👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

SCAR15 is inherited in an autosomal recessive manner. It was originally mapped by linkage / homozygosity mapping in a consanguineous Saudi Arabian pedigree, with affected individuals homozygous for a truncating RUBCN (KIAA0226) frameshift variant that cosegregated with disease; unaffected parents are heterozygous carriers. A shared ancient founder haplotype underlies the recurrent mutation in the Arabian Peninsula.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:20826435 SUPPORT Human Clinical

"We have identified a novel form of recessive ataxia that segregates in three children of a large consanguineous Saudi Arabian family."

Establishes autosomal recessive inheritance segregating in a consanguineous pedigree.

PMID:32450808 SUPPORT Human Clinical

"Autozygome and exome analysis showed both affected have previously reported homoallelic mutation in RUBCN (NM_014687:exon18:c.2624delC:p.A875fs), whereas the parents are carriers."

Affected individuals are homozygous and parents are heterozygous carriers, consistent with autosomal recessive inheritance.

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Pathophysiology

4

RUBCN (Rubicon) Loss of Function

Biallelic truncating variants in RUBCN abolish or truncate Rubicon (rundataxin), a protein with an N-terminal RUN domain and a C-terminal diacylglycerol-binding-like / Rubicon Homology (RH) domain that assembles with the Beclin-1 / class III PI3K (VPS34) complex. Rubicon's principal function is to negatively regulate macroautophagy (and LC3-associated phagocytosis). The recurrent founder allele is an exon 18/19 single-base deletion (c.2624delC / historically 2927delC; p.Ala875ValfsX146 / p.Ala943ValfsX146) that frameshifts and deletes the C-terminal domain.

negative regulation of macroautophagy GO:0010507 ↓ DECREASED

Downstream

Impaired Rubicon Endolysosomal Localization Deletion of the C-terminal diacylglycerol-binding / RH domain mislocalizes Rubicon away from Rab7-positive late endosomes.

Show evidence (2 references)

PMID:20826435 SUPPORT Human Clinical

"The KIAA0226 gene encodes a protein that we named rundataxin, with two conserved domains: an N-terminal RUN domain and a C-terminal domain containing a diacylglycerol binding-like motif."

Identifies the causative gene and the domain architecture of the encoded protein.

PMID:39520129 SUPPORT Other

"The RUBCN gene encodes a widely expressed protein called Rubicon, the main function of which is to negatively regulate macroautophagy."

Background statement of Rubicon's principal molecular function (review/background prose, not a human clinical observation).

Impaired Rubicon Endolysosomal Localization

Wild-type Rubicon colocalizes with the late-endosome GTPase Rab7 and with the lysosomal marker LAMP1. The Salih-ataxia truncation, which removes the diacylglycerol-binding-like / RH domain, causes a diffuse cytosolic redistribution and loss of late-endosomal localization, establishing pathogenicity and linking the disorder to endosomal/lysosomal machinery rather than to the mitochondrial or nuclear pathways of other recessive ataxias.

neuron CL:0000540

late endosome to lysosome transport GO:1902774 ⚠ ABNORMAL

Downstream

Dysregulated Autophagy and Endolysosomal Trafficking Mislocalized Rubicon dysregulates autophagosome maturation and endolysosomal trafficking.

Show evidence (3 references)

PMID:23728897 SUPPORT In Vitro

"We confirm that Rubicon colocalizes with the late endosome marker Rab7 and demonstrate that it also colocalizes with LampI at lysosomes."

Localizes Rubicon to Rab7 late endosomes and LAMP1 lysosomes in cultured cells.

PMID:23728897 SUPPORT In Vitro

"The Salih ataxia mutation leads to a diffuse cytosolic distribution and mislocalized protein from the late endosomes, indicating that deletion of the diacylglycerol binding-like motif in the mutant protein interferes with normal Rubicon subcellular localization and confirming the pathogenicity..."

The truncating mutation mislocalizes Rubicon from late endosomes, demonstrating the pathogenic cellular mechanism.

PMID:39520129 SUPPORT In Vitro

"This variant is responsible for the deletion of the highly conserved Rubicon Homology (RH) domain, which is important for the colocalization of Rubicon with Rab7 in the late endosome."

Independently implicates loss of the RH domain and Rab7 late-endosomal colocalization in a second RUBCN allele.

Dysregulated Autophagy and Endolysosomal Trafficking

Loss of correctly localized Rubicon perturbs the late (maturation) step of autophagy and endosome-to-lysosome trafficking, impairing neuronal protein and organelle quality control.

neuron CL:0000540

autophagy GO:0006914 ⚠ ABNORMAL autophagosome maturation GO:0097352 ⚠ ABNORMAL

Downstream

Cerebellar Neurodegeneration Chronic autophagic-endolysosomal dysfunction contributes to cerebellar neuronal loss.

Show evidence (1 reference)

PMID:39520129 SUPPORT Other

"The resulting truncated protein lacks the RH domain, which may lead to defective endosomal trafficking as previously described."

Mechanistic inference (not a direct observation) that RH-domain loss leads to defective endosomal trafficking; the paper's own functional work is RNA/in-vitro.

Cerebellar Neurodegeneration

Cerebellar (predominantly superior vermian) atrophy on MRI underlies the gait/limb ataxia, dysarthria, and oculomotor signs. Atrophy is often subtle and may be absent early, consistent with the slowly progressive course. Purkinje cells are the presumptively vulnerable cerebellar cortical neuron on mechanistic grounds; direct evidence of Purkinje-cell loss in SCAR15 tissue has not been reported, so this cell-type attribution is an inference from the imaging phenotype rather than a documented histopathological finding.

cerebellar Purkinje cell CL:0000121 cerebellar granule cell CL:0001031

cerebellum UBERON:0002037

Show evidence (1 reference)

PMID:32450808 SUPPORT Human Clinical

"Brain MRI showed normal cerebellar volume and folia in the older sibling at the age of 6 years, and revealed minimal superior vermian atrophy at the age of 16 years."

Documents progressive superior vermian (cerebellar) atrophy on neuroimaging.

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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

14

Ear 1

Hearing impairment HP:0000365

Show evidence (1 reference)

PMID:32450808 SUPPORT Human Clinical

"brain auditory evoked response (BAER) revealed increased hearing threshold in left (40 dB) and right (60 dB) ears"

Documents an increased auditory threshold (hearing impairment) on BAER in an affected patient.

Eye 1

Nystagmus HP:0000639

Show evidence (1 reference)

PMID:32450808 SUPPORT Human Clinical

"nystagmus or saccadic pursuit (in the second decade)"

Documents nystagmus among the oculomotor findings, developing in the second decade.

Nervous System 8

Gait ataxia HP:0002066

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:20826435 SUPPORT Human Clinical

"The three patients presented with childhood onset gait and limb ataxia, dysarthria and had limited walking without aid into their teenage years."

Documents childhood-onset gait ataxia with limited independent walking.

Dysarthria HP:0001260

Show evidence (1 reference)

PMID:20826435 SUPPORT Human Clinical

"The three patients presented with childhood onset gait and limb ataxia, dysarthria and had limited walking without aid into their teenage years."

Dysarthria is present in the originally described patients.

Intellectual disability HP:0001249

Show evidence (2 references)

PMID:20826435 SUPPORT Human Clinical

"Two patients developed epilepsy at 7 months without relapse after treatment, and mental retardation."

Intellectual disability (reported as mental retardation) is part of the core phenotype.

PMID:32450808 SUPPORT Human Clinical

"Cognitive abilities were mildly impaired in the younger sibling (IQ 67) and borderline in the older patient (IQ 72)."

Quantifies mild cognitive impairment in a second family.

Seizures HP:0001250

Show evidence (1 reference)

PMID:20826435 SUPPORT Human Clinical

"Two patients developed epilepsy at 7 months without relapse after treatment, and mental retardation."

Documents infantile-onset epilepsy responsive to treatment.

Cerebellar atrophy HP:0001272

Show evidence (1 reference)

PMID:32450808 SUPPORT Human Clinical

"revealed minimal superior vermian atrophy at the age of 16 years"

Documents superior vermian cerebellar atrophy on MRI.

Motor delay HP:0001270

Show evidence (1 reference)

PMID:32450808 SUPPORT Human Clinical

"He sat unsupported at 1 year, walked at 30 months and showed unsteadiness since starting to walk."

Documents delayed gross-motor milestones (walking at 30 months).

Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:32450808 SUPPORT Human Clinical

"Speech acquisition was delayed till 5 years."

Documents delayed speech and language development.

Dystonia HP:0001332

Show evidence (1 reference)

PMID:38934208 SUPPORT Human Clinical

"Dystonia in a Patient with Genetically Proven Salih Ataxia Due to a Novel Truncating Variant: Expanding the Genotypic and Phenotypic Spectrum."

Reports dystonia in a genetically confirmed Salih ataxia (SCAR15) patient (single case; abstract text not available, title used).

Other 4

Limb ataxia HP:0002070

Show evidence (1 reference)

PMID:32450808 SUPPORT Human Clinical

"The older patient had saccadic eye movement, dysarthria, mild upper and lower limb and gait ataxia (on tandem walking), and enhanced reflexes in the lower limbs."

Documents upper and lower limb ataxia in an affected patient.

Epileptic encephalopathy HP:0200134

Show evidence (1 reference)

PMID:39520129 SUPPORT Human Clinical

"we describe a female patient with childhood-onset epileptic encephalopathy and neurodevelopmental delay carrying a novel homozygous variant in RUBCN"

Reports epileptic encephalopathy in a RUBCN-mutant patient.

Lower limb hyperreflexia HP:0002395

Show evidence (1 reference)

PMID:32450808 SUPPORT Human Clinical

"and enhanced reflexes in the lower limbs"

Documents lower-limb hyperreflexia in an affected patient.

Saccadic pursuit (impaired ocular smooth pursuit) Abnormality of ocular smooth pursuit HP:0000617

Show evidence (1 reference)

PMID:32450808 SUPPORT Human Clinical

"ocular examination revealed saccadic pursuit"

Documents saccadic (interrupted) smooth pursuit, an ocular smooth-pursuit abnormality.

🧬

Genetic Associations

1

RUBCN

Gene: RUBCN hgnc:28991 relationship_type: CAUSATIVE

Show evidence (2 references)

PMID:20826435 SUPPORT Human Clinical

"Mutation screening of all coding sequences revealed a single nucleotide deletion, 2927delC, in exon 19 of the KIAA0226 gene, which results in a frame shift of the C-terminal domain (p.Ala943ValfsX146)."

Identifies the causative KIAA0226 (RUBCN) truncating frameshift variant.

PMID:32450808 SUPPORT Human Clinical

"Autozygome and exome analysis showed both affected have previously reported homoallelic mutation in RUBCN (NM_014687:exon18:c.2624delC:p.A875fs), whereas the parents are carriers."

Confirms the recurrent homozygous RUBCN founder mutation in a second family.

Variants (2)

RUBCN c.2624delC (p.Ala875ValfsX146) Pathogenic

frameshift LOF

Recurrent Arab founder single-base frameshift deletion in RUBCN exon 18/19 (NM_014687:c.2624delC, p.A875fs; the same allele reported in the original family as 2927delC / p.Ala943ValfsX146 under earlier transcript/protein numbering). Truncates the C-terminal diacylglycerol-binding / RH domain; homozygous in the two reported Saudi families.

Show evidence (1 reference)

PMID:32450808 SUPPORT Human Clinical

"Autozygome and exome analysis showed both affected have previously reported homoallelic mutation in RUBCN (NM_014687:exon18:c.2624delC:p.A875fs), whereas the parents are carriers."

Establishes the homozygous founder frameshift allele in a second family.

RUBCN c.2126+1G>A (splice donor) Pathogenic

splice site LOF

Novel homozygous splice-donor variant abolishing the exon 14/intron 14 consensus donor site; produces frameshifted alternative transcripts and a truncated protein lacking the RH domain. First RUBCN splice variant, reported in a patient with epileptic encephalopathy.

Show evidence (1 reference)

PMID:39520129 SUPPORT In Vitro

"A functional study of the RNA revealed that this variant completely abolishes the consensus donor site at the exon 14/intron 14 junction, resulting in the absence of expression of the reference transcript."

Functional RNA study establishes the splice-donor loss-of-function effect.

💊

Medical Actions

2

Antiseizure Medication

Action: Pharmacotherapy NCIT:C15986

Symptomatic pharmacologic management of epilepsy. In the originally described patients, infantile-onset seizures responded to antiseizure treatment without relapse.

Show evidence (1 reference)

PMID:20826435 SUPPORT Human Clinical

"Two patients developed epilepsy at 7 months without relapse after treatment, and mental retardation."

Epilepsy in affected patients was controlled with antiseizure treatment without relapse.

Rehabilitation and Physical Therapy

Action: Physical Therapy NCIT:C15302

Supportive physiotherapy and rehabilitation for gait ataxia and motor impairment. No disease-modifying therapy exists; management is symptomatic and multidisciplinary.

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Diagnosis

1

Molecular Genetic Testing

Diagnosis is established by identifying biallelic pathogenic RUBCN variants, typically through exome sequencing combined with autozygosity (autozygome) mapping in consanguineous families; targeted testing for the recurrent Arab founder allele is informative in that population. Nerve conduction studies are normal, helping distinguish SCAR15 from recessive ataxias with peripheral neuropathy.

Show evidence (2 references)

PMID:32450808 SUPPORT Human Clinical

"Autozygome and exome analysis showed both affected have previously reported homoallelic mutation in RUBCN (NM_014687:exon18:c.2624delC:p.A875fs), whereas the parents are carriers."

Molecular diagnosis is achieved by autozygome/exome analysis identifying biallelic RUBCN variants.

PMID:32450808 SUPPORT Human Clinical

"Nerve conduction studies were normal in both patients."

Normal nerve conduction studies help distinguish SCAR15 from recessive ataxias with peripheral neuropathy.

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Progression

1

Age: childhood onset

Slowly progressive (near-stationary in some) cerebellar course. Onset is in early childhood, usually as unsteadiness when learning to walk; independent walking is preserved but limited into the teens. Reported disability stage ranges from 0 to 3 of 7 across patients. Early brain MRI can be normal, with mild superior vermian / cerebellar atrophy emerging with age.

Show evidence (1 reference)

PMID:32450808 SUPPORT Human Clinical

"Our findings validate the slowly progressive phenotype of Salih ataxia"

Confirms the slowly progressive course across two families.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Ultra-rare; a small number of reported patients, largely from consanguineous families of the Arabian Peninsula sharing an ancient RUBCN founder haplotype, plus isolated non-founder variants.

Show evidence (1 reference)

PMID:32450808 SUPPORT Human Clinical

"Haplotype sharing attests to a common founder, an ancient RUBCN mutation in the Arab population."

Documents a shared ancient founder mutation in the Arab population, consistent with the disorder's rarity and geographic clustering.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Autosomal Recessive Spinocerebellar Ataxia 15:

Autosomal dominant spinocerebellar ataxia 15/16 (ITPR1)

Overlapping Features Autosomal dominant, ITPR1-related, predominantly pure cerebellar ataxia. This is the recurrent name collision the NEC preflight guards against — distinguished by dominant inheritance, the ITPR1 gene, and the absence of the epilepsy / intellectual-disability triad.

Distinguishing Features

Autosomal dominant inheritance (heterozygous ITPR1 loss-of-function / deletion)
Predominantly pure cerebellar ataxia without prominent epilepsy or intellectual disability

Autosomal recessive spinocerebellar ataxia 17 (CWF19L1)

Overlapping Features CWF19L1-related recessive cerebellar ataxia with intellectual disability. Genomically and clinically adjacent to SCAR15; distinguished by the causal gene (CWF19L1 vs RUBCN).

Distinguishing Features

Biallelic CWF19L1 variants rather than RUBCN

Other recessive cerebellar ataxias with epilepsy and intellectual disability

Overlapping Features Broad differential of recessive ataxia-epilepsy-ID syndromes (e.g. Friedreich ataxia, ataxia with vitamin E deficiency, ataxia-telangiectasia, ARSACS, SCAN1), distinguished by additional system involvement.

Show evidence (1 reference)

PMID:32450808 SUPPORT Human Clinical

"other autosomal recessive cerebellar ataxias associated with epilepsy and ID can be differentiated by the associated presence of abnormalities in the peripheral nerves, basal ganglia, pyramidal tract, hearing or vision"

Provides the clinical criteria distinguishing SCAR15 from other recessive ataxia-epilepsy-ID syndromes.

{ }

Source YAML

click to show

name: Autosomal Recessive Spinocerebellar Ataxia 15
creation_date: "2026-08-05T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: autosomal recessive spinocerebellar ataxia 15
  term:
    id: MONDO:0014311
    label: autosomal recessive spinocerebellar ataxia 15
description: >
  Autosomal recessive spinocerebellar ataxia 15 (SCAR15; OMIM 615705), also called Salih
  ataxia and, in MONDO, the RUBCN autosomal recessive cerebellar ataxia-epilepsy-intellectual
  disability syndrome, is a rare childhood-onset neurodevelopmental and neurodegenerative
  disorder caused by biallelic loss-of-function variants in RUBCN (formerly KIAA0226), the
  gene encoding Rubicon (originally named "rundataxin"). It was first defined in a large
  consanguineous Saudi Arabian family and subsequently confirmed by an ancient founder
  mutation shared across unrelated Arab families. The core clinical picture is early-onset,
  slowly progressive (or relatively non-progressive) gait and limb ataxia with dysarthria,
  intellectual disability / delayed psychomotor development, and epilepsy; brain MRI shows
  variable, often mild superior vermian / cerebellar atrophy. Rubicon is a negative regulator
  of macroautophagy and of LC3-associated phagocytosis that localizes to Rab7-positive late
  endosomes and lysosomes; disease-causing truncations delete its C-terminal
  diacylglycerol-binding / Rubicon Homology (RH) domain and mislocalize the protein,
  dysregulating autophagic and endolysosomal trafficking in neurons. The phenotypic spectrum
  has since been broadened to include dystonia and a childhood-onset epileptic encephalopathy.

inheritance:
- name: Autosomal recessive inheritance
  description: >
    SCAR15 is inherited in an autosomal recessive manner. It was originally mapped by linkage /
    homozygosity mapping in a consanguineous Saudi Arabian pedigree, with affected individuals
    homozygous for a truncating RUBCN (KIAA0226) frameshift variant that cosegregated with
    disease; unaffected parents are heterozygous carriers. A shared ancient founder haplotype
    underlies the recurrent mutation in the Arabian Peninsula.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20826435
    reference_title: "Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified a novel form of recessive ataxia that segregates in three children of a large consanguineous Saudi Arabian family."
    explanation: Establishes autosomal recessive inheritance segregating in a consanguineous pedigree.
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autozygome and exome analysis showed both affected have previously reported homoallelic mutation in RUBCN (NM_014687:exon18:c.2624delC:p.A875fs), whereas the parents are carriers."
    explanation: Affected individuals are homozygous and parents are heterozygous carriers, consistent with autosomal recessive inheritance.

pathophysiology:
- name: RUBCN (Rubicon) Loss of Function
  biological_scale: MOLECULAR
  description: >
    Biallelic truncating variants in RUBCN abolish or truncate Rubicon (rundataxin), a protein
    with an N-terminal RUN domain and a C-terminal diacylglycerol-binding-like / Rubicon
    Homology (RH) domain that assembles with the Beclin-1 / class III PI3K (VPS34) complex.
    Rubicon's principal function is to negatively regulate macroautophagy (and LC3-associated
    phagocytosis). The recurrent founder allele is an exon 18/19 single-base deletion
    (c.2624delC / historically 2927delC; p.Ala875ValfsX146 / p.Ala943ValfsX146) that frameshifts
    and deletes the C-terminal domain.
  biological_processes:
  - preferred_term: negative regulation of macroautophagy
    term:
      id: GO:0010507
      label: negative regulation of autophagy
    modifier: DECREASED
  evidence:
  - reference: PMID:20826435
    reference_title: "Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The KIAA0226 gene encodes a protein that we named rundataxin, with two conserved domains: an N-terminal RUN domain and a C-terminal domain containing a diacylglycerol binding-like motif."
    explanation: Identifies the causative gene and the domain architecture of the encoded protein.
  - reference: PMID:39520129
    reference_title: "A second RUBCN variant associated with epileptic encephalopathy and neurodevelopmental delay."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The RUBCN gene encodes a widely expressed protein called Rubicon, the main function of which is to negatively regulate macroautophagy."
    explanation: Background statement of Rubicon's principal molecular function (review/background prose, not a human clinical observation).
  downstream:
  - target: Impaired Rubicon Endolysosomal Localization
    description: >-
      Deletion of the C-terminal diacylglycerol-binding / RH domain mislocalizes Rubicon away
      from Rab7-positive late endosomes.

- name: Impaired Rubicon Endolysosomal Localization
  biological_scale: CELLULAR
  description: >
    Wild-type Rubicon colocalizes with the late-endosome GTPase Rab7 and with the lysosomal
    marker LAMP1. The Salih-ataxia truncation, which removes the diacylglycerol-binding-like /
    RH domain, causes a diffuse cytosolic redistribution and loss of late-endosomal
    localization, establishing pathogenicity and linking the disorder to endosomal/lysosomal
    machinery rather than to the mitochondrial or nuclear pathways of other recessive ataxias.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: late endosome to lysosome transport
    term:
      id: GO:1902774
      label: late endosome to lysosome transport
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23728897
    reference_title: "The Salih ataxia mutation impairs Rubicon endosomal localization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We confirm that Rubicon colocalizes with the late endosome marker Rab7 and demonstrate that it also colocalizes with LampI at lysosomes."
    explanation: Localizes Rubicon to Rab7 late endosomes and LAMP1 lysosomes in cultured cells.
  - reference: PMID:23728897
    reference_title: "The Salih ataxia mutation impairs Rubicon endosomal localization."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The Salih ataxia mutation leads to a diffuse cytosolic distribution and mislocalized protein from the late endosomes, indicating that deletion of the diacylglycerol binding-like motif in the mutant protein interferes with normal Rubicon subcellular localization and confirming the pathogenicity of the mutation."
    explanation: The truncating mutation mislocalizes Rubicon from late endosomes, demonstrating the pathogenic cellular mechanism.
  - reference: PMID:39520129
    reference_title: "A second RUBCN variant associated with epileptic encephalopathy and neurodevelopmental delay."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This variant is responsible for the deletion of the highly conserved Rubicon Homology (RH) domain, which is important for the colocalization of Rubicon with Rab7 in the late endosome."
    explanation: Independently implicates loss of the RH domain and Rab7 late-endosomal colocalization in a second RUBCN allele.
  downstream:
  - target: Dysregulated Autophagy and Endolysosomal Trafficking
    description: >-
      Mislocalized Rubicon dysregulates autophagosome maturation and endolysosomal trafficking.

- name: Dysregulated Autophagy and Endolysosomal Trafficking
  biological_scale: CELLULAR
  description: >
    Loss of correctly localized Rubicon perturbs the late (maturation) step of autophagy and
    endosome-to-lysosome trafficking, impairing neuronal protein and organelle quality control.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: autophagy
    term:
      id: GO:0006914
      label: autophagy
    modifier: ABNORMAL
  - preferred_term: autophagosome maturation
    term:
      id: GO:0097352
      label: autophagosome maturation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:39520129
    reference_title: "A second RUBCN variant associated with epileptic encephalopathy and neurodevelopmental delay."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The resulting truncated protein lacks the RH domain, which may lead to defective endosomal trafficking as previously described."
    explanation: Mechanistic inference (not a direct observation) that RH-domain loss leads to defective endosomal trafficking; the paper's own functional work is RNA/in-vitro.
  downstream:
  - target: Cerebellar Neurodegeneration
    description: >-
      Chronic autophagic-endolysosomal dysfunction contributes to cerebellar neuronal loss.

- name: Cerebellar Neurodegeneration
  biological_scale: TISSUE
  description: >
    Cerebellar (predominantly superior vermian) atrophy on MRI underlies the gait/limb ataxia,
    dysarthria, and oculomotor signs. Atrophy is often subtle and may be absent early,
    consistent with the slowly progressive course. Purkinje cells are the presumptively
    vulnerable cerebellar cortical neuron on mechanistic grounds; direct evidence of
    Purkinje-cell loss in SCAR15 tissue has not been reported, so this cell-type attribution
    is an inference from the imaging phenotype rather than a documented histopathological
    finding.
  cell_types:
  - preferred_term: cerebellar Purkinje cell
    term:
      id: CL:0000121
      label: Purkinje cell
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI showed normal cerebellar volume and folia in the older sibling at the age of 6 years, and revealed minimal superior vermian atrophy at the age of 16 years."
    explanation: Documents progressive superior vermian (cerebellar) atrophy on neuroimaging.

phenotypes:
- name: Gait ataxia
  description: >
    Early-onset, slowly progressive gait ataxia; unsteadiness typically apparent from the time
    the child learns to walk, with preserved but limited independent ambulation into the teens.
  phenotype_term:
    preferred_term: Gait ataxia
    term:
      id: HP:0002066
      label: Gait ataxia
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20826435
    reference_title: "Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The three patients presented with childhood onset gait and limb ataxia, dysarthria and had limited walking without aid into their teenage years."
    explanation: Documents childhood-onset gait ataxia with limited independent walking.

- name: Limb ataxia
  description: Upper and lower limb ataxia accompanying the gait disorder.
  phenotype_term:
    preferred_term: Limb ataxia
    term:
      id: HP:0002070
      label: Limb ataxia
  evidence:
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The older patient had saccadic eye movement, dysarthria, mild upper and lower limb and gait ataxia (on tandem walking), and enhanced reflexes in the lower limbs."
    explanation: Documents upper and lower limb ataxia in an affected patient.

- name: Dysarthria
  description: Cerebellar dysarthria.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:20826435
    reference_title: "Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The three patients presented with childhood onset gait and limb ataxia, dysarthria and had limited walking without aid into their teenage years."
    explanation: Dysarthria is present in the originally described patients.

- name: Intellectual disability
  description: >
    Delayed psychomotor development with intellectual disability, ranging from borderline to
    moderate across reported patients.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:20826435
    reference_title: "Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients developed epilepsy at 7 months without relapse after treatment, and mental retardation."
    explanation: Intellectual disability (reported as mental retardation) is part of the core phenotype.
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cognitive abilities were mildly impaired in the younger sibling (IQ 67) and borderline in the older patient (IQ 72)."
    explanation: Quantifies mild cognitive impairment in a second family.

- name: Seizures
  description: >
    Epilepsy, frequently with onset in infancy and typically responsive to antiseizure
    treatment; a severe childhood-onset epileptic encephalopathy has also been reported.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:20826435
    reference_title: "Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients developed epilepsy at 7 months without relapse after treatment, and mental retardation."
    explanation: Documents infantile-onset epilepsy responsive to treatment.

- name: Epileptic encephalopathy
  description: >
    Childhood-onset epileptic encephalopathy with neurodevelopmental delay reported in a
    patient with a novel RUBCN splice variant, broadening the phenotypic spectrum toward more
    severe epilepsy.
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:39520129
    reference_title: "A second RUBCN variant associated with epileptic encephalopathy and neurodevelopmental delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we describe a female patient with childhood-onset epileptic encephalopathy and neurodevelopmental delay carrying a novel homozygous variant in RUBCN"
    explanation: Reports epileptic encephalopathy in a RUBCN-mutant patient.

- name: Cerebellar atrophy
  description: >
    Variable, often mild superior vermian / cerebellar atrophy on brain MRI; may be normal
    early in the disease course and become apparent with age.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealed minimal superior vermian atrophy at the age of 16 years"
    explanation: Documents superior vermian cerebellar atrophy on MRI.

- name: Lower limb hyperreflexia
  description: Enhanced deep tendon reflexes in the lower limbs (pyramidal sign).
  phenotype_term:
    preferred_term: Lower limb hyperreflexia
    term:
      id: HP:0002395
      label: Lower limb hyperreflexia
  evidence:
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "and enhanced reflexes in the lower limbs"
    explanation: Documents lower-limb hyperreflexia in an affected patient.

- name: Saccadic pursuit (impaired ocular smooth pursuit)
  description: >
    Broken-up (saccadic) smooth pursuit on ocular examination — an impairment of smooth-pursuit
    eye movements, distinct from a primary saccade abnormality.
  phenotype_term:
    preferred_term: Saccadic pursuit
    term:
      id: HP:0000617
      label: Abnormality of ocular smooth pursuit
  evidence:
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ocular examination revealed saccadic pursuit"
    explanation: Documents saccadic (interrupted) smooth pursuit, an ocular smooth-pursuit abnormality.

- name: Nystagmus
  description: Nystagmus reported among the oculomotor abnormalities, emerging in older patients.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "nystagmus or saccadic pursuit (in the second decade)"
    explanation: Documents nystagmus among the oculomotor findings, developing in the second decade.

- name: Hearing impairment
  description: >
    Sensorineural hearing impairment detected as an increased hearing threshold on brainstem
    auditory evoked response (BAER) testing in some patients; BAER is normal in others.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "brain auditory evoked response (BAER) revealed increased hearing threshold in left (40 dB) and right (60 dB) ears"
    explanation: Documents an increased auditory threshold (hearing impairment) on BAER in an affected patient.

- name: Motor delay
  description: Delayed acquisition of motor milestones, e.g. delayed independent walking.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He sat unsupported at 1 year, walked at 30 months and showed unsteadiness since starting to walk."
    explanation: Documents delayed gross-motor milestones (walking at 30 months).

- name: Delayed speech and language development
  description: Delayed speech acquisition.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Speech acquisition was delayed till 5 years."
    explanation: Documents delayed speech and language development.

- name: Dystonia
  description: >
    Dystonia reported in a genetically confirmed Salih ataxia patient with a novel truncating
    RUBCN variant, expanding the movement-disorder spectrum. Reported in a single case.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:38934208
    reference_title: "Dystonia in a Patient with Genetically Proven Salih Ataxia Due to a Novel Truncating Variant: Expanding the Genotypic and Phenotypic Spectrum."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dystonia in a Patient with Genetically Proven Salih Ataxia Due to a Novel Truncating Variant: Expanding the Genotypic and Phenotypic Spectrum."
    explanation: Reports dystonia in a genetically confirmed Salih ataxia (SCAR15) patient (single case; abstract text not available, title used).

genetic:
- name: RUBCN
  notes: >
    Biallelic loss-of-function variants in RUBCN (formerly KIAA0226; chromosome 3q28-qter)
    cause SCAR15. The recurrent Arab founder allele is a single-base frameshift deletion in
    exon 18/19 (NM_014687 c.2624delC, p.A875fs; originally reported as 2927delC,
    p.Ala943ValfsX146) that deletes the C-terminal diacylglycerol-binding / RH domain. A novel
    homozygous splice variant (c.2126+1G>A) has also been reported. Rubicon negatively
    regulates macroautophagy and localizes to Rab7 late endosomes.
  gene_term:
    preferred_term: RUBCN
    term:
      id: hgnc:28991
      label: RUBCN
  relationship_type: CAUSATIVE
  variants:
  - name: RUBCN c.2624delC (p.Ala875ValfsX146)
    description: >
      Recurrent Arab founder single-base frameshift deletion in RUBCN exon 18/19
      (NM_014687:c.2624delC, p.A875fs; the same allele reported in the original family as
      2927delC / p.Ala943ValfsX146 under earlier transcript/protein numbering). Truncates the
      C-terminal diacylglycerol-binding / RH domain; homozygous in the two reported Saudi families.
    type: frameshift
    clinical_significance: PATHOGENIC
    regulatory_category: LOF
    evidence:
    - reference: PMID:32450808
      reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Autozygome and exome analysis showed both affected have previously reported homoallelic mutation in RUBCN (NM_014687:exon18:c.2624delC:p.A875fs), whereas the parents are carriers."
      explanation: Establishes the homozygous founder frameshift allele in a second family.
  - name: RUBCN c.2126+1G>A (splice donor)
    description: >
      Novel homozygous splice-donor variant abolishing the exon 14/intron 14 consensus donor
      site; produces frameshifted alternative transcripts and a truncated protein lacking the RH
      domain. First RUBCN splice variant, reported in a patient with epileptic encephalopathy.
    type: splice site
    clinical_significance: PATHOGENIC
    regulatory_category: LOF
    evidence:
    - reference: PMID:39520129
      reference_title: "A second RUBCN variant associated with epileptic encephalopathy and neurodevelopmental delay."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "A functional study of the RNA revealed that this variant completely abolishes the consensus donor site at the exon 14/intron 14 junction, resulting in the absence of expression of the reference transcript."
      explanation: Functional RNA study establishes the splice-donor loss-of-function effect.
  evidence:
  - reference: PMID:20826435
    reference_title: "Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation screening of all coding sequences revealed a single nucleotide deletion, 2927delC, in exon 19 of the KIAA0226 gene, which results in a frame shift of the C-terminal domain (p.Ala943ValfsX146)."
    explanation: Identifies the causative KIAA0226 (RUBCN) truncating frameshift variant.
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autozygome and exome analysis showed both affected have previously reported homoallelic mutation in RUBCN (NM_014687:exon18:c.2624delC:p.A875fs), whereas the parents are carriers."
    explanation: Confirms the recurrent homozygous RUBCN founder mutation in a second family.

diagnosis:
- name: Molecular Genetic Testing
  description: >
    Diagnosis is established by identifying biallelic pathogenic RUBCN variants, typically
    through exome sequencing combined with autozygosity (autozygome) mapping in consanguineous
    families; targeted testing for the recurrent Arab founder allele is informative in that
    population. Nerve conduction studies are normal, helping distinguish SCAR15 from recessive
    ataxias with peripheral neuropathy.
  evidence:
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Autozygome and exome analysis showed both affected have previously reported homoallelic mutation in RUBCN (NM_014687:exon18:c.2624delC:p.A875fs), whereas the parents are carriers."
    explanation: Molecular diagnosis is achieved by autozygome/exome analysis identifying biallelic RUBCN variants.
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nerve conduction studies were normal in both patients."
    explanation: Normal nerve conduction studies help distinguish SCAR15 from recessive ataxias with peripheral neuropathy.

progression:
- age_range: childhood onset
  notes: >
    Slowly progressive (near-stationary in some) cerebellar course. Onset is in early childhood,
    usually as unsteadiness when learning to walk; independent walking is preserved but limited
    into the teens. Reported disability stage ranges from 0 to 3 of 7 across patients. Early brain
    MRI can be normal, with mild superior vermian / cerebellar atrophy emerging with age.
  evidence:
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings validate the slowly progressive phenotype of Salih ataxia"
    explanation: Confirms the slowly progressive course across two families.

differential_diagnoses:
- name: Autosomal dominant spinocerebellar ataxia 15/16 (ITPR1)
  description: >
    Autosomal dominant, ITPR1-related, predominantly pure cerebellar ataxia. This is the
    recurrent name collision the NEC preflight guards against — distinguished by dominant
    inheritance, the ITPR1 gene, and the absence of the epilepsy / intellectual-disability triad.
  distinguishing_features:
  - Autosomal dominant inheritance (heterozygous ITPR1 loss-of-function / deletion)
  - Predominantly pure cerebellar ataxia without prominent epilepsy or intellectual disability
- name: Autosomal recessive spinocerebellar ataxia 17 (CWF19L1)
  description: >
    CWF19L1-related recessive cerebellar ataxia with intellectual disability. Genomically and
    clinically adjacent to SCAR15; distinguished by the causal gene (CWF19L1 vs RUBCN).
  distinguishing_features:
  - Biallelic CWF19L1 variants rather than RUBCN
- name: Other recessive cerebellar ataxias with epilepsy and intellectual disability
  description: >
    Broad differential of recessive ataxia-epilepsy-ID syndromes (e.g. Friedreich ataxia, ataxia
    with vitamin E deficiency, ataxia-telangiectasia, ARSACS, SCAN1), distinguished by additional
    system involvement.
  evidence:
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "other autosomal recessive cerebellar ataxias associated with epilepsy and ID can be differentiated by the associated presence of abnormalities in the peripheral nerves, basal ganglia, pyramidal tract, hearing or vision"
    explanation: Provides the clinical criteria distinguishing SCAR15 from other recessive ataxia-epilepsy-ID syndromes.

prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >
    Ultra-rare; a small number of reported patients, largely from consanguineous families of
    the Arabian Peninsula sharing an ancient RUBCN founder haplotype, plus isolated non-founder
    variants.
  evidence:
  - reference: PMID:32450808
    reference_title: "Ancient founder mutation in RUBCN: a second unrelated family confirms Salih ataxia (SCAR15)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Haplotype sharing attests to a common founder, an ancient RUBCN mutation in the Arab population."
    explanation: Documents a shared ancient founder mutation in the Arab population, consistent with the disorder's rarity and geographic clustering.

treatments:
- name: Antiseizure Medication
  description: >
    Symptomatic pharmacologic management of epilepsy. In the originally described patients,
    infantile-onset seizures responded to antiseizure treatment without relapse.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:20826435
    reference_title: "Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two patients developed epilepsy at 7 months without relapse after treatment, and mental retardation."
    explanation: Epilepsy in affected patients was controlled with antiseizure treatment without relapse.

- name: Rehabilitation and Physical Therapy
  description: >
    Supportive physiotherapy and rehabilitation for gait ataxia and motor impairment. No
    disease-modifying therapy exists; management is symptomatic and multidisciplinary.
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  therapeutic_modality: BEHAVIORAL

📚

References & Deep Research

Deep Research

1

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Autosomal Recessive Spinocerebellar Ataxia 15 (SCAR15): Disease-Characteristics Report

Edison Scientific Literature 13 citations 2026-08-05T21:59:12.407122

Autosomal Recessive Spinocerebellar Ataxia 15 (SCAR15): Disease-Characteristics Report

Executive summary and evidence boundary

Autosomal recessive spinocerebellar ataxia 15 (SCAR15), or Salih ataxia, is an exceptionally rare, childhood-onset neurodevelopmental and slowly progressive cerebellar disorder caused by biallelic pathogenic variants in RUBCN (formerly KIAA0226). It must not be confused with autosomal-dominant SCA15, usually associated with ITPR1, or with CWF19L1-related SCAR17. The historical evidence base comprises only five patients from two Saudi families carrying the same founder frameshift; therefore, percentages below are descriptive, not robust population estimates. Open Targets maps MONDO:0014311 specifically to RUBCN and cites the foundational human studies (OpenTargets Search: autosomal recessive spinocerebellar ataxia 15).

The principal primary reports are Assoum et al., Brain, August 2010, PMID 20826435, DOI 10.1093/brain/awq181, and Seidahmed et al., BMC Neurology, 21 May 2020, PMID 32450808, DOI 10.1186/s12883-020-01761-w. The latter’s abstract states that its findings “validate the slowly progressive phenotype of Salih ataxia” and that “haplotype sharing attests to a common founder” (seidahmed2020ancientfoundermutation pages 1-3).

The following evidence matrix summarizes the central findings and their limitations.

Domain	Established finding	Quantitative/patient evidence	Evidence type/source and date	Confidence/limitations
Identifiers / nomenclature	SCAR15 is Salih ataxia, an autosomal recessive spinocerebellar ataxia distinct from dominant SCA15; OMIM 615705; MONDO 0014311; disease gene now standardized as RUBCN (former KIAA0226; protein previously named rundataxin)	Disease entity consistently linked to one recessive syndrome in reported families; Open Targets maps MONDO_0014311 to RUBCN	Human disease report and follow-up case report (2010, 2020); disease-target database mapping (Open Targets) (assoum2010rundataxinanovel pages 1-2, seidahmed2020ancientfoundermutation pages 1-3, OpenTargets Search: autosomal recessive spinocerebellar ataxia 15)	High for nomenclature resolution; major caveat is historical confusion with dominant SCA15 and older KIAA0226 nomenclature
Gene / variant	Causal mechanism is biallelic truncating RUBCN loss-of-function, specifically the Saudi founder frameshift: NM_014687:c.2624delC, p.A875fs; older report used another transcript/protein numbering: 2927delC, p.Ala943ValfsX146	Same underlying deletion reported across both families; parents are carriers in family 2	Primary human genetics reports (2010, 2020) (assoum2010rundataxinanovel pages 4-5, seidahmed2020ancientfoundermutation pages 1-3)	High; transcript/protein numbering differs between publications and should be normalized during curation
Case count / ascertainment	Literature support is extremely small and patient-based	5 total patients from 2 unrelated Saudi families: family 1 = 3 affected sisters; family 2 = 2 affected brothers	Aggregated from primary reports/table (2010, 2020) (assoum2010rundataxinanovel pages 1-2, seidahmed2020ancientfoundermutation pages 5-6, seidahmed2020ancientfoundermutation media 0e4549a2)	High for known published cases through 2020; ultra-rare disorder, likely under-ascertained
Phenotype frequency note	Percentages below are descriptive only because n=5	Example: 3/5 = 60%; 2/5 = 40%	Derived from case table across all 5 patients (seidahmed2020ancientfoundermutation pages 5-6, seidahmed2020ancientfoundermutation media 0e4549a2)	Very limited inferential value; no population-based denominator
Core neurologic phenotype	Childhood-onset cerebellar syndrome with gait ataxia, limb ataxia, and dysarthria	Gait ataxia 5/5 (100%); dysarthria 5/5 (100%); upper-limb ataxia 4/5 (80%); lower-limb ataxia 4/5 (80%)	Primary human clinical reports (2010, 2020) (assoum2010rundataxinanovel pages 1-2, seidahmed2020ancientfoundermutation pages 5-6, seidahmed2020ancientfoundermutation media 0e4549a2)	Moderate-high for core syndrome; severity grading is based on very few patients
Developmental features	Delayed motor and speech development are common and may precede/overlap with ataxia	Delayed walking 5/5 (100%); delayed speech acquisition 5/5 (100%)	Case table and narrative clinical descriptions (2020 with comparison to 2010 family) (seidahmed2020ancientfoundermutation pages 3-5, seidahmed2020ancientfoundermutation pages 5-6, seidahmed2020ancientfoundermutation media 0e4549a2)	Moderate-high; ascertainment is through pediatric neurology in consanguineous families
Cognition / neurodevelopment	Cognitive involvement ranges from none/borderline to moderate intellectual disability	Cognitive deficit or low IQ documented in 4/5 (80%); one patient had no cognitive deficit; family 2 IQs 67 and 72	Primary patient reports (2010, 2020) (assoum2010rundataxinanovel pages 4-5, seidahmed2020ancientfoundermutation pages 3-5, seidahmed2020ancientfoundermutation pages 5-6)	Moderate; formal psychometrics were incomplete in original family
Epilepsy	Infantile epilepsy can occur but is not universal	Epilepsy in 2/5 (40%); both onset at 7 months in family 1; seizure-free after treatment; 0/2 in family 2	Primary human reports (2010, 2020) (assoum2010rundataxinanovel pages 1-2, assoum2010rundataxinanovel pages 4-5, seidahmed2020ancientfoundermutation pages 5-6)	Moderate; phenotype variability evident even with same founder variant
Eye movement abnormalities	Oculomotor abnormalities emerge in some older patients	Nystagmus or saccadic pursuit in 4/5 (80%) overall; absent in younger family-2 proband at 6.5 y	Primary patient comparison table (2020) (seidahmed2020ancientfoundermutation pages 3-5, seidahmed2020ancientfoundermutation pages 5-6, seidahmed2020ancientfoundermutation media 0e4549a2)	Moderate; age dependence likely, but longitudinal data are sparse
Reflexes / pyramidal signs	Reflex pattern is variable, with lower-limb hyperreflexia in some patients	Lower-limb reflexes enhanced in 3/5 (60%), diminished in 1/5 (20%), normal in 1/5 (20%); plantar responses flexor in 5/5 (100%)	Human clinical comparison table (2020) (seidahmed2020ancientfoundermutation pages 5-6, seidahmed2020ancientfoundermutation media 0e4549a2)	Moderate; mixed reflex findings suggest variable corticospinal involvement but no strong proof of pyramidal degeneration
Onset / temporal course	Onset is early childhood, usually when learning to walk; course is slowly progressive	Initial symptom: unsteadiness at 2, 2, 2.5, 3, and 7 years across the 5 patients; disability stage reached 3/7 in 3 original patients, 1/7 and 0/7 in younger family-2 siblings at assessment	Primary longitudinal clinical reports (2010, 2020) (assoum2010rundataxinanovel pages 1-2, seidahmed2020ancientfoundermutation pages 5-6, seidahmed2020ancientfoundermutation pages 1-3)	Moderate-high for slow progression; no formal natural history study or survival analysis
MRI / neuroimaging	Early MRI can be normal; cerebellar atrophy appears mild and late in some patients	Normal MRI in early scans at 2.5, 6, 8, 9, 16 years depending on patient; later abnormalities: mild cerebellar atrophy/prominent folia at 18 y in one patient and minimal superior vermian atrophy at 16 y in another	Human MRI findings from both families (2010, 2020) (assoum2010rundataxinanovel pages 4-5, seidahmed2020ancientfoundermutation pages 3-5, seidahmed2020ancientfoundermutation pages 5-6, seidahmed2020ancientfoundermutation pages 1-3)	High for pattern of delayed/subtle imaging change; limited by tiny sample and irregular follow-up ages
Electrophysiology / sensory testing	Large-fiber peripheral neuropathy is not a consistent feature; some auditory/visual pathway abnormalities may occur	Motor/sensory nerve conduction studies normal in 5/5 when tested; BAER abnormal hearing thresholds in 2/4 tested; VEP abnormal in 1/4 tested	Human neurophysiology table and narratives (2020) (seidahmed2020ancientfoundermutation pages 3-5, seidahmed2020ancientfoundermutation pages 5-6, seidahmed2020ancientfoundermutation media 0e4549a2)	Moderate; testing not complete in every patient, and BAER/VEP abnormalities were subtle/variable
Inheritance / founder effect	Inheritance is autosomal recessive with strong evidence of an Arab/Saudi founder mutation	Family 2 parents are first cousins; identical homozygous haplotype/variant in both families; mutation age estimated at ~1550 years (~62 generations)	Human segregation, autozygosity, haplotype, and age analysis (2020) (seidahmed2020ancientfoundermutation pages 3-5, seidahmed2020ancientfoundermutation pages 1-3, seidahmed2020ancientfoundermutation pages 6-7)	High for founder effect within reported Saudi cases; carrier frequency/prevalence in broader populations unknown
Molecular mechanism — SCAR15-specific evidence	Disease-associated truncation disrupts Rubicon localization/function in endolysosomal trafficking	SCAR15-specific functional conclusion: truncated Rubicon loses ability to colocalize with Rab7 at late endosomes, implying defective endosomal trafficking	SCAR15-specific human variant follow-up summarized in 2020 report citing 2013 functional study (seidahmed2020ancientfoundermutation pages 6-7, seidahmed2020ancientfoundermutation pages 5-6)	Moderate; mechanism is disease-specific but based on limited experimental work around a single truncating allele
Molecular mechanism — general RUBCN biology (not SCAR15-specific)	Rubicon is a regulator of endosomal maturation, canonical autophagy, and LC3-associated phagocytosis (LAP); interacts with RAB7, UVRAG/BECN1/PIK3C3(VPS34) complexes	General cell-biology evidence shows inhibitory role in canonical autophagy and required role in LAP; RUBCN-deficient cells can show increased autophagic flux and altered endosome maturation	Mechanistic reviews and broader RUBCN studies (2018, 2023, 2020 kidney model) (wong2018rubiconlc3‐associatedphagocytosis pages 9-12, wong2018rubiconlc3‐associatedphagocytosis pages 5-9)	Moderate for relevance to SCAR15; these data are biologically informative but not direct proof of pathogenesis in patient neurons
Diagnosis	Recommended practical diagnosis is phenotype recognition plus genomic confirmation of biallelic RUBCN variants; WES/autozygosity was effective in published families	In family 2, diagnosis came from WES + autozygome; original work used linkage/homozygosity mapping plus candidate sequencing; original screen of 172 non-Friedreich ataxia families found no additional KIAA0226 mutations	Primary reports (2010, 2020) (assoum2010rundataxinanovel pages 4-5, seidahmed2020ancientfoundermutation pages 3-5, seidahmed2020ancientfoundermutation pages 1-3)	High for published diagnostic utility; no SCAR15-specific guideline, and repeat expansion testing still remains important in general ataxia workups
Current ataxia diagnostic practice	In broader hereditary ataxia practice, genome-scale testing is increasingly recommended, with attention to repeat expansions	Recent expert/consensus work in ataxia supports WGS/WES/NGS data-sharing approaches because many ataxia cases remain unsolved; not SCAR15-specific	Ataxia practice recommendations and AGI standards (2024-2025) (OpenTargets Search: autosomal recessive spinocerebellar ataxia 15)	Moderate relevance; supports real-world implementation context rather than disease-specific evidence
Treatment / management	No disease-modifying SCAR15 therapy reported; management is supportive and symptom-directed	Epilepsy in family 1 responded to vigabatrin ± clonazepam; no SCAR15-targeted drug, gene therapy, ASO, or registered interventional trial identified	Human case data and trial search context (2010, 2020; no SCAR15-specific trial hit) (assoum2010rundataxinanovel pages 4-5, seidahmed2020ancientfoundermutation pages 1-3)	High for absence of specific therapy in available evidence; supportive rehab use is extrapolated from broader ataxia practice
Treatment / broader ataxia trials	Non-SCAR15 ataxia trials exist for symptomatic or rehabilitative approaches, but applicability to SCAR15 is unknown	Examples include riluzole, N-acetyl-L-leucine, VR/rehabilitation, tDCS studies in mixed ataxia cohorts; none are genotype-specific for RUBCN	Clinical trial search results in ataxia field (2024-2025 retrieval context) (OpenTargets Search: autosomal recessive spinocerebellar ataxia 15-CWF19L1)	Low-moderate relevance to SCAR15; should not be interpreted as evidence of efficacy in SCAR15
Epidemiology	SCAR15 is ultra-rare; published prevalence/incidence not available	Only 2 reported families / 5 patients in primary literature available here; no population prevalence estimate	Published case literature through 2020 and database mapping (assoum2010rundataxinanovel pages 1-2, seidahmed2020ancientfoundermutation pages 1-3, OpenTargets Search: autosomal recessive spinocerebellar ataxia 15)	Low for epidemiologic precision; case-based rarity only
Population / demography	Reported families are Saudi/Arab and consanguineous, consistent with founder enrichment	5/5 reported patients from Saudi Arabia; one family with multiple consanguinity loops, one with first-cousin parents	Primary human reports (2010, 2020) (assoum2010rundataxinanovel pages 1-2, seidahmed2020ancientfoundermutation pages 3-5, seidahmed2020ancientfoundermutation pages 1-3)	Moderate; may reflect ascertainment and founder effect rather than exclusive ancestry distribution
Prognosis / outcomes	Functional impairment can remain moderate into adolescence/adulthood, with preserved ambulation but limited running/walking endurance in more affected individuals	Original family patients had disability stage 3/7 (moderate, unable to run, limited walking without aid); family-2 patients were stage 0/7 and 1/7 at 6.5 and 17 y	Human case series comparison (2020) (seidahmed2020ancientfoundermutation pages 5-6, seidahmed2020ancientfoundermutation media 0e4549a2)	Moderate; no mortality, survival, or adult late-stage outcome data
Models / omics	No dedicated SCAR15 animal model or patient omics dataset was identified in the available evidence; mechanistic interpretation relies mainly on cell-biologic RUBCN literature	None specific for Salih ataxia found here	Negative/limited finding from available search and evidence synthesis; general RUBCN biology available (wong2018rubiconlc3‐associatedphagocytosis pages 9-12, wong2018rubiconlc3‐associatedphagocytosis pages 5-9)	Low evidence availability; important knowledge gap for disease modeling and biomarker development

Table: This table compiles the highest-yield disease-characteristics evidence for autosomal recessive spinocerebellar ataxia 15 (Salih ataxia), emphasizing the tiny five-patient evidence base. It separates SCAR15-specific findings from broader RUBCN biology so the strength and limits of mechanistic inference are clear.

1. Disease information

Definition

SCAR15 is a Mendelian autosomal-recessive ataxia characterized by delayed walking and speech, childhood-onset gait incoordination, dysarthria, variable limb ataxia and cognitive impairment, occasional infantile epilepsy, and mild cerebellar atrophy that may not become visible until adolescence. The original abstract described “childhood onset gait and limb ataxia, dysarthria” and limited unaided walking into the teenage years (assoum2010rundataxinanovel pages 1-2).

Identifiers and synonyms

MONDO: MONDO:0014311.
OMIM: 615705.
Preferred names: autosomal recessive spinocerebellar ataxia 15; SCAR15; Salih ataxia.
Historical terminology: KIAA0226-related recessive ataxia; rundataxin-related ataxia.
Gene/protein: RUBCN, rubicon autophagy regulator; aliases KIAA0226, RUBICON; protein initially called rundataxin/RDTX.
Orphanet: no confidently verified disease-specific ORPHA number was recovered.
ICD-10/ICD-11 and MeSH: no unique SCAR15 code or heading was identified; coding generally falls under hereditary/cerebellar ataxia categories. A specific code should not be inferred.

The knowledge summarized here is principally aggregated from published family case reports, whose underlying observations are individual-patient clinical, imaging, electrophysiologic, and germline-genetic data—not EHR-derived population evidence (assoum2010rundataxinanovel pages 1-2, seidahmed2020ancientfoundermutation pages 1-3).

2. Etiology, risk, and protective factors

The necessary cause is biallelic germline RUBCN dysfunction. The demonstrated allele is a homozygous one-base deletion producing a C-terminal frameshift. The original paper reported 2927delC, p.Ala943ValfsX146; the updated transcript annotation is NM_014687:c.2624delC, p.Ala875fs. These represent transcript/numbering differences for the same founder deletion and should be normalized carefully rather than entered as independent variants (assoum2010rundataxinanovel pages 4-5, seidahmed2020ancientfoundermutation pages 3-5).

Genetic risk is greatest in relatives of a carrier and in endogamous populations in which the founder allele circulates. Both pedigrees were consanguineous; the second family’s parents were first cousins. The shared haplotype placed the mutation approximately 1,550 years, or 62 generations, in the past (seidahmed2020ancientfoundermutation pages 6-7, seidahmed2020ancientfoundermutation pages 1-3).

No susceptibility loci, modifier genes, protective alleles, environmental causes, toxins, infections, lifestyle risk factors, or validated gene–environment interactions have been reported. Consanguinity does not mechanistically cause the mutation but increases the probability that descendants inherit two copies of a rare founder allele. No diet, exposure, or behavior is known to prevent phenotypic expression in a biallelic individual.

3. Phenotypes

Across the five-patient comparison, delayed walking and delayed speech occurred in 5/5, dysarthria in 5/5, gait ataxia in 5/5, upper- and lower-limb ataxia in 4/5, cognitive impairment or low/borderline IQ in 4/5, abnormal ocular pursuit or nystagmus in 4/5, and epilepsy in 2/5. These fractions are highly unstable because the denominator is five and all patients carried one founder allele (seidahmed2020ancientfoundermutation pages 5-6, seidahmed2020ancientfoundermutation media 0e4549a2).

Motor-developmental delay: walking occurred at 22–42 months; speech at approximately 3 to >4–5 years. Suggested HPO: Delayed gross motor development (HP:0002194) and Delayed speech and language development (HP:0000750).
Gait and appendicular ataxia: unsteadiness generally appeared while learning to walk, at 2–3 years, although one patient’s recognized onset was 7 years. Severity ranged from examination-only signs to inability to run and limited unaided walking. Suggested HPO: Gait ataxia (HP:0002066), Limb ataxia (HP:0002070), Cerebellar ataxia (HP:0001251).
Dysarthria: present from speech acquisition, mild to severe. Suggested HPO: Dysarthria (HP:0001260).
Cognition: IQs in the second family were 67 and 72; two original-family patients had moderate intellectual disability without formal IQ testing, while one reportedly had no cognitive deficit. Suggested HPO: Intellectual disability (HP:0001249) or Borderline intellectual functioning (HP:0006889) where appropriate (assoum2010rundataxinanovel pages 4-5, seidahmed2020ancientfoundermutation pages 3-5).
Epilepsy: two sisters developed seizures/infantile spasms at 7 months. One documented EEG had generalized and focal spikes, polyspikes, and slow waves. Seizures resolved with treatment. Suggested HPO: Infantile spasms (HP:0012469), Abnormal EEG (HP:0002353).
Oculomotor signs: nystagmus or saccadic pursuit, generally in older patients. Suggested HPO: Nystagmus (HP:0000639) and Abnormality of ocular smooth pursuit (HP:0000617).
Reflexes: lower-limb reflexes were enhanced in 3/5, diminished in 1/5, and normal in 1/5; plantar responses were flexor in all. Suggested HPO: Hyperreflexia in lower limbs (HP:0002395).
Imaging: early MRI may be normal. One patient developed mild hemispheric/vermal atrophy with prominent folia at 18 years after normal imaging at 9 years; another had minimal superior vermian atrophy at 16 after a normal scan at 6. Suggested HPO: Cerebellar atrophy (HP:0001272) (assoum2010rundataxinanovel pages 4-5, seidahmed2020ancientfoundermutation pages 3-5).
Neurophysiology: motor and sensory nerve conduction was normal in all five when tested, arguing against a consistent large-fiber neuropathy. BAER showed increased hearing thresholds in 2/4 tested, and VEP was abnormal in 1/4; these remain variable associated findings rather than defining features (seidahmed2020ancientfoundermutation pages 5-6, seidahmed2020ancientfoundermutation media 0e4549a2).

Quality-of-life instruments such as EQ-5D, SF-36, PROMIS, or ataxia-specific patient-reported outcomes have not been published. Nevertheless, delayed communication, impaired balance, inability to run, restricted unaided walking, special-education needs, and seizure burden plausibly affect independence, schooling, participation, and caregiver demands. This functional interpretation is supported clinically but has not been quantified with standardized QoL scales.

4. Genetic and molecular information

RUBCN is the only established causal gene. Open Targets identifies ENSG00000145016, “rubicon autophagy regulator,” as the associated target for MONDO:0014311 (OpenTargets Search: autosomal recessive spinocerebellar ataxia 15). The reported pathogenic allele is germline, homozygous, frameshifting, segregates with disease, is heterozygous in parents, was absent from 622 control chromosomes in the original work, and removes/replaces the conserved C-terminal region. The original authors considered loss of function the likely consequence (assoum2010rundataxinanovel pages 4-5).

The original screen of 172 non-Friedreich ataxia families, including nine Saudi families, detected no additional KIAA0226 mutation, emphasizing rarity. Reliable ancestry-specific gnomAD/TOPMed allele frequencies and current ClinVar classifications were not recovered and should be imported directly from those databases using the normalized HGVS expression rather than guessed (assoum2010rundataxinanovel pages 4-5).

No pathogenic missense series, dominant-negative mechanism, somatic mutation, repeat expansion, large chromosomal rearrangement, modifier gene, disease-specific methylation signature, or epigenetic mechanism has been established. CMA, karyotype, and FISH are therefore not first-line confirmation methods unless an independent chromosomal disorder is suspected.

5. Environmental information

SCAR15 is not an infectious, toxic, occupational, nutritional, radiation-associated, or lifestyle-mediated disease. There is no evidence that smoking, alcohol, exercise, diet, pollution, or pathogen exposure changes penetrance. General factors such as sedating medication, alcohol, intercurrent illness, and unsafe environments may worsen balance or falls in any ataxic person, but that is clinical prudence rather than a demonstrated SCAR15 gene–environment interaction.

6. Mechanism and pathophysiology

Disease-specific causal chain

The best-supported chain is: biallelic RUBCN frameshift → abnormal C-terminal Rubicon → failure to colocalize normally with RAB7-positive late endosomes → defective endosomal trafficking/maturation → disturbance of neuronal endolysosomal homeostasis → cerebellar circuit dysfunction and slowly developing cerebellar atrophy → gait/limb ataxia and dysarthria. The disease-specific functional follow-up concluded that truncated Rubicon lost late-endosomal RAB7 colocalization (seidahmed2020ancientfoundermutation pages 6-7, seidahmed2020ancientfoundermutation pages 5-6).

Broader RUBCN biology

Rubicon interacts with the UVRAG–BECN1–PIK3C3/VPS34 machinery. In canonical macroautophagy it generally restrains autophagosome maturation, whereas in LC3-associated phagocytosis/noncanonical autophagy it is required for PI(3)P production, NOX2-complex stabilization, and LC3 recruitment. Rubicon also participates in early-to-late endosome maturation and receptor recycling. These conclusions arise largely from cell and animal systems not carrying the human SCAR15 allele and therefore provide biological plausibility, not proof that every pathway drives the human neurologic phenotype (wong2018rubiconlc3‐associatedphagocytosis pages 9-12, wong2018rubiconlc3‐associatedphagocytosis pages 5-9).

Suggested annotations include endosomal transport (GO:0016197), late endosome to lysosome transport (GO:1902774), autophagy (GO:0006914), macroautophagy (GO:0016236), and phagocytosis (GO:0006909). Relevant cellular components include late endosome (GO:0005770), early endosome (GO:0005769), autophagosome (GO:0005776), and lysosome (GO:0005764).

No SCAR15 patient-neuron transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, CRISPR-screen, or integrated multi-omics study was identified. Claims of oxidative stress, inflammation, mitochondrial failure, or immune-mediated tissue damage should not be entered as established SCAR15 mechanisms.

7. Anatomical structures affected

The primary organ is the central nervous system, particularly the cerebellum. Imaging implicates the superior vermis and, in one patient, cerebellar hemispheres. Relevant suggestions are cerebellum (UBERON:0002037), cerebellar vermis (UBERON:0004728), and cerebellar cortex. Disease laterality is bilateral/diffuse rather than unilateral (assoum2010rundataxinanovel pages 4-5, seidahmed2020ancientfoundermutation pages 3-5).

Purkinje neurons and cerebellar granule neurons are biologically plausible vulnerable populations, but no SCAR15 neuropathology or cell-type-resolved study directly demonstrates selective loss. Suggested—not confirmed—Cell Ontology terms are Purkinje cell (CL:0000121) and cerebellar granule cell (CL:0001031). At the subcellular level, late endosomes, lysosomes, autophagosomes, and associated membrane-trafficking complexes are implicated. Peripheral nerves are not a primary demonstrated site because nerve-conduction studies were normal (seidahmed2020ancientfoundermutation pages 5-6).

8. Temporal development

Onset is pediatric and usually insidious: delayed milestones followed by unsteadiness from the acquisition of walking. The course is chronic, lifelong, and slowly progressive rather than episodic or relapsing. Ocular signs and mild MRI atrophy may emerge in the second decade. The available disability stages ranged from 0–1 in the second family to 3 in the original family; stage 3 denoted inability to run and limited walking without aid, not wheelchair dependence (seidahmed2020ancientfoundermutation pages 5-6, seidahmed2020ancientfoundermutation media 0e4549a2).

There is no validated staging system, progression-rate estimate, remission pattern, or critical therapeutic window. Seizures can remit with medication, but the underlying ataxia has not been shown to remit.

9. Inheritance and population

Inheritance is autosomal recessive. For two confirmed heterozygous parents, each pregnancy has the conventional Mendelian probabilities of 25% affected, 50% carrier, and 25% inheriting neither familial allele, assuming no unusual reproductive mechanism. Penetrance among reported homozygotes appears high, but five ascertained patients cannot establish complete penetrance. Expressivity is variable: epilepsy, cognition, reflexes, oculomotor findings, and severity differ despite the shared allele (seidahmed2020ancientfoundermutation pages 5-6).

Only two Saudi families and five historical patients were represented in the core published case literature; hence prevalence, incidence, carrier frequency, sex ratio, and global geographic distribution are unknown. Three patients were female and two male, providing no evidence for sex bias. The founder estimate and shared haplotype support enrichment in an Arab/Saudi ancestral group but do not imply ethnic exclusivity (seidahmed2020ancientfoundermutation pages 6-7, seidahmed2020ancientfoundermutation pages 1-3).

Anticipation is not expected for a frameshift disorder and has not been observed. Germline mosaicism has not been reported. Consanguinity facilitated homozygosity and discovery.

10. Diagnostics

Diagnosis requires clinical recognition plus molecular confirmation. Initial evaluation should document development, three-generation pedigree and consanguinity, cerebellar examination, eye movements, cognition, hearing/vision, seizures, and functional status. Brain MRI may be normal early and therefore cannot exclude SCAR15. EEG is indicated for suspected seizures; audiology/BAER, ophthalmologic assessment/VEP, and nerve-conduction studies are phenotype-directed. Routine CBC, electrolytes, CK, liver/renal tests, and metabolic screening were normal in the second family and are useful mainly for differential diagnosis (seidahmed2020ancientfoundermutation pages 3-5).

Genetic workflow: (1) exclude common/treatable acquired and metabolic causes; (2) use a hereditary-ataxia/neurodevelopmental panel that includes RUBCN, or WES/WGS with CNV analysis; (3) in consanguineous pedigrees, use runs of homozygosity/autozygosity; (4) confirm and segregate candidate variants by Sanger sequencing; and (5) interpret using ACMG/AMP criteria and transcript-correct HGVS. WES plus autozygome analysis diagnosed the second family (seidahmed2020ancientfoundermutation pages 3-5, seidahmed2020ancientfoundermutation pages 1-3).

WGS can detect coding, splice, CNV, and some structural variants but remains subject to interpretation limits. RNA sequencing may help resolve a suspected splice variant but is not an established SCAR15 diagnostic. CMA, karyotype, FISH, mitochondrial-DNA testing, and repeat-expansion assays do not directly test the known founder frameshift; nevertheless, repeat-expansion testing remains important in the broader ataxia differential.

Differentials include dominant ITPR1-related SCA15, CWF19L1-related SCAR17, Friedreich ataxia, ataxia with vitamin E deficiency, ataxia-telangiectasia, ARSACS, SCAN1, mitochondrial ataxias, congenital cerebellar malformations, epileptic encephalopathies, and cerebral palsy. Preserved nerve conduction, subtle late MRI change, delayed development, AR inheritance, and biallelic RUBCN variants favor SCAR15.

No newborn-screening program or biochemical biomarker exists. Once a familial variant is known, cascade carrier testing, predictive testing of at-risk siblings with appropriate counseling, prenatal diagnosis, and preimplantation genetic testing are technically feasible.

11. Outcome and prognosis

Available evidence supports slow neurologic progression with survival into at least late adolescence/young adulthood and retained walking, albeit limited in the more affected patients. No 5- or 10-year survival rate, mortality rate, life-expectancy estimate, cause-of-death pattern, or adult end-stage natural history is available. Nerve-conduction preservation and subtle MRI evolution suggest a predominantly cerebellar rather than widespread peripheral neurodegenerative course, but long-term multisystem surveillance data are absent (seidahmed2020ancientfoundermutation pages 5-6).

Morbidity includes impaired balance, falls risk, dysarthria, limited mobility, learning/intellectual disability, special-education needs, possible hearing/visual pathway abnormalities, and treatable epilepsy. Recovery of the genetic ataxia has not been documented. No molecular prognostic biomarker exists; age, baseline functional severity, cognition, epilepsy, or MRI atrophy may be clinically relevant but are unvalidated predictors.

12. Treatment

There is no approved disease-modifying, gene, cell, RNA, targeted, or immunologic therapy for SCAR15 and no RUBCN-specific interventional trial was identified. Because Rubicon inhibits canonical autophagy but supports LAP and endosomal functions, indiscriminate pharmacologic activation or inhibition of autophagy is not presently justified; pathway directionality is context-dependent (wong2018rubiconlc3‐associatedphagocytosis pages 9-12, wong2018rubiconlc3‐associatedphagocytosis pages 5-9).

Management is multidisciplinary and supportive: physical therapy for balance, coordination, strength, conditioning, and fall prevention; occupational therapy and mobility/adaptive equipment; speech-language therapy for dysarthria and swallowing assessment when indicated; developmental, educational, and neuropsychological support; audiology/vision care; and routine management of spasticity, dystonia, pain, nutrition, sleep, and mental health if they arise. Suggested NCIT concepts include Physical Therapy (NCIT:C15308), Occupational Therapy, Speech Therapy, Genetic Counseling, and Supportive Care.

In the original family, infantile spasms were treated with vigabatrin and clonazepam; the documented patient became seizure-free by age 3 and was weaned from vigabatrin by age 7. This is individual clinical evidence, not a SCAR15-specific comparative treatment trial (assoum2010rundataxinanovel pages 4-5). Riluzole, acetyl-leucine, neuromodulation, or other interventions studied in different ataxias cannot be assumed effective in SCAR15.

13. Prevention

There is no vaccine, chemoprophylaxis, lifestyle prevention, or population screening program. Primary genetic prevention consists of voluntary carrier identification and reproductive counseling in an affected family. Options include partner testing, prenatal diagnosis, preimplantation genetic testing for monogenic disease, donor gametes, or natural conception with informed risk. These must remain nondirective.

Secondary prevention comprises early molecular diagnosis, seizure recognition, developmental intervention, hearing/vision assessment, and cascade testing. Tertiary prevention includes rehabilitation, fall-proofing, mobility aids, aspiration and nutritional assessment when clinically indicated, seizure control, and prevention of contractures and deconditioning.

14. Other species and natural disease

No naturally occurring RUBCN-associated Salih-ataxia equivalent was identified in companion animals, livestock, or wildlife. The disorder is not infectious and has no zoonotic or cross-species transmission potential. RUBCN orthologs and conserved autophagy/endolysosomal functions occur broadly among vertebrates, but orthology alone does not establish natural veterinary disease.

General conditional Rubcn-deficient mouse and cellular studies demonstrate effects on autophagic flux, metabolism, bone, kidney, immunity, and neuronal protein handling; these are pathway models, not faithful natural or engineered SCAR15 models. Their phenotypes should not be imported directly into the human disease record.

15. Model organisms and research gaps

No knock-in mouse, zebrafish, Drosophila, organoid, or patient-derived iPSC model reproducing the human SCAR15 founder allele was identified. The disease-specific experimental evidence is limited principally to cellular localization/trafficking analysis of truncated Rubicon. General RUBCN-null cells and tissue-specific knockout mice are valuable for dissecting canonical autophagy, LC3-associated phagocytosis, RAB7/endosomal maturation, lipid handling, and tissue-specific consequences, but complete knockout may not model the unusual C-terminal frameshift accurately (wong2018rubiconlc3‐associatedphagocytosis pages 9-12, wong2018rubiconlc3‐associatedphagocytosis pages 5-9, seidahmed2020ancientfoundermutation pages 6-7).

Priority research needs are: ascertainment of additional ancestries and alleles; current ClinVar/gnomAD normalization of the founder deletion; international natural-history collection using SARA and patient-reported outcomes; serial quantitative MRI and digital gait measures; patient iPSC-derived Purkinje-like neurons and cerebellar organoids; knock-in models of the exact founder allele; autophagic-flux and endosomal-cargo assays in disease-relevant neurons; and transcriptomic, proteomic, and lipidomic profiling. These are prerequisites for determining whether treatment should restore Rubicon localization, correct the transcript, replace RUBCN, or modulate a specific downstream trafficking pathway.

Overall assessment

The disease–gene relationship is well supported by homozygosity, segregation, recurrence of the same allele in an unrelated family, founder-haplotype evidence, protein-domain disruption, and disease-specific localization studies. The clinical picture—early developmental delay, childhood gait/dysarthric ataxia, variable intellectual disability and epilepsy, normal nerve conduction, and subtle late cerebellar atrophy—is coherent. However, virtually every estimate of frequency, penetrance, prognosis, and treatment effect remains low-confidence because the foundational quantitative dataset contains only five patients from two related-population pedigrees (assoum2010rundataxinanovel pages 1-2, seidahmed2020ancientfoundermutation pages 1-3, seidahmed2020ancientfoundermutation media 0e4549a2).

References

(OpenTargets Search: autosomal recessive spinocerebellar ataxia 15): Open Targets Query (autosomal recessive spinocerebellar ataxia 15, 14 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.
(seidahmed2020ancientfoundermutation pages 1-3): Mohammed Z. Seidahmed, Muddathir H. Hamad, Albandary AlBakheet, Salah A. Elmalik, Abdulmajeed AlDrees, Jumanah Al-Sufayan, Ibrahim Alorainy, Ibrahim M. Ghozzi, Dilek Colak, Mustafa A. Salih, and Namik Kaya. Ancient founder mutation in rubcn: a second unrelated family confirms salih ataxia (scar15). BMC Neurology, May 2020. URL: https://doi.org/10.1186/s12883-020-01761-w, doi:10.1186/s12883-020-01761-w. This article has 20 citations and is from a peer-reviewed journal.
(assoum2010rundataxinanovel pages 1-2): Mirna Assoum, Mustafa A. Salih, Nathalie Drouot, Dorra H'Mida-Ben Brahim, Clotilde Lagier-Tourenne, Abdulmajeed AlDrees, Salah A. Elmalik, Taha S. Ahmed, Mohammad Z. Seidahmed, Mohammad M. Kabiraj, and Michel Koenig. Rundataxin, a novel protein with run and diacylglycerol binding domains, is mutant in a new recessive ataxia. Brain : a journal of neurology, 133 Pt 8:2439-47, Aug 2010. URL: https://doi.org/10.1093/brain/awq181, doi:10.1093/brain/awq181. This article has 59 citations.
(assoum2010rundataxinanovel pages 4-5): Mirna Assoum, Mustafa A. Salih, Nathalie Drouot, Dorra H'Mida-Ben Brahim, Clotilde Lagier-Tourenne, Abdulmajeed AlDrees, Salah A. Elmalik, Taha S. Ahmed, Mohammad Z. Seidahmed, Mohammad M. Kabiraj, and Michel Koenig. Rundataxin, a novel protein with run and diacylglycerol binding domains, is mutant in a new recessive ataxia. Brain : a journal of neurology, 133 Pt 8:2439-47, Aug 2010. URL: https://doi.org/10.1093/brain/awq181, doi:10.1093/brain/awq181. This article has 59 citations.
(seidahmed2020ancientfoundermutation pages 5-6): Mohammed Z. Seidahmed, Muddathir H. Hamad, Albandary AlBakheet, Salah A. Elmalik, Abdulmajeed AlDrees, Jumanah Al-Sufayan, Ibrahim Alorainy, Ibrahim M. Ghozzi, Dilek Colak, Mustafa A. Salih, and Namik Kaya. Ancient founder mutation in rubcn: a second unrelated family confirms salih ataxia (scar15). BMC Neurology, May 2020. URL: https://doi.org/10.1186/s12883-020-01761-w, doi:10.1186/s12883-020-01761-w. This article has 20 citations and is from a peer-reviewed journal.
(seidahmed2020ancientfoundermutation media 0e4549a2): Mohammed Z. Seidahmed, Muddathir H. Hamad, Albandary AlBakheet, Salah A. Elmalik, Abdulmajeed AlDrees, Jumanah Al-Sufayan, Ibrahim Alorainy, Ibrahim M. Ghozzi, Dilek Colak, Mustafa A. Salih, and Namik Kaya. Ancient founder mutation in rubcn: a second unrelated family confirms salih ataxia (scar15). BMC Neurology, May 2020. URL: https://doi.org/10.1186/s12883-020-01761-w, doi:10.1186/s12883-020-01761-w. This article has 20 citations and is from a peer-reviewed journal.
(seidahmed2020ancientfoundermutation pages 3-5): Mohammed Z. Seidahmed, Muddathir H. Hamad, Albandary AlBakheet, Salah A. Elmalik, Abdulmajeed AlDrees, Jumanah Al-Sufayan, Ibrahim Alorainy, Ibrahim M. Ghozzi, Dilek Colak, Mustafa A. Salih, and Namik Kaya. Ancient founder mutation in rubcn: a second unrelated family confirms salih ataxia (scar15). BMC Neurology, May 2020. URL: https://doi.org/10.1186/s12883-020-01761-w, doi:10.1186/s12883-020-01761-w. This article has 20 citations and is from a peer-reviewed journal.
(seidahmed2020ancientfoundermutation pages 6-7): Mohammed Z. Seidahmed, Muddathir H. Hamad, Albandary AlBakheet, Salah A. Elmalik, Abdulmajeed AlDrees, Jumanah Al-Sufayan, Ibrahim Alorainy, Ibrahim M. Ghozzi, Dilek Colak, Mustafa A. Salih, and Namik Kaya. Ancient founder mutation in rubcn: a second unrelated family confirms salih ataxia (scar15). BMC Neurology, May 2020. URL: https://doi.org/10.1186/s12883-020-01761-w, doi:10.1186/s12883-020-01761-w. This article has 20 citations and is from a peer-reviewed journal.
(wong2018rubiconlc3‐associatedphagocytosis pages 9-12): Sing‐Wai Wong, Payel Sil, and Jennifer Martinez. Rubicon: lc3‐associated phagocytosis and beyond. The FEBS Journal, 285:1379-1388, Apr 2018. URL: https://doi.org/10.1111/febs.14354, doi:10.1111/febs.14354. This article has 127 citations.
(wong2018rubiconlc3‐associatedphagocytosis pages 5-9): Sing‐Wai Wong, Payel Sil, and Jennifer Martinez. Rubicon: lc3‐associated phagocytosis and beyond. The FEBS Journal, 285:1379-1388, Apr 2018. URL: https://doi.org/10.1111/febs.14354, doi:10.1111/febs.14354. This article has 127 citations.
(OpenTargets Search: autosomal recessive spinocerebellar ataxia 15-CWF19L1): Open Targets Query (autosomal recessive spinocerebellar ataxia 15-CWF19L1, 0 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

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Autosomal Recessive Spinocerebellar Ataxia 15

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Autosomal Recessive Spinocerebellar Ataxia 15 (SCAR15): Disease-Characteristics Report

Executive summary and evidence boundary

1. Disease information

Definition

Identifiers and synonyms

2. Etiology, risk, and protective factors

3. Phenotypes

4. Genetic and molecular information

5. Environmental information

6. Mechanism and pathophysiology

Disease-specific causal chain

Broader RUBCN biology

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

11. Outcome and prognosis

12. Treatment

13. Prevention

14. Other species and natural disease

15. Model organisms and research gaps

Overall assessment

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