Clinical features, treatment responses, and outcomes in TBK1-deficient patients
| Individual | Family 1 | Family 2 | Family 3 | Family 4 | Family 5 | Family 6 | Family 7 | |||
|---|---|---|---|---|---|---|---|---|---|---|
| P1 | P2 | P3 | P4 | P5 | P6 | P7 | P8 | P9 | P10 | |
| TBK1 variant | p.W619* | p.W619* | p.Y212D | p.R440* | p. R574Sfs*11 | p. R574Sfs*11 | p. R574Sfs*11 | p.R440* | p.T77_L180del | p.L717Sfs*18 |
| cDNA annotation | c.1857G>A | c.1857G>A | c.634T>G | c.1318C>T | c.1760+4_1760+7del | c.1760+4_1760+7del | c.1760+4_1760+7del | c.1318C>T | c.228+?_540-?del | c.2150_2153del |
| Transcript reference (GRCh38) | g.64497045 G>A | g.64497045 G>A | g.64474323 T>G | g.64485995 C>T | g. 64496403-ATAAG-A | g. 64496403-ATAAG-A | g. 64496403-ATAAG-A | g.64485995 C>T | g.64463877_64473125del | g.64501340 TTAAC>T |
| gnomAD (v.4.1.0) frequency | 6.21E-07 | 6.21E-07 | Private | 1.89E-06 | 7.94E-07 | 7.94E-07 | 7.94E-07 | 1.89E-06 | Private | Private |
| Predicted consequence/CADD PHRED (GRCh38-v1.7; MSC = 10.854) | 39 | 39 | 30 | 36 | Predicted LoF (frameshift) | Predicted LoF (frameshift) | Predicted LoF (frameshift) | 36 | Predicted LoF (deletion of exons 4–5) | Predicted LoF (frameshift) |
| Age at last evaluation (years)/Sex | 34/F | 26/M | 7/M | 11.9/F | 2.4/F | 1.6/F | 3.5/F | 4.5/M | 19/M | 5/F |
| Systemic features | ||||||||||
| Recurrent fever | + | + | − | + | + | + | − | + | + | + |
| Arthritis/joint swelling | + | + | + | + with contractures | + oligoarticular, mostly distal/small joints | + episodic, oligoarticular, small and large joints | + | + | + polyarthritis, recurrent, self-limited | + |
| Rash/urticarial or pustular lesions | − | − | + | + erythematous | + maculopapular rash | − | + exanthema | + | + urticarial rash, pustulosis, neutrophilic dermatosis | + urticarial rash |
| Vasculitis | + | + | − | − | + IgG-vasculitis like | − | − | − | − | − |
| Lymphadenopathy/organomegaly | − | − | − | + | + | − | − | − | − | − |
| Aphthous ulcers/mucosal involvement | − | + | − | + | − | − | − | − | + | − |
| Growth failure/poor growth | + | + | + | + | − | − | − | + | − | − |
| Other systemic (GI, renal, etc.) issues | + celiac disease | + abdominal pain | + nephrotic syndrome | − | − | − | − | − | + abdominal pain 1–2×/mo, since 2016, without diarrhea and fever | − |
| Neurologic features | ||||||||||
| Developmental delay/regression | + | + | − | + cognitive and motor retardation | + | + | − | − | + | − |
| Seizures (type/frequency) | + | + convulsion (1 year of age), generalized seizure (24 years of age) | + one episode of seizures with status epilepticus | + febrile convulsion | + | − | + several tonic-clonic seizures | + generalized seizure | + seizures from 1 mo of age, initially myoclonus and fixed gaze; status epilepticus at 3 and 6 mo; later focal epilepsy with absence seizures | − |
| Autoimmune/autoinflammatory) encephalitis | − | − | − | − | − | + | − | − | − | − |
| MRI/CT findings | + frontal/temporal infarction involving basal ganglia due to cerebral intermediate-vessel vasculitis; hyperdense lesions in basal ganglia and corona radiata | + multiple white matter lesions in brain and spinal cord | Normal | + cerebral and white matter atrophy with ventriculomegaly, bilateral thalamic lesions, corpus collosum thinning, and right hippocampal sclerosis; stable chronic encephalomalacic changes | + brain atrophy, ventriculomegaly/hydrocephalus, lenticular/thalamic lesions, maculopathy | + brain atrophy, ventriculomegaly, lenticular/thalamic lesions | + mild diffuse cerebral edema, hyperdense internal veins, and bilateral thalami hypodensities | − | + hippocampal sclerosis; white matter abnormalities (periventricular, parietal); thalamic atrophy; cavitary sequelae of both lenticular nuclei and the right pulvinar | − |
| Other | + stenosis/occlusion of carotid artery; frontal gliosis | + MS-like disease | | | + microcephaly | + microcephaly, bilateral central visual impairment, delayed motor development, persistent urinary incontinence | + urinary incontinence | − | + microcephaly (z −3); impaired fine motor skills; bilateral maculopathy | − |
| Viral encephalitis/infections | ||||||||||
| Viral encephalitis | − | − | − | + ANEC and ARDS triggered by influenza A/H1N1 | + influenza B | + influenza B, hemorrhagic encephalitis | − | − | − | − |
| Other overt viral infections | + two episodes of severe rhabdomyolysis following viral infection with undefined enterovirus | − | − | − | − | + CMV (5 mo) | − | + influenza | + recurrent HSV-1 (up to 2×/mo, 2010–2018; cheek, labial, oral) | − |
| Vaccine tolerance/adverse reactions | − | − | − | − | − | − | − | Not reported | − | − |
| Treatment and response | ||||||||||
| Corticosteroids | + | + | + | + | + | + | + | + | − | + |
| Anakinra/Canakinumab | − | + | − | + | − | − | Not reported | − | − | − |
| Anti-TNF (adalimumab, infliximab, etanercept) | + | + | + | − | + | + | Not reported | + | + | + |
| DMARDs/immuno-suppressants (MTX, AZA, THAL, COL) | + MTX, AZA, THAL, COL | − | − | − | − | − | + MTX | + MTX | + COL | + MTX |
| Antivirals | − | − | − | + enfluvir | − | − | + acyclovir | − | + acyclovir | − |
| Treatment efficacy | Was responsive to infliximab | Adverse allergic reaction to infliximab and adalimumab; systemic symptoms partially controlled with anakinra and prednisone | | Systemic symptoms partially responsive to canakinumab; minimal corticosteroid response; encephalitic episodes refractory | Unresponsive to corticosteroids, partial resolution of fever, arthritis, and skin involvement following treatment with adalimumab | Good initial response to corticosteroids; partial improvement of arthritis and fever under adalimumab therapy; severe neurologic damage following influenza B–associated encephalitis | Prednisolone and methotrexate resolved arthritis | Systemic disease partially controlled with adalimumab; neurologically stable | Partial response to adalimumab with overall improvement, but persistence of brief articular pain episodes and low-grade inflammatory syndrome; neurologic features persist | Arthritis flares under etanercept and acute phase reactants remain elevated, switching to adalimumab |
| Outcome | ||||||||||
| Alive | | + | | | | + | | + | + | + |
| Deceased (cause) | + cause unknown | | | + from influenza A–associated ADEM | + from influenza B–associated encephalitis | | + SARS-CoV-2–asscoiated multi-organ insufficiency | | | |
| Lost to follow-up | | | + | | | | | | | |
| Individual | Family 1 | Family 2 | Family 3 | Family 4 | Family 5 | Family 6 | Family 7 | |||
|---|---|---|---|---|---|---|---|---|---|---|
| P1 | P2 | P3 | P4 | P5 | P6 | P7 | P8 | P9 | P10 | |
| TBK1 variant | p.W619* | p.W619* | p.Y212D | p.R440* | p. R574Sfs*11 | p. R574Sfs*11 | p. R574Sfs*11 | p.R440* | p.T77_L180del | p.L717Sfs*18 |
| cDNA annotation | c.1857G>A | c.1857G>A | c.634T>G | c.1318C>T | c.1760+4_1760+7del | c.1760+4_1760+7del | c.1760+4_1760+7del | c.1318C>T | c.228+?_540-?del | c.2150_2153del |
| Transcript reference (GRCh38) | g.64497045 G>A | g.64497045 G>A | g.64474323 T>G | g.64485995 C>T | g. 64496403-ATAAG-A | g. 64496403-ATAAG-A | g. 64496403-ATAAG-A | g.64485995 C>T | g.64463877_64473125del | g.64501340 TTAAC>T |
| gnomAD (v.4.1.0) frequency | 6.21E-07 | 6.21E-07 | Private | 1.89E-06 | 7.94E-07 | 7.94E-07 | 7.94E-07 | 1.89E-06 | Private | Private |
| Predicted consequence/CADD PHRED (GRCh38-v1.7; MSC = 10.854) | 39 | 39 | 30 | 36 | Predicted LoF (frameshift) | Predicted LoF (frameshift) | Predicted LoF (frameshift) | 36 | Predicted LoF (deletion of exons 4–5) | Predicted LoF (frameshift) |
| Age at last evaluation (years)/Sex | 34/F | 26/M | 7/M | 11.9/F | 2.4/F | 1.6/F | 3.5/F | 4.5/M | 19/M | 5/F |
| Recurrent fever | + | + | − | + | + | + | − | + | + | + |
| Arthritis/joint swelling | + | + | + | + with contractures | + oligoarticular, mostly distal/small joints | + episodic, oligoarticular, small and large joints | + | + | + polyarthritis, recurrent, self-limited | + |
| Rash/urticarial or pustular lesions | − | − | + | + erythematous | + maculopapular rash | − | + exanthema | + | + urticarial rash, pustulosis, neutrophilic dermatosis | + urticarial rash |
| Vasculitis | + | + | − | − | + IgG-vasculitis like | − | − | − | − | − |
| Lymphadenopathy/organomegaly | − | − | − | + | + | − | − | − | − | − |
| Aphthous ulcers/mucosal involvement | − | + | − | + | − | − | − | − | + | − |
| Growth failure/poor growth | + | + | + | + | − | − | − | + | − | − |
| Other systemic (GI, renal, etc.) issues | + celiac disease | + abdominal pain | + nephrotic syndrome | − | − | − | − | − | + abdominal pain 1–2×/mo, since 2016, without diarrhea and fever | − |
| Developmental delay/regression | + | + | − | + cognitive and motor retardation | + | + | − | − | + | − |
| Seizures (type/frequency) | + | + convulsion (1 year of age), generalized seizure (24 years of age) | + one episode of seizures with status epilepticus | + febrile convulsion | + | − | + several tonic-clonic seizures | + generalized seizure | + seizures from 1 mo of age, initially myoclonus and fixed gaze; status epilepticus at 3 and 6 mo; later focal epilepsy with absence seizures | − |
| Autoimmune/autoinflammatory) encephalitis | − | − | − | − | − | + | − | − | − | − |
| MRI/CT findings | + frontal/temporal infarction involving basal ganglia due to cerebral intermediate-vessel vasculitis; hyperdense lesions in basal ganglia and corona radiata | + multiple white matter lesions in brain and spinal cord | Normal | + cerebral and white matter atrophy with ventriculomegaly, bilateral thalamic lesions, corpus collosum thinning, and right hippocampal sclerosis; stable chronic encephalomalacic changes | + brain atrophy, ventriculomegaly/hydrocephalus, lenticular/thalamic lesions, maculopathy | + brain atrophy, ventriculomegaly, lenticular/thalamic lesions | + mild diffuse cerebral edema, hyperdense internal veins, and bilateral thalami hypodensities | − | + hippocampal sclerosis; white matter abnormalities (periventricular, parietal); thalamic atrophy; cavitary sequelae of both lenticular nuclei and the right pulvinar | − |
| Other | + stenosis/occlusion of carotid artery; frontal gliosis | + MS-like disease | | | + microcephaly | + microcephaly, bilateral central visual impairment, delayed motor development, persistent urinary incontinence | + urinary incontinence | − | + microcephaly (z −3); impaired fine motor skills; bilateral maculopathy | − |
| Viral encephalitis | − | − | − | + ANEC and ARDS triggered by influenza A/H1N1 | + influenza B | + influenza B, hemorrhagic encephalitis | − | − | − | − |
| Other overt viral infections | + two episodes of severe rhabdomyolysis following viral infection with undefined enterovirus | − | − | − | − | + CMV (5 mo) | − | + influenza | + recurrent HSV-1 (up to 2×/mo, 2010–2018; cheek, labial, oral) | − |
| Vaccine tolerance/adverse reactions | − | − | − | − | − | − | − | Not reported | − | − |
| Corticosteroids | + | + | + | + | + | + | + | + | − | + |
| Anakinra/Canakinumab | − | + | − | + | − | − | Not reported | − | − | − |
| Anti-TNF (adalimumab, infliximab, etanercept) | + | + | + | − | + | + | Not reported | + | + | + |
| DMARDs/immuno-suppressants (MTX, AZA, THAL, COL) | + MTX, AZA, THAL, COL | − | − | − | − | − | + MTX | + MTX | + COL | + MTX |
| Antivirals | − | − | − | + enfluvir | − | − | + acyclovir | − | + acyclovir | − |
| Treatment efficacy | Was responsive to infliximab | Adverse allergic reaction to infliximab and adalimumab; systemic symptoms partially controlled with anakinra and prednisone | | Systemic symptoms partially responsive to canakinumab; minimal corticosteroid response; encephalitic episodes refractory | Unresponsive to corticosteroids, partial resolution of fever, arthritis, and skin involvement following treatment with adalimumab | Good initial response to corticosteroids; partial improvement of arthritis and fever under adalimumab therapy; severe neurologic damage following influenza B–associated encephalitis | Prednisolone and methotrexate resolved arthritis | Systemic disease partially controlled with adalimumab; neurologically stable | Partial response to adalimumab with overall improvement, but persistence of brief articular pain episodes and low-grade inflammatory syndrome; neurologic features persist | Arthritis flares under etanercept and acute phase reactants remain elevated, switching to adalimumab |
| Alive | | + | | | | + | | + | + | + |
| Deceased (cause) | + cause unknown | | | + from influenza A–associated ADEM | + from influenza B–associated encephalitis | | + SARS-CoV-2–asscoiated multi-organ insufficiency | | | |
| Lost to follow-up | | | + | | | | | | | |
LoF, loss of function; GI, gastrointestinal; MRI, magnetic resonance imaging; CT, computed tomography; ANEC, acute necrotizing encephalopathy of childhood; ARDS, acute respiratory distress syndrome; CMV, cytomegalovirus; ADEM, acute disseminated encephalomyelitis; DMARDs, disease-modifying antirheumatic drugs; MTX, methotrexate; AZA, azathioprine; THAL, thalidomide; COL, colchicine; HSV-1, herpes simplex virus type 1; CADD, combined annotation dependent depletion; PHRED, Phred-scaled CADD score; MSC, mutation significance cutoff.
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