Spinocerebellar Ataxia, Autosomal Recessive 29

Mendelian MONDO:0030312 Pathograph 13 Show in embeddings browser Autosomal recessive cerebellar ataxia HOPS-associated neurological disorder

Spinocerebellar ataxia, autosomal recessive 29 (SCAR29) is an ultra-rare progressive neurodevelopmental disorder caused by biallelic variants in VPS41, which encodes a subunit specific to the HOPS (homotypic fusion and protein sorting) tethering complex. HOPS mediates fusion of late endosomes and autophagosomes with lysosomes; VPS41 and VPS39 are its two HOPS-specific subunits, while VPS11, VPS16, VPS18 and VPS33A are shared with the CORVET complex. Patients present in infancy or early childhood with hypotonia, developmental delay, intellectual disability with speech delay, cerebellar ataxia, dystonia, dysarthria and nystagmus, usually without independent ambulation; lower-limb spasticity and retinal pigment changes occur in some. Brain MRI shows cerebellar (mainly vermian) atrophy that progresses on serial imaging, often with a thin corpus callosum and sometimes pallidal iron deposition. Therapy-resistant epilepsy has been reported in one sibship. Pathogenic variants prevent assembly of a functional HOPS complex, so endocytic and autophagic cargo reaches enzymatically competent lysosomes late; the disease is therefore a trafficking (delivery) disorder of lysosomal function rather than a hydrolase deficiency. Patient cells also show mTORC1 redistribution and constitutive nuclear TFE3, and zebrafish vps41 crispants show lysosomal accumulation in microglia and cerebellar dysfunction. SCAR29 belongs to the proposed group of HOPS-associated neurological disorders (HOPSANDs), which also includes VPS16- and VPS11-related dystonia.

Ask OpenScientist

Ask a research question about Spinocerebellar Ataxia, Autosomal Recessive 29. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

🏷

Classifications

Harrison's Part
NEUROLOGIC GENETICS ENVIRONMENT DISEASE
👪

Inheritance

1
Autosomal recessive inheritance HP:0000007
Homozygous VPS41 variants in five unrelated families in the defining series, and compound heterozygous variants in later patients, including one whose two alleles were phased in trans by long-read sequencing.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:33764426 SUPPORT Human clinical
"Here, we report five unrelated families with nine affected individuals with homozygous missense variants in VPS41, presenting with an autosomal recessive, progressive developmental disorder"
Defining series establishing recessive inheritance with homozygous VPS41 variants across five unrelated families.
PMID:33851776 SUPPORT Human clinical
"Here, we report three patients with compound heterozygous mutations in VPS41"
Independent report of compound heterozygous biallelic VPS41 variants.
PMID:42656169 SUPPORT Human clinical
"Long-read genome sequencing demonstrated that two VPS41 variants were in trans."
Phasing confirms a biallelic (compound heterozygous) configuration in a further patient.
⚙

Pathophysiology

7
VPS41 Loss of Function
Biallelic VPS41 variants reduce or abolish the function of the HOPS-specific VPS41 subunit. Disease missense variants fail to restore lysosomal function in VPS41 knockout cells, and in one compound heterozygote the two splice alleles (one producing an NMD-targeted out-of-frame transcript, one an in-frame exon-skipped transcript) jointly reduced VPS41 transcript and protein. VPS41 acts as an adaptor linking the HOPS complex to the lysosomal small GTPase ARL8B via its effector SKIP.
VPS41 hgnc:12713 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves VPS41 (hgnc:12713). hgnc:12713 is a gene from the HUGO Gene Nomenclature Committee.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Biallelic germline variants, homozygous or compound heterozygous; missense, nonsense and splice alleles are reported.
molecular adaptor activity (HOPS-to-lysosome linkage) GO:0060090 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased molecular adaptor activity (HOPS-to-lysosome linkage), annotated with molecular adaptor activity (GO:0060090). GO:0060090 is a molecular function from the Gene Ontology.
Downstream
HOPS Tethering Complex Dysfunction Without functional VPS41, a functional HOPS complex does not form.
Show evidence (2 references)
PMID:42656169 SUPPORT In vitro / ex vivo
"These complementary defects reduced VPS41 expression at both transcript and protein levels, supporting pathogenicity and variant reclassification."
Patient-derived RNA and protein analysis shows reduced VPS41 from the two splice alleles.
PMID:33764426 SUPPORT BACKGROUND In vitro / ex vivo
"The interaction of VPS41 with ARL8B through its effector SKIP (SifA and kinesin-interacting protein) contributes to lysosomal localization and trafficking and degradation of EGFR"
Background statement of the adaptor role of VPS41 between HOPS and the lysosomal ARL8B-SKIP machinery, the activity whose loss this node records.
HOPS Tethering Complex Dysfunction
VPS41 is one of the two HOPS-specific subunits. All tested disease variants prevented formation of a functional HOPS complex. Because VPS41 is not part of CORVET, the defect is confined to the late endosome/autophagosome-to-lysosome fusion arm, in contrast to VPS33A (Mucopolysaccharidosis-Plus Syndrome), whose loss compromises both complexes. A HOPS-independent function of VPS41 in regulated secretion was preserved for the p.Ser285Pro allele.
HOPS complex GO:0030897 Gene Ontology (GO) Relation: this pathophysiological event involves this protein complex This pathophysiological event involves decreased HOPS complex (GO:0030897). GO:0030897 is a protein complex from the Gene Ontology.
Downstream
Delayed Lysosomal Delivery of Endocytic and Autophagic Cargo HOPS tethers late endosomes and autophagosomes to lysosomes for fusion; its loss delays cargo delivery.
Show evidence (2 references)
PMID:33851776 SUPPORT In vitro / ex vivo
"All mutants prevented formation of a functional HOPS complex, causing delayed lysosomal delivery of endocytic and autophagic cargo."
Patient fibroblasts and VPS41-depleted cells show loss of functional HOPS with all tested variants.
PMID:33764426 SUPPORT BACKGROUND In vitro / ex vivo
"VPS39 and VPS41, which are HOPS-specific, as well as VPS11, VPS16, VPS18 and VPS33A, which are also present in the CORVET complex"
States that VPS41 is HOPS-specific, which restricts the lesion to HOPS rather than CORVET.
Delayed Lysosomal Delivery of Endocytic and Autophagic Cargo
Endocytic and autophagic cargo reaches enzymatically active lysosomes late. The lysosomes themselves remain functional; the defect is insufficient delivery, which places SCAR29 among lysosomal disorders of trafficking rather than of hydrolase activity.
late endosome to lysosome transport GO:1902774 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased late endosome to lysosome transport (GO:1902774). GO:1902774 is a biological process from the Gene Ontology. autophagosome-lysosome fusion GO:0061909 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased autophagosome-lysosome fusion (GO:0061909). GO:0061909 is a biological process from the Gene Ontology.
Downstream
Abnormal Lysosomal Compartment Undelivered and partially processed material accumulates in abnormal membrane-bound vesicles.
mTORC1 Redistribution and Constitutive TFE3 Activation Loss of HOPS function disrupts lysosome-dependent mTORC1 control of TFE3/TFEB.
Show evidence (2 references)
PMID:33851776 SUPPORT In vitro / ex vivo
"All mutants prevented formation of a functional HOPS complex, causing delayed lysosomal delivery of endocytic and autophagic cargo."
Direct cellular readout of delayed delivery of endocytic and autophagic cargo to lysosomes.
PMID:33851776 SUPPORT In vitro / ex vivo
"Our study shows that VPS41 patients represent a new class of lysosomal disorders in which lysosomes are functional, but insufficiently reached by cargo due to a trafficking defect."
Characterizes the lesion as a delivery defect with functional lysosomes.
mTORC1 Redistribution and Constitutive TFE3 Activation
In VPS41-deficient cells mTORC1 redistributes to the cytosol and TFE3 is continuously nuclear, while phosphorylation of the mTORC1 substrates S6K1 and 4EBP1 is unaffected; the defect is selective for the TFEB/TFE3 arm. Lysosomal biogenesis and autophagosome formation are continuously upregulated regardless of nutrient status, and the autophagic response to starvation is reduced.
lysosome organization (lysosomal biogenesis) GO:0007040 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased lysosome organization (lysosomal biogenesis), annotated with lysosome organization (GO:0007040). GO:0007040 is a biological process from the Gene Ontology.
Downstream
Abnormal Lysosomal Compartment Continuous TFE3-driven lysosomal biogenesis is consistent with the raised lysosomal membrane protein (LAMP2) seen in VPS41 knockout cells; the two observations come from different studies and the link is an inference.
Show evidence (2 references)
PMID:33851776 SUPPORT In vitro / ex vivo
"Strikingly, loss of VPS41 function caused a cytosolic redistribution of mTORC1, continuous nuclear localization of Transcription Factor E3 (TFE3), enhanced levels of LC3II, and a reduced autophagic response to nutrient starvation."
Direct cellular evidence for the mTORC1/TFE3 dysregulation.
PMID:33851776 SUPPORT In vitro / ex vivo
"As a result, lysosomal biogenesis and autophagosome formation is continuously upregulated independent of nutrient conditions."
Supports the INCREASED modifier on lysosome organization (biogenesis).
Abnormal Lysosomal Compartment
Patient lymphocytes, lymphoblastoid cells and fibroblasts show excess multilayered membrane-bound vesicles and vacuolar abnormalities on electron microscopy, and VPS41 knockout cells show raised LAMP2 that disease alleles fail to correct. This is the cellular storage-like phenotype shared by the HOPS-associated neurological disorders.
Downstream
Microglial Lysosomal Accumulation Highly endocytic and phagocytic microglia accumulate enlarged or excess acidic lysosomal compartments.
Cerebellar Neurodegeneration Membrane trafficking defects in neurons are proposed to underlie the cerebellar atrophy; reduced Purkinje cell viability is plausible but not demonstrated.
Dystonia Lysosomal and autophagic dysfunction is the proposed shared mechanism of dystonia across the HOPS-associated neurological disorders; the circuit-level route is not established.
Show evidence (3 references)
PMID:33764426 SUPPORT In vitro / ex vivo
"Transmission electron microscopy (TEM) on peripheral blood lymphocytes from Subject 2 and lymphoblastoid cells from Subject 3 revealed more multilayered vesicles compared to control cells"
Ultrastructural evidence of abnormal vesicles in patient-derived cells.
PMID:33764426 SUPPORT In vitro / ex vivo
"Whereas transfection of wild-type VPS41 resulted in downregulation of LAMP2 in transfected KO ESCs, expression of Ser285Pro, Cys791Phe, and to a lesser extent Arg633Pro, failed to downregulate LAMP2 at a population level"
Disease alleles fail to rescue the lysosomal phenotype of VPS41 knockout cells.
PMID:32808683 SUPPORT In vitro / ex vivo
"Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function."
Independent ultrastructural evidence in a VPS41 patient's cells.
Microglial Lysosomal Accumulation
In zebrafish vps41 crispants, brain acidity (LysoTracker) is increased, concentrated within microglia, and is reduced by wild-type vps41 mRNA; microglia show morphology suggestive of larger or more numerous lysosomal compartments. Microglial lysosomal dysfunction is proposed to impair brain development, including of the cerebellum. Human tissue confirmation is lacking.
microglial cell CL:0000129 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves microglial cell (CL:0000129). CL:0000129 is a cell type from the Cell Ontology.
Animal models
Zebrafish vps41 crispant Zebrafish recapitulates Microglial lysosomal accumulation rescued by wild-type vps41 mRNA.
Downstream
Cerebellar Neurodegeneration Lysosomal accumulation impairs microglial function, and microglial loss is known to cause brain abnormalities including cerebellar hypoplasia; this contribution is proposed from the zebrafish data.
Show evidence (1 reference)
PMID:33764426 SUPPORT Model organism
"This revealed that vps41-deficient microglia have distinct morphological abnormalities suggestive of larger, or possibly more numerous, lysosomal compartments compared to microglia from control larvae."
Zebrafish evidence of microglial lysosomal abnormality.
Cerebellar Neurodegeneration
Brain MRI shows mild cerebellar and vermian atrophy or hypoplasia in most patients, with anterior-predominant cerebellar atrophy in a later case; serial MRI in two siblings showed the vermis, normal at first, losing volume on follow-up, so the process is degenerative. Zebrafish crispants show a reduced optokinetic response, used as a readout of cerebellar dysfunction.
cerebellum UBERON:0002037 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebellum (UBERON:0002037). UBERON:0002037 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Zebrafish vps41 crispant Zebrafish partially recapitulates Reduced optokinetic response, used as a cerebellar-function assay.
Downstream
Cerebellar Vermis Atrophy Cerebellar tissue loss is visible on MRI.
Cerebellar Ataxia Cerebellar dysfunction produces ataxia.
Nystagmus Nystagmus is a common cerebellar oculomotor sign; the specific substrate in SCAR29 has not been studied.
Show evidence (3 references)
PMID:33764426 SUPPORT Human clinical
"Brain MRI revealed mild cerebellar atrophy and vermian atrophy without other major structural abnormalities in most affected individuals"
Neuroimaging evidence of cerebellar involvement in patients.
PMID:42656169 SUPPORT Human clinical
"He also developed pes cavus, anterior-predominant cerebellar atrophy on brain MRI"
Cerebellar atrophy in a later, independently reported patient.
PMID:33851776 SUPPORT Human clinical
"brain MRI done on the younger brother (patient 2) at 10 years of age confirmed the thin corpus callosum, mild progression of the cerebellar atrophy"
Serial MRI shows the cerebellar atrophy progressing, supporting a degenerative rather than purely malformative process.
⬡

Pathograph

Use Group by to collapse related nodes into one box. Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Spinocerebellar Ataxia, Autosomal Recessive 29 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

16
Eye 2
Nystagmus FREQUENT HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33764426 SUPPORT Human clinical
"Likewise, nystagmus was commonly described."
Nystagmus was common in the defining series.
Abnormal Retinal Pigmentation OCCASIONAL HP:0007703 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal retinal pigmentation (HP:0007703). HP:0007703 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33764426 SUPPORT Human clinical
"In two individuals, retinal pigment alterations were noticed."
Retinal pigment changes in two of nine patients.
PMID:33851776 SUPPORT Human clinical
"both had ophthalmological examination showing hypopigmented and underdeveloped retina which disappeared at 1 year of age"
Transient retinal hypopigmentation in two siblings.
Limbs 2
Swan Neck Deformities of the Fingers VERY_RARE Swan neck-like deformities of the fingers HP:0006150 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Swan neck-like deformities of the fingers (HP:0006150). HP:0006150 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42656169 SUPPORT Human clinical
"progressive swan-neck deformities of the second to fourth fingers bilaterally"
Single-patient finding.
Pes Cavus VERY_RARE HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42656169 SUPPORT Human clinical
"In addition to typical SCAR29 features, the patient showed previously unreported findings, including swan-neck deformities and pes cavus."
Single-patient finding.
Musculoskeletal 2
Hypotonia VERY_FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33764426 SUPPORT Human clinical
"Various degrees of ataxia, hypotonia, and dystonia were present in all affected individuals, preventing independent ambulation."
Hypotonia in all nine patients.
Lower Limb Spasticity OCCASIONAL HP:0002061 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lower limb spasticity (HP:0002061), qualified as course progressive. HP:0002061 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:33851776 SUPPORT Human clinical
"Both brothers developed progressive spasticity of the lower limbs"
Progressive lower-limb spasticity in two siblings.
PMID:33764426 SUPPORT Human clinical
"Spastic for the lower extremities"
Clinical table entry for one patient of the defining series.
Nervous System 10
Cerebellar Ataxia VERY_FREQUENT HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar ataxia, annotated with Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33764426 SUPPORT Human clinical
"Various degrees of ataxia, hypotonia, and dystonia were present in all affected individuals, preventing independent ambulation."
Ataxia in all nine patients of the defining series.
Dystonia VERY_FREQUENT HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33764426 SUPPORT Human clinical
"Various degrees of ataxia, hypotonia, and dystonia were present in all affected individuals, preventing independent ambulation."
Dystonia in all nine patients.
PMID:32808683 SUPPORT Human clinical
"We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia."
Generalized dystonia as the presenting feature in an independent patient.
Intellectual Disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33764426 SUPPORT Human clinical
"In addition, all affected individuals displayed intellectual disability and speech delay."
Intellectual disability in all nine patients.
Speech Delay VERY_FREQUENT Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33764426 SUPPORT Human clinical
"In addition, all affected individuals displayed intellectual disability and speech delay."
Speech delay in all nine patients.
Cerebellar Vermis Atrophy FREQUENT HP:0006855 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar vermis atrophy (HP:0006855), qualified as course progressive. HP:0006855 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:33764426 SUPPORT Human clinical
"Brain MRI revealed mild cerebellar atrophy and vermian atrophy without other major structural abnormalities in most affected individuals"
Vermian atrophy on MRI in most patients.
PMID:33851776 SUPPORT Human clinical
"the vermis, although normal in configuration and size initially, demonstrated volume loss on follow-up examinations"
Serial MRI documents progressive vermian volume loss.
Global Developmental Delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33764426 SUPPORT Human clinical
"Affected individuals were born after uneventful pregnancies and presented in most cases early in life with developmental delay"
Developmental delay as the presenting feature in the defining series.
PMID:33851776 SUPPORT Human clinical
"Patients 1 and 2, two brothers, were diagnosed with global developmental delay, hypotonia, ataxia, and dystonia."
Global developmental delay in an independent sibship.
Dysarthria FREQUENT HP:0001260 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysarthria (HP:0001260). HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33764426 SUPPORT Human clinical
"Dysarthria | Yes | Yes | Yes | Absent speech | Yes | Yes | Absent speech | Absent speech | Yes"
Clinical table row giving dysarthria in six and absent speech in three of nine patients.
Thin Corpus Callosum FREQUENT HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33851776 SUPPORT Human clinical
"brain MRI characterized by thinning of the corpus callosum and atrophy of the cerebellar vermis"
Thin corpus callosum across the reported patients of this study.
Basal Ganglia Iron Deposition OCCASIONAL Iron accumulation in brain HP:0012675 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Basal ganglia iron deposition, annotated with Iron accumulation in brain (HP:0012675). HP:0012675 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33851776 SUPPORT Human clinical
"bilateral hypointensity in the globus pallidus (GP) compatible with early iron deposition"
Pallidal iron deposition on follow-up MRI.
PMID:33764426 SUPPORT Human clinical
"abnormal iron deposition in the globus pallidus and substantia nigra"
Clinical table MRI entry for one patient of the defining series.
Seizures OCCASIONAL HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Therapy-resistant epilepsy, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33764426 SUPPORT Human clinical
"Two siblings further presented with therapy-resistant epilepsy."
Epilepsy in a single sibship.
🧬

Genetic Associations

1
VPS41 (Biallelic VPS41 variants: homozygous missense variants (including p.Ser285Pro, p.Arg633Pro and p.Cys791Phe) in the defining series, compound heterozygous missense, nonsense (p.Arg662*) and splice variants in later reports, and biallelic loss-of-function variants in a patient ascertained for infantile-onset generalized dystonia.)
Gene: VPS41 hgnc:12713 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is VPS41 (hgnc:12713). hgnc:12713 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:33764426 SUPPORT Human clinical
"Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function."
Links homozygous VPS41 variants to the disorder in five families with functional support.
PMID:32808683 SUPPORT Human clinical
"We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia."
Independent ascertainment of biallelic VPS41 loss-of-function variants through a dystonia cohort.
🔬

Diagnosis

2
Molecular genetic testing
Diagnosis rests on finding biallelic VPS41 variants by exome or genome sequencing. When phase cannot be set from parents, long-read sequencing can show that two variants lie in trans, and RNA analysis can establish the effect of splice variants.
Show evidence (1 reference)
PMID:42656169 SUPPORT Human clinical
"Because maternal DNA was unavailable, long-read genome sequencing was performed to determine allelic configuration, followed by RNA and protein analyses."
Describes the sequencing, phasing and RNA route used to confirm the diagnosis.
Electron microscopy of patient cells
Electron microscopy of lymphocytes, lymphoblastoid cells or fibroblasts shows abnormal multilayered vesicles or vacuoles. It supports variant interpretation but is not specific to VPS41.
Show evidence (1 reference)
PMID:32808683 SUPPORT In vitro / ex vivo
"Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function."
Ultrastructural abnormality in patient cells, shared with VPS16 disease.
🐁

Animal Models

1
Zebrafish vps41 crispant
F0 crispants of the single zebrafish vps41 homologue show hypopigmentation, absent swim bladder inflation with loss of viability, increased brain lysosomal acidity concentrated in microglia, and a reduced optokinetic response.
Species
Zebrafish
Genotype
vps41 F0 CRISPR/Cas9 crispant (60-90% disruption efficiency)
Publication
PMID:33764426
Pathograph links
Microglial Lysosomal Accumulation recapitulates fidelity: moderate observes: cellular Microglial lysosomal accumulation rescued by wild-type vps41 mRNA.
Limitations: Mosaic F0 knockout rather than the patients' hypomorphic missense or splice alleles; larval stage only, and the microglial finding has not been examined in human tissue.
Show evidence (1 reference)
PMID:33764426 SUPPORT Model organism
"This revealed that vps41-deficient microglia have distinct morphological abnormalities suggestive of larger, or possibly more numerous, lysosomal compartments compared to microglia from control larvae."
Supports the model as informative for the microglial node.
Cerebellar Neurodegeneration partially recapitulates fidelity: low observes: organism Reduced optokinetic response, used as a cerebellar-function assay.
Limitations: The optokinetic deficit may also reflect retinal pigment epithelium or photoreceptor dysfunction (crispants have reduced retinal pigmentation), and gross brain morphology and size were normal, so cerebellar degeneration itself was not shown.
Show evidence (1 reference)
PMID:33764426 SUPPORT Model organism
"In contrast to control injected larvae, which demonstrated normal responses to visual stimuli, vps41 crispants showed a dramatically reduced response"
Optokinetic deficit in crispants.
{ }

Source YAML

click to show 
name: Spinocerebellar Ataxia, Autosomal Recessive 29
creation_date: "2026-10-23T02:04:54Z"
category: Mendelian
synonyms:
- SCAR29
- Barakat-Van Ham-Kaya syndrome
- neurodevelopmental disorder with hypotonia and cerebellar ataxia
- VPS41-related neurodevelopmental disorder
description: >-
  Spinocerebellar ataxia, autosomal recessive 29 (SCAR29) is an ultra-rare
  progressive neurodevelopmental disorder caused by biallelic variants in
  VPS41, which encodes a subunit specific to the HOPS (homotypic fusion and
  protein sorting) tethering complex. HOPS mediates fusion of late endosomes
  and autophagosomes with lysosomes; VPS41 and VPS39 are its two HOPS-specific
  subunits, while VPS11, VPS16, VPS18 and VPS33A are shared with the CORVET
  complex. Patients present in infancy or early childhood with hypotonia,
  developmental delay, intellectual disability with speech delay, cerebellar
  ataxia, dystonia, dysarthria and nystagmus, usually without independent
  ambulation; lower-limb spasticity and retinal pigment changes occur in some.
  Brain MRI shows cerebellar (mainly vermian) atrophy that progresses on
  serial imaging, often with a thin corpus callosum and sometimes pallidal
  iron deposition. Therapy-resistant epilepsy has been reported in one
  sibship. Pathogenic variants
  prevent assembly of a functional HOPS complex, so endocytic and autophagic
  cargo reaches enzymatically competent lysosomes late; the disease is
  therefore a trafficking (delivery) disorder of lysosomal function rather
  than a hydrolase deficiency. Patient cells also show mTORC1 redistribution
  and constitutive nuclear TFE3, and zebrafish vps41 crispants show lysosomal
  accumulation in microglia and cerebellar dysfunction. SCAR29 belongs to the
  proposed group of HOPS-associated neurological disorders (HOPSANDs), which
  also includes VPS16- and VPS11-related dystonia.
disease_term:
  preferred_term: spinocerebellar ataxia, autosomal recessive 29
  term:
    id: MONDO:0030312
    label: spinocerebellar ataxia, autosomal recessive 29
parents:
- Autosomal recessive cerebellar ataxia
- HOPS-associated neurological disorder
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: >-
      Presents and is managed as a progressive cerebellar ataxia with dystonia
      and intellectual disability; the reported phenotype is neurological.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: >-
      A Mendelian recessive disorder diagnosed by exome or genome sequencing.
references:
- reference: PMID:33764426
  title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
- reference: PMID:33851776
  title: "Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation."
- reference: PMID:32808683
  title: "Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities."
- reference: PMID:33871597
  title: "HOPS-associated neurological disorders (HOPSANDs): linking endolysosomal dysfunction to the pathogenesis of dystonia."
- reference: PMID:42656169
  title: "Biallelic VPS41 Variants in Autosomal Recessive Spinocerebellar Ataxia 29 Resolved by Long-Read Sequencing and RNA Analysis."
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Homozygous VPS41 variants in five unrelated families in the defining
    series, and compound heterozygous variants in later patients, including
    one whose two alleles were phased in trans by long-read sequencing.
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report five unrelated families with nine affected individuals with homozygous missense variants in VPS41, presenting with an autosomal recessive, progressive developmental disorder"
    explanation: Defining series establishing recessive inheritance with homozygous VPS41 variants across five unrelated families.
  - reference: PMID:33851776
    reference_title: "Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we report three patients with compound heterozygous mutations in VPS41"
    explanation: Independent report of compound heterozygous biallelic VPS41 variants.
  - reference: PMID:42656169
    reference_title: "Biallelic VPS41 Variants in Autosomal Recessive Spinocerebellar Ataxia 29 Resolved by Long-Read Sequencing and RNA Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Long-read genome sequencing demonstrated that two VPS41 variants were in trans."
    explanation: Phasing confirms a biallelic (compound heterozygous) configuration in a further patient.
genetic:
- name: VPS41
  gene_term:
    preferred_term: VPS41
    term:
      id: hgnc:12713
      label: VPS41
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    Biallelic VPS41 variants: homozygous missense variants (including
    p.Ser285Pro, p.Arg633Pro and p.Cys791Phe) in the defining series,
    compound heterozygous missense, nonsense (p.Arg662*) and splice variants
    in later reports, and biallelic loss-of-function variants in a patient
    ascertained for infantile-onset generalized dystonia.
  notes: >-
    No ClinGen gene-disease validity assertion for VPS41 was recorded here, so
    gene_disease_validity is left absent.
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here, we describe five unrelated families with nine affected individuals, all carrying homozygous variants in VPS41 that we show impact protein function."
    explanation: Links homozygous VPS41 variants to the disorder in five families with functional support.
  - reference: PMID:32808683
    reference_title: "Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia."
    explanation: Independent ascertainment of biallelic VPS41 loss-of-function variants through a dystonia cohort.
pathophysiology:
- name: VPS41 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic VPS41 variants reduce or abolish the function of the
    HOPS-specific VPS41 subunit. Disease missense variants fail to restore
    lysosomal function in VPS41 knockout cells, and in one compound
    heterozygote the two splice alleles (one producing an NMD-targeted
    out-of-frame transcript, one an in-frame exon-skipped transcript) jointly
    reduced VPS41 transcript and protein. VPS41 acts as an adaptor linking the
    HOPS complex to the lysosomal small GTPase ARL8B via its effector SKIP.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Biallelic germline variants, homozygous or compound heterozygous;
      missense, nonsense and splice alleles are reported.
  genes:
  - preferred_term: VPS41
    term:
      id: hgnc:12713
      label: VPS41
  molecular_functions:
  - preferred_term: molecular adaptor activity (HOPS-to-lysosome linkage)
    term:
      id: GO:0060090
      label: molecular adaptor activity
    modifier: DECREASED
  evidence:
  - reference: PMID:42656169
    reference_title: "Biallelic VPS41 Variants in Autosomal Recessive Spinocerebellar Ataxia 29 Resolved by Long-Read Sequencing and RNA Analysis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These complementary defects reduced VPS41 expression at both transcript and protein levels, supporting pathogenicity and variant reclassification."
    explanation: Patient-derived RNA and protein analysis shows reduced VPS41 from the two splice alleles.
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "The interaction of VPS41 with ARL8B through its effector SKIP (SifA and kinesin-interacting protein) contributes to lysosomal localization and trafficking and degradation of EGFR"
    explanation: Background statement of the adaptor role of VPS41 between HOPS and the lysosomal ARL8B-SKIP machinery, the activity whose loss this node records.
  downstream:
  - target: HOPS Tethering Complex Dysfunction
    causal_link_type: DIRECT
    description: >-
      Without functional VPS41, a functional HOPS complex does not form.

- name: HOPS Tethering Complex Dysfunction
  biological_scale: MOLECULAR
  description: >-
    VPS41 is one of the two HOPS-specific subunits. All tested disease
    variants prevented formation of a functional HOPS complex. Because VPS41
    is not part of CORVET, the defect is confined to the late
    endosome/autophagosome-to-lysosome fusion arm, in contrast to VPS33A
    (Mucopolysaccharidosis-Plus Syndrome), whose loss compromises both
    complexes. A HOPS-independent function of VPS41 in regulated secretion was
    preserved for the p.Ser285Pro allele.
  protein_complexes:
  - preferred_term: HOPS complex
    term:
      id: GO:0030897
      label: HOPS complex
    modifier: DECREASED
  evidence:
  - reference: PMID:33851776
    reference_title: "Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All mutants prevented formation of a functional HOPS complex, causing delayed lysosomal delivery of endocytic and autophagic cargo."
    explanation: Patient fibroblasts and VPS41-depleted cells show loss of functional HOPS with all tested variants.
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: BACKGROUND
    snippet: "VPS39 and VPS41, which are HOPS-specific, as well as VPS11, VPS16, VPS18 and VPS33A, which are also present in the CORVET complex"
    explanation: States that VPS41 is HOPS-specific, which restricts the lesion to HOPS rather than CORVET.
  downstream:
  - target: Delayed Lysosomal Delivery of Endocytic and Autophagic Cargo
    causal_link_type: DIRECT
    description: >-
      HOPS tethers late endosomes and autophagosomes to lysosomes for fusion;
      its loss delays cargo delivery.

- name: Delayed Lysosomal Delivery of Endocytic and Autophagic Cargo
  biological_scale: CELLULAR
  description: >-
    Endocytic and autophagic cargo reaches enzymatically active lysosomes
    late. The lysosomes themselves remain functional; the defect is
    insufficient delivery, which places SCAR29 among lysosomal disorders of
    trafficking rather than of hydrolase activity.
  biological_processes:
  - preferred_term: late endosome to lysosome transport
    term:
      id: GO:1902774
      label: late endosome to lysosome transport
    modifier: DECREASED
  - preferred_term: autophagosome-lysosome fusion
    term:
      id: GO:0061909
      label: autophagosome-lysosome fusion
    modifier: DECREASED
  evidence:
  - reference: PMID:33851776
    reference_title: "Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "All mutants prevented formation of a functional HOPS complex, causing delayed lysosomal delivery of endocytic and autophagic cargo."
    explanation: Direct cellular readout of delayed delivery of endocytic and autophagic cargo to lysosomes.
  - reference: PMID:33851776
    reference_title: "Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our study shows that VPS41 patients represent a new class of lysosomal disorders in which lysosomes are functional, but insufficiently reached by cargo due to a trafficking defect."
    explanation: Characterizes the lesion as a delivery defect with functional lysosomes.
  downstream:
  - target: Abnormal Lysosomal Compartment
    causal_link_type: DIRECT
    description: >-
      Undelivered and partially processed material accumulates in abnormal
      membrane-bound vesicles.
  - target: mTORC1 Redistribution and Constitutive TFE3 Activation
    causal_link_type: DIRECT
    description: >-
      Loss of HOPS function disrupts lysosome-dependent mTORC1 control of
      TFE3/TFEB.

- name: mTORC1 Redistribution and Constitutive TFE3 Activation
  biological_scale: CELLULAR
  description: >-
    In VPS41-deficient cells mTORC1 redistributes to the cytosol and TFE3 is
    continuously nuclear, while phosphorylation of the mTORC1 substrates S6K1
    and 4EBP1 is unaffected; the defect is selective for the TFEB/TFE3 arm.
    Lysosomal biogenesis and autophagosome formation are continuously
    upregulated regardless of nutrient status, and the autophagic response to
    starvation is reduced.
  biological_processes:
  - preferred_term: lysosome organization (lysosomal biogenesis)
    term:
      id: GO:0007040
      label: lysosome organization
    modifier: INCREASED
  evidence:
  - reference: PMID:33851776
    reference_title: "Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Strikingly, loss of VPS41 function caused a cytosolic redistribution of mTORC1, continuous nuclear localization of Transcription Factor E3 (TFE3), enhanced levels of LC3II, and a reduced autophagic response to nutrient starvation."
    explanation: Direct cellular evidence for the mTORC1/TFE3 dysregulation.
  - reference: PMID:33851776
    reference_title: "Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "As a result, lysosomal biogenesis and autophagosome formation is continuously upregulated independent of nutrient conditions."
    explanation: Supports the INCREASED modifier on lysosome organization (biogenesis).
  downstream:
  - target: Abnormal Lysosomal Compartment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Continuous TFE3-driven lysosomal biogenesis is consistent with the
      raised lysosomal membrane protein (LAMP2) seen in VPS41 knockout cells;
      the two observations come from different studies and the link is an
      inference.

- name: Abnormal Lysosomal Compartment
  biological_scale: CELLULAR
  description: >-
    Patient lymphocytes, lymphoblastoid cells and fibroblasts show excess
    multilayered membrane-bound vesicles and vacuolar abnormalities on
    electron microscopy, and VPS41 knockout cells show raised LAMP2 that
    disease alleles fail to correct. This is the cellular storage-like
    phenotype shared by the HOPS-associated neurological disorders.
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Transmission electron microscopy (TEM) on peripheral blood lymphocytes from Subject 2 and lymphoblastoid cells from Subject 3 revealed more multilayered vesicles compared to control cells"
    explanation: Ultrastructural evidence of abnormal vesicles in patient-derived cells.
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Whereas transfection of wild-type VPS41 resulted in downregulation of LAMP2 in transfected KO ESCs, expression of Ser285Pro, Cys791Phe, and to a lesser extent Arg633Pro, failed to downregulate LAMP2 at a population level"
    explanation: Disease alleles fail to rescue the lysosomal phenotype of VPS41 knockout cells.
  - reference: PMID:32808683
    reference_title: "Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function."
    explanation: Independent ultrastructural evidence in a VPS41 patient's cells.
  downstream:
  - target: Microglial Lysosomal Accumulation
    causal_link_type: DIRECT
    description: >-
      Highly endocytic and phagocytic microglia accumulate enlarged or
      excess acidic lysosomal compartments.
  - target: Cerebellar Neurodegeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Membrane trafficking defects in neurons are proposed to underlie the
      cerebellar atrophy; reduced Purkinje cell viability is plausible but
      not demonstrated.
  - target: Dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Lysosomal and autophagic dysfunction is the proposed shared mechanism
      of dystonia across the HOPS-associated neurological disorders; the
      circuit-level route is not established.
    evidence:
    - reference: PMID:33871597
      reference_title: "HOPS-associated neurological disorders (HOPSANDs): linking endolysosomal dysfunction to the pathogenesis of dystonia."
      supports: SUPPORT
      evidence_source: OTHER
      quote_role: REVIEW_SYNTHESIS
      snippet: "The delineation of HOPSANDs further confirms the connection of lysosomal and autophagic dysfunction with the pathogenesis of dystonia"
      explanation: Review synthesis linking HOPS-related lysosomal/autophagic dysfunction to dystonia.

- name: Microglial Lysosomal Accumulation
  biological_scale: CELLULAR
  description: >-
    In zebrafish vps41 crispants, brain acidity (LysoTracker) is increased,
    concentrated within microglia, and is reduced by wild-type vps41 mRNA;
    microglia show morphology suggestive of larger or more numerous
    lysosomal compartments. Microglial lysosomal dysfunction is proposed to
    impair brain development, including of the cerebellum. Human tissue
    confirmation is lacking.
  cell_types:
  - preferred_term: microglial cell
    term:
      id: CL:0000129
      label: microglial cell
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This revealed that vps41-deficient microglia have distinct morphological abnormalities suggestive of larger, or possibly more numerous, lysosomal compartments compared to microglia from control larvae."
    explanation: Zebrafish evidence of microglial lysosomal abnormality.
  downstream:
  - target: Cerebellar Neurodegeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Lysosomal accumulation impairs microglial function, and microglial loss
      is known to cause brain abnormalities including cerebellar hypoplasia;
      this contribution is proposed from the zebrafish data.

- name: Cerebellar Neurodegeneration
  biological_scale: TISSUE
  description: >-
    Brain MRI shows mild cerebellar and vermian atrophy or hypoplasia in most
    patients, with anterior-predominant cerebellar atrophy in a later case;
    serial MRI in two siblings showed the vermis, normal at first, losing
    volume on follow-up, so the process is degenerative. Zebrafish crispants
    show a reduced optokinetic response, used as a readout of cerebellar
    dysfunction.
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI revealed mild cerebellar atrophy and vermian atrophy without other major structural abnormalities in most affected individuals"
    explanation: Neuroimaging evidence of cerebellar involvement in patients.
  - reference: PMID:42656169
    reference_title: "Biallelic VPS41 Variants in Autosomal Recessive Spinocerebellar Ataxia 29 Resolved by Long-Read Sequencing and RNA Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He also developed pes cavus, anterior-predominant cerebellar atrophy on brain MRI"
    explanation: Cerebellar atrophy in a later, independently reported patient.
  - reference: PMID:33851776
    reference_title: "Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "brain MRI done on the younger brother (patient 2) at 10 years of age confirmed the thin corpus callosum, mild progression of the cerebellar atrophy"
    explanation: Serial MRI shows the cerebellar atrophy progressing, supporting a degenerative rather than purely malformative process.
  downstream:
  - target: Cerebellar Vermis Atrophy
    causal_link_type: DIRECT
    description: Cerebellar tissue loss is visible on MRI.
  - target: Cerebellar Ataxia
    causal_link_type: DIRECT
    description: Cerebellar dysfunction produces ataxia.
  - target: Nystagmus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Nystagmus is a common cerebellar oculomotor sign; the specific
      substrate in SCAR29 has not been studied.

phenotypes:
- name: Cerebellar Ataxia
  category: Neurological
  frequency: VERY_FREQUENT
  description: Ataxia of variable degree in all affected individuals, usually preventing independent ambulation.
  phenotype_term:
    preferred_term: Cerebellar ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Various degrees of ataxia, hypotonia, and dystonia were present in all affected individuals, preventing independent ambulation."
    explanation: Ataxia in all nine patients of the defining series.
- name: Dystonia
  category: Neurological
  frequency: VERY_FREQUENT
  description: Dystonia in all patients of the defining series; one patient was ascertained for infantile-onset generalized dystonia.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Various degrees of ataxia, hypotonia, and dystonia were present in all affected individuals, preventing independent ambulation."
    explanation: Dystonia in all nine patients.
  - reference: PMID:32808683
    reference_title: "Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also identified biallelic loss-of-function variants in VPS41, another HOPS-complex encoding gene, in an individual with infantile-onset generalized dystonia."
    explanation: Generalized dystonia as the presenting feature in an independent patient.
- name: Hypotonia
  category: Neurological
  frequency: VERY_FREQUENT
  description: Hypotonia, generalized or axial, in all affected individuals.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Various degrees of ataxia, hypotonia, and dystonia were present in all affected individuals, preventing independent ambulation."
    explanation: Hypotonia in all nine patients.
- name: Intellectual Disability
  category: Neurological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, all affected individuals displayed intellectual disability and speech delay."
    explanation: Intellectual disability in all nine patients.
- name: Speech Delay
  category: Neurological
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition, all affected individuals displayed intellectual disability and speech delay."
    explanation: Speech delay in all nine patients.
- name: Nystagmus
  category: Neurological
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Likewise, nystagmus was commonly described."
    explanation: Nystagmus was common in the defining series.
- name: Cerebellar Vermis Atrophy
  category: Neurological
  frequency: FREQUENT
  description: >-
    Mild cerebellar and vermian atrophy or hypoplasia on MRI in most patients;
    on serial imaging the vermis lost volume over time.
  phenotype_term:
    preferred_term: Cerebellar vermis atrophy
    term:
      id: HP:0006855
      label: Cerebellar vermis atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI revealed mild cerebellar atrophy and vermian atrophy without other major structural abnormalities in most affected individuals"
    explanation: Vermian atrophy on MRI in most patients.
  - reference: PMID:33851776
    reference_title: "Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the vermis, although normal in configuration and size initially, demonstrated volume loss on follow-up examinations"
    explanation: Serial MRI documents progressive vermian volume loss.
- name: Global Developmental Delay
  category: Neurological
  frequency: VERY_FREQUENT
  description: Developmental delay from early life is the usual presenting feature.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected individuals were born after uneventful pregnancies and presented in most cases early in life with developmental delay"
    explanation: Developmental delay as the presenting feature in the defining series.
  - reference: PMID:33851776
    reference_title: "Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients 1 and 2, two brothers, were diagnosed with global developmental delay, hypotonia, ataxia, and dystonia."
    explanation: Global developmental delay in an independent sibship.
- name: Dysarthria
  category: Neurological
  frequency: FREQUENT
  description: Dysarthria in 6 of 9 patients of the defining series; the other 3 had absent speech.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysarthria | Yes | Yes | Yes | Absent speech | Yes | Yes | Absent speech | Absent speech | Yes"
    explanation: Clinical table row giving dysarthria in six and absent speech in three of nine patients.
- name: Thin Corpus Callosum
  category: Neurological
  frequency: FREQUENT
  description: >-
    Thinning of the corpus callosum on MRI in the three patients of the 2021
    functional study, one with agenesis; corpus callosum atrophy was also
    noted in one patient of the defining series.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:33851776
    reference_title: "Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "brain MRI characterized by thinning of the corpus callosum and atrophy of the cerebellar vermis"
    explanation: Thin corpus callosum across the reported patients of this study.
- name: Lower Limb Spasticity
  category: Neurological
  frequency: OCCASIONAL
  description: >-
    Progressive lower-limb spasticity in the three patients of the 2021
    functional study and in one patient of the defining series.
  phenotype_term:
    preferred_term: Lower limb spasticity
    term:
      id: HP:0002061
      label: Lower limb spasticity
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33851776
    reference_title: "Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both brothers developed progressive spasticity of the lower limbs"
    explanation: Progressive lower-limb spasticity in two siblings.
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spastic for the lower extremities"
    explanation: Clinical table entry for one patient of the defining series.
- name: Abnormal Retinal Pigmentation
  category: Ophthalmological
  frequency: OCCASIONAL
  description: >-
    Retinal pigment alterations (salt-and-pepper lesions) in two patients of
    the defining series, and a hypopigmented, underdeveloped retina in two
    siblings that had resolved by one year of age.
  phenotype_term:
    preferred_term: Abnormal retinal pigmentation
    term:
      id: HP:0007703
      label: Abnormal retinal pigmentation
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In two individuals, retinal pigment alterations were noticed."
    explanation: Retinal pigment changes in two of nine patients.
  - reference: PMID:33851776
    reference_title: "Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "both had ophthalmological examination showing hypopigmented and underdeveloped retina which disappeared at 1 year of age"
    explanation: Transient retinal hypopigmentation in two siblings.
- name: Basal Ganglia Iron Deposition
  category: Neurological
  frequency: OCCASIONAL
  description: >-
    Iron deposition in the globus pallidus (with substantia nigra or
    subthalamic nuclei) on MRI in one patient of the defining series and in
    the 2021 sibship, where it was absent on earlier imaging.
  phenotype_term:
    preferred_term: Basal ganglia iron deposition
    term:
      id: HP:0012675
      label: Iron accumulation in brain
  evidence:
  - reference: PMID:33851776
    reference_title: "Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "bilateral hypointensity in the globus pallidus (GP) compatible with early iron deposition"
    explanation: Pallidal iron deposition on follow-up MRI.
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "abnormal iron deposition in the globus pallidus and substantia nigra"
    explanation: Clinical table MRI entry for one patient of the defining series.
- name: Seizures
  category: Neurological
  frequency: OCCASIONAL
  description: >-
    Therapy-resistant epilepsy in two siblings of the defining series. Bound
    to Seizure because an OLS search of HPO for drug-resistant, refractory,
    intractable and pharmacoresistant epilepsy returned no epilepsy term.
  phenotype_term:
    preferred_term: Therapy-resistant epilepsy
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:33764426
    reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two siblings further presented with therapy-resistant epilepsy."
    explanation: Epilepsy in a single sibship.
- name: Swan Neck Deformities of the Fingers
  category: Musculoskeletal
  frequency: VERY_RARE
  description: Progressive swan-neck deformities of the second to fourth fingers in one adult patient; not reported in earlier cases.
  phenotype_term:
    preferred_term: Swan neck-like deformities of the fingers
    term:
      id: HP:0006150
      label: Swan neck-like deformities of the fingers
  evidence:
  - reference: PMID:42656169
    reference_title: "Biallelic VPS41 Variants in Autosomal Recessive Spinocerebellar Ataxia 29 Resolved by Long-Read Sequencing and RNA Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "progressive swan-neck deformities of the second to fourth fingers bilaterally"
    explanation: Single-patient finding.
- name: Pes Cavus
  category: Musculoskeletal
  frequency: VERY_RARE
  description: >-
    Pes cavus in one adult patient with preserved motor nerve conduction
    velocities; the authors could not exclude a coincidental finding.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:42656169
    reference_title: "Biallelic VPS41 Variants in Autosomal Recessive Spinocerebellar Ataxia 29 Resolved by Long-Read Sequencing and RNA Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to typical SCAR29 features, the patient showed previously unreported findings, including swan-neck deformities and pes cavus."
    explanation: Single-patient finding.

diagnosis:
- name: Molecular genetic testing
  description: >-
    Diagnosis rests on finding biallelic VPS41 variants by exome or genome
    sequencing. When phase cannot be set from parents, long-read sequencing
    can show that two variants lie in trans, and RNA analysis can establish
    the effect of splice variants.
  evidence:
  - reference: PMID:42656169
    reference_title: "Biallelic VPS41 Variants in Autosomal Recessive Spinocerebellar Ataxia 29 Resolved by Long-Read Sequencing and RNA Analysis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Because maternal DNA was unavailable, long-read genome sequencing was performed to determine allelic configuration, followed by RNA and protein analyses."
    explanation: Describes the sequencing, phasing and RNA route used to confirm the diagnosis.
- name: Electron microscopy of patient cells
  description: >-
    Electron microscopy of lymphocytes, lymphoblastoid cells or fibroblasts
    shows abnormal multilayered vesicles or vacuoles. It supports variant
    interpretation but is not specific to VPS41.
  evidence:
  - reference: PMID:32808683
    reference_title: "Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Electron microscopy of patient-derived lymphocytes and fibroblasts from both patients with VPS16 and VPS41 showed vacuolar abnormalities suggestive of impaired lysosomal function."
    explanation: Ultrastructural abnormality in patient cells, shared with VPS16 disease.

animal_models:
- name: Zebrafish vps41 crispant
  species: Zebrafish
  genotype: vps41 F0 CRISPR/Cas9 crispant (60-90% disruption efficiency)
  publication: PMID:33764426
  description: >-
    F0 crispants of the single zebrafish vps41 homologue show hypopigmentation,
    absent swim bladder inflation with loss of viability, increased brain
    lysosomal acidity concentrated in microglia, and a reduced optokinetic
    response.
  modeled_mechanisms:
  - target: Microglial Lysosomal Accumulation
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Microglial lysosomal accumulation rescued by wild-type vps41 mRNA.
    limitations: >-
      Mosaic F0 knockout rather than the patients' hypomorphic missense or
      splice alleles; larval stage only, and the microglial finding has not
      been examined in human tissue.
    evidence:
    - reference: PMID:33764426
      reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This revealed that vps41-deficient microglia have distinct morphological abnormalities suggestive of larger, or possibly more numerous, lysosomal compartments compared to microglia from control larvae."
      explanation: Supports the model as informative for the microglial node.
  - target: Cerebellar Neurodegeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: ORGANISM
    description: Reduced optokinetic response, used as a cerebellar-function assay.
    limitations: >-
      The optokinetic deficit may also reflect retinal pigment epithelium or
      photoreceptor dysfunction (crispants have reduced retinal pigmentation),
      and gross brain morphology and size were normal, so cerebellar
      degeneration itself was not shown.
    evidence:
    - reference: PMID:33764426
      reference_title: "Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In contrast to control injected larvae, which demonstrated normal responses to visual stimuli, vps41 crispants showed a dramatically reduced response"
      explanation: Optokinetic deficit in crispants.
notes: >-
  No GeneReviews chapter or specific treatment is known for SCAR29; management
  is supportive and no treatment is curated. Differentials within the HOPS
  group are Mucopolysaccharidosis-Plus Syndrome (VPS33A, HOPS and CORVET) and
  VPS16-related dystonia (heterozygous loss of function). Fewer than twenty
  patients had been reported by 2026. The reported VPS41 knockout mouse is
  embryonic lethal and was not usable as a disease model.
📚

References & Deep Research

References

5
PMID:33764426
Bi-allelic variants in HOPS complex subunit VPS41 cause cerebellar ataxia and abnormal membrane trafficking.
No top-level findings curated for this source.
PMID:33851776
Neurodegenerative VPS41 variants inhibit HOPS function and mTORC1-dependent TFEB/TFE3 regulation.
No top-level findings curated for this source.
PMID:32808683
Loss-of-Function Variants in HOPS Complex Genes VPS16 and VPS41 Cause Early Onset Dystonia Associated with Lysosomal Abnormalities.
No top-level findings curated for this source.
PMID:33871597
HOPS-associated neurological disorders (HOPSANDs): linking endolysosomal dysfunction to the pathogenesis of dystonia.
No top-level findings curated for this source.
PMID:42656169
Biallelic VPS41 Variants in Autosomal Recessive Spinocerebellar Ataxia 29 Resolved by Long-Read Sequencing and RNA Analysis.
No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Spinocerebellar Ataxia, Autosomal Recessive 29 (VPS41) · 2026-10-23T02:04:54Z · View source

New entry for SCAR29 (MONDO:0030312), caused by biallelic VPS41 variants. Curated from the defining series (PMID:33764426), the HOPS/mTORC1-TFE3 functional study (PMID:33851776), the VPS16/VPS41 dystonia cohort (PMID:32808683), the HOPSAND review (PMID:33871597) and a 2026 long-read case (PMID:42656169). The pathograph runs VPS41 loss of adaptor function -> HOPS dysfunction -> delayed lysosomal cargo delivery -> abnormal lysosomal compartment and mTORC1/TFE3 dysregulation -> microglial lysosomal accumulation and cerebellar neurodegeneration -> ataxia, vermis atrophy, nystagmus, dystonia. A claude_code deep-research report was used as leads only. Validated with just validate, validate-terms, count-verified-snippets (all snippets verified), check-entity-refs, check-causal-targets and validate-disorders. preflight-dr was not run (no local MONDO build).

Claude Code ▸
Spinocerebellar Ataxia, Autosomal Recessive 29 (SCAR29; MONDO:0030312): research report
claude-haiku-5-5, claude-opus-5-5 8 citations 2026-10-23T01:58:47.754800

PubMed MCP isn't permitted; I'll use the shell and web search.

Cached the three core papers (Sanderson 2021, van der Welle 2021, Steel 2020); now reading them for exact quotes.

Now the van der Welle and Steel abstracts.

Fetching Monfrini review and the 2026 Nakamura paper.

Looking up remaining ontology terms (GO, CL, VPS41 gene ID) before writing the report.

Spinocerebellar Ataxia, Autosomal Recessive 29 (SCAR29; MONDO:0030312): research report

Causal gene: VPS41. VPS41 is a subunit of the HOPS complex, which is specific to HOPS and not shared with the related CORVET complex. The gene is at 7p14.1. OMIM lists the gene as 605485 and the disease as 619389. MONDO records VPS41 as the causal gene through the dismech stub. The same gene appears in the working branch name (curate-scar29-vps41) and in the stub's source_tags: mondo_causal_gene=VPS41. The OMIM numbers come from NCBI MedGen and were not checked against OMIM directly.

Evidence base. Every quote below is copied from a file in references_cache/, generated with just fetch-reference. These are the core sources:

Reference Study Cached content
PMID:33764426 Sanderson et al., Brain 2021: 5 families, 9 homozygous patients, ESC and zebrafish work full text
PMID:33851776 van der Welle et al., EMBO Mol Med 2021: 3 compound-heterozygous patients, fibroblast and HeLa mechanism work, C. elegans full text
DOI:10.1002/ana.25879 Steel et al., Ann Neurol 2020: one biallelic VPS41 patient with infantile dystonia abstract
DOI:10.1093/brain/awab161 Monfrini et al., Brain 2021: the "HOPSANDs" concept abstract
DOI:10.1002/mgg3.70285 Nakamura et al., Mol Genet Genomic Med 2026: compound-heterozygous splice variants resolved by long-read sequencing abstract

I did not retrieve PMIDs for the three DOI-keyed papers. The DOI is a valid reference key in dismech.

1. Disease information

  • Overview. SCAR29 is an autosomal recessive, progressive neurodevelopmental disorder. Its main features are cerebellar ataxia, hypotonia, dystonia, intellectual disability, nystagmus and cerebellar (especially vermian) atrophy. It is caused by biallelic VPS41 variants that impair the HOPS complex's role in endolysosomal and autophagosomal fusion.

    "All affected individuals presented with a progressive neurodevelopmental disorder consisting of cognitive impairment, cerebellar atrophy/hypoplasia, motor dysfunction with ataxia and dystonia, and nystagmus." (PMID:33764426)

  • Identifiers.
  • MONDO:0030312
  • OMIM 619389 (disease) and 605485 (gene), per MedGen
  • MedGen 1788435
  • No disease-specific ICD-10 code; the nearest is G11.1 (early-onset cerebellar ataxia).
  • No disease-specific Orphanet code was found.
  • Synonyms (from the MONDO stub): SCAR29; Barakat-Van Ham-Kaya syndrome; neurodevelopmental disorder with hypotonia and cerebellar ataxia.
  • Nosology. The disorder belongs to the proposed group "HOPS-associated neurological disorders (HOPSANDs)", together with VPS16 and VPS11 disease.

    "We propose to name this group of diseases HOPS-associated neurological disorders (HOPSANDs), which are mainly characterized by dystonic presentations." (DOI:10.1093/brain/awab161)

  • Data type. Everything known comes from individual case series, about 13 published patients. There is no registry or EHR data.

2. Etiology

  • Cause. The disease is monogenic: biallelic loss-of-function or hypomorphic variants in VPS41.
  • Risk factors.
  • Consanguinity: several families were consanguineous (Saudi, Iranian and Turkish families; Family 2 in van der Welle).
  • Founder allele: p.Ser285Pro occurred in two unrelated Saudi families.
  • Not reported: environmental risk factors, protective factors, modifier genes and gene-environment interactions.

3. Phenotypes

Frequencies use the 9 patients in Sanderson (Table 1, PMID:33764426), plus van der Welle (n=3), Steel (n=1) and Nakamura (n=1).

Phenotype Suggested HP term Frequency and notes Supporting quote
Global developmental delay / delayed early motor milestones HP:0001263 Global developmental delay 9/9; onset in infancy "presented in most cases early in life with developmental delay" (PMID:33764426)
Cerebellar ataxia HP:0001251 Ataxia 7/7 assessable "Various degrees of ataxia, hypotonia, and dystonia were present in all affected individuals, preventing independent ambulation." (PMID:33764426)
Hypotonia HP:0001252 8/9 (one patient had lower-limb spasticity instead); neonatal hypotonia in van der Welle as above; "Both presented with neonatal hypotonia" (PMID:33851776)
Dystonia HP:0001332 All Sanderson patients; infantile-onset generalized dystonia in Steel "biallelic loss‐of‐function variants in VPS41 … in an individual with infantile‐onset generalized dystonia" (DOI:10.1002/ana.25879)
Intellectual disability HP:0001249 9/9 (mild in 1/9) "all affected individuals displayed intellectual disability and speech delay" (PMID:33764426)
Speech delay or absent speech; dysarthria HP:0000750; HP:0001260 Dysarthria 6/9; absent speech 3/9 same quote
Nystagmus HP:0000639 About 5/9 (horizontal on lateral gaze) "nystagmus was commonly described" (PMID:33764426)
Abnormal smooth pursuit HP:0007772 (verify) Abnormal in 2/9 Table 1
Cerebellar vermis atrophy / cerebellar atrophy or hypoplasia HP:0006855; HP:0001272; HP:0001321 Most patients; progressive vermis volume loss on serial MRI "Brain MRI revealed mild cerebellar atrophy and vermian atrophy" (PMID:33764426)
Thin or hypoplastic corpus callosum (agenesis in one patient) HP:0002079 3/3 in van der Welle "brain MRI findings of cerebellar atrophy and thin corpus callosum" (PMID:33851776)
Retinal pigment abnormality or transient retinal dystrophy HP:0007703 2/9 in Sanderson ("salt and pepper"); 3/3 in van der Welle (hypopigmented retina) "In two individuals, retinal pigment alterations were noticed." (PMID:33764426)
Seizures (therapy-resistant epilepsy) HP:0001250 2/9 (one sib pair) "Two siblings further presented with therapy-resistant epilepsy." (PMID:33764426)
Neurodevelopmental regression HP:0002376 (verify) 2/9 Table 1
Myopathic facies HP:0002058 (verify) 4/9 Table 1
Spasticity (lower limbs) HP:0001257 1/9; also van der Welle patient 3 from age 5 Table 1; PMID:33851776
Basal ganglia iron deposition HP:0012675 (verify) 2 patients (one in Sanderson, one in van der Welle) PMID:33851776 figure legend
Failure to thrive, contractures HP:0001508 Sporadic Fig. 1 legend, PMID:33764426
Swan-neck deformity, pes cavus HP:0001001 / HP:0001761 (verify) 1 patient; newly reported "previously unreported findings, including swan‐neck deformities and pes cavus" (DOI:10.1002/mgg3.70285)
Abnormal multilayered vesicles in lymphocytes (laboratory finding) No HP term; cellular 2 tested "revealed more multilayered vesicles compared to control cells" (PMID:33764426)
  • Onset: infancy, from the neonatal period to the first year.
  • Course: progressive.
  • Severity: usually severe. Most patients cannot walk independently, and several use wheelchairs.
  • Quality of life: no formal quality-of-life studies exist.
  • Normal findings: nerve conduction was normal where tested.

4. Genetic and molecular information

  • Gene: VPS41 (VPS41 subunit of HOPS complex), transcript NM_014396.
  • HGNC ID: I believe it is HGNC:12713. This is unverified. The ID is not in cache/hgnc/terms.csv, and the OLS lookup was not permitted in this session. Confirm it with just validate-terms before binding.
  • Reported variants:
Variant Zygosity / origin Notes
c.853T>C p.(Ser285Pro) Homozygous in 2 Saudi families; in trans with R662* in van der Welle WD40 β-propeller domain; gnomAD MAF 0.000007; possibly affects ARL8B binding
c.1898G>C p.(Arg633Pro) Homozygous, Iran CHCR α-helix kink; reduced protein
c.2372G>T p.(Cys791Phe) Homozygous, Brazil First cysteine of the RING zinc finger; predicted to abolish zinc binding
c.38A>G p.(Glu13Gly) Homozygous, Turkey Acidic N-terminal region; normal protein level but reduced TFE3 rescue
c.1984C>T p.(Arg662*) Compound heterozygous (3 patients) Shared nonsense allele
c.1423-2A>G Compound heterozygous Canonical splice-acceptor variant; about 10% residual protein
Two splice variants (Nakamura 2026) Compound heterozygous One allele gives an out-of-frame transcript (NMD); the other an in-frame exon skip
  • Variant origin: all germline.
  • Mechanism: loss of function or hypomorphic alleles. Complete loss is probably lethal, since the Vps41 knockout mouse dies in early embryogenesis.

    "VPS41 knockout mice die early in utero, signifying VPS41 as an essential protein for embryonic development" (PMID:33851776)

  • ClinGen / ClinVar: no ClinGen gene-disease validity curation was found, so leave gene_disease_validity absent. PanelApp Australia rates VPS41 green.
  • Not reported: modifier genes, epigenetic contributions and chromosomal abnormalities.
  • Incidental findings: van der Welle patient 1 also carried a 1q21.1 duplication, and patient 3 a homozygous UPF3A variant of uncertain significance.

5. Environmental information

Not applicable. No environmental, lifestyle or infectious factors have been reported.

6. Mechanism and pathophysiology

Ordered causal chain

  1. Biallelic VPS41 variants (missense, nonsense or splice) reduce VPS41 protein abundance or function. This is shown directly: patient and rescue constructs had lower protein, and the Nakamura alleles reduced transcript and protein.
  2. This prevents assembly of a functional HOPS tethering complex (demonstrated in patient fibroblasts and HeLa cells).

    "All mutants prevented formation of a functional HOPS complex, causing delayed lysosomal delivery of endocytic and autophagic cargo." (PMID:33851776)

  3. Endolysosomal and autophagosome-lysosome fusion is impaired, which delays cargo delivery to lysosomes that are otherwise functional (demonstrated).

    "VPS41 patients represent a new class of lysosomal disorders in which lysosomes are functional, but insufficiently reached by cargo due to a trafficking defect." (PMID:33851776)

  4. The pathway branches at this point (demonstrated in vitro):
  5. 4a. mTORC1 cannot regulate TFEB/TFE3. mTORC1 redistributes to the cytosol, and TFE3/TFEB stay constitutively nuclear. This leads to continuous upregulation of lysosomal biogenesis (LAMP2 up) and autophagosome formation (LC3-II up). Autophagy responds less to starvation. Phosphorylation of S6K1 and 4EBP1 is preserved, so the defect is specific to the TFEB/TFE3 arm. > "the disease‐causing mutations specifically impair mTORC1 activity toward TFE3 and TFEB, causing constitutive activation of these transcription factors" (PMID:33851776)
  6. 4b. Abnormal lysosome-related organelles accumulate: multilayered vesicles in lymphocytes, enlarged acidic compartments, and pigment defects in zebrafish melanosomes and retinal pigment epithelium.
  7. 4c. VPS41's HOPS-independent role in regulated secretion is preserved for S285P. This is a negative result.
  8. Lysosomal dysfunction in neural cells. In zebrafish vps41 crispants (mosaic F0 knockouts):
  9. microglia are swollen and amoeboid with large acidic compartments, and LysoTracker signal rises across the whole brain;
  10. wild-type mRNA rescues the brain LysoTracker signal.

The evidence here is from a model organism. 6. Purkinje cell and cerebellar dysfunction, then cerebellar atrophy. This step is inferred. Zebrafish showed a cerebellar-type optokinetic defect, but no visible Purkinje cell loss. VPS41 is highly expressed in Purkinje cells.

"A scenario of reduced viability of Purkinje cells is also plausible for VPS41-related ataxia" (PMID:33764426) 7. Clinical outcome: ataxia, dystonia, nystagmus, developmental delay and intellectual disability, with progressive vermian atrophy. Dystonia probably also involves basal ganglia circuits. This is inferred from the HOPSAND parallel; iron deposition was seen in 2 patients.

A second, protective role is also lost. VPS41 normally protects dopaminergic neurons against α-synuclein, and patient alleles lose this activity in C. elegans:

"co-expression of VPS41S285P /VPS41R662* abolished the neuroprotective function of VPS41 against α-synuclein aggregates" (PMID:33851776)

Suggested ontology terms

  • GO biological processes:
  • GO:1902774 late endosome to lysosome transport
  • GO:0061909 autophagosome-lysosome fusion
  • GO:0097352 autophagosome maturation
  • GO:0007040 lysosome organization
  • GO:0016236 macroautophagy
  • GO:0008333 endosome to lysosome transport
  • GO:0032008 positive regulation of TOR signaling (use with care; the defect is selective to TFEB/TFE3)
  • GO cellular component: GO:0030897 HOPS complex
  • CL cell types:
  • CL:0000121 Purkinje cell
  • CL:0000129 microglial cell
  • CL:0000057 fibroblast (patient cells)
  • CL:0000542 lymphocyte
  • CL:0000148 melanocyte (zebrafish)
  • CL:0000700 dopaminergic neuron (C. elegans)
  • Molecular profiling: no transcriptomic, proteomic, metabolomic, single-cell or CRISPR-screen data exist for this disease. Sanderson did a co-expression analysis (105 genes) enriched for vesicle transport, phagosome maturation and autophagy terms.

7. Anatomical structures affected

  • Primary: cerebellum (UBERON:0002037), especially the cerebellar vermis (UBERON:0004720).
  • Also affected:
  • corpus callosum (UBERON:0002336)
  • basal ganglia (UBERON:0002420): iron deposition, caudate hyperintensity
  • retina (UBERON:0000966): pigmentary changes
  • brainstem and cerebral cortex atrophy in severe cases
  • Musculoskeletal (secondary): contractures, thoracic deformity, kyphosis, swan-neck deformity, pes cavus.
  • Subcellular: late endosome, lysosome and autophagosome compartments; the HOPS complex.
  • Laterality: bilateral and symmetric.

8. Temporal development

  • Onset: congenital or infantile (neonatal hypotonia; developmental delay in the first year).
  • Course: chronic and progressive.
  • Serial MRI showed vermis volume loss: normal vermis at 21 months, volume loss at 4 years 7 months.
  • Two patients regressed.
  • Lower-limb spasticity appeared from age 5 in one patient.
  • Survival: patients reached at least 27–28 years of age.
  • Not described: formal disease stages and remission.

9. Inheritance and population

  • Inheritance: autosomal recessive (HP:0000007).
  • Both homozygous variants (often in consanguineous families) and compound heterozygous variants occur.
  • Parents and sibling carriers are unaffected.
  • Not reported: penetrance (appears complete), anticipation, and mosaicism.
  • Prevalence: unknown, ultra-rare. About 14 published patients:
  • 9 in Sanderson
  • 3 in van der Welle
  • 1 in Steel
  • 1 in Nakamura

Use measure_type: CASES_IN_LITERATURE. - Ancestries reported: Saudi Arab (founder p.Ser285Pro), Iranian, Brazilian, Turkish, Jewish (van der Welle family 2), European (van der Welle family 1, and Steel's patient) and Japanese. - Sex ratio: no bias evident (about 9 male, 4 female).

10. Diagnostics

  • Genetic testing is the diagnostic test.
  • Exome or genome sequencing, or an ataxia or dystonia gene panel. VPS41 is on PanelApp Australia panels.
  • Long-read sequencing can establish phase when parental DNA is unavailable.
  • RNA analysis can show splicing consequences.

    "Long‐read genome sequencing demonstrated that two VPS41 variants were in trans." (DOI:10.1002/mgg3.70285)

  • Supportive tests:
  • Brain MRI: vermian atrophy, thin corpus callosum, delayed myelination, basal ganglia iron.
  • Electron microscopy of lymphocytes or fibroblasts: multilayered or vacuolar vesicles.
  • Ophthalmologic examination.
  • Standard lysosomal and metabolic screens (mucopolysaccharides, oligosaccharides, CDG) were normal, which helps the differential diagnosis.
  • Differential diagnosis:
  • other SCARs
  • other HOPSANDs (VPS16, VPS11, VPS33A/mucopolysaccharidosis-plus)
  • neurodegeneration with brain iron accumulation (NBIA)
  • Hermansky-Pudlak syndrome
  • congenital disorders of glycosylation (CDG)
  • lysosomal storage disorders
  • Clinical criteria and screening: there are no formal diagnostic criteria. Carrier testing and cascade testing apply to known families.

11. Outcome and prognosis

  • Most patients have a severe, lifelong disability and cannot walk independently.
  • No mortality data are available. Patients are reported alive into their late 20s.
  • Complications include contractures, scoliosis or kyphosis, epilepsy (2 patients), recurrent infections and hearing loss (van der Welle patient 3).
  • No prognostic biomarkers are known.

12. Treatment

  • No disease-modifying therapy and no clinical trials were found.
  • Supportive care, with suggested NCIT terms:
  • Physical Therapy (NCIT:C15302)
  • Occupational Therapy (NCIT:C121351)
  • Speech-language therapy (NCIT:C159273)
  • antiseizure Pharmacotherapy (NCIT:C15986)
  • Supportive Care (NCIT:C15747)
  • Genetic Counseling (NCIT:C15240)
  • Proposed only, not tested: targeting the mTORC1–TFEB/TFE3 axis or lysosomal-autophagy pathways.

    "potential importance for treatment of HOPS‐related disorders" (PMID:33851776)

13. Prevention

There is no primary prevention. Options are: - genetic counseling (25% recurrence risk for carrier parents) - carrier testing of relatives - prenatal or preimplantation diagnosis once the familial variants are known

Tertiary prevention means managing orthopaedic complications and seizures.

14. Other species

No naturally occurring animal disease was found; OMIA was not checked. VPS41 is conserved: zebrafish vps41 shares 82% amino-acid identity with the human protein, and yeast Vps41 is the founding vacuolar-sorting gene.

15. Model organisms

Model Phenotype How well it matches human disease, and limits Source
Zebrafish vps41 crispant (F0, CRISPR) Hypopigmentation; swim bladder not inflated; lethal; reduced OKR saccades, consistent with cerebellar dysfunction; brain-wide increase in LysoTracker signal; swollen microglia; rescued by mRNA Partially reproduces the lysosomal and cerebellar features. Mosaic F0 animals; no Purkinje cell loss seen; larval lethality PMID:33764426
Human ESC VPS41 knockout (CRISPR) Nuclear TFE3; LAMP2 up; used to test variant rescue In vitro PMID:33764426
Patient fibroblasts and VPS41-depleted HeLa cells HOPS assembly lost; delayed cargo delivery; mTORC1 mislocalized; TFEB/TFE3 constitutively nuclear In vitro PMID:33851776
C. elegans α-synuclein dopaminergic neuron model Patient alleles lose neuroprotection Parkinson's disease context, not ataxia PMID:33851776
Vps41 knockout mouse Early embryonic lethal Cannot model the postnatal disease; a conditional or hypomorphic model is needed Aoyama et al. 2012, as cited in PMID:33764426 / PMID:33851776

Open items before curating the entry

  • Confirm the VPS41 HGNC CURIE.
  • The HP terms marked "(verify)" are not in cache/hp/terms.csv. Check each against HPO before binding it.
  • PubMed PMIDs for Steel 2020, Monfrini 2021 and Nakamura 2026 were not retrieved. The DOI-keyed cache files can be cited as they are.
  • No GeneReviews chapter is expected for this disease, but this was not confirmed. just check-genereviews will answer it offline.
  • The five reference cache files fetched in this session have not been committed yet:
  • PMID_33764426.md
  • PMID_33851776.md
  • DOI_10.1002_ana.25879.md
  • DOI_10.1093_brain_awab161.md
  • DOI_10.1002_mgg3.70285.md

Sources: Sanderson 2021, PMC8041041 · van der Welle 2021, PMC8103106 · Steel 2020, Ann Neurol · Monfrini 2021 (UCL Discovery) · Nakamura 2026, MGGM · NCBI MedGen 1788435 · MalaCards SCAR29 · PanelApp Australia VPS41

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome Count
References checked 7
Resolved 7
Unresolved (possible confabulation) 0
Unverifiable 0
Quoted claims checked 22
Quoted claims found in source 21
Quoted claims not found in source 1
References weighed for topical relevance 7
On topic 7
Off topic 0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

  • DOI:10.1002/ana.25879 (abstract only): "biallelic loss‐of‐function variants in VPS41 … in an individual with infantile‐onset generalized dystonia"
  • closest text in source: "We also identified biallelic loss‐of‐function variants in VPS41 , another HOPS‐complex encoding gene, in an individual with infantile‐onset generalized dystonia"

Term Validation

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

Outcome Count
Terms checked 50
Resolved 49
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 1
Terms whose name was checked 24
Terms named correctly 12
Terms named as a different term 5
Terms whose name is worth a second look 7

Terms the report names something else

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

  • HP:0007772 (1 mention) - the report calls it "verify"; HP calls it Impaired smooth pursuit
  • HP:0001250 (1 mention) - the report calls it "Seizures (therapy-resistant epilepsy)"; HP calls it Seizure
  • HP:0002376 (1 mention) - the report calls it "verify"; HP calls it Developmental regression
  • HP:0002058 (1 mention) - the report calls it "verify"; HP calls it Myopathic facies
  • HP:0012675 (1 mention) - the report calls it "verify"; HP calls it Iron accumulation in brain

Terms whose name is worth a second look

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

  • HP:0002079 (1 mention) - the report calls it "Thin or hypoplastic corpus callosum (agenesis in one patient)"; HP calls it Hypoplasia of the corpus callosum, and lists "Hypoplastic corpus callosum" among its other names
  • HP:0007703 (1 mention) - the report calls it "Retinal pigment abnormality or transient retinal dystrophy"; HP calls it Abnormal retinal pigmentation, and lists "Retinal pigmentary anomaly" among its other names
  • HP:0001257 (1 mention) - the report calls it "Spasticity (lower limbs)"; HP calls it Spasticity
  • HP:0001508 (1 mention) - the report calls it "Failure to thrive, contractures"; HP calls it Failure to thrive
  • UBERON:0002037 (1 mention) - the report calls it "Primary: cerebellum"; UBERON calls it cerebellum**
  • UBERON:0002420 (1 mention) - the report calls it "basal ganglia"; UBERON calls it basal ganglion, and lists "basal ganglia" among its other names
  • NCIT:C15986 (1 mention) - the report calls it "antiseizure Pharmacotherapy"; NCIT calls it Pharmacotherapy