👪

Inheritance

1

Autosomal recessive HP:0000007

Biallelic variants, compound heterozygous in one non-consanguineous family and homozygous in two consanguineous Pakistani families; an unaffected sibling of the first patient was heterozygous.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:28002403 SUPPORT Human Clinical

"The mutations were confirmed by Sanger sequencing as c.1293G>C (p.K431N) and c.1393C>T (p.Q465*) and were present in trans, with the unaffected sibling of the proband heterozygous for c.1293G>C"

The two variants are in trans, and a heterozygous sibling is unaffected.

PMID:29472272 SUPPORT Human Clinical

"Patient 2 was also born to consanguineous parents"

Consanguinity in the homozygous families.

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Discussions and Knowledge Gaps

2

Can PARP1 be reduced pharmacologically in a way that reproduces the genetic rescue seen in mice and zebrafish?

KNOWLEDGE GAP scar26_parp1_therapy

Attached to

pathophysiology#PARP1 Trapping and Hyperactivation

Genetic deletion of Parp1 reduces the neuron loss and ataxia of Xrcc1-deficient mice, prevents their seizure-related defects, extends their lifespan, and rescues the cerebellar defect of xrcc1 zebrafish. The PARP inhibitor veliparib, given to Xrcc1-deficient mice, prevented the seizure-like activity in hippocampal slices and the calcium defects in isolated neurons but did not significantly extend lifespan. Clinical PARP inhibitors trap PARP1 on DNA, the very effect XRCC1 loss already produces, so they may not mimic deletion. No drug has been tested in patients.

Show evidence (3 references)

PMID:33932076 SUPPORT Model Organism

"Moreover, we show that these defects are prevented by Parp1 inhibition or deletion and, in the case of Parp1 deletion, that the lifespan of Xrcc1Nes-Cre mice is greatly extended."

Inhibition or deletion prevents the ex vivo and in vitro defects; only deletion extends lifespan.

PMID:33932076 SUPPORT Model Organism

"this may explain why we have so far been unable to extend significantly the lifespan of XRCC1Nes-Cre mice by PARP inhibition."

Pharmacological inhibition did not reproduce the lifespan rescue.

PMID:28002403 SUPPORT Other

"Inhibition of PARP1 with currently available chemical inhibitors may not be useful in this context, however, because these inhibitors “trap” PARP1 on DNA"

The authors' caution about trapping inhibitors.

How well does a lethal, developmental, neural-null mouse model a slowly progressive human disease caused by hypomorphic alleles, and what causes the peripheral neuropathy?

HUMAN MODEL MISMATCH scar26_mouse_severity_mismatch

Attached to

pathophysiology#Cerebellar Interneuron and Granule Neuron Loss phenotypes#Peripheral axonal neuropathy

The mouse loses cerebellar interneurons during development and dies of seizures within weeks. The three described patients have onset from infancy to the late twenties, no seizures, and a prominent axonal neuropathy that no model has examined; one further, undescribed patient reportedly had seizures and microcephaly. A hypomorphic knock-in of the recurrent c.1293G>C allele, assessed for peripheral nerve pathology, would bridge the gap.

Show evidence (1 reference)

PMID:33932076 SUPPORT Model Organism

"Here, we show that hyperactivity of the DNA strand break sensor protein Parp1 in mice in which the central SSBR protein Xrcc1 is conditionally deleted (Xrcc1Nes-Cre ) results in lethal seizures and shortened lifespan."

The mouse phenotype is much more severe than the described human disease.

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Pathophysiology

7

Biallelic XRCC1 Variants

Mechanism confidence: Established

Two pathogenic XRCC1 alleles. The recurrent c.1293G>C p.(Lys431Asn) sits at the last base of exon 11, in the intron 11 donor splice site, and causes aberrant splicing and reduced XRCC1 mRNA. It was found in trans with the nonsense variant p.(Gln465*) in the first patient, and homozygous in two Pakistani patients from consanguineous families who share a haplotype around the variant. The alleles are hypomorphic: Xrcc1-null mice are embryonic lethal, and the small amount of XRCC1 left in patient cells is thought to allow normal development.

XRCC1 hgnc:12828

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Germline, homozygous or compound heterozygous; the splice-site variant reduces XRCC1 transcript and protein, leaving residual function.

Downstream

Reduced XRCC1 and DNA Ligase III Alpha Protein

Show evidence (5 references)

PMID:28002403 SUPPORT Human Clinical

"The mutations were confirmed by Sanger sequencing as c.1293G>C (p.K431N) and c.1393C>T (p.Q465*) and were present in trans, with the unaffected sibling of the proband heterozygous for c.1293G>C"

Compound heterozygous variants in the first patient.

PMID:28002403 SUPPORT Human Clinical

"1293G>C mutation is located at the end of exon 11 and is also part of the donor splice site for intron 11, most likely affecting splicing and inducing premature stop codons/nonsense-mediated decay and/or encoding XRCC1 with the missense mutation, K431N."

The position and predicted effect of the recurrent variant.

PMID:29472272 SUPPORT Human Clinical

"This identified a homozygous mutation, c.G1293C (p.K431N), in exon 11 of XRCC1 (NM_006297) in the affected individuals."

The same variant homozygous in two further patients.

+ 2 more references

Reduced XRCC1 and DNA Ligase III Alpha Protein

Mechanism confidence: Established

Patient fibroblasts and lymphoblastoid cells keep only about 5% of normal XRCC1, and its partner DNA ligase III alpha, which XRCC1 stabilises, is reduced by more than 80%. The XRCC1-organised repair complexes therefore cannot assemble normally.

fibroblast CL:0000057

XRCC1 hgnc:12828

molecular scaffold activity of XRCC1 GO:0030674 ↓ DECREASED

Downstream

Defective DNA Single-Strand Break Repair

PARP1 Trapping and Hyperactivation

Show evidence (3 references)

PMID:28002403 SUPPORT BACKGROUND In Vitro

"XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair."

XRCC1's molecular role is to scaffold repair complexes, the function lost when the protein is reduced.

PMID:28002403 SUPPORT In Vitro

"Western blotting suggested that patient fibroblasts and LCLs both retained a small amount (∼5%) of residual XRCC1"

XRCC1 protein is reduced to about 5% in patient cells.

PMID:28002403 SUPPORT In Vitro

"Levels of DNA ligase IIIα (Lig3α) were also greatly reduced (by >80%) in patient cells, consistent with the established impact of XRCC1 on the cellular stability of this partner protein"

Loss of the XRCC1 partner protein in patient cells.

Defective DNA Single-Strand Break Repair

Mechanism confidence: Established

Single-strand breaks and base excision repair intermediates are repaired slowly in patient cells and persist throughout the nervous system of Xrcc1-deficient mice. The link from persistent breaks to the peripheral neuropathy is inferred; no model has examined peripheral nerve.

single strand break repair GO:0000012 ↓ DECREASED base-excision repair GO:0006284 ↓ DECREASED

Downstream

Peripheral axonal neuropathy

Show evidence (2 references)

PMID:28002403 SUPPORT In Vitro

"Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation."

Slower single-strand break repair in patient cells.

PMID:19633665 SUPPORT Model Organism

"Loss of Xrcc1 also led to the persistence of DNA strand breaks throughout the nervous system and abnormal hippocampal function."

Unrepaired strand breaks persist in the Xrcc1-deficient nervous system.

PARP1 Trapping and Hyperactivation

Mechanism confidence: Established

XRCC1 normally limits how long PARP1 stays bound and active at repair intermediates. Without it, PARP1 is trapped on the DNA and overactive, producing excess poly- and mono-ADP-ribosylation. Trapped PARP1 also blocks DNA polymerase beta, which slows repair further. Elevated ADP-ribose is present in patient cells and in the cerebellum of Xrcc1-deficient mice.

PARP1 hgnc:270

protein poly-ADP-ribosylation GO:0070212 ↑ INCREASED

Animal models

Xrcc1 neural-specific knockout mouse Mouse partially recapitulates

Downstream

Defective DNA Single-Strand Break Repair

Failed Transcriptional Recovery After DNA Damage

Cerebellar Interneuron and Granule Neuron Loss

Deregulated Neuronal Calcium Signalling

Progressive cerebellar ataxia

Show evidence (2 references)

PMID:28002403 SUPPORT Model Organism

"Strikingly, we detected elevated levels of ADP-ribose in the cerebellum of Xrcc1Nes-Cre mice suggesting that the loss of Xrcc1 can trigger Parp1 hyperactivation in brain even at endogenous levels of SSBs"

PARP1 hyperactivity occurs in the brain at endogenous levels of DNA damage.

PMID:41922367 SUPPORT In Vitro

"These tools reveal that, upon DNA damage, XRCC1 deficiency dramatically elevates the mono-ADP-ribosylation wave of PARP1 signalling, in addition to increasing poly(ADP-ribosyl)ation."

XRCC1 loss raises both mono- and poly-ADP-ribosylation.

Failed Transcriptional Recovery After DNA Damage

Mechanism confidence: Provisional

After DNA base damage, cells lacking XRCC1 fail to restart transcription rapidly, because hyperactive PARP1 recruits excess USP3 and depletes monoubiquitinated histones. Shown in patient fibroblasts and Xrcc1-null mouse neurons; its contribution to neurodegeneration in patients has not been tested.

gene expression GO:0010467 ↓ DECREASED

Downstream

Cerebellar Interneuron and Granule Neuron Loss

Show evidence (1 reference)

PMID:34811483 SUPPORT In Vitro

"Here we show that human cells lacking XRCC1 fail to rapidly recover transcription following DNA base damage, a phenotype also observed in patient-derived fibroblasts with XRCC1 mutations and Xrcc1-/- mouse neurons."

The defect is present in patient cells and in neurons.

Deregulated Neuronal Calcium Signalling

Mechanism confidence: Provisional

In Xrcc1-defective mouse hippocampus and isolated neurons, PARP1 hyperactivity deregulates presynaptic calcium signalling and triggers seizure-like activity, and Xrcc1-deficient mice die of seizures. Shown only in mouse tissue and neurons. Seizures are not reported in the three described patients, although a further, undescribed XRCC1 patient was mentioned as having seizures and microcephaly.

Downstream

Seizure

Show evidence (1 reference)

PMID:33932076 SUPPORT Model Organism

"Using electrophysiological recording and synaptic imaging approaches, we demonstrate that aberrant Parp1 activation triggers seizure-like activity in Xrcc1-defective hippocampus ex vivo and deregulated presynaptic calcium signalling in isolated hippocampal neurons in vitro."

The calcium defect in Xrcc1-defective neurons.

Cerebellar Interneuron and Granule Neuron Loss

Mechanism confidence: Established

In mice with neural Xrcc1 deletion, cerebellar interneurons (basket, stellate and Golgi cells) are lost through p53-dependent cell-cycle arrest as their progenitors differentiate, granule neurons die by apoptosis, and Purkinje cell spike activity falls. Patients show cerebellar atrophy on MRI, but the cell types lost in human cerebellum have not been examined.

cerebellar basket cell CL:2000027 cerebellar stellate cell CL:0010010 cerebellar Golgi cell CL:0000119 cerebellar granule cell CL:0001031

Animal models

Xrcc1 neural-specific knockout mouse Mouse recapitulates

xrcc1 mutant zebrafish Zebrafish partially recapitulates

Downstream

Progressive cerebellar ataxia

Cerebellar atrophy

Pontocerebellar atrophy

Dysarthria

Nystagmus

Hypometric saccades

Oculomotor apraxia

Show evidence (2 references)

PMID:19633665 SUPPORT Model Organism

"This cell loss was linked to p53-dependent cell cycle arrest and occurred as interneuron progenitors commenced differentiation."

The developmental mechanism of interneuron loss.

PMID:28002403 SUPPORT Model Organism

"Xrcc1Nes-Cre mice exhibit pronounced cerebellar histopathology including increased apoptosis of cerebellar granule neurons, greatly reduced numbers of cerebellar interneurons and decreased electrophysiological spike activity in Purkinje cells"

The cerebellar pathology of the mouse model.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

15

Eye 3

Oculomotor apraxia HP:0000657

Show evidence (1 reference)

PMID:28002403 SUPPORT Human Clinical

"A forty-seven year old woman of East Indian descent and non-consanguineous parents was diagnosed at age forty-one with cerebellar atrophy, gait and limb ataxia, ocular motor apraxia, and peripheral neuropathy"

Ocular motor apraxia in the first patient.

Hypometric saccades HP:0000571

Show evidence (1 reference)

PMID:29472272 SUPPORT Human Clinical

"Eye examination shows slow saccadic initiation, hypometria, jerky pursuit and horizontal nystagmus on extreme gaze."

Hypometric saccades in one patient.

Nystagmus HP:0000639

Show evidence (2 references)

PMID:29472272 SUPPORT Human Clinical

"Eye examination shows slow saccadic initiation, hypometria, jerky pursuit and horizontal nystagmus on extreme gaze."

Gaze-evoked nystagmus in one patient.

PMID:29472272 SUPPORT Human Clinical

"Examination of his eye movements reveal jerky pursuit with nystagmus on lateral gaze."

Gaze-evoked nystagmus in the other patient.

Genitourinary 1

Azoospermia HP:0000027

Show evidence (1 reference)

PMID:29472272 SUPPORT Human Clinical

"In addition to his neurological symptoms, he is infertile due to hypogonadism and azoospermia."

Single-case report.

Musculoskeletal 1

Distal amyotrophy HP:0003693

Show evidence (1 reference)

PMID:29472272 SUPPORT Human Clinical

"His examination was notable for prominent bilateral calf wasting and pes planus with impaired coordination and dysdiadochokinesis."

Distal muscle wasting consistent with the motor neuropathy.

Nervous System 10

Progressive cerebellar ataxia HP:0002073

Show evidence (2 references)

PMID:28002403 SUPPORT Human Clinical

"Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia."

The defining triad in the first patient.

PMID:29472272 SUPPORT Human Clinical

"Aged 3 years, he had a persistent ataxic gait and recurrent falls."

Childhood ataxia in a homozygous patient.

Cerebellar atrophy HP:0001272

Show evidence (3 references)

PMID:28002403 SUPPORT Human Clinical

"A forty-seven year old woman of East Indian descent and non-consanguineous parents was diagnosed at age forty-one with cerebellar atrophy, gait and limb ataxia, ocular motor apraxia, and peripheral neuropathy"

Cerebellar atrophy in the first patient.

PMID:29472272 SUPPORT Human Clinical

"Aged 15 years, he underwent an MRI brain, which was unremarkable."

An early normal MRI in one patient, before atrophy developed.

PMID:29472272 SUPPORT Human Clinical

"His recent MRI revealed cerebellar atrophy"

Atrophy on later imaging in the same patient.

Pontocerebellar atrophy HP:0006879

Show evidence (2 references)

PMID:29472272 SUPPORT Human Clinical

"disproportionate volume loss of the cerebellum and pons"

Pontine as well as cerebellar volume loss in one patient.

PMID:29472272 SUPPORT Human Clinical

"diminution of cervical spinal cord volume for age"

Reduced cervical cord volume in the same patient.

Peripheral axonal neuropathy HP:0003477

Sequelae: Impaired vibratory sensation Distal amyotrophy Areflexia

Show evidence (3 references)

PMID:28002403 SUPPORT Human Clinical

"nerve conduction studies revealed chronic length-dependent sensory-motor predominantly axonal peripheral neuropathy"

Nerve conduction findings in the first patient.

PMID:29472272 SUPPORT Human Clinical

"Nerve conduction studies and electromyogram (EMG) showed a length-dependent moderately severe sensorimotor neuropathy of axonal type"

The same neuropathy in the second patient.

PMID:29472272 SUPPORT Human Clinical

"EMG and MRI revealed a sensorimotor axonal neuropathy (online supplementary table 1) and cerebellar atrophy"

The same neuropathy in the third patient.

Impaired vibratory sensation HP:0002495

Show evidence (1 reference)

PMID:29472272 SUPPORT Human Clinical

"Sensation to light touch and pain is normal with impaired vibration sense and proprioception."

Large-fibre sensory loss consistent with the neuropathy.

Areflexia HP:0001284

Show evidence (1 reference)

PMID:29472272 SUPPORT Human Clinical

"He is areflexic throughout with flexor plantar responses and impaired sensation in the lower limbs below the knee."

Areflexia and distal sensory loss.

Babinski sign HP:0003487

Show evidence (1 reference)

PMID:29472272 SUPPORT Human Clinical

"Reflexes are absent in the lower limbs and planters are extensor on the left"

Single-patient finding.

Dysarthria HP:0001260

Show evidence (3 references)

PMID:28002403 SUPPORT Human Clinical

"multiple ataxic abnormalities including dysmetria, dysdiadochokinesis, and dysarthria"

Dysarthria with other cerebellar signs in the first patient.

PMID:29472272 SUPPORT Human Clinical

"In school, he had mild learning disabilities, dysarthria and difficulties playing sports with painful cramps particularly after prolonged exertion."

Dysarthria in the second patient.

PMID:29472272 SUPPORT Human Clinical

"He was dysarthric and had mild learning difficulties."

Dysarthria in the third patient.

Specific learning disability HP:0001328

Show evidence (2 references)

PMID:29472272 SUPPORT Human Clinical

"In school, he had mild learning disabilities, dysarthria and difficulties playing sports with painful cramps particularly after prolonged exertion."

Learning difficulty in one patient.

PMID:29472272 SUPPORT Human Clinical

"He was dysarthric and had mild learning difficulties."

Learning difficulty in the other.

Seizure HP:0001250

Show evidence (1 reference)

PMID:28002403 SUPPORT Human Clinical

"Intriguingly, patients with mutations in the XRCC1 partner protein PNKP exhibit not only ataxia but also microcephaly and seizures, and we have more recently identified a second patient with rare putative pathogenic mutations (<0.01% allele frequency and not present in ExAC in homozygous state)..."

The authors report a further XRCC1 patient with the same combination of ataxia, microcephaly and seizures; no clinical details are given.

🧬

Genetic Associations

1

XRCC1 (Biallelic XRCC1 variants in three described patients from three families. The homozygous c.1293G>C p.(Lys431Asn) in two Pakistani patients not known to be related, who share a haplotype, was reported as replication of the first, compound heterozygous case. No XRCC1 variants were found among 52 Brazilian patients with ataxia and oculomotor apraxia.)

Gene: XRCC1 hgnc:12828 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:29472272 SUPPORT Human Clinical

"Here we recapitulate and broaden this phenotype in two patients of Pakistani decent who were not known to be related. This confirms the role of XRCC1 in cerebellar ataxia."

Independent replication in two further patients.

PMID:35426160 SUPPORT Human Clinical

"Mutations in PIK3R5 and XRCC1 were not part of this genetic spectrum."

XRCC1 is a rare cause; none was found in a Brazilian cohort of 52 patients.

💊

Medical Actions

3

Physical Therapy

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

Gait, balance and fall-prevention training. No disease-modifying therapy exists.

Target Phenotypes: Progressive cerebellar ataxia HP:0002073

Speech Language Therapy

Action: speech language therapy Ontology label: Speech Language Therapy NCIT:C159273

Platform: Behavioral / lifestyle

Speech therapy for dysarthria.

Target Phenotypes: Dysarthria HP:0001260

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counseling on recessive inheritance; carrier testing is possible once familial variants are known.

🔬

Diagnosis

2

Exome sequencing for biallelic XRCC1 variants

Exome or genome sequencing, or a hereditary ataxia panel, after common genetic and metabolic causes of ataxia are excluded; confirming the phase of two variants and, for the c.1293G>C splice variant, RNA studies support the diagnosis.

genetic testing NCIT:C15709

Show evidence (1 reference)

PMID:28002403 SUPPORT Human Clinical

"After ruling out more than ten known spinocerebellar at axias by genetic and metabolic screening (Supplementary Information) exome sequencing of the proband identified compound heterozygous mutations in XRCC1 (NM_006297)."

Exome sequencing made the diagnosis in the first patient after other causes were excluded.

Elevated ADP-ribose in patient cells (research marker)

Elevated protein ADP-ribosylation in patient fibroblasts marks PARP1 hyperactivity. It is a research observation, not a validated clinical test.

Show evidence (1 reference)

PMID:28002403 SUPPORT In Vitro

"Collectively, these data identify elevated ADP-ribose levels as a biomarker of PARP1 hyperactivity and as a cause of cerebellar ataxia induced by unrepaired SSBs"

The authors propose ADP-ribose as a biomarker of PARP1 hyperactivity.

📈

Progression

1

Onset

Age: infancy to 28 years

Onset with falls and clumsiness in infancy and persistent ataxic gait by age 3 in homozygous patients, and with balance and gait problems at 28 in the compound heterozygous patient. A 2026 report titled as late-onset could not be read, so the upper bound may be higher.

Show evidence (2 references)

PMID:29472272 SUPPORT Human Clinical

"He had recurrent falls and excessive clumsiness as an infant."

Infantile onset in a homozygous patient.

PMID:28002403 SUPPORT Human Clinical

"Prenatal and early developmental history was completely normal and difficulties with balance and gait were first noticed at twenty-eight years, but this was not fully investigated until age forty."

Adult onset in the first patient.

📊

Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Three patients are described in detail in accessible publications (one compound heterozygous, two homozygous for c.1293G>C). A further patient was mentioned in 2017 without detail, and two 2026 case reports could not be read. That is a case count, not a prevalence.

Show evidence (1 reference)

PMID:29472272 SUPPORT Human Clinical

"Here we recapitulate and broaden this phenotype in two patients of Pakistani decent who were not known to be related. This confirms the role of XRCC1 in cerebellar ataxia."

Brings the described total to three patients.

🐁

Animal Models

2

Xrcc1 neural-specific knockout mouse

Neural deletion of Xrcc1 causes progressive ataxia, loss of cerebellar interneurons and granule neurons, reduced Purkinje cell activity, elevated cerebellar ADP-ribose and lethal seizures. Parp1 deletion reduces the interneuron loss and ataxia, prevents the seizure-related defects and extends lifespan.

Species

Mouse

Genotype

Xrcc1 loxP/loxP; Nestin-Cre

Publication

PMID:19633665

Pathograph links

Cerebellar Interneuron and Granule Neuron Loss recapitulates fidelity: moderate observes: organism

Limitations: A complete neural null, whereas patients carry hypomorphic alleles; the mice are far more severe, with lethal seizures and a median lifespan of weeks, and the peripheral nerves were not studied.

Show evidence (1 reference)

PMID:19633665 SUPPORT Model Organism

"Using murine neural-specific inactivation of Xrcc1, a factor that is critical for the repair of DNA single strand breaks, we found a profound neuropathology that is characterized by the loss of cerebellar interneurons."

The model reproduces cerebellar neuron loss.

PARP1 Trapping and Hyperactivation partially recapitulates fidelity: moderate observes: organism

Limitations: Only elevated ADP-ribose was measured in the mouse brain; PARP1 trapping itself was shown in cultured cells.

Show evidence (1 reference)

PMID:28002403 SUPPORT Model Organism

"Strikingly, we detected elevated levels of ADP-ribose in the cerebellum of Xrcc1Nes-Cre mice suggesting that the loss of Xrcc1 can trigger Parp1 hyperactivation in brain even at endogenous levels of SSBs"

PARP1 hyperactivity in the mouse cerebellum.

Show evidence (1 reference)

PMID:33932076 SUPPORT Model Organism

"Here, we show that hyperactivity of the DNA strand break sensor protein Parp1 in mice in which the central SSBR protein Xrcc1 is conditionally deleted (Xrcc1Nes-Cre ) results in lethal seizures and shortened lifespan."

The seizure phenotype of the model.

xrcc1 mutant zebrafish

Larvae have hypotrophy of the cerebellar plate, rescued by parp1 knockdown. Behaviour was examined and was normal.

Species

Zebrafish

Genotype

xrcc1 G0 crispant

Publication

PMID:40379758

Pathograph links

Cerebellar Interneuron and Granule Neuron Loss partially recapitulates fidelity: low observes: tissue

Limitations: Mosaic G0 larvae examined at an early developmental stage, with a cerebellar size readout only; no behavioural change was detected.

Show evidence (1 reference)

PMID:40379758 SUPPORT Model Organism

"Here, we demonstrate that xrcc1 knockdown impairs development of the cerebellar plate in zebrafish."

Cerebellar hypotrophy in xrcc1 mutant fish.

Show evidence (2 references)

PMID:40379758 SUPPORT Model Organism

"In contrast, parp1 knockdown alone does not significantly affect neural development, and instead rescues the cerebellar defects observed in xrcc1 mutant larvae."

PARP1-dependent rescue.

PMID:40379758 SUPPORT Model Organism

"We did not detect behavioral changes in xrcc1 crispants."

No behavioural ataxia in the fish model.

{ }

Source YAML

click to show

name: Spinocerebellar Ataxia, Autosomal Recessive 26
creation_date: "2026-10-08T00:00:00Z"
category: Mendelian
synonyms:
- SCAR26
- autosomal recessive spinocerebellar ataxia 26
- XRCC1-related cerebellar ataxia
- ataxia with oculomotor apraxia type 5
- AOA5
description: >-
  Spinocerebellar ataxia, autosomal recessive 26 (SCAR26) is a very rare
  recessive cerebellar ataxia caused by biallelic variants in XRCC1, the
  scaffold protein of DNA single-strand break repair. Patients have
  progressive gait and limb ataxia with cerebellar atrophy, a length-dependent
  sensorimotor axonal neuropathy, dysarthria and eye movement abnormalities,
  including ocular motor apraxia in the first reported case. Onset ranges from
  infancy to the late twenties. Patient cells retain only a small amount of
  XRCC1, repair single-strand breaks slowly, and leave PARP1 trapped and
  hyperactive on repair intermediates. In Xrcc1-deficient mice and zebrafish,
  deleting Parp1 reduces the loss of cerebellar neurons and the ataxia, which
  makes PARP1 hyperactivity the central disease mechanism and a candidate
  therapeutic target. Three patients are described in detail in accessible
  publications; a further patient with seizures and microcephaly has been
  mentioned but not described.
disease_term:
  preferred_term: spinocerebellar ataxia, autosomal recessive 26
  term:
    id: MONDO:0033116
    label: spinocerebellar ataxia, autosomal recessive 26
references:
- reference: PMID:28002403
  title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
- reference: PMID:29472272
  title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
- reference: PMID:34102106
  title: XRCC1 prevents toxic PARP1 trapping during DNA base excision repair.
- reference: PMID:34811483
  title: XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair.
- reference: PMID:19633665
  title: The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1.
- reference: PMID:33932076
  title: Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures.
- reference: PMID:40379758
  title: Parp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish.
- reference: PMID:41922367
  title: Versatile and sensitive detection of mono- and poly(ADP-ribosyl)ation reveals XRCC1-dependent remodelling of PARP1 signalling.
- reference: PMID:35426160
  title: Clinical and Genetic Characterization of Brazilian Patients with Ataxia and Oculomotor Apraxia.
pathophysiology:
- name: Biallelic XRCC1 Variants
  biological_scale: MOLECULAR
  role: initiating genetic lesion
  mechanism_confidence: ESTABLISHED
  description: >-
    Two pathogenic XRCC1 alleles. The recurrent c.1293G>C p.(Lys431Asn) sits
    at the last base of exon 11, in the intron 11 donor splice site, and
    causes aberrant splicing and reduced XRCC1 mRNA. It was found in trans
    with the nonsense variant p.(Gln465*) in the first patient, and
    homozygous in two Pakistani patients from consanguineous families who
    share a haplotype around the variant. The alleles are hypomorphic:
    Xrcc1-null mice are embryonic lethal, and the small amount of XRCC1
    left in patient cells is thought to allow normal development.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Germline, homozygous or compound heterozygous; the splice-site variant
      reduces XRCC1 transcript and protein, leaving residual function.
  genes:
  - preferred_term: XRCC1
    term:
      id: hgnc:12828
      label: XRCC1
  downstream:
  - target: Reduced XRCC1 and DNA Ligase III Alpha Protein
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28002403
      reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Consistent with this, reduced total levels of XRCC1 mRNA were observed in patient cells, as well as aberrant splicing of XRCC1 transcripts if nonsense-mediated decay was inhibited with cycloheximide"
      explanation: The splice-site variant reduces and mis-splices XRCC1 transcripts in patient cells.
  evidence:
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutations were confirmed by Sanger sequencing as c.1293G>C (p.K431N) and c.1393C>T (p.Q465*) and were present in trans, with the unaffected sibling of the proband heterozygous for c.1293G>C"
    explanation: Compound heterozygous variants in the first patient.
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "1293G>C mutation is located at the end of exon 11 and is also part of the donor splice site for intron 11, most likely affecting splicing and inducing premature stop codons/nonsense-mediated decay and/or encoding XRCC1 with the missense mutation, K431N."
    explanation: The position and predicted effect of the recurrent variant.
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This identified a homozygous mutation, c.G1293C (p.K431N), in exon 11 of XRCC1 (NM_006297) in the affected individuals."
    explanation: The same variant homozygous in two further patients.
  - reference: PMID:34102106
    reference_title: XRCC1 prevents toxic PARP1 trapping during DNA base excision repair.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: BACKGROUND
    snippet: "deletion of this gene in mouse is embryonic lethal"
    explanation: Complete Xrcc1 loss is lethal in mice, so the human alleles must be hypomorphic.
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we suggest that the small amount of XRCC1 remaining in the patient was important for embryonic viability"
    explanation: The authors attribute the patient's survival to residual XRCC1.
- name: Reduced XRCC1 and DNA Ligase III Alpha Protein
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Patient fibroblasts and lymphoblastoid cells keep only about 5% of normal
    XRCC1, and its partner DNA ligase III alpha, which XRCC1 stabilises, is
    reduced by more than 80%. The XRCC1-organised repair complexes therefore
    cannot assemble normally.
  molecular_functions:
  - preferred_term: molecular scaffold activity of XRCC1
    modifier: DECREASED
    term:
      id: GO:0030674
      label: protein-macromolecule adaptor activity
  genes:
  - preferred_term: XRCC1
    term:
      id: hgnc:12828
      label: XRCC1
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  downstream:
  - target: Defective DNA Single-Strand Break Repair
    causal_link_type: DIRECT
  - target: PARP1 Trapping and Hyperactivation
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34102106
      reference_title: XRCC1 prevents toxic PARP1 trapping during DNA base excision repair.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Here, we show that protein complexes containing DNA polymerase β and DNA ligase III that are assembled by XRCC1 prevent excessive engagement and activity of PARP1 during BER."
      explanation: XRCC1 complexes normally restrain PARP1.
    - reference: PMID:34102106
      reference_title: XRCC1 prevents toxic PARP1 trapping during DNA base excision repair.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "As a result, PARP1 becomes \"trapped\" on BER intermediates in XRCC1-deficient cells in a manner similar to that induced by PARP inhibitors, including in patient fibroblasts from XRCC1-mutated disease."
      explanation: Without them, PARP1 is trapped on repair intermediates, including in patient fibroblasts.
  evidence:
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "XRCC1 is a molecular scaffold protein that assembles multi-protein complexes involved in DNA single-strand break repair."
    explanation: XRCC1's molecular role is to scaffold repair complexes, the function lost when the protein is reduced.
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Western blotting suggested that patient fibroblasts and LCLs both retained a small amount (∼5%) of residual XRCC1"
    explanation: XRCC1 protein is reduced to about 5% in patient cells.
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Levels of DNA ligase IIIα (Lig3α) were also greatly reduced (by >80%) in patient cells, consistent with the established impact of XRCC1 on the cellular stability of this partner protein"
    explanation: Loss of the XRCC1 partner protein in patient cells.
- name: Defective DNA Single-Strand Break Repair
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    Single-strand breaks and base excision repair intermediates are repaired
    slowly in patient cells and persist throughout the nervous system of
    Xrcc1-deficient mice. The link from persistent breaks to the peripheral
    neuropathy is inferred; no model has examined peripheral nerve.
  biological_processes:
  - preferred_term: single strand break repair
    modifier: DECREASED
    term:
      id: GO:0000012
      label: single strand break repair
  - preferred_term: base-excision repair
    modifier: DECREASED
    term:
      id: GO:0006284
      label: base-excision repair
  downstream:
  - target: Peripheral axonal neuropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation."
    explanation: Slower single-strand break repair in patient cells.
  - reference: PMID:19633665
    reference_title: The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of Xrcc1 also led to the persistence of DNA strand breaks throughout the nervous system and abnormal hippocampal function."
    explanation: Unrepaired strand breaks persist in the Xrcc1-deficient nervous system.
- name: PARP1 Trapping and Hyperactivation
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    XRCC1 normally limits how long PARP1 stays bound and active at repair
    intermediates. Without it, PARP1 is trapped on the DNA and overactive,
    producing excess poly- and mono-ADP-ribosylation. Trapped PARP1 also
    blocks DNA polymerase beta, which slows repair further. Elevated
    ADP-ribose is present in patient cells and in the cerebellum of
    Xrcc1-deficient mice.
  genes:
  - preferred_term: PARP1
    term:
      id: hgnc:270
      label: PARP1
  biological_processes:
  - preferred_term: protein poly-ADP-ribosylation
    modifier: INCREASED
    term:
      id: GO:0070212
      label: protein poly-ADP-ribosylation
  downstream:
  - target: Defective DNA Single-Strand Break Repair
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34102106
      reference_title: XRCC1 prevents toxic PARP1 trapping during DNA base excision repair.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "This excessive PARP1 engagement and trapping renders BER intermediates inaccessible to enzymes such as DNA polymerase β and impedes their repair."
      explanation: Trapped PARP1 itself obstructs repair, a self-reinforcing loop.
  - target: Failed Transcriptional Recovery After DNA Damage
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34811483
      reference_title: XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "We show that aberrant PARP1 activity suppresses transcriptional recovery during base excision repair by promoting excessive recruitment and activity of the ubiquitin protease USP3, which as a result reduces the level of monoubiquitinated histones important for normal transcriptional regulation."
      explanation: PARP1 hyperactivity blocks transcriptional recovery through USP3.
  - target: Cerebellar Interneuron and Granule Neuron Loss
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28002403
      reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Indeed, the deletion of Parp1 ablated both the elevated level of ADP-ribose and the characteristic loss of cerebellar interneurons in Xrcc1Nes-Cre mice, thereby increasing neuronal density in the molecular layer ∼4-fold to wild type levels"
      explanation: Removing Parp1 prevents the interneuron loss, showing that PARP1 hyperactivity drives it.
    - reference: PMID:40379758
      reference_title: Parp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast, parp1 knockdown alone does not significantly affect neural development, and instead rescues the cerebellar defects observed in xrcc1 mutant larvae."
      explanation: The same PARP1 dependence in a second species.
  - target: Deregulated Neuronal Calcium Signalling
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:33932076
      reference_title: Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Using electrophysiological recording and synaptic imaging approaches, we demonstrate that aberrant Parp1 activation triggers seizure-like activity in Xrcc1-defective hippocampus ex vivo and deregulated presynaptic calcium signalling in isolated hippocampal neurons in vitro."
      explanation: PARP1 hyperactivity disturbs neuronal calcium signalling and excitability in Xrcc1-defective tissue.
  - target: Progressive cerebellar ataxia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28002403
      reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice"
      explanation: Removing Parp1 reduces the ataxia in mice.
    - reference: PMID:28002403
      reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Indeed, remarkably, whereas Xrcc1Nes-Cre mice were profoundly ataxic and unable to remain on the rotarod for more than a few seconds the additional deletion of Parp1 improved the rotarod performance of Xrcc1Nes-Cre mice >30-fold, increasing their mean retention time to ∼30 sec"
      explanation: >-
        The improvement is large but partial: retention rises from a few
        seconds to about 30 seconds.
  evidence:
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Strikingly, we detected elevated levels of ADP-ribose in the cerebellum of Xrcc1Nes-Cre mice suggesting that the loss of Xrcc1 can trigger Parp1 hyperactivation in brain even at endogenous levels of SSBs"
    explanation: PARP1 hyperactivity occurs in the brain at endogenous levels of DNA damage.
  - reference: PMID:41922367
    reference_title: Versatile and sensitive detection of mono- and poly(ADP-ribosyl)ation reveals XRCC1-dependent remodelling of PARP1 signalling.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These tools reveal that, upon DNA damage, XRCC1 deficiency dramatically elevates the mono-ADP-ribosylation wave of PARP1 signalling, in addition to increasing poly(ADP-ribosyl)ation."
    explanation: XRCC1 loss raises both mono- and poly-ADP-ribosylation.
- name: Failed Transcriptional Recovery After DNA Damage
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    After DNA base damage, cells lacking XRCC1 fail to restart transcription
    rapidly, because hyperactive PARP1 recruits excess USP3 and depletes
    monoubiquitinated histones. Shown in patient fibroblasts and Xrcc1-null
    mouse neurons; its contribution to neurodegeneration in patients has not
    been tested.
  biological_processes:
  - preferred_term: gene expression
    modifier: DECREASED
    term:
      id: GO:0010467
      label: gene expression
  downstream:
  - target: Cerebellar Interneuron and Granule Neuron Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:34811483
    reference_title: XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here we show that human cells lacking XRCC1 fail to rapidly recover transcription following DNA base damage, a phenotype also observed in patient-derived fibroblasts with XRCC1 mutations and Xrcc1-/- mouse neurons."
    explanation: The defect is present in patient cells and in neurons.
- name: Deregulated Neuronal Calcium Signalling
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    In Xrcc1-defective mouse hippocampus and isolated neurons, PARP1
    hyperactivity deregulates presynaptic calcium signalling and triggers
    seizure-like activity, and Xrcc1-deficient mice die of seizures. Shown
    only in mouse tissue and neurons. Seizures are not reported in the three
    described patients, although a further, undescribed XRCC1 patient was
    mentioned as having seizures and microcephaly.
  downstream:
  - target: Seizure
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33932076
      reference_title: Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we show that hyperactivity of the DNA strand break sensor protein Parp1 in mice in which the central SSBR protein Xrcc1 is conditionally deleted (Xrcc1Nes-Cre ) results in lethal seizures and shortened lifespan."
      explanation: The mouse model develops lethal seizures through PARP1 hyperactivity.
  evidence:
  - reference: PMID:33932076
    reference_title: Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Using electrophysiological recording and synaptic imaging approaches, we demonstrate that aberrant Parp1 activation triggers seizure-like activity in Xrcc1-defective hippocampus ex vivo and deregulated presynaptic calcium signalling in isolated hippocampal neurons in vitro."
    explanation: The calcium defect in Xrcc1-defective neurons.
- name: Cerebellar Interneuron and Granule Neuron Loss
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    In mice with neural Xrcc1 deletion, cerebellar interneurons (basket,
    stellate and Golgi cells) are lost through p53-dependent cell-cycle
    arrest as their progenitors differentiate, granule neurons die by
    apoptosis, and Purkinje cell spike activity falls. Patients show
    cerebellar atrophy on MRI, but the cell types lost in human cerebellum
    have not been examined.
  cell_types:
  - preferred_term: cerebellar basket cell
    term:
      id: CL:2000027
      label: cerebellar basket cell
  - preferred_term: cerebellar stellate cell
    term:
      id: CL:0010010
      label: cerebellar stellate cell
  - preferred_term: cerebellar Golgi cell
    term:
      id: CL:0000119
      label: cerebellar Golgi cell
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  downstream:
  - target: Progressive cerebellar ataxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cerebellar atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Pontocerebellar atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Dysarthria
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Nystagmus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hypometric saccades
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Oculomotor apraxia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:19633665
    reference_title: The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This cell loss was linked to p53-dependent cell cycle arrest and occurred as interneuron progenitors commenced differentiation."
    explanation: The developmental mechanism of interneuron loss.
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Xrcc1Nes-Cre mice exhibit pronounced cerebellar histopathology including increased apoptosis of cerebellar granule neurons, greatly reduced numbers of cerebellar interneurons and decreased electrophysiological spike activity in Purkinje cells"
    explanation: The cerebellar pathology of the mouse model.
phenotypes:
- category: Neurologic
  name: Progressive cerebellar ataxia
  diagnostic: true
  description: >-
    Gait and limb ataxia with dysmetria and dysdiadochokinesis, in all three
    described patients, beginning between infancy and age 28.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia."
    explanation: The defining triad in the first patient.
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aged 3 years, he had a persistent ataxic gait and recurrent falls."
    explanation: Childhood ataxia in a homozygous patient.
- category: Neurologic
  name: Cerebellar atrophy
  diagnostic: true
  description: >-
    Cerebellar atrophy on MRI in all three patients; in one, an MRI at age 15
    was normal and atrophy appeared later.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A forty-seven year old woman of East Indian descent and non-consanguineous parents was diagnosed at age forty-one with cerebellar atrophy, gait and limb ataxia, ocular motor apraxia, and peripheral neuropathy"
    explanation: Cerebellar atrophy in the first patient.
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Aged 15 years, he underwent an MRI brain, which was unremarkable."
    explanation: An early normal MRI in one patient, before atrophy developed.
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His recent MRI revealed cerebellar atrophy"
    explanation: Atrophy on later imaging in the same patient.
- category: Neurologic
  name: Pontocerebellar atrophy
  description: >-
    Disproportionate volume loss of the cerebellum and pons, with volume loss
    of the middle and superior cerebellar peduncles and a small cervical
    cord, in one homozygous patient.
  phenotype_term:
    preferred_term: Pontocerebellar atrophy
    term:
      id: HP:0006879
      label: Pontocerebellar atrophy
  evidence:
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "disproportionate volume loss of the cerebellum and pons"
    explanation: Pontine as well as cerebellar volume loss in one patient.
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "diminution of cervical spinal cord volume for age"
    explanation: Reduced cervical cord volume in the same patient.
- category: Neurologic
  name: Peripheral axonal neuropathy
  diagnostic: true
  description: >-
    Chronic length-dependent sensorimotor, predominantly axonal neuropathy,
    present in all three patients.
  phenotype_term:
    preferred_term: Peripheral axonal neuropathy
    term:
      id: HP:0003477
      label: Peripheral axonal neuropathy
  sequelae:
  - target: Impaired vibratory sensation
    causal_link_type: DIRECT
    description: Large-fibre sensory loss is the sensory expression of the axonal neuropathy.
  - target: Distal amyotrophy
    causal_link_type: DIRECT
    description: Distal calf wasting reflects the motor axonal component.
  - target: Areflexia
    causal_link_type: DIRECT
    description: Loss of reflexes follows from the sensorimotor neuropathy.
  evidence:
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nerve conduction studies revealed chronic length-dependent sensory-motor predominantly axonal peripheral neuropathy"
    explanation: Nerve conduction findings in the first patient.
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nerve conduction studies and electromyogram (EMG) showed a length-dependent moderately severe sensorimotor neuropathy of axonal type"
    explanation: The same neuropathy in the second patient.
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EMG and MRI revealed a sensorimotor axonal neuropathy (online supplementary table 1) and cerebellar atrophy"
    explanation: The same neuropathy in the third patient.
- category: Neurologic
  name: Impaired vibratory sensation
  description: Impaired vibration sense and proprioception in the lower limbs.
  phenotype_term:
    preferred_term: Impaired vibratory sensation
    term:
      id: HP:0002495
      label: Impaired vibratory sensation
  evidence:
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sensation to light touch and pain is normal with impaired vibration sense and proprioception."
    explanation: Large-fibre sensory loss consistent with the neuropathy.
- category: Neurologic
  name: Distal amyotrophy
  description: Prominent bilateral calf wasting in a homozygous patient.
  phenotype_term:
    preferred_term: Distal amyotrophy
    term:
      id: HP:0003693
      label: Distal amyotrophy
  evidence:
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His examination was notable for prominent bilateral calf wasting and pes planus with impaired coordination and dysdiadochokinesis."
    explanation: Distal muscle wasting consistent with the motor neuropathy.
- category: Neurologic
  name: Areflexia
  description: Absent reflexes, generalized or in the lower limbs, in both homozygous patients.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He is areflexic throughout with flexor plantar responses and impaired sensation in the lower limbs below the knee."
    explanation: Areflexia and distal sensory loss.
- category: Neurologic
  name: Babinski sign
  description: A unilateral extensor plantar response in one homozygous patient.
  phenotype_term:
    preferred_term: Babinski sign
    term:
      id: HP:0003487
      label: Babinski sign
  evidence:
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reflexes are absent in the lower limbs and planters are extensor on the left"
    explanation: Single-patient finding.
- category: Neurologic
  name: Oculomotor apraxia
  description: Ocular motor apraxia, reported in the first patient.
  phenotype_term:
    preferred_term: Oculomotor apraxia
    term:
      id: HP:0000657
      label: Oculomotor apraxia
  evidence:
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A forty-seven year old woman of East Indian descent and non-consanguineous parents was diagnosed at age forty-one with cerebellar atrophy, gait and limb ataxia, ocular motor apraxia, and peripheral neuropathy"
    explanation: Ocular motor apraxia in the first patient.
- category: Neurologic
  name: Hypometric saccades
  description: >-
    Hypometric saccades with delayed saccade initiation and jerky pursuit in
    one homozygous patient.
  phenotype_term:
    preferred_term: Hypometric saccades
    term:
      id: HP:0000571
      label: Hypometric saccades
  evidence:
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eye examination shows slow saccadic initiation, hypometria, jerky pursuit and horizontal nystagmus on extreme gaze."
    explanation: Hypometric saccades in one patient.
- category: Neurologic
  name: Nystagmus
  description: Horizontal nystagmus on lateral gaze in both homozygous patients.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Eye examination shows slow saccadic initiation, hypometria, jerky pursuit and horizontal nystagmus on extreme gaze."
    explanation: Gaze-evoked nystagmus in one patient.
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Examination of his eye movements reveal jerky pursuit with nystagmus on lateral gaze."
    explanation: Gaze-evoked nystagmus in the other patient.
- category: Neurologic
  name: Dysarthria
  description: Cerebellar dysarthria, in all three patients.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multiple ataxic abnormalities including dysmetria, dysdiadochokinesis, and dysarthria"
    explanation: Dysarthria with other cerebellar signs in the first patient.
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In school, he had mild learning disabilities, dysarthria and difficulties playing sports with painful cramps particularly after prolonged exertion."
    explanation: Dysarthria in the second patient.
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was dysarthric and had mild learning difficulties."
    explanation: Dysarthria in the third patient.
- category: Neurologic
  name: Specific learning disability
  description: >-
    Mild learning difficulties in both homozygous, childhood-onset patients.
    The source does not say the difficulty is domain-specific; HP:0001328 is
    the closest available term rather than an exact match.
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  evidence:
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In school, he had mild learning disabilities, dysarthria and difficulties playing sports with painful cramps particularly after prolonged exertion."
    explanation: Learning difficulty in one patient.
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He was dysarthric and had mild learning difficulties."
    explanation: Learning difficulty in the other.
- category: Neurologic
  name: Seizure
  description: >-
    Not reported in the three described patients. One further XRCC1 patient,
    mentioned but not described, was said to have seizures with
    microcephaly, and Xrcc1-deficient mice die of seizures. Recorded as a
    possible but unconfirmed feature.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Intriguingly, patients with mutations in the XRCC1 partner protein PNKP exhibit not only ataxia but also microcephaly and seizures, and we have more recently identified a second patient with rare putative pathogenic mutations (<0.01% allele frequency and not present in ExAC in homozygous state) in XRCC1 that exhibits this same combination of phenotypes"
    explanation: >-
      The authors report a further XRCC1 patient with the same combination of
      ataxia, microcephaly and seizures; no clinical details are given.
- category: Reproductive
  name: Azoospermia
  description: >-
    Infertility with hypogonadism and azoospermia in one patient. The authors
    raise a possible link through DNA repair in Sertoli cells, but other
    causes were not excluded.
  phenotype_term:
    preferred_term: Azoospermia
    term:
      id: HP:0000027
      label: Azoospermia
  evidence:
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to his neurological symptoms, he is infertile due to hypogonadism and azoospermia."
    explanation: Single-case report.
genetic:
- name: XRCC1
  gene_term:
    preferred_term: XRCC1
    term:
      id: hgnc:12828
      label: XRCC1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Biallelic XRCC1 variants in three described patients from three
    families. The homozygous c.1293G>C p.(Lys431Asn) in two Pakistani
    patients not known to be related, who share a haplotype, was reported as
    replication of the first, compound heterozygous case. No XRCC1 variants
    were found among 52 Brazilian patients with ataxia and oculomotor
    apraxia.
  evidence:
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we recapitulate and broaden this phenotype in two patients of Pakistani decent who were not known to be related. This confirms the role of XRCC1 in cerebellar ataxia."
    explanation: Independent replication in two further patients.
  - reference: PMID:35426160
    reference_title: Clinical and Genetic Characterization of Brazilian Patients with Ataxia and Oculomotor Apraxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in PIK3R5 and XRCC1 were not part of this genetic spectrum."
    explanation: XRCC1 is a rare cause; none was found in a Brazilian cohort of 52 patients.
  notes: >-
    No ClinGen gene-disease validity record for XRCC1 is cached in this
    repository, and MONDO records no causal gene for MONDO:0033116, so
    gene_disease_validity is left empty.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic variants, compound heterozygous in one non-consanguineous
    family and homozygous in two consanguineous Pakistani families; an
    unaffected sibling of the first patient was heterozygous.
  evidence:
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutations were confirmed by Sanger sequencing as c.1293G>C (p.K431N) and c.1393C>T (p.Q465*) and were present in trans, with the unaffected sibling of the proband heterozygous for c.1293G>C"
    explanation: The two variants are in trans, and a heterozygous sibling is unaffected.
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patient 2 was also born to consanguineous parents"
    explanation: Consanguinity in the homozygous families.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Three patients are described in detail in accessible publications (one
    compound heterozygous, two homozygous for c.1293G>C). A further patient
    was mentioned in 2017 without detail, and two 2026 case reports could not
    be read. That is a case count, not a prevalence.
  evidence:
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we recapitulate and broaden this phenotype in two patients of Pakistani decent who were not known to be related. This confirms the role of XRCC1 in cerebellar ataxia."
    explanation: Brings the described total to three patients.
progression:
- phase: Onset
  age_range: infancy to 28 years
  notes: >-
    Onset with falls and clumsiness in infancy and persistent ataxic gait by
    age 3 in homozygous patients, and with balance and gait problems at 28 in
    the compound heterozygous patient. A 2026 report titled as late-onset
    could not be read, so the upper bound may be higher.
  evidence:
  - reference: PMID:29472272
    reference_title: Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had recurrent falls and excessive clumsiness as an infant."
    explanation: Infantile onset in a homozygous patient.
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prenatal and early developmental history was completely normal and difficulties with balance and gait were first noticed at twenty-eight years, but this was not fully investigated until age forty."
    explanation: Adult onset in the first patient.
treatments:
- name: Physical Therapy
  therapeutic_modality: BEHAVIORAL
  description: Gait, balance and fall-prevention training. No disease-modifying therapy exists.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  notes: >-
    Standard supportive care for recessive ataxia; no study has evaluated it
    in SCAR26, so it carries no evidence block.
- name: Speech Language Therapy
  therapeutic_modality: BEHAVIORAL
  description: Speech therapy for dysarthria.
  treatment_term:
    preferred_term: speech language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  target_phenotypes:
  - preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  notes: Standard supportive care; no disease-specific study, so no evidence block.
- name: Genetic Counseling
  description: Counseling on recessive inheritance; carrier testing is possible once familial variants are known.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  notes: Standard care; no disease-specific study, so no evidence block.
diagnosis:
- name: Exome sequencing for biallelic XRCC1 variants
  description: >-
    Exome or genome sequencing, or a hereditary ataxia panel, after common
    genetic and metabolic causes of ataxia are excluded; confirming the
    phase of two variants and, for the c.1293G>C splice variant, RNA
    studies support the diagnosis.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After ruling out more than ten known spinocerebellar at axias by genetic and metabolic screening (Supplementary Information) exome sequencing of the proband identified compound heterozygous mutations in XRCC1 (NM_006297)."
    explanation: Exome sequencing made the diagnosis in the first patient after other causes were excluded.
- name: Elevated ADP-ribose in patient cells (research marker)
  description: >-
    Elevated protein ADP-ribosylation in patient fibroblasts marks PARP1
    hyperactivity. It is a research observation, not a validated clinical
    test.
  evidence:
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Collectively, these data identify elevated ADP-ribose levels as a biomarker of PARP1 hyperactivity and as a cause of cerebellar ataxia induced by unrepaired SSBs"
    explanation: The authors propose ADP-ribose as a biomarker of PARP1 hyperactivity.
animal_models:
- name: Xrcc1 neural-specific knockout mouse
  species: Mouse
  genotype: Xrcc1 loxP/loxP; Nestin-Cre
  description: >-
    Neural deletion of Xrcc1 causes progressive ataxia, loss of cerebellar
    interneurons and granule neurons, reduced Purkinje cell activity,
    elevated cerebellar ADP-ribose and lethal seizures. Parp1 deletion
    reduces the interneuron loss and ataxia, prevents the seizure-related
    defects and extends lifespan.
  publication: PMID:19633665
  modeled_mechanisms:
  - target: Cerebellar Interneuron and Granule Neuron Loss
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    limitations: >-
      A complete neural null, whereas patients carry hypomorphic alleles; the
      mice are far more severe, with lethal seizures and a median lifespan of
      weeks, and the peripheral nerves were not studied.
    evidence:
    - reference: PMID:19633665
      reference_title: The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Using murine neural-specific inactivation of Xrcc1, a factor that is critical for the repair of DNA single strand breaks, we found a profound neuropathology that is characterized by the loss of cerebellar interneurons."
      explanation: The model reproduces cerebellar neuron loss.
  - target: PARP1 Trapping and Hyperactivation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    limitations: >-
      Only elevated ADP-ribose was measured in the mouse brain; PARP1
      trapping itself was shown in cultured cells.
    evidence:
    - reference: PMID:28002403
      reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Strikingly, we detected elevated levels of ADP-ribose in the cerebellum of Xrcc1Nes-Cre mice suggesting that the loss of Xrcc1 can trigger Parp1 hyperactivation in brain even at endogenous levels of SSBs"
      explanation: PARP1 hyperactivity in the mouse cerebellum.
  evidence:
  - reference: PMID:33932076
    reference_title: Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we show that hyperactivity of the DNA strand break sensor protein Parp1 in mice in which the central SSBR protein Xrcc1 is conditionally deleted (Xrcc1Nes-Cre ) results in lethal seizures and shortened lifespan."
    explanation: The seizure phenotype of the model.
- name: xrcc1 mutant zebrafish
  species: Zebrafish
  genotype: xrcc1 G0 crispant
  description: >-
    Larvae have hypotrophy of the cerebellar plate, rescued by parp1
    knockdown. Behaviour was examined and was normal.
  publication: PMID:40379758
  modeled_mechanisms:
  - target: Cerebellar Interneuron and Granule Neuron Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: TISSUE
    limitations: >-
      Mosaic G0 larvae examined at an early developmental stage, with a
      cerebellar size readout only; no behavioural change was detected.
    evidence:
    - reference: PMID:40379758
      reference_title: Parp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Here, we demonstrate that xrcc1 knockdown impairs development of the cerebellar plate in zebrafish."
      explanation: Cerebellar hypotrophy in xrcc1 mutant fish.
  evidence:
  - reference: PMID:40379758
    reference_title: Parp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In contrast, parp1 knockdown alone does not significantly affect neural development, and instead rescues the cerebellar defects observed in xrcc1 mutant larvae."
    explanation: PARP1-dependent rescue.
  - reference: PMID:40379758
    reference_title: Parp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We did not detect behavioral changes in xrcc1 crispants."
    explanation: No behavioural ataxia in the fish model.
discussions:
- discussion_id: scar26_parp1_therapy
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#PARP1 Trapping and Hyperactivation
  prompt: >-
    Can PARP1 be reduced pharmacologically in a way that reproduces the
    genetic rescue seen in mice and zebrafish?
  rationale: >-
    Genetic deletion of Parp1 reduces the neuron loss and ataxia of
    Xrcc1-deficient mice, prevents their seizure-related defects, extends
    their lifespan, and rescues the cerebellar defect of xrcc1 zebrafish. The
    PARP inhibitor veliparib, given to Xrcc1-deficient mice, prevented the
    seizure-like activity in hippocampal slices and the calcium defects in
    isolated neurons but did not significantly extend lifespan. Clinical PARP
    inhibitors trap PARP1 on DNA, the very effect XRCC1 loss already
    produces, so they may not mimic deletion. No drug has been tested in
    patients.
  evidence:
  - reference: PMID:33932076
    reference_title: Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Moreover, we show that these defects are prevented by Parp1 inhibition or deletion and, in the case of Parp1 deletion, that the lifespan of Xrcc1Nes-Cre mice is greatly extended."
    explanation: Inhibition or deletion prevents the ex vivo and in vitro defects; only deletion extends lifespan.
  - reference: PMID:33932076
    reference_title: Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "this may explain why we have so far been unable to extend significantly the lifespan of XRCC1Nes-Cre mice by PARP inhibition."
    explanation: Pharmacological inhibition did not reproduce the lifespan rescue.
  - reference: PMID:28002403
    reference_title: XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Inhibition of PARP1 with currently available chemical inhibitors may not be useful in this context, however, because these inhibitors “trap” PARP1 on DNA"
    explanation: The authors' caution about trapping inhibitors.
- discussion_id: scar26_mouse_severity_mismatch
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Cerebellar Interneuron and Granule Neuron Loss
  - phenotypes#Peripheral axonal neuropathy
  prompt: >-
    How well does a lethal, developmental, neural-null mouse model a slowly
    progressive human disease caused by hypomorphic alleles, and what causes
    the peripheral neuropathy?
  rationale: >-
    The mouse loses cerebellar interneurons during development and dies of
    seizures within weeks. The three described patients have onset from
    infancy to the late twenties, no seizures, and a prominent axonal
    neuropathy that no model has examined; one further, undescribed patient
    reportedly had seizures and microcephaly. A hypomorphic knock-in of the
    recurrent c.1293G>C allele, assessed for peripheral nerve pathology,
    would bridge the gap.
  evidence:
  - reference: PMID:33932076
    reference_title: Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Here, we show that hyperactivity of the DNA strand break sensor protein Parp1 in mice in which the central SSBR protein Xrcc1 is conditionally deleted (Xrcc1Nes-Cre ) results in lethal seizures and shortened lifespan."
    explanation: The mouse phenotype is much more severe than the described human disease.
notes: >-
  SCAR26 belongs with the other single-strand break repair ataxias: AOA1
  (APTX), SCAN1 (TDP1) and AOA4 (PNKP). One 2022 cohort paper calls it AOA5
  (PMID:35426160). Two 2026 case reports (PMID:41631675, PMID:41506093) have
  no abstract or full text available and are not used. One homozygous
  patient also has myotonia congenita from homozygous CLCN1 deletion, so his
  myotonia, and probably his cramps, are not attributed to SCAR26. No
  GeneReviews chapter exists for SCAR26 (just check-genereviews --online
  returned NO_CHAPTER). The laboratory markers used to separate other
  single-strand break repair ataxias (alpha-fetoprotein, albumin,
  cholesterol) have not been reported for SCAR26 patients, so their status
  is unknown rather than normal.

📚

References & Deep Research

References

9

PMID:28002403

XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia.

No top-level findings curated for this source.

PMID:29472272

Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy.

No top-level findings curated for this source.

PMID:34102106

XRCC1 prevents toxic PARP1 trapping during DNA base excision repair.

No top-level findings curated for this source.

PMID:34811483

XRCC1 protects transcription from toxic PARP1 activity during DNA base excision repair.

No top-level findings curated for this source.

PMID:19633665

The genesis of cerebellar interneurons and the prevention of neural DNA damage require XRCC1.

No top-level findings curated for this source.

PMID:33932076

Parp1 hyperactivity couples DNA breaks to aberrant neuronal calcium signalling and lethal seizures.

No top-level findings curated for this source.

PMID:40379758

Parp1 deletion rescues cerebellar hypotrophy in xrcc1 mutant zebrafish.

No top-level findings curated for this source.

PMID:41922367

Versatile and sensitive detection of mono- and poly(ADP-ribosyl)ation reveals XRCC1-dependent remodelling of PARP1 signalling.

No top-level findings curated for this source.

PMID:35426160

Clinical and Genetic Characterization of Brazilian Patients with Ataxia and Oculomotor Apraxia.

No top-level findings curated for this source.

Deep Research

1

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_26 · 2026-10-08T17:16:19Z · View source

New entry for SCAR26 (MONDO:0033116, XRCC1). Deep research: falcon requested, fell back to claude_code (16/16 references resolved; an off-topic cached reference PMID:33779029 from the run was removed). Causal chain from biallelic XRCC1 variants through reduced XRCC1/LIG3 alpha, defective single-strand break repair and PARP1 trapping and hyperactivation to cerebellar interneuron and granule neuron loss, with the Parp1-deletion rescues in mouse (PMID:28002403) and zebrafish (PMID:40379758) as the key causal evidence. Phenotypes from the three described patients (PMID:28002403, PMID:29472272). The myotonia of one patient (CLCN1) is excluded. Two 2026 case reports had no retrievable text and are not used. No GeneReviews chapter or ClinGen curation. A pre-PR review corrected three statements against the full texts: veliparib was tested in Xrcc1-deficient mice (PMID:33932076) without extending lifespan; a further XRCC1 patient with seizures and microcephaly is mentioned in PMID:28002403; and xrcc1 zebrafish behaviour was examined and normal. It also added a calcium/seizure branch, residual XRCC1 protein (~5%), the PARP1 to repair feedback edge, and phenotypes from PMID:29472272 (pontocerebellar volume loss, sensory loss, calf wasting, Babinski sign). Validated with just validate (68/68 snippets) and the offline gates.

Claude Code ▸

Spinocerebellar Ataxia, Autosomal Recessive 26 (SCAR26; XRCC1-related ataxia): Research Report

claude-haiku-5-5, claude-opus-5-5 12 citations 2026-10-08T13:10:05.149003

Spinocerebellar Ataxia, Autosomal Recessive 26 (SCAR26; XRCC1-related ataxia): Research Report

Prepared: 2026-10-08 · Target: MONDO:0033116 · Category: Mendelian

About this report. The quotes marked "verbatim" were checked against the cache files I fetched in this session with just fetch-reference (references_cache/PMID_*.md), so they can be used as snippets. Ontology IDs marked (verify) came from memory. They are leads only and must be checked with runoak or the term caches before binding. Two 2026 case reports have no abstract in PubMed (PMIDs 41631675 and 41506093), and their publisher pages blocked retrieval. They are listed but not quoted.

1. Disease Information

Overview. SCAR26 is a very rare autosomal recessive cerebellar ataxia caused by biallelic variants in XRCC1. XRCC1 is the scaffold protein for DNA single-strand break repair (SSBR) and base excision repair (BER). The core phenotype is: - progressive cerebellar ataxia with cerebellar atrophy - sensorimotor, predominantly axonal, length-dependent peripheral neuropathy - oculomotor abnormalities (ocular motor apraxia in the index case; slow saccade initiation and nystagmus in later cases)

The disease belongs to the SSBR-defective ataxia family with AOA1 (APTX), SCAN1 (TDP1) and AOA4 (PNKP). One 2022 Brazilian cohort paper calls it "AOA5" (PMID:35426160). I could not confirm that synonym in OMIM or Orphanet.

Verbatim (PMID:28002403, Hoch et al., Nature 2017): "Here we show that biallelic mutations in the human XRCC1 gene are associated with ocular motor apraxia, axonal neuropathy, and progressive cerebellar ataxia."

Identifiers

Resource	ID
MONDO	MONDO:0033116
OMIM (phenotype)	#617633
OMIM (gene)	*194360 (XRCC1)
HGNC	hgnc:12828 (XRCC1; 19q13.31; UniProt P18887; Ensembl ENSG00000073050; MANE NM_006297.3) — from `kb/genes/ingest/hgnc.tsv`
Disease Ontology	DOID:0080260
MedGen	C4539948
Orphanet	No distinct ORPHA code found; no Orphadata cache row mentions XRCC1
ICD-10/11	No specific code; falls under G11.x hereditary ataxia (non-specific)

Synonyms: SCAR26; autosomal recessive spinocerebellar ataxia 26; XRCC1-related cerebellar ataxia; "AOA5" (single source, unconfirmed).

Source of information: Essentially all data come from individual patient reports. At most about 4–6 published probands are known (see §9). No registry or aggregated cohort exists.

2. Etiology

Cause: Biallelic germline loss-of-function variants in XRCC1.
Genetic risk factors:
c.1293G>C (p.Lys431Asn) is recurrent in South Asian (Pakistani and East Indian) families. It sits at the last base of exon 11 and disrupts the intron 11 donor splice site.
O'Connor et al. found it heterozygous in four South Asian ExAC individuals (AF 0.0002449). They wrote that it "likely exists at a higher frequency than previously described" (PMID:29472272).
Modifier genes: None in humans. In mice, Parp1 dosage strongly modifies the phenotype: losing one Parp1 allele extended lifespan more than losing both (PMID:33932076).
Environmental, protective and gene–environment factors: None documented. Mechanistically, endogenous oxidative single-strand breaks are the relevant "exposure". This is inferred; no human exposure data exist.

3. Phenotypes

The sources below are the index patient (PMID:28002403) and two homozygous c.1293G>C patients (PMID:29472272). With N≈3, every frequency is qualitative.

Phenotype	Notes / frequency	Suggested HPO (verify)
Progressive cerebellar ataxia (gait and limb)	3/3	HP:0002073 Progressive cerebellar ataxia
Cerebellar atrophy (MRI)	3/3; P1 in O'Connor had a normal MRI at 15 and atrophy later	HP:0001272 Cerebellar atrophy
Pontine / middle and superior cerebellar peduncle volume loss	1/3	HP:0006879 Pontocerebellar atrophy
Sensorimotor axonal, length-dependent neuropathy	3/3	HP:0003477 Peripheral axonal neuropathy; HP:0007141 Sensorimotor neuropathy
Ocular motor apraxia	Index case	HP:0000657 Oculomotor apraxia
Slow saccade initiation, hypometric saccades, jerky pursuit	O'Connor P1	HP:0000570 Abnormality of saccadic eye movements
Gaze-evoked / horizontal nystagmus	2/3	HP:0000639 Nystagmus
Dysarthria	3/3	HP:0001260 Dysarthria
Dysmetria, dysdiadochokinesis	≥2/3	HP:0001310; HP:0002075
Areflexia (lower limbs or generalized)	2/3	HP:0001284 Areflexia
Impaired vibration sense and proprioception	1–2/3	HP:0002495 Impaired vibratory sensation
Distal calf wasting, pes planus / cavus	2/3	HP:0003693 Distal amyotrophy; HP:0001761 Pes cavus
Muscle cramps	2/3	HP:0003394 Muscle spasm/cramps
Mild learning difficulties	2/3 (childhood-onset cases)	HP:0001328 Specific learning disability
Extensor plantar response	1/3	HP:0003487 Babinski sign
Male infertility (hypogonadism, azoospermia)	1/3; authors say alternative causes are not excluded	HP:0000027 Azoospermia

Onset - Adult onset in the index case: balance and gait difficulties "first noticed at twenty-eight years", with diagnosis at 41 (PMID:28002403). - Early childhood onset in O'Connor's patients: observable signs by about 3 years. - 2026 reports describe one childhood-onset homozygous c.1293G>C patient (PMID:41631675) and one late-onset case (PMID:41506093). I could not read either.

Course: Slowly progressive. Secondary sources (e.g., MalaCards/OMIM synopsis) mention eventual loss of independent ambulation.

Confounder: O'Connor P2 also carried homozygous CLCN1 myotonia congenita. Myotonia, calf hypertrophy and probably the cramps in that patient should not be attributed to SCAR26.

Quality of life: No formal QoL data exist. Expect impact on mobility and falls, fine motor function, speech, and possibly fertility.

4. Genetic / Molecular Information

Gene: XRCC1, X-ray repair cross-complementing 1. It is a non-enzymatic scaffold with: - an N-terminal domain that binds POLβ - a central BRCT1 domain that binds PAR and DNA - a C-terminal BRCT2 domain that binds LIG3α - a CK2-phosphorylated linker that binds PNKP, APTX and APLF

Reported pathogenic variants

Variant (NM_006297)	Effect	Zygosity / cases	Source
c.1293G>C, p.(Lys431Asn)	Last base of exon 11 / intron 11 donor. In patient LCLs (cycloheximide-treated) it causes aberrant splicing including intron 11 retention, plus reduced total XRCC1 mRNA. The missense effect lies in the BRCTa/linker region	Compound heterozygous in the index case; homozygous in 2 Pakistani consanguineous families with a shared haplotype; homozygous in the 2026 MDCP case	PMID:28002403; 29472272; 41631675
c.1393C>T, p.(Gln465*)	Nonsense, predicted NMD	In trans with K431N in the index case	PMID:28002403

Verbatim (PMID:28002403): "1293G>C mutation is located at the end of exon 11 and is also part of the donor splice site for intron 11, most likely affecting splicing and inducing premature stop codons/nonsense-mediated decay and/or encoding XRCC1 with the missense mutation, K431N."
Protein consequence (PMID:28002403): XRCC1 protein is reduced in patient cells. The partner protein is also destabilized: "Levels of DNA ligase IIIα (Lig3α) were also greatly reduced (by >80%) in patient cells".
Functional class: Loss of function, hypomorphic. Complete XRCC1 loss is embryonic lethal in mice, so the human alleles must retain some residual function (inference).
Other recorded SCAR26 variants: ClinVar lists about 13 XRCC1 variants under SCAR26 with mixed classifications. A 2026 Cell Death Differ study tested three "SCAR26-associated" missense constructs: c.1196A>G (BRCT1), c.1293G>C (linker) and c.1738C>T (BRCT2). It found that one variant disrupts TADA2B binding while LIG3 binding is preserved (PMID:42399641). Their individual clinical provenance is unverified, so do not curate them as patient variants without a primary report.
Gene–disease validity: A ClinGen GDV record for XRCC1–SCAR26 was not found in the local cache; check before asserting a tier. PanelApp England and Australia rate XRCC1 Green (high evidence) for hereditary ataxia in current versions; earlier versions were Amber/Red.
Origin: Germline. No somatic, epigenetic or chromosomal mechanisms are described.
Common polymorphisms: p.Arg399Gln and similar variants are extensively studied cancer-association SNPs, unrelated to SCAR26. Avoid confusing them with disease variants. Hoch used R399Q only as a phasing marker.

5. Environmental Information

There are no environmental, lifestyle or infectious factors. The relevant "lesions" are endogenous oxidative and topoisomerase-1–induced single-strand breaks. Not applicable for environmental:.

6. Mechanism / Pathophysiology

Ordered causal chain

Biallelic hypomorphic XRCC1 variants (splice / missense K431N, nonsense Q465) lead to* reduced XRCC1 mRNA and protein (human patient cells, demonstrated; PMID:28002403).
Reduced XRCC1 leads to destabilization and loss of LIG3α (>80% reduced), so the XRCC1–LIG3α–POLβ–PNKP repair complexes fail to assemble (demonstrated in patient cells; PMID:28002403).
Loss of XRCC1 complexes results in slow repair of single-strand breaks and BER intermediates (demonstrated in patient cells and XRCC1⁻/⁻ RPE-1 cells; PMID:28002403, 34102106).
Verbatim (PMID:28002403): "Cells from a patient with mutations in XRCC1 exhibited not only reduced rates of single-strand break repair but also elevated levels of protein ADP-ribosylation."
Unrepaired breaks plus the missing "anti-trapper" lead to PARP1 trapping on BER intermediates and PARP1 hyperactivation (excess poly- and mono-ADP-ribosylation).
Verbatim (PMID:34102106): "As a result, PARP1 becomes "trapped" on BER intermediates in XRCC1-deficient cells in a manner similar to that induced by PARP inhibitors, including in patient fibroblasts from XRCC1-mutated disease."
Also shown in mouse cerebellum: "Strikingly, we detected elevated levels of ADP-ribose in the cerebellum of Xrcc1Nes-Cre mice…" (PMID:28002403).
XRCC1 loss also amplifies mono-ADPr and RNF114 recruitment (PMID:41922367).
Feedback: trapped PARP1 blocks POLβ access and further impedes repair, which sustains step 3: "This excessive PARP1 engagement and trapping renders BER intermediates inaccessible to enzymes such as DNA polymerase β and impedes their repair." (PMID:34102106)
PARP1 hyperactivity then branches into three effects:
5a. Transcriptional failure. PARP1 hyperactivity leads to excessive USP3 recruitment, loss of H2A/H2B monoubiquitination, and failed recovery of RNA polymerase I and II transcription after oxidative damage. This was shown in XRCC1 patient fibroblasts and Xrcc1-deficient cerebellar neurons (PMID:34811483).
- Verbatim: "We show that aberrant PARP1 activity suppresses transcriptional recovery during base excision repair by promoting excessive recruitment and activity of the ubiquitin protease USP3, which as a result reduces the level of monoubiquitinated histones important for normal transcriptional regulation."
5b. NAD⁺ depletion / PAR toxicity. Proposed and supported in zebrafish discussion, but not directly measured in human SCAR26 (inferred; PMID:40379758).
5c. Deregulated presynaptic Ca²⁺ signalling. Leads to hyperexcitability and seizures in mice (PMID:33932076). Seizures have not been reported in human SCAR26.
In parallel, persistent DNA damage in differentiating cerebellar interneuron progenitors leads to p53-dependent cell-cycle arrest. This produces loss of basket, stellate and Golgi interneurons, granule-neuron apoptosis and reduced Purkinje-cell spike activity (mouse; PMID:19633665, 28002403).
Verbatim (PMID:19633665): "This cell loss was linked to p53-dependent cell cycle arrest and occurred as interneuron progenitors commenced differentiation."
Upstream of this branch: PARP1 deletion restores interneuron density about 4-fold, so PARP1 acts upstream of much of the neuron loss (PMID:28002403).
Cerebellar neuron loss and dysfunction result in cerebellar atrophy and progressive ataxia. This is direct in mice, and inferred in humans from MRI and the clinical picture.
PARP1 is causal: "genetic deletion of Parp1 rescued normal cerebellar ADP-ribose levels and reduced the loss of cerebellar neurons and ataxia in Xrcc1-defective mice" (PMID:28002403).
Zebrafish give the same answer: "parp1 knockdown alone does not significantly affect neural development, and instead rescues the cerebellar defects observed in xrcc1 mutant larvae" (PMID:40379758).
Peripheral axonal neuropathy and oculomotor apraxia presumably arise from the same SSBR/PARP1 mechanism in long peripheral axons and brainstem/cerebellar oculomotor circuits. This is inferred: no model has studied the peripheral nerve.

Upstream vs downstream: steps 1–3 form the lesion; step 4 is the pivotal hub node (PARP1 hyperactivation); steps 5–6 are cellular effectors; steps 7–8 are the organ and clinical phenotypes.

Suggested terms (verify all)

Kind	Terms
GO	GO:0000012 single strand break repair (DECREASED); GO:0006284 base-excision repair (DECREASED); GO:0070212 protein poly-ADP-ribosylation (INCREASED); GO:0006281 DNA repair; GO:0006977 DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; GO:0021680 cerebellar Purkinje cell layer development or a cerebellar interneuron differentiation term; GO:0006351 DNA-templated transcription (DECREASED recovery)
CL	cerebellar granule cell (CL:0001031); Purkinje cell (CL:0000121); cerebellar stellate / basket / Golgi interneurons (check CL); peripheral sensory and motor neurons; fibroblast (CL:0000057) for patient-cell evidence
GO-CC	nucleus, nucleolus (XRCC1 is nucleolar at baseline), chromatin
CHEBI	NAD⁺ (CHEBI:57540); poly(ADP-ribose)

Molecular profiling: No omics, single-cell or spatial datasets specific to SCAR26 were found.

7. Anatomical Structures

Primary: cerebellum (UBERON:0002037), with vermis and hemispheres; peripheral nerves (UBERON:0001021).
Secondary: pons and middle/superior cerebellar peduncles (O'Connor P1); oculomotor control circuits.
Possible: testis/gonad (one patient, unconfirmed).
Cells: cerebellar interneurons, granule and Purkinje cells; peripheral sensory and motor axons.
Subcellular: nucleus, nucleolus, chromatin at single-strand break sites.
Distribution: bilateral and symmetric; length-dependent neuropathy.

8. Temporal Development

Onset: ranges from early childhood (~3 y; homozygous c.1293G>C) to adult (28 y; compound heterozygote) to late onset (PMID:41506093, unread).
Onset pattern: insidious.
Course: chronic, slowly progressive. Cerebellar atrophy can develop after a normal adolescent MRI (O'Connor P1).
Remission and staging: no remission; no formal staging.
Critical period (mouse, inferred): XRCC1 is most needed as cerebellar interneuron progenitors differentiate around birth (PMID:19633665).

9. Inheritance and Population

Inheritance: autosomal recessive (HP:0000007). LOVD labels it "digenic". That looks erroneous because all cases are biallelic at one locus.
Penetrance: apparently complete in reported biallelic individuals; an unaffected heterozygous sibling was reported.
Expressivity: variable, with age of onset from ~3 to ~28 years or more. No anticipation.
Consanguinity and founder effect: consanguinity was present in both Pakistani families. They share a chromosome 19 haplotype around c.1293G>C, which suggests a South Asian founder allele. The index patient was of East Indian descent with non-consanguineous parents.
Carrier frequency: c.1293G>C AF about 2.4×10⁻⁴ overall in ExAC, enriched in South Asians. Re-check gnomAD v4 before quoting.
Prevalence: unknown. Fewer than 10 published patients. Suggested prevalence_class: CASES_IN_LITERATURE + ULTRA_RARE.
Negative cohort data: a Brazilian ataxia-with-oculomotor-apraxia cohort found no XRCC1 variants (PMID:35426160).
Sex ratio: reported cases are 1 female (index) and 2 males (O'Connor).

10. Diagnostics

Genetic testing: the mainstay. Use a hereditary ataxia multigene panel (XRCC1 is on PanelApp hereditary ataxia panels) or exome/genome sequencing. RNA studies can help confirm splice variants such as c.1293G>C. Single-variant testing is reasonable in South Asian probands with a consistent phenotype.
Imaging: brain MRI showing cerebellar (± pontine) atrophy.
Electrophysiology: NCS/EMG showing length-dependent sensorimotor axonal neuropathy.
Biomarkers: No validated clinical biomarker. Research-level elevated ADP-ribose / PARP1 activity in patient fibroblasts was proposed as a "biomarker of PARP1 hyperactivity" (PMID:28002403). Labs such as AFP, albumin and cholesterol (useful in AOA1/2/4) are not reported for SCAR26.
Differential diagnosis:
AOA1 (APTX): hypoalbuminemia, hypercholesterolemia
AOA2 (SETX): elevated AFP
AOA4 (PNKP): plus microcephaly and seizures
SCAN1 (TDP1)
ataxia-telangiectasia (ATM)
Friedreich ataxia
ARCA with neuropathy (SYNE1, POLG, RFC1/CANVAS)
Screening: no newborn screening. Cascade carrier testing is possible in affected families.

11. Outcome / Prognosis

No survival or mortality data exist. Patients surveyed were alive at ages 22–47.
Morbidity comes from progressive gait and limb ataxia, falls, dysarthria, distal weakness and sensory loss. Secondary sources mention possible loss of independent ambulation.
No prognostic biomarkers. Earlier onset appears to go with the homozygous splice genotype (N too small to conclude).
The mouse Xrcc1^Nes-Cre^ median lifespan of 3–4 weeks (seizures) is far more severe than the human disease. Do not extrapolate it to human prognosis.

12. Treatment

No disease-modifying therapy and no clinical trials. Management is supportive.

Intervention	Notes	NCIT (verify)
Physical therapy / rehabilitation for ataxia, falls and gait aids	Standard ARCA care	NCIT:C15302 Physical Therapy; NCIT:C15315 Rehabilitation
Occupational therapy	Fine motor	NCIT:C121351
Speech-language therapy	Dysarthria	NCIT:C159273
Orthotics for foot deformity, distal weakness	Neuropathy	—
Genetic counseling	AR recurrence 25%	NCIT:C15240

Experimental and preclinical directions - PARP1 suppression is the leading therapeutic hypothesis. Genetic deletion rescues the mouse ataxia and interneuron loss (PMID:28002403), the zebrafish cerebellar hypotrophy (PMID:40379758), and the mouse seizures and lifespan (PMID:33932076). - Caution: current clinical PARP inhibitors trap PARP1 and "do not mimic PARP1 genetic deletion" (PMID:28002403). Non-trapping PARP1 inhibitors are suggested instead. Note also that in mice, losing one Parp1 allele beat losing both, so dosage matters. - USP3 is a second candidate target (PMID:34811483). NAD⁺ repletion is hypothesized (an inference from the NAD⁺-depletion model; the ALS NAD⁺–PARP1–XRCC1 review PMID:42086408 is not SCAR26-specific). - Pharmacogenomics: none.

13. Prevention

Primary: none.
Secondary: cascade carrier testing and prenatal or preimplantation diagnosis once familial variants are known. Consider c.1293G>C in carrier screening for consanguineous South Asian families.
Tertiary: fall prevention and neuropathy foot care.
No vaccines, prophylaxis or public-health measures apply.

14. Other Species / Natural Disease

No naturally occurring XRCC1 ataxia was found (OMIA not checked in detail).
Orthologs: mouse Xrcc1 and zebrafish xrcc1. XRCC1 recruitment strategies vary by species (PMID:35026705).
Not zoonotic.

15. Model Organisms

Model	Phenotype recapitulation	Rescue / limitations	PMID
*Mouse Xrcc1^loxP/loxP^;Nestin-Cre* (neural-specific KO)	Progressive ataxia with episodic spasms; loss of cerebellar basket, stellate and Golgi interneurons; p53-dependent arrest; ~4-fold more strand breaks in neurons; hippocampal dysfunction; elevated cerebellar ADP-ribose; reduced Purkinje spike activity	p53⁻/⁻ rescues interneurons. Parp1⁻/⁻ rescues ADP-ribose, interneuron density (~4-fold) and rotarod time (>30-fold). Limitations: complete neural null vs human hypomorph; developmental rather than adult onset; lethal seizures (median lifespan 3–4 weeks) not seen in humans; no peripheral neuropathy modeled	19633665; 28002403; 33932076
*Zebrafish xrcc1* crispants** (F0 CRISPR)	Hypotrophy of the lateral cerebellar plate, involving granule-cell markers	parp1 co-deletion restores cerebellar plate volume. Limitations: F0 mosaic, larval stage only, no behavioral ataxia readout	40379758
Human cells: XRCC1 patient fibroblasts and LCLs; XRCC1⁻/⁻, PARP1⁻/⁻ and double KO RPE-1 and U2OS cells	Reduced SSBR; PARP1-dependent elevated ADP-ribose; PARP1 trapping; failed transcription recovery	PARP1 deletion or PARPi restores transcription recovery and BER (PARPi does not restore SSBR rate). Limitations: non-neuronal cells	28002403; 34102106; 34811483; 41922367

Possible model divergences to type when curating (per CLAUDE.md taxonomy): - SPECIES_MISMATCH - BOUNDARY_OMISSION: no peripheral nerve in any model - INCOMPLETE_PHENOTYPE: zebrafish has no ataxia readout - a severity mismatch: the mouse null is far more severe than the human disease

Evidence gaps and curation notes

Very small case base: about 3 well-described patients plus 2 unread 2026 case reports. Retry fetching PMID:41631675 and PMID:41506093 later. Both are currently cached with content_type: unavailable and must not be quoted.
No quotable gene–disease validity tier: no ClinGen GDV, Orphanet or GeneReviews chapter was found. Run just check-genereviews on the entry.
No human data on NAD⁺ depletion, seizures, or the peripheral nerve mechanism. These are candidate KNOWLEDGE_GAP / HUMAN_MODEL_MISMATCH discussions.
Repository housekeeping from this session:
I cached PMID_28002403, 29472272, 41631675, 41506093, 40379758, 19633665, 34811483, 34102106, 41922367 and 33932076 in references_cache/.
I also fetched PMID_33779029.md by mistake. It is an unrelated FXR2P seizure paper and should be deleted; my rm was blocked by permissions.
Prune any of the others the entry does not end up citing.

Key references

PMID	Citation	Evidence type
28002403	Hoch NC et al. Nature 2017;541:87–91. XRCC1 mutation is associated with PARP1 hyperactivation and cerebellar ataxia	Human clinical + IN_VITRO + MODEL_ORGANISM; split items
29472272	O'Connor E et al. J Neurol Neurosurg Psychiatry 2018;89:1230–1232. Mutations in XRCC1 cause cerebellar ataxia and peripheral neuropathy	Human clinical
41631675	Ribeiro G et al. Mov Disord Clin Pract 2026;13:1776–1778	Human clinical; no text available
41506093	Mahale R, Mailankody P. Parkinsonism Relat Disord 2026;144:108184	Human clinical; no text available
19633665	Lee Y et al. Nat Neurosci 2009;12:973–980	Model organism
33932076	Komulainen E et al. EMBO Rep 2021;22:e51851	Model organism
40379758	Semenova SA et al. Sci Rep 2025;15:17043	Model organism (zebrafish)
34102106	Demin AA et al. Mol Cell 2021;81:3018	In vitro
34811483	Adamowicz M et al. Nat Cell Biol 2021;23:1287	In vitro + mouse neurons
41922367	Dauben H et al. Nat Commun 2026;17:3216	In vitro
42399641	Kim K et al. Cell Death Differ 2026 (SCAR26 variants vs TADA2B/LIG3)	In vitro; abstract not cached
31324530	Caldecott KW. DNA Repair 2019;81:102664. XRCC1 protein; form and function	Review
35426160	Brazilian AOA cohort, 2022 (no XRCC1 variants found)	Human clinical (negative)

Web sources: - PubMed 28002403 - PMC6227798 (O'Connor 2018) - Komulainen 2021, PMC8097344 - OMIM 617633 - MedGen C4539948 - Disease Ontology DOID:0080260 - LOVD disease 06425 - PanelApp England XRCC1 - PanelApp Australia XRCC1 - MalaCards SCAR26 - Brazilian AOA cohort, PubMed 35426160 - Kim 2026, PubMed 42399641

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	16
Resolved	16
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	16
On topic	11
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	40
Resolved	39
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	0
Terms whose name was checked	8
Terms named correctly	1
Terms named as a different term	5
Terms whose name is worth a second look	2

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:0033116 (2 mentions) - the report calls it "MONDO"; MONDO calls it spinocerebellar ataxia, autosomal recessive 26
DOID:0080260 (4 mentions) - the report calls it "Disease Ontology"; DOID calls it autosomal recessive spinocerebellar ataxia 26
NCIT:C121351 (1 mention) - the report calls it "Fine motor"; NCIT calls it Occupational Therapy
NCIT:C159273 (1 mention) - the report calls it "Dysarthria"; NCIT calls it Speech Language Therapy
NCIT:C15240 (1 mention) - the report calls it "AR recurrence 25%"; NCIT calls it Genetic Counseling

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:0006977 (obsolete DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest) (1 mention) - replaced by GO:0030330

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:

CHEBI:57540 (1 mention) - the report calls it "NAD⁺"; CHEBI calls it NAD(1-), and lists "NAD(+)" among its other names
UBERON:0002037 (1 mention) - the report calls it "Primary: cerebellum"; UBERON calls it cerebellum**

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References & Deep Research

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Spinocerebellar Ataxia, Autosomal Recessive 26 (SCAR26; XRCC1-related ataxia): Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain

7. Anatomical Structures

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Evidence gaps and curation notes

Key references

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look