Spinocerebellar Ataxia, Autosomal Recessive, With Axonal Neuropathy 3

Mendelian MONDO:0020770 Pathograph 61 Show in embeddings browser Mitochondrial Disease Autosomal Recessive Cerebellar Ataxia Hereditary Axonal Neuropathy

Spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3) is an autosomal recessive mitochondrial disorder caused by biallelic loss-of-function variants in COA7, which encodes a metazoan-specific cytochrome c oxidase (complex IV) assembly factor of the mitochondrial intermembrane space. The core picture is an early-onset, slowly progressive axonal sensorimotor neuropathy resembling Charcot-Marie-Tooth disease combined with cerebellar ataxia and cerebellar atrophy. Leukoencephalopathy (cavitating in the first reported patient), spinal cord atrophy, mild cognitive impairment, subclinical mitochondrial myopathy, and, in a few patients, dystonia or levodopa-responsive parkinsonism make up a wider COA7-related spectrum; onset ranges from infancy to the fourth decade. Patient cells show isolated or predominant complex IV deficiency with reduced assembled complex IV that is rescued by wild-type COA7. Only a small number of patients, most of them Japanese, have been described.

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Overview

Inheritance1

Mechanism

Pathophysiology16

Phenotypes & genetics

Phenotypes38 Genes1 Variants7

Treatment & exposures

Medical actions5

Course & epidemiology

Prevalence1 Differentials2

Research

Models2 Deep research1

Pathograph 61 nodes · 23/38 phenotypes connected

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Inheritance

Autosomal recessive inheritance HP:0000007

Disease requires biallelic COA7 variants, homozygous (including in a child of consanguineous parents) or compound heterozygous, and variants segregate with disease in the reported families.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:29718187 SUPPORT Human clinical

"Validated mutations were located at highly conserved residues among different species and segregated with the disease in each family."

Segregation of biallelic COA7 variants with disease in four families.

PMID:42182620 SUPPORT BACKGROUND Human clinical

"Biallelic pathogenic variants in COA7 have been reported to date, consistent with recessive inheritance."

Summarizes the recessive inheritance pattern across reported patients.

PMID:35603692 SUPPORT BACKGROUND Human clinical

"Spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3) is a very rare autosomal recessive hereditary disease."

States the autosomal recessive mode of inheritance of SCAN3.

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Pathophysiology

Reduced Mitochondrial COA7 Protein

Pathogenic COA7 missense and in-frame alleles produce proteins that are imported into the mitochondrial intermembrane space more slowly than wild type through the MIA (CHCHD4) disulfide-relay pathway; mutant protein left in the cytosol is degraded by the proteasome, so little or no COA7 accumulates in mitochondria. In fibroblasts from the first reported patient no COA7 protein was detectable. Truncating alleles are presumed to abolish the protein, but this has not been tested.

protein import into mitochondrial intermembrane space GO:0045041 ↓ DECREASED proteasomal degradation of mislocalized COA7 GO:0043161 ↑ INCREASED

Downstream

Loss of COA7 Disulfide Reductase Activity With little COA7 in the intermembrane space, its heme-binding disulfide reductase activity toward the copper chaperones is lost.

Show evidence (3 references)

PMID:30885959 SUPPORT In vitro / ex vivo

"We also found that pathogenic mutant versions of COA7 are imported slower than the wild-type protein, and mislocalized proteins are degraded in the cytosol by the proteasome."

Shows slowed import and proteasomal degradation of patient COA7 variants.

PMID:30885959 SUPPORT In vitro / ex vivo

"We found that COA7 requires the mitochondrial IMS import and assembly (MIA) pathway for efficient accumulation in the IMS"

Identifies the import route whose inefficiency lowers mitochondrial COA7.

PMID:27683825 SUPPORT In vitro / ex vivo

"No COA7 cross-reacting material was immunodetectable, and the amount of two COX structural subunits (MT-CO2 and MT-CO3) was reduced in the mutant sample, relative to control cells"

COA7 protein is absent from patient fibroblasts.

Loss of COA7 Disulfide Reductase Activity

COA7 is a heme-binding protein built from five helix-turn-helix (Sel1-like) repeats that interacts transiently with the copper metallochaperones SCO1 and SCO2 and reduces disulfide bonds in them, which is proposed to regenerate the copper relay that delivers copper to COX2. Loss of COA7 removes this activity. The step is shown biochemically and in COA7 knockout cells; that patient variants act through it is inferred.

COA7 hgnc:25716 ↓ DECREASED

protein-disulfide reductase activity GO:0015035 ↓ DECREASED heme binding GO:0020037 ↓ DECREASED

Downstream

Complex IV Assembly Stall After COX1 Module Formation Without COA7, complex IV assembly stops after the COX1 module forms, at the step that needs copper incorporation and addition of the COX2 and COX3 modules.

Show evidence (2 references)

PMID:35210360 SUPPORT In vitro / ex vivo

"COA7 interacts transiently with the copper metallochaperones SCO1 and SCO2 and catalyzes the reduction of disulfide bonds within these proteins, which are crucial for copper relay to COX2."

Defines the disulfide reductase activity toward SCO1 and SCO2 that is lost.

PMID:35210360 SUPPORT In vitro / ex vivo

"COA7 binds heme with micromolar affinity, through axial ligation to the central iron atom by histidine and methionine residues."

Establishes heme binding as part of COA7 function.

Complex IV Assembly Stall After COX1 Module Formation

Cytochrome c oxidase cannot progress past the COX1 module, so the mtDNA-encoded subunits MT-CO2 and MT-CO3 and the fully assembled holoenzyme and the complex III2-IV supercomplex are reduced in patient cells. Re-expression of wild-type COA7 restores normal complex IV amount, and COA7 knockdown or knockout in human cell lines reproduces the assembly defect. COA7 is the substituted early assembly factor in this instance of the complex IV biogenesis failure module.

mitochondrial respiratory chain complex IV assembly GO:0033617 ↓ DECREASED

Experimental models

COA7 patient-derived skin fibroblasts PRIMARY CELL CULTURE Patient fibroblasts show the complex IV assembly defect and its rescue.

Downstream

Deficient Cytochrome c Oxidase Electron Transfer and Respiration Too little assembled holoenzyme leaves too little complex IV activity.

Show evidence (3 references)

PMID:29718187 SUPPORT In vitro / ex vivo

"BN-PAGE immunoblotting and densitometry analysis indicated dramatically reduced levels of fully assembled complex IV of Patients 2 and 3 (3.8% and 9.9% remained, respectively)."

Patient fibroblasts have very little fully assembled complex IV.

PMID:27683825 SUPPORT In vitro / ex vivo

"In patient-derived immortalised fibroblasts, the levels of fully assembled cIV and of the cIII2+cIV supercomplex were clearly lower relative to controls"

Reduced assembled complex IV and supercomplex in patient fibroblasts.

PMID:24333015 SUPPORT In vitro / ex vivo

"The activity of complexes I and IV is reduced in C1orf163-depleted cells, and we observe the strongest defects in the assembly of complex IV."

COA7 (C1orf163) knockdown in human cells chiefly impairs complex IV assembly.

Deficient Cytochrome c Oxidase Electron Transfer and Respiration

Complex IV activity is reduced in patient fibroblasts, skeletal muscle and skin, and mitochondrial respiration falls. One patient's fibroblasts instead showed a decrease in complex I activity with only a slight reduction in assembled complex IV, and one Chinese patient had normal fibroblast respiratory chain activities despite mitochondrial abnormalities in muscle, so fibroblast testing can miss the defect.

mitochondrial electron transport, cytochrome c to oxygen GO:0006123 ↓ DECREASED mitochondrial ATP synthesis coupled electron transport GO:0042775 ↓ DECREASED

Downstream

Glycolytic Shift With Increased Lactate Production Impaired oxidative metabolism shifts pyruvate toward lactate, raising lactate and pyruvate in blood and CSF.

Bioenergetic Failure in Energy-Demanding Neural and Muscle Tissue Reduced respiratory chain capacity limits oxidative energy supply to tissues with high demand, chiefly the long peripheral axons, cerebellum, white matter, spinal cord and muscle.

Show evidence (4 references)

PMID:29718187 SUPPORT In vitro / ex vivo

"With regard to Patients 2 and 3, MRC enzyme assay revealed a significant decrease in complex IV activity (24% and 9% of control, respectively)"

Complex IV activity in patient fibroblasts is well below control.

PMID:27683825 SUPPORT Human clinical

"Biochemical analysis of the mitochondrial respiratory chain revealed the presence of isolated deficiency of cytochrome c oxidase (COX) activity in skin fibroblasts and skeletal muscle."

Isolated complex IV deficiency in patient fibroblasts and muscle.

PMID:34322155 SUPPORT In vitro / ex vivo

"Functional validation experiments revealed isolated complex IV deficiency and a significantly reduced mitochondrial respiration rate in patient-derived fibroblasts."

Reduced complex IV activity lowers cellular respiration.

+ 1 more reference

Glycolytic Shift With Increased Lactate Production

Lactate and pyruvate are mildly elevated in blood or CSF in several patients. Overt lactic acidosis or metabolic decompensation has not been described; the lactate rise is the mild end of the module's anaerobic-glycolysis arm.

lactate biosynthetic process GO:0019249 ↑ INCREASED

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

"Laboratory studies showed elevated lactate and pyruvate levels in blood or CSF with mild elevation of serum creatine kinase levels (Table 1)."

Elevated lactate and pyruvate indicate increased glycolytic lactate production.

Bioenergetic Failure in Energy-Demanding Neural and Muscle Tissue

Energy failure in the tissues the disease affects: peripheral nerve, cerebellum, cerebral white matter, spinal cord, the nigrostriatal system and skeletal muscle. This is the module's high-energy tissue step with the COA7-specific tissue tropism substituted. It is inferred from the biochemical defect and the tissue findings; no study has measured energy status in patient neural tissue, and why these tissues are selectively affected is not known.

aerobic respiration GO:0009060 ↓ DECREASED

Downstream

Peripheral Nerve Bioenergetic Insult Long peripheral axons and their Schwann cells are exposed to the energy deficit.

Cerebellar Neuron Bioenergetic Insult Cerebellar neurons are exposed to the energy deficit.

Cerebral White Matter Injury Energy failure is associated with white matter lesions in some patients.

Cerebral Neurodegeneration Energy failure in the developing brain is associated with progressive brain atrophy in the infantile form.

Nigrostriatal Dopaminergic Terminal Loss Dopaminergic nigrostriatal neurons are a proposed vulnerable population; the mechanism is inferred by analogy with other mitochondrial parkinsonism genes.

Subclinical Mitochondrial Myopathy The respiratory chain defect is expressed in skeletal muscle fibres.

Atrophy of the spinal cord Spinal cord atrophy is seen on MRI in some patients.

Peripheral Nerve Bioenergetic Insult

Peripheral motor and sensory neurons with long axons, and the Schwann cells that ensheathe them, are the initiating site of the neuropathy. COA7 is expressed in the cytoplasm of Schwann cells in human sural nerve, and neuron-specific knockdown of the fly orthologue impairs motor neuron terminals and locomotion, supporting a requirement in neurons. Oxidative stress, which the module records at this node, has not been examined in COA7 disease.

motor neuron CL:0000100 sensory neuron CL:0000101 Schwann cell CL:0002573

aerobic respiration GO:0009060 ↓ DECREASED

sural nerve UBERON:0015488

Downstream

Length-Dependent Peripheral Axonal Degeneration The insult leads to chronic degeneration of large and medium myelinated axons.

Show evidence (2 references)

PMID:29718187 SUPPORT Human clinical

"An immunohistochemical assay with an anti-COA7 antibody in the sural nerve from the control patient showed the positive expression of COA7 in the cytoplasm of Schwann cells."

COA7 is expressed in peripheral nerve Schwann cells.

PMID:29718187 SUPPORT Model organism

"These results suggest that dCOA7 regulates the formation and/or maintenance of motor neurons at presynaptic terminals at the NMJ."

Neuron-specific loss of the fly orthologue damages motor neuron terminals.

Length-Dependent Peripheral Axonal Degeneration

Sural nerve biopsies show chronic axonal degeneration with marked loss of large and medium myelinated fibres, small thinly myelinated fibres, and no onion bulbs or inflammation. The process is axonal in nearly all patients; the first reported patient had a mixed axonal and demyelinating neuropathy.

motor neuron CL:0000100 sensory neuron CL:0000101

sural nerve UBERON:0015488

Animal models

Drosophila neuron-specific dCOA7 RNAi knockdown Drosophila melanogaster partially recapitulates Neuronal loss of dCOA7 damages motor neuron presynaptic terminals and motor function, in line with the motor axonal neuropathy.

Downstream

Length-Dependent Sensorimotor Nerve Fiber Dysfunction Loss of large motor and sensory axons abolishes distal motor and sensory responses.

Show evidence (4 references)

PMID:29718187 SUPPORT Human clinical

"Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large and medium myelinated fibres."

Direct histological evidence of chronic axonal degeneration.

PMID:29718187 SUPPORT Human clinical

"Inflammatory cells, onion-bulb formation and clusters of myelinated fibres were absent. These features are compatible with chronic axonal degeneration."

Excludes a primary demyelinating or inflammatory process.

PMID:35603692 SUPPORT Human clinical

"Nerve conduction studies and sural nerve biopsies revealed sensorimotor axonal neuropathy."

Independent biopsy confirmation in a Chinese patient.

+ 1 more reference

Length-Dependent Sensorimotor Nerve Fiber Dysfunction

Nerve conduction shows absent or severely reduced motor and sensory action potentials in the lower limbs with near-normal median motor conduction velocity, the electrophysiological signature of a length-dependent axonal neuropathy. Clinically this gives distal weakness and wasting, distal sensory loss, reduced or absent reflexes, foot deformity, steppage gait and a sensory component to the ataxia.

motor neuron CL:0000100 sensory neuron CL:0000101

transmission of nerve impulse GO:0019226 ↓ DECREASED

Downstream

Peripheral axonal neuropathy

Distal muscle weakness

Distal amyotrophy

Distal sensory impairment

Hyporeflexia

Areflexia

Sensory ataxia

Steppage gait

Pes cavus Long-standing distal weakness produces the cavus foot deformity typical of CMT-like neuropathy.

Respiratory failure In the one patient with respiratory failure the authors judged severe axonal impairment, especially of the phrenic nerve, to be the main cause. They also list myopathy of the respiratory muscles and airway narrowing from progressive vocal cord paralysis as possible contributors.

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

"In all four patients, nerve conduction studies showed axonal sensorimotor neuropathy with mild decrease in motor conduction velocity (49.6 to 51.5 m/s) in the median nerve and absence or severe decrease of compound muscle action potential and sensory nerve action potential in lower limb nerves (Table 1)."

Length-dependent loss of motor and sensory responses in all four patients.

Cerebellar Neuron Bioenergetic Insult

The mitochondrial energy deficit stresses cerebellar neurons, the trigger substitution the module lists for mitochondrial proteins in autosomal recessive ataxias. Which cerebellar cell populations are affected is unknown: there is no neuropathology of SCAN3, so Purkinje cell involvement is not documented and the cell type is recorded generically. Cerebellar hypoperfusion on SPECT in two patients is consistent with reduced cerebellar activity.

cerebellar neuron CL:1001611

aerobic respiration GO:0009060 ↓ DECREASED

cerebellum UBERON:0002037

Downstream

Cerebellar Neurodegeneration The insult leads to cerebellar tissue loss seen as atrophy on MRI.

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

"Single-photon emission computed tomography (SPECT) revealed hypoperfusion in the cerebellum in Patients 1 and 3 (data not shown)."

Reduced cerebellar perfusion is consistent with cerebellar neuronal dysfunction.

Cerebellar Neurodegeneration

Mild cerebellar atrophy on MRI in most patients. The two Italian siblings and the first reported patient had a spared cerebellum on MRI. Not conformed to the Purkinje Neuron Degeneration module node because Purkinje cell loss has not been shown histologically.

cerebellum UBERON:0002037

Downstream

Progressive cerebellar ataxia

Dysarthria Cerebellar dysarthria accompanies the ataxia.

Intention tremor Intention tremor is a cerebellar sign.

Show evidence (2 references)

PMID:29718187 SUPPORT Human clinical

"Brain MRI showed mild cerebellar atrophy (Fig. 2) in all four patients; Patient 2 and 4 had mild white matter lesions (Fig. 2F, M and N), while Patient 3 had spinal cord atrophy (Fig. 2J and K)."

Cerebellar atrophy in all four index patients.

PMID:35603692 SUPPORT Human clinical

"Magnetic resonance imaging showed cerebellum and spinal cord atrophy."

Cerebellar atrophy in an independent Chinese patient.

Cerebral White Matter Injury

White matter lesions range from mild bilateral periventricular hyperintensity to the extensive cavitating leukodystrophy of the first reported patient and progressive periventricular diffusion restriction in the infantile form. The cellular target in white matter is not known, so no oligodendrocyte or myelin-specific mechanism is asserted.

cerebral white matter UBERON:0002437

Downstream

Leukoencephalopathy

Cavitating leukodystrophy

Cognitive impairment White matter disease is a proposed contributor to cognitive impairment; the two do not always occur together.

Mild intellectual disability Proposed contributor; the patient with mild intellectual disability also had white matter lesions, but white matter lesions occur without intellectual disability in other patients.

Show evidence (2 references)

PMID:27683825 SUPPORT Human clinical

"Brain and spinal cord MRI showed mild extension of signal abnormalities and extensive cavitations in the cerebral white matter; the cerebellum and brainstem were spared but the spinal cord was thin with no obvious focal lesions"

Cavitating cerebral white matter disease in the first reported patient.

PMID:29718187 SUPPORT Human clinical

"Brain MRI showed mild cerebellar atrophy (Fig. 2) in all four patients; Patient 2 and 4 had mild white matter lesions (Fig. 2F, M and N), while Patient 3 had spinal cord atrophy (Fig. 2J and K)."

Milder white matter lesions in two of four SCAN3 patients.

Cerebral Neurodegeneration

Progressive cerebral atrophy on serial MRI in the infantile-onset Chinese patient, with developmental regression from three months of age; cerebral atrophy is also recorded in a few of the Japanese patients.

brain UBERON:0000955

Downstream

Developmental regression

Lower limb spasticity Spasticity developed alongside the progressive encephalopathy in the infantile form.

Global developmental delay

Show evidence (1 reference)

PMID:34322155 SUPPORT Human clinical

"Brain MRIs at age 9, 11, 16, and 21 months showed progressive brain atrophy (see Figures 1A–D) with extended diffusion restriction in the bilateral periventricular areas."

Serial MRI documents progressive brain atrophy.

Nigrostriatal Dopaminergic Terminal Loss

Reduced striatal dopamine transporter binding on 123I-ioflupane SPECT in patients with parkinsonism or dystonia indicates loss of presynaptic nigrostriatal dopaminergic terminals. The mechanism is inferred by analogy with other mitochondrial parkinsonism genes; no neuropathology is available.

dopaminergic neuron CL:0000700

striatum UBERON:0002435

Downstream

Striatal Dopamine Deficiency Loss of nigrostriatal terminals reduces dopamine available to the striatum.

Show evidence (2 references)

PMID:37264311 SUPPORT Human clinical

"Dopamine transporter single-photon emission computed tomography using a 123I-Ioflupane revealed clear hypo-accumulation in the bilateral striatum."

Presynaptic dopaminergic terminal loss in the striatum.

PMID:37750949 SUPPORT Human clinical

"Dopamine transporter SPECT showed decreased uptake in the bilateral putamen in both patients."

Reduced putaminal dopamine transporter binding in the dystonia and parkinsonism patients.

Striatal Dopamine Deficiency

Reduced striatal dopaminergic transmission, supported by the improvement of parkinsonism with levodopa in two patients and a transient levodopa response in the infantile dystonia patient.

synaptic transmission, dopaminergic GO:0001963 ↓ DECREASED

striatum UBERON:0002435

Downstream

Parkinsonism

Dystonia Dystonia accompanied reduced striatal dopamine transporter binding and responded transiently to levodopa in one patient.

Show evidence (1 reference)

PMID:37264311 SUPPORT INDIRECT Human clinical

"Levodopa administration improved parkinsonism in this patient."

A levodopa response implies a dopamine-deficient striatum.

Subclinical Mitochondrial Myopathy

Muscle biopsy shows a few ragged-red fibres and some cytochrome c oxidase-negative fibres, with mildly raised serum creatine kinase, without clinical myopathy.

skeletal muscle fibre CL:0000188

Show evidence (2 references)

PMID:29718187 SUPPORT Human clinical

"We also observed mildly elevated serum creatine kinase levels in all patients and the presence of a few ragged-red fibres and some cytochrome c oxidase-negative fibres in a muscle biopsy obtained from one patient, which was suggestive of subclinical mitochondrial myopathy."

Muscle biopsy and CK findings define the subclinical myopathy.

PMID:35603692 SUPPORT Human clinical

"Muscle biopsies showed mitochondrial abnormalities."

Mitochondrial muscle pathology in an independent patient.

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Pathograph

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Phenotypes

Digestive 2

Feeding difficulties HP:0011968

Show evidence (1 reference)

PMID:37750949 SUPPORT Human clinical

"Patient 3 exhibited severe muscle weakness, respiratory failure, and feeding difficulties."

Feeding difficulties at the severe end of the spectrum.

Dysphagia HP:0002015

Show evidence (2 references)

PMID:37750949 SUPPORT Human clinical

"Subsequently, he developed severe painful dystonia, accompanied by dysarthria and dysphagia"

Patient 1 developed dysphagia together with severe dystonia.

PMID:37750949 SUPPORT Human clinical

"During her 20 s, she developed hoarseness (vocal cord paralysis) and dysphagia and underwent a percutaneous endoscopic gastrostomy."

Patient 3 developed dysphagia severe enough to need gastrostomy.

Limbs 1

Pes cavus HP:0001761

Show evidence (2 references)

PMID:29718187 SUPPORT Human clinical

"Patient 1, a 63-year-old male born to healthy consanguineous parents, had a pes cavus deformity and clumsy hands since his infancy."

Pes cavus from infancy.

PMID:42182620 SUPPORT Human clinical

"Shared features included distal weakness, impaired gait, areflexia, tremor, pes cavus, sensory disturbances, and cognitive difficulties, which were milder in the older brother."

Pes cavus in both siblings.

Metabolism 4

Increased circulating lactate concentration HP:0002151

Show evidence (2 references)

PMID:29718187 SUPPORT Human clinical

"Laboratory studies showed elevated lactate and pyruvate levels in blood or CSF with mild elevation of serum creatine kinase levels (Table 1)."

Elevated blood lactate.

PMID:34322155 SUPPORT Human clinical

"Serum lactate was elevated (2.98 μmol/L, normal range 0.5–2.2 μmol/L)."

Elevated serum lactate in the infantile form.

Increased CSF lactate HP:0002490

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

"Laboratory studies showed elevated lactate and pyruvate levels in blood or CSF with mild elevation of serum creatine kinase levels (Table 1)."

Elevated lactate in blood or CSF.

Increased circulating pyruvate concentration HP:0003542

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

"Laboratory studies showed elevated lactate and pyruvate levels in blood or CSF with mild elevation of serum creatine kinase levels (Table 1)."

Elevated pyruvate in blood or CSF.

Elevated circulating creatine kinase activity HP:0003236

Show evidence (2 references)

PMID:29718187 SUPPORT Human clinical

Mild CK elevation in all four index patients.

PMID:34322155 SUPPORT Human clinical

"Extensive diagnostic screening showed elevated serum CK (488 U/L, normal range 5–220 U/L)"

Elevated CK in the infantile form.

Musculoskeletal 6

Distal muscle weakness HP:0002460

Show evidence (2 references)

PMID:29718187 SUPPORT Human clinical

"Neurological examination revealed a predominant distal muscle atrophy/weakness in all limbs, distal sensory loss, absent ankle reflexes and ataxic gait."

Distal weakness on examination.

PMID:42182620 SUPPORT Human clinical

"Shared features included distal weakness, impaired gait, areflexia, tremor, pes cavus, sensory disturbances, and cognitive difficulties, which were milder in the older brother."

Distal weakness in both siblings.

Distal amyotrophy HP:0003693

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

"Neurological examination revealed truncal and limb ataxia along with predominant distal muscle atrophy/weakness of the four limbs."

Distal muscle atrophy on examination.

Lower limb spasticity HP:0002061

Show evidence (1 reference)

PMID:34322155 SUPPORT Human clinical

"In the following months, she lost previously acquired skills and developed progressive spasticity of the lower extremities."

Progressive lower-limb spasticity.

Scoliosis HP:0002650

Show evidence (1 reference)

PMID:27683825 SUPPORT Human clinical

"At her last follow-up examination, at 19 years of age, she was able to walk alone only with ankle-foot orthotic aids and had developed a marked dorsal-lumbar scoliosis."

Scoliosis in the first reported patient.

Ragged-red muscle fibers HP:0003200

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

Ragged-red fibres on muscle biopsy.

Cytochrome C oxidase-negative muscle fibers HP:0003688

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

COX-negative fibres on muscle biopsy.

Nervous System 22

Progressive cerebellar ataxia HP:0002073

Show evidence (3 references)

PMID:29718187 SUPPORT Human clinical

"We also found that all four patients had characteristic neurological features of peripheral neuropathy and ataxia with cerebellar atrophy, and some patients showed leukoencephalopathy or spinal cord atrophy on MRI scans."

Ataxia in all four index patients.

PMID:27683825 SUPPORT Human clinical

"Whole exome sequencing was carried out on a 19 year old woman, affected by early onset, progressive severe ataxia and peripheral neuropathy, mild cognitive impairment and a cavitating leukodystrophy of the brain with spinal cord hypotrophy."

Progressive ataxia in the first reported patient.

PMID:35603692 SUPPORT Human clinical

"The patient was a 31-year-old woman who presented with early-onset peripheral neuropathy and progressive ataxia."

Progressive ataxia in a Chinese patient.

Peripheral axonal neuropathy HP:0003477

Show evidence (3 references)

PMID:29718187 SUPPORT Human clinical

"Nerve conduction studies showed axonal sensorimotor neuropathy."

Axonal sensorimotor neuropathy on nerve conduction.

PMID:42182620 SUPPORT Human clinical

"Both presented with early-onset, slowly progressive axonal sensorimotor neuropathy, with differences in severity and associated features."

Axonal neuropathy as the presenting feature in two siblings.

PMID:37264311 SUPPORT Human clinical

"We report the case of a patient who developed cerebellar symptoms and slowly progressive sensory and motor neuropathy in the extremities, similar to Charcot-Marie-Tooth disease, at age 30, followed by parkinsonism at age 58."

Adult-onset CMT-like neuropathy with ataxia and later parkinsonism.

Decreased number of large peripheral myelinated nerve fibers HP:0003387

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

"Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large and medium myelinated fibres."

Documents loss of large myelinated fibres.

Distal sensory impairment HP:0002936

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

"Neurological examination revealed a predominant distal muscle atrophy/weakness in all limbs, distal sensory loss, absent ankle reflexes and ataxic gait."

Distal sensory loss on examination.

Hyporeflexia HP:0001265

Show evidence (2 references)

PMID:29718187 SUPPORT Human clinical

"The neurological features included all-modality sensory loss, attenuated deep tendon reflexes in the four limbs, dysarthria and mixed sensory and cerebellar ataxia."

Attenuated reflexes in the oldest index patient.

PMID:27683825 SUPPORT Human clinical

"The neurological evaluation showed dysarthria, dysmetria, ataxic gait and hyporeflexia in the four limbs with muscle wasting."

Hyporeflexia in the first reported patient.

Areflexia HP:0001284

Show evidence (1 reference)

PMID:42182620 SUPPORT Human clinical

"Shared features included distal weakness, impaired gait, areflexia, tremor, pes cavus, sensory disturbances, and cognitive difficulties, which were milder in the older brother."

Areflexia in both siblings.

Sensory ataxia HP:0010871

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

"The neurological features included all-modality sensory loss, attenuated deep tendon reflexes in the four limbs, dysarthria and mixed sensory and cerebellar ataxia."

Mixed sensory and cerebellar ataxia.

Steppage gait HP:0003376

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

"She had gait abnormalities (steppage gait) at age 4."

Steppage gait as an early sign.

Cerebellar atrophy HP:0001272

Show evidence (2 references)

PMID:29718187 SUPPORT Human clinical

"Brain MRI showed mild cerebellar atrophy (Fig. 2) in all four patients; Patient 2 and 4 had mild white matter lesions (Fig. 2F, M and N), while Patient 3 had spinal cord atrophy (Fig. 2J and K)."

Cerebellar atrophy in all four index patients.

PMID:42182620 REFUTE Human clinical

"Brain MRI findings were unremarkable in both siblings."

Cerebellar atrophy is not universal; both siblings had a normal brain MRI.

Dysarthria HP:0001260

Show evidence (2 references)

PMID:29718187 SUPPORT Human clinical

"The neurological features included all-modality sensory loss, attenuated deep tendon reflexes in the four limbs, dysarthria and mixed sensory and cerebellar ataxia."

Dysarthria in an index patient.

PMID:27683825 SUPPORT Human clinical

"The neurological evaluation showed dysarthria, dysmetria, ataxic gait and hyporeflexia in the four limbs with muscle wasting."

Dysarthria in the first reported patient.

Intention tremor HP:0002080

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

"She was hospitalized because she had difficulty standing and an intention tremor at age 6."

Intention tremor at age 6.

Leukoencephalopathy HP:0002352

Show evidence (2 references)

PMID:29718187 SUPPORT Human clinical

Leukoencephalopathy in some index patients.

PMID:37750949 SUPPORT Human clinical

"COA7-related disorders typically encompass a spectrum of conditions characterized by a variety of major (cerebellar ataxia and axonal polyneuropathy) and minor (leukoencephalopathy, dystonia, and parkinsonism) symptoms, but may also display a dystonia-predominant phenotype."

Places leukoencephalopathy among the minor features of the spectrum.

Cavitating leukodystrophy HP:0033369

Show evidence (1 reference)

PMID:27683825 SUPPORT Human clinical

Cavitating leukodystrophy in the first reported patient.

Atrophy of the spinal cord HP:0006827

Show evidence (2 references)

PMID:35603692 SUPPORT Human clinical

"Magnetic resonance imaging showed cerebellum and spinal cord atrophy."

Spinal cord atrophy in a Chinese patient.

PMID:27683825 SUPPORT Human clinical

Thin spinal cord in the first reported patient.

Cognitive impairment HP:0100543

Show evidence (2 references)

PMID:27683825 SUPPORT Human clinical

Mild cognitive impairment in the first reported patient.

PMID:35603692 SUPPORT REVIEW SYNTHESIS Human clinical

"Compared with SCAN1 and SCAN2 patients, SCAN3 patients had earlier onset age, less cognitive impairment, and no ocular signs."

Cognitive impairment is less common in SCAN3 than in SCAN1 or SCAN2.

Mild intellectual disability HP:0001256

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

"She also manifested mild intellectual disability: the Wechsler Preschool and Primary Scale of Intelligence (WPPSI) revealed a verbal score of 76, performance score of 71 and full-scale IQ of 68."

Documents mild intellectual disability.

Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:27683825 SUPPORT Human clinical

"The perinatal period was uneventful and her early development was referred to as normal, but after 1 year of age, psychomotor delay became evident."

Psychomotor delay after the first year.

Developmental regression HP:0002376

Show evidence (1 reference)

PMID:34322155 SUPPORT Human clinical

"A Chinese girl was referred at 9 months of age with a history of developmental delay and regression since 3 months of age."

Developmental regression from three months.

Cerebral atrophy HP:0002059

Show evidence (1 reference)

PMID:34322155 SUPPORT Human clinical

"Brain MRIs at age 9, 11, 16, and 21 months showed progressive brain atrophy (see Figures 1A–D) with extended diffusion restriction in the bilateral periventricular areas."

Progressive brain atrophy.

Parkinsonism HP:0001300

Show evidence (2 references)

PMID:37264311 SUPPORT Human clinical

Parkinsonism at 58 years after decades of ataxia and neuropathy.

PMID:37750949 SUPPORT Human clinical

"Patient 2 presented with cerebellar ataxia, neuropathy, as well as parkinsonism, and showed a slight improvement upon levodopa administration."

Parkinsonism in a second patient.

Dystonia HP:0001332

Show evidence (2 references)

PMID:37750949 SUPPORT Human clinical

"Patient 1 presented with an infantile-onset generalized dystonia without cerebellar ataxia."

A dystonia-predominant presentation.

PMID:37264311 SUPPORT Human clinical

"Bradykinesia and dystonia were observed in both hands."

Hand dystonia accompanying parkinsonism.

Vocal cord paralysis HP:0001605

Show evidence (1 reference)

PMID:37750949 SUPPORT Human clinical

"During her 20 s, she developed hoarseness (vocal cord paralysis) and dysphagia and underwent a percutaneous endoscopic gastrostomy."

Patient 3 developed vocal cord paralysis in her twenties.

Respiratory 1

Respiratory failure HP:0002878

Show evidence (1 reference)

PMID:37750949 SUPPORT Human clinical

"Patient 3 exhibited severe muscle weakness, respiratory failure, and feeding difficulties."

Respiratory failure at the severe end of the spectrum.

Cellular 2

Decreased activity of mitochondrial complex IV HP:0008347

Show evidence (2 references)

PMID:27683825 SUPPORT Human clinical

"Biochemical analysis of the mitochondrial respiratory chain revealed the presence of isolated deficiency of cytochrome c oxidase (COX) activity in skin fibroblasts and skeletal muscle."

Isolated complex IV deficiency.

PMID:42182620 SUPPORT Human clinical

"Skin biopsy revealed reduced mitochondrial complex IV activity."

Reduced complex IV activity in skin.

Decreased activity of mitochondrial complex I HP:0011923

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

"Respiratory chain enzyme assay of skin fibroblasts from Patient 1 showed a definite and significant decrease in complex I activity (37% of control)"

Complex I deficiency in one patient's fibroblasts.

🧬

Genetic Associations

COA7

Gene: COA7 hgnc:25716 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:29718187 SUPPORT Human clinical

"Here we identified four unrelated patients with recessive mutations in COA7 among a Japanese case series of 1396 patients with Charcot-Marie-Tooth disease (CMT) or other inherited peripheral neuropathies, including complex forms of CMT."

Gene identification in the founding series.

PMID:27683825 SUPPORT In vitro / ex vivo

"Lentiviral-mediated expression of recombinant wild-type COA7 cDNA in the patient fibroblasts led to the recovery of the defect in COX activity and restoration of normal COX amount."

Complementation with wild-type COA7 confirms causality.

PMID:27683825 SUPPORT BACKGROUND Other

"COA7 is a 231aa-long mitochondrial protein present in animals, containing five Sel1-like tetratricopeptide repeat sequences, which are likely to interact with partner proteins."

Describes the COA7 protein.

Variants (7)

c.17A>G (p.Asp6Gly) Pathogenic

missense

Recurrent missense allele, homozygous or compound heterozygous in most Japanese patients and in one Chinese patient, carried on a common haplotype in Japan. Classified pathogenic by ACMG criteria in the 2023 Japanese series.

Show evidence (3 references)

PMID:37750949 SUPPORT Human clinical

"A haplotype analysis of the mutation hotspot in Japan, c.17A > G (p.D6G), uncovered a common haplotype block."

Recurrent Japanese allele on a shared haplotype.

PMID:37750949 SUPPORT Human clinical

"Taken together, both variants were classified as pathogenic according to the ACMG guideline."

ACMG pathogenic classification of p.Asp6Gly and p.Arg39Trp.

PMID:37264311 SUPPORT Human clinical

"Exome analysis revealed COA7 missense mutation in homozygotes (NM_023077.2:c.17A > G, NP_075565.2: p.Asp6Gly)."

Homozygous p.Asp6Gly in the adult-onset patient.

c.115C>T (p.Arg39Trp) Pathogenic

missense

Missense allele found in trans with an exon 2 deletion in one patient and homozygous in another; classified pathogenic in the 2023 Japanese series.

Show evidence (2 references)

PMID:29718187 SUPPORT Human clinical

"These findings suggest that Patient 2 has a compound heterozygous genotype that comprises a deletion of exon 2 (inherited from mother) and a missense variant (inherited from father)."

p.Arg39Trp in trans with an exon 2 deletion.

PMID:37750949 SUPPORT Human clinical

"Taken together, both variants were classified as pathogenic according to the ACMG guideline."

ACMG pathogenic classification of p.Asp6Gly and p.Arg39Trp.

c.410A>G (p.Tyr137Cys) / c.287+1G>T

missense

Compound heterozygous missense and splice-donor alleles in the first reported patient; the splice variant causes in-frame skipping of exon 2. Both mutant proteins are imported poorly and degraded by the proteasome.

Show evidence (3 references)

PMID:27683825 SUPPORT Human clinical

"We found compound heterozygous mutations in COA7: a paternal c.410A>G, p.Y137C, and a maternal c.287+1G>T variants."

Identifies the two alleles in the first patient.

PMID:27683825 SUPPORT In vitro / ex vivo

"whereas the splice site mutation produces the in-frame deletion of the 47 amino acids encoded by exon 2"

The splice-donor variant causes in-frame loss of exon 2.

PMID:30885959 SUPPORT In vitro / ex vivo

"We also found that pathogenic mutant versions of COA7 are imported slower than the wild-type protein, and mislocalized proteins are degraded in the cytosol by the proteasome."

The Y137C and exon 2-deleted proteins are imported slowly and degraded.

c.554G>A (p.Trp185*)

nonsense

Nonsense allele in trans with p.Asp6Gly in a Chinese patient.

Show evidence (1 reference)

PMID:35603692 SUPPORT Human clinical

"Whole exome next-generation sequencing identified a novel compound heterozygous mutation of COA7 (c.17A>G p.D6G; c.554G>A, p.W185*) in this patient."

Identifies the nonsense allele.

c.511G>A (p.Ala171Thr) / c.566A>G (p.Asn189Ser)

missense

Compound heterozygous missense alleles in the infantile encephalopathic form.

Show evidence (1 reference)

PMID:34322155 SUPPORT Human clinical

"Trio-exome sequencing revealed compound heterzygous variants in COA7 (c.511G > A/p.Ala171Thr and c.566A > G/p.Asn189Ser)."

Identifies the two alleles.

c.449G>A (p.Cys150Tyr) Likely pathogenic

missense

Missense allele in the fourth Sel1-like repeat, in trans with p.Asp6Gly in the infantile dystonia patient; classified likely pathogenic.

Show evidence (2 references)

PMID:37750949 SUPPORT Human clinical

"In addition to our original report, which involved four patients until 2018, we identified biallelic variants of the COA7 gene in another three unrelated patients, and the variants were c.17A > G (p.D6G), c.115C > T (p.R39W), and c.449G > A (p.C150Y; novel)."

Identifies p.Cys150Tyr.

PMID:37750949 SUPPORT Human clinical

"Altogether, we classified these variants as likely pathogenic according to the ACMG guideline."

ACMG likely pathogenic classification.

c.457C>T (p.Leu153Phe)

missense

Novel missense allele carried in compound heterozygosity by two Italian siblings.

Show evidence (1 reference)

PMID:42182620 SUPPORT Human clinical

"We describe 2 siblings carrying compound heterozygous COA7 variants, one of which (c.457C>T; p.Leu153Phe) is novel."

Identifies p.Leu153Phe.

💊

Medical Actions

Levodopa

Action: Pharmacotherapy NCIT:C15986

Agent: levodopa CHEBI:15765

Platform: Small molecule

Levodopa improved parkinsonism in one patient and slightly in a second, and gave an initial transient response in the infantile generalized dystonia patient. There is no disease-modifying therapy for SCAN3.

Mechanism Target:

Striatal Dopamine Deficiency — Levodopa replaces striatal dopamine lost with nigrostriatal terminal degeneration.

Show evidence (2 references)

PMID:37264311 SUPPORT Human clinical

"Levodopa administration improved parkinsonism in this patient."

Levodopa response in an adult-onset patient.

PMID:37750949 SUPPORT Human clinical

"Patient 2 presented with cerebellar ataxia, neuropathy, as well as parkinsonism, and showed a slight improvement upon levodopa administration."

Slight levodopa response in a second patient.

Deep Brain Stimulation

Action: deep brain stimulation Ontology label: Deep Brain Stimulation NCIT:C21024

Platform: Device

Deep brain stimulation gave an initial transient benefit for infantile-onset generalized dystonia in one patient, who nonetheless became bedridden by age 19.

Show evidence (1 reference)

PMID:37750949 SUPPORT Human clinical

"Despite experiencing an initial transient positive response to levodopa and deep brain stimulation, he became bedridden by the age of 19."

Transient response to levodopa and deep brain stimulation for dystonia.

Baclofen

Action: Pharmacotherapy NCIT:C15986

Agent: baclofen CHEBI:2972

Platform: Small molecule

Baclofen partially controlled progressive spasticity in the infantile encephalopathic form.

Show evidence (1 reference)

PMID:34322155 SUPPORT Human clinical

"During the following 5 months, the spasticity worsened, repeatedly induced by intestinal infection but was reasonably controlled with baclofen treatment."

Baclofen controlled spasticity in one patient.

Protirelin Tartrate

Action: Pharmacotherapy NCIT:C15986

Agent: protirelin CHEBI:35940

Platform: Peptide

Protirelin tartrate, a thyrotropin-releasing hormone preparation used for ataxia in Japan, gave only slight transient improvement in ataxia in one patient before the symptoms became refractory.

Show evidence (1 reference)

PMID:29718187 SUPPORT Human clinical

"treatment with protirelin tartrate (TRH-T) resulted in slight transient improvement in ataxia. However, the symptoms progressively worsened and became refractory."

Only a slight, transient benefit in a single patient.

Supportive Care and Orthoses

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Management is supportive, including ankle-foot orthoses for distal weakness and walking aids; no COA7-specific supportive regimen has been evaluated.

Show evidence (1 reference)

PMID:27683825 SUPPORT Human clinical

"At her last follow-up examination, at 19 years of age, she was able to walk alone only with ankle-foot orthotic aids and had developed a marked dorsal-lumbar scoliosis."

Use of ankle-foot orthoses for walking.

📊

Prevalence

Worldwide (published case reports)

Cases/families reported in the literature Ultra-rare

No population prevalence estimate exists. The disease is known only from case reports and small series; four of 1396 Japanese patients screened for inherited peripheral neuropathy carried biallelic COA7 variants in the founding study, and the 2022 Chinese report counted five previously documented patients. Later reports have added a few more Japanese and Italian patients.

Show evidence (2 references)

PMID:35603692 SUPPORT BACKGROUND Human clinical

"So far, only five SCAN3 patients with COA7 mutations have been documented."

Documents the very small number of reported patients as of 2022.

PMID:29718187 SUPPORT Human clinical

Gives the diagnostic yield in a large Japanese inherited-neuropathy series.

🔀

Differential Diagnoses

Conditions with similar clinical presentations that must be differentiated from Spinocerebellar Ataxia, Autosomal Recessive, With Axonal Neuropathy 3:

Spinocerebellar ataxia with axonal neuropathy type 1 Not Yet Curated MONDO:0011801

Overlapping Features TDP1-related recessive ataxia with axonal neuropathy.

Distinguishing Features

Later onset than SCAN3

Show evidence (1 reference)

PMID:35603692 SUPPORT REVIEW SYNTHESIS Human clinical

"Compared with SCAN1 and SCAN2 patients, SCAN3 patients had earlier onset age, less cognitive impairment, and no ocular signs."

Literature comparison of SCAN1, SCAN2 and SCAN3.

Ataxia with oculomotor apraxia type 2 MONDO:0018996

Overlapping Features SETX-related recessive ataxia with axonal neuropathy (SCAN2).

Distinguishing Features

Ocular signs such as oculomotor apraxia, absent in SCAN3
More cognitive impairment than SCAN3

Show evidence (1 reference)

PMID:35603692 SUPPORT REVIEW SYNTHESIS Human clinical

"Compared with SCAN1 and SCAN2 patients, SCAN3 patients had earlier onset age, less cognitive impairment, and no ocular signs."

Literature comparison of SCAN1, SCAN2 and SCAN3.

🧫

Experimental Models

COA7 patient-derived skin fibroblasts PRIMARY_CELL_CULTURE

Primary and immortalized fibroblasts from patients carrying biallelic COA7 variants, used to measure complex IV assembly and activity, to test complementation with wild-type COA7, and to test rescue by proteasome inhibitors.

Publication

PMID:27683825

Pathograph links

Complex IV Assembly Stall After COX1 Module Formation recapitulates fidelity: moderate observes: molecular Patient fibroblasts show the complex IV assembly defect and its rescue.

Limitations: Fibroblasts are not the affected neural cells, and in one patient fibroblast respiratory chain activity was normal despite muscle mitochondrial abnormalities, so fibroblasts can under-report the defect.

Readouts

Complex IV activity after proteasome inhibition

Direction: RESTORED

Interpretation: Proteasome inhibitors raised mitochondrial COA7 and complex IV activity in patient fibroblasts, an in vitro rescue only.

Show evidence (1 reference)

PMID:30885959 SUPPORT In vitro / ex vivo

"Interestingly, proteasome inhibition rescued both the mitochondrial localization of COA7 and complex IV activity in patient-derived fibroblasts."

Reports the partial rescue of complex IV activity.

Show evidence (1 reference)

PMID:27683825 SUPPORT In vitro / ex vivo

"In patient-derived immortalised fibroblasts, the levels of fully assembled cIV and of the cIII2+cIV supercomplex were clearly lower relative to controls"

Patient fibroblasts reproduce the assembly defect.

🐁

Animal Models

Drosophila neuron-specific dCOA7 RNAi knockdown

Pan-neuronal knockdown of the fly COA7 orthologue shortens lifespan, causes an age-dependent climbing defect and shortens larval motor neuron synaptic branches at the neuromuscular junction; eye-specific knockdown gives a rough eye.

Species

Drosophila melanogaster

Genotype

elav-GAL4 driven UAS-dCOA7 RNAi (CG13865), two independent RNAi lines

Publication

PMID:29718187

Pathograph links

Length-Dependent Peripheral Axonal Degeneration partially recapitulates fidelity: low observes: cellular Neuronal loss of dCOA7 damages motor neuron presynaptic terminals and motor function, in line with the motor axonal neuropathy.

Limitations: RNAi knockdown rather than patient alleles, in an invertebrate without myelinating Schwann cells; axonal degeneration of peripheral nerve and complex IV activity were not measured in the flies, so the link to human axonal degeneration is inferred from terminal morphology and locomotion.

Readouts

Larval neuromuscular junction synaptic branch length

Direction: DECREASED

Interpretation: Shorter motor neuron terminal branches after neuronal dCOA7 knockdown.

Show evidence (1 reference)

PMID:29718187 SUPPORT Model organism

"Measurement of the total length of synaptic branches of motor neurons in these larvae indicated that the total branch length was significantly decreased"

Reports the decreased synaptic branch length.

Show evidence (1 reference)

PMID:29718187 SUPPORT Model organism

"In addition, Drosophila COA7 (dCOA7) knockdown models showed rough eye phenotype, reduced lifespan, impaired locomotive ability and shortened synaptic branches of motor neurons."

Summarizes the neurodegenerative phenotype of the fly model.

{ }

Source YAML

click to show

name: Spinocerebellar Ataxia, Autosomal Recessive, With Axonal Neuropathy 3
category: Mendelian
creation_date: '2026-10-27T00:00:00Z'
synonyms:
- SCAN3
- Spinocerebellar ataxia with axonal neuropathy type 3
- COA7-related spinocerebellar ataxia with axonal neuropathy
- COA7-related disorder
description: >-
  Spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3) is an autosomal
  recessive mitochondrial disorder caused by biallelic loss-of-function variants in
  COA7, which encodes a metazoan-specific cytochrome c oxidase (complex IV) assembly
  factor of the mitochondrial intermembrane space. The core picture is an early-onset,
  slowly progressive axonal sensorimotor neuropathy resembling Charcot-Marie-Tooth
  disease combined with cerebellar ataxia and cerebellar atrophy. Leukoencephalopathy
  (cavitating in the first reported patient), spinal cord atrophy, mild cognitive
  impairment, subclinical mitochondrial myopathy, and, in a few patients, dystonia or
  levodopa-responsive parkinsonism make up a wider COA7-related spectrum; onset ranges
  from infancy to the fourth decade. Patient cells show isolated or predominant complex
  IV deficiency with reduced assembled complex IV that is rescued by wild-type COA7.
  Only a small number of patients, most of them Japanese, have been described.
disease_term:
  preferred_term: spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3
  term:
    id: MONDO:0020770
    label: spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3
parents:
- Mitochondrial Disease
- Autosomal Recessive Cerebellar Ataxia
- Hereditary Axonal Neuropathy
notes: >-
  No GeneReviews chapter names this disease (just check-genereviews, Bookshelf index
  snapshot 2026-09-10 plus live PubMed title search, returned NO_CHAPTER), so the
  primary case reports are the clinical baseline. The subcellular location of COA7 was
  first reported as the mitochondrial matrix (PMID:27683825); later import and
  structural studies place it in the intermembrane space (PMID:24333015,
  PMID:30885959, PMID:35210360), which is the location used here.
inheritance:
- name: Autosomal recessive inheritance
  description: >-
    Disease requires biallelic COA7 variants, homozygous (including in a child of
    consanguineous parents) or compound heterozygous, and variants segregate with
    disease in the reported families.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Validated mutations were located at highly conserved residues among different
      species and segregated with the disease in each family.
    explanation: Segregation of biallelic COA7 variants with disease in four families.
  - reference: PMID:42182620
    reference_title: Compound Heterozygous COA7 Variants Presenting With Childhood-Onset Axonal Neuropathy in 2 Siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Biallelic pathogenic variants in COA7 have been reported to date, consistent with
      recessive inheritance.
    explanation: Summarizes the recessive inheritance pattern across reported patients.
  - reference: PMID:35603692
    reference_title: A novel compound heterozygous mutation in the COA7 gene responsible for a Chinese patient with spinocerebellar ataxia with axonal neuropathy type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: >-
      Spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3) is a very rare
      autosomal recessive hereditary disease.
    explanation: States the autosomal recessive mode of inheritance of SCAN3.
prevalence:
- population: Worldwide (published case reports)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population prevalence estimate exists. The disease is known only from case
    reports and small series; four of 1396 Japanese patients screened for inherited
    peripheral neuropathy carried biallelic COA7 variants in the founding study, and
    the 2022 Chinese report counted five previously documented patients. Later reports
    have added a few more Japanese and Italian patients.
  evidence:
  - reference: PMID:35603692
    reference_title: A novel compound heterozygous mutation in the COA7 gene responsible for a Chinese patient with spinocerebellar ataxia with axonal neuropathy type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: So far, only five SCAN3 patients with COA7 mutations have been documented.
    explanation: Documents the very small number of reported patients as of 2022.
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we identified four unrelated patients with recessive mutations in COA7 among
      a Japanese case series of 1396 patients with Charcot-Marie-Tooth disease (CMT) or
      other inherited peripheral neuropathies, including complex forms of CMT.
    explanation: Gives the diagnostic yield in a large Japanese inherited-neuropathy series.
pathophysiology:
- name: Reduced Mitochondrial COA7 Protein
  description: >-
    Pathogenic COA7 missense and in-frame alleles produce proteins that are imported
    into the mitochondrial intermembrane space more slowly than wild type through the
    MIA (CHCHD4) disulfide-relay pathway; mutant protein left in the cytosol is degraded
    by the proteasome, so little or no COA7 accumulates in mitochondria. In fibroblasts
    from the first reported patient no COA7 protein was detectable. Truncating alleles
    are presumed to abolish the protein, but this has not been tested.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: protein import into mitochondrial intermembrane space
    term:
      id: GO:0045041
      label: protein import into mitochondrial intermembrane space
    modifier: DECREASED
  - preferred_term: proteasomal degradation of mislocalized COA7
    term:
      id: GO:0043161
      label: proteasome-mediated ubiquitin-dependent protein catabolic process
    modifier: INCREASED
  evidence:
  - reference: PMID:30885959
    reference_title: Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We also found that pathogenic mutant versions of COA7 are imported slower than the
      wild-type protein, and mislocalized proteins are degraded in the cytosol by the
      proteasome.
    explanation: Shows slowed import and proteasomal degradation of patient COA7 variants.
  - reference: PMID:30885959
    reference_title: Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found that COA7 requires the mitochondrial IMS import and assembly (MIA) pathway
      for efficient accumulation in the IMS
    explanation: Identifies the import route whose inefficiency lowers mitochondrial COA7.
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      No COA7 cross-reacting material was immunodetectable, and the amount of two COX
      structural subunits (MT-CO2 and MT-CO3) was reduced in the mutant sample, relative
      to control cells
    explanation: COA7 protein is absent from patient fibroblasts.
  downstream:
  - target: Loss of COA7 Disulfide Reductase Activity
    causal_link_type: DIRECT
    description: >-
      With little COA7 in the intermembrane space, its heme-binding disulfide reductase
      activity toward the copper chaperones is lost.
- name: Loss of COA7 Disulfide Reductase Activity
  description: >-
    COA7 is a heme-binding protein built from five helix-turn-helix (Sel1-like) repeats
    that interacts transiently with the copper metallochaperones SCO1 and SCO2 and
    reduces disulfide bonds in them, which is proposed to regenerate the copper relay
    that delivers copper to COX2. Loss of COA7 removes this activity. The step is shown
    biochemically and in COA7 knockout cells; that patient variants act through it is
    inferred.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: COA7
    term:
      id: hgnc:25716
      label: COA7
    modifier: DECREASED
  molecular_functions:
  - preferred_term: protein-disulfide reductase activity
    term:
      id: GO:0015035
      label: protein-disulfide reductase activity
    modifier: DECREASED
  - preferred_term: heme binding
    term:
      id: GO:0020037
      label: heme binding
    modifier: DECREASED
  evidence:
  - reference: PMID:35210360
    reference_title: "Mitochondrial COA7 is a heme-binding protein with disulfide reductase activity, which acts in the early stages of complex IV assembly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      COA7 interacts transiently with the copper metallochaperones SCO1 and SCO2 and
      catalyzes the reduction of disulfide bonds within these proteins, which are crucial
      for copper relay to COX2.
    explanation: Defines the disulfide reductase activity toward SCO1 and SCO2 that is lost.
  - reference: PMID:35210360
    reference_title: "Mitochondrial COA7 is a heme-binding protein with disulfide reductase activity, which acts in the early stages of complex IV assembly."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      COA7 binds heme with micromolar affinity, through axial ligation to the central
      iron atom by histidine and methionine residues.
    explanation: Establishes heme binding as part of COA7 function.
  downstream:
  - target: Complex IV Assembly Stall After COX1 Module Formation
    causal_link_type: DIRECT
    description: >-
      Without COA7, complex IV assembly stops after the COX1 module forms, at the step
      that needs copper incorporation and addition of the COX2 and COX3 modules.
    evidence:
    - reference: PMID:35210360
      reference_title: "Mitochondrial COA7 is a heme-binding protein with disulfide reductase activity, which acts in the early stages of complex IV assembly."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, we show that loss of COA7 blocks complex IV assembly after the initial step
        where the COX1 module is built, progression from which requires the incorporation
        of copper and addition of the COX2 and COX3 modules.
      explanation: COA7 knockout cells show the assembly block that follows loss of COA7.
    - reference: PMID:35210360
      reference_title: "Mitochondrial COA7 is a heme-binding protein with disulfide reductase activity, which acts in the early stages of complex IV assembly."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We therefore propose that COA7 is a heme-binding disulfide reductase for
        regenerating the copper relay system that underpins complex IV assembly.
      explanation: Proposes the link between the reductase activity and complex IV assembly.
- name: Complex IV Assembly Stall After COX1 Module Formation
  conforms_to: complex_iv_assembly_deficiency#Complex IV Biogenesis Failure
  description: >-
    Cytochrome c oxidase cannot progress past the COX1 module, so the mtDNA-encoded
    subunits MT-CO2 and MT-CO3 and the fully assembled holoenzyme and the complex
    III2-IV supercomplex are reduced in patient cells. Re-expression of wild-type COA7
    restores normal complex IV amount, and COA7 knockdown or knockout in human cell lines
    reproduces the assembly defect. COA7 is the substituted early assembly factor in this
    instance of the complex IV biogenesis failure module.
  biological_scale: MOLECULAR
  biological_processes:
  - preferred_term: mitochondrial respiratory chain complex IV assembly
    term:
      id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
    modifier: DECREASED
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      BN-PAGE immunoblotting and densitometry analysis indicated dramatically reduced
      levels of fully assembled complex IV of Patients 2 and 3 (3.8% and 9.9% remained,
      respectively).
    explanation: Patient fibroblasts have very little fully assembled complex IV.
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In patient-derived immortalised fibroblasts, the levels of fully assembled cIV and
      of the cIII2+cIV supercomplex were clearly lower relative to controls
    explanation: Reduced assembled complex IV and supercomplex in patient fibroblasts.
  - reference: PMID:24333015
    reference_title: C1orf163/RESA1 is a novel mitochondrial intermembrane space protein connected to respiratory chain assembly.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The activity of complexes I and IV is reduced in C1orf163-depleted cells, and we
      observe the strongest defects in the assembly of complex IV.
    explanation: COA7 (C1orf163) knockdown in human cells chiefly impairs complex IV assembly.
  downstream:
  - target: Deficient Cytochrome c Oxidase Electron Transfer and Respiration
    causal_link_type: DIRECT
    description: Too little assembled holoenzyme leaves too little complex IV activity.
    evidence:
    - reference: PMID:27683825
      reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Lentiviral-mediated expression of recombinant wild-type COA7 cDNA in the patient
        fibroblasts led to the recovery of the defect in COX activity and restoration of
        normal COX amount.
      explanation: >-
        Restoring COA7 restores both complex IV amount and activity together, tying the
        activity deficit to the assembly defect.
- name: Deficient Cytochrome c Oxidase Electron Transfer and Respiration
  conforms_to: complex_iv_assembly_deficiency#Impaired Terminal Electron Transfer and ATP Synthesis
  description: >-
    Complex IV activity is reduced in patient fibroblasts, skeletal muscle and skin, and
    mitochondrial respiration falls. One patient's fibroblasts instead showed a decrease
    in complex I activity with only a slight reduction in assembled complex IV, and one
    Chinese patient had normal fibroblast respiratory chain activities despite
    mitochondrial abnormalities in muscle, so fibroblast testing can miss the defect.
  biological_scale: CELLULAR
  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
  - preferred_term: mitochondrial ATP synthesis coupled electron transport
    term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
    modifier: DECREASED
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      With regard to Patients 2 and 3, MRC enzyme assay revealed a significant decrease
      in complex IV activity (24% and 9% of control, respectively)
    explanation: Complex IV activity in patient fibroblasts is well below control.
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemical analysis of the mitochondrial respiratory chain revealed the presence
      of isolated deficiency of cytochrome c oxidase (COX) activity in skin fibroblasts
      and skeletal muscle.
    explanation: Isolated complex IV deficiency in patient fibroblasts and muscle.
  - reference: PMID:34322155
    reference_title: Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional validation experiments revealed isolated complex IV deficiency and a
      significantly reduced mitochondrial respiration rate in patient-derived
      fibroblasts.
    explanation: Reduced complex IV activity lowers cellular respiration.
  - reference: PMID:35603692
    reference_title: A novel compound heterozygous mutation in the COA7 gene responsible for a Chinese patient with spinocerebellar ataxia with axonal neuropathy type 3.
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      Respiratory chain enzyme assay of skin fibroblasts showed normal respiratory chain
      complex activities.
    explanation: >-
      In one patient fibroblast respiratory chain activity was normal, so the deficit is
      not detectable in every patient's fibroblasts.
  downstream:
  - target: Glycolytic Shift With Increased Lactate Production
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Impaired oxidative metabolism shifts pyruvate toward lactate, raising lactate and
      pyruvate in blood and CSF.
  - target: Bioenergetic Failure in Energy-Demanding Neural and Muscle Tissue
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Reduced respiratory chain capacity limits oxidative energy supply to tissues with
      high demand, chiefly the long peripheral axons, cerebellum, white matter, spinal
      cord and muscle.
    evidence:
    - reference: PMID:29718187
      reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        we identified recessive mutations in COA7, and showed that loss-of-function
        mutations in COA7 result impair MRC activities and could cause early onset,
        progressive axonal neuropathy and ataxia with or without leukoencephalopathy or
        spinal cord atrophy.
      explanation: >-
        The founding study's conclusion links impaired respiratory chain activity to the
        neurological disease; the tissue energy-failure step is inferred.
- name: Glycolytic Shift With Increased Lactate Production
  conforms_to: complex_iv_assembly_deficiency#Lactic Acidosis and Metabolic Decompensation
  description: >-
    Lactate and pyruvate are mildly elevated in blood or CSF in several patients. Overt
    lactic acidosis or metabolic decompensation has not been described; the lactate
    rise is the mild end of the module's anaerobic-glycolysis arm.
  biological_scale: CELLULAR
  biological_processes:
  - preferred_term: lactate biosynthetic process
    term:
      id: GO:0019249
      label: lactate biosynthetic process
    modifier: INCREASED
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Laboratory studies showed elevated lactate and pyruvate levels in blood or CSF with
      mild elevation of serum creatine kinase levels (Table 1).
    explanation: Elevated lactate and pyruvate indicate increased glycolytic lactate production.
- name: Bioenergetic Failure in Energy-Demanding Neural and Muscle Tissue
  conforms_to: complex_iv_assembly_deficiency#High-Energy Tissue Dysfunction
  description: >-
    Energy failure in the tissues the disease affects: peripheral nerve, cerebellum,
    cerebral white matter, spinal cord, the nigrostriatal system and skeletal muscle.
    This is the module's high-energy tissue step with the COA7-specific tissue tropism
    substituted. It is inferred from the biochemical defect and the tissue findings; no
    study has measured energy status in patient neural tissue, and why these tissues are
    selectively affected is not known.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: aerobic respiration
    term:
      id: GO:0009060
      label: aerobic respiration
    modifier: DECREASED
  downstream:
  - target: Peripheral Nerve Bioenergetic Insult
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Long peripheral axons and their Schwann cells are exposed to the energy deficit.
  - target: Cerebellar Neuron Bioenergetic Insult
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cerebellar neurons are exposed to the energy deficit.
  - target: Cerebral White Matter Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Energy failure is associated with white matter lesions in some patients.
  - target: Cerebral Neurodegeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Energy failure in the developing brain is associated with progressive brain atrophy in the infantile form.
  - target: Nigrostriatal Dopaminergic Terminal Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dopaminergic nigrostriatal neurons are a proposed vulnerable population; the
      mechanism is inferred by analogy with other mitochondrial parkinsonism genes.
  - target: Subclinical Mitochondrial Myopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The respiratory chain defect is expressed in skeletal muscle fibres.
  - target: Atrophy of the spinal cord
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Spinal cord atrophy is seen on MRI in some patients.
    evidence:
    - reference: PMID:29718187
      reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        we identified recessive mutations in COA7, and showed that loss-of-function
        mutations in COA7 result impair MRC activities and could cause early onset,
        progressive axonal neuropathy and ataxia with or without leukoencephalopathy or
        spinal cord atrophy.
      explanation: Attributes spinal cord atrophy to the COA7 respiratory chain defect.
- name: Peripheral Nerve Bioenergetic Insult
  conforms_to: peripheral_axonal_degeneration#Insult to Peripheral Neurons and Schwann Cells
  description: >-
    Peripheral motor and sensory neurons with long axons, and the Schwann cells that
    ensheathe them, are the initiating site of the neuropathy. COA7 is expressed in the
    cytoplasm of Schwann cells in human sural nerve, and neuron-specific knockdown of the
    fly orthologue impairs motor neuron terminals and locomotion, supporting a
    requirement in neurons. Oxidative stress, which the module records at this node, has
    not been examined in COA7 disease.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  - preferred_term: sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: aerobic respiration
    term:
      id: GO:0009060
      label: aerobic respiration
    modifier: DECREASED
  locations:
  - preferred_term: sural nerve
    term:
      id: UBERON:0015488
      label: sural nerve
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An immunohistochemical assay with an anti-COA7 antibody in the sural nerve from
      the control patient showed the positive expression of COA7 in the cytoplasm of
      Schwann cells.
    explanation: COA7 is expressed in peripheral nerve Schwann cells.
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These results suggest that dCOA7 regulates the formation and/or maintenance of
      motor neurons at presynaptic terminals at the NMJ.
    explanation: Neuron-specific loss of the fly orthologue damages motor neuron terminals.
  downstream:
  - target: Length-Dependent Peripheral Axonal Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The insult leads to chronic degeneration of large and medium myelinated axons.
- name: Length-Dependent Peripheral Axonal Degeneration
  conforms_to: peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination
  description: >-
    Sural nerve biopsies show chronic axonal degeneration with marked loss of large and
    medium myelinated fibres, small thinly myelinated fibres, and no onion bulbs or
    inflammation. The process is axonal in nearly all patients; the first reported
    patient had a mixed axonal and demyelinating neuropathy.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  - preferred_term: sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  locations:
  - preferred_term: sural nerve
    term:
      id: UBERON:0015488
      label: sural nerve
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large
      and medium myelinated fibres.
    explanation: Direct histological evidence of chronic axonal degeneration.
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Inflammatory cells, onion-bulb formation and clusters of myelinated fibres were
      absent. These features are compatible with chronic axonal degeneration.
    explanation: Excludes a primary demyelinating or inflammatory process.
  - reference: PMID:35603692
    reference_title: A novel compound heterozygous mutation in the COA7 gene responsible for a Chinese patient with spinocerebellar ataxia with axonal neuropathy type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Nerve conduction studies and sural nerve biopsies revealed sensorimotor axonal
      neuropathy.
    explanation: Independent biopsy confirmation in a Chinese patient.
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurophysiological studies confirmed worsening of her mixed axonal demyelinating
      peripheral neuropathy.
    explanation: Records the mixed axonal-demyelinating exception in the first patient.
  downstream:
  - target: Length-Dependent Sensorimotor Nerve Fiber Dysfunction
    causal_link_type: DIRECT
    description: Loss of large motor and sensory axons abolishes distal motor and sensory responses.
- name: Length-Dependent Sensorimotor Nerve Fiber Dysfunction
  conforms_to: peripheral_axonal_degeneration#Length-Dependent Nerve Fiber Dysfunction
  description: >-
    Nerve conduction shows absent or severely reduced motor and sensory action potentials
    in the lower limbs with near-normal median motor conduction velocity, the
    electrophysiological signature of a length-dependent axonal neuropathy. Clinically
    this gives distal weakness and wasting, distal sensory loss, reduced or absent
    reflexes, foot deformity, steppage gait and a sensory component to the ataxia.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: motor neuron
    term:
      id: CL:0000100
      label: motor neuron
  - preferred_term: sensory neuron
    term:
      id: CL:0000101
      label: sensory neuron
  biological_processes:
  - preferred_term: transmission of nerve impulse
    term:
      id: GO:0019226
      label: transmission of nerve impulse
    modifier: DECREASED
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all four patients, nerve conduction studies showed axonal sensorimotor
      neuropathy with mild decrease in motor conduction velocity (49.6 to 51.5 m/s) in
      the median nerve and absence or severe decrease of compound muscle action potential
      and sensory nerve action potential in lower limb nerves (Table 1).
    explanation: Length-dependent loss of motor and sensory responses in all four patients.
  downstream:
  - target: Peripheral axonal neuropathy
    causal_link_type: DIRECT
  - target: Distal muscle weakness
    causal_link_type: DIRECT
  - target: Distal amyotrophy
    causal_link_type: DIRECT
  - target: Distal sensory impairment
    causal_link_type: DIRECT
  - target: Hyporeflexia
    causal_link_type: DIRECT
  - target: Areflexia
    causal_link_type: DIRECT
  - target: Sensory ataxia
    causal_link_type: DIRECT
  - target: Steppage gait
    causal_link_type: DIRECT
  - target: Pes cavus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Long-standing distal weakness produces the cavus foot deformity typical of CMT-like neuropathy.
  - target: Respiratory failure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In the one patient with respiratory failure the authors judged severe
      axonal impairment, especially of the phrenic nerve, to be the main
      cause. They also list myopathy of the respiratory muscles and airway
      narrowing from progressive vocal cord paralysis as possible
      contributors.
    evidence:
    - reference: PMID:37750949
      reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Therefore, we believe that the main factor contributing to respiratory
        failure in this patient is severe axonal impairment, particularly
        affecting the phrenic nerve.
      explanation: >-
        The authors attribute Patient 3's respiratory failure mainly to axonal
        neuropathy involving the phrenic nerve.
- name: Cerebellar Neuron Bioenergetic Insult
  conforms_to: cerebellar_purkinje_degeneration#Cerebellar Neuron Insult
  description: >-
    The mitochondrial energy deficit stresses cerebellar neurons, the trigger
    substitution the module lists for mitochondrial proteins in autosomal recessive
    ataxias. Which cerebellar cell populations are affected is unknown: there is no
    neuropathology of SCAN3, so Purkinje cell involvement is not documented and the cell
    type is recorded generically. Cerebellar hypoperfusion on SPECT in two patients is
    consistent with reduced cerebellar activity.
  biological_scale: CELLULAR
  cell_types:
  - preferred_term: cerebellar neuron
    term:
      id: CL:1001611
      label: cerebellar neuron
  biological_processes:
  - preferred_term: aerobic respiration
    term:
      id: GO:0009060
      label: aerobic respiration
    modifier: DECREASED
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Single-photon emission computed tomography (SPECT) revealed hypoperfusion in the
      cerebellum in Patients 1 and 3 (data not shown).
    explanation: Reduced cerebellar perfusion is consistent with cerebellar neuronal dysfunction.
  downstream:
  - target: Cerebellar Neurodegeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The insult leads to cerebellar tissue loss seen as atrophy on MRI.
- name: Cerebellar Neurodegeneration
  description: >-
    Mild cerebellar atrophy on MRI in most patients. The two Italian siblings and the first reported
    patient had a spared cerebellum on MRI. Not conformed to the Purkinje Neuron
    Degeneration module node because Purkinje cell loss has not been shown histologically.
  biological_scale: TISSUE
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI showed mild cerebellar atrophy (Fig. 2) in all four patients; Patient 2
      and 4 had mild white matter lesions (Fig. 2F, M and N), while Patient 3 had spinal
      cord atrophy (Fig. 2J and K).
    explanation: Cerebellar atrophy in all four index patients.
  - reference: PMID:35603692
    reference_title: A novel compound heterozygous mutation in the COA7 gene responsible for a Chinese patient with spinocerebellar ataxia with axonal neuropathy type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Magnetic resonance imaging showed cerebellum and spinal cord atrophy.
    explanation: Cerebellar atrophy in an independent Chinese patient.
  downstream:
  - target: Progressive cerebellar ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29718187
      reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      directness: INDIRECT
      snippet: >-
        We also found that all four patients had characteristic neurological features of
        peripheral neuropathy and ataxia with cerebellar atrophy, and some patients
        showed leukoencephalopathy or spinal cord atrophy on MRI scans.
      explanation: Ataxia occurs together with cerebellar atrophy in every index patient.
  - target: Dysarthria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cerebellar dysarthria accompanies the ataxia.
  - target: Intention tremor
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Intention tremor is a cerebellar sign.
- name: Cerebral White Matter Injury
  description: >-
    White matter lesions range from mild bilateral periventricular hyperintensity to the
    extensive cavitating leukodystrophy of the first reported patient and progressive
    periventricular diffusion restriction in the infantile form. The cellular target in
    white matter is not known, so no oligodendrocyte or myelin-specific mechanism is
    asserted.
  biological_scale: TISSUE
  locations:
  - preferred_term: cerebral white matter
    term:
      id: UBERON:0002437
      label: cerebral hemisphere white matter
  evidence:
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain and spinal cord MRI showed mild extension of signal abnormalities and
      extensive cavitations in the cerebral white matter; the cerebellum and brainstem
      were spared but the spinal cord was thin with no obvious focal lesions
    explanation: Cavitating cerebral white matter disease in the first reported patient.
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI showed mild cerebellar atrophy (Fig. 2) in all four patients; Patient 2
      and 4 had mild white matter lesions (Fig. 2F, M and N), while Patient 3 had spinal
      cord atrophy (Fig. 2J and K).
    explanation: Milder white matter lesions in two of four SCAN3 patients.
  downstream:
  - target: Leukoencephalopathy
    causal_link_type: DIRECT
  - target: Cavitating leukodystrophy
    causal_link_type: DIRECT
  - target: Cognitive impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      White matter disease is a proposed contributor to cognitive impairment; the two do
      not always occur together.
  - target: Mild intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Proposed contributor; the patient with mild intellectual disability also had white
      matter lesions, but white matter lesions occur without intellectual disability in
      other patients.
- name: Cerebral Neurodegeneration
  description: >-
    Progressive cerebral atrophy on serial MRI in the infantile-onset Chinese patient,
    with developmental regression from three months of age; cerebral atrophy is also
    recorded in a few of the Japanese patients.
  biological_scale: TISSUE
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:34322155
    reference_title: Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRIs at age 9, 11, 16, and 21 months showed progressive brain atrophy (see
      Figures 1A–D) with extended diffusion restriction in the bilateral periventricular
      areas.
    explanation: Serial MRI documents progressive brain atrophy.
  downstream:
  - target: Developmental regression
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34322155
      reference_title: Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In contrast, our patient was reported to show developmental delay from 3 months
        of age, which was found to be due to a rapidly progressive encephalopathy and
        brain atrophy seen at 9 months of age.
      explanation: The authors attribute the developmental delay and regression to the progressive encephalopathy.
  - target: Lower limb spasticity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Spasticity developed alongside the progressive encephalopathy in the infantile form.
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34322155
      reference_title: Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In contrast, our patient was reported to show developmental delay from 3 months
        of age, which was found to be due to a rapidly progressive encephalopathy and
        brain atrophy seen at 9 months of age.
      explanation: The authors attribute the developmental delay to the progressive encephalopathy and brain atrophy.
- name: Nigrostriatal Dopaminergic Terminal Loss
  conforms_to: parkinsonism_dopaminergic_degeneration#Nigrostriatal Dopaminergic Neurodegeneration
  description: >-
    Reduced striatal dopamine transporter binding on 123I-ioflupane SPECT in patients
    with parkinsonism or dystonia indicates loss of presynaptic nigrostriatal
    dopaminergic terminals. The mechanism is inferred by analogy with other mitochondrial
    parkinsonism genes; no neuropathology is available.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: dopaminergic neuron
    term:
      id: CL:0000700
      label: dopaminergic neuron
  locations:
  - preferred_term: striatum
    term:
      id: UBERON:0002435
      label: striatum
  evidence:
  - reference: PMID:37264311
    reference_title: "Parkinsonism in spinocerebellar ataxia with axonal neuropathy caused by adult-onset COA7 variants: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dopamine transporter single-photon emission computed tomography using a
      123I-Ioflupane revealed clear hypo-accumulation in the bilateral striatum.
    explanation: Presynaptic dopaminergic terminal loss in the striatum.
  - reference: PMID:37750949
    reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Dopamine transporter SPECT showed decreased uptake in the bilateral putamen in both patients.
    explanation: Reduced putaminal dopamine transporter binding in the dystonia and parkinsonism patients.
  downstream:
  - target: Striatal Dopamine Deficiency
    causal_link_type: DIRECT
    description: Loss of nigrostriatal terminals reduces dopamine available to the striatum.
- name: Striatal Dopamine Deficiency
  conforms_to: parkinsonism_dopaminergic_degeneration#Striatal Dopamine Deficiency and Basal Ganglia Circuit Dysfunction
  description: >-
    Reduced striatal dopaminergic transmission, supported by the improvement of
    parkinsonism with levodopa in two patients and a transient levodopa response in the
    infantile dystonia patient.
  biological_scale: TISSUE
  biological_processes:
  - preferred_term: synaptic transmission, dopaminergic
    term:
      id: GO:0001963
      label: synaptic transmission, dopaminergic
    modifier: DECREASED
  locations:
  - preferred_term: striatum
    term:
      id: UBERON:0002435
      label: striatum
  evidence:
  - reference: PMID:37264311
    reference_title: "Parkinsonism in spinocerebellar ataxia with axonal neuropathy caused by adult-onset COA7 variants: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: Levodopa administration improved parkinsonism in this patient.
    explanation: A levodopa response implies a dopamine-deficient striatum.
  downstream:
  - target: Parkinsonism
    causal_link_type: DIRECT
  - target: Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Dystonia accompanied reduced striatal dopamine transporter binding and responded
      transiently to levodopa in one patient.
- name: Subclinical Mitochondrial Myopathy
  description: >-
    Muscle biopsy shows a few ragged-red fibres and some cytochrome c oxidase-negative
    fibres, with mildly raised serum creatine kinase, without clinical myopathy.
  biological_scale: TISSUE
  cell_types:
  - preferred_term: skeletal muscle fibre
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also observed mildly elevated serum creatine kinase levels in all patients and
      the presence of a few ragged-red fibres and some cytochrome c oxidase-negative
      fibres in a muscle biopsy obtained from one patient, which was suggestive of
      subclinical mitochondrial myopathy.
    explanation: Muscle biopsy and CK findings define the subclinical myopathy.
  - reference: PMID:35603692
    reference_title: A novel compound heterozygous mutation in the COA7 gene responsible for a Chinese patient with spinocerebellar ataxia with axonal neuropathy type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Muscle biopsies showed mitochondrial abnormalities.
    explanation: Mitochondrial muscle pathology in an independent patient.
phenotypes:
- name: Progressive cerebellar ataxia
  category: Neurological
  description: >-
    Slowly progressive truncal, limb and gait ataxia, usually beginning in childhood,
    mixed with a sensory component; absent in the infantile dystonia and
    encephalopathy presentations.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also found that all four patients had characteristic neurological features of
      peripheral neuropathy and ataxia with cerebellar atrophy, and some patients
      showed leukoencephalopathy or spinal cord atrophy on MRI scans.
    explanation: Ataxia in all four index patients.
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing was carried out on a 19 year old woman, affected by early
      onset, progressive severe ataxia and peripheral neuropathy, mild cognitive
      impairment and a cavitating leukodystrophy of the brain with spinal cord
      hypotrophy.
    explanation: Progressive ataxia in the first reported patient.
  - reference: PMID:35603692
    reference_title: A novel compound heterozygous mutation in the COA7 gene responsible for a Chinese patient with spinocerebellar ataxia with axonal neuropathy type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was a 31-year-old woman who presented with early-onset peripheral
      neuropathy and progressive ataxia.
    explanation: Progressive ataxia in a Chinese patient.
- name: Peripheral axonal neuropathy
  category: Neurological
  description: >-
    Early-onset, slowly progressive axonal sensorimotor polyneuropathy resembling
    Charcot-Marie-Tooth disease; onset at 30 years in one patient.
  phenotype_term:
    preferred_term: Axonal sensorimotor neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Nerve conduction studies showed axonal sensorimotor neuropathy.
    explanation: Axonal sensorimotor neuropathy on nerve conduction.
  - reference: PMID:42182620
    reference_title: Compound Heterozygous COA7 Variants Presenting With Childhood-Onset Axonal Neuropathy in 2 Siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both presented with early-onset, slowly progressive axonal sensorimotor
      neuropathy, with differences in severity and associated features.
    explanation: Axonal neuropathy as the presenting feature in two siblings.
  - reference: PMID:37264311
    reference_title: "Parkinsonism in spinocerebellar ataxia with axonal neuropathy caused by adult-onset COA7 variants: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the case of a patient who developed cerebellar symptoms and slowly
      progressive sensory and motor neuropathy in the extremities, similar to
      Charcot-Marie-Tooth disease, at age 30, followed by parkinsonism at age 58.
    explanation: Adult-onset CMT-like neuropathy with ataxia and later parkinsonism.
- name: Decreased number of large peripheral myelinated nerve fibers
  category: Neurological
  description: Loss of large and medium myelinated fibres on sural nerve biopsy.
  phenotype_term:
    preferred_term: Decreased number of large peripheral myelinated nerve fibers
    term:
      id: HP:0003387
      label: Decreased number of large peripheral myelinated nerve fibers
  reports_on:
  - target: Length-Dependent Peripheral Axonal Degeneration
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: The biopsy fibre loss is the histological measure of axonal degeneration.
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large
      and medium myelinated fibres.
    explanation: Documents loss of large myelinated fibres.
- name: Distal muscle weakness
  category: Neuromuscular
  description: Slowly progressive distal limb weakness.
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological examination revealed a predominant distal muscle atrophy/weakness in
      all limbs, distal sensory loss, absent ankle reflexes and ataxic gait.
    explanation: Distal weakness on examination.
  - reference: PMID:42182620
    reference_title: Compound Heterozygous COA7 Variants Presenting With Childhood-Onset Axonal Neuropathy in 2 Siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Shared features included distal weakness, impaired gait, areflexia, tremor, pes
      cavus, sensory disturbances, and cognitive difficulties, which were milder in the
      older brother.
    explanation: Distal weakness in both siblings.
- name: Distal amyotrophy
  category: Neuromuscular
  description: Distal limb muscle wasting.
  phenotype_term:
    preferred_term: Distal amyotrophy
    term:
      id: HP:0003693
      label: Distal amyotrophy
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological examination revealed truncal and limb ataxia along with predominant
      distal muscle atrophy/weakness of the four limbs.
    explanation: Distal muscle atrophy on examination.
- name: Distal sensory impairment
  category: Neurological
  description: Distal, all-modality sensory loss.
  phenotype_term:
    preferred_term: Distal sensory impairment
    term:
      id: HP:0002936
      label: Distal sensory impairment
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neurological examination revealed a predominant distal muscle atrophy/weakness in
      all limbs, distal sensory loss, absent ankle reflexes and ataxic gait.
    explanation: Distal sensory loss on examination.
- name: Hyporeflexia
  category: Neurological
  description: Attenuated deep tendon reflexes in the four limbs.
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The neurological features included all-modality sensory loss, attenuated deep
      tendon reflexes in the four limbs, dysarthria and mixed sensory and cerebellar
      ataxia.
    explanation: Attenuated reflexes in the oldest index patient.
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The neurological evaluation showed dysarthria, dysmetria, ataxic gait and
      hyporeflexia in the four limbs with muscle wasting.
    explanation: Hyporeflexia in the first reported patient.
- name: Areflexia
  category: Neurological
  description: Absent ankle or generalized reflexes.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:42182620
    reference_title: Compound Heterozygous COA7 Variants Presenting With Childhood-Onset Axonal Neuropathy in 2 Siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Shared features included distal weakness, impaired gait, areflexia, tremor, pes
      cavus, sensory disturbances, and cognitive difficulties, which were milder in the
      older brother.
    explanation: Areflexia in both siblings.
- name: Sensory ataxia
  category: Neurological
  description: A sensory component to the ataxia, from large-fibre sensory loss.
  phenotype_term:
    preferred_term: Sensory ataxia
    term:
      id: HP:0010871
      label: Sensory ataxia
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The neurological features included all-modality sensory loss, attenuated deep
      tendon reflexes in the four limbs, dysarthria and mixed sensory and cerebellar
      ataxia.
    explanation: Mixed sensory and cerebellar ataxia.
- name: Steppage gait
  category: Neuromuscular
  description: Steppage gait from distal leg weakness, a presenting sign in early childhood.
  phenotype_term:
    preferred_term: Steppage gait
    term:
      id: HP:0003376
      label: Steppage gait
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She had gait abnormalities (steppage gait) at age 4.
    explanation: Steppage gait as an early sign.
- name: Pes cavus
  category: Musculoskeletal
  description: Cavus foot deformity, sometimes with hammer toes, from infancy or childhood.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 1, a 63-year-old male born to healthy consanguineous parents, had a pes
      cavus deformity and clumsy hands since his infancy.
    explanation: Pes cavus from infancy.
  - reference: PMID:42182620
    reference_title: Compound Heterozygous COA7 Variants Presenting With Childhood-Onset Axonal Neuropathy in 2 Siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Shared features included distal weakness, impaired gait, areflexia, tremor, pes
      cavus, sensory disturbances, and cognitive difficulties, which were milder in the
      older brother.
    explanation: Pes cavus in both siblings.
- name: Cerebellar atrophy
  category: Neurological
  description: Mild cerebellar atrophy on brain MRI.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  reports_on:
  - target: Cerebellar Neurodegeneration
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: MRI cerebellar atrophy is the imaging measure of cerebellar tissue loss.
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI showed mild cerebellar atrophy (Fig. 2) in all four patients; Patient 2
      and 4 had mild white matter lesions (Fig. 2F, M and N), while Patient 3 had spinal
      cord atrophy (Fig. 2J and K).
    explanation: Cerebellar atrophy in all four index patients.
  - reference: PMID:42182620
    reference_title: Compound Heterozygous COA7 Variants Presenting With Childhood-Onset Axonal Neuropathy in 2 Siblings.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI findings were unremarkable in both siblings.
    explanation: Cerebellar atrophy is not universal; both siblings had a normal brain MRI.
- name: Dysarthria
  category: Neurological
  description: Dysarthria in several patients with the ataxic phenotype.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The neurological features included all-modality sensory loss, attenuated deep
      tendon reflexes in the four limbs, dysarthria and mixed sensory and cerebellar
      ataxia.
    explanation: Dysarthria in an index patient.
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The neurological evaluation showed dysarthria, dysmetria, ataxic gait and
      hyporeflexia in the four limbs with muscle wasting.
    explanation: Dysarthria in the first reported patient.
- name: Intention tremor
  category: Neurological
  description: Intention tremor in childhood.
  phenotype_term:
    preferred_term: Intention tremor
    term:
      id: HP:0002080
      label: Intention tremor
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She was hospitalized because she had difficulty standing and an intention tremor
      at age 6.
    explanation: Intention tremor at age 6.
- name: Leukoencephalopathy
  category: Neurological
  description: Cerebral white matter lesions on MRI in a subset of patients, usually mild and periventricular.
  phenotype_term:
    preferred_term: Leukoencephalopathy
    term:
      id: HP:0002352
      label: Leukoencephalopathy
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also found that all four patients had characteristic neurological features of
      peripheral neuropathy and ataxia with cerebellar atrophy, and some patients
      showed leukoencephalopathy or spinal cord atrophy on MRI scans.
    explanation: Leukoencephalopathy in some index patients.
  - reference: PMID:37750949
    reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      COA7-related disorders typically encompass a spectrum of conditions characterized
      by a variety of major (cerebellar ataxia and axonal polyneuropathy) and minor
      (leukoencephalopathy, dystonia, and parkinsonism) symptoms, but may also display
      a dystonia-predominant phenotype.
    explanation: Places leukoencephalopathy among the minor features of the spectrum.
- name: Cavitating leukodystrophy
  category: Neurological
  description: Extensive cavitation of the cerebral white matter in the first reported patient.
  phenotype_term:
    preferred_term: Cavitating leukodystrophy
    term:
      id: HP:0033369
      label: Cavitating leukodystrophy
  evidence:
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing was carried out on a 19 year old woman, affected by early
      onset, progressive severe ataxia and peripheral neuropathy, mild cognitive
      impairment and a cavitating leukodystrophy of the brain with spinal cord
      hypotrophy.
    explanation: Cavitating leukodystrophy in the first reported patient.
- name: Atrophy of the spinal cord
  category: Neurological
  description: Thin spinal cord without focal lesions on MRI in some patients.
  phenotype_term:
    preferred_term: Spinal cord atrophy
    term:
      id: HP:0006827
      label: Atrophy of the spinal cord
  evidence:
  - reference: PMID:35603692
    reference_title: A novel compound heterozygous mutation in the COA7 gene responsible for a Chinese patient with spinocerebellar ataxia with axonal neuropathy type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Magnetic resonance imaging showed cerebellum and spinal cord atrophy.
    explanation: Spinal cord atrophy in a Chinese patient.
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain and spinal cord MRI showed mild extension of signal abnormalities and
      extensive cavitations in the cerebral white matter; the cerebellum and brainstem
      were spared but the spinal cord was thin with no obvious focal lesions
    explanation: Thin spinal cord in the first reported patient.
- name: Cognitive impairment
  category: Neurological
  description: Mild cognitive impairment or mild intellectual disability in a minority of patients.
  phenotype_term:
    preferred_term: Cognitive impairment
    term:
      id: HP:0100543
      label: Cognitive impairment
  evidence:
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing was carried out on a 19 year old woman, affected by early
      onset, progressive severe ataxia and peripheral neuropathy, mild cognitive
      impairment and a cavitating leukodystrophy of the brain with spinal cord
      hypotrophy.
    explanation: Mild cognitive impairment in the first reported patient.
  - reference: PMID:35603692
    reference_title: A novel compound heterozygous mutation in the COA7 gene responsible for a Chinese patient with spinocerebellar ataxia with axonal neuropathy type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Compared with SCAN1 and SCAN2 patients, SCAN3 patients had earlier onset age, less
      cognitive impairment, and no ocular signs.
    explanation: Cognitive impairment is less common in SCAN3 than in SCAN1 or SCAN2.
- name: Mild intellectual disability
  category: Neurological
  description: Mild intellectual disability (full-scale IQ 68) in one patient.
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She also manifested mild intellectual disability: the Wechsler Preschool and
      Primary Scale of Intelligence (WPPSI) revealed a verbal score of 76, performance
      score of 71 and full-scale IQ of 68.
    explanation: Documents mild intellectual disability.
- name: Global developmental delay
  category: Neurological
  description: Psychomotor delay in the first year in the earliest-onset patients.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The perinatal period was uneventful and her early development was referred to as
      normal, but after 1 year of age, psychomotor delay became evident.
    explanation: Psychomotor delay after the first year.
- name: Developmental regression
  category: Neurological
  description: Loss of acquired skills from three months of age in the infantile encephalopathic form.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:34322155
    reference_title: Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A Chinese girl was referred at 9 months of age with a history of developmental
      delay and regression since 3 months of age.
    explanation: Developmental regression from three months.
- name: Lower limb spasticity
  category: Neurological
  description: Progressive lower-limb spasticity in the infantile form; pyramidal signs in a few other patients.
  phenotype_term:
    preferred_term: Lower limb spasticity
    term:
      id: HP:0002061
      label: Lower limb spasticity
  evidence:
  - reference: PMID:34322155
    reference_title: Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the following months, she lost previously acquired skills and developed
      progressive spasticity of the lower extremities.
    explanation: Progressive lower-limb spasticity.
- name: Cerebral atrophy
  category: Neurological
  description: Progressive brain atrophy on serial MRI in the infantile form.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  reports_on:
  - target: Cerebral Neurodegeneration
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: MRI brain atrophy is the imaging measure of cerebral neurodegeneration.
  evidence:
  - reference: PMID:34322155
    reference_title: Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRIs at age 9, 11, 16, and 21 months showed progressive brain atrophy (see
      Figures 1A–D) with extended diffusion restriction in the bilateral periventricular
      areas.
    explanation: Progressive brain atrophy.
- name: Parkinsonism
  category: Neurological
  description: Levodopa-responsive parkinsonism developing in adulthood in two Japanese patients.
  phenotype_term:
    preferred_term: Parkinsonism
    term:
      id: HP:0001300
      label: Parkinsonism
  evidence:
  - reference: PMID:37264311
    reference_title: "Parkinsonism in spinocerebellar ataxia with axonal neuropathy caused by adult-onset COA7 variants: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We report the case of a patient who developed cerebellar symptoms and slowly
      progressive sensory and motor neuropathy in the extremities, similar to
      Charcot-Marie-Tooth disease, at age 30, followed by parkinsonism at age 58.
    explanation: Parkinsonism at 58 years after decades of ataxia and neuropathy.
  - reference: PMID:37750949
    reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 2 presented with cerebellar ataxia, neuropathy, as well as parkinsonism,
      and showed a slight improvement upon levodopa administration.
    explanation: Parkinsonism in a second patient.
- name: Dystonia
  category: Neurological
  description: >-
    Dystonia, including infantile-onset generalized dystonia without cerebellar ataxia
    in one patient and hand dystonia with parkinsonism in another.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:37750949
    reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patient 1 presented with an infantile-onset generalized dystonia without cerebellar ataxia.
    explanation: A dystonia-predominant presentation.
  - reference: PMID:37264311
    reference_title: "Parkinsonism in spinocerebellar ataxia with axonal neuropathy caused by adult-onset COA7 variants: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Bradykinesia and dystonia were observed in both hands.
    explanation: Hand dystonia accompanying parkinsonism.
- name: Respiratory failure
  category: Respiratory
  description: Respiratory failure with severe weakness in one patient.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:37750949
    reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patient 3 exhibited severe muscle weakness, respiratory failure, and feeding difficulties.
    explanation: Respiratory failure at the severe end of the spectrum.
- name: Feeding difficulties
  category: Gastrointestinal
  description: Feeding difficulties in severely affected patients.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:37750949
    reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patient 3 exhibited severe muscle weakness, respiratory failure, and feeding difficulties.
    explanation: Feeding difficulties at the severe end of the spectrum.
- name: Dysphagia
  category: Gastrointestinal
  description: >-
    Dysphagia in two patients of one series: with severe painful dystonia in a
    young man, and with vocal cord paralysis in a woman who needed a
    percutaneous endoscopic gastrostomy.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:37750949
    reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Subsequently, he developed severe painful dystonia, accompanied by
      dysarthria and dysphagia
    explanation: Patient 1 developed dysphagia together with severe dystonia.
  - reference: PMID:37750949
    reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During her 20 s, she developed hoarseness (vocal cord paralysis) and
      dysphagia and underwent a percutaneous endoscopic gastrostomy.
    explanation: Patient 3 developed dysphagia severe enough to need gastrostomy.
- name: Vocal cord paralysis
  category: Respiratory
  description: >-
    Progressive vocal cord paralysis with hoarseness in one patient, which the
    authors list as a possible contributor to her respiratory failure through
    airway narrowing.
  phenotype_term:
    preferred_term: Vocal cord paralysis
    term:
      id: HP:0001605
      label: Vocal cord paralysis
  evidence:
  - reference: PMID:37750949
    reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During her 20 s, she developed hoarseness (vocal cord paralysis) and
      dysphagia and underwent a percutaneous endoscopic gastrostomy.
    explanation: Patient 3 developed vocal cord paralysis in her twenties.
- name: Scoliosis
  category: Musculoskeletal
  description: Marked dorsal-lumbar scoliosis in adolescence in the first reported patient.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At her last follow-up examination, at 19 years of age, she was able to walk alone
      only with ankle-foot orthotic aids and had developed a marked dorsal-lumbar
      scoliosis.
    explanation: Scoliosis in the first reported patient.
- name: Decreased activity of mitochondrial complex IV
  category: Metabolic
  description: Reduced complex IV activity in fibroblasts, muscle or skin in most tested patients.
  phenotype_term:
    preferred_term: Decreased activity of mitochondrial complex IV
    term:
      id: HP:0008347
      label: Decreased activity of mitochondrial complex IV
  reports_on:
  - target: Deficient Cytochrome c Oxidase Electron Transfer and Respiration
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Enzyme assay of complex IV directly measures the respiratory chain defect.
  evidence:
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Biochemical analysis of the mitochondrial respiratory chain revealed the presence
      of isolated deficiency of cytochrome c oxidase (COX) activity in skin fibroblasts
      and skeletal muscle.
    explanation: Isolated complex IV deficiency.
  - reference: PMID:42182620
    reference_title: Compound Heterozygous COA7 Variants Presenting With Childhood-Onset Axonal Neuropathy in 2 Siblings.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Skin biopsy revealed reduced mitochondrial complex IV activity.
    explanation: Reduced complex IV activity in skin.
- name: Decreased activity of mitochondrial complex I
  category: Metabolic
  description: >-
    Complex I activity was reduced in fibroblasts of one patient; complex I activity is
    also reduced when COA7 is knocked down in cell lines.
  phenotype_term:
    preferred_term: Decreased activity of mitochondrial complex I
    term:
      id: HP:0011923
      label: Decreased activity of mitochondrial complex I
  reports_on:
  - target: Deficient Cytochrome c Oxidase Electron Transfer and Respiration
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: A secondary complex I deficit is part of the respiratory chain defect in some patients.
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Respiratory chain enzyme assay of skin fibroblasts from Patient 1 showed a definite
      and significant decrease in complex I activity (37% of control)
    explanation: Complex I deficiency in one patient's fibroblasts.
- name: Increased circulating lactate concentration
  category: Metabolic
  description: Mildly elevated blood lactate.
  phenotype_term:
    preferred_term: Increased circulating lactate concentration
    term:
      id: HP:0002151
      label: Increased circulating lactate concentration
  reports_on:
  - target: Glycolytic Shift With Increased Lactate Production
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Blood lactate measures increased glycolytic lactate production.
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Laboratory studies showed elevated lactate and pyruvate levels in blood or CSF with
      mild elevation of serum creatine kinase levels (Table 1).
    explanation: Elevated blood lactate.
  - reference: PMID:34322155
    reference_title: Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Serum lactate was elevated (2.98 μmol/L, normal range 0.5–2.2 μmol/L).
    explanation: Elevated serum lactate in the infantile form.
- name: Increased CSF lactate
  category: Metabolic
  description: Elevated CSF lactate.
  phenotype_term:
    preferred_term: Increased CSF lactate
    term:
      id: HP:0002490
      label: Increased CSF lactate
  reports_on:
  - target: Glycolytic Shift With Increased Lactate Production
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: CSF lactate measures increased glycolytic lactate production in the CNS.
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Laboratory studies showed elevated lactate and pyruvate levels in blood or CSF with
      mild elevation of serum creatine kinase levels (Table 1).
    explanation: Elevated lactate in blood or CSF.
- name: Increased circulating pyruvate concentration
  category: Metabolic
  description: Elevated blood pyruvate.
  phenotype_term:
    preferred_term: Increased circulating pyruvate concentration
    term:
      id: HP:0003542
      label: Increased circulating pyruvate concentration
  reports_on:
  - target: Glycolytic Shift With Increased Lactate Production
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Raised pyruvate accompanies the glycolytic shift.
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Laboratory studies showed elevated lactate and pyruvate levels in blood or CSF with
      mild elevation of serum creatine kinase levels (Table 1).
    explanation: Elevated pyruvate in blood or CSF.
- name: Elevated circulating creatine kinase activity
  category: Metabolic
  description: Mildly elevated serum creatine kinase.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase activity
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase activity
  reports_on:
  - target: Subclinical Mitochondrial Myopathy
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Raised CK reflects muscle fibre involvement.
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also observed mildly elevated serum creatine kinase levels in all patients and
      the presence of a few ragged-red fibres and some cytochrome c oxidase-negative
      fibres in a muscle biopsy obtained from one patient, which was suggestive of
      subclinical mitochondrial myopathy.
    explanation: Mild CK elevation in all four index patients.
  - reference: PMID:34322155
    reference_title: Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Extensive diagnostic screening showed elevated serum CK (488 U/L, normal range 5–220 U/L)
    explanation: Elevated CK in the infantile form.
- name: Ragged-red muscle fibers
  category: Neuromuscular
  description: A few ragged-red fibres on muscle biopsy.
  phenotype_term:
    preferred_term: Ragged-red muscle fibers
    term:
      id: HP:0003200
      label: Ragged-red muscle fibers
  reports_on:
  - target: Subclinical Mitochondrial Myopathy
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Ragged-red fibres are the histological marker of mitochondrial myopathy.
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also observed mildly elevated serum creatine kinase levels in all patients and
      the presence of a few ragged-red fibres and some cytochrome c oxidase-negative
      fibres in a muscle biopsy obtained from one patient, which was suggestive of
      subclinical mitochondrial myopathy.
    explanation: Ragged-red fibres on muscle biopsy.
- name: Cytochrome C oxidase-negative muscle fibers
  category: Neuromuscular
  description: Some COX-negative fibres on muscle biopsy.
  phenotype_term:
    preferred_term: Cytochrome C oxidase-negative muscle fibers
    term:
      id: HP:0003688
      label: Cytochrome C oxidase-negative muscle fibers
  reports_on:
  - target: Subclinical Mitochondrial Myopathy
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: COX-negative fibres show the complex IV defect in muscle.
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also observed mildly elevated serum creatine kinase levels in all patients and
      the presence of a few ragged-red fibres and some cytochrome c oxidase-negative
      fibres in a muscle biopsy obtained from one patient, which was suggestive of
      subclinical mitochondrial myopathy.
    explanation: COX-negative fibres on muscle biopsy.
genetic:
- name: COA7
  notes: >-
    COA7 (formerly C1orf163, SELRC1, RESA1) encodes a 231-residue protein with five
    Sel1-like repeats that is present in animals but absent from yeast. Reported alleles
    are mostly missense, with a frameshift, a nonsense, a splice-donor and a whole-exon-2
    deletion; the exon deletion was found by MLPA after sequencing detected only one
    allele. c.17A>G (p.Asp6Gly) recurs in Japanese patients on a shared haplotype. No
    ClinGen gene-disease validity record for COA7 is cached, so none is recorded.
  gene_term:
    preferred_term: COA7
    term:
      id: hgnc:25716
      label: COA7
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we identified four unrelated patients with recessive mutations in COA7 among
      a Japanese case series of 1396 patients with Charcot-Marie-Tooth disease (CMT) or
      other inherited peripheral neuropathies, including complex forms of CMT.
    explanation: Gene identification in the founding series.
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Lentiviral-mediated expression of recombinant wild-type COA7 cDNA in the patient
      fibroblasts led to the recovery of the defect in COX activity and restoration of
      normal COX amount.
    explanation: Complementation with wild-type COA7 confirms causality.
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: >-
      COA7 is a 231aa-long mitochondrial protein present in animals, containing five
      Sel1-like tetratricopeptide repeat sequences, which are likely to interact with
      partner proteins.
    explanation: Describes the COA7 protein.
  variants:
  - name: c.17A>G (p.Asp6Gly)
    description: >-
      Recurrent missense allele, homozygous or compound heterozygous in most Japanese
      patients and in one Chinese patient, carried on a common haplotype in Japan.
      Classified pathogenic by ACMG criteria in the 2023 Japanese series.
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:37750949
      reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A haplotype analysis of the mutation hotspot in Japan, c.17A > G (p.D6G),
        uncovered a common haplotype block.
      explanation: Recurrent Japanese allele on a shared haplotype.
    - reference: PMID:37750949
      reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Taken together, both variants were classified as pathogenic according to the
        ACMG guideline.
      explanation: ACMG pathogenic classification of p.Asp6Gly and p.Arg39Trp.
    - reference: PMID:37264311
      reference_title: "Parkinsonism in spinocerebellar ataxia with axonal neuropathy caused by adult-onset COA7 variants: a case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Exome analysis revealed COA7 missense mutation in homozygotes (NM_023077.2:c.17A
        > G, NP_075565.2: p.Asp6Gly).
      explanation: Homozygous p.Asp6Gly in the adult-onset patient.
  - name: c.115C>T (p.Arg39Trp)
    description: >-
      Missense allele found in trans with an exon 2 deletion in one patient and
      homozygous in another; classified pathogenic in the 2023 Japanese series.
    type: missense
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:29718187
      reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        These findings suggest that Patient 2 has a compound heterozygous genotype that
        comprises a deletion of exon 2 (inherited from mother) and a missense variant
        (inherited from father).
      explanation: p.Arg39Trp in trans with an exon 2 deletion.
    - reference: PMID:37750949
      reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Taken together, both variants were classified as pathogenic according to the
        ACMG guideline.
      explanation: ACMG pathogenic classification of p.Asp6Gly and p.Arg39Trp.
  - name: c.410A>G (p.Tyr137Cys) / c.287+1G>T
    description: >-
      Compound heterozygous missense and splice-donor alleles in the first reported
      patient; the splice variant causes in-frame skipping of exon 2. Both
      mutant proteins are imported poorly and degraded by the proteasome.
    type: missense
    evidence:
    - reference: PMID:27683825
      reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We found compound heterozygous mutations in COA7: a paternal c.410A>G, p.Y137C,
        and a maternal c.287+1G>T variants.
      explanation: Identifies the two alleles in the first patient.
    - reference: PMID:27683825
      reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        whereas the splice site mutation produces the in-frame deletion of the 47 amino
        acids encoded by exon 2
      explanation: The splice-donor variant causes in-frame loss of exon 2.
    - reference: PMID:30885959
      reference_title: Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We also found that pathogenic mutant versions of COA7 are imported slower than the
        wild-type protein, and mislocalized proteins are degraded in the cytosol by the
        proteasome.
      explanation: The Y137C and exon 2-deleted proteins are imported slowly and degraded.
  - name: c.554G>A (p.Trp185*)
    description: Nonsense allele in trans with p.Asp6Gly in a Chinese patient.
    type: nonsense
    evidence:
    - reference: PMID:35603692
      reference_title: A novel compound heterozygous mutation in the COA7 gene responsible for a Chinese patient with spinocerebellar ataxia with axonal neuropathy type 3.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Whole exome next-generation sequencing identified a novel compound heterozygous
        mutation of COA7 (c.17A>G p.D6G; c.554G>A, p.W185*) in this patient.
      explanation: Identifies the nonsense allele.
  - name: c.511G>A (p.Ala171Thr) / c.566A>G (p.Asn189Ser)
    description: Compound heterozygous missense alleles in the infantile encephalopathic form.
    type: missense
    evidence:
    - reference: PMID:34322155
      reference_title: Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Trio-exome sequencing revealed compound heterzygous variants in COA7 (c.511G >
        A/p.Ala171Thr and c.566A > G/p.Asn189Ser).
      explanation: Identifies the two alleles.
  - name: c.449G>A (p.Cys150Tyr)
    description: >-
      Missense allele in the fourth Sel1-like repeat, in trans with p.Asp6Gly in the
      infantile dystonia patient; classified likely pathogenic.
    type: missense
    clinical_significance: LIKELY_PATHOGENIC
    evidence:
    - reference: PMID:37750949
      reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In addition to our original report, which involved four patients until 2018, we
        identified biallelic variants of the COA7 gene in another three unrelated
        patients, and the variants were c.17A > G (p.D6G), c.115C > T (p.R39W), and
        c.449G > A (p.C150Y; novel).
      explanation: Identifies p.Cys150Tyr.
    - reference: PMID:37750949
      reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Altogether, we classified these variants as likely pathogenic according to the
        ACMG guideline.
      explanation: ACMG likely pathogenic classification.
  - name: c.457C>T (p.Leu153Phe)
    description: Novel missense allele carried in compound heterozygosity by two Italian siblings.
    type: missense
    evidence:
    - reference: PMID:42182620
      reference_title: Compound Heterozygous COA7 Variants Presenting With Childhood-Onset Axonal Neuropathy in 2 Siblings.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We describe 2 siblings carrying compound heterozygous COA7 variants, one of which
        (c.457C>T; p.Leu153Phe) is novel.
      explanation: Identifies p.Leu153Phe.
treatments:
- name: Levodopa
  description: >-
    Levodopa improved parkinsonism in one patient and slightly in a second, and gave
    an initial transient response in the infantile generalized dystonia patient.
    There is no disease-modifying therapy for SCAN3.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levodopa
      term:
        id: CHEBI:15765
        label: L-dopa
  target_mechanisms:
  - target: Striatal Dopamine Deficiency
    description: Levodopa replaces striatal dopamine lost with nigrostriatal terminal degeneration.
  evidence:
  - reference: PMID:37264311
    reference_title: "Parkinsonism in spinocerebellar ataxia with axonal neuropathy caused by adult-onset COA7 variants: a case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Levodopa administration improved parkinsonism in this patient.
    explanation: Levodopa response in an adult-onset patient.
  - reference: PMID:37750949
    reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Patient 2 presented with cerebellar ataxia, neuropathy, as well as parkinsonism,
      and showed a slight improvement upon levodopa administration.
    explanation: Slight levodopa response in a second patient.
- name: Deep Brain Stimulation
  description: >-
    Deep brain stimulation gave an initial transient benefit for infantile-onset
    generalized dystonia in one patient, who nonetheless became bedridden by age 19.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: deep brain stimulation
    term:
      id: NCIT:C21024
      label: Deep Brain Stimulation
  evidence:
  - reference: PMID:37750949
    reference_title: "Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Despite experiencing an initial transient positive response to levodopa and deep
      brain stimulation, he became bedridden by the age of 19.
    explanation: Transient response to levodopa and deep brain stimulation for dystonia.
- name: Baclofen
  description: Baclofen partially controlled progressive spasticity in the infantile encephalopathic form.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: baclofen
      term:
        id: CHEBI:2972
        label: baclofen
  evidence:
  - reference: PMID:34322155
    reference_title: Biallelic COA7-Variants Leading to Developmental Regression With Progressive Spasticity and Brain Atrophy in a Chinese Patient.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      During the following 5 months, the spasticity worsened, repeatedly induced by
      intestinal infection but was reasonably controlled with baclofen treatment.
    explanation: Baclofen controlled spasticity in one patient.
- name: Protirelin Tartrate
  description: >-
    Protirelin tartrate, a thyrotropin-releasing hormone preparation used for ataxia in
    Japan, gave only slight transient improvement in ataxia in one patient before the
    symptoms became refractory.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: protirelin
      term:
        id: CHEBI:35940
        label: protirelin
  evidence:
  - reference: PMID:29718187
    reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      treatment with protirelin tartrate (TRH-T) resulted in slight transient
      improvement in ataxia. However, the symptoms progressively worsened and became
      refractory.
    explanation: Only a slight, transient benefit in a single patient.
- name: Supportive Care and Orthoses
  description: >-
    Management is supportive, including ankle-foot orthoses for distal weakness and
    walking aids; no COA7-specific supportive regimen has been evaluated.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:27683825
    reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At her last follow-up examination, at 19 years of age, she was able to walk alone
      only with ankle-foot orthotic aids and had developed a marked dorsal-lumbar
      scoliosis.
    explanation: Use of ankle-foot orthoses for walking.
animal_models:
- name: Drosophila neuron-specific dCOA7 RNAi knockdown
  species: Drosophila melanogaster
  genotype: elav-GAL4 driven UAS-dCOA7 RNAi (CG13865), two independent RNAi lines
  publication: PMID:29718187
  description: >-
    Pan-neuronal knockdown of the fly COA7 orthologue shortens lifespan, causes an
    age-dependent climbing defect and shortens larval motor neuron synaptic branches at
    the neuromuscular junction; eye-specific knockdown gives a rough eye.
  modeled_mechanisms:
  - target: Length-Dependent Peripheral Axonal Degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: >-
      Neuronal loss of dCOA7 damages motor neuron presynaptic terminals and motor
      function, in line with the motor axonal neuropathy.
    limitations: >-
      RNAi knockdown rather than patient alleles, in an invertebrate without myelinating
      Schwann cells; axonal degeneration of peripheral nerve and complex IV activity were
      not measured in the flies, so the link to human axonal degeneration is inferred
      from terminal morphology and locomotion.
    readouts:
    - name: Larval neuromuscular junction synaptic branch length
      target: Length-Dependent Peripheral Axonal Degeneration
      direction: DECREASED
      interpretation: Shorter motor neuron terminal branches after neuronal dCOA7 knockdown.
      evidence:
      - reference: PMID:29718187
        reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          Measurement of the total length of synaptic branches of motor neurons in these
          larvae indicated that the total branch length was significantly decreased
        explanation: Reports the decreased synaptic branch length.
    evidence:
    - reference: PMID:29718187
      reference_title: Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        In addition, Drosophila COA7 (dCOA7) knockdown models showed rough eye
        phenotype, reduced lifespan, impaired locomotive ability and shortened synaptic
        branches of motor neurons.
      explanation: Summarizes the neurodegenerative phenotype of the fly model.
experimental_models:
- name: COA7 patient-derived skin fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary and immortalized fibroblasts from patients carrying biallelic COA7 variants,
    used to measure complex IV assembly and activity, to test complementation with
    wild-type COA7, and to test rescue by proteasome inhibitors.
  publication: PMID:27683825
  modeled_mechanisms:
  - target: Complex IV Assembly Stall After COX1 Module Formation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: Patient fibroblasts show the complex IV assembly defect and its rescue.
    limitations: >-
      Fibroblasts are not the affected neural cells, and in one patient fibroblast
      respiratory chain activity was normal despite muscle mitochondrial abnormalities,
      so fibroblasts can under-report the defect.
    readouts:
    - name: Complex IV activity after proteasome inhibition
      target: Complex IV Assembly Stall After COX1 Module Formation
      direction: RESTORED
      interpretation: >-
        Proteasome inhibitors raised mitochondrial COA7 and complex IV activity in
        patient fibroblasts, an in vitro rescue only.
      evidence:
      - reference: PMID:30885959
        reference_title: Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Interestingly, proteasome inhibition rescued both the mitochondrial
          localization of COA7 and complex IV activity in patient-derived fibroblasts.
        explanation: Reports the partial rescue of complex IV activity.
    evidence:
    - reference: PMID:27683825
      reference_title: COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In patient-derived immortalised fibroblasts, the levels of fully assembled cIV
        and of the cIII2+cIV supercomplex were clearly lower relative to controls
      explanation: Patient fibroblasts reproduce the assembly defect.
differential_diagnoses:
- name: Spinocerebellar ataxia with axonal neuropathy type 1
  description: TDP1-related recessive ataxia with axonal neuropathy.
  disease_term:
    preferred_term: SCAN1
    term:
      id: MONDO:0011801
      label: spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1
  distinguishing_features:
  - Later onset than SCAN3
  evidence:
  - reference: PMID:35603692
    reference_title: A novel compound heterozygous mutation in the COA7 gene responsible for a Chinese patient with spinocerebellar ataxia with axonal neuropathy type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Compared with SCAN1 and SCAN2 patients, SCAN3 patients had earlier onset age, less
      cognitive impairment, and no ocular signs.
    explanation: Literature comparison of SCAN1, SCAN2 and SCAN3.
- name: Ataxia with oculomotor apraxia type 2
  description: SETX-related recessive ataxia with axonal neuropathy (SCAN2).
  disease_term:
    preferred_term: SCAN2 / AOA2
    term:
      id: MONDO:0018996
      label: spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2
  distinguishing_features:
  - Ocular signs such as oculomotor apraxia, absent in SCAN3
  - More cognitive impairment than SCAN3
  evidence:
  - reference: PMID:35603692
    reference_title: A novel compound heterozygous mutation in the COA7 gene responsible for a Chinese patient with spinocerebellar ataxia with axonal neuropathy type 3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Compared with SCAN1 and SCAN2 patients, SCAN3 patients had earlier onset age, less
      cognitive impairment, and no ocular signs.
    explanation: Literature comparison of SCAN1, SCAN2 and SCAN3.

📚

References & Deep Research

Deep Research

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: Spinocerebellar_Ataxia_Autosomal_Recessive_With_Axonal_Neuropathy_3 · 2026-10-27T22:37:57Z · View source

New entry for SCAN3 (MONDO:0020770), caused by biallelic COA7 variants. Sources. One claude_code deep-research report (research/Spinocerebellar_Ataxia_Autosomal_Recessive_With_Axonal_Neuropathy_3-deep-research-claude_code.md). Its reference validation resolved 18/18 references and matched 6/6 quotes, with no unresolved or off-topic references. Term validation flagged needs_review only for labelling artefacts (MONDO:0020770 and DOID:0070465 called "MONDO"/"DOID"), one obsolete GO cellular-component term (GO:0005751, not used) and unresolvable GARD xrefs (not used). just preflight-dr returned PASS (COA7 mentioned 54 times, OMIM 618387 matches). No CURIE was copied from the report without a cache or OLS lookup. Every cited paper was fetched and its cached text read before quoting: the founding Japanese series (PMID:29718187), the first patient (PMID:27683825), the COA7 knockdown, import and structure studies (PMID:24333015, PMID:30885959, PMID:35210360), and later case reports (PMID:34322155, PMID:35603692, PMID:37264311, PMID:37750949, PMID:42182620). Fetching PMID:37750949 upgraded its existing abstract-only cache file to PMC full text; the full text is needed for the ACMG classification sentences. Not used: PMID:42552261 (Turkish neuropathy cohort; COA7 details not in the abstract) and PMID:40830826 (COX18, a differential the report suggested without a COA7-specific comparison). GeneReviews. just check-genereviews --online returned NO_CHAPTER for the entry name and all four synonyms, so the case reports are the baseline. Pathophysiology. Fifteen nodes, one scale each: reduced mitochondrial COA7 protein (slow MIA import, proteasomal degradation) -> loss of COA7 heme-binding disulfide reductase activity -> complex IV assembly stall after the COX1 module -> deficient complex IV electron transfer -> glycolytic lactate rise, and -> bioenergetic failure in energy-demanding tissue, which branches to peripheral nerve (insult -> axonal degeneration -> length-dependent nerve dysfunction -> neuropathy phenotypes), cerebellum (insult -> cerebellar neurodegeneration -> ataxia, dysarthria, intention tremor), cerebral white matter, cerebral neurodegeneration (infantile form), nigrostriatal terminals -> striatal dopamine deficiency -> parkinsonism and dystonia, and subclinical mitochondrial myopathy. Laboratory, biopsy and imaging findings are attached as READOUT_OF reports_on links. 22 of 36 phenotypes are causally connected; the rest are 11 readouts plus respiratory failure, feeding difficulties and scoliosis, left unconnected where no source states a mechanism. Conformance added: complex_iv_assembly_deficiency at Complex IV Biogenesis Failure, Impaired Terminal Electron Transfer and ATP Synthesis, Lactic Acidosis and Metabolic Decompensation (mild lactate elevation only) and High-Energy Tissue Dysfunction; peripheral_axonal_degeneration at Insult to Peripheral Neurons and Schwann Cells, Distal Axonal Degeneration and Demyelination and Length-Dependent Nerve Fiber Dysfunction; cerebellar_purkinje_degeneration at Cerebellar Neuron Insult; parkinsonism_dopaminergic_degeneration at Nigrostriatal Dopaminergic Neurodegeneration and Striatal Dopamine Deficiency and Basal Ganglia Circuit Dysfunction. Considered and not used: cerebellar_purkinje_degeneration Purkinje Neuron Degeneration (no neuropathology; Purkinje loss not shown); mitochondrial_dysfunction (aging-hallmark module, excludes monogenic respiratory chain lesions); cns_myelin_failure (primary defect is not in oligodendrocytes or myelin, and myelin loss is not histologically evidenced); schwann_cell_myelin_maintenance (the neuropathy is axonal); corticospinal_tract_axonopathy (spasticity in a few patients but no evidence of corticospinal degeneration); complex_i_deficiency (complex I reduction is secondary and seen in one patient). Treatments: levodopa, deep brain stimulation, baclofen and protirelin tartrate, each from single-patient reports, and supportive care. Proteasome inhibition is recorded only as an in vitro rescue readout on the patient-fibroblast experimental model. An infection-triggered worsening in one infant was not modelled as an environmental factor because it rests on one case. Validation: just validate passed; count-verified-snippets 125/125; check-entity-refs, check-causal-targets, check-logical-rules, check-coarse-phenotypes, check-enum-values, check-duplicate-keys and check-block-scalar-comments clean; whole-tree snippet-length, title-snippet, reference-title, snippet-grading and retired-support-prose gates passed; check-gene-activity-grounding reports nothing for this file; just validate-disorders passed. Review response (PR 15783): rebound the cerebellar insult node's cell type from CL:0000540 neuron to CL:1001611 cerebellar neuron. Connected Respiratory failure downstream of the length-dependent nerve fiber node, citing the PMID:37750949 Discussion sentence that attributes it mainly to phrenic nerve axonal impairment. Added Dysphagia (HP:0002015, two patients) and Vocal cord paralysis (HP:0001605, one patient) from the same full text. The optional diagnosis section and cardiomyopathy phenotype were not added in this round.

Claude Code ▸

Spinocerebellar Ataxia, Autosomal Recessive, With Axonal Neuropathy 3 (SCAN3; COA7-related disorder): research report

claude-haiku-5-5, claude-opus-5-5 16 citations 2026-10-27T22:08:38.485545

Stub-like entry. Let me fetch primary sources.

I'm pulling abstracts for the remaining COA7 papers from Europe PMC, because the PMC pages are blocked behind a verification check.

I have the core papers. One last check for animal models, then I'll write the report.

Spinocerebellar Ataxia, Autosomal Recessive, With Axonal Neuropathy 3 (SCAN3; COA7-related disorder): research report

Causal gene: COA7 (cytochrome c oxidase assembly factor 7; formerly C1orf163 / RESA1; HGNC:25716; OMIM gene 615623; UniProt Q96BR5; chromosome 1p32.3). All findings below are tied to MONDO:0020770 and OMIM #618387. SCAN1 (TDP1) and SCAN2 (SETX*/AOA2) are different diseases caused by different genes. They are not covered here.

Note on ontology IDs. The HP, GO, CL, UBERON, NCIT and CHEBI identifiers in this report are candidates to check with a lookup (runoak, OLS or cache/*/terms.csv) before they are written into the KB. Several were suggested from memory. The disease identifiers (MONDO xrefs, OMIM, PMIDs) and the quoted abstract text were checked against Europe PMC or OLS in this session.

1. Disease information

Overview. SCAN3 is an autosomal recessive mitochondrial disease. It usually starts in the first or second decade and has two main features: - an axonal sensorimotor polyneuropathy that looks like Charcot-Marie-Tooth disease; - cerebellar ataxia with cerebellar atrophy.

Some patients also have leukoencephalopathy, spinal cord atrophy, mild intellectual disability, subclinical mitochondrial myopathy, and later dystonia or parkinsonism. The cause is biallelic loss-of-function variants in COA7, which lead to cytochrome c oxidase (complex IV) deficiency.

The disease was named in 2018: "this new entity of disease would be referred to as spinocerebellar ataxia with axonal neuropathy type 3" (Higuchi et al., Brain 2018, PMID:29718187).

The field now treats it as a broader COA7-related disorder spectrum: "COA7-related disorders typically encompass a spectrum of conditions characterized by a variety of major (cerebellar ataxia and axonal polyneuropathy) and minor (leukoencephalopathy, dystonia, and parkinsonism) symptoms" (Higuchi et al., J Neurol 2024, PMID:37750949).

Identifiers (from the MONDO record via OLS):

Resource	ID
MONDO	MONDO:0020770
OMIM (phenotype)	618387
OMIM (gene)	615623
DOID	DOID:0070465
GARD	GARD:0025244
MedGen	1673607
UMLS	C5193070
Orphanet	No disease-specific ORPHA code found. MONDO lists no Orphanet xref. It probably sits under a broader Orphanet grouping; check before citing.
ICD-10/ICD-11	No specific code. The best available is G11.x (hereditary ataxia) or G60.x (hereditary neuropathy).
MeSH	No specific descriptor.

Synonyms. SCAN3; spinocerebellar ataxia with axonal neuropathy type 3; COA7-related spinocerebellar ataxia with axonal neuropathy; COA7-related disorder; COA7-related mitochondrial leukoencephalopathy with COX deficiency (the first-reported presentation).

Nature of the data. All knowledge comes from individual case reports and small case series, roughly 11–13 published individuals. There are no registries, no natural-history cohorts and no EHR-derived data.

2. Etiology

Cause. The disease is genetic and monogenic. It requires biallelic (homozygous or compound heterozygous) pathogenic COA7 variants.
Genetic risk factors. The only established risk factor is the COA7 genotype. The recurrent missense c.17A>G p.(Asp6Gly) appears in most Japanese patients and in one Chinese patient. It was rare in ExAC (1/120,268 alleles, PMID:29718187). It may be an East Asian founder or recurrent allele, but no haplotype analysis has been published.
Modifier genes. None reported.
Environmental risk or protective factors. None reported, and none expected for a Mendelian loss-of-function disorder.
One possible trigger: in the Ban et al. 2021 patient, regression worsened after an episode of diarrhea and fever (PMID:34322155). This is anecdotal. It fits the general pattern of metabolic decompensation in mitochondrial disease, but has not been shown specifically for COA7.
Gene–environment interactions. None documented.

3. Phenotypes

The frequencies below are drawn from about 12 published individuals. Denominators are small and the reporting is uneven.

Phenotype	Candidate HP term	Type	Onset	Course	Approx. frequency	Key evidence
Axonal sensorimotor polyneuropathy	HP:0003477 Peripheral axonal neuropathy (consider HP:0007141 sensorimotor axonal polyneuropathy, verify)	sign / electrophysiology	early childhood to adolescence (one adult onset at 30 y)	slowly progressive	~10/12 (absent in the infantile-encephalopathy and pure-dystonia cases)	PMID:29718187; PMID:35603692; PMID:42182620
Cerebellar ataxia (limb, truncal, gait)	HP:0001251 Ataxia; HP:0001252? (verify) / HP:0002066 Gait ataxia	sign	childhood	progressive	~9/12	PMID:29718187
Sensory ataxia	HP:0010871 Sensory ataxia (verify)	sign	childhood	progressive	reported (Higuchi patient 1)	PMID:29718187
Cerebellar atrophy (MRI)	HP:0001272 Cerebellar atrophy	imaging	—	—	all 4 index Japanese patients; Tang patient; absent in Cicala siblings	PMID:29718187; PMID:35603692
Spinal cord atrophy / thin cord	HP:0002251? → verify; candidate "Spinal cord atrophy"	imaging	—	—	~3 (Higuchi patient 3, Martinez Lyons, Tang)	PMID:27683825; PMID:35603692
Leukoencephalopathy / cavitating white-matter disease	HP:0002352 Leukoencephalopathy; HP:0002415 Leukodystrophy	imaging	infancy–childhood	progressive	~4/12	PMID:27683825; PMID:29718187; PMID:34322155
Distal muscle weakness and atrophy	HP:0002460 Distal muscle weakness; HP:0003693 Distal amyotrophy	sign	childhood	progressive; wheelchair by age 9 in one patient	most	PMID:29718187
Distal sensory loss	HP:0002936 Distal sensory impairment	sign	childhood	progressive	most	PMID:29718187
Areflexia / hyporeflexia	HP:0001284 Areflexia; HP:0001265 Hyporeflexia	sign	—	—	most	PMID:29718187; PMID:42182620
Steppage gait	HP:0003376 Steppage gait	sign	early childhood (presenting sign)	—	≥1	PMID:29718187
Pes cavus / foot deformity	HP:0001761 Pes cavus	physical	<5 y (presenting sign)	—	several	PMID:29718187; PMID:42182620
Dysarthria	HP:0001260 Dysarthria	sign	—	—	several	PMID:29718187; PMID:27683825
Tremor	HP:0001337 Tremor	sign	—	—	several	PMID:27683825; PMID:42182620
Dysmetria	HP:0001310 Dysmetria	sign	—	—	≥1	PMID:27683825
Mild intellectual disability / cognitive difficulty	HP:0001256 Intellectual disability, mild	behavioral/cognitive	childhood	stable	~4/12 (IQ 68 and 75 in two patients)	PMID:27683825; PMID:29718187; PMID:42182620
Psychomotor / motor delay	HP:0001263 Global developmental delay; HP:0001270 Motor delay	developmental	infancy	—	2	PMID:27683825; PMID:34322155
Developmental regression	HP:0002376 Developmental regression	behavioral	3 mo	rapidly progressive	1	PMID:34322155
Spasticity / hypertonia / hyperreflexia	HP:0001257 Spasticity; HP:0001276 Hypertonia	sign	infancy	progressive	1 (atypical)	PMID:34322155
Generalized dystonia	HP:0007325 Generalized dystonia (verify) / HP:0001332 Dystonia	sign	infancy	—	1–2	PMID:37750949; PMID:34322155 (tonic dystonia)
Parkinsonism (levodopa-responsive)	HP:0001300 Parkinsonism	sign	late adult (58 y)	progressive	2 (possible overlap, see §9)	PMID:37264311; PMID:37750949
Severe weakness, respiratory failure, feeding difficulty	HP:0002093 Respiratory insufficiency (verify); HP:0011968 Feeding difficulties	sign	—	—	1	PMID:37750949
Scoliosis	HP:0002650 Scoliosis	physical	adolescence	—	≥1	PMID:27683825
Elevated serum or CSF lactate	HP:0002151 Increased serum lactate; HP:0002490 Increased CSF lactate	lab	—	—	~4	PMID:27683825; PMID:29718187; PMID:34322155
Mildly elevated CK	HP:0003236 Elevated circulating creatine kinase concentration	lab	—	—	≥2 (189–577 IU/L; 488 U/L)	PMID:29718187; PMID:34322155
Ragged-red fibres, COX-negative fibres, SDH-increased fibres	HP:0003200 Ragged-red muscle fibers; HP:0003688 Cytochrome C oxidase-negative muscle fibers	lab/biopsy	—	subclinical	≥1; "mitochondrial abnormalities" in the Tang patient	PMID:29718187; PMID:35603692
Decreased complex IV activity (fibroblasts, muscle, skin)	HP:0008347 Decreased activity of mitochondrial complex IV	lab	—	—	nearly all tested (Tang fibroblasts normal)	PMID:27683825; PMID:29718187; PMID:34322155; PMID:42182620
Decreased complex I activity	HP:0011923 Decreased activity of mitochondrial complex I	lab	—	—	1	PMID:29718187
Cardiac hypertrophy (septal/LV wall thickening)	HP:0001639 Hypertrophic cardiomyopathy (verify; a softer term may fit better)	sign	infancy	—	1 (atypical)	PMID:34322155

Absent features. Higuchi et al. state there was no nystagmus or oculomotor apraxia, which separates SCAN3 from AOA1/AOA2. Both Cicala siblings had normal brain MRI (PMID:42182620): "Brain MRI findings were unremarkable in both siblings."

Quality of life. No formal QoL instruments (EQ-5D, SF-36) have been reported. The functional burden is mostly mobility: - one patient used a wheelchair from age 9 (PMID:29718187); - one walked only with ankle-foot orthoses at age 19 (PMID:27683825).

Dysarthria, mild cognitive impairment and, in severe cases, feeding difficulty and respiratory failure add to the burden.

Key quotes - "all four patients had characteristic neurological features of peripheral neuropathy and ataxia with cerebellar atrophy" (PMID:29718187) - "Both presented with early-onset, slowly progressive axonal sensorimotor neuropathy" (PMID:42182620) - "infantile-onset generalized dystonia without cerebellar ataxia" (PMID:37750949) - "Levodopa administration improved parkinsonism in this patient." (PMID:37264311)

4. Genetic and molecular information

Gene. COA7, HGNC:25716 (repository form hgnc:25716). It encodes a small (~231 aa) cysteine-rich protein (13 Cys) with five Sel1-like repeats, a subclass of the TPR fold.

Published pathogenic variants (NM_023077.2):

Variant	Protein	Type	Zygosity / patient	Source
c.17A>G	p.Asp6Gly (D6G)	missense, recurrent	homozygous (Higuchi P1; Ouchi 2023); compound het with S149I, G144fs (Higuchi 2018), W185* (Tang 2022), C150Y (Higuchi 2023)	PMID:29718187; PMID:37264311; PMID:35603692; PMID:37750949
c.115C>T	p.Arg39Trp (R39W)	missense	in trans with exon 2 deletion (Higuchi P2); also in Higuchi 2023	PMID:29718187; PMID:37750949
exon 2 deletion	in-frame loss of 47 aa	CNV, detected by MLPA	Higuchi P2	PMID:29718187
c.287+1G>T	exon 2 skipping (141 bp, in-frame)	splice donor	Martinez Lyons patient, maternal allele	PMID:27683825
c.410A>G	p.Tyr137Cys (Y137C)	missense	Martinez Lyons patient, paternal allele	PMID:27683825
c.430delG	p.Gly144fs	frameshift	Higuchi P4	PMID:29718187
c.446G>T	p.Ser149Ile	missense	Higuchi P3	PMID:29718187
c.449G>A	p.Cys150Tyr (novel 2023)	missense (loses a cysteine)	dystonia patient, with D6G	PMID:37750949
c.457C>T	p.Leu153Phe (novel 2026)	missense	Cicala siblings; the second allele is not named in the abstract	PMID:42182620
c.511G>A	p.Ala171Thr	missense	Ban 2021, maternal	PMID:34322155
c.554G>A	p.Trp185* (novel 2022)	nonsense	Tang 2022, with D6G	PMID:35603692
c.566A>G	p.Asn189Ser	missense (3 gnomAD alleles)	Ban 2021, paternal	PMID:34322155

Variant classes. Mostly missense, plus a frameshift, a nonsense, a splice-site variant and an exon deletion. The exon deletion means MLPA/CNV analysis is needed when only one variant is found.
ACMG classification. The ClinVar status of each variant was not retrieved here; check ClinVar before entering a clinical_significance. PanelApp (Genomics England) lists COA7 with biallelic inheritance.
ClinGen / GenCC. A GenCC submission exists (SGC-107318.2, which lists PMID:37750949 among six publications). No ClinGen CGGV record for COA7 is cached locally, so do not assign a validity tier (CLAUDE.md: a tier is copied from a source, never assigned).
Population frequency. D6G was 1/120,268 in ExAC (PMID:29718187). N189S has 3 alleles in gnomAD and A171T is absent (PMID:34322155).
Origin. All variants are germline. There are no somatic or mosaic reports.
Functional consequence. Loss of function / hypomorphic (functional_impact_category: LOSS_OF_FUNCTION; partial LOF is plausible for the missense alleles).
Wild-type COA7 re-expression rescued COX assembly and activity in patient fibroblasts (PMID:27683825).
Y137C and the exon-2-deleted protein are imported into mitochondria less efficiently (about 50% and 70% lower) and are degraded by the cytosolic proteasome (PMID:30885959).
Modifier genes, epigenetics, chromosomal abnormalities. None reported. Not applicable.

5. Environmental information

No environmental, lifestyle or infectious causes are known. The intercurrent febrile or diarrheal illness before regression in one infant (PMID:34322155) should be recorded at most as a possible exacerbating factor (environmental_effect: EXACERBATES, with low confidence). Otherwise this section is not applicable.

6. Mechanism and pathophysiology

Ordered causal chain

Biallelic COA7 loss-of-function variants (missense, truncating, splice, exon deletion) lead to reduced levels of functional COA7 protein. COA7 was undetectable by western blot in Martinez Lyons patient cells (PMID:27683825).
Branch 1a (shown for missense and in-frame alleles): the mutant precursors are imported more slowly through the MIA40/CHCHD4 disulfide-relay (MIA) pathway. COA7 forms a disulfide intermediate with MIA40 through Cys55. The unimported protein is degraded by the cytosolic ubiquitin–proteasome system (PMID:30885959): "mislocalized proteins are degraded in the cytosol by the proteasome."
Branch 1b: truncating alleles (G144fs, W185*) probably cause loss of protein outright. This is inferred; NMD and protein loss were not tested.
Loss of COA7 in mitochondria results in failure of its proposed heme-dependent disulfide-reductase activity. COA7 binds heme with His/Met axial ligation (reduction potential −353 mV), interacts transiently with the copper metallochaperones SCO1 and SCO2, and reduces the disulfides in their copper-binding sites. This regenerates the copper relay to COX2 (Formosa et al., PNAS 2022, PMID:35210360): "COA7 interacts transiently with the copper metallochaperones SCO1 and SCO2."
Shown biochemically and in knockout cells. That patient variants act through this route is inferred.
Impaired Cu_A delivery stalls complex IV assembly after the COX1 module forms and before COX2/COX3 are added (PMID:35210360): "loss of COA7 blocks complex IV assembly after the initial step where the COX1 module is built." The result is lower levels of MT-CO2 and MT-CO3 and of assembled CIV and the III₂+IV supercomplex (PMID:27683825). Assembled CIV fell to 3.8–9.9% of control in Higuchi fibroblasts (PMID:29718187).
Complex IV deficiency results in reduced mitochondrial oxygen consumption and OXPHOS capacity. Maximal respiration was about 46% of control (PMID:34322155). Secondary complex I reduction was seen in one patient (PMID:29718187). Elevated lactate shows the shift to glycolysis.
Bioenergetic failure in high-demand, long-axon neurons (inferred) leads to length-dependent axonal degeneration of motor and sensory peripheral nerves. Sural nerve biopsy showed loss of large and medium myelinated fibres, with no onion bulbs or inflammation (PMID:29718187).
Drosophila neuron-specific dCOA7 knockdown shortens neuromuscular-junction synaptic branches by about 50% and impairs climbing (PMID:29718187). This supports a cell-autonomous neuronal requirement.
In parallel (branching), energy failure in CNS neurons and glia (inferred) produces:
6a cerebellar atrophy, leading to cerebellar ataxia and dysarthria;
6b degeneration of the spinal cord long tracts and dorsal columns, leading to spinal cord atrophy and sensory ataxia;
6c white-matter injury and cavitating leukoencephalopathy (the oligodendrocyte or myelin vulnerability is inferred), leading to cognitive impairment and spasticity;
6d nigrostriatal dopaminergic involvement, leading to dystonia or levodopa-responsive parkinsonism. Striatal hypo-uptake on DaT SPECT is shown (PMID:37264311); the mechanism is inferred.
Skeletal muscle (mild) shows ragged-red, COX-negative and SDH-increased fibres and mildly raised CK, i.e. a subclinical mitochondrial myopathy (PMID:29718187). Neurogenic atrophy adds to the distal weakness.
Clinical result: a progressive axonal sensorimotor neuropathy plus cerebellar ataxia (SCAN3), with variable CNS features.

Unresolved controversy (subcellular location). Martinez Lyons et al. found COA7 behaving "as the soluble matrix protein Citrate Synthase," which suggests a matrix location (PMID:27683825). Mohanraj et al. 2019 (PMID:30885959) and Formosa et al. 2022 (PMID:35210360) place it in the intermembrane space (IMS), imported by MIA. The IMS location also fits the SCO1/SCO2 function. Curate the IMS location as the better-supported current view and record the earlier matrix report in a note.

Genotype–biochemistry discordance. The Tang 2022 patient had normal respiratory-chain activity in fibroblasts despite pathogenic variants and abnormal muscle (PMID:35603692). Fibroblast testing can therefore give false-negative results, which is a useful diagnostic caveat.

Ontology suggestions (verify)

GO biological process: GO:0033617 mitochondrial cytochrome c oxidase assembly; GO:0045333 cellular respiration; GO:0006123 mitochondrial electron transport, cytochrome c to oxygen; GO:0045041 protein import into mitochondrial intermembrane space; GO:0008090? (check for a "retrograde/axonal transport" term only if justified; not shown for COA7).
GO molecular function: GO:0020037 heme binding; a disulfide oxidoreductase activity term (for example GO:0015036 disulfide oxidoreductase activity, verify).
GO cellular component: GO:0005758 mitochondrial intermembrane space; GO:0005759 mitochondrial matrix (historical report); GO:0005751 mitochondrial respiratory chain complex IV.
Cell types (CL): CL:0000100 motor neuron; CL:0000101 sensory neuron; CL:0000121 Purkinje cell (inferred from cerebellar atrophy; not directly shown); CL:0000128 oligodendrocyte (inferred); CL:0000700 dopaminergic neuron; CL:0000057 fibroblast (assay system); CL:0000188 cell of skeletal muscle.
Molecular profiling. No transcriptomic, proteomic, metabolomic, single-cell or spatial datasets are reported for COA7 disease. A future datasets: search (just discover-datasets) is likely to return none.

7. Anatomical structures affected

Primary. Peripheral nervous system: peripheral nerves, length-dependent and lower limbs first (UBERON:0001021 nerve; sural nerve, verify the UBERON ID). Cerebellum (UBERON:0002037).
Secondary or variable. Spinal cord (UBERON:0002240); cerebral white matter (UBERON:0002437); striatum / basal ganglia (UBERON:0002435 striatum); skeletal muscle (UBERON:0001134 skeletal muscle tissue); heart in one atypical infant (UBERON:0000948).
Body systems. Nervous (central and peripheral), neuromuscular, and possibly cardiovascular.
Subcellular. Mitochondrial intermembrane space and inner membrane, specifically respiratory complex IV.
Lateralization. Bilateral and symmetric. DaT hypo-uptake was bilateral (PMID:37264311).

8. Temporal development

Onset. Usually <5 years: foot deformity, steppage gait or poor dexterity. The range runs from 3 months (encephalopathic form) through adolescence (15 y) to 30 years (adult-onset D6G homozygote, PMID:37264311). Cicala siblings: 5 y and 12 y.
Pattern. Insidious onset, then a chronic, slowly progressive course. The infantile form progressed rapidly (PMID:34322155).
Progression.
Wheelchair from age 9 in one patient.
Ankle-foot orthoses at 19 in another.
The oldest reported patient was 63 years old and still described as alive.
Parkinsonism can appear decades after onset (age 58).
Stages, remission and critical periods. No staging system exists and no remission has been reported. Possible vulnerability to intercurrent illness in infancy.

9. Inheritance and population

Inheritance. Autosomal recessive, HP:0000007. Consanguinity was present in Higuchi patient 1, who was homozygous.
Penetrance and expressivity.
Penetrance appears complete in biallelic individuals. Heterozygous parents are unaffected, with normal CIV in parents' fibroblasts (PMID:34322155).
Expressivity is highly variable, from isolated axonal neuropathy with a normal MRI to infantile encephalopathy, generalized dystonia, or adult-onset ataxia with parkinsonism.
Some genotypes recur: D6G homozygosity was seen with both childhood onset (Higuchi patient 1) and adult onset (Ouchi).
Anticipation and mosaicism. None.
Prevalence. Unknown, ultra-rare. Prevalence would be measure_type: CASES_IN_LITERATURE with prevalence_class: ULTRA_RARE or RARE.
Published count: Martinez Lyons 1; Higuchi 2018 4; Ban 2021 1; Tang 2022 1; Ouchi 2023 1; Higuchi 2023 3 new (giving 7 Japanese patients in that series); Cicala 2026 2 siblings. That is about 11–13 individuals, plus an unknown number in a 2026 Turkish hereditary-polyneuropathy cohort (Avcı et al., PMID:42552261).
Possible double count: the Ouchi 2023 patient (homozygous D6G, levodopa-responsive parkinsonism) and Higuchi 2023 patient 2 (ataxia, neuropathy and parkinsonism with a slight levodopa response) are both Japanese. Check whether they are the same person before counting.
Sex discrepancy in the literature: Martinez Lyons describe their patient as a 19-year-old woman, but Ban et al.'s summary table lists that patient as M. Use the primary report.
Diagnostic yield. 4 of 1,396 in a Japanese inherited-neuropathy / CMT series (~0.3%) (PMID:29718187): "identified four unrelated patients with recessive mutations in COA7 among a Japanese case series of 1396 patients."
Populations. Japanese (most patients, recurrent D6G), Chinese (2), Italian (Martinez Lyons; Cicala siblings), Turkish (2026 cohort).
Carrier frequency and sex ratio. Carrier frequency is unknown. The sex ratio is roughly balanced (M ≈ F).

10. Diagnostics

Genetic testing (first line). Exome or genome sequencing, or ataxia/CMT gene panels that include COA7.
Add CNV/MLPA when only one heterozygous variant is found, because the exon 2 deletion was missed by sequencing (PMID:29718187).
Trio sequencing helps establish phase.
Sequence mtDNA to exclude mtDNA COX defects (done in PMID:34322155).
Electrophysiology. Nerve conduction studies show an axonal sensorimotor neuropathy. Lower-limb CMAPs and SNAPs are absent or severely reduced, and median motor conduction velocity is near normal (49.6–51.5 m/s). One patient had a mixed axonal-demyelinating picture (PMID:27683825).
Imaging.
Brain MRI: cerebellar atrophy; ± white-matter T2 hyperintensity or cavitation; ± cerebral atrophy.
Spinal MRI: cord atrophy.
DaT SPECT (¹²³I-ioflupane) when parkinsonism is present; MIBG was normal in the reported case.
Biochemistry.
Respiratory-chain enzyme assays in fibroblasts, muscle or skin show isolated complex IV deficiency.
BN-PAGE shows reduced assembled CIV.
Fibroblast results can be normal (PMID:35603692), so muscle is preferred.
Serum and CSF lactate; CK.
Relevant LOINC targets: lactate in serum/plasma and CSF, creatine kinase. Bind the LOINC Part or panel codes after a lookup.
Pathology.
Sural nerve: chronic axonal degeneration with loss of large and medium myelinated fibres.
Muscle: ragged-red, COX-negative and SDH-increased fibres.
Differential diagnosis.
SCAN1 (TDP1); AOA1 (APTX); AOA2/SCAN2 (SETX), which have oculomotor apraxia and raised AFP, both absent in SCAN3.
Friedreich ataxia (FXN); ataxia-telangiectasia.
POLG-related ataxia-neuropathy; other COX-assembly disorders (SCO2, COA8/APOPT1 cavitating leukoencephalopathy, COX18-related neuropathy, PMID:40830826).
Axonal CMT types; SACS (ARSACS); PNPLA6.
Clinical criteria. None standardized.
Screening. No newborn screening. Carrier and cascade testing are possible in families with known variants.

11. Outcome and prognosis

Survival into the 7th decade is documented (Higuchi patient 1, aged 63).
The infantile encephalopathic form (Ban 2021, last seen at 2 y) and the form with respiratory failure and feeding difficulty (Higuchi 2023 patient 3) suggest worse outcomes at the severe end. No mortality data exist.
Morbidity comes from progressive loss of mobility (wheelchair or orthoses), falls, dysarthria and mild cognitive impairment.
No prognostic biomarkers or validated QoL data exist.
Possible negative prognostic signs, from anecdote only: infantile onset, leukoencephalopathy, cardiac involvement.

12. Treatment

There is no disease-modifying therapy. Management is supportive.

Intervention	Candidate NCIT	Evidence
Physical therapy and rehabilitation; orthoses (AFOs)	NCIT:C15302 Physical Therapy; NCIT:C15315 Rehabilitation	standard care; AFO use reported (PMID:27683825)
Orthopedic management of foot deformity and scoliosis	NCIT:C16186 Orthopedic Surgical Procedure (only if surgery is documented)	not specifically reported
Levodopa for parkinsonism	NCIT:C15986 Pharmacotherapy + `therapeutic_agent` levodopa (CHEBI:15765, verify)	improved parkinsonism (PMID:37264311); slight improvement (PMID:37750949)
Baclofen for spasticity	NCIT:C15986 + baclofen (CHEBI, verify)	partial control (PMID:34322155)
Protirelin tartrate (TRH analogue) for ataxia	NCIT:C15986 + agent (verify)	slight, transient improvement, then decline (PMID:29718187)
Mitochondrial "cocktail" (CoQ10, riboflavin, etc.)	NCIT:C15747 Supportive Care	no COA7-specific data; do not assert efficacy
Genetic counseling	NCIT:C15240 Genetic Counseling	standard

Experimental and preclinical. - Proteasome inhibitors (MG132 in HEK293; bortezomib, carfilzomib in patient fibroblasts) rescued COA7 mitochondrial localization and raised complex IV activity by about 35% (PMID:30885959): "proteasome inhibition rescued both the mitochondrial localization of COA7 and complex IV activity." - This is IN_VITRO only. Clinical use is limited by proteasome-inhibitor toxicity, including bortezomib-induced peripheral neuropathy, which is a direct concern in this disease. No clinical trials were found. - Gene therapy, ASO, cell therapy: none. - Pharmacogenomics: none.

13. Prevention

Primary. Genetic counseling for carrier couples; preimplantation or prenatal diagnosis once familial variants are known.
Secondary. Early genetic diagnosis in children with axonal neuropathy plus ataxia.
Tertiary.
Physical therapy and orthotics.
Avoid neurotoxic drugs, especially those that cause neuropathy. This is general mitochondrial-disease advice and not COA7-specific evidence.
Prompt management of intercurrent illness.
Vaccines, prophylaxis and public-health measures: not applicable.

14. Other species and natural disease

Natural animal disease. None reported. No OMIA entry was found.
Orthologs. COA7 is conserved across metazoans but absent from yeast (PMID:27683825). Orthologs: mouse Coa7; Drosophila dCOA7 (CG?, check the FlyBase ID; FlyBase FBrf0238967 refers to the Higuchi 2018 paper).

15. Model organisms

Model	Type	Phenotype	Recapitulation	Source
Drosophila melanogaster neuron- or eye-specific dCOA7 RNAi knockdown (NCBITaxon:7227)	invertebrate genetic knockdown	rough eye (ommatidial fusion, bristle loss); median lifespan 43/40 d vs 51 d; age-dependent climbing defect; larval NMJ branch length 38 vs 77 µm	PARTIALLY_RECAPITULATES the motor-neuron/axonal degeneration node. Limitations: knockdown, not patient alleles; no cerebellum homologue; complex IV not measured in flies	PMID:29718187 ("showed rough eye phenotype, reduced lifespan, impaired locomotive ability")
Patient fibroblasts (immortalized mt4229i; others)	IN_VITRO	isolated CIV deficiency, reduced assembly, rescue by WT COA7 and by proteasome inhibition	RECAPITULATES the biochemical node; no neuronal context (BOUNDARY_OMISSION)	PMID:27683825; PMID:30885959; PMID:34322155
COA7-knockout human cell lines (HEK293-derived)	IN_VITRO	CIV assembly stalled after the COX1 module	MEASURES the assembly node	PMID:35210360
Mouse / zebrafish	—	No published Coa7 knockout phenotype found. Only commercial catalogue lines exist.	knowledge gap	—

Suggested knowledge gaps. No vertebrate model; no iPSC-derived motor-neuron or cerebellar model; the basis of the selective neuronal vulnerability; why fibroblast CIV is normal in some patients. A HUMAN_MODEL_MISMATCH discussion is not warranted yet because there is no model that diverges from the human picture.

Key references (verified in this session via Europe PMC/PMC)

PMID	Citation	Evidence type
27683825	Martinez Lyons A et al. COA7 (C1orf163/RESA1) mutations associated with mitochondrial leukoencephalopathy and cytochrome c oxidase deficiency. J Med Genet 2016;53:846–849	HUMAN_CLINICAL + IN_VITRO
29718187	Higuchi Y et al. Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy. Brain 2018;141:1622–1636	HUMAN_CLINICAL + IN_VITRO + MODEL_ORGANISM (split items)
30885959	Mohanraj K et al. Inhibition of proteasome rescues a pathogenic variant of respiratory chain assembly factor COA7. EMBO Mol Med 2019;11:e9561	IN_VITRO
34322155	Ban R et al. Biallelic COA7-variants leading to developmental regression with progressive spasticity and brain atrophy in a Chinese patient. Front Genet 2021;12:685035	HUMAN_CLINICAL + IN_VITRO
35210360	Formosa LE et al. Mitochondrial COA7 is a heme-binding protein with disulfide reductase activity, which acts in the early stages of complex IV assembly. PNAS 2022;119:e2110357119	IN_VITRO
35603692	Tang Y et al. A novel compound heterozygous mutation in the COA7 gene… SCAN3. Clin Neuropathol 2022;41:202–210	HUMAN_CLINICAL
37264311	Ouchi S et al. Parkinsonism in spinocerebellar ataxia with axonal neuropathy caused by adult-onset COA7 variants. BMC Neurol 2023;23:211	HUMAN_CLINICAL
37750949	Higuchi Y et al. Dystonia and parkinsonism in COA7-related disorders: expanding the phenotypic spectrum. J Neurol 2024;271:419–430	HUMAN_CLINICAL
42182620	Cicala G et al. Compound heterozygous COA7 variants presenting with childhood-onset axonal neuropathy in 2 siblings. Neurol Genet 2026;12(3):e200394	HUMAN_CLINICAL
40830826	Armirola-Ricaurte C et al. Biallelic variants in COX18 cause a mitochondrial disorder primarily manifesting as peripheral neuropathy. Brain 2026 (differential diagnosis or related complex IV assembly neuropathy)	HUMAN_CLINICAL
42552261	Avcı Ş et al. Hereditary polyneuropathy experience of a tertiary single-center in Türkiye. Clin Genet 2026 (includes COA7 case(s); details not retrieved)	HUMAN_CLINICAL

Curation notes - The quoted strings above come from abstracts as returned by Europe PMC, but some were relayed through a summarizing fetch tool. Run just fetch-reference and just count-verified-snippets on each before using it as an exact snippet. - The existing kb/disorders/Spinocerebellar_Ataxia_Autosomal_Recessive_With_Axonal_Neuropathy_3.yaml is a 25-line stub with only MONDO and one HP term, so almost everything here is new content.

Sources: - Higuchi 2018, Brain (PMC5972596) - Martinez Lyons 2016, J Med Genet (PMC5264227) - Mohanraj 2019, EMBO Mol Med (PMC6505684) - Ban 2021, Front Genet (PMC8312223) - Formosa 2022, PNAS (PMC8892353) - Formosa bioRxiv preprint - Higuchi 2023, J Neurol (PMC10769979) - Ouchi 2023, BMC Neurol (PMC10234071) - Europe PMC search results (Cicala 2026, Tang 2022, Avcı 2026, COX18 2026) - MONDO:0020770 via OLS - MalaCards SCAN3 - KEGG H02573 - GenCC submission - PanelApp COA7 - Alliance COA7 - RCSB 7MQZ

Reference Validation

Checked with linkml-reference-validator 0.4.0.

Outcome	Count
References checked	18
Resolved	18
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	6
Quoted claims found in source	6
Quoted claims not found in source	0
References weighed for topical relevance	18
On topic	17
Off topic	0

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome	Count
Terms checked	77
Resolved	74
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	2
Terms whose name was checked	3
Terms named correctly	0
Terms named as a different term	2
Terms whose name is worth a second look	1

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

MONDO:0020770 (5 mentions) - the report calls it "MONDO"; MONDO calls it spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 3
DOID:0070465 (1 mention) - the report calls it "DOID"; DOID calls it autosomal recessive spinocerebellar ataxia with axonal neuropathy 3

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0005751 (obsolete mitochondrial respiratory chain complex IV) (1 mention) - replaced by GO:0045277

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

NCBITaxon:7227 (1 mention) - the report calls it "Drosophila melanogaster neuron- or eye-specific dCOA7 RNAi knockdown"; NCBITaxon calls it Drosophila melanogaster*

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: GARD.

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Spinocerebellar Ataxia, Autosomal Recessive, With Axonal Neuropathy 3 (SCAN3; COA7-related disorder): research report

1. Disease information

2. Etiology

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Ordered causal chain

Ontology suggestions (verify)

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms

Key references (verified in this session via Europe PMC/PMC)

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Prefixes with no resolver