Mitochondrial complex III deficiency, nuclear type 2 (MC3DN2) is an autosomal recessive progressive neurodegenerative disease caused by biallelic loss-of-function variants in TTC19. TTC19 is not a conventional assembly factor: it binds the fully assembled complex III dimer after the iron-sulfur Rieske protein UQCRFS1 has been incorporated, and its role is to clear the N-terminal polypeptides that in situ maturation of UQCRFS1 leaves bound to the holocomplex. Without TTC19 those fragments accumulate inside complex III and compromise it structurally and functionally, reducing quinol-cytochrome c oxidoreductase activity and raising reactive oxygen species production. The clinical picture is a Leigh or Leigh-like neurodegeneration with striatal and brainstem lesions, cerebellar atrophy, and the distinctive finding of hypertrophic olivary degeneration; children typically show non-specific developmental delay followed by regression, ataxia, dystonia and loss of speech, either as a chronic progressive decline or as acute Leigh episodes with stepwise deterioration. No approved disease-modifying therapy exists.
Ask a research question about TTC19-related mitochondrial complex III deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).
Do not include personal health information in your question. Questions and results are cached in your browser's local storage.
name: TTC19-related mitochondrial complex III deficiency
creation_date: "2026-08-24T22:20:00Z"
category: Mendelian
description: >-
Mitochondrial complex III deficiency, nuclear type 2 (MC3DN2) is an autosomal
recessive progressive neurodegenerative disease caused by biallelic
loss-of-function variants in TTC19. TTC19 is not a conventional assembly
factor: it binds the fully assembled complex III dimer after the iron-sulfur
Rieske protein UQCRFS1 has been incorporated, and its role is to clear the
N-terminal polypeptides that in situ maturation of UQCRFS1 leaves bound to the
holocomplex. Without TTC19 those fragments accumulate inside complex III and
compromise it structurally and functionally, reducing quinol-cytochrome c
oxidoreductase activity and raising reactive oxygen species production. The
clinical picture is a Leigh or Leigh-like neurodegeneration with striatal and
brainstem lesions, cerebellar atrophy, and the distinctive finding of
hypertrophic olivary degeneration; children typically show non-specific
developmental delay followed by regression, ataxia, dystonia and loss of
speech, either as a chronic progressive decline or as acute Leigh episodes
with stepwise deterioration. No approved disease-modifying therapy exists.
disease_term:
preferred_term: mitochondrial complex III deficiency nuclear type 2
term:
id: MONDO:0014063
label: mitochondrial complex III deficiency nuclear type 2
parents:
- mitochondrial complex III deficiency, nuclear type
synonyms:
- mitochondrial complex III deficiency nuclear type 2
- MC3DN2
- TTC19 deficiency
- TTC19-related mitochondrial disease
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
Disease requires biallelic TTC19 variants. Homozygous nonsense variants were
identified in the founding consanguineous families, and homozygous missense,
frameshift and in-frame deletion alleles have since been reported.
evidence:
- reference: PMID:21278747
reference_title: "Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified a homozygous nonsense mutation in the gene encoding
tetratricopeptide 19 (TTC19) in individuals from two families affected by
progressive encephalopathy associated with profound cIII deficiency and
accumulation of cIII-specific assembly intermediates.
explanation: >-
Homozygous nonsense variants in two independent families establish
autosomal recessive inheritance.
notes: >-
**The mechanism was revised after the disease was described, and the entry
curates the revision rather than the original framing.** PMID:21278747 named
TTC19 "a putative cIII assembly factor" on the strength of its physical
association with complex III and the accumulation of assembly intermediates in
patients. PMID:28673544 then showed that TTC19 binds the complex *after* the
Rieske protein has been incorporated, and that what it actually does is remove
the UQCRFS1 N-terminal fragments that maturation leaves behind. The
pathophysiology chain here follows the 2017 mechanism, and the trigger node
says explicitly that "assembly factor" is the earlier and less accurate
description. Curating the disorder as a defect of *assembly* would misplace
the lesion by one step and make the accumulating fragments look like a
by-product rather than the proximate cause.
**Normal complex III activity does not exclude the diagnosis**, and this is
curated as a diagnostic caveat with its own evidence: PMID:25887401 reports a
patient with normal complex III activity in two independent muscle biopsies.
Enzymology is therefore not a rule-out, and the biochemical phenotype node is
worded accordingly.
**The NEC preflight returned WARN for this entry's research report, and that
warning was acted on.** UQCRC2 was mentioned 49 times against TTC19's 178.
UQCRC2 causes mitochondrial complex III deficiency nuclear type 5, a different
MONDO entity. No UQCRC2 content was carried into this entry, and no claim here
rests on a source about that gene. The report's OMIM list also included 124000
alongside the correct 615157.
**Pyocyanin is curated as a mechanism, not as a treatment option.** It is an
experimental bacterial redox cycler shown to shunt electrons past a defective
complex III in patient fibroblasts and in fly and zebrafish models. There is no
human trial, and the only mammalian in vivo data cited is a two-month toxicity
study in control mice. It is entered with `treatment_effect: BYPASSES` because
that is exactly what it does mechanistically, and the entry states the
evidence level in the treatment description so it cannot be read as clinical
guidance.
**The paediatric weighting is a consequence of the sources, not a scoping
decision.** The two cohorts that anchor this entry (PMID:41818954 and
PMID:42480132) are paediatric, and the 2015 literature review is explicitly of
paediatric cases, so the natural history curated here is the childhood one.
The adult-onset arm is real and is now represented: severe psychiatric disease
and peripheral neuropathy are curated as phenotypes, and the mean age at onset
in the French cohort was 5.7 years with a range extending to 15. What is still
under-represented is the adult spinocerebellar-ataxia presentation, for which
the case reports are individually small and none is cited here; that is a gap
in this entry's sources rather than a boundary it draws deliberately.
Research input: `research/Mitochondrial_Complex_III_Deficiency_Nuclear_Type_2-deep-research-perplexity.md`.
It returned no PMIDs in its body, so all references were located independently
in PubMed and fetched with `just fetch-reference`.
pathophysiology:
- name: TTC19 Loss of Function
biological_scale: MOLECULAR
description: >-
Biallelic loss-of-function TTC19 variants remove the protein or its function.
TTC19 is embedded in the inner mitochondrial membrane as part of
high-molecular-weight complexes, one of which coincides with complex III, and
it interacts with complex III physically. It was originally described as a
putative complex III assembly factor; the more precise account established
later is that it acts on the already-assembled complex, which is how this
entry models it.
genes:
- preferred_term: TTC19
term:
id: hgnc:26006
label: TTC19
cellular_components:
- preferred_term: mitochondrial inner membrane
term:
id: GO:0005743
label: mitochondrial inner membrane
evidence:
- reference: PMID:21278747
reference_title: "Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We demonstrated that TTC19 is embedded in the inner mitochondrial membrane
as part of two high-molecular-weight complexes, one of which coincides with
cIII. We then showed a physical interaction between TTC19 and cIII by
coimmunoprecipitation.
explanation: >-
Establishes the submitochondrial localization and the physical association
with complex III.
- reference: PMID:41818954
reference_title: "TTC19-related mitochondrial complex III deficiency: Clinical and genetic characterization of 10 patients from 5 unrelated Arab families."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In this cohort, exome sequencing (ES) identified three distinct pathogenic
variants in the TTC19 gene across the five unrelated families, highlighting
both genetic heterogeneity and regional clustering.
explanation: >-
Recent multi-family cohort confirming allelic heterogeneity of pathogenic
TTC19 variants.
downstream:
- target: Failure to Clear UQCRFS1 N-Terminal Fragments from Complex III
description: >-
Loss of TTC19 removes the activity that normally clears the UQCRFS1
maturation fragments retained by the holocomplex.
causal_link_type: DIRECT
evidence:
- reference: PMID:28673544
reference_title: "TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We show that, in normal conditions, these UQCRFS1 fragments are rapidly
removed, but when TTC19 is absent they accumulate within complex III,
causing its structural and functional impairment.
explanation: >-
Directly demonstrates that absence of TTC19 is what allows the fragments
to accumulate.
- name: Failure to Clear UQCRFS1 N-Terminal Fragments from Complex III
biological_scale: MOLECULAR
description: >-
TTC19 binds the fully assembled complex III dimer, that is after
incorporation of the iron-sulfur Rieske protein UQCRFS1. In situ maturation
of UQCRFS1 generates N-terminal polypeptides that remain bound to
holocomplex III and are normally cleared rapidly. Without TTC19 they are
retained inside the complex. This is a post-assembly housekeeping failure,
not a failure to build the complex, which is the distinction that separates
TTC19 from BCS1L and LYRM7.
biological_processes:
- preferred_term: mitochondrial respiratory chain complex III assembly
term:
id: GO:0034551
label: mitochondrial respiratory chain complex III assembly
modifier: ABNORMAL
evidence:
- reference: PMID:28673544
reference_title: "TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
we demonstrate that TTC19 binds to the fully assembled complex III dimer,
i.e., after the incorporation of the iron-sulfur Rieske protein (UQCRFS1).
The in situ maturation of UQCRFS1 produces N-terminal polypeptides, which
remain bound to holocomplex III.
explanation: >-
Establishes both the timing of TTC19 binding and the origin of the retained
fragments, which is what makes this a post-assembly defect.
downstream:
- target: Complex III Structural and Functional Impairment
description: >-
Fragments retained within the holocomplex compromise its structure and
catalytic function.
causal_link_type: DIRECT
evidence:
- reference: PMID:28673544
reference_title: "TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
when TTC19 is absent they accumulate within complex III, causing its
structural and functional impairment
explanation: Names the structural and functional consequence directly.
- name: Complex III Structural and Functional Impairment
biological_scale: CELLULAR
description: >-
Quinol-cytochrome c oxidoreductase activity falls, complex III-specific
assembly intermediates accumulate, and reactive oxygen species production
rises. In the mouse knockout the biochemical phenotype is accompanied by
progressive neurological and metabolic decline. Importantly, the enzymatic
defect is not always measurable: one reported patient had normal complex III
activity in two independent muscle biopsies.
molecular_functions:
- preferred_term: quinol-cytochrome-c reductase activity
term:
id: GO:0008121
label: quinol-cytochrome-c reductase activity
modifier: DECREASED
biological_processes:
- preferred_term: reactive oxygen species metabolic process
term:
id: GO:0072593
label: reactive oxygen species metabolic process
modifier: INCREASED
evidence:
- reference: PMID:28673544
reference_title: "TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III."
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
mouse model that shows progressive neurological and metabolic decline,
decreased complex III activity, and increased production of reactive oxygen
species
explanation: >-
Establishes reduced complex III activity and raised ROS in a mouse knockout,
alongside the progressive phenotype.
- reference: PMID:25887401
reference_title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Notably, one patient revealed normal activities of MRC complex III in two
independent muscle biopsies.
explanation: >-
Qualifies the node: the biochemical defect is not detectable in every
patient or every tissue, which is why this item is PARTIAL and why the
diagnostic section carries an explicit caveat.
downstream:
- target: Progressive Neurodegeneration with Leigh-like Lesions
description: >-
Impaired oxidative phosphorylation is most damaging in high-energy-demand
tissue, and the brain bears the disease.
causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
evidence:
- reference: PMID:21278747
reference_title: "Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
TTC19 is a putative cIII assembly factor whose disruption is associated
with severe neurological abnormalities in humans and flies.
explanation: >-
Links TTC19 disruption to the neurological phenotype across two species.
Quoted as the paper's own summary; note the "assembly factor" wording is
the 2011 framing, superseded by PMID:28673544.
- name: Progressive Neurodegeneration with Leigh-like Lesions
biological_scale: ORGANISM
description: >-
A progressive neurodegenerative course with a characteristic lesion
distribution: striatal (putamen and caudate) lesions, brainstem involvement,
cerebellar atrophy and hypertrophic olivary degeneration. Two clinical
patterns are recognised — chronic progressive decline, and acute or subacute
Leigh episodes producing stepwise deterioration — and some patients are
stable between episodes. Onset is typically in childhood with non-specific
developmental delay and hypotonia, followed by regression, ataxia, dystonia
and loss of speech.
locations:
- preferred_term: brain
term:
id: UBERON:0000955
label: brain
evidence:
- reference: PMID:42480132
reference_title: "TTC19-related mitochondrial disease: A characteristic neuroimaging signature?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Neuroimaging consistently revealed striatal lesions in all patients and
brainstem involvement in almost all of them.
explanation: >-
Establishes the lesion distribution across an 11-patient multicentre
cohort with centrally reviewed MRI.
- reference: PMID:42480132
reference_title: "TTC19-related mitochondrial disease: A characteristic neuroimaging signature?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients exhibited two distinct clinical patterns: progressive
neurodegenerative disease (chronic Leigh syndrome) and acute/subacute Leigh
syndrome.
explanation: Establishes the two clinical courses curated in this node.
- reference: PMID:25887401
reference_title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
patterns consistent with Leigh or Leigh-like syndrome were found in almost
all, hypertrophic olivary nucleus degeneration in all patients reported so
far
explanation: >-
Establishes the Leigh-like pattern and the hypertrophic olivary degeneration
that distinguishes this disorder radiologically.
phenotypes:
- name: Hypertrophic Olivary Degeneration
category: Neuroimaging
description: >-
Hypertrophic degeneration of the inferior olivary nuclei is the most
distinctive imaging feature of this disorder. A 2015 review of the published
paediatric cases found it in every patient reported at that time, which is
what makes it a pointer to TTC19 rather than a generic Leigh-syndrome finding.
phenotype_term:
preferred_term: Olivary degeneration
term:
id: HP:0008303
label: Olivary degeneration
evidence:
- reference: PMID:25887401
reference_title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
patterns consistent with Leigh or Leigh-like syndrome were found in almost
all, hypertrophic olivary nucleus degeneration in all patients reported so
far
explanation: >-
Reports the finding in every patient published at the time of that
literature review.
- reference: PMID:25887401
reference_title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
lesions in putamen and caudate nuclei, cerebellar atrophy, and the unusual
finding of hypertrophic olivary nuclei degeneration
explanation: >-
Places the olivary finding alongside the striatal and cerebellar changes in
the same patients.
- name: Psychiatric Manifestations
category: Psychiatric
description: >-
Severe psychiatric disease is part of the reported neurological spectrum of
TTC19 deficiency, alongside progressive encephalomyopathy, Leigh syndrome and
cerebellar ataxia. The cited source names the category rather than a specific
diagnosis, so no frequency band and no finer term is asserted. An earlier
draft bound HP:0000709 Psychosis, which asserts hallucinations or delusions
and is therefore one step more specific than the evidence supports; the
binding was widened to match what the source actually says.
phenotype_term:
preferred_term: Severe psychiatric disorder
term:
id: HP:0000708
label: Atypical behavior
evidence:
- reference: PMID:33833234
reference_title: "Exploiting pyocyanin to treat mitochondrial disease due to respiratory complex III dysfunction."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
including progressive encephalomyopathy15, severe psychiatric disorders16,
Leigh syndrome17, and cerebellar ataxia
explanation: >-
Lists severe psychiatric disorders within the TTC19 phenotypic spectrum.
PARTIAL because it is a review sentence naming a category with a downstream
citation, not a primary description of the psychiatric phenotype. The
embedded digits are flattened superscript citation markers in the cached
text.
- name: Peripheral Neuropathy
category: Neurological
description: >-
Peripheral neuropathy occurs in a subset of patients and is not part of the
core Leigh-like presentation.
phenotype_term:
preferred_term: Peripheral neuropathy
term:
id: HP:0009830
label: Peripheral neuropathy
evidence:
- reference: PMID:37927170
reference_title: "A TTC19 mutation associated with progressive movement disorders and peripheral neuropathy: Case report and systematic review."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Some patients had peripheral neuropathy.
explanation: >-
PARTIAL, and no frequency band, because the source's own phrasing is "some
patients" without a denominator.
- name: Developmental Regression
category: Neurological
description: >-
An initially non-specific developmental delay is followed by regression, with
loss of previously acquired skills including speech.
phenotype_term:
preferred_term: Developmental regression
term:
id: HP:0002376
label: Developmental regression
frequency: VERY_FREQUENT
evidence:
- reference: PMID:25887401
reference_title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The clinical course in pediatric patients is characterized by an initially
unspecific developmental delay, followed by regression, progressive signs
and symptoms of cerebellar, basal ganglia and brainstem affection
explanation: >-
Describes regression as a defining element of the paediatric clinical
course.
- name: Ataxia
category: Neurological
phenotype_term:
preferred_term: Ataxia
term:
id: HP:0001251
label: Ataxia
evidence:
- reference: PMID:25887401
reference_title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
global developmental delay followed by regression, ataxia, loss of speech,
and rapid neurological deterioration
explanation: Names ataxia among the core progressive features.
- name: Dystonia
category: Neurological
description: >-
Dystonia, cerebellar ataxia and orofacial apraxia dominate the motor
phenotype in the paediatric cohort.
phenotype_term:
preferred_term: Dystonia
term:
id: HP:0001332
label: Dystonia
evidence:
- reference: PMID:42480132
reference_title: "TTC19-related mitochondrial disease: A characteristic neuroimaging signature?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Clinical manifestations were predominantly neurological, with motor
involvement including, dystonia, cerebellar ataxia, and orofacial apraxia
and frequently cognitive impairments.
explanation: Documents dystonia within the motor phenotype of the cohort.
- name: Loss of Speech
category: Neurological
phenotype_term:
preferred_term: Loss of speech
term:
id: HP:0002371
label: Loss of speech
evidence:
- reference: PMID:25887401
reference_title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
global developmental delay followed by regression, ataxia, loss of speech,
and rapid neurological deterioration
explanation: Documents loss of speech as part of the regression.
- name: Hypotonia
category: Neurological
description: >-
Muscular hypotonia is a common early and non-specific presenting sign.
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
evidence:
- reference: PMID:25887401
reference_title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
patients from three unrelated families presenting with initially unspecific
clinical signs of muscular hypotonia and global developmental delay
explanation: Documents hypotonia as a presenting sign across three families.
- name: Abnormal Basal Ganglia Morphology
category: Neuroimaging
description: >-
Striatal lesions involving putamen and caudate nuclei were present in every
patient in a centrally reviewed multicentre imaging cohort.
phenotype_term:
preferred_term: Abnormal basal ganglia morphology
term:
id: HP:0002134
label: Abnormal basal ganglia morphology
frequency: VERY_FREQUENT
evidence:
- reference: PMID:42480132
reference_title: "TTC19-related mitochondrial disease: A characteristic neuroimaging signature?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Neuroimaging consistently revealed striatal lesions in all patients and
brainstem involvement in almost all of them.
explanation: >-
Striatal lesions in all patients of the cohort support the VERY_FREQUENT
band.
- name: Abnormal Brainstem Morphology
category: Neuroimaging
phenotype_term:
preferred_term: Abnormal brainstem morphology
term:
id: HP:0002363
label: Abnormal brainstem morphology
evidence:
- reference: PMID:42480132
reference_title: "TTC19-related mitochondrial disease: A characteristic neuroimaging signature?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Neuroimaging consistently revealed striatal lesions in all patients and
brainstem involvement in almost all of them.
explanation: Documents brainstem involvement in almost all patients.
- name: Cerebellar Atrophy
category: Neuroimaging
phenotype_term:
preferred_term: Cerebellar atrophy
term:
id: HP:0001272
label: Cerebellar atrophy
evidence:
- reference: PMID:25887401
reference_title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Neuroimaging of the severely affected patients demonstrated lesions in
putamen and caudate nuclei, cerebellar atrophy, and the unusual finding of
hypertrophic olivary nuclei degeneration.
explanation: Documents cerebellar atrophy alongside the other imaging features.
- name: Lactic Acidosis
category: Laboratory
description: >-
Lactic acidosis is not universal but can be severe, and one patient presented
with it in the neonatal period and during intercurrent illness. A lactate
peak on MR spectroscopy is also reported.
phenotype_term:
preferred_term: Lactic acidosis
term:
id: HP:0003128
label: Lactic acidosis
evidence:
- reference: PMID:25887401
reference_title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
One patient showed severe lactic acidosis at the neonatal age and during
intercurrent illness.
explanation: >-
Documents lactic acidosis in one patient; no frequency band is asserted
because the source reports it as a single-patient finding.
genetic:
- name: TTC19
gene_term:
preferred_term: TTC19
term:
id: hgnc:26006
label: TTC19
association: Biallelic loss-of-function variants
relationship_type: CAUSATIVE
features: >-
Reported alleles include homozygous nonsense variants in the founding
families, homozygous missense variants (c.544T>C p.Leu185Pro, c.917T>C
p.Leu324Pro), a recurrent frameshift deletion, and an in-frame deletion
removing ten amino acids. A recent cohort of ten patients from five unrelated
Arab families identified three distinct pathogenic variants with regional
clustering, including a recurrent p.Tyr260 termination allele shared by three
independent Syrian families.
evidence:
- reference: PMID:25887401
reference_title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We identified homozygous mutations in all three index cases, in two families
novel missense mutations (c.544 T > C/p.Leu185Pro; c.917 T > C/p.Leu324Pro).
explanation: Documents the missense alleles and their homozygous state.
- reference: PMID:41818954
reference_title: "TTC19-related mitochondrial complex III deficiency: Clinical and genetic characterization of 10 patients from 5 unrelated Arab families."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We report 10 patients from five unrelated Arab families, all presenting with
variable severity of a progressive neurodegenerative disorder characterized
by loss of ambulation, speech impairment, and cognitive regression.
explanation: >-
The largest reported cohort, establishing the phenotype across ten patients
and five families.
progression:
- phase: Non-specific infantile presentation
notes: >-
Muscular hypotonia and global developmental delay without distinguishing
features, which is why diagnosis is typically delayed.
evidence:
- reference: PMID:25887401
reference_title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
patients from three unrelated families presenting with initially unspecific
clinical signs of muscular hypotonia and global developmental delay
explanation: Establishes the non-specific opening phase.
- phase: Regression and neurological deterioration
notes: >-
Regression with ataxia, dystonia, loss of speech and progressive cerebellar,
basal ganglia and brainstem involvement. Deterioration may be continuous or
stepwise via acute Leigh episodes; in the most severely affected reported
patients it progresses to a vegetative state.
evidence:
- reference: PMID:25887401
reference_title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Subsequently, neurological deterioration leading to a vegetative state
occurs.
explanation: Documents the endpoint of the progressive course.
- reference: PMID:42480132
reference_title: "TTC19-related mitochondrial disease: A characteristic neuroimaging signature?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The disease progression varied, with patients experiencing progressive
decline, stepwise declines and others remaining stable between episodes.
explanation: >-
Qualifies the course: not all patients decline continuously, and some are
stable between acute episodes.
diagnosis:
- name: Exome Sequencing
description: >-
Genetic confirmation is the diagnostic standard. Exome sequencing identified
the causal variants in the recent multi-family cohorts, and it is the route
that does not depend on the enzymology being abnormal.
diagnosis_term:
preferred_term: Molecular Analysis
term:
id: NCIT:C19770
label: Molecular Analysis
evidence:
- reference: PMID:41818954
reference_title: "TTC19-related mitochondrial complex III deficiency: Clinical and genetic characterization of 10 patients from 5 unrelated Arab families."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In this cohort, exome sequencing (ES) identified three distinct pathogenic
variants in the TTC19 gene across the five unrelated families
explanation: Documents exome sequencing as the diagnostic route in the cohort.
- name: Brain MRI Pattern Recognition
description: >-
The imaging pattern is distinctive enough to raise the diagnosis: striatal
lesions, brainstem involvement, cerebellar atrophy and hypertrophic olivary
degeneration, the last of which was present in every patient reported at the
time of a 2015 literature review.
diagnosis_term:
preferred_term: Diagnostic Procedure
term:
id: NCIT:C18020
label: Diagnostic Procedure
evidence:
- reference: PMID:25887401
reference_title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
TTC19 deficient patients do show characteristic clinical and neuroimaging
features, which may facilitate diagnosis of this yet rare disorder.
explanation: >-
States that the clinical and imaging pattern is characteristic enough to aid
diagnosis.
- name: Respiratory Chain Enzymology
description: >-
Complex III activity in muscle is commonly reduced, but a normal result does
not exclude the diagnosis: one reported patient had normal complex III
activity in two independent muscle biopsies. Enzymology should therefore be
treated as supportive rather than as a rule-out test.
diagnosis_term:
preferred_term: Diagnostic Procedure
term:
id: NCIT:C18020
label: Diagnostic Procedure
evidence:
- reference: PMID:25887401
reference_title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Normal MRC complex III activity does not exclude the diagnosis.
explanation: >-
The source's own conclusion, and the reason this entry does not treat
enzymology as a rule-out.
treatments:
- name: Pyocyanin Electron Shunt (experimental, preclinical only)
description: >-
Pyocyanin is a bacterial redox cycler that can substitute for the redox
function of complex III, acting as an electron shunt around the defective
enzyme. In fibroblasts from patients carrying TTC19, BCS1L or LYRM7 variants
it restored respiration and increased ATP production at sub-micromolar
concentrations, and it improved movement in TTC19 fly and zebrafish models.
THIS IS NOT A CLINICAL TREATMENT. There is no human study; the only mammalian
in vivo data cited is a two-month administration to control mice showing no
toxicity. It is curated because the bypass mechanism is a real and
well-evidenced property of the pathway, not because it is an option for
patients.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: pyocyanin
term:
id: CHEBI:8653
label: pyocyanine
target_mechanisms:
- target: Complex III Structural and Functional Impairment
treatment_effect: BYPASSES
description: >-
Pyocyanin transfers electrons past the impaired complex, restoring
respiratory flux without repairing the complex itself.
evidence:
- reference: PMID:33833234
reference_title: "Exploiting pyocyanin to treat mitochondrial disease due to respiratory complex III dysfunction."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We show that pyocyanin, a bacterial redox cycler, can replace the redox
functions of complex III, acting as an electron shunt.
explanation: >-
States the bypass mechanism that justifies the BYPASSES treatment effect.
evidence:
- reference: PMID:33833234
reference_title: "Exploiting pyocyanin to treat mitochondrial disease due to respiratory complex III dysfunction."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Sub-μM pyocyanin was harmless, restored respiration and increased ATP
production in fibroblasts from five patients harboring pathogenic mutations
in TTC19, BCS1L or LYRM7, involved in assembly/stabilization of complex III.
explanation: >-
Patient-derived fibroblasts including TTC19 cases. PARTIAL rather than
SUPPORT because the claim being evaluated is therapeutic usefulness, and the
evidence is cellular and animal only.
discussions:
- discussion_id: gap_ttc19_genotype_phenotype_and_enzymology_discordance
kind: KNOWLEDGE_GAP
attaches_to:
- pathophysiology#Complex III Structural and Functional Impairment
prompt: >-
Why do some TTC19 patients have normal muscle complex III activity, and why
does severity vary so widely — including a homozygous sibling who was only
mildly affected?
rationale: >-
Two observations in the same report resist the simple model that residual
complex III activity sets severity. PMID:25887401 found normal complex III
activity in two independent muscle biopsies from a patient with the disease,
and separately reported that the younger sister of a severely affected
patient, homozygous for the same variant, showed only mild motor delay and
hypotonia. PMID:42480132 adds that some patients remain stable between acute
episodes while others decline continuously. Together these mean neither
genotype nor muscle enzymology predicts the course, and the tissue in which
the biochemical lesion matters may not be the tissue that is biopsied. This
is not merely academic: enzymology is still used as a rule-out in practice,
and the paper says explicitly that it should not be.
proposed_experiments:
- experiment_id: exp_ttc19_tissue_specific_enzymology
name: Tissue-comparative complex III activity and UQCRFS1 fragment load
description: >-
Measure complex III activity and, separately, the abundance of retained
UQCRFS1 N-terminal fragments in muscle, fibroblasts and, where available,
post-mortem brain from the same TTC19 patients, including one with normal
muscle enzymology.
decision_criterion: >-
Fragment load tracking disease severity where activity does not would make
the retained fragment, rather than residual catalytic activity, the
measurable disease marker, and would explain the normal-enzymology cases.
- experiment_id: exp_ttc19_intrafamilial_modifier_search
name: Modifier analysis in discordant same-genotype siblings
description: >-
Compare genomes and mitochondrial haplogroups of the severely and mildly
affected siblings homozygous for the same TTC19 variant, and of other
intrafamilial discordant pairs, to test for a nuclear or mitochondrial
modifier of severity.
decision_criterion: >-
A recurrent modifier across independent discordant pairs would give a
prognostic marker; its absence would push the explanation towards stochastic
or environmental triggering of the acute Leigh episodes.
references:
- reference: PMID:21278747
title: "Mutations in TTC19 cause mitochondrial complex III deficiency and neurological impairment in humans and flies."
- reference: PMID:25887401
title: "Mutations in TTC19: expanding the molecular, clinical and biochemical phenotype."
- reference: PMID:28673544
title: "TTC19 Plays a Husbandry Role on UQCRFS1 Turnover in the Biogenesis of Mitochondrial Respiratory Complex III."
- reference: PMID:33833234
title: "Exploiting pyocyanin to treat mitochondrial disease due to respiratory complex III dysfunction."
- reference: PMID:41818954
title: "TTC19-related mitochondrial complex III deficiency: Clinical and genetic characterization of 10 patients from 5 unrelated Arab families."
- reference: PMID:37927170
title: "A TTC19 mutation associated with progressive movement disorders and peripheral neuropathy: Case report and systematic review."
- reference: PMID:42480132
title: "TTC19-related mitochondrial disease: A characteristic neuroimaging signature?"
- reference: PMID:26425749
title: "Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview."
tags:
- GeneReviews