behavior since his teens. At the age of 24, he was hospitalized and found, on psychiatric examination, to be a healthy young man who displayed childish behavior and frequently used “lies to communicate.” The patient, at that time, also complained of generalized anxiety and a sleep disorder. Medical records also contained reports of episodes of mysticism and visual hallucinations (the patient often said “I can see dead people talking to me”). His neurological examination was unremarkable. A few years later, his clinical profile also included abulia and bradypsychism with episodes of confusion and spatial disorientation. A neurological examination performed during hospitalization at the age of 27 years revealed mild cerebellar ataxia with dysarthria, pyramidal tract signs in the lower limbs (leg stiffness, enhanced deep tendon reflexes, bilateral Babinski sign), and generalized muscle atrophy and wasting. The cranial nerves and peripheral nervous system were spared. The patient's disease progressed rapidly; he became mutacic and cachectic, and died at the age of 33 of respiratory insufficiency.

Case II-05 was a 30-year-old man who was prone to violent behavior during his teens and had physically attacked an officer during his compulsory military service at age 18. Once expelled from the army, he was committed to a psychiatric unit until the age of 22 years. When he was 23, he was reported for domestic violence and aggression in the workplace. Medical records from that time describe a mutacic patient with mild cognitive impairment and a combination of depressive and psychotic symptoms, as well as dysphagia and dysarthria. Neurological examination also revealed the presence of “primitive” reflexes (sucking, palmomental, and grasping), ataxic gait with bilateral pyramidal syndrome, and extrapyramidal features (bradykinesia and hand dystonia). He died of cardiac arrest aged 30 years.

Case II-06 is a 38-year-old woman who had no significant medical complaints until the age of 34. In view of her three older brothers' clinical symptoms, she had been carefully monitored since the age of 15 years and her parents had reported only mild clumsiness and swerving while riding a bike. At the age of 34, she began to display rude manners, compulsory polyphagia, a major mood disorder, and auditory hallucinations (often saying that dead relatives were inciting her to commit suicide). Neurological examination at this time revealed gait ataxia, bilateral finger–nose dysmetria, and inability to perform tandem gait. Neuropsychological assessment revealed significant impairment of attention, psychomotor speed and language, as well as ideomotor apraxia and memory loss. There were also clinical features suggestive of pyramidal and extrapyramidal tract dysfunction. Treatment with idebenone and haloperidol was attempted without success.

All the patients were, at some time during the disease course, screened for genetic alterations associated with Friedreich ataxia, SCA1, SCA2, MJD1/SCA3 (Machado–Joseph disease), SCA6, SCA7, SCA12, SCA17, dentatorubropallidoluysian atrophy, and FXTAS. Screening of the POLG, APTX, and SETX genes was negative in patient II-01, as were whole mtDNA sequencing and screening of the genes encoding the structural component of CIII (II-01 and II-04) and BCS1L (II-01 and II-06).