FASTKD5-Related COX Deficiency

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Inheritance

1

Autosomal recessive

Show evidence (1 reference)

PMID:40499538 SUPPORT Human Clinical

"compound heterozygous variants of unknown significance in FASTKD5"

The clinical series identified biallelic variants, with functional studies supporting disease causality.

⚙

Pathophysiology

10

Reduced FASTKD5 protein abundance

Patient fibroblasts have reduced steady-state FASTKD5. The p.Tyr125Cys allele destabilizes the protein while retaining partial function; the two frameshift alleles are predicted to alter translation. Reduced abundance is distinct from functional failure of a stably expressed missense protein.

FASTKD5 hgnc:25790

Experimental models

Patient-derived immortalized fibroblasts CELL LINE

Downstream

Impaired noncanonical mitochondrial RNA processing Reduced functional FASTKD5 limits maturation of susceptible mitochondrial transcripts.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"Immunoblot analysis of fibroblasts showed decreased steady-state levels of FASTKD5 protein in two subjects for whom fibroblast cultures were available: 24% of con- trols in subject 1 and 45% of controls in subject 2 (Figures 2A and 2B),"

Patient fibroblasts from subjects 1 and 2 have reduced FASTKD5 protein abundance.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"The p.Tyr125Cys FASTKD5 protein was unstable, as it was ex- pressed at levels significantly lower than the WT protein in fibroblasts from both the subjects and control individ- uals (Figure 4A). However, expression of this variant was able to double the COX activity in subject 2 (from 32% to..."

The p.Tyr125Cys protein is unstable but retains activity: overexpression partly restores COX activity in subject 2 cells.

Loss of FASTKD5 processing function

The patient p.Arg404Cys and p.Leu634Pro proteins fail to restore CO1 expression or COX activity despite wild-type-comparable expression. Recombinant experiments establish intrinsic FASTKD5 endonuclease activity. Engineered D429N impairs cleavage while retaining RNA binding; it is a mechanistic probe, not a reported patient allele.

FASTKD5 hgnc:25790

RNA endonuclease activity GO:0004521 ↓ DECREASED

Downstream

Impaired noncanonical mitochondrial RNA processing Loss of processing function disrupts maturation of the noncanonical substrates.

Show evidence (3 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"We were able to express the p.Arg404Cys and p.Leu634Pro FASTKD5 protein to the same level as WT- FASTKD5; however, expression of either variant was unable to rescue the MT-CO1 expression in the subjects’ cells (Figure 4A) or COX activity (Figure 4B), supporting that these variants result in the..."

The two missense proteins fail functional complementation despite expression comparable to wild type.

PMID:40637235 SUPPORT In Vitro

"We demonstrate unequivocally, using an in vitro reconstituted system, that FASTKD5 possesses intrinsic activity sufficient to correctly process three different synthetic pre-mRNA substrates of the primary polycistronic mitochondrial transcript."

Purified FASTKD5 cleaves its noncanonical RNA substrates directly.

PMID:40637235 SUPPORT In Vitro

"The results indicate that both WT FASTKD5 and the D429N mutant can bind substrate RNAs with comparable affinities"

RNA binding and cleavage can be experimentally separated.

Impaired noncanonical mitochondrial RNA processing

Cleavage at the CO1 5-prime end and ATP8/6-CO3 junction is severely impaired in patient fibroblasts. Precursors accumulate and mature CO1 and CO3 decline. Mature CYB remains available with residual FASTKD5 function; complete knockout also disrupts ND5-CYB processing. CO3 can still be translated from the tricistronic precursor, so impaired processing does not imply loss of every encoded protein.

mitochondrial mRNA processing GO:0090615 ↓ DECREASED

Experimental models

Patient-derived immortalized fibroblasts CELL LINE

Complete FASTKD5 knockout in 143B and HEK293T cells CELL LINE

Downstream

Reduced CO1 translation Failure to mature CO1 RNA impairs its translation.

Reduced CYB translation in complete-knockout cells Complete loss additionally impairs CYB translation; this branch is restricted to null cell models.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"the accumulation of unprocessed 5 ′ end MT-CO1, MT-ATP8/6-CO3, and MT-ND5-CYB transcripts, with a lack of mature MT-CO1 and MT-CO3 (Figure 2E), but normal levels of mature MT-CYB, suggesting that residual activity of the FASTKD5 variants in the subjects’ fibro- blasts was sufficient to process..."

Processing defects preferentially deplete mature CO1 and CO3; residual function preserves mature CYB in patient fibroblasts.

PMID:40637235 SUPPORT In Vitro

"The translation of CO3 was, however, not affected in the KO cells, although the level of the mature CO3 mRNA was virtually undetectable by Northern blot. This directly demonstrates that CO3 encoded by a tricistronic mRNA (ATP8/6-CO3) can be synthesized by the mitochondrial ribosome as has been..."

Unprocessed RNA is not uniformly untranslatable: CO3 translation persists.

Reduced CO1 translation

Failure to remove the CO1 5-prime extension strongly reduces synthesis of the mtDNA-encoded CO1 catalytic subunit in patient fibroblasts and complete-knockout cells.

mitochondrial translation GO:0032543 ↓ DECREASED

Experimental models

FASTKD5-disrupted HAP1 cells CELL LINE

Downstream

Reduced complex IV assembly Insufficient CO1 limits accumulation of the assembled complex IV holoenzyme.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"The lack of mature MT-CO1 mRNA resulted in a substan- tial decrease in the synthesis of the MT-CO1 polypeptide (Figures 2F and S3)."

Loss of mature CO1 RNA reduces synthesis of its encoded protein.

PMID:40637235 SUPPORT In Vitro

"Quantification of these results (Supplementary Fig. S1F) showed that the translation of CO1 and CYB was specifically decreased, to near zero, consistent with the results of the Northern blot analysis (Fig. 1C) demonstrating that the presence of 5′-UTRs on these transcripts prevents translation..."

Complete knockout causes a broader translation defect than the residual-function patient cells.

Reduced complex IV assembly

Fully assembled complex IV is reduced in patient fibroblasts without detectable abnormal subcomplex accumulation. Wild-type FASTKD5 complementation restores assembly.

mitochondrial respiratory chain complex IV assembly GO:0033617 ↓ DECREASED

Experimental models

Patient-derived immortalized fibroblasts CELL LINE

Downstream

Reduced complex IV activity Reduced holoenzyme abundance lowers cytochrome c oxidase activity.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"This resulted in a severe decrease in the steady-state levels of the cytochrome c ox- idase subunit 1 (MT-CO1; Figures 2A and 2B), a conse- quent reduction in the level of the fully assembled COX complex (complex IV; Figure 2C), and reduced COX enzy- matic activity (Figure 2D)."

Patient fibroblasts show reduced fully assembled complex IV and COX enzymatic activity.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"Stable expres- sion of FLAG-tagged FASTKD5 protein (to 1.6 and 4.2 times of endogenous control FASTKD5 levels in subjects 1 and 2, respectively; Figures 2A and 2B) resulted in the rescue of MT-CO1 and MT-CO3 processing (Figures 2E and 3), an increase in the translation of the MT-CO1 poly-..."

Wild-type complementation rescues RNA processing, CO1 translation, complex IV assembly and activity in patient cells.

Reduced complex IV activity

COX enzymatic activity is reduced in affected fibroblasts and muscle. The patient fibroblast defect is predominantly complex IV; subject 3 muscle also has abnormal combined I+III and II+III assays.

mitochondrial electron transport, cytochrome c to oxygen GO:0006123 ↓ DECREASED

Downstream

Impaired mitochondrial respiration The complex IV deficit compromises respiration, demonstrated directly in engineered cells.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"This resulted in a severe decrease in the steady-state levels of the cytochrome c ox- idase subunit 1 (MT-CO1; Figures 2A and 2B), a conse- quent reduction in the level of the fully assembled COX complex (complex IV; Figure 2C), and reduced COX enzy- matic activity (Figure 2D)."

Patient fibroblasts show reduced fully assembled complex IV and COX enzymatic activity.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"The activity of the OXPHOS complexes was measured in a muscle biopsy specimen from subject 3. This analysis showed a severe deficiency in complex IV activity. Addition- ally, complex II activity was profoundly increased, while complex II+III activity was only slightly elevated, indicating a..."

Subject 3 muscle has severe complex IV deficiency and additional combined-assay abnormalities; an isolated defect is not universal.

Impaired mitochondrial respiration

FASTKD5-disrupted HAP1 cells have markedly reduced oxygen consumption. Respiratory-chain dysfunction provides a mechanistic context for the Leigh phenotype, but the intermediates producing individual brain lesions and clinical findings remain incompletely resolved. These assays do not directly establish neuronal ATP depletion in patients.

aerobic respiration GO:0009060 ↓ DECREASED

Experimental models

FASTKD5-disrupted HAP1 cells CELL LINE

Downstream

Developmental regression Mitochondrial disease is associated with loss of acquired skills in the severe early-onset case; specific neural intermediates are unmeasured.

Brainstem lesions Leigh brainstem injury accompanies the respiratory-chain disorder; lesion-specific intermediates remain uncertain.

Basal ganglia lesions Basal ganglia lesions occur in the clinical syndrome without a demonstrated cell-specific injury cascade.

Lactic acidosis Severe metabolic decompensation with lactate accumulation occurs in affected disease; exact flux changes were not measured in patients.

Global developmental delay The clinical series associates the respiratory-chain disorder with this neurological manifestation; the cellular and tissue intermediates are not directly established.

Hypotonia The clinical series associates the respiratory-chain disorder with this neurological manifestation; the cellular and tissue intermediates are not directly established.

Show evidence (1 reference)

PMID:34748562 SUPPORT In Vitro

"In contrast, oxygen consumption was dramatically reduced in both the FASTKD5-sKO and the FASTKD4&5-dKO cells."

Respiration was directly measured in engineered HAP1 cells; it was not a patient neuronal ATP assay.

Reduced CYB translation in complete-knockout cells

Complete FASTKD5 knockout prevents efficient translation of unprocessed CYB RNA in 143B and HEK293T models. This additional defect is not established in residual-function patient fibroblasts, where mature CYB and complex III assembly are preserved.

mitochondrial translation GO:0032543 ↓ DECREASED

Experimental models

Complete FASTKD5 knockout in 143B and HEK293T cells CELL LINE

Downstream

Reduced complex III assembly in complete-knockout cells Loss of cytochrome b synthesis prevents complex III assembly in null models.

Show evidence (2 references)

PMID:40637235 SUPPORT In Vitro

"Quantification of these results (Supplementary Fig. S1F) showed that the translation of CO1 and CYB was specifically decreased, to near zero, consistent with the results of the Northern blot analysis (Fig. 1C) demonstrating that the presence of 5′-UTRs on these transcripts prevents translation..."

Complete knockout causes a broader translation defect than the residual-function patient cells.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"the accumulation of unprocessed 5 ′ end MT-CO1, MT-ATP8/6-CO3, and MT-ND5-CYB transcripts, with a lack of mature MT-CO1 and MT-CO3 (Figure 2E), but normal levels of mature MT-CYB, suggesting that residual activity of the FASTKD5 variants in the subjects’ fibro- blasts was sufficient to process..."

Processing defects preferentially deplete mature CO1 and CO3; residual function preserves mature CYB in patient fibroblasts.

Reduced complex III assembly in complete-knockout cells

Complex III assembly fails in complete-knockout cells. The broader null-model defect must not be assumed in every patient tissue.

Experimental models

Complete FASTKD5 knockout in 143B and HEK293T cells CELL LINE

Downstream

Impaired mitochondrial respiration The additional complex III defect contributes to the severe null-model OXPHOS impairment.

Secondary complex I loss in complete-knockout cells Assembled complex I depends on complex III in these cells.

Show evidence (2 references)

PMID:40637235 SUPPORT In Vitro

"Analysis of the assembly of the OXPHOS complexes by BN-PAGE demonstrated that complexes III and IV failed to assemble, as expected from the mitochondrial translation experiments (Fig. 1E)."

The additional complex III defect belongs to complete-knockout models.

PMID:40637235 SUPPORT In Vitro

"The complex I assembly defect can be ascribed to the complete absence of complex III, whose presence is necessary for the biogenesis/stability of complex I [36, 37]."

The authors interpret complex I loss as secondary to complex III failure.

Secondary complex I loss in complete-knockout cells

Assembled complex I is nearly absent in null models despite near-normal translation of its mtDNA-encoded subunits. This is interpreted as secondary to complex III deficiency, rather than defective maturation of complex I transcripts.

Downstream

Impaired mitochondrial respiration Additional complex I loss contributes to the respiratory-chain defect in null models.

Show evidence (1 reference)

PMID:40637235 SUPPORT In Vitro

"The complex I assembly defect can be ascribed to the complete absence of complex III, whose presence is necessary for the biogenesis/stability of complex I [36, 37]."

The authors attribute secondary complex I loss in null cells to absent complex III.

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Histopathology

1

Variable skeletal muscle pathology

Adult subject 2 had diffuse COX deficiency, small fibers and mild connective-tissue/inflammatory changes with multiple mtDNA deletions. Subject 3 had no significant routine pathologic abnormality and normal mtDNA content/sequence despite deficient enzymology; neither mtDNA depletion nor abnormal muscle histology is universal.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Muscle biopsy revealed modest myopathic changes, including diffuse cytochrome c oxidase (COX) defi- ciency, hypo-atrophic fibers, rare sandwich-type fibers, rare chronic inflammatory lymphomonocytes, and a slight increase in endomysial and perimysial connective tissue, ... deletions in mtDNA."

Subject 2 muscle had COX-deficient myopathic changes.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"age and showed no significant pathologic abnormalities with normal mitochondrial DNA content and sequencing."

Subject 3 routine muscle evaluation was normal.

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Pathograph

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Phenotypes

34

Cardiovascular 1

Ventricular septal hypertrophy HP:0005144

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Echocardiography and cardiac MRI showed interventricular septum hypertrophy."

Cardiac imaging documented the specific septal finding.

Digestive 2

Dysphagia HP:0002015

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"At the age of 14.5 months, the subject received a percutaneous endoscopic gastrostomy tube due to dysphagia."

Subject 1 required gastrostomy for dysphagia.

Gastroparesis HP:0002578

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"After 1 month, she was readmitted due to gastroparesis with aspi- ration pneumonia, which temporarily required orotracheal intu- bation. Prokinetic therapy was started."

The adult case had gastrointestinal dysmotility with aspiration requiring temporary intubation.

Eye 4

Nystagmus HP:0000639

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"showed nystagmus and esotropia but no retinal pathology."

Nystagmus and esotropia were reported in subject 1.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"vertical nystagmus in the primary position and horizontal nystagmus in bilateral gaze settings, and complete deficit of ocular pursuit movements in the vertical plane)."

Subject 2 also had nystagmus during the initial presentation.

Esotropia HP:0000565

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"showed nystagmus and esotropia but no retinal pathology."

Nystagmus and esotropia were reported in subject 1.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"mild convergent strabismus in the left eye with mild abduction deficit"

Subject 2 also had convergent strabismus at the adult presentation.

Ptosis HP:0000508

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Two months after discharge, the sub- ject had rigid-akinetic parkinsonism with severe axial rigidity, right foot dystonia, slight ideo-motor slowing, left eye stra- bismus, limitation of slow horizontal eye movements, a mild deficit of ocular pursuit movements in the vertical plane, binoc- ular..."

Subject 2 developed parkinsonism, foot dystonia, ocular motor abnormalities, reduced visual acuity and ptosis.

Visual impairment HP:0000505

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Ophthalmolog- ical examination showed no signs of retinopathy but profoundly reduced visual acuity with increased latency of visual evoked po- tentials."

The visual deficit was not attributed to retinopathy in the case report.

Head and Neck 9

Microcephaly HP:0000252

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url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"microcephaly with a fronto-occipital circumference of 41 cm"

The early-onset case had reduced head circumference.

Midface retrusion HP:0011800

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"dysmorphic facial features, including midfacial hypoplasia, prominent cheeks, micro/retrognathia, epicanthus, down-slanting palpebral fissures, smooth philtrum, and thin upper lip;"

These findings were reported in subject 3; facial features in subject 2 are confounded by a separate 1q21.1 deletion.

Micrognathia HP:0000347

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"dysmorphic facial features, including midfacial hypoplasia, prominent cheeks, micro/retrognathia, epicanthus, down-slanting palpebral fissures, smooth philtrum, and thin upper lip;"

These findings were reported in subject 3; facial features in subject 2 are confounded by a separate 1q21.1 deletion.

Retrognathia HP:0000278

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"dysmorphic facial features, including midfacial hypoplasia, prominent cheeks, micro/retrognathia, epicanthus, down-slanting palpebral fissures, smooth philtrum, and thin upper lip;"

These findings were reported in subject 3; facial features in subject 2 are confounded by a separate 1q21.1 deletion.

Epicanthus HP:0000286

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"dysmorphic facial features, including midfacial hypoplasia, prominent cheeks, micro/retrognathia, epicanthus, down-slanting palpebral fissures, smooth philtrum, and thin upper lip;"

These findings were reported in subject 3; facial features in subject 2 are confounded by a separate 1q21.1 deletion.

Downslanted palpebral fissures HP:0000494

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"dysmorphic facial features, including midfacial hypoplasia, prominent cheeks, micro/retrognathia, epicanthus, down-slanting palpebral fissures, smooth philtrum, and thin upper lip;"

These findings were reported in subject 3; facial features in subject 2 are confounded by a separate 1q21.1 deletion.

Smooth philtrum HP:0000319

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"dysmorphic facial features, including midfacial hypoplasia, prominent cheeks, micro/retrognathia, epicanthus, down-slanting palpebral fissures, smooth philtrum, and thin upper lip;"

These findings were reported in subject 3; facial features in subject 2 are confounded by a separate 1q21.1 deletion.

Thin upper lip vermilion HP:0000219

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"dysmorphic facial features, including midfacial hypoplasia, prominent cheeks, micro/retrognathia, epicanthus, down-slanting palpebral fissures, smooth philtrum, and thin upper lip;"

These findings were reported in subject 3; facial features in subject 2 are confounded by a separate 1q21.1 deletion.

Full cheeks HP:0000293

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"dysmorphic facial features, including midfacial hypoplasia, prominent cheeks, micro/retrognathia, epicanthus, down-slanting palpebral fissures, smooth philtrum, and thin upper lip;"

These findings were reported in subject 3; facial features in subject 2 are confounded by a separate 1q21.1 deletion.

Metabolism 3

Lactic acidosis HP:0003128

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"This was accompanied by severe lactic acidosis (pH 6, lactate: 28 mmol/ L)."

Severe lactic acidosis accompanied subject 1 respiratory decompensation.

Increased circulating lactate Increased circulating lactate concentration HP:0002151

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url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Blood lactate concentra- tions ranged from 3.3 to over 10 mmol/L (reference < 2.2 for venous samples)."

Subject 1 had variable hyperlactatemia.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Cerebrospinal fluid analysis was unre- markable except for a moderate elevation in lactate concentra- tion (4 mmol/L) and the presence of HHV-6 DNA. Blood lactate concentrations ranged from 2.6 to 3 mmol/L."

Subject 2 had elevated CSF and blood lactate.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"intermittent mild lactatemia as high as 4.2 mmol/L."

Subject 3 had intermittent mild lactatemia.

Increased CSF lactate HP:0002490

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Cerebrospinal fluid analysis was unre- markable except for a moderate elevation in lactate concentra- tion (4 mmol/L) and the presence of HHV-6 DNA. Blood lactate concentrations ranged from 2.6 to 3 mmol/L."

Subject 2 had elevated CSF and blood lactate.

Musculoskeletal 1

Hypotonia HP:0001252

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Neurodevelopmental features included hypoto- nia, gross motor skills under the 4-months-of-age skill level, and fine motor skills at the 6-months-of-age level,"

The subject 1 case description documents hypotonia and motor delay.

Nervous System 9

Global developmental delay HP:0001263

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url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Additional features include global developmental delay without regression, most notably in gross motor skills, first walking at age 2, and expressive speech, first babbling at 16 months and able to sign 20–30 words at 21 months;"

Subject 3 had global delay, particularly gross motor and expressive language development.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical

"may present with nonspecific features such as poor weight gain, feeding difficulties, persistent vomiting, hypotonia, and developmental delay."

General LSS clinical context agrees with the childhood case descriptions; these general cohort findings do not establish FASTKD5-specific frequencies.

Expressive language delay HP:0002474

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Additional features include global developmental delay without regression, most notably in gross motor skills, first walking at age 2, and expressive speech, first babbling at 16 months and able to sign 20–30 words at 21 months;"

Subject 3 had global delay, particularly gross motor and expressive language development.

Developmental regression HP:0002376

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"He had lost gross motor skills and his single non-specific word."

Subject 1 lost previously acquired motor and language skills; subject 3 had no reported regression at the available follow-up.

Parkinsonism HP:0001300

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Two months after discharge, the sub- ject had rigid-akinetic parkinsonism with severe axial rigidity, right foot dystonia, slight ideo-motor slowing, left eye stra- bismus, limitation of slow horizontal eye movements, a mild deficit of ocular pursuit movements in the vertical plane, binoc- ular..."

Subject 2 developed parkinsonism, foot dystonia, ocular motor abnormalities, reduced visual acuity and ptosis.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"the subject was breathing spontaneously and had no com- plaints of dysphagia, and parkinsonism had resolved."

The later adult assessment documents improvement rather than universal progression.

Dystonia HP:0001332

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Two months after discharge, the sub- ject had rigid-akinetic parkinsonism with severe axial rigidity, right foot dystonia, slight ideo-motor slowing, left eye stra- bismus, limitation of slow horizontal eye movements, a mild deficit of ocular pursuit movements in the vertical plane, binoc- ular..."

Subject 2 developed parkinsonism, foot dystonia, ocular motor abnormalities, reduced visual acuity and ptosis.

Brainstem lesions Focal T2 hyperintense brainstem lesion HP:0012748

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url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Axial T2-weighted brain MRI images (i–iii) of subject 1 (at 1 year of age) show abnormal hyperintense signal at the level of the entire brainstem, extending from the medulla to the midbrain and at the level of the putamina bilaterally."

The clinical figure documents T2 hyperintense brainstem and bilateral putaminal lesions.

Basal ganglia lesions Focal T2 hyperintense basal ganglia lesion HP:0007183

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url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Brain MRI (Figure 1E) at 31 months of age showed symmetric areas of abnormal T2 hyperintensity involving the bilateral basal ganglia, thalami, and dorsal medulla, consistent with Leigh syndrome."

Subject 3 had bilateral basal ganglia, thalamic and dorsal medullary T2 lesions.

Impaired executive functioning HP:0033051

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url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"she exhibited profound exercise intolerance, visual acuity loss, and executive dysfunction with reduced autonomy."

The adult case had persisting executive impairment.

Elevated brain lactate by MRS Elevated brain lactate level by MRS HP:0012707

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url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"with extension along the medial longitudinal fasciculus, with modest mass effect, linear enhancement, increased perfusion indices, and a lactic acid peak on spectroscopy."

Adult MRI and MRS support mitochondrial encephalopathy.

Respiratory 2

Respiratory failure HP:0002878

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url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"His final hospital admission followed a rhinovirus infection leading to acute respi- ratory failure that required mechanical ventilation."

Respiratory failure followed an intercurrent infection in the severe case.

Aspiration HP:0002835

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"After 1 month, she was readmitted due to gastroparesis with aspi- ration pneumonia, which temporarily required orotracheal intu- bation. Prokinetic therapy was started."

The adult case had gastrointestinal dysmotility with aspiration requiring temporary intubation.

Constitutional 1

Exercise intolerance HP:0003546

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"she exhibited profound exercise intolerance, visual acuity loss, and executive dysfunction with reduced autonomy."

Persistent adult functional limitations included exercise intolerance.

Growth 2

Failure to thrive HP:0001508

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"he developed a failure to thrive and had gastrostomy tube placement at 11 months of age."

Subject 3 developed poor growth requiring gastrostomy.

Small for gestational age HP:0001518

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Subject 3 (a male patient) was born small for gestational age after a full-term pregnancy complicated by preeclampsia."

The obstetric context limits attribution of the birth-size finding.

🧬

Genetic Associations

1

FASTKD5

Gene: FASTKD5 hgnc:25790

Autosomal recessive

Show evidence (3 references)

PMID:40499538 SUPPORT Human Clinical

"we identified three missense variants and two frameshift variants leading to a premature stop codon"

The study defines the reported allele spectrum.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"We were able to express the p.Arg404Cys and p.Leu634Pro FASTKD5 protein to the same level as WT- FASTKD5; however, expression of either variant was unable to rescue the MT-CO1 expression in the subjects’ cells (Figure 4A) or COX activity (Figure 4B), supporting that these variants result in the..."

The two missense proteins fail functional complementation despite expression comparable to wild type.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"The p.Tyr125Cys FASTKD5 protein was unstable, as it was ex- pressed at levels significantly lower than the WT protein in fibroblasts from both the subjects and control individ- uals (Figure 4A). However, expression of this variant was able to double the COX activity in subject 2 (from 32% to..."

The p.Tyr125Cys protein is unstable but retains activity: overexpression partly restores COX activity in subject 2 cells.

Variants (5)

NM_021826.5:c.1716dup Pathogenic

Gene: FASTKD5 hgnc:25790 insertion

p.Pro573Alafs*17. Subject 1 maternal frameshift allele, in trans with p.Leu634Pro.

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"c.1716dup (GenBank: NM_021826.5) (p.Pro573Alafs*17) and c.1901T>C (GenBank: NM_021826.5) (p.Leu634Pro) in FASTKD5 of maternal and paternal origin, respectively (Figure 1B)."

The clinical sequencing description gives the transcript, allele and phase.

NM_021826.5:c.1901T>C Pathogenic

Gene: FASTKD5 hgnc:25790 single nucleotide variant

p.Leu634Pro. Subject 1 paternal missense allele. The expressed mutant fails complementation despite wild-type-comparable abundance.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"c.1716dup (GenBank: NM_021826.5) (p.Pro573Alafs*17) and c.1901T>C (GenBank: NM_021826.5) (p.Leu634Pro) in FASTKD5 of maternal and paternal origin, respectively (Figure 1B)."

The clinical sequencing description gives the transcript, allele and phase.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"We were able to express the p.Arg404Cys and p.Leu634Pro FASTKD5 protein to the same level as WT- FASTKD5; however, expression of either variant was unable to rescue the MT-CO1 expression in the subjects’ cells (Figure 4A) or COX activity (Figure 4B), supporting that these variants result in the..."

The two missense proteins fail functional complementation despite expression comparable to wild type.

NM_021826.5:c.1210C>T Pathogenic

Gene: FASTKD5 hgnc:25790 single nucleotide variant

p.Arg404Cys. Subject 2 paternal missense allele. The expressed mutant fails complementation despite wild-type-comparable abundance.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Exome sequencing revealed the presence of c.1210C>T (GenBank: NM_021826.5) (p.Arg404Cys) (gnomAD allele frequency: 109/ 1,614,226 alleles, always heterozygous) and c.374A>G (GenBank: NM_021826.5) (p.Tyr125Cys) (gnomAD allele frequency: 7/1,614,184 alleles, always heterozygous) in FASTKD5 of..."

The clinical sequencing description gives the transcript, allele and phase.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"We were able to express the p.Arg404Cys and p.Leu634Pro FASTKD5 protein to the same level as WT- FASTKD5; however, expression of either variant was unable to rescue the MT-CO1 expression in the subjects’ cells (Figure 4A) or COX activity (Figure 4B), supporting that these variants result in the..."

The two missense proteins fail functional complementation despite expression comparable to wild type.

NM_021826.5:c.374A>G Pathogenic

Gene: FASTKD5 hgnc:25790 single nucleotide variant

p.Tyr125Cys. Shared by subjects 2 and 3; maternally inherited in subject 2. The protein is unstable but hypomorphic, with partial rescue on overexpression.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Exome sequencing revealed the presence of c.1210C>T (GenBank: NM_021826.5) (p.Arg404Cys) (gnomAD allele frequency: 109/ 1,614,226 alleles, always heterozygous) and c.374A>G (GenBank: NM_021826.5) (p.Tyr125Cys) (gnomAD allele frequency: 7/1,614,184 alleles, always heterozygous) in FASTKD5 of..."

The clinical sequencing description gives the transcript, allele and phase.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"The p.Tyr125Cys FASTKD5 protein was unstable, as it was ex- pressed at levels significantly lower than the WT protein in fibroblasts from both the subjects and control individ- uals (Figure 4A). However, expression of this variant was able to double the COX activity in subject 2 (from 32% to..."

The p.Tyr125Cys protein is unstable but retains activity: overexpression partly restores COX activity in subject 2 cells.

NM_021826.5:c.2028_2029del Pathogenic

Gene: FASTKD5 hgnc:25790 deletion

p.Ala678Hisfs*79. Subject 3 frameshift allele, in trans with p.Tyr125Cys; the frameshift alters the C-terminal translated sequence.

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Exome sequencing at 14 months of age demonstrated c.2028_2029del (GenBank: NM_021826.5) (p.Ala678Hisfs*79) (gnomAD allele frequency: 8/1,614,088 alleles, always heterozygous) and c.374 A>G (Gen- Bank: NM_021826.5) (p.Tyr125Cys) (gnomAD allele frequency: 7/1,614,184 alleles, always heterozygous)..."

The clinical sequencing description gives the transcript, allele and phase.

💊

Medical Actions

12

Multidisciplinary supportive care

Action: Supportive Care NCIT:C15747

Care is directed to neurological, feeding, respiratory, visual, cardiac and developmental complications. General Leigh syndrome spectrum recommendations provide a framework; no disease-modifying treatment was established by the three-case study.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical

"Supportive care to improve quality of life, maximize function, and reduce complications is recommended."

General LSS supportive-care guidance.

Feeding support and gastrostomy

Action: Gastrostomy Tube Procedure NCIT:C157864

Swallowing assessment, nutritional support and gastrostomy may be needed. Both childhood cases received gastrostomy; aspiration risk warrants assessment.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"At the age of 14.5 months, the subject received a percutaneous endoscopic gastrostomy tube due to dysphagia."

Gastrostomy was used for subject 1 dysphagia.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"he developed a failure to thrive and had gastrostomy tube placement at 11 months of age."

Subject 3 also required feeding support.

Respiratory support

Action: Mechanical Ventilation NCIT:C70909

Provide respiratory assessment and ventilatory support during compromise. Both the severe child and adult case required mechanical airway support during acute complications.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"His final hospital admission followed a rhinovirus infection leading to acute respi- ratory failure that required mechanical ventilation."

Subject 1 required mechanical ventilation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical

"Ventilatory support for persons w/LSS ... respiratory compromise"

General LSS care supports ventilation when respiratory compromise is present.

Management of metabolic acidosis

Action: Pharmacotherapy NCIT:C15986

Specialist-directed correction of significant acidosis follows general LSS guidance. IV acetate and enteral sodium citrate/citric acid did not correct acidosis in subject 1; reported use does not establish efficacy for FASTKD5 deficiency.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Supplemental alkali from acetate administered intravenously (i.v.) or enteral sodium citrate/citric acid did not shift the lactate concentration or correct the acidosis."

Alkali therapy failed to correct subject 1 acidosis.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical

"Sodium bicarbonate or sodium citrate for significant acidosis"

General LSS management recommendation.

Symptomatic movement-disorder treatment

Action: Pharmacotherapy NCIT:C15986

The adult case received a dopamine agonist. Parkinsonism later resolved, but concurrent therapies and the uncontrolled course prevent attribution to a specific drug. Dystonia management should be individualized.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"She was treated with a dopamine agonist and idebenone."

The adult patient received symptomatic dopaminergic treatment.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"the subject was breathing spontaneously and had no com- plaints of dysphagia, and parkinsonism had resolved."

The adult course showed later improvement without a controlled efficacy assessment.

Treatment of gastrointestinal dysmotility

Action: Pharmacotherapy NCIT:C15986

Prokinetic treatment was used for adult gastroparesis after an aspiration complication; monitor nutritional intake and swallowing safety.

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"After 1 month, she was readmitted due to gastroparesis with aspi- ration pneumonia, which temporarily required orotracheal intu- bation. Prokinetic therapy was started."

Reported symptomatic treatment of gastroparesis.

Empiric mitochondrial supplements

Action: Pharmacotherapy NCIT:C15986

Agent: riboflavin CHEBI:17015 coenzyme Q10 CHEBI:46245 idebenone CHEBI:31687

Riboflavin and coenzyme Q10 were given initially to subject 2, and idebenone later. The report does not establish FASTKD5-specific efficacy of these agents.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"At this point, i.v. immunoglobulin, i.v. steroids, and a mitochon- drial cocktail (100 mg/day riboflavin and 600 mg/day CoQ10) were administered."

The adult case received multiple empiric therapies.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"She was treated with a dopamine agonist and idebenone."

Idebenone was another reported intervention; benefit cannot be separated from other treatment or natural fluctuation.

Empiric immunotherapy during initial adult evaluation

IV immunoglobulin and corticosteroids were administered during the initial adult presentation. They are reported historical interventions, without evidence of disease-modifying efficacy for the genetic RNA-processing disorder.

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"At this point, i.v. immunoglobulin, i.v. steroids, and a mitochon- drial cocktail (100 mg/day riboflavin and 600 mg/day CoQ10) were administered."

Records the empiric interventions without recommending them for FASTKD5 deficiency.

Developmental, visual and cardiac follow-up

Provide physical and occupational therapy, communication support, ophthalmologic care and cardiology follow-up according to manifestations. General LSS surveillance includes regular neurological, eye, hearing and cardiac assessment.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical

"Neurologic, ophthalmologic, audiologic, and cardiologic evaluations are recommended"

General LSS surveillance framework.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical

"Equipment to prevent falling, maintain independent mobility as appropriate"

Rehabilitation aims to preserve safe function.

Perioperative and metabolic precautions

General mitochondrial-disease guidance recommends limiting fasting and catabolism, assessing anesthetic respiratory risk, avoiding lactate-containing fluids when acidosis is a risk, and avoiding valproate when possible. The absolute POLG-specific valproate contraindication is not a FASTKD5-specific finding.

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical

"Catabolism should be prevented by minimizing preoperative fasting"

General LSS perioperative recommendation.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical

"Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes."

General LSS medication caution.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical

"Avoid lactate-containing agents (e.g., Ringer's lactate) in those at risk of lactic acidosis"

General LSS guidance addresses patients at risk of lactic acidosis.

Genetic counseling and reproductive options

Action: Genetic Counseling NCIT:C15240

For confirmed autosomal recessive disease with both parents carrying a familial variant, recurrence risk is 25% per pregnancy. Offer segregation/carrier testing and discuss prenatal or preimplantation testing once the familial variants are established.

Show evidence (2 references)

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical

"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic ... carrier ... and a 25% chance of being unaffected and not a carrier."

The general recessive LSS counseling model applies to established biallelic FASTKD5 disease.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical

"Once the LSS-related ... have been identified in an affected family member, prenatal and ... preimplantation genetic testing ... are possible."

General LSS guidance permits prenatal and preimplantation testing after familial variants are identified.

Experimental FASTKD5 complementation and protein stabilization concept

Wild-type gene complementation rescues patient fibroblast defects. Overexpressed p.Tyr125Cys partly restores COX activity, motivating a proposal to stabilize that protein. No stabilizing compound or clinical gene therapy was tested in this report.

Show evidence (3 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"Stable expres- sion of FLAG-tagged FASTKD5 protein (to 1.6 and 4.2 times of endogenous control FASTKD5 levels in subjects 1 and 2, respectively; Figures 2A and 2B) resulted in the rescue of MT-CO1 and MT-CO3 processing (Figures 2E and 3), an increase in the translation of the MT-CO1 poly-..."

Wild-type complementation rescues RNA processing, CO1 translation, complex IV assembly and activity in patient cells.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"The p.Tyr125Cys FASTKD5 protein was unstable, as it was ex- pressed at levels significantly lower than the WT protein in fibroblasts from both the subjects and control individ- uals (Figure 4A). However, expression of this variant was able to double the COX activity in subject 2 (from 32% to..."

The p.Tyr125Cys protein is unstable but retains activity: overexpression partly restores COX activity in subject 2 cells.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"Stabilizing this variant could poten- tially ameliorate the clinical phenotype in this subject."

Protein stabilization is a proposed strategy, not a demonstrated treatment.

🔬

Biochemical Markers

2

Reduced cytochrome c oxidase activity (Decreased)

Context: Patient fibroblasts have predominantly complex IV deficiency; subject 3 muscle also has abnormal combined respiratory-chain assays. Normal routine muscle morphology does not exclude the enzymatic defect.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"This resulted in a severe decrease in the steady-state levels of the cytochrome c ox- idase subunit 1 (MT-CO1; Figures 2A and 2B), a conse- quent reduction in the level of the fully assembled COX complex (complex IV; Figure 2C), and reduced COX enzy- matic activity (Figure 2D)."

Patient fibroblasts show reduced fully assembled complex IV and COX enzymatic activity.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"The activity of the OXPHOS complexes was measured in a muscle biopsy specimen from subject 3. This analysis showed a severe deficiency in complex IV activity. Addition- ally, complex II activity was profoundly increased, while complex II+III activity was only slightly elevated, indicating a..."

Subject 3 muscle has severe complex IV deficiency and additional combined-assay abnormalities; an isolated defect is not universal.

Elevated blood and cerebrospinal-fluid lactate (Increased)

Context: Blood lactate was elevated in all three reported cases with variable magnitude. CSF lactate and an MRS lactate peak were documented in the adult case. Mild lactatemia is distinct from the severe acidosis of subject 1.

Show evidence (3 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Blood lactate concentra- tions ranged from 3.3 to over 10 mmol/L (reference < 2.2 for venous samples)."

Subject 1 had variable hyperlactatemia.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Cerebrospinal fluid analysis was unre- markable except for a moderate elevation in lactate concentra- tion (4 mmol/L) and the presence of HHV-6 DNA. Blood lactate concentrations ranged from 2.6 to 3 mmol/L."

Subject 2 had elevated CSF and blood lactate.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"intermittent mild lactatemia as high as 4.2 mmol/L."

Subject 3 had intermittent mild lactatemia.

🔬

Diagnosis

4

Molecular diagnosis and family segregation

Identify biallelic FASTKD5 variants by genomic testing and establish phase. The clinical series used exome sequencing; general Leigh syndrome spectrum guidance favors genome sequencing when available to assess both nuclear and mitochondrial causes.

Genetic Testing NCIT:C15709

Show evidence (2 references)

PMID:40499538 SUPPORT Human Clinical

"Using exome sequencing, we identified compound heterozygous variants of unknown significance in FASTKD5"

Exome sequencing identified the candidate variants in the founding series.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/ SUPPORT Human Clinical

"Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate."

General LSS diagnostic guidance; the chapter does not contain a FASTKD5-specific section.

Brain MRI and magnetic resonance spectroscopy

Evaluate characteristic brainstem and basal ganglia lesions and possible thalamic involvement. MRS may show a lactate peak. These findings support Leigh syndrome spectrum but do not identify the causal gene.

Magnetic Resonance Imaging NCIT:C16809

Show evidence (3 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Axial T2-weighted brain MRI images (i–iii) of subject 1 (at 1 year of age) show abnormal hyperintense signal at the level of the entire brainstem, extending from the medulla to the midbrain and at the level of the putamina bilaterally."

The clinical figure documents T2 hyperintense brainstem and bilateral putaminal lesions.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"Brain MRI (Figure 1E) at 31 months of age showed symmetric areas of abnormal T2 hyperintensity involving the bilateral basal ganglia, thalami, and dorsal medulla, consistent with Leigh syndrome."

Subject 3 had bilateral basal ganglia, thalamic and dorsal medullary T2 lesions.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"with extension along the medial longitudinal fasciculus, with modest mass effect, linear enhancement, increased perfusion indices, and a lactic acid peak on spectroscopy."

Adult MRI and MRS support mitochondrial encephalopathy.

Respiratory-chain enzyme and muscle evaluation

Enzymology can support variant interpretation. Subject 2 had COX-deficient muscle histochemistry; subject 3 had normal routine pathology but severe complex IV enzymatic deficiency and abnormal combined assays. An isolated complex IV pattern is not a required finding in every tissue.

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT Human Clinical

"The activity of the OXPHOS complexes was measured in a muscle biopsy specimen from subject 3. This analysis showed a severe deficiency in complex IV activity. Addition- ally, complex II activity was profoundly increased, while complex II+III activity was only slightly elevated, indicating a..."

Subject 3 muscle has severe complex IV deficiency and additional combined-assay abnormalities; an isolated defect is not universal.

Functional RNA processing and complementation studies

Northern blotting or RNA sequencing, CO1 protein/translation assays and wild-type complementation can substantiate pathogenicity of uncertain variants. These are specialized cellular investigations, not established population screening assays.

Show evidence (2 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"the accumulation of unprocessed 5 ′ end MT-CO1, MT-ATP8/6-CO3, and MT-ND5-CYB transcripts, with a lack of mature MT-CO1 and MT-CO3 (Figure 2E), but normal levels of mature MT-CYB, suggesting that residual activity of the FASTKD5 variants in the subjects’ fibro- blasts was sufficient to process..."

Processing defects preferentially deplete mature CO1 and CO3; residual function preserves mature CYB in patient fibroblasts.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"Stable expres- sion of FLAG-tagged FASTKD5 protein (to 1.6 and 4.2 times of endogenous control FASTKD5 levels in subjects 1 and 2, respectively; Figures 2A and 2B) resulted in the rescue of MT-CO1 and MT-CO3 processing (Figures 2E and 3), an increase in the translation of the MT-CO1 poly-..."

Wild-type complementation rescues RNA processing, CO1 translation, complex IV assembly and activity in patient cells.

📊

Related Datasets

1

FASTKD5 processes mitochondrial pre-mRNAs at non-canonical cleavage sites geo:GSE290841

Mitochondrial RNA structure profiling in wild-type and engineered FASTKD5-knockout HEK293T cells. This is not the patient-fibroblast clinical series; those RNA/proteomic data were described as available on request.

PMID:40637235

Show evidence (2 references)

GEO:GSE290841 SUPPORT Other

"To investigate the molecular mechanism involved, we created knockout human cell lines to use as assay systems."

The GEO record identifies an engineered-cell experiment.

PMID:40637235 SUPPORT Other

"Sequencing data have been uploaded to Gene Expression Omnibus with accession number GSE290841."

The primary paper links its sequencing data to this accession.

🧫

Experimental Models

4

Patient-derived immortalized fibroblasts CELL_LINE

Fibroblasts from subjects 1 and 2 support RNA, protein, assembly and complementation experiments. Subject 3 muscle data are distinct. Residual FASTKD5 function preserves mature CYB and complex III assembly in the tested patient lines.

Publication

PMID:40499538

Pathograph links

Reduced FASTKD5 protein abundance partially recapitulates fidelity: high observes: cellular

Limitations: Patient-derived fibroblasts reproduce the measured cellular defect; immortalization and absence of neural tissue limit inference about brain injury or clinical treatment efficacy.

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"Immunoblot analysis of fibroblasts showed decreased steady-state levels of FASTKD5 protein in two subjects for whom fibroblast cultures were available: 24% of con- trols in subject 1 and 45% of controls in subject 2 (Figures 2A and 2B),"

Patient fibroblasts from subjects 1 and 2 have reduced FASTKD5 protein abundance.

Impaired noncanonical mitochondrial RNA processing partially recapitulates fidelity: high observes: cellular

Limitations: Patient-derived fibroblasts reproduce the measured cellular defect; immortalization and absence of neural tissue limit inference about brain injury or clinical treatment efficacy.

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"the accumulation of unprocessed 5 ′ end MT-CO1, MT-ATP8/6-CO3, and MT-ND5-CYB transcripts, with a lack of mature MT-CO1 and MT-CO3 (Figure 2E), but normal levels of mature MT-CYB, suggesting that residual activity of the FASTKD5 variants in the subjects’ fibro- blasts was sufficient to process..."

Processing defects preferentially deplete mature CO1 and CO3; residual function preserves mature CYB in patient fibroblasts.

Reduced complex IV assembly partially recapitulates fidelity: high observes: cellular

Limitations: Patient-derived fibroblasts reproduce the measured cellular defect; immortalization and absence of neural tissue limit inference about brain injury or clinical treatment efficacy.

Show evidence (1 reference)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"This resulted in a severe decrease in the steady-state levels of the cytochrome c ox- idase subunit 1 (MT-CO1; Figures 2A and 2B), a conse- quent reduction in the level of the fully assembled COX complex (complex IV; Figure 2C), and reduced COX enzy- matic activity (Figure 2D)."

Patient fibroblasts show reduced fully assembled complex IV and COX enzymatic activity.

Show evidence (4 references)

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"Immunoblot analysis of fibroblasts showed decreased steady-state levels of FASTKD5 protein in two subjects for whom fibroblast cultures were available: 24% of con- trols in subject 1 and 45% of controls in subject 2 (Figures 2A and 2B),"

Patient fibroblasts from subjects 1 and 2 have reduced FASTKD5 protein abundance.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"the accumulation of unprocessed 5 ′ end MT-CO1, MT-ATP8/6-CO3, and MT-ND5-CYB transcripts, with a lack of mature MT-CO1 and MT-CO3 (Figure 2E), but normal levels of mature MT-CYB, suggesting that residual activity of the FASTKD5 variants in the subjects’ fibro- blasts was sufficient to process..."

Processing defects preferentially deplete mature CO1 and CO3; residual function preserves mature CYB in patient fibroblasts.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf SUPPORT In Vitro

"Stable expres- sion of FLAG-tagged FASTKD5 protein (to 1.6 and 4.2 times of endogenous control FASTKD5 levels in subjects 1 and 2, respectively; Figures 2A and 2B) resulted in the rescue of MT-CO1 and MT-CO3 processing (Figures 2E and 3), an increase in the translation of the MT-CO1 poly-..."

Wild-type complementation rescues RNA processing, CO1 translation, complex IV assembly and activity in patient cells.

+ 1 more reference

FASTKD5-disrupted HAP1 cells CELL_LINE

Single and double FASTK-family disruption models reveal CO1 translation and respiration defects. The later 2025 study found residual FASTKD5 in the HAP1 system; these lines should not be equated with complete-null 143B or HEK293T cells. CO3 translation effects differ across cellular contexts.

Publication

PMID:34748562

Pathograph links

Reduced CO1 translation partially recapitulates fidelity: moderate observes: cellular

Limitations: Engineered HAP1 cells retain residual FASTKD5 and differ from patient fibroblasts in other mitochondrial RNA factors; the assay does not establish a neuronal phenotype.

Show evidence (1 reference)

PMID:34748562 SUPPORT In Vitro

"Remarkably, COX1 protein synthesis was strongly perturbed in the cells lacking FASTKD5, consistent with the severe defect in pre-CO1 RNA processing"

Pulse labeling in the HAP1 disruption model demonstrates reduced CO1 synthesis.

Impaired mitochondrial respiration partially recapitulates fidelity: moderate observes: cellular

Limitations: Engineered HAP1 cells retain residual FASTKD5 and differ from patient fibroblasts in other mitochondrial RNA factors; the assay does not establish a neuronal phenotype.

Show evidence (1 reference)

PMID:34748562 SUPPORT In Vitro

"In contrast, oxygen consumption was dramatically reduced in both the FASTKD5-sKO and the FASTKD4&5-dKO cells."

Respiration was directly measured in engineered HAP1 cells; it was not a patient neuronal ATP assay.

Show evidence (2 references)

PMID:34748562 SUPPORT In Vitro

"In contrast, oxygen consumption was dramatically reduced in both the FASTKD5-sKO and the FASTKD4&5-dKO cells."

Respiration was directly measured in engineered HAP1 cells; it was not a patient neuronal ATP assay.

PMID:40637235 SUPPORT In Vitro

"However, in that study KO cells retained residual FASTKD5 protein, which could partially compensate for processing defects."

The later paper explains why the HAP1 disruption model is not equivalent to complete loss.

Complete FASTKD5 knockout in 143B and HEK293T cells CELL_LINE

True knockout models show failure of all three noncanonical RNA-processing events, reduced CO1 and CYB translation, loss of complexes III and IV and secondary complex I loss. Uridine supports culture of respiratory-deficient cells; this does not establish uridine therapy in patients.

Publication

PMID:40637235

Pathograph links

Impaired noncanonical mitochondrial RNA processing partially recapitulates fidelity: low observes: cellular

Limitations: Complete-null engineered cells exaggerate loss of function relative to residual-function patient fibroblasts, which retain mature CYB and complex III assembly; clinical transfer requires corroboration.

Show evidence (1 reference)

PMID:40637235 SUPPORT In Vitro

"We next proceeded to investigate the effects of the FASTKD5 KO on RNA processing by Northern blot analysis (Fig. 1C) which showed near complete loss of the mature, processed forms of the CO1, CO3, and CYB mRNAs, a phenotype rescued by expression of the FLAG-tagged WT construct."

The complete-knockout model abolishes processing at all three noncanonical junctions.

Reduced CYB translation in complete-knockout cells partially recapitulates fidelity: low observes: cellular

Limitations: Complete-null engineered cells exaggerate loss of function relative to residual-function patient fibroblasts, which retain mature CYB and complex III assembly; clinical transfer requires corroboration.

Show evidence (1 reference)

PMID:40637235 SUPPORT In Vitro

"Quantification of these results (Supplementary Fig. S1F) showed that the translation of CO1 and CYB was specifically decreased, to near zero, consistent with the results of the Northern blot analysis (Fig. 1C) demonstrating that the presence of 5′-UTRs on these transcripts prevents translation..."

Complete knockout causes a broader translation defect than the residual-function patient cells.

Reduced complex III assembly in complete-knockout cells partially recapitulates fidelity: low observes: cellular

Limitations: Complete-null engineered cells exaggerate loss of function relative to residual-function patient fibroblasts, which retain mature CYB and complex III assembly; clinical transfer requires corroboration.

Show evidence (1 reference)

PMID:40637235 SUPPORT In Vitro

"Analysis of the assembly of the OXPHOS complexes by BN-PAGE demonstrated that complexes III and IV failed to assemble, as expected from the mitochondrial translation experiments (Fig. 1E)."

The additional complex III defect belongs to complete-knockout models.

Show evidence (3 references)

PMID:40637235 SUPPORT In Vitro

"Quantification of these results (Supplementary Fig. S1F) showed that the translation of CO1 and CYB was specifically decreased, to near zero, consistent with the results of the Northern blot analysis (Fig. 1C) demonstrating that the presence of 5′-UTRs on these transcripts prevents translation..."

Complete knockout causes a broader translation defect than the residual-function patient cells.

PMID:40637235 SUPPORT In Vitro

"Analysis of the assembly of the OXPHOS complexes by BN-PAGE demonstrated that complexes III and IV failed to assemble, as expected from the mitochondrial translation experiments (Fig. 1E)."

The additional complex III defect belongs to complete-knockout models.

PMID:40637235 SUPPORT In Vitro

"The translation of CO3 was, however, not affected in the KO cells, although the level of the mature CO3 mRNA was virtually undetectable by Northern blot. This directly demonstrates that CO3 encoded by a tricistronic mRNA (ATP8/6-CO3) can be synthesized by the mitochondrial ribosome as has been..."

Unprocessed RNA is not uniformly untranslatable: CO3 translation persists.

Reconstituted recombinant FASTKD5 cleavage assay OTHER

Purified wild-type and engineered D429N proteins distinguish intrinsic endonuclease activity from RNA binding. CCA and upstream RNA structural features contribute to substrate recognition, but a complete substrate-bound structure and the role of auxiliary factors remain unresolved.

Publication

PMID:40637235

Show evidence (3 references)

PMID:40637235 SUPPORT In Vitro

"We demonstrate unequivocally, using an in vitro reconstituted system, that FASTKD5 possesses intrinsic activity sufficient to correctly process three different synthetic pre-mRNA substrates of the primary polycistronic mitochondrial transcript."

Purified FASTKD5 cleaves its noncanonical RNA substrates directly.

PMID:40637235 SUPPORT In Vitro

"the D429N variant showed markedly diminished processing activity for all three noncanonical transcripts."

The engineered mutant is a cleavage-defective mechanistic control.

PMID:40637235 SUPPORT In Vitro

"These data imply that the CCA motif in the CO1 and CYB pre-mRNAs is important but not sufficient for FASTKD5 recognition of the cleavage site."

Sequence recognition contributes to the assay mechanism without establishing the full recognition structure.

{ }

Source YAML

click to show

name: FASTKD5-Related COX Deficiency
category: Mendelian
creation_date: '2026-06-24T00:00:00Z'
synonyms:
- FASTKD5 deficiency
- Mitochondrial complex IV deficiency, nuclear type 24
- MC4DN24
- FASTKD5-related cytochrome c oxidase deficiency
- Leigh syndrome due to FASTKD5 deficiency
description: FASTKD5-related COX deficiency (MC4DN24) is an autosomal recessive mitochondrial RNA-processing disorder caused by biallelic FASTKD5 variants. FASTKD5 is an endonuclease required at noncanonical junctions of mitochondrial polycistronic RNA. Impaired CO1 mRNA maturation reduces CO1 translation and complex IV assembly and activity. The founding series describes three unrelated individuals with Leigh syndrome spectrum, ranging from severe infantile disease with fatal decompensation to childhood developmental delay and adult-onset movement and ocular abnormalities. Residual-function patient fibroblasts show predominantly complex IV deficiency, whereas muscle assays and complete-knockout cell models can show broader respiratory-chain abnormalities. The small series does not establish population frequencies or a reliable genotype-based prognosis.
disease_term:
  preferred_term: FASTKD5-related COX deficiency (MC4DN24)
  term:
    id: MONDO:0980755
    label: mitochondrial complex IV deficiency, nuclear type 24
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
references:
- reference: PMID:40499538
  title: Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome.
- reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
  title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
- reference: PMID:40637235
  title: FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
- reference: PMID:34748562
  title: The FASTK family proteins fine-tune mitochondrial RNA processing.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
  title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: GEO:GSE290841
  title: FASTKD5 processes mitochondrial pre-mRNAs at non-canonical cleavage sites
pathophysiology:
- name: Reduced FASTKD5 protein abundance
  description: Patient fibroblasts have reduced steady-state FASTKD5. The p.Tyr125Cys allele destabilizes the protein while retaining partial function; the two frameshift alleles are predicted to alter translation. Reduced abundance is distinct from functional failure of a stably expressed missense protein.
  genes:
  - &id001
    preferred_term: FASTKD5
    term:
      id: hgnc:25790
      label: FASTKD5
  evidence:
  - &id029
    reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: 'Immunoblot analysis of fibroblasts showed decreased steady-state levels of FASTKD5 protein in two subjects for whom fibroblast cultures were available: 24% of con- trols in subject 1 and 45% of controls in subject 2 (Figures 2A and 2B),'
    explanation: Patient fibroblasts from subjects 1 and 2 have reduced FASTKD5 protein abundance.
  - &id026
    reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The p.Tyr125Cys FASTKD5 protein was unstable, as it was ex- pressed at levels significantly lower than the WT protein in fibroblasts from both the subjects and control individ- uals (Figure 4A). However, expression of this variant was able to double the COX activity in subject 2 (from 32% to 66%), confirming that the effect of the variant p. Tyr125Cys is hypomorphic due to the reduced stability of the protein (Figure 4B).
    explanation: 'The p.Tyr125Cys protein is unstable but retains activity: overexpression partly restores COX activity in subject 2 cells.'
  downstream:
  - target: Impaired noncanonical mitochondrial RNA processing
    causal_link_type: DIRECT
    description: Reduced functional FASTKD5 limits maturation of susceptible mitochondrial transcripts.
    evidence:
    - &id004
      reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: the accumulation of unprocessed 5 ′ end MT-CO1, MT-ATP8/6-CO3, and MT-ND5-CYB transcripts, with a lack of mature MT-CO1 and MT-CO3 (Figure 2E), but normal levels of mature MT-CYB, suggesting that residual activity of the FASTKD5 variants in the subjects’ fibro- blasts was sufficient to process MT-ND5-CYB pre-mRNA, resembling the situation in FASTKD5 knockdown cells.
      explanation: Processing defects preferentially deplete mature CO1 and CO3; residual function preserves mature CYB in patient fibroblasts.
    - &id007
      reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Stable expres- sion of FLAG-tagged FASTKD5 protein (to 1.6 and 4.2 times of endogenous control FASTKD5 levels in subjects 1 and 2, respectively; Figures 2A and 2B) resulted in the rescue of MT-CO1 and MT-CO3 processing (Figures 2E and 3), an increase in the translation of the MT-CO1 poly- peptide (Figure 2F), rescue of the steady-state level of the MT-CO1 protein (Figures 2A and 2B), and concomitant rescue of COX assembly (Figure 2C) and enzymatic activ- ity (Figure 2D).
      explanation: Wild-type complementation rescues RNA processing, CO1 translation, complex IV assembly and activity in patient cells.
- name: Loss of FASTKD5 processing function
  description: The patient p.Arg404Cys and p.Leu634Pro proteins fail to restore CO1 expression or COX activity despite wild-type-comparable expression. Recombinant experiments establish intrinsic FASTKD5 endonuclease activity. Engineered D429N impairs cleavage while retaining RNA binding; it is a mechanistic probe, not a reported patient allele.
  genes:
  - *id001
  evidence:
  - &id002
    reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We were able to express the p.Arg404Cys and p.Leu634Pro FASTKD5 protein to the same level as WT- FASTKD5; however, expression of either variant was unable to rescue the MT-CO1 expression in the subjects’ cells (Figure 4A) or COX activity (Figure 4B), supporting that these variants result in the loss of function.
    explanation: The two missense proteins fail functional complementation despite expression comparable to wild type.
  - &id003
    reference: PMID:40637235
    reference_title: FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We demonstrate unequivocally, using an in vitro reconstituted system, that FASTKD5 possesses intrinsic activity sufficient to correctly process three different synthetic pre-mRNA substrates of the primary polycistronic mitochondrial transcript.
    explanation: Purified FASTKD5 cleaves its noncanonical RNA substrates directly.
  - reference: PMID:40637235
    reference_title: FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The results indicate that both WT FASTKD5 and the D429N mutant can bind substrate RNAs with comparable affinities
    explanation: RNA binding and cleavage can be experimentally separated.
  downstream:
  - target: Impaired noncanonical mitochondrial RNA processing
    causal_link_type: DIRECT
    description: Loss of processing function disrupts maturation of the noncanonical substrates.
    evidence:
    - *id002
    - *id003
  molecular_functions:
  - preferred_term: RNA endonuclease activity
    term:
      id: GO:0004521
      label: RNA endonuclease activity
    modifier: DECREASED
- name: Impaired noncanonical mitochondrial RNA processing
  description: Cleavage at the CO1 5-prime end and ATP8/6-CO3 junction is severely impaired in patient fibroblasts. Precursors accumulate and mature CO1 and CO3 decline. Mature CYB remains available with residual FASTKD5 function; complete knockout also disrupts ND5-CYB processing. CO3 can still be translated from the tricistronic precursor, so impaired processing does not imply loss of every encoded protein.
  biological_processes:
  - preferred_term: mitochondrial mRNA processing
    term:
      id: GO:0090615
      label: mitochondrial mRNA processing
    modifier: DECREASED
  evidence:
  - *id004
  - &id030
    reference: PMID:40637235
    reference_title: FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The translation of CO3 was, however, not affected in the KO cells, although the level of the mature CO3 mRNA was virtually undetectable by Northern blot. This directly demonstrates that CO3 encoded by a tricistronic mRNA (ATP8/6-CO3) can be synthesized by the mitochondrial ribosome as has been suggested previously [35].
    explanation: 'Unprocessed RNA is not uniformly untranslatable: CO3 translation persists.'
  downstream:
  - target: Reduced CO1 translation
    causal_link_type: DIRECT
    description: Failure to mature CO1 RNA impairs its translation.
    evidence:
    - &id005
      reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The lack of mature MT-CO1 mRNA resulted in a substan- tial decrease in the synthesis of the MT-CO1 polypeptide (Figures 2F and S3).
      explanation: Loss of mature CO1 RNA reduces synthesis of its encoded protein.
  - target: Reduced CYB translation in complete-knockout cells
    causal_link_type: DIRECT
    description: Complete loss additionally impairs CYB translation; this branch is restricted to null cell models.
    evidence:
    - &id006
      reference: PMID:40637235
      reference_title: FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Quantification of these results (Supplementary Fig. S1F) showed that the translation of CO1 and CYB was specifically decreased, to near zero, consistent with the results of the Northern blot analysis (Fig. 1C) demonstrating that the presence of 5′-UTRs on these transcripts prevents translation on mitochondrial ribosomes.
      explanation: Complete knockout causes a broader translation defect than the residual-function patient cells.
- name: Reduced CO1 translation
  description: Failure to remove the CO1 5-prime extension strongly reduces synthesis of the mtDNA-encoded CO1 catalytic subunit in patient fibroblasts and complete-knockout cells.
  biological_processes:
  - preferred_term: mitochondrial translation
    term:
      id: GO:0032543
      label: mitochondrial translation
    modifier: DECREASED
  evidence:
  - *id005
  - *id006
  downstream:
  - target: Reduced complex IV assembly
    causal_link_type: DIRECT
    description: Insufficient CO1 limits accumulation of the assembled complex IV holoenzyme.
    evidence:
    - &id008
      reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: This resulted in a severe decrease in the steady-state levels of the cytochrome c ox- idase subunit 1 (MT-CO1; Figures 2A and 2B), a conse- quent reduction in the level of the fully assembled COX complex (complex IV; Figure 2C), and reduced COX enzy- matic activity (Figure 2D).
      explanation: Patient fibroblasts show reduced fully assembled complex IV and COX enzymatic activity.
    - *id007
- name: Reduced complex IV assembly
  conforms_to: complex_iv_assembly_deficiency#Complex IV Biogenesis Failure
  description: Fully assembled complex IV is reduced in patient fibroblasts without detectable abnormal subcomplex accumulation. Wild-type FASTKD5 complementation restores assembly.
  biological_processes:
  - preferred_term: mitochondrial respiratory chain complex IV assembly
    term:
      id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
    modifier: DECREASED
  evidence:
  - *id008
  - *id007
  downstream:
  - target: Reduced complex IV activity
    causal_link_type: DIRECT
    description: Reduced holoenzyme abundance lowers cytochrome c oxidase activity.
    evidence:
    - *id008
- name: Reduced complex IV activity
  description: COX enzymatic activity is reduced in affected fibroblasts and muscle. The patient fibroblast defect is predominantly complex IV; subject 3 muscle also has abnormal combined I+III and II+III assays.
  biological_processes:
  - preferred_term: mitochondrial electron transport, cytochrome c to oxygen
    term:
      id: GO:0006123
      label: mitochondrial electron transport, cytochrome c to oxygen
    modifier: DECREASED
  evidence:
  - *id008
  - &id024
    reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The activity of the OXPHOS complexes was measured in a muscle biopsy specimen from subject 3. This analysis showed a severe deficiency in complex IV activity. Addition- ally, complex II activity was profoundly increased, while complex II+III activity was only slightly elevated, indicating a deficiency in complex III activity. Rotenone-sensitive complex I+III activity was also decreased (Table S2).
    explanation: Subject 3 muscle has severe complex IV deficiency and additional combined-assay abnormalities; an isolated defect is not universal.
  downstream:
  - target: Impaired mitochondrial respiration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The complex IV deficit compromises respiration, demonstrated directly in engineered cells.
    evidence:
    - &id009
      reference: PMID:34748562
      reference_title: The FASTK family proteins fine-tune mitochondrial RNA processing.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In contrast, oxygen consumption was dramatically reduced in both the FASTKD5-sKO and the FASTKD4&5-dKO cells.
      explanation: Respiration was directly measured in engineered HAP1 cells; it was not a patient neuronal ATP assay.
- name: Impaired mitochondrial respiration
  description: FASTKD5-disrupted HAP1 cells have markedly reduced oxygen consumption. Respiratory-chain dysfunction provides a mechanistic context for the Leigh phenotype, but the intermediates producing individual brain lesions and clinical findings remain incompletely resolved. These assays do not directly establish neuronal ATP depletion in patients.
  biological_processes:
  - preferred_term: aerobic respiration
    term:
      id: GO:0009060
      label: aerobic respiration
    modifier: DECREASED
  evidence:
  - *id009
  downstream:
  - target: Developmental regression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Mitochondrial disease is associated with loss of acquired skills in the severe early-onset case; specific neural intermediates are unmeasured.
    evidence:
    - &id016
      reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: He had lost gross motor skills and his single non-specific word.
      explanation: Subject 1 lost previously acquired motor and language skills; subject 3 had no reported regression at the available follow-up.
    - &id010
      reference: PMID:40499538
      reference_title: Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: three subjects with Leigh syndrome, a progressive neurodegenerative disease characterized by lesions in the brainstem and basal ganglia
      explanation: The founding series links biallelic FASTKD5 variants to a Leigh syndrome spectrum phenotype; individual courses differ.
  - target: Brainstem lesions
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Leigh brainstem injury accompanies the respiratory-chain disorder; lesion-specific intermediates remain uncertain.
    evidence:
    - &id020
      reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Axial T2-weighted brain MRI images (i–iii) of subject 1 (at 1 year of age) show abnormal hyperintense signal at the level of the entire brainstem, extending from the medulla to the midbrain and at the level of the putamina bilaterally.
      explanation: The clinical figure documents T2 hyperintense brainstem and bilateral putaminal lesions.
    - *id010
  - target: Basal ganglia lesions
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Basal ganglia lesions occur in the clinical syndrome without a demonstrated cell-specific injury cascade.
    evidence:
    - &id021
      reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Brain MRI (Figure 1E) at 31 months of age showed symmetric areas of abnormal T2 hyperintensity involving the bilateral basal ganglia, thalami, and dorsal medulla, consistent with Leigh syndrome.
      explanation: Subject 3 had bilateral basal ganglia, thalamic and dorsal medullary T2 lesions.
    - *id010
  - target: Lactic acidosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Severe metabolic decompensation with lactate accumulation occurs in affected disease; exact flux changes were not measured in patients.
    evidence:
    - &id017
      reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'This was accompanied by severe lactic acidosis (pH 6, lactate: 28 mmol/ L).'
      explanation: Severe lactic acidosis accompanied subject 1 respiratory decompensation.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The clinical series associates the respiratory-chain disorder with this neurological manifestation; the cellular and tissue intermediates are not directly established.
    evidence:
    - &id013
      reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Additional features include global developmental delay without regression, most notably in gross motor skills, first walking at age 2, and expressive speech, first babbling at 16 months and able to sign 20–30 words at 21 months;
      explanation: Subject 3 had global delay, particularly gross motor and expressive language development.
    - *id010
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The clinical series associates the respiratory-chain disorder with this neurological manifestation; the cellular and tissue intermediates are not directly established.
    evidence:
    - &id014
      reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Neurodevelopmental features included hypoto- nia, gross motor skills under the 4-months-of-age skill level, and fine motor skills at the 6-months-of-age level,
      explanation: The subject 1 case description documents hypotonia and motor delay.
    - *id010
- name: Reduced CYB translation in complete-knockout cells
  description: Complete FASTKD5 knockout prevents efficient translation of unprocessed CYB RNA in 143B and HEK293T models. This additional defect is not established in residual-function patient fibroblasts, where mature CYB and complex III assembly are preserved.
  biological_processes:
  - preferred_term: mitochondrial translation
    term:
      id: GO:0032543
      label: mitochondrial translation
    modifier: DECREASED
  evidence:
  - *id006
  - *id004
  downstream:
  - target: Reduced complex III assembly in complete-knockout cells
    causal_link_type: DIRECT
    description: Loss of cytochrome b synthesis prevents complex III assembly in null models.
    evidence:
    - &id011
      reference: PMID:40637235
      reference_title: FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Analysis of the assembly of the OXPHOS complexes by BN-PAGE demonstrated that complexes III and IV failed to assemble, as expected from the mitochondrial translation experiments (Fig. 1E).
      explanation: The additional complex III defect belongs to complete-knockout models.
- name: Reduced complex III assembly in complete-knockout cells
  description: Complex III assembly fails in complete-knockout cells. The broader null-model defect must not be assumed in every patient tissue.
  evidence:
  - *id011
  - reference: PMID:40637235
    reference_title: FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The complex I assembly defect can be ascribed to the complete absence of complex III, whose presence is necessary for the biogenesis/stability of complex I [36, 37].
    explanation: The authors interpret complex I loss as secondary to complex III failure.
  downstream:
  - target: Impaired mitochondrial respiration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The additional complex III defect contributes to the severe null-model OXPHOS impairment.
    evidence:
    - *id011
  - target: Secondary complex I loss in complete-knockout cells
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Assembled complex I depends on complex III in these cells.
    evidence:
    - &id012
      reference: PMID:40637235
      reference_title: FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The complex I assembly defect can be ascribed to the complete absence of complex III, whose presence is necessary for the biogenesis/stability of complex I [36, 37].
      explanation: The authors attribute secondary complex I loss in null cells to absent complex III.
- name: Secondary complex I loss in complete-knockout cells
  description: Assembled complex I is nearly absent in null models despite near-normal translation of its mtDNA-encoded subunits. This is interpreted as secondary to complex III deficiency, rather than defective maturation of complex I transcripts.
  evidence:
  - *id012
  downstream:
  - target: Impaired mitochondrial respiration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Additional complex I loss contributes to the respiratory-chain defect in null models.
    evidence:
    - *id012
phenotypes:
- name: Global developmental delay
  description: Marked developmental delay in the two childhood cases; subject 3 had no reported regression at the available follow-up.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - *id013
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: may present with nonspecific features such as poor weight gain, feeding difficulties, persistent vomiting, hypotonia, and developmental delay.
    explanation: General LSS clinical context agrees with the childhood case descriptions; these general cohort findings do not establish FASTKD5-specific frequencies.
- name: Expressive language delay
  description: Expressive communication was substantially delayed in the childhood cases.
  phenotype_term:
    preferred_term: Expressive language delay
    term:
      id: HP:0002474
      label: Expressive language delay
  evidence:
  - *id013
- name: Hypotonia
  description: Hypotonia was documented in subject 1 with severe early developmental impairment.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - *id014
- name: Microcephaly
  description: Microcephaly was reported in subject 1 at presentation.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: microcephaly with a fronto-occipital circumference of 41 cm
    explanation: The early-onset case had reduced head circumference.
- name: Failure to thrive
  description: Both childhood cases required gastrostomy support in the setting of poor growth and feeding problems.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: he developed a failure to thrive and had gastrostomy tube placement at 11 months of age.
    explanation: Subject 3 developed poor growth requiring gastrostomy.
- name: Dysphagia
  description: Swallowing difficulty required gastrostomy in subject 1; persistent dysphagia was absent at the latest adult follow-up.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At the age of 14.5 months, the subject received a percutaneous endoscopic gastrostomy tube due to dysphagia.
    explanation: Subject 1 required gastrostomy for dysphagia.
- name: Nystagmus
  description: Reported in the early-onset and adult cases.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - &id015
    reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: showed nystagmus and esotropia but no retinal pathology.
    explanation: Nystagmus and esotropia were reported in subject 1.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: vertical nystagmus in the primary position and horizontal nystagmus in bilateral gaze settings, and complete deficit of ocular pursuit movements in the vertical plane).
    explanation: Subject 2 also had nystagmus during the initial presentation.
- name: Esotropia
  description: Subject 1 had esotropia; the adult case also had convergent strabismus.
  phenotype_term:
    preferred_term: Esotropia
    term:
      id: HP:0000565
      label: Esotropia
  evidence:
  - *id015
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: mild convergent strabismus in the left eye with mild abduction deficit
    explanation: Subject 2 also had convergent strabismus at the adult presentation.
- name: Developmental regression
  description: Subject 1 lost motor and language skills. Regression is not universal at the available follow-up.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - *id016
- name: Respiratory failure
  description: Subject 1 developed acute respiratory failure after a rhinovirus infection during terminal metabolic decompensation.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His final hospital admission followed a rhinovirus infection leading to acute respi- ratory failure that required mechanical ventilation.
    explanation: Respiratory failure followed an intercurrent infection in the severe case.
- name: Lactic acidosis
  description: Subject 1 had persistent acidosis progressing to severe lactic acidosis during terminal decompensation; milder lactate elevation in other cases is recorded separately as a biochemical finding.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - *id017
- name: Parkinsonism
  description: Adult subject 2 developed rigid-akinetic parkinsonism; it had resolved by the latest assessment after three years of follow-up.
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - &id018
    reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Two months after discharge, the sub- ject had rigid-akinetic parkinsonism with severe axial rigidity, right foot dystonia, slight ideo-motor slowing, left eye stra- bismus, limitation of slow horizontal eye movements, a mild deficit of ocular pursuit movements in the vertical plane, binoc- ular reduced visual acuity, and mild eyelid ptosis.
    explanation: Subject 2 developed parkinsonism, foot dystonia, ocular motor abnormalities, reduced visual acuity and ptosis.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the subject was breathing spontaneously and had no com- plaints of dysphagia, and parkinsonism had resolved.
    explanation: The later adult assessment documents improvement rather than universal progression.
- name: Dystonia
  description: Right foot dystonia occurred in adult subject 2.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - *id018
- name: Ptosis
  description: Mild eyelid ptosis was reported in the adult case.
  phenotype_term:
    preferred_term: Ptosis
    term:
      id: HP:0000508
      label: Ptosis
  evidence:
  - *id018
- name: Visual impairment
  description: The adult case had profound visual acuity loss without retinopathy and with increased visual evoked potential latency.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ophthalmolog- ical examination showed no signs of retinopathy but profoundly reduced visual acuity with increased latency of visual evoked po- tentials.
    explanation: The visual deficit was not attributed to retinopathy in the case report.
- name: Exercise intolerance
  description: Reported in the childhood subject 3 and persistently in adult subject 2.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: she exhibited profound exercise intolerance, visual acuity loss, and executive dysfunction with reduced autonomy.
    explanation: Persistent adult functional limitations included exercise intolerance.
- name: Gastroparesis
  description: Subject 2 was readmitted with gastroparesis complicated by aspiration pneumonia.
  phenotype_term:
    preferred_term: Gastroparesis
    term:
      id: HP:0002578
      label: Gastroparesis
  evidence:
  - &id019
    reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After 1 month, she was readmitted due to gastroparesis with aspi- ration pneumonia, which temporarily required orotracheal intu- bation. Prokinetic therapy was started.
    explanation: The adult case had gastrointestinal dysmotility with aspiration requiring temporary intubation.
- name: Aspiration
  description: Aspiration pneumonia complicated adult gastroparesis; it is a disease complication rather than an infectious etiology of FASTKD5 deficiency.
  phenotype_term:
    preferred_term: Aspiration
    term:
      id: HP:0002835
      label: Aspiration
  evidence:
  - *id019
- name: Brainstem lesions
  description: Brainstem T2 hyperintense lesions involve the medulla, pons and midbrain in variable distributions.
  phenotype_term:
    preferred_term: Focal T2 hyperintense brainstem lesion
    term:
      id: HP:0012748
      label: Focal T2 hyperintense brainstem lesion
  evidence:
  - *id020
- name: Basal ganglia lesions
  description: Bilateral putaminal or basal ganglia T2 lesions were reported in the childhood cases.
  phenotype_term:
    preferred_term: Focal T2 hyperintense basal ganglia lesion
    term:
      id: HP:0007183
      label: Focal T2 hyperintense basal ganglia lesion
  evidence:
  - *id021
- name: Small for gestational age
  description: Subject 3 was small for gestational age after a pregnancy complicated by preeclampsia; this single observation does not establish a disease-specific prenatal pattern.
  phenotype_term:
    preferred_term: Small for gestational age
    term:
      id: HP:0001518
      label: Small for gestational age
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Subject 3 (a male patient) was born small for gestational age after a full-term pregnancy complicated by preeclampsia.
    explanation: The obstetric context limits attribution of the birth-size finding.
- name: Midface retrusion
  description: Reported in subject 3. The founding series is too small to establish a characteristic facial gestalt; subject 2 also carries a separate 1q21.1 deletion.
  phenotype_term:
    preferred_term: Midface retrusion
    term:
      id: HP:0011800
      label: Midface retrusion
  evidence:
  - &id022
    reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: dysmorphic facial features, including midfacial hypoplasia, prominent cheeks, micro/retrognathia, epicanthus, down-slanting palpebral fissures, smooth philtrum, and thin upper lip;
    explanation: These findings were reported in subject 3; facial features in subject 2 are confounded by a separate 1q21.1 deletion.
- name: Micrognathia
  description: Reported in subject 3. The founding series is too small to establish a characteristic facial gestalt; subject 2 also carries a separate 1q21.1 deletion.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - *id022
- name: Retrognathia
  description: Reported in subject 3. The founding series is too small to establish a characteristic facial gestalt; subject 2 also carries a separate 1q21.1 deletion.
  phenotype_term:
    preferred_term: Retrognathia
    term:
      id: HP:0000278
      label: Retrognathia
  evidence:
  - *id022
- name: Epicanthus
  description: Reported in subject 3. The founding series is too small to establish a characteristic facial gestalt; subject 2 also carries a separate 1q21.1 deletion.
  phenotype_term:
    preferred_term: Epicanthus
    term:
      id: HP:0000286
      label: Epicanthus
  evidence:
  - *id022
- name: Downslanted palpebral fissures
  description: Reported in subject 3. The founding series is too small to establish a characteristic facial gestalt; subject 2 also carries a separate 1q21.1 deletion.
  phenotype_term:
    preferred_term: Downslanted palpebral fissures
    term:
      id: HP:0000494
      label: Downslanted palpebral fissures
  evidence:
  - *id022
- name: Smooth philtrum
  description: Reported in subject 3. The founding series is too small to establish a characteristic facial gestalt; subject 2 also carries a separate 1q21.1 deletion.
  phenotype_term:
    preferred_term: Smooth philtrum
    term:
      id: HP:0000319
      label: Smooth philtrum
  evidence:
  - *id022
- name: Thin upper lip vermilion
  description: Reported in subject 3. The founding series is too small to establish a characteristic facial gestalt; subject 2 also carries a separate 1q21.1 deletion.
  phenotype_term:
    preferred_term: Thin upper lip vermilion
    term:
      id: HP:0000219
      label: Thin upper lip vermilion
  evidence:
  - *id022
- name: Ventricular septal hypertrophy
  description: Interventricular septal hypertrophy was documented in the adult case; this does not establish a universal cardiomyopathy phenotype.
  phenotype_term:
    preferred_term: Ventricular septal hypertrophy
    term:
      id: HP:0005144
      label: Ventricular septal hypertrophy
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Echocardiography and cardiac MRI showed interventricular septum hypertrophy.
    explanation: Cardiac imaging documented the specific septal finding.
- name: Impaired executive functioning
  description: Persistent executive dysfunction reduced autonomy at the latest adult assessment.
  phenotype_term:
    preferred_term: Impaired executive functioning
    term:
      id: HP:0033051
      label: Impaired executive functioning
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: she exhibited profound exercise intolerance, visual acuity loss, and executive dysfunction with reduced autonomy.
    explanation: The adult case had persisting executive impairment.
- name: Full cheeks
  description: Prominent cheeks were reported in subject 3, alongside other facial findings of uncertain specificity.
  phenotype_term:
    preferred_term: Full cheeks
    term:
      id: HP:0000293
      label: Full cheeks
  evidence:
  - *id022
- name: Increased circulating lactate
  description: Lactate elevation ranged from mild intermittent lactatemia to severe decompensation; elevation alone is distinct from lactic acidosis.
  phenotype_term:
    preferred_term: Increased circulating lactate concentration
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  evidence: &id025
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Blood lactate concentra- tions ranged from 3.3 to over 10 mmol/L (reference < 2.2 for venous samples).
    explanation: Subject 1 had variable hyperlactatemia.
  - &id023
    reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Cerebrospinal fluid analysis was unre- markable except for a moderate elevation in lactate concentra- tion (4 mmol/L) and the presence of HHV-6 DNA. Blood lactate concentrations ranged from 2.6 to 3 mmol/L.
    explanation: Subject 2 had elevated CSF and blood lactate.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: intermittent mild lactatemia as high as 4.2 mmol/L.
    explanation: Subject 3 had intermittent mild lactatemia.
- name: Increased CSF lactate
  description: CSF lactate was elevated in the adult case.
  phenotype_term:
    preferred_term: Increased CSF lactate
    term:
      id: HP:0002490
      label: Increased CSF lactate
  evidence:
  - *id023
- name: Elevated brain lactate by MRS
  description: The adult midbrain lesion showed a lactate peak on magnetic resonance spectroscopy.
  phenotype_term:
    preferred_term: Elevated brain lactate level by MRS
    term:
      id: HP:0012707
      label: Elevated brain lactate level by MRS
  evidence:
  - &id028
    reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: with extension along the medial longitudinal fasciculus, with modest mass effect, linear enhancement, increased perfusion indices, and a lactic acid peak on spectroscopy.
    explanation: Adult MRI and MRS support mitochondrial encephalopathy.
biochemical:
- name: Reduced cytochrome c oxidase activity
  presence: Decreased
  context: Patient fibroblasts have predominantly complex IV deficiency; subject 3 muscle also has abnormal combined respiratory-chain assays. Normal routine muscle morphology does not exclude the enzymatic defect.
  evidence:
  - *id008
  - *id024
- name: Elevated blood and cerebrospinal-fluid lactate
  presence: Increased
  context: Blood lactate was elevated in all three reported cases with variable magnitude. CSF lactate and an MRS lactate peak were documented in the adult case. Mild lactatemia is distinct from the severe acidosis of subject 1.
  evidence: *id025
genetic:
- name: FASTKD5
  gene_term: *id001
  inheritance:
  - &id027
    name: Autosomal recessive
    evidence:
    - reference: PMID:40499538
      reference_title: Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: compound heterozygous variants of unknown significance in FASTKD5
      explanation: The clinical series identified biallelic variants, with functional studies supporting disease causality.
  features: The founding series contains three missense and two frameshift alleles in three unrelated compound heterozygous subjects. Protein instability and impaired processing function are distinct mechanisms. The shared p.Tyr125Cys allele retains function; residual activity in cultured cells is not a validated individual prognostic test. Subject 2 additionally has a maternally inherited 1q21.1 deletion, which may contribute to dysmorphism and is not a FASTKD5 structural variant.
  variants:
  - name: NM_021826.5:c.1716dup
    description: p.Pro573Alafs*17. Subject 1 maternal frameshift allele, in trans with p.Leu634Pro.
    gene: *id001
    variant_type: insertion
    clinical_significance: PATHOGENIC
    evidence:
    - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'c.1716dup (GenBank: NM_021826.5) (p.Pro573Alafs*17) and c.1901T>C (GenBank: NM_021826.5) (p.Leu634Pro) in FASTKD5 of maternal and paternal origin, respectively (Figure 1B).'
      explanation: The clinical sequencing description gives the transcript, allele and phase.
  - name: NM_021826.5:c.1901T>C
    description: p.Leu634Pro. Subject 1 paternal missense allele. The expressed mutant fails complementation despite wild-type-comparable abundance.
    gene: *id001
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'c.1716dup (GenBank: NM_021826.5) (p.Pro573Alafs*17) and c.1901T>C (GenBank: NM_021826.5) (p.Leu634Pro) in FASTKD5 of maternal and paternal origin, respectively (Figure 1B).'
      explanation: The clinical sequencing description gives the transcript, allele and phase.
    - *id002
  - name: NM_021826.5:c.1210C>T
    description: p.Arg404Cys. Subject 2 paternal missense allele. The expressed mutant fails complementation despite wild-type-comparable abundance.
    gene: *id001
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Exome sequencing revealed the presence of c.1210C>T (GenBank: NM_021826.5) (p.Arg404Cys) (gnomAD allele frequency: 109/ 1,614,226 alleles, always heterozygous) and c.374A>G (GenBank: NM_021826.5) (p.Tyr125Cys) (gnomAD allele frequency: 7/1,614,184 alleles, always heterozygous) in FASTKD5 of paternal and maternal origin, respectively (Figure 1B).'
      explanation: The clinical sequencing description gives the transcript, allele and phase.
    - *id002
  - name: NM_021826.5:c.374A>G
    description: p.Tyr125Cys. Shared by subjects 2 and 3; maternally inherited in subject 2. The protein is unstable but hypomorphic, with partial rescue on overexpression.
    gene: *id001
    variant_type: single nucleotide variant
    clinical_significance: PATHOGENIC
    evidence:
    - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Exome sequencing revealed the presence of c.1210C>T (GenBank: NM_021826.5) (p.Arg404Cys) (gnomAD allele frequency: 109/ 1,614,226 alleles, always heterozygous) and c.374A>G (GenBank: NM_021826.5) (p.Tyr125Cys) (gnomAD allele frequency: 7/1,614,184 alleles, always heterozygous) in FASTKD5 of paternal and maternal origin, respectively (Figure 1B).'
      explanation: The clinical sequencing description gives the transcript, allele and phase.
    - *id026
  - name: NM_021826.5:c.2028_2029del
    description: p.Ala678Hisfs*79. Subject 3 frameshift allele, in trans with p.Tyr125Cys; the frameshift alters the C-terminal translated sequence.
    gene: *id001
    variant_type: deletion
    clinical_significance: PATHOGENIC
    evidence:
    - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: 'Exome sequencing at 14 months of age demonstrated c.2028_2029del (GenBank: NM_021826.5) (p.Ala678Hisfs*79) (gnomAD allele frequency: 8/1,614,088 alleles, always heterozygous) and c.374 A>G (Gen- Bank: NM_021826.5) (p.Tyr125Cys) (gnomAD allele frequency: 7/1,614,184 alleles, always heterozygous) in FASTKD5 in trans (Figure 1B).'
      explanation: The clinical sequencing description gives the transcript, allele and phase.
  evidence:
  - reference: PMID:40499538
    reference_title: Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: we identified three missense variants and two frameshift variants leading to a premature stop codon
    explanation: The study defines the reported allele spectrum.
  - *id002
  - *id026
treatments:
- name: Multidisciplinary supportive care
  description: Care is directed to neurological, feeding, respiratory, visual, cardiac and developmental complications. General Leigh syndrome spectrum recommendations provide a framework; no disease-modifying treatment was established by the three-case study.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Supportive care to improve quality of life, maximize function, and reduce complications is recommended.
    explanation: General LSS supportive-care guidance.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Feeding support and gastrostomy
  description: Swallowing assessment, nutritional support and gastrostomy may be needed. Both childhood cases received gastrostomy; aspiration risk warrants assessment.
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At the age of 14.5 months, the subject received a percutaneous endoscopic gastrostomy tube due to dysphagia.
    explanation: Gastrostomy was used for subject 1 dysphagia.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: he developed a failure to thrive and had gastrostomy tube placement at 11 months of age.
    explanation: Subject 3 also required feeding support.
  treatment_term:
    preferred_term: Gastrostomy Tube Procedure
    term:
      id: NCIT:C157864
      label: Gastrostomy Tube Procedure
- name: Respiratory support
  description: Provide respiratory assessment and ventilatory support during compromise. Both the severe child and adult case required mechanical airway support during acute complications.
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: His final hospital admission followed a rhinovirus infection leading to acute respi- ratory failure that required mechanical ventilation.
    explanation: Subject 1 required mechanical ventilation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ventilatory support for persons w/LSS ... respiratory compromise
    explanation: General LSS care supports ventilation when respiratory compromise is present.
  treatment_term:
    preferred_term: Mechanical Ventilation
    term:
      id: NCIT:C70909
      label: Mechanical Ventilation
- name: Management of metabolic acidosis
  description: Specialist-directed correction of significant acidosis follows general LSS guidance. IV acetate and enteral sodium citrate/citric acid did not correct acidosis in subject 1; reported use does not establish efficacy for FASTKD5 deficiency.
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Supplemental alkali from acetate administered intravenously (i.v.) or enteral sodium citrate/citric acid did not shift the lactate concentration or correct the acidosis.
    explanation: Alkali therapy failed to correct subject 1 acidosis.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sodium bicarbonate or sodium citrate for significant acidosis
    explanation: General LSS management recommendation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Symptomatic movement-disorder treatment
  description: The adult case received a dopamine agonist. Parkinsonism later resolved, but concurrent therapies and the uncontrolled course prevent attribution to a specific drug. Dystonia management should be individualized.
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She was treated with a dopamine agonist and idebenone.
    explanation: The adult patient received symptomatic dopaminergic treatment.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the subject was breathing spontaneously and had no com- plaints of dysphagia, and parkinsonism had resolved.
    explanation: The adult course showed later improvement without a controlled efficacy assessment.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Treatment of gastrointestinal dysmotility
  description: Prokinetic treatment was used for adult gastroparesis after an aspiration complication; monitor nutritional intake and swallowing safety.
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After 1 month, she was readmitted due to gastroparesis with aspi- ration pneumonia, which temporarily required orotracheal intu- bation. Prokinetic therapy was started.
    explanation: Reported symptomatic treatment of gastroparesis.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
- name: Empiric mitochondrial supplements
  description: Riboflavin and coenzyme Q10 were given initially to subject 2, and idebenone later. The report does not establish FASTKD5-specific efficacy of these agents.
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At this point, i.v. immunoglobulin, i.v. steroids, and a mitochon- drial cocktail (100 mg/day riboflavin and 600 mg/day CoQ10) were administered.
    explanation: The adult case received multiple empiric therapies.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She was treated with a dopamine agonist and idebenone.
    explanation: Idebenone was another reported intervention; benefit cannot be separated from other treatment or natural fluctuation.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: riboflavin
      term:
        id: CHEBI:17015
        label: riboflavin
    - preferred_term: coenzyme Q10
      term:
        id: CHEBI:46245
        label: coenzyme Q10
    - preferred_term: idebenone
      term:
        id: CHEBI:31687
        label: idebenone
- name: Empiric immunotherapy during initial adult evaluation
  description: IV immunoglobulin and corticosteroids were administered during the initial adult presentation. They are reported historical interventions, without evidence of disease-modifying efficacy for the genetic RNA-processing disorder.
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At this point, i.v. immunoglobulin, i.v. steroids, and a mitochon- drial cocktail (100 mg/day riboflavin and 600 mg/day CoQ10) were administered.
    explanation: Records the empiric interventions without recommending them for FASTKD5 deficiency.
- name: Developmental, visual and cardiac follow-up
  description: Provide physical and occupational therapy, communication support, ophthalmologic care and cardiology follow-up according to manifestations. General LSS surveillance includes regular neurological, eye, hearing and cardiac assessment.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neurologic, ophthalmologic, audiologic, and cardiologic evaluations are recommended
    explanation: General LSS surveillance framework.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Equipment to prevent falling, maintain independent mobility as appropriate
    explanation: Rehabilitation aims to preserve safe function.
- name: Perioperative and metabolic precautions
  description: General mitochondrial-disease guidance recommends limiting fasting and catabolism, assessing anesthetic respiratory risk, avoiding lactate-containing fluids when acidosis is a risk, and avoiding valproate when possible. The absolute POLG-specific valproate contraindication is not a FASTKD5-specific finding.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Catabolism should be prevented by minimizing preoperative fasting
    explanation: General LSS perioperative recommendation.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sodium valproate should be avoided if possible, because of its inhibitory effect on respiratory chain enzymes.
    explanation: General LSS medication caution.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Avoid lactate-containing agents (e.g., Ringer's lactate) in those at risk of lactic acidosis
    explanation: General LSS guidance addresses patients at risk of lactic acidosis.
- name: Genetic counseling and reproductive options
  description: For confirmed autosomal recessive disease with both parents carrying a familial variant, recurrence risk is 25% per pregnancy. Offer segregation/carrier testing and discuss prenatal or preimplantation testing once the familial variants are established.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic ... carrier ... and a 25% chance of being unaffected and not a carrier.
    explanation: The general recessive LSS counseling model applies to established biallelic FASTKD5 disease.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Once the LSS-related ... have been identified in an affected family member, prenatal and ... preimplantation genetic testing ... are possible.
    explanation: General LSS guidance permits prenatal and preimplantation testing after familial variants are identified.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: Experimental FASTKD5 complementation and protein stabilization concept
  description: Wild-type gene complementation rescues patient fibroblast defects. Overexpressed p.Tyr125Cys partly restores COX activity, motivating a proposal to stabilize that protein. No stabilizing compound or clinical gene therapy was tested in this report.
  evidence:
  - *id007
  - *id026
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Stabilizing this variant could poten- tially ameliorate the clinical phenotype in this subject.
    explanation: Protein stabilization is a proposed strategy, not a demonstrated treatment.
inheritance:
- *id027
diagnosis:
- name: Molecular diagnosis and family segregation
  description: Identify biallelic FASTKD5 variants by genomic testing and establish phase. The clinical series used exome sequencing; general Leigh syndrome spectrum guidance favors genome sequencing when available to assess both nuclear and mitochondrial causes.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:40499538
    reference_title: Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Using exome sequencing, we identified compound heterozygous variants of unknown significance in FASTKD5
    explanation: Exome sequencing identified the candidate variants in the founding series.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/
    reference_title: Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genome sequencing is preferred (if available), as it allows analysis of the mitochondrial and nuclear genome, and typically has the highest diagnostic rate.
    explanation: General LSS diagnostic guidance; the chapter does not contain a FASTKD5-specific section.
- name: Brain MRI and magnetic resonance spectroscopy
  description: Evaluate characteristic brainstem and basal ganglia lesions and possible thalamic involvement. MRS may show a lactate peak. These findings support Leigh syndrome spectrum but do not identify the causal gene.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - *id020
  - *id021
  - *id028
- name: Respiratory-chain enzyme and muscle evaluation
  description: Enzymology can support variant interpretation. Subject 2 had COX-deficient muscle histochemistry; subject 3 had normal routine pathology but severe complex IV enzymatic deficiency and abnormal combined assays. An isolated complex IV pattern is not a required finding in every tissue.
  evidence:
  - *id024
- name: Functional RNA processing and complementation studies
  description: Northern blotting or RNA sequencing, CO1 protein/translation assays and wild-type complementation can substantiate pathogenicity of uncertain variants. These are specialized cellular investigations, not established population screening assays.
  evidence:
  - *id004
  - *id007
histopathology:
- name: Variable skeletal muscle pathology
  description: Adult subject 2 had diffuse COX deficiency, small fibers and mild connective-tissue/inflammatory changes with multiple mtDNA deletions. Subject 3 had no significant routine pathologic abnormality and normal mtDNA content/sequence despite deficient enzymology; neither mtDNA depletion nor abnormal muscle histology is universal.
  evidence:
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Muscle biopsy revealed modest myopathic changes, including diffuse cytochrome c oxidase (COX) defi- ciency, hypo-atrophic fibers, rare sandwich-type fibers, rare chronic inflammatory lymphomonocytes, and a slight increase in endomysial and perimysial connective tissue, ... deletions in mtDNA.
    explanation: Subject 2 muscle had COX-deficient myopathic changes.
  - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: age and showed no significant pathologic abnormalities with normal mitochondrial DNA content and sequencing.
    explanation: Subject 3 routine muscle evaluation was normal.
experimental_models:
- name: Patient-derived immortalized fibroblasts
  experimental_model_type: CELL_LINE
  description: Fibroblasts from subjects 1 and 2 support RNA, protein, assembly and complementation experiments. Subject 3 muscle data are distinct. Residual FASTKD5 function preserves mature CYB and complex III assembly in the tested patient lines.
  publication: PMID:40499538
  evidence:
  - *id029
  - *id004
  - *id007
  - *id026
  modeled_mechanisms:
  - target: Reduced FASTKD5 protein abundance
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Patient-derived fibroblasts reproduce the measured cellular defect; immortalization and absence of neural tissue limit inference about brain injury or clinical treatment efficacy.
    fidelity: HIGH
    evidence:
    - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: 'Immunoblot analysis of fibroblasts showed decreased steady-state levels of FASTKD5 protein in two subjects for whom fibroblast cultures were available: 24% of con- trols in subject 1 and 45% of controls in subject 2 (Figures 2A and 2B),'
      explanation: Patient fibroblasts from subjects 1 and 2 have reduced FASTKD5 protein abundance.
  - target: Impaired noncanonical mitochondrial RNA processing
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Patient-derived fibroblasts reproduce the measured cellular defect; immortalization and absence of neural tissue limit inference about brain injury or clinical treatment efficacy.
    fidelity: HIGH
    evidence:
    - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: the accumulation of unprocessed 5 ′ end MT-CO1, MT-ATP8/6-CO3, and MT-ND5-CYB transcripts, with a lack of mature MT-CO1 and MT-CO3 (Figure 2E), but normal levels of mature MT-CYB, suggesting that residual activity of the FASTKD5 variants in the subjects’ fibro- blasts was sufficient to process MT-ND5-CYB pre-mRNA, resembling the situation in FASTKD5 knockdown cells.
      explanation: Processing defects preferentially deplete mature CO1 and CO3; residual function preserves mature CYB in patient fibroblasts.
  - target: Reduced complex IV assembly
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Patient-derived fibroblasts reproduce the measured cellular defect; immortalization and absence of neural tissue limit inference about brain injury or clinical treatment efficacy.
    fidelity: HIGH
    evidence:
    - reference: url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      reference_title: https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: This resulted in a severe decrease in the steady-state levels of the cytochrome c ox- idase subunit 1 (MT-CO1; Figures 2A and 2B), a conse- quent reduction in the level of the fully assembled COX complex (complex IV; Figure 2C), and reduced COX enzy- matic activity (Figure 2D).
      explanation: Patient fibroblasts show reduced fully assembled complex IV and COX enzymatic activity.
- name: FASTKD5-disrupted HAP1 cells
  experimental_model_type: CELL_LINE
  description: Single and double FASTK-family disruption models reveal CO1 translation and respiration defects. The later 2025 study found residual FASTKD5 in the HAP1 system; these lines should not be equated with complete-null 143B or HEK293T cells. CO3 translation effects differ across cellular contexts.
  publication: PMID:34748562
  evidence:
  - *id009
  - reference: PMID:40637235
    reference_title: FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: However, in that study KO cells retained residual FASTKD5 protein, which could partially compensate for processing defects.
    explanation: The later paper explains why the HAP1 disruption model is not equivalent to complete loss.
  modeled_mechanisms:
  - target: Reduced CO1 translation
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Engineered HAP1 cells retain residual FASTKD5 and differ from patient fibroblasts in other mitochondrial RNA factors; the assay does not establish a neuronal phenotype.
    fidelity: MODERATE
    evidence:
    - reference: PMID:34748562
      reference_title: The FASTK family proteins fine-tune mitochondrial RNA processing.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Remarkably, COX1 protein synthesis was strongly perturbed in the cells lacking FASTKD5, consistent with the severe defect in pre-CO1 RNA processing
      explanation: Pulse labeling in the HAP1 disruption model demonstrates reduced CO1 synthesis.
  - target: Impaired mitochondrial respiration
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Engineered HAP1 cells retain residual FASTKD5 and differ from patient fibroblasts in other mitochondrial RNA factors; the assay does not establish a neuronal phenotype.
    fidelity: MODERATE
    evidence:
    - reference: PMID:34748562
      reference_title: The FASTK family proteins fine-tune mitochondrial RNA processing.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In contrast, oxygen consumption was dramatically reduced in both the FASTKD5-sKO and the FASTKD4&5-dKO cells.
      explanation: Respiration was directly measured in engineered HAP1 cells; it was not a patient neuronal ATP assay.
- name: Complete FASTKD5 knockout in 143B and HEK293T cells
  experimental_model_type: CELL_LINE
  description: True knockout models show failure of all three noncanonical RNA-processing events, reduced CO1 and CYB translation, loss of complexes III and IV and secondary complex I loss. Uridine supports culture of respiratory-deficient cells; this does not establish uridine therapy in patients.
  publication: PMID:40637235
  evidence:
  - *id006
  - *id011
  - *id030
  modeled_mechanisms:
  - target: Impaired noncanonical mitochondrial RNA processing
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Complete-null engineered cells exaggerate loss of function relative to residual-function patient fibroblasts, which retain mature CYB and complex III assembly; clinical transfer requires corroboration.
    fidelity: LOW
    evidence:
    - reference: PMID:40637235
      reference_title: FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We next proceeded to investigate the effects of the FASTKD5 KO on RNA processing by Northern blot analysis (Fig. 1C) which showed near complete loss of the mature, processed forms of the CO1, CO3, and CYB mRNAs, a phenotype rescued by expression of the FLAG-tagged WT construct.
      explanation: The complete-knockout model abolishes processing at all three noncanonical junctions.
  - target: Reduced CYB translation in complete-knockout cells
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Complete-null engineered cells exaggerate loss of function relative to residual-function patient fibroblasts, which retain mature CYB and complex III assembly; clinical transfer requires corroboration.
    fidelity: LOW
    evidence:
    - reference: PMID:40637235
      reference_title: FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Quantification of these results (Supplementary Fig. S1F) showed that the translation of CO1 and CYB was specifically decreased, to near zero, consistent with the results of the Northern blot analysis (Fig. 1C) demonstrating that the presence of 5′-UTRs on these transcripts prevents translation on mitochondrial ribosomes.
      explanation: Complete knockout causes a broader translation defect than the residual-function patient cells.
  - target: Reduced complex III assembly in complete-knockout cells
    relationship: PARTIALLY_RECAPITULATES
    model_scale: CELLULAR
    limitations: Complete-null engineered cells exaggerate loss of function relative to residual-function patient fibroblasts, which retain mature CYB and complex III assembly; clinical transfer requires corroboration.
    fidelity: LOW
    evidence:
    - reference: PMID:40637235
      reference_title: FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Analysis of the assembly of the OXPHOS complexes by BN-PAGE demonstrated that complexes III and IV failed to assemble, as expected from the mitochondrial translation experiments (Fig. 1E).
      explanation: The additional complex III defect belongs to complete-knockout models.
- name: Reconstituted recombinant FASTKD5 cleavage assay
  experimental_model_type: OTHER
  description: Purified wild-type and engineered D429N proteins distinguish intrinsic endonuclease activity from RNA binding. CCA and upstream RNA structural features contribute to substrate recognition, but a complete substrate-bound structure and the role of auxiliary factors remain unresolved.
  publication: PMID:40637235
  evidence:
  - *id003
  - reference: PMID:40637235
    reference_title: FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the D429N variant showed markedly diminished processing activity for all three noncanonical transcripts.
    explanation: The engineered mutant is a cleavage-defective mechanistic control.
  - reference: PMID:40637235
    reference_title: FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: These data imply that the CCA motif in the CO1 and CYB pre-mRNAs is important but not sufficient for FASTKD5 recognition of the cleavage site.
    explanation: Sequence recognition contributes to the assay mechanism without establishing the full recognition structure.
datasets:
- accession: geo:GSE290841
  title: FASTKD5 processes mitochondrial pre-mRNAs at non-canonical cleavage sites
  description: Mitochondrial RNA structure profiling in wild-type and engineered FASTKD5-knockout HEK293T cells. This is not the patient-fibroblast clinical series; those RNA/proteomic data were described as available on request.
  publication: PMID:40637235
  evidence:
  - reference: GEO:GSE290841
    reference_title: FASTKD5 processes mitochondrial pre-mRNAs at non-canonical cleavage sites
    supports: SUPPORT
    evidence_source: OTHER
    snippet: To investigate the molecular mechanism involved, we created knockout human cell lines to use as assay systems.
    explanation: The GEO record identifies an engineered-cell experiment.
  - reference: PMID:40637235
    reference_title: FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Sequencing data have been uploaded to Gene Expression Omnibus with accession number GSE290841.
    explanation: The primary paper links its sequencing data to this accession.
notes: The three reported individuals do not establish separate severity subtypes, penetrance, population prevalence or feature frequencies. The general Nuclear Gene-Encoded Leigh Syndrome Spectrum GeneReview supplies care and counseling context but has no FASTKD5-specific section; its cohort frequencies are not transferred to MC4DN24. Patient and null-model findings differ with residual function and tissue context. A co-occurring 1q21.1 deletion in subject 2 complicates attribution of facial features. The mmc2.pdf reference contains the full clinical article and its supplemental material.

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References & Deep Research

References

6

PMID:40499538

Bi-allelic mutations in FASTKD5 are associated with cytochrome c oxidase deficiency and early- to late-onset Leigh syndrome.

No top-level findings curated for this source.

url:https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf

https://ars.els-cdn.com/content/image/1-s2.0-S0002929725001880-mmc2.pdf

No top-level findings curated for this source.

PMID:40637235

FASTKD5 processes mitochondrial pre-mRNAs at noncanonical cleavage sites.

No top-level findings curated for this source.

PMID:34748562

The FASTK family proteins fine-tune mitochondrial RNA processing.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/sites/books/NBK320989/

Nuclear Gene-Encoded Leigh Syndrome Spectrum Overview - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

GEO:GSE290841

FASTKD5 processes mitochondrial pre-mRNAs at non-canonical cleavage sites

No top-level findings curated for this source.

FASTKD5-Related COX Deficiency

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