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Inheritance

1

Autosomal dominant HP:0000006

Transmission from an affected father to sons and daughters in the Dutch family.

Autosomal dominant inheritance

Show evidence (1 reference)

PMID:8595484 SUPPORT Human Clinical

"As the disease is inherited from the affected father to his sons and daughters, this is the first description of a probably autosomal dominant form of late onset hereditary sensory neuropathy with predominant sensory ataxia and minor other neurological abnormalities."

Father-to-child transmission in both sexes.

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Discussions and Knowledge Gaps

2

Is PLD3 p.Leu308Pro the cause of SCA46, or a rare variant that happens to segregate in a single family?

CONTROVERSY sca46_pld3_causality

Attached to

genetic#PLD3

The association rests on one family. The variant abolishes exonuclease activity in transfected cells, but Pld3 knockout mice have no cerebellar phenotype and PLD3 is least expressed in the adult cerebellum. The challengers did not dispute the genetic data itself, and a reply from the original authors was published (PMID:30312384). The second reported patient carries a different variant, has a different phenotype (early onset, hearing loss, optic atrophy), has an unremarkable family history and has no segregation data, so it does not settle the question. Additional families with PLD3 variants segregating with a late-onset sensory-cerebellar ataxia would.

Show evidence (3 references)

PMID:30312375 SUPPORT Model Organism

"Our PLD3 KO mouse analysis challenges the interpretation of PLD3 mutations as the causative SCA46 gene and further characterization of additional patients will be required to clarify a role of PLD3 in spinocerebellar ataxia."

The published statement of the dispute.

PMID:30312375 SUPPORT Other

"While there is little doubt about the genetic data, we have concerns regarding the cell biology follow up experiments, particularly the localization studies and functional assay for PLD3 performed by Nibbeling et al."

The challenge concerns the functional evidence, not the segregation data.

PMID:38059248 SUPPORT Human Clinical

"Her childhood medical history and family history were unremarkable."

The second patient has no reported affected relatives, so she adds no segregation evidence.

Why do Pld3 knockout mice lack the cerebellar phenotype, and do they have the sensory neuropathy that dominates the human disease?

HUMAN MODEL MISMATCH sca46_knockout_mismatch

Attached to

pathophysiology#Cerebellar Dysfunction pathophysiology#Large-Fiber Sensory Axonal Degeneration

The knockout study examined the cerebellum and motor performance but did not report dorsal root ganglia or peripheral nerves, although sensory neuropathy is the predominant human feature. PLD4 compensation, the short mouse lifespan relative to onset after 40 in humans, and a possible dominant-negative action of the missense protein that a null allele would not reproduce could each explain the mismatch. A heterozygous L308P knock-in mouse examined for sensory nerve pathology in old age would address it.

Show evidence (2 references)

PMID:30312375 SUPPORT Other

"suggest a dominant loss-of-function mechanism due to the PLD3-L308P mutation, suggesting that the PLD3 knockout reflects the situation observed in SCA patients."

The premise under which the knockout should have reproduced the disease.

PMID:39423811 SUPPORT In Vitro

"How the PLD3 L308P mutation would act dominantly is currently unclear."

The dominant mechanism of a heterozygous loss-of-function variant remains unexplained.

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Pathophysiology

6

Heterozygous PLD3 Leu308Pro Variant

Mechanism confidence: Provisional

A heterozygous germline missense variant, PLD3 c.923T>C p.(Leu308Pro), in the second phosphodiesterase domain, found by exome sequencing in the Dutch family. It is the only variant with family segregation data. A different variant, p.(Ile26Thr), was reported in one Indian patient without segregation or zygosity data.

PLD3 hgnc:17158

Genetic context variant_origin: GERMLINE zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Heterozygous germline missense. Loss of function rests on overexpression assays; a dominant-negative effect has not been tested.

Downstream

Mutant PLD3 Retention in the ER and Loss of Exonuclease Activity

Show evidence (2 references)

PMID:29053796 SUPPORT Human Clinical

"Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons."

The report that proposed PLD3 as the SCA46 gene.

PMID:30312375 SUPPORT In Vitro

"our data support the finding by Nibbeling et al. that the PLD3-L308P mutation leads to a loss of function"

An independent group confirms loss of function of the variant in cells.

Mutant PLD3 Retention in the ER and Loss of Exonuclease Activity

Mechanism confidence: Provisional

Wild-type PLD3 travels to lysosomes as a type II transmembrane protein by an ESCRT-dependent route and is cleaved there into a stable soluble enzyme. In transfected cells the L308P protein instead accumulates in the endoplasmic reticulum, is barely processed and has no 5' exonuclease activity. These results come from overexpression in cell lines, not from patient cells.

PLD3 hgnc:17158

5'-3' exonuclease activity GO:0008409 ↓ DECREASED

endoplasmic reticulum GO:0005783 lysosome GO:0005764

Downstream

Impaired Lysosomal Degradation of Single-Stranded Nucleic Acids

Reduced Lysosomal S,S-BMP Synthesis

Show evidence (3 references)

PMID:30312375 SUPPORT In Vitro

"However, detection of the luminal domain of PLD3-L308P revealed a significantly reduced lysosomal localization, but increased co-localization with the ER marker KDEL, implicating sorting or folding defects due to the patient's point mutation."

The mutant protein is retained in the ER instead of reaching lysosomes.

PMID:30312375 SUPPORT In Vitro

"In contrast, the PLD3-L308P mutation led to strikingly reduced proteolytic cleavage of full-length PLD3, and both the 50 kDa and 12 kDa fragment were almost completely absent"

The mutant protein is not processed into its mature lysosomal form.

PMID:29386126 SUPPORT In Vitro

"PLD3 reaches lysosomes as a type II transmembrane protein via a (for mammalian cells) uncommon intracellular biosynthetic route that depends on the ESCRT (endosomal sorting complex required for transport) machinery."

The normal trafficking route that the mutant fails to complete.

Impaired Lysosomal Degradation of Single-Stranded Nucleic Acids

Mechanism confidence: Hypothetical

PLD3 is the main acid 5' exonuclease in cultured cells, and its major physiological substrate is mitochondrial DNA. In PLD3-deficient neurons and cell lines, mtDNA builds up in lysosomes and leaks into the cytosol, where it activates cGAS-STING signalling. These consequences come from PLD3-deficient cells studied in an Alzheimer's disease context; none has been shown in SCA46 patients or tested for the L308P variant, so the node records the expected cellular result of losing PLD3 exonuclease activity.

neuron CL:0000540

DNA catabolic process GO:0006308 ↓ DECREASED

lysosome GO:0005764

Animal models

Pld3 Pld4 double knockout mouse Mouse perturbs

Downstream

Large-Fiber Sensory Axonal Degeneration

Cerebellar Dysfunction

Show evidence (3 references)

PMID:33288674 SUPPORT In Vitro

"Our experiments revealed PLD3 as the principal acid 5' exonuclease in HeLa cells, where it showed a markedly higher specific activity compared with PLD4."

PLD3 is the main lysosomal enzyme of this kind in cultured cells.

PMID:37225734 SUPPORT In Vitro

"We identified mitochondrial DNA (mtDNA) as a major physiological substrate and show its manifest build-up in lysosomes of PLD3-defective cells."

Loss of PLD3 causes undegraded mtDNA to accumulate in lysosomes.

PMID:37225734 SUPPORT In Vitro

"Lysosomal leakage of mtDNA to the cytosol activates cGAS-STING signaling that upregulates autophagy and induces amyloid precursor C-terminal fragment (APP-CTF) and cholesterol accumulation."

A downstream consequence shown in PLD3-deficient cells, studied in an Alzheimer's disease context.

Reduced Lysosomal S,S-BMP Synthesis

Mechanism confidence: Provisional

PLD3 also synthesizes S,S-bis(monoacylglycero)phosphate (BMP), a lysosomal phospholipid needed to degrade lipids such as gangliosides. Pld3 deletion lowers brain BMP in mice. In transfected cells the L308P protein reached lysosomes poorly, was poorly processed and did not raise BMP levels, so the variant loses this function too. Whether reduced BMP contributes to neuropathy or ataxia in patients is unknown.

PLD3 hgnc:17158

lysobisphosphatidic acid biosynthetic process GO:2001312 ↓ DECREASED

bis(monoacylglycero)phosphate synthase activity GO:0160121 ↓ DECREASED

Downstream

Large-Fiber Sensory Axonal Degeneration

Cerebellar Dysfunction

Show evidence (3 references)

PMID:39423811 SUPPORT Model Organism

"Deletion of PLD3 or PLD4 markedly reduced BMP levels in cells or in murine tissues where either enzyme is highly expressed (brain for PLD3; spleen for PLD4), leading to gangliosidosis and lysosomal abnormalities."

Loss of PLD3 lowers BMP in mouse brain.

PMID:39423811 SUPPORT In Vitro

"We tested one such missense mutation, PLD3 L308P, and found reduced lysosomal localization and no detectable increase in BMP levels compared with mock transfection control"

The SCA46 variant fails to support BMP synthesis in transfected cells.

PMID:39423811 SUPPORT In Vitro

"Immunoblotting also revealed decreased processing of the enzyme to its soluble form"

Independent confirmation that the L308P protein is poorly processed.

Large-Fiber Sensory Axonal Degeneration

Mechanism confidence: Established

Axonal degeneration of myelinated sensory fibres, shown on sural nerve biopsy in the Dutch family, producing a sensory polyneuropathy. Whether the primary lesion is in dorsal root ganglion neurons has not been examined. The pathology is established in patients; its link to PLD3 is not.

sural nerve UBERON:0015488

Downstream

Sensory axonal neuropathy

Sensory ataxia

Show evidence (1 reference)

PMID:8595484 SUPPORT Human Clinical

"Clinical, electrophysiological and sural nerve biopsy findings revealed a sensory polyneuropathy due to axonal degeneration of myelinated nerve fibres in four of five investigated siblings."

Biopsy-proven axonal degeneration in four of five examined siblings.

Cerebellar Dysfunction

Mechanism confidence: Provisional

Mild cerebellar involvement, inferred from the oculomotor signs and dysarthria in the Dutch family. Pld3 knockout mice show no Purkinje cell loss, no cerebellar atrophy and normal rotarod performance, and PLD3 expression is lowest in the adult cerebellum of all brain regions, so a direct effect of PLD3 loss on the cerebellum is unsupported in mice.

cerebellum UBERON:0002037

Animal models

Pld3 knockout mouse Mouse fails to recapitulate

Downstream

Progressive cerebellar ataxia

Dysarthria

Oculomotor abnormalities

Show evidence (2 references)

PMID:8595484 SUPPORT Human Clinical

"Other neurological abnormalities in the affected family members consisted only of mild eye movement disturbances, probably due to cerebellar involvement."

Clinical evidence of mild cerebellar involvement in the family.

PMID:38059248 SUPPORT Human Clinical

"Magnetic resonance imaging of the brain revealed diffuse cerebellar atrophy"

Cerebellar atrophy in the second, atypical PLD3 carrier.

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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

9

Ear 1

Sensorineural hearing impairment HP:0000407

Show evidence (1 reference)

PMID:38059248 SUPPORT Human Clinical

"We report a rare case of a young female presenting with autosomal dominant cerebellar ataxia associated with sensorineural hearing loss,peripheral neuropathy and mutation in phospholipase D3 gene."

Single-case report.

Eye 3

Oculomotor abnormalities Abnormality of eye movement HP:0000496

Show evidence (1 reference)

PMID:38059248 SUPPORT BACKGROUND Human Clinical

"Most of the affected members showed dysarthria and variable oculomotor abnormalities such as jerky pursuits, square wave jerks, downbeat nystagmus, gaze-evoked nystagmus, slow saccades, and saccadic dysmetria."

The range of eye movement abnormalities in the Dutch family.

Nystagmus HP:0000639

Show evidence (2 references)

PMID:38059248 SUPPORT BACKGROUND Human Clinical

"Most of the affected members showed dysarthria and variable oculomotor abnormalities such as jerky pursuits, square wave jerks, downbeat nystagmus, gaze-evoked nystagmus, slow saccades, and saccadic dysmetria."

Downbeat and gaze-evoked nystagmus in the Dutch family.

PMID:38059248 SUPPORT Human Clinical

"Oculomotor examination demonstrated bilateral horizontal gaze-evoked nystagmus."

Gaze-evoked nystagmus in the second reported patient.

Optic atrophy HP:0000648

Show evidence (1 reference)

PMID:38059248 SUPPORT Human Clinical

"She also had early optic atrophy and gaze-evoked nystagmus on examination."

Single-case report.

Nervous System 5

Sensory ataxia HP:0010871

Show evidence (1 reference)

PMID:8595484 SUPPORT Human Clinical

"We describe a Dutch family with sensory ataxia in two generations, late onset of symptoms (over the age of 40 years) and slow progression."

Late-onset sensory ataxia in the defining family.

Sensory axonal neuropathy HP:0003390

Show evidence (1 reference)

PMID:8595484 SUPPORT Human Clinical

"Clinical, electrophysiological and sural nerve biopsy findings revealed a sensory polyneuropathy due to axonal degeneration of myelinated nerve fibres in four of five investigated siblings."

Neuropathy in four of five examined siblings.

Progressive cerebellar ataxia HP:0002073

Show evidence (2 references)

PMID:38059248 SUPPORT BACKGROUND Human Clinical

"re-evaluation of the Dutch kindred by Nibbeling et al. revealed a combination phenotype of cerebellar ataxia and sensory neuropathy"

The reclassified Dutch family has cerebellar ataxia as well as sensory neuropathy.

PMID:38059248 SUPPORT BACKGROUND Human Clinical

"All the affected had late disease onset after the fourth decade with the average age of onset being 53.5 years and had a slowly progressive disease course."

Slow progression in the Dutch family.

Dysarthria HP:0001260

Show evidence (1 reference)

PMID:38059248 SUPPORT BACKGROUND Human Clinical

"Most of the affected members showed dysarthria and variable oculomotor abnormalities such as jerky pursuits, square wave jerks, downbeat nystagmus, gaze-evoked nystagmus, slow saccades, and saccadic dysmetria."

Dysarthria in most affected members of the Dutch family.

Cerebellar atrophy HP:0001272

Show evidence (1 reference)

PMID:38059248 SUPPORT Human Clinical

"Magnetic resonance imaging of the brain revealed diffuse cerebellar atrophy"

Single-case report.

🧬

Genetic Associations

1

PLD3 (Provisional and disputed. The association rests on one Dutch family with the heterozygous p.Leu308Pro variant. Pld3 knockout mice have no cerebellar phenotype, and the group that generated them questioned PLD3 as the SCA46 gene; a reply from the original authors was published (PMID:30312384). One further patient carries a different variant, with no segregation data and an unremarkable family history.)

Gene: PLD3 hgnc:17158 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:29053796 SUPPORT Human Clinical

"Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons."

The original gene report.

PMID:30312375 REFUTE INDIRECT Model Organism

"Importantly, we generated PLD3 knockout (KO) mice that do not present signs of cerebellar degeneration or spinocerebellar ataxia, challenging the interpretation of the suggested loss-of-function mechanism or PLD3 as the SCA46-causative gene."

Published challenge to the gene-disease association.

PMID:38059248 SUPPORT Human Clinical

"Clinical exome sequencing detected phospholipase D family member 3 (PLD3) mutation associated with spinocerebellar ataxia (SCA) 46, carrying the c.77T>C"

A second, different PLD3 variant (p.Ile26Thr) in an atypical patient; segregation and zygosity are not reported, so it does not independently confirm the association.

💊

Medical Actions

2

Physical Therapy

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

Platform: Behavioral / lifestyle

Gait and balance training for sensory and cerebellar ataxia. No disease-specific therapy exists.

Target Phenotypes: Sensory ataxia HP:0010871

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Counseling on dominant inheritance and on the provisional status of the PLD3 association.

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Progression

1

Late adult onset with slow progression

Age: over 40 years

Symptoms begin after age 40, with a mean onset of 53.5 years in the Dutch family, and progress slowly.

Show evidence (2 references)

PMID:38059248 SUPPORT BACKGROUND Human Clinical

"All the affected had late disease onset after the fourth decade with the average age of onset being 53.5 years and had a slowly progressive disease course."

Mean age at onset in the Dutch family.

PMID:8595484 SUPPORT Human Clinical

"We describe a Dutch family with sensory ataxia in two generations, late onset of symptoms (over the age of 40 years) and slow progression."

Age at onset and tempo in the Dutch family.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

One family with segregation data and one further single patient have been published. That is a case count, not a prevalence.

Show evidence (1 reference)

PMID:38059248 SUPPORT BACKGROUND Human Clinical

"this is the first reported case of SCA 46 from India and outside the Dutch kindred described earlier."

Before this report the disease was known only in the Dutch family.

🐁

Animal Models

2

Pld3 knockout mouse

Mice lacking Pld3 have normal rotarod performance at 5 and 9 months, and at 20 months a normal-sized cerebellum with no Purkinje cell loss.

Species

Mouse

Genotype

Pld3 -/-

Publication

PMID:30312375

Pathograph links

Cerebellar Dysfunction fails to recapitulate fidelity: low observes: organism

Limitations: The model is a homozygous null, whereas the patients are heterozygous for a missense variant, and the sensory nerves were not reported. The paralog Pld4 may compensate, and a mouse lifespan may be too short for a late-onset human disease.

Show evidence (1 reference)

PMID:30312375 SUPPORT Model Organism

"These data do not reveal a major degenerative phenotype of the cerebellum in PLD3 KO mice."

The negative result that defines this link.

Show evidence (1 reference)

PMID:30312375 SUPPORT Model Organism

"PLD3 expression in the cerebellum is low and PLD3 KO mice do not show any signs of cerebellar degeneration."

Summary of the knockout phenotype.

Pld3 Pld4 double knockout mouse

Mice lacking both paralogs develop fatal liver inflammation in early life, showing that the two nucleases are needed in vivo; the phenotype is inflammatory, not neurological.

Species

Mouse

Genotype

Pld3 -/- Pld4 -/-

Publication

PMID:30111894

Pathograph links

Impaired Lysosomal Degradation of Single-Stranded Nucleic Acids perturbs fidelity: low observes: organism

Limitations: Digenic loss in immune cells; it shows the in vivo exonuclease function but not a neurological phenotype.

Show evidence (1 reference)

PMID:30111894 SUPPORT Model Organism

"Mice deficient in both PLD3 and PLD4 developed lethal liver inflammation in early life, which indicates that both enzymes are needed to regulate inflammatory cytokine responses via the degradation of nucleic acids."

In vivo evidence for the nuclease function of PLD3 and PLD4.

Show evidence (1 reference)

PMID:30111894 SUPPORT In Vitro

"Although PLD4 and PLD3 were presumed to be phospholipases, we found that they are 5' exonucleases, probably identical to spleen phosphodiesterase, that break down TLR9 ligands."

Establishes PLD3 as a 5' exonuclease.

{ }

Source YAML

click to show

name: Spinocerebellar Ataxia 46
creation_date: "2026-10-08T00:00:00Z"
category: Mendelian
synonyms:
- SCA46
- spinocerebellar ataxia, 46, autosomal dominant, with sensory axonal neuropathy
- spinocerebellar ataxia with sensory axonal neuropathy
description: >-
  Spinocerebellar ataxia 46 (SCA46) is a late-onset, slowly progressive,
  autosomal dominant ataxia that combines sensory axonal neuropathy with mild
  cerebellar signs: gait ataxia, dysarthria and oculomotor abnormalities. The
  disease is defined by a single Dutch family, first described in 1995 as a
  dominant sensory ataxic neuropathy and later found to carry the heterozygous
  PLD3 missense variant p.Leu308Pro. PLD3 encodes a lysosomal 5' exonuclease
  that degrades single-stranded DNA. In cells the mutant protein is held in
  the endoplasmic reticulum and has lost exonuclease activity. The gene-disease
  link is provisional: no second family with segregation has been published,
  and Pld3 knockout mice show neither cerebellar degeneration nor ataxia. How
  loss of PLD3 would damage sensory neurons or the cerebellum is unknown.
disease_term:
  preferred_term: spinocerebellar ataxia 46
  term:
    id: MONDO:0033481
    label: spinocerebellar ataxia 46
references:
- reference: PMID:29053796
  title: Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia.
- reference: PMID:8595484
  title: A new variant of sensory ataxic neuropathy with autosomal dominant inheritance.
- reference: PMID:30312375
  title: PLD3 and spinocerebellar ataxia.
- reference: PMID:38059248
  title: Spinocerebellar ataxia 46 in a young female.
- reference: PMID:39423811
  title: "PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes."
- reference: PMID:37225734
  title: Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism.
- reference: PMID:33288674
  title: "Quantification and characterization of the 5' exonuclease activity of the lysosomal nuclease PLD3 by a novel cell-based assay."
- reference: PMID:30111894
  title: PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing.
- reference: PMID:29386126
  title: Unconventional Trafficking of Mammalian Phospholipase D3 to Lysosomes.
- reference: PMID:34815492
  title: Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation.
pathophysiology:
- name: Heterozygous PLD3 Leu308Pro Variant
  biological_scale: MOLECULAR
  role: initiating genetic lesion
  mechanism_confidence: PROVISIONAL
  description: >-
    A heterozygous germline missense variant, PLD3 c.923T>C p.(Leu308Pro), in
    the second phosphodiesterase domain, found by exome sequencing in the
    Dutch family. It is the only variant with family segregation data. A
    different variant, p.(Ile26Thr), was reported in one Indian patient
    without segregation or zygosity data.
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Heterozygous germline missense. Loss of function rests on
      overexpression assays; a dominant-negative effect has not been tested.
  genes:
  - preferred_term: PLD3
    term:
      id: hgnc:17158
      label: PLD3
  downstream:
  - target: Mutant PLD3 Retention in the ER and Loss of Exonuclease Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30312375
      reference_title: PLD3 and spinocerebellar ataxia.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Testing 5′ exonuclease activity against single stranded DNA after transfection of HeLa cells with wild-type and L308P-mutant PLD3 revealed efficient cleavage of the DNA-oligo-substrate in wildtype-transfected cells, but not in the L308P-mutant-transfected cells, demonstrating a loss of exonuclease activity of the L308P mutation"
      explanation: The patient variant abolishes exonuclease activity in transfected cells.
  evidence:
  - reference: PMID:29053796
    reference_title: Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons."
    explanation: The report that proposed PLD3 as the SCA46 gene.
  - reference: PMID:30312375
    reference_title: PLD3 and spinocerebellar ataxia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "our data support the finding by Nibbeling et al. that the PLD3-L308P mutation leads to a loss of function"
    explanation: An independent group confirms loss of function of the variant in cells.
- name: Mutant PLD3 Retention in the ER and Loss of Exonuclease Activity
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Wild-type PLD3 travels to lysosomes as a type II transmembrane protein by
    an ESCRT-dependent route and is cleaved there into a stable soluble
    enzyme. In transfected cells the L308P protein instead accumulates in the
    endoplasmic reticulum, is barely processed and has no 5' exonuclease
    activity. These results come from overexpression in cell lines, not from
    patient cells.
  genes:
  - preferred_term: PLD3
    term:
      id: hgnc:17158
      label: PLD3
  molecular_functions:
  - preferred_term: 5'-3' exonuclease activity
    modifier: DECREASED
    term:
      id: GO:0008409
      label: 5'-3' exonuclease activity
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  downstream:
  - target: Impaired Lysosomal Degradation of Single-Stranded Nucleic Acids
    causal_link_type: DIRECT
  - target: Reduced Lysosomal S,S-BMP Synthesis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30312375
    reference_title: PLD3 and spinocerebellar ataxia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "However, detection of the luminal domain of PLD3-L308P revealed a significantly reduced lysosomal localization, but increased co-localization with the ER marker KDEL, implicating sorting or folding defects due to the patient's point mutation."
    explanation: The mutant protein is retained in the ER instead of reaching lysosomes.
  - reference: PMID:30312375
    reference_title: PLD3 and spinocerebellar ataxia.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In contrast, the PLD3-L308P mutation led to strikingly reduced proteolytic cleavage of full-length PLD3, and both the 50 kDa and 12 kDa fragment were almost completely absent"
    explanation: The mutant protein is not processed into its mature lysosomal form.
  - reference: PMID:29386126
    reference_title: Unconventional Trafficking of Mammalian Phospholipase D3 to Lysosomes.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "PLD3 reaches lysosomes as a type II transmembrane protein via a (for mammalian cells) uncommon intracellular biosynthetic route that depends on the ESCRT (endosomal sorting complex required for transport) machinery."
    explanation: The normal trafficking route that the mutant fails to complete.
- name: Impaired Lysosomal Degradation of Single-Stranded Nucleic Acids
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    PLD3 is the main acid 5' exonuclease in cultured cells, and its major
    physiological substrate is mitochondrial DNA. In PLD3-deficient neurons
    and cell lines, mtDNA builds up in lysosomes and leaks into the cytosol,
    where it activates cGAS-STING signalling. These consequences come from
    PLD3-deficient cells studied in an Alzheimer's disease context; none has
    been shown in SCA46 patients or tested for the L308P variant, so the node
    records the expected cellular result of losing PLD3 exonuclease
    activity.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: DNA catabolic process
    modifier: DECREASED
    term:
      id: GO:0006308
      label: DNA catabolic process
  cellular_components:
  - preferred_term: lysosome
    term:
      id: GO:0005764
      label: lysosome
  downstream:
  - target: Large-Fiber Sensory Axonal Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cerebellar Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30312375
      reference_title: PLD3 and spinocerebellar ataxia.
      supports: REFUTE
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Importantly, we generated PLD3 knockout (KO) mice that do not present signs of cerebellar degeneration or spinocerebellar ataxia, challenging the interpretation of the suggested loss-of-function mechanism or PLD3 as the SCA46-causative gene."
      explanation: >-
        Complete loss of Pld3 in mice does not affect the cerebellum, which argues against this step.
    - reference: PMID:30312375
      reference_title: PLD3 and spinocerebellar ataxia.
      supports: REFUTE
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "We were surprised at the suggested causative role of PLD3 for cerebellar ataxia, since our protein expression data generated by immunoblot with a PLD3-specific antibody showed lowest PLD3 expression levels in the adult cerebellum compared to all other brain regions"
      explanation: >-
        Low cerebellar expression makes a cell-autonomous cerebellar effect of PLD3 loss less likely.
    - reference: PMID:34815492
      reference_title: Loss of zinc-finger protein 212 leads to Purkinje cell death and locomotive abnormalities with phospholipase D3 downregulation.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "We confirmed the reduction of Zfp212 and Pld3 in the Cb of an alcohol-induced cerebellar degeneration mouse model, suggesting that the ZNF212-PLD3 relationship is important for Purkinje cell survival."
      explanation: >-
        Reduced Pld3 accompanies Purkinje cell loss in Zfp212 knockout and alcohol-exposed mice; correlational, since Pld3 itself was not manipulated.
  evidence:
  - reference: PMID:33288674
    reference_title: "Quantification and characterization of the 5' exonuclease activity of the lysosomal nuclease PLD3 by a novel cell-based assay."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our experiments revealed PLD3 as the principal acid 5' exonuclease in HeLa cells, where it showed a markedly higher specific activity compared with PLD4."
    explanation: PLD3 is the main lysosomal enzyme of this kind in cultured cells.
  - reference: PMID:37225734
    reference_title: Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We identified mitochondrial DNA (mtDNA) as a major physiological substrate and show its manifest build-up in lysosomes of PLD3-defective cells."
    explanation: Loss of PLD3 causes undegraded mtDNA to accumulate in lysosomes.
  - reference: PMID:37225734
    reference_title: Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Lysosomal leakage of mtDNA to the cytosol activates cGAS-STING signaling that upregulates autophagy and induces amyloid precursor C-terminal fragment (APP-CTF) and cholesterol accumulation."
    explanation: A downstream consequence shown in PLD3-deficient cells, studied in an Alzheimer's disease context.
- name: Reduced Lysosomal S,S-BMP Synthesis
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    PLD3 also synthesizes S,S-bis(monoacylglycero)phosphate (BMP), a lysosomal
    phospholipid needed to degrade lipids such as gangliosides. Pld3 deletion
    lowers brain BMP in mice. In transfected cells the L308P protein reached
    lysosomes poorly, was poorly processed and did not raise BMP levels, so
    the variant loses this function too. Whether reduced BMP contributes to
    neuropathy or ataxia in patients is unknown.
  genes:
  - preferred_term: PLD3
    term:
      id: hgnc:17158
      label: PLD3
  molecular_functions:
  - preferred_term: bis(monoacylglycero)phosphate synthase activity
    modifier: DECREASED
    term:
      id: GO:0160121
      label: bis(monoacylglycero)phosphate synthase activity
  biological_processes:
  - preferred_term: lysobisphosphatidic acid biosynthetic process
    modifier: DECREASED
    term:
      id: GO:2001312
      label: lysobisphosphatidic acid biosynthetic process
  downstream:
  - target: Large-Fiber Sensory Axonal Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cerebellar Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:30312375
      reference_title: PLD3 and spinocerebellar ataxia.
      supports: REFUTE
      directness: INDIRECT
      evidence_source: MODEL_ORGANISM
      snippet: "Importantly, we generated PLD3 knockout (KO) mice that do not present signs of cerebellar degeneration or spinocerebellar ataxia, challenging the interpretation of the suggested loss-of-function mechanism or PLD3 as the SCA46-causative gene."
      explanation: >-
        Complete loss of Pld3 in mice, which removes this function too, does not affect the cerebellum.
  evidence:
  - reference: PMID:39423811
    reference_title: "PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Deletion of PLD3 or PLD4 markedly reduced BMP levels in cells or in murine tissues where either enzyme is highly expressed (brain for PLD3; spleen for PLD4), leading to gangliosidosis and lysosomal abnormalities."
    explanation: Loss of PLD3 lowers BMP in mouse brain.
  - reference: PMID:39423811
    reference_title: "PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We tested one such missense mutation, PLD3 L308P, and found reduced lysosomal localization and no detectable increase in BMP levels compared with mock transfection control"
    explanation: The SCA46 variant fails to support BMP synthesis in transfected cells.
  - reference: PMID:39423811
    reference_title: "PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Immunoblotting also revealed decreased processing of the enzyme to its soluble form"
    explanation: Independent confirmation that the L308P protein is poorly processed.
- name: Large-Fiber Sensory Axonal Degeneration
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Axonal degeneration of myelinated sensory fibres, shown on sural nerve
    biopsy in the Dutch family, producing a sensory polyneuropathy. Whether
    the primary lesion is in dorsal root ganglion neurons has not been
    examined. The pathology is established in patients; its link to PLD3 is
    not.
  locations:
  - preferred_term: sural nerve
    term:
      id: UBERON:0015488
      label: sural nerve
  downstream:
  - target: Sensory axonal neuropathy
    causal_link_type: DIRECT
  - target: Sensory ataxia
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:8595484
      reference_title: A new variant of sensory ataxic neuropathy with autosomal dominant inheritance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "this is the first description of a probably autosomal dominant form of late onset hereditary sensory neuropathy with predominant sensory ataxia and minor other neurological abnormalities"
      explanation: The family's ataxia is attributed to the sensory neuropathy.
  evidence:
  - reference: PMID:8595484
    reference_title: A new variant of sensory ataxic neuropathy with autosomal dominant inheritance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical, electrophysiological and sural nerve biopsy findings revealed a sensory polyneuropathy due to axonal degeneration of myelinated nerve fibres in four of five investigated siblings."
    explanation: Biopsy-proven axonal degeneration in four of five examined siblings.
- name: Cerebellar Dysfunction
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Mild cerebellar involvement, inferred from the oculomotor signs and
    dysarthria in the Dutch family. Pld3 knockout mice show no Purkinje cell
    loss, no cerebellar atrophy and normal rotarod performance, and PLD3
    expression is lowest in the adult cerebellum of all brain regions, so a
    direct effect of PLD3 loss on the cerebellum is unsupported in mice.
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  downstream:
  - target: Progressive cerebellar ataxia
    causal_link_type: DIRECT
  - target: Dysarthria
    causal_link_type: DIRECT
  - target: Oculomotor abnormalities
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:8595484
      reference_title: A new variant of sensory ataxic neuropathy with autosomal dominant inheritance.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Other neurological abnormalities in the affected family members consisted only of mild eye movement disturbances, probably due to cerebellar involvement."
      explanation: The eye movement disturbances are attributed to cerebellar involvement.
  evidence:
  - reference: PMID:8595484
    reference_title: A new variant of sensory ataxic neuropathy with autosomal dominant inheritance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Other neurological abnormalities in the affected family members consisted only of mild eye movement disturbances, probably due to cerebellar involvement."
    explanation: Clinical evidence of mild cerebellar involvement in the family.
  - reference: PMID:38059248
    reference_title: Spinocerebellar ataxia 46 in a young female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging of the brain revealed diffuse cerebellar atrophy"
    explanation: Cerebellar atrophy in the second, atypical PLD3 carrier.
phenotypes:
- category: Neurologic
  name: Sensory ataxia
  diagnostic: true
  description: >-
    Gait ataxia with large-fibre sensory loss, beginning after age 40 and
    progressing slowly; the predominant feature in the Dutch family.
  phenotype_term:
    preferred_term: Sensory ataxia
    term:
      id: HP:0010871
      label: Sensory ataxia
  evidence:
  - reference: PMID:8595484
    reference_title: A new variant of sensory ataxic neuropathy with autosomal dominant inheritance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a Dutch family with sensory ataxia in two generations, late onset of symptoms (over the age of 40 years) and slow progression."
    explanation: Late-onset sensory ataxia in the defining family.
- category: Neurologic
  name: Sensory axonal neuropathy
  diagnostic: true
  description: Axonal sensory polyneuropathy confirmed by nerve conduction and sural nerve biopsy.
  phenotype_term:
    preferred_term: Sensory axonal neuropathy
    term:
      id: HP:0003390
      label: Sensory axonal neuropathy
  evidence:
  - reference: PMID:8595484
    reference_title: A new variant of sensory ataxic neuropathy with autosomal dominant inheritance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical, electrophysiological and sural nerve biopsy findings revealed a sensory polyneuropathy due to axonal degeneration of myelinated nerve fibres in four of five investigated siblings."
    explanation: Neuropathy in four of five examined siblings.
- category: Neurologic
  name: Progressive cerebellar ataxia
  description: >-
    Slowly progressive ataxia with a cerebellar component, as described when
    the family was reclassified as SCA46.
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:38059248
    reference_title: Spinocerebellar ataxia 46 in a young female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "re-evaluation of the Dutch kindred by Nibbeling et al. revealed a combination phenotype of cerebellar ataxia and sensory neuropathy"
    explanation: The reclassified Dutch family has cerebellar ataxia as well as sensory neuropathy.
  - reference: PMID:38059248
    reference_title: Spinocerebellar ataxia 46 in a young female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "All the affected had late disease onset after the fourth decade with the average age of onset being 53.5 years and had a slowly progressive disease course."
    explanation: Slow progression in the Dutch family.
- category: Neurologic
  name: Dysarthria
  description: Cerebellar dysarthria, present in most affected members of the Dutch family.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:38059248
    reference_title: Spinocerebellar ataxia 46 in a young female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Most of the affected members showed dysarthria and variable oculomotor abnormalities such as jerky pursuits, square wave jerks, downbeat nystagmus, gaze-evoked nystagmus, slow saccades, and saccadic dysmetria."
    explanation: Dysarthria in most affected members of the Dutch family.
- category: Neurologic
  name: Oculomotor abnormalities
  description: >-
    Jerky pursuit, square-wave jerks, downbeat and gaze-evoked nystagmus,
    slow saccades and saccadic dysmetria, varying between family members.
  phenotype_term:
    preferred_term: Oculomotor abnormalities
    term:
      id: HP:0000496
      label: Abnormality of eye movement
  evidence:
  - reference: PMID:38059248
    reference_title: Spinocerebellar ataxia 46 in a young female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Most of the affected members showed dysarthria and variable oculomotor abnormalities such as jerky pursuits, square wave jerks, downbeat nystagmus, gaze-evoked nystagmus, slow saccades, and saccadic dysmetria."
    explanation: The range of eye movement abnormalities in the Dutch family.
- category: Neurologic
  name: Nystagmus
  description: Downbeat or gaze-evoked nystagmus in the Dutch family and in the Indian patient.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:38059248
    reference_title: Spinocerebellar ataxia 46 in a young female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "Most of the affected members showed dysarthria and variable oculomotor abnormalities such as jerky pursuits, square wave jerks, downbeat nystagmus, gaze-evoked nystagmus, slow saccades, and saccadic dysmetria."
    explanation: Downbeat and gaze-evoked nystagmus in the Dutch family.
  - reference: PMID:38059248
    reference_title: Spinocerebellar ataxia 46 in a young female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Oculomotor examination demonstrated bilateral horizontal gaze-evoked nystagmus."
    explanation: Gaze-evoked nystagmus in the second reported patient.
- category: Neurologic
  name: Cerebellar atrophy
  description: >-
    Diffuse cerebellar atrophy on MRI, reported only in the atypical Indian
    patient; the only imaging evidence of cerebellar involvement in a PLD3
    variant carrier.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:38059248
    reference_title: Spinocerebellar ataxia 46 in a young female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging of the brain revealed diffuse cerebellar atrophy"
    explanation: Single-case report.
- category: Neurologic
  name: Sensorineural hearing impairment
  description: >-
    Reported only in the atypical Indian patient with PLD3 p.(Ile26Thr), from
    age 13. Not described in the Dutch family, so it is not an established
    feature of SCA46.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:38059248
    reference_title: Spinocerebellar ataxia 46 in a young female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a rare case of a young female presenting with autosomal dominant cerebellar ataxia associated with sensorineural hearing loss,peripheral neuropathy and mutation in phospholipase D3 gene."
    explanation: Single-case report.
- category: Ophthalmologic
  name: Optic atrophy
  description: Early optic atrophy, reported only in the atypical Indian patient.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:38059248
    reference_title: Spinocerebellar ataxia 46 in a young female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She also had early optic atrophy and gaze-evoked nystagmus on examination."
    explanation: Single-case report.
genetic:
- name: PLD3
  gene_term:
    preferred_term: PLD3
    term:
      id: hgnc:17158
      label: PLD3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Provisional and disputed. The association rests on one Dutch family with
    the heterozygous p.Leu308Pro variant. Pld3 knockout mice have no
    cerebellar phenotype, and the group that generated them questioned
    PLD3 as the SCA46 gene; a reply from the original authors was published
    (PMID:30312384). One further patient carries a different variant, with no
    segregation data and an unremarkable family history.
  evidence:
  - reference: PMID:29053796
    reference_title: Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons."
    explanation: The original gene report.
  - reference: PMID:30312375
    reference_title: PLD3 and spinocerebellar ataxia.
    supports: REFUTE
    directness: INDIRECT
    evidence_source: MODEL_ORGANISM
    snippet: "Importantly, we generated PLD3 knockout (KO) mice that do not present signs of cerebellar degeneration or spinocerebellar ataxia, challenging the interpretation of the suggested loss-of-function mechanism or PLD3 as the SCA46-causative gene."
    explanation: Published challenge to the gene-disease association.
  - reference: PMID:38059248
    reference_title: Spinocerebellar ataxia 46 in a young female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical exome sequencing detected phospholipase D family member 3 (PLD3) mutation associated with spinocerebellar ataxia (SCA) 46, carrying the c.77T>C"
    explanation: >-
      A second, different PLD3 variant (p.Ile26Thr) in an atypical patient;
      segregation and zygosity are not reported, so it does not independently
      confirm the association.
  notes: >-
    No ClinGen gene-disease validity curation exists for PLD3 and MONDO
    records no causal gene for MONDO:0033481, so gene_disease_validity is left
    empty. The authors' reply to the challenge (PMID:30312384) has no abstract
    or full text in the reference cache and is not quoted.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Transmission from an affected father to sons and daughters in the Dutch
    family.
  evidence:
  - reference: PMID:8595484
    reference_title: A new variant of sensory ataxic neuropathy with autosomal dominant inheritance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As the disease is inherited from the affected father to his sons and daughters, this is the first description of a probably autosomal dominant form of late onset hereditary sensory neuropathy with predominant sensory ataxia and minor other neurological abnormalities."
    explanation: Father-to-child transmission in both sexes.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    One family with segregation data and one further single patient have been
    published. That is a case count, not a prevalence.
  evidence:
  - reference: PMID:38059248
    reference_title: Spinocerebellar ataxia 46 in a young female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "this is the first reported case of SCA 46 from India and outside the Dutch kindred described earlier."
    explanation: Before this report the disease was known only in the Dutch family.
progression:
- phase: Late adult onset with slow progression
  age_range: over 40 years
  notes: >-
    Symptoms begin after age 40, with a mean onset of 53.5 years in the Dutch
    family, and progress slowly.
  evidence:
  - reference: PMID:38059248
    reference_title: Spinocerebellar ataxia 46 in a young female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: BACKGROUND
    snippet: "All the affected had late disease onset after the fourth decade with the average age of onset being 53.5 years and had a slowly progressive disease course."
    explanation: Mean age at onset in the Dutch family.
  - reference: PMID:8595484
    reference_title: A new variant of sensory ataxic neuropathy with autosomal dominant inheritance.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a Dutch family with sensory ataxia in two generations, late onset of symptoms (over the age of 40 years) and slow progression."
    explanation: Age at onset and tempo in the Dutch family.
treatments:
- name: Physical Therapy
  therapeutic_modality: BEHAVIORAL
  description: Gait and balance training for sensory and cerebellar ataxia. No disease-specific therapy exists.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_phenotypes:
  - preferred_term: Sensory ataxia
    term:
      id: HP:0010871
      label: Sensory ataxia
  notes: >-
    Standard supportive care for hereditary ataxia; no study has evaluated it
    in SCA46, so it carries no evidence block.
- name: Genetic Counseling
  description: Counseling on dominant inheritance and on the provisional status of the PLD3 association.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  notes: Standard care; no disease-specific study, so no evidence block.
animal_models:
- name: Pld3 knockout mouse
  species: Mouse
  genotype: Pld3 -/-
  description: >-
    Mice lacking Pld3 have normal rotarod performance at 5 and 9 months, and
    at 20 months a normal-sized cerebellum with no Purkinje cell loss.
  publication: PMID:30312375
  modeled_mechanisms:
  - target: Cerebellar Dysfunction
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    limitations: >-
      The model is a homozygous null, whereas the patients are heterozygous
      for a missense variant, and the sensory nerves were not reported. The
      paralog Pld4 may compensate, and a mouse lifespan may be too short for a
      late-onset human disease.
    evidence:
    - reference: PMID:30312375
      reference_title: PLD3 and spinocerebellar ataxia.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "These data do not reveal a major degenerative phenotype of the cerebellum in PLD3 KO mice."
      explanation: The negative result that defines this link.
  evidence:
  - reference: PMID:30312375
    reference_title: PLD3 and spinocerebellar ataxia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "PLD3 expression in the cerebellum is low and PLD3 KO mice do not show any signs of cerebellar degeneration."
    explanation: Summary of the knockout phenotype.
- name: Pld3 Pld4 double knockout mouse
  species: Mouse
  genotype: Pld3 -/- Pld4 -/-
  description: >-
    Mice lacking both paralogs develop fatal liver inflammation in early life,
    showing that the two nucleases are needed in vivo; the phenotype is
    inflammatory, not neurological.
  publication: PMID:30111894
  modeled_mechanisms:
  - target: Impaired Lysosomal Degradation of Single-Stranded Nucleic Acids
    relationship: PERTURBS
    fidelity: LOW
    model_scale: ORGANISM
    limitations: >-
      Digenic loss in immune cells; it shows the in vivo exonuclease function
      but not a neurological phenotype.
    evidence:
    - reference: PMID:30111894
      reference_title: PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mice deficient in both PLD3 and PLD4 developed lethal liver inflammation in early life, which indicates that both enzymes are needed to regulate inflammatory cytokine responses via the degradation of nucleic acids."
      explanation: In vivo evidence for the nuclease function of PLD3 and PLD4.
  evidence:
  - reference: PMID:30111894
    reference_title: PLD3 and PLD4 are single-stranded acid exonucleases that regulate endosomal nucleic-acid sensing.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Although PLD4 and PLD3 were presumed to be phospholipases, we found that they are 5' exonucleases, probably identical to spleen phosphodiesterase, that break down TLR9 ligands."
    explanation: Establishes PLD3 as a 5' exonuclease.
discussions:
- discussion_id: sca46_pld3_causality
  kind: CONTROVERSY
  attaches_to:
  - genetic#PLD3
  prompt: >-
    Is PLD3 p.Leu308Pro the cause of SCA46, or a rare variant that happens to
    segregate in a single family?
  rationale: >-
    The association rests on one family. The variant abolishes exonuclease
    activity in transfected cells, but Pld3 knockout mice have no cerebellar
    phenotype and PLD3 is least expressed in the adult cerebellum. The
    challengers did not dispute the genetic data itself, and a reply from the
    original authors was published (PMID:30312384). The second reported
    patient carries a different variant, has a different phenotype (early
    onset, hearing loss, optic atrophy), has an unremarkable family history
    and has no segregation data, so it
    does not settle the question. Additional families with PLD3 variants
    segregating with a late-onset sensory-cerebellar ataxia would.
  evidence:
  - reference: PMID:30312375
    reference_title: PLD3 and spinocerebellar ataxia.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our PLD3 KO mouse analysis challenges the interpretation of PLD3 mutations as the causative SCA46 gene and further characterization of additional patients will be required to clarify a role of PLD3 in spinocerebellar ataxia."
    explanation: The published statement of the dispute.
  - reference: PMID:30312375
    reference_title: PLD3 and spinocerebellar ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While there is little doubt about the genetic data, we have concerns regarding the cell biology follow up experiments, particularly the localization studies and functional assay for PLD3 performed by Nibbeling et al."
    explanation: The challenge concerns the functional evidence, not the segregation data.
  - reference: PMID:38059248
    reference_title: Spinocerebellar ataxia 46 in a young female.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Her childhood medical history and family history were unremarkable."
    explanation: The second patient has no reported affected relatives, so she adds no segregation evidence.
- discussion_id: sca46_knockout_mismatch
  kind: HUMAN_MODEL_MISMATCH
  attaches_to:
  - pathophysiology#Cerebellar Dysfunction
  - pathophysiology#Large-Fiber Sensory Axonal Degeneration
  prompt: >-
    Why do Pld3 knockout mice lack the cerebellar phenotype, and do they have
    the sensory neuropathy that dominates the human disease?
  rationale: >-
    The knockout study examined the cerebellum and motor performance but did
    not report dorsal root ganglia or peripheral nerves, although sensory
    neuropathy is the predominant human feature. PLD4 compensation, the short
    mouse lifespan relative to onset after 40 in humans, and a possible
    dominant-negative action of the missense protein that a null allele would
    not reproduce could each explain the mismatch. A heterozygous L308P
    knock-in mouse examined for sensory nerve pathology in old age would
    address it.
  evidence:
  - reference: PMID:30312375
    reference_title: PLD3 and spinocerebellar ataxia.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "suggest a dominant loss-of-function mechanism due to the PLD3-L308P mutation, suggesting that the PLD3 knockout reflects the situation observed in SCA patients."
    explanation: The premise under which the knockout should have reproduced the disease.
  - reference: PMID:39423811
    reference_title: "PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "How the PLD3 L308P mutation would act dominantly is currently unclear."
    explanation: The dominant mechanism of a heterozygous loss-of-function variant remains unexplained.
notes: >-
  The 1995 report (PMID:8595484) describes the same Dutch family before the
  gene was found. The detailed family data in the 2017 gene report (onset age
  range, segregation in eight affected carriers, enzyme activity values) are
  in its full text, which is not cached, so they are not quoted here. No
  GeneReviews chapter exists for SCA46 (just check-genereviews --online
  returned NO_CHAPTER). Orphanet lists the disease as ORPHA:589522, which is
  not cached and not cited.

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References & Deep Research

References

10

PMID:29053796

Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia.