Autism Spectrum Disorder-Epilepsy-Arthrogryposis Syndrome

Mendelian MONDO:0014248 Pathograph 8 Show in embeddings browser congenital disorder of glycosylation distal arthrogryposis

Autism spectrum disorder-epilepsy-arthrogryposis syndrome (SLC35A3-CDG) is a rare autosomal recessive congenital disorder of N-linked glycosylation caused by biallelic pathogenic variants in SLC35A3 (1p21), which encodes the major Golgi UDP-N-acetylglucosamine (UDP-GlcNAc) transporter. Loss of transporter activity reduces lumenal UDP-GlcNAc, the nucleotide-sugar donor for the N-acetylglucosaminyltransferases (GnTs) that build multiantennary N-glycans, producing a marked decrease in highly branched tri- and tetraantennary N-glycans and a reciprocal accumulation of lower-branched glycoforms at the cell surface (a type II CDG signature). The clinical spectrum is dominated by a neurodevelopmental triad of autism spectrum disorder, epilepsy (including early-onset epileptic encephalopathy with infantile spasms), and intellectual disability, combined with distal arthrogryposis and additional skeletal defects (vertebral anomalies, scoliosis, camptodactyly), acquired microcephaly, quadriplegia, and dysmorphic features. The human disease phenocopies the bovine SLC35A3 disorder Complex Vertebral Malformation syndrome. It is ultra-rare, reported in a small number of families since its 2013 description.

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1
Inheritance
8
Pathophys.
24
Phenotypes
3
Gaps
8
Pathograph
1
Genes
3
Medical Actions
7
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Autosomal recessive; affected individuals carry biallelic (homozygous or compound heterozygous) SLC35A3 variants. The disorder was first defined in a large kindred with eight affected individuals carrying deleterious SLC35A3 variants; subsequent families have carried compound heterozygous or homozygous variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:28328131 SUPPORT Human Clinical
"two siblings, a boy and a girl, manifesting a severe epileptic encephalopathy (EE) with skeletal abnormalities, carried novel SLC35A3 compound heterozygous mutations."
Documents compound heterozygous (recessive) SLC35A3 variants in affected siblings.
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Discussions and Knowledge Gaps

3
Is SLC35A3 truly the sole/primary Golgi UDP-GlcNAc transporter in humans, or do redundant transport routes compensate in a cell-type-dependent manner?
HUMAN MODEL MISMATCH OPEN slc35a3_sole_transporter_model_mismatch
Attached to
pathophysiology#Impaired Golgi UDP-GlcNAc Transport
Patient fibroblasts show reduced Golgi UDP-GlcNAc transport and loss of highly branched N-glycans, supporting SLC35A3 as the major transporter. However, CRISPR knockout of SLC35A3 in CHO, HEK293T, and HepG2 cell lines gives cell-context-dependent results: in CHO cells N-glycan branching was impaired even though vesicular UDP-GlcNAc transport was not decreased, and in HepG2 cells no qualitative N-glycan change was seen — implying redundant or alternative UDP-GlcNAc transport routes. Whether this redundancy operates in the human neural and skeletal tissues that drive the disease phenotype is unresolved, so a negative cell-line transport result should not be treated as disproof of the human patient-fibroblast lesion.
Show evidence (2 references)
PMID:32938718 SUPPORT In Vitro
"These findings suggest that SLC35A3 may not be the primary UDP-GlcNAc transporter and/or different mechanisms of UDP-GlcNAc transport into the Golgi apparatus may exist."
Knockout cell-line data question whether SLC35A3 is the sole/primary UDP-GlcNAc transporter, defining the model-vs-human gap.
PMID:32938718 SUPPORT In Vitro
"in SLC35A3-knockout CHO cells, only limited changes were observed; GlcNAc was still incorporated into N-glycans, but complex type N-glycan branching was impaired, although UDP-GlcNAc transport into Golgi vesicles was not decreased."
Shows the dissociation between branching defect and measurable transport in one knockout cell model, motivating the mismatch.
Does SLC35A3 loss disrupt somite formation specifically by starving LFNG of UDP-GlcNAc and thereby dysregulating Notch segmentation-clock signaling in the presomitic mesoderm, or through another route?
KNOWLEDGE GAP OPEN slc35a3_lfng_notch_segmentation_untested
Attached to
pathophysiology#Impaired Somite Segmentation
The SLC35A3→LFNG→Notch segmentation-clock mechanism is currently inferred from Slc35a3 presomitic-mesoderm expression and the CVM-like vertebral phenotype of Slc35a3-null mice, not from direct measurement of Notch signaling. The originating study explicitly frames it as a hypothesis still requiring test: the expression of segmentation-clock Notch molecules in Slc35a3-null embryos has not yet been examined.
Proposed experiments
Segmentation-clock Notch profiling in Slc35a3-null presomitic mesoderm
exp_slc35a3_notch_clock_psm
Examine the expression and cyclic oscillation of Notch segmentation-clock molecules (e.g., Lfng, Hes7, and cyclic Notch target genes) in the presomitic mesoderm of Slc35a3-null embryos during somite formation, compared with wild-type littermates.
Decision criterion
Disrupted or dampened cyclic Notch/Lfng expression in the Slc35a3-null PSM would support the LFNG-substrate-supply model; preserved oscillation would point to a Notch-independent route to malsegmentation.
Show evidence (1 reference)
PMID:37053259 SUPPORT Model Organism
"To investigate this hypothesis, the expression of Notch signaling molecules involved in the segmentation clock should be examined in detail during somite formation"
The originating mouse study frames the SLC35A3-LFNG-Notch segmentation-clock mechanism as an untested hypothesis requiring direct examination.
Which specific neuronal glycoproteins, hypoglycosylated as a consequence of SLC35A3 deficiency, drive the autism / epilepsy / intellectual-disability phenotype?
KNOWLEDGE GAP OPEN slc35a3_neuronal_glycoprotein_targets_unknown
Attached to
pathophysiology#Neurodevelopmental Dysfunction
The neurodevelopmental phenotype is attributed to impaired glycosylation of central-nervous-system proteins, but the specific responsible glycoproteins remain unidentified and the causal link is stated only as a possibility. This is why Neurodevelopmental Dysfunction is deliberately modeled as a single coarse node rather than a resolved molecular cascade.
Proposed experiments
Glycoproteomics of SLC35A3-deficient patient-derived neural cells
exp_slc35a3_neural_glycoproteomics
Perform site-specific N-glycoproteomics (lectin/HILIC enrichment with mass spectrometry) on SLC35A3-patient-derived or iPSC-derived neurons versus isogenic controls to identify the neuronal glycoproteins whose branched N-glycans are selectively lost, prioritizing candidates in neurodevelopmental and synaptic pathways.
Decision criterion
Reproducible loss of highly branched N-glycans on a defined set of CNS-expressed glycoproteins, enriched for neurodevelopmental function, would nominate specific molecular effectors of the phenotype; a diffuse, non-selective glycosylation shift would instead support a global, non-target-specific mechanism.
Show evidence (1 reference)
PMID:28328131 SUPPORT Human Clinical
"Neurological symptoms and skeletal abnormalities might result from impaired glycosylation of proteins involved in normal development and function of the central nervous system"
The mechanistic link to CNS-protein glycosylation is stated only as a possibility, leaving the specific target glycoproteins undefined.
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Pathophysiology

8
Impaired Golgi UDP-GlcNAc Transport
Biallelic pathogenic variants in SLC35A3 reduce transport of UDP-N-acetylglucosamine (UDP-GlcNAc), the nucleotide-sugar donor for N-acetylglucosaminylation, from the cytosol into the lumen of the Golgi apparatus. SLC35A3 is regarded as the major Golgi UDP-GlcNAc transporter in mammals, so loss of its activity is the primary biochemical lesion; in Golgi vesicles from patient fibroblasts, transport of the nucleotide sugar is significantly reduced. Depletion of the lumenal UDP-GlcNAc pool is the shared upstream defect that feeds three parallel GlcNAc-dependent pathways: complex N-glycan antenna branching (via the MGAT GnTs), LFNG-mediated O-fucose elongation on Notch EGF repeats (segmentation clock), and glycosaminoglycan chain synthesis — so those three consequences are siblings of one another, not sequential.
UDP-N-acetylglucosamine transmembrane transport GO:1990569 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased UDP-N-acetylglucosamine transmembrane transport (GO:1990569). GO:1990569 is a biological process from the Gene Ontology. ↓ DECREASED
UDP-N-acetylglucosamine transmembrane transporter activity GO:0005462 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased UDP-N-acetylglucosamine transmembrane transporter activity (GO:0005462). GO:0005462 is a molecular function from the Gene Ontology. ↓ DECREASED
Golgi membrane GO:0000139 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves Golgi membrane (GO:0000139). GO:0000139 is a cellular component from the Gene Ontology.
Downstream
Reduced N-Glycan Branching
Impaired Somite Segmentation
Impaired Glycosaminoglycan Biosynthesis
Show evidence (3 references)
PMID:24031089 SUPPORT In Vitro
"SLC35A3 encodes the major Golgi uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) transporter. In Golgi vesicles isolated from patient fibroblasts the transport of the respective nucleotide sugar was significantly reduced"
Establishes reduced Golgi UDP-GlcNAc transport as the core molecular defect in patient fibroblasts.
PMID:23766508 SUPPORT In Vitro
"SLC35A3 is considered the main UDP-N-acetylglucosamine transporter (NGT) in mammals."
Confirms SLC35A3 as the principal mammalian Golgi UDP-GlcNAc transporter whose loss is the primary lesion.
PMID:41554664 SUPPORT Other
"Most CDG are enzymatic deficiencies, but 13 (6.5%) are defects in the ER, Golgi apparatus (GA), and plasma membrane transporters."
Places SLC35A3-CDG within the membrane-transporter subgroup of congenital disorders of glycosylation.
Reduced N-Glycan Branching
Reduced lumenal UDP-GlcNAc limits the N-acetylglucosaminyltransferases (e.g., MGAT4/MGAT5) that add the GlcNAc branch points of complex N-glycans, causing a massive decrease in highly branched tri- and tetraantennary N-glycans at the cell surface and a reciprocal accumulation of lower-branched (mono- and diantennary) glycoforms. Follow-up biochemical testing in patients confirms abnormal protein glycosylation consistent with a defective Golgi UDP-GlcNAc transporter. This altered branching signature has been associated with growth arrest and induction of differentiation. As a Golgi N-glycan maturation defect producing a type II CDG transferrin/glycoform signature, this node conforms to the conserved congenital-disorder-of-glycosylation module.
N-glycan processing GO:0006491 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased N-glycan processing (GO:0006491). GO:0006491 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Neurodevelopmental Dysfunction
Show evidence (2 references)
PMID:24031089 SUPPORT In Vitro
"a massive decrease in the content of cell surface expressed highly branched N-glycans and a concomitant sharp increase of lower branched glycoforms."
Documents the loss of highly branched N-glycans with a reciprocal increase in lower-branched glycoforms.
PMID:23766508 SUPPORT In Vitro
"cells deficient in NGT activity displayed a decrease in the amount of highly branched tri- and tetraantennary N-glycans, whereas monoantennary and diantennary ones remained unchanged or even were accumulated."
In vitro NGT-deficient cells recapitulate the reduced multiantennary branching with accumulation of lower-branched glycans.
Neurodevelopmental Dysfunction
Abnormal N-glycosylation of neural glycoproteins is proposed to impair normal development and function of the central nervous system, manifesting as autism spectrum disorder, epilepsy (including early-onset epileptic encephalopathy with infantile spasms and a suppression-burst EEG pattern), intellectual disability, and acquired microcephaly. The neurodevelopmental triad of autism, epilepsy, and intellectual disability is the clinical hallmark of the syndrome.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Show evidence (2 references)
PMID:24031089 SUPPORT Human Clinical
"eight patients from a large kindred, who suffered from autism spectrum disorder, arthrogryposis and epilepsy."
Establishes the neurodevelopmental triad (autism, epilepsy) as the presenting phenotype of the founding kindred.
PMID:28328131 SUPPORT Human Clinical
"Neurological symptoms and skeletal abnormalities might result from impaired glycosylation of proteins involved in normal development and function of the central nervous system and skeletal apparatus."
Links the neurological phenotype mechanistically to impaired glycosylation of CNS proteins.
Impaired Somite Segmentation
SLC35A3 supplies UDP-GlcNAc to the Golgi GlcNAc-transferases — notably LFNG (Lunatic fringe), a beta-1,3-N-acetylglucosaminyltransferase that elongates O-fucose glycans on the Notch receptor EGF repeats with GlcNAc (the O-fucose itself is added by POFUT1). Fringe-mediated GlcNAc elongation tunes Notch activity in the segmentation clock of the presomitic mesoderm, so a UDP-GlcNAc supply defect is proposed to impair this GlcNAc-transferring step and the sugar modification essential for somite formation. Slc35a3 mRNA is expressed in the presomitic mesoderm of wild-type mice, and Slc35a3-null mice develop CVM-like vertebral malsegmentation, which supports — but does not yet directly prove — the SLC35A3→LFNG substrate-supply model: the originating study frames it as a hypothesis still requiring test (see knowledge gap). This node conforms to the conserved axial-segmentation serial-homology module.
Presomitic (Paraxial) Mesoderm Cell CL:0011007 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Presomitic (Paraxial) Mesoderm Cell, annotated with paraxial cell (CL:0011007). CL:0011007 is a cell type from the Cell Ontology.
Segmentation GO:0035282 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal Segmentation (GO:0035282). GO:0035282 is a biological process from the Gene Ontology. ⚠ ABNORMAL somitogenesis GO:0001756 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal somitogenesis (GO:0001756). GO:0001756 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Vertebral Malsegmentation
Show evidence (1 reference)
PMID:37053259 SUPPORT Model Organism
"SLC35A3 transports UDP-GlcNAc used for the sugar modification that is essential for somite formation"
Implicates the UDP-GlcNAc supply defect in impaired somite formation, the segmentation-clock mechanism.
Vertebral Malsegmentation
Mis-specification of the metameric somite template produces vertebral malsegmentation — butterfly and hemivertebrae throughout the spine — the axial-skeletal outcome of the segmentation defect, phenocopying the bovine Complex Vertebral Malformation syndrome.
Show evidence (1 reference)
PMID:28777481 SUPPORT Human Clinical
"anomalous vertebrae, including butterfly, and hemivertebrae throughout the spine,"
Documents the human vertebral malsegmentation outcome of the segmentation defect.
Impaired Glycosaminoglycan Biosynthesis
Beyond N-glycan branching, SLC35A3 loss reduces the UDP-GlcNAc supply for glycosaminoglycan (GAG) chain synthesis. In Slc35a3-null mice the amounts of heparan sulfate, keratan sulfate, and chondroitin/dermatan sulfate are all significantly decreased, implicating impaired GAG (and therefore proteoglycan) biosynthesis as a distinct arm of the skeletal pathology.
glycosaminoglycan biosynthetic process GO:0006024 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycosaminoglycan biosynthetic process (GO:0006024). GO:0006024 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Growth Plate Cartilage ECM Deficiency
Show evidence (1 reference)
PMID:37053259 SUPPORT Model Organism
"the amounts of heparan sulfate, keratan sulfate, and chondroitin sulfate/dermatan sulfate, were significantly decreased"
Establishes decreased glycosaminoglycan biosynthesis as a discrete downstream lesion.
Growth Plate Cartilage ECM Deficiency
Decreased GAG/proteoglycan biosynthesis degrades the quality of the growth-plate cartilage extracellular matrix. In Slc35a3-null embryos the growth-plate extracellular space is drastically reduced and proliferative chondrocytes are reshaped, with proliferation, apoptosis, and differentiation unaffected — indicating the chondrodysplasia arises from abnormal ECM quality rather than chondrocyte loss.
chondrocyte CL:0000138 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves chondrocyte (CL:0000138). CL:0000138 is a cell type from the Cell Ontology.
Downstream
Skeletal and Joint Dysgenesis
Show evidence (1 reference)
PMID:37053259 SUPPORT Model Organism
"extracellular space was drastically reduced, and many flat proliferative chondrocytes were reshaped"
Localizes the lesion to growth-plate cartilage ECM quality, the intermediate step to skeletal dysgenesis.
Skeletal and Joint Dysgenesis
Abnormal cartilage extracellular matrix and impaired glycosylation of proteins required for normal skeletal and joint development produce distal arthrogryposis (congenital contractures predominant in the hands), scoliosis, camptodactyly, chondrodysplasia, and additional skeletal defects. The bovine SLC35A3 disorder Complex Vertebral Malformation syndrome recapitulates the same arthrogryposis-with-skeletal-defects phenotype, supporting a conserved glycosylation-dependent mechanism of skeletal patterning.
Show evidence (3 references)
PMID:28328131 SUPPORT Human Clinical
"General examination showed distal arthrogryposis predominant in the hands in both siblings and severe left dorso-lumbar convex scoliosis in one."
Documents distal arthrogryposis and scoliosis as the skeletal/joint consequences.
PMID:24031089 SUPPORT Model Organism
"Spontaneous mutation in SLC35A3 has been discovered in cattle worldwide, recapitulating the human phenotype with arthrogryposis and additional skeletal defects known as Complex Vertebral Malformation syndrome."
Bovine SLC35A3 model recapitulates the human arthrogryposis and skeletal-defect phenotype.
PMID:37053259 SUPPORT Model Organism
"perinatal lethal and exhibited chondrodysplasia recapitulating CVM-like vertebral anomalies"
Slc35a3-null mice recapitulate the CVM-like chondrodysplasia/skeletal phenotype, providing in vivo causal evidence.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Autism Spectrum Disorder-Epilepsy-Arthrogryposis Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

24
Cardiovascular 1
Patent ductus arteriosus HP:0001643 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patent ductus arteriosus (HP:0001643). HP:0001643 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28777481 SUPPORT Human Clinical
"patent foramen ovale, patent ductus arteriosus, posterior embryotoxon, short limbs,"
Documents patent ductus arteriosus in an affected patient.
Eye 1
Posterior embryotoxon HP:0000627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Posterior embryotoxon (HP:0000627). HP:0000627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28777481 SUPPORT Human Clinical
"patent ductus arteriosus, posterior embryotoxon, short limbs,"
Documents posterior embryotoxon in an affected patient.
Head and Neck 4
Acquired microcephaly HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28328131 SUPPORT Human Clinical
"In addition both had quadriplegia, acquired microcephaly, and severe intellectual disability."
Documents acquired microcephaly.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28777481 SUPPORT Human Clinical
"as well as cleft palate, micrognathia, patent foramen ovale,"
Documents micrognathia in a patient with SLC35A3-related skeletal dysplasia.
Cleft palate HP:0000175 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cleft palate (HP:0000175). HP:0000175 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28777481 SUPPORT Human Clinical
"as well as cleft palate, micrognathia, patent foramen ovale,"
Documents cleft palate in an affected patient.
Facial dysmorphism Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Facial dysmorphism, annotated with Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28777481 SUPPORT Human Clinical
"camptodactyly, talipes valgus, rocker bottom feet, and facial dysmorphism"
Documents facial dysmorphism in an affected patient.
Limbs 1
Short limbs Limb undergrowth HP:0009826 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Short limbs, annotated with Limb undergrowth (HP:0009826). HP:0009826 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28777481 SUPPORT Human Clinical
"posterior embryotoxon, short limbs, camptodactyly,"
Documents short limbs in an affected patient.
Musculoskeletal 4
Muscle hypotonia Generalized hypotonia HP:0001290 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle hypotonia, annotated with Generalized hypotonia (HP:0001290). HP:0001290 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:370943 SUPPORT Other
"general muscle hypotonia, delayed psychomotor development"
Orphanet's definition lists general muscle hypotonia among the defining features of SLC35A3-CDG.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28328131 SUPPORT Human Clinical
"severe left dorso-lumbar convex scoliosis in one."
Documents severe scoliosis in an affected sibling.
Vertebral anomalies Hemivertebrae HP:0002937 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hemivertebrae (HP:0002937). HP:0002937 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28777481 SUPPORT Human Clinical
"anomalous vertebrae, including butterfly, and hemivertebrae throughout the spine,"
Documents butterfly vertebrae and hemivertebrae in a patient with SLC35A3-related skeletal dysplasia.
Camptodactyly HP:0012385 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Camptodactyly (HP:0012385). HP:0012385 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28777481 SUPPORT Human Clinical
"short limbs, camptodactyly, talipes valgus, rocker bottom feet, and facial dysmorphism"
Documents camptodactyly and additional distal limb anomalies.
Nervous System 5
Autism spectrum disorder HP:0000717 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autism (HP:0000717). HP:0000717 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24031089 SUPPORT Human Clinical
"eight patients from a large kindred, who suffered from autism spectrum disorder, arthrogryposis and epilepsy."
Autism spectrum disorder is a core presenting feature of the founding kindred.
Epilepsy Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:24031089 SUPPORT Human Clinical
"who suffered from autism spectrum disorder, arthrogryposis and epilepsy."
Epilepsy is one of the three defining features of the syndrome.
Suppression-burst EEG pattern EEG with burst suppression HP:0010851 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EEG with burst suppression (HP:0010851). HP:0010851 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28328131 SUPPORT Human Clinical
"EEG recordings showed a suppression-burst (SB) pattern and multifocal paroxysmal activity in both."
Documents the suppression-burst EEG pattern in both affected siblings.
Intellectual disability 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:28328131 SUPPORT Human Clinical
"In addition both had quadriplegia, acquired microcephaly, and severe intellectual disability."
Documents severe intellectual disability in affected siblings.
Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed psychomotor development, annotated with Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:370943 SUPPORT Other
"general muscle hypotonia, delayed psychomotor development"
Orphanet's definition lists delayed psychomotor development among the defining features of SLC35A3-CDG.
Other 8
Epileptic encephalopathy HP:0200134 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epileptic encephalopathy (HP:0200134). HP:0200134 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28328131 SUPPORT Human Clinical
"manifesting a severe epileptic encephalopathy (EE) with skeletal abnormalities,"
Documents severe early-onset epileptic encephalopathy in affected siblings.
Infantile spasms HP:0012469 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Infantile spasms (HP:0012469). HP:0012469 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28328131 SUPPORT Human Clinical
"Both siblings exhibited infantile spasms, associated with focal, and tonic vibratory seizures from early infancy."
Documents infantile spasms with focal and tonic seizures from early infancy.
Distal arthrogryposis HP:0005684 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal arthrogryposis (HP:0005684). HP:0005684 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28328131 SUPPORT Human Clinical
"General examination showed distal arthrogryposis predominant in the hands in both siblings"
Documents distal arthrogryposis predominant in the hands.
Swan neck-like finger deformities 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)
ORPHA:370943 SUPPORT Other
"deviation of the distal phalanges, swan-neck deformity"
Orphanet's definition of SLC35A3-CDG characterizes the distal arthrogryposis as including finger flexion contractures, distal-phalangeal deviation, and swan-neck deformity.
Quadriplegia Tetraplegia HP:0002445 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Tetraplegia (HP:0002445). HP:0002445 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28328131 SUPPORT Human Clinical
"In addition both had quadriplegia, acquired microcephaly, and severe intellectual disability."
Documents quadriplegia in both affected siblings.
Talipes Talipes valgus HP:0004684 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Talipes valgus (HP:0004684). HP:0004684 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28777481 SUPPORT Human Clinical
"camptodactyly, talipes valgus, rocker bottom feet, and facial dysmorphism"
Documents talipes valgus in an affected patient.
Patent foramen ovale HP:0001655 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Patent foramen ovale (HP:0001655). HP:0001655 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28777481 SUPPORT Human Clinical
"as well as cleft palate, micrognathia, patent foramen ovale,"
Documents patent foramen ovale in an affected patient.
Rocker-bottom feet Rocker bottom foot HP:0001838 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rocker bottom feet, annotated with Rocker bottom foot (HP:0001838). HP:0001838 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28777481 SUPPORT Human Clinical
"talipes valgus, rocker bottom feet, and facial dysmorphism"
Documents rocker-bottom feet in an affected patient.
🧬

Genetic Associations

1
SLC35A3 (Loss of function mutation)
Gene: SLC35A3 hgnc:11023 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC35A3 (hgnc:11023). hgnc:11023 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE
Show evidence (2 references)
PMID:24031089 SUPPORT Human Clinical
"we identified deleterious mutations in SLC35A3 in these patients. SLC35A3 encodes the major Golgi uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) transporter."
Establishes SLC35A3 as the causal gene via linkage and exome sequencing.
PMID:28328131 SUPPORT Human Clinical
"identified novel compound heterozygous mutations in SLC35A3 in both children."
Independent family confirming recessive SLC35A3 variants as causal.
💊

Medical Actions

3
Antiseizure medication therapy
Action: anticonvulsant agent therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is anticonvulsant agent therapy, annotated with Anticonvulsant Therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. Ontology label: Anticonvulsant Therapy NCIT:C64172
Symptomatic management of epilepsy and epileptic encephalopathy with antiseizure medications; no disease-modifying therapy is established for SLC35A3-CDG.
Show evidence (1 reference)
PMID:28328131 SUPPORT Human Clinical
"manifesting a severe epileptic encephalopathy (EE) with skeletal abnormalities,"
The severe epileptic encephalopathy phenotype is the target of symptomatic antiseizure therapy.
Orthopedic and rehabilitative management
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Supportive orthopedic and rehabilitative care for distal arthrogryposis, contractures, scoliosis, and vertebral anomalies (physical therapy, bracing, and surgical correction as indicated).
Show evidence (1 reference)
PMID:28328131 SUPPORT Human Clinical
"General examination showed distal arthrogryposis predominant in the hands in both siblings and severe left dorso-lumbar convex scoliosis in one."
The arthrogryposis and scoliosis burden is the target of orthopedic and rehabilitative management.
Genetic counseling
Action: genetic counselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is genetic counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. Ontology label: Genetic Counseling NCIT:C15240
Genetic counseling is indicated given the documented autosomal recessive inheritance, with a 25% recurrence risk for future pregnancies of carrier couples; carrier testing, prenatal diagnosis, and preimplantation genetic testing are reproductive options once the familial variants are known.
Show evidence (1 reference)
PMID:28328131 SUPPORT Human Clinical
"identified novel compound heterozygous mutations in SLC35A3 in both children."
The documented recessive (compound heterozygous) inheritance is what makes genetic counseling and recurrence-risk assessment appropriate.
🔬

Biochemical Markers

1
Reduced highly branched N-glycans
Show evidence (1 reference)
PMID:28777481 SUPPORT Human Clinical
"biochemical analysis confirmed abnormal protein glycosylation, consistent with a defective Golgi UDP-GlcNAc transporter, validating the mutations."
Patient biochemical testing confirms abnormal glycosylation from a defective Golgi UDP-GlcNAc transporter.
🔬

Diagnosis

2
Trio exome or genome sequencing
Molecular diagnosis rests on genomic sequencing — trio whole-exome or whole-genome sequencing (or a CDG/arthrogryposis/epileptic-encephalopathy gene panel with deletion/duplication analysis) to identify biallelic SLC35A3 variants, confirmed by parental segregation.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:28777481 SUPPORT Human Clinical
"Clinical exome sequencing revealed a novel missense homozygous mutation in SLC35A3."
Clinical exome sequencing established the molecular diagnosis in an affected patient.
PMID:28328131 SUPPORT Human Clinical
"WGS of the siblings-parents quartet identified novel compound heterozygous mutations in SLC35A3 in both children."
Quartet whole-genome sequencing with parental segregation identified the biallelic variants.
Functional glycosylation confirmation
Biochemical/functional testing supports variant interpretation: patient fibroblasts can be assayed for reduced Golgi UDP-GlcNAc transport and loss of highly branched N-glycans. Because the lesion is in N-glycan branching rather than whole-transferrin galactosylation/sialylation, routine serum transferrin screening is frequently insensitive and a normal result does not exclude the diagnosis.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:28777481 SUPPORT Human Clinical
"biochemical analysis confirmed abnormal protein glycosylation, consistent with a defective Golgi UDP-GlcNAc transporter, validating the mutations."
Follow-up biochemical glycosylation analysis functionally validated the SLC35A3 variants.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Ultra-rare; only a small number of families/patients have been reported since the 2013 description (a founding kindred of eight affected individuals plus subsequent sibling pairs and isolated cases). No population prevalence, incidence, or carrier-frequency estimate is available.
{ }

Source YAML

click to show 
name: Autism Spectrum Disorder-Epilepsy-Arthrogryposis Syndrome
creation_date: "2026-07-30T00:00:00Z"
description: >-
  Autism spectrum disorder-epilepsy-arthrogryposis syndrome (SLC35A3-CDG) is a
  rare autosomal recessive congenital disorder of N-linked glycosylation caused
  by biallelic pathogenic variants in SLC35A3 (1p21), which encodes the major
  Golgi UDP-N-acetylglucosamine (UDP-GlcNAc) transporter. Loss of transporter
  activity reduces lumenal UDP-GlcNAc, the nucleotide-sugar donor for the
  N-acetylglucosaminyltransferases (GnTs) that build multiantennary N-glycans,
  producing a marked decrease in highly branched tri- and tetraantennary
  N-glycans and a reciprocal accumulation of lower-branched glycoforms at the
  cell surface (a type II CDG signature). The clinical spectrum is dominated by
  a neurodevelopmental triad of autism spectrum disorder, epilepsy (including
  early-onset epileptic encephalopathy with infantile spasms), and intellectual
  disability, combined with distal arthrogryposis and additional skeletal
  defects (vertebral anomalies, scoliosis, camptodactyly), acquired
  microcephaly, quadriplegia, and dysmorphic features. The human disease
  phenocopies the bovine SLC35A3 disorder Complex Vertebral Malformation
  syndrome. It is ultra-rare, reported in a small number of families since its
  2013 description.
category: Mendelian
disease_term:
  preferred_term: autism spectrum disorder - epilepsy - arthrogryposis syndrome
  term:
    id: MONDO:0014248
    label: autism spectrum disorder - epilepsy - arthrogryposis syndrome
synonyms:
- SLC35A3-CDG
- SLC35A3-congenital disorder of glycosylation
- arthrogryposis, intellectual disability, and seizures
- AMRS
- UDP-N-acetylglucosamine transporter deficiency
parents:
- congenital disorder of glycosylation
- distal arthrogryposis
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Autosomal recessive; affected individuals carry biallelic (homozygous or
    compound heterozygous) SLC35A3 variants. The disorder was first defined in a
    large kindred with eight affected individuals carrying deleterious SLC35A3
    variants; subsequent families have carried compound heterozygous or
    homozygous variants.
  evidence:
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two siblings, a boy and a girl, \nmanifesting a severe epileptic encephalopathy (EE) with skeletal abnormalities, \ncarried novel SLC35A3 compound heterozygous mutations."
    explanation: Documents compound heterozygous (recessive) SLC35A3 variants in affected siblings.
pathophysiology:
- name: Impaired Golgi UDP-GlcNAc Transport
  biological_scale: MOLECULAR
  description: >
    Biallelic pathogenic variants in SLC35A3 reduce transport of
    UDP-N-acetylglucosamine (UDP-GlcNAc), the nucleotide-sugar donor for
    N-acetylglucosaminylation, from the cytosol into the lumen of the Golgi
    apparatus. SLC35A3 is regarded as the major Golgi UDP-GlcNAc transporter in
    mammals, so loss of its activity is the primary biochemical lesion; in Golgi
    vesicles from patient fibroblasts, transport of the nucleotide sugar is
    significantly reduced. Depletion of the lumenal UDP-GlcNAc pool is the shared
    upstream defect that feeds three parallel GlcNAc-dependent pathways: complex
    N-glycan antenna branching (via the MGAT GnTs), LFNG-mediated O-fucose
    elongation on Notch EGF repeats (segmentation clock), and glycosaminoglycan
    chain synthesis — so those three consequences are siblings of one another,
    not sequential.
  biological_processes:
  - preferred_term: UDP-N-acetylglucosamine transmembrane transport
    term:
      id: GO:1990569
      label: UDP-N-acetylglucosamine transmembrane transport
    modifier: DECREASED
  molecular_functions:
  - preferred_term: UDP-N-acetylglucosamine transmembrane transporter activity
    term:
      id: GO:0005462
      label: UDP-N-acetylglucosamine transmembrane transporter activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: Golgi membrane
    term:
      id: GO:0000139
      label: Golgi membrane
  chemical_entities:
  - preferred_term: UDP-N-acetylglucosamine
    term:
      id: CHEBI:16264
      label: UDP-N-acetyl-alpha-D-glucosamine
  downstream:
  - target: Reduced N-Glycan Branching
    causal_link_type: DIRECT
  - target: Impaired Somite Segmentation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired Glycosaminoglycan Biosynthesis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:24031089
    reference_title: "Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SLC35A3 encodes the major \nGolgi uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) transporter. In Golgi \nvesicles isolated from patient fibroblasts the transport of the respective \nnucleotide sugar was significantly reduced"
    explanation: Establishes reduced Golgi UDP-GlcNAc transport as the core molecular defect in patient fibroblasts.
  - reference: PMID:23766508
    reference_title: "UDP-N-acetylglucosamine transporter (SLC35A3) regulates biosynthesis of highly branched N-glycans and keratan sulfate."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SLC35A3 is considered the main UDP-N-acetylglucosamine transporter (NGT) in \nmammals."
    explanation: Confirms SLC35A3 as the principal mammalian Golgi UDP-GlcNAc transporter whose loss is the primary lesion.
  - reference: PMID:41554664
    reference_title: "CDG due to Defective Membrane Transporters: Update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Most CDG are enzymatic \ndeficiencies, but 13 (6.5%) are defects in the ER, Golgi apparatus (GA), and \nplasma membrane transporters."
    explanation: Places SLC35A3-CDG within the membrane-transporter subgroup of congenital disorders of glycosylation.
- name: Reduced N-Glycan Branching
  biological_scale: MOLECULAR
  description: >
    Reduced lumenal UDP-GlcNAc limits the N-acetylglucosaminyltransferases
    (e.g., MGAT4/MGAT5) that add the GlcNAc branch points of complex N-glycans,
    causing a massive decrease in highly branched tri- and tetraantennary
    N-glycans at the cell surface and a reciprocal accumulation of lower-branched
    (mono- and diantennary) glycoforms. Follow-up biochemical testing in patients
    confirms abnormal protein glycosylation consistent with a defective Golgi
    UDP-GlcNAc transporter. This altered branching signature has been associated
    with growth arrest and induction of differentiation. As a Golgi N-glycan
    maturation defect producing a type II CDG transferrin/glycoform signature,
    this node conforms to the conserved congenital-disorder-of-glycosylation
    module.
  conforms_to: "congenital_disorder_of_glycosylation#Golgi N-Glycan Processing and Trafficking Defect"
  biological_processes:
  - preferred_term: N-glycan processing
    term:
      id: GO:0006491
      label: N-glycan processing
    modifier: DECREASED
  chemical_entities:
  - preferred_term: UDP-N-acetylglucosamine
    term:
      id: CHEBI:16264
      label: UDP-N-acetyl-alpha-D-glucosamine
    modifier: DECREASED
  downstream:
  - target: Neurodevelopmental Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:24031089
    reference_title: "Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "a massive decrease in the \ncontent of cell surface expressed highly branched N-glycans and a concomitant \nsharp increase of lower branched glycoforms."
    explanation: Documents the loss of highly branched N-glycans with a reciprocal increase in lower-branched glycoforms.
  - reference: PMID:23766508
    reference_title: "UDP-N-acetylglucosamine transporter (SLC35A3) regulates biosynthesis of highly branched N-glycans and keratan sulfate."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "cells deficient in NGT activity displayed a \ndecrease in the amount of highly branched tri- and tetraantennary N-glycans, \nwhereas monoantennary and diantennary ones remained unchanged or even were \naccumulated."
    explanation: In vitro NGT-deficient cells recapitulate the reduced multiantennary branching with accumulation of lower-branched glycans.
- name: Neurodevelopmental Dysfunction
  biological_scale: ORGANISM
  description: >
    Abnormal N-glycosylation of neural glycoproteins is proposed to impair normal
    development and function of the central nervous system, manifesting as autism
    spectrum disorder, epilepsy (including early-onset epileptic encephalopathy
    with infantile spasms and a suppression-burst EEG pattern), intellectual
    disability, and acquired microcephaly. The neurodevelopmental triad of
    autism, epilepsy, and intellectual disability is the clinical hallmark of the
    syndrome.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:24031089
    reference_title: "Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "eight patients from a \nlarge kindred, who suffered from autism spectrum disorder, arthrogryposis and \nepilepsy."
    explanation: Establishes the neurodevelopmental triad (autism, epilepsy) as the presenting phenotype of the founding kindred.
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological symptoms and skeletal abnormalities might result from impaired \nglycosylation of proteins involved in normal development and function of the \ncentral nervous system and skeletal apparatus."
    explanation: Links the neurological phenotype mechanistically to impaired glycosylation of CNS proteins.
- name: Impaired Somite Segmentation
  biological_scale: CELLULAR
  description: >
    SLC35A3 supplies UDP-GlcNAc to the Golgi GlcNAc-transferases — notably LFNG
    (Lunatic fringe), a beta-1,3-N-acetylglucosaminyltransferase that elongates
    O-fucose glycans on the Notch receptor EGF repeats with GlcNAc (the O-fucose
    itself is added by POFUT1). Fringe-mediated GlcNAc elongation tunes Notch
    activity in the segmentation clock of the presomitic mesoderm, so a
    UDP-GlcNAc supply defect is proposed to impair this GlcNAc-transferring step
    and the sugar modification essential for somite formation. Slc35a3 mRNA is
    expressed in the presomitic mesoderm of wild-type mice, and Slc35a3-null mice
    develop CVM-like vertebral malsegmentation, which supports — but does not yet
    directly prove — the SLC35A3→LFNG substrate-supply model: the originating
    study frames it as a hypothesis still requiring test (see knowledge gap).
    This node conforms to the conserved axial-segmentation serial-homology
    module.
  conforms_to: "axial_segmentation_serial_homology#Disrupted Somite Boundary Formation"
  biological_processes:
  - preferred_term: Segmentation
    term:
      id: GO:0035282
      label: segmentation
    modifier: ABNORMAL
  - preferred_term: somitogenesis
    term:
      id: GO:0001756
      label: somitogenesis
    modifier: ABNORMAL
  cell_types:
  - preferred_term: Presomitic (Paraxial) Mesoderm Cell
    term:
      id: CL:0011007
      label: paraxial cell
  downstream:
  - target: Vertebral Malsegmentation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  evidence:
  - reference: PMID:37053259
    reference_title: "Mice lacking nucleotide sugar transporter SLC35A3 exhibit lethal chondrodysplasia with vertebral anomalies and impaired glycosaminoglycan biosynthesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "SLC35A3 transports UDP-GlcNAc used for the sugar modification that is essential for somite formation"
    explanation: Implicates the UDP-GlcNAc supply defect in impaired somite formation, the segmentation-clock mechanism.
- name: Vertebral Malsegmentation
  biological_scale: TISSUE
  description: >
    Mis-specification of the metameric somite template produces vertebral
    malsegmentation — butterfly and hemivertebrae throughout the spine — the
    axial-skeletal outcome of the segmentation defect, phenocopying the bovine
    Complex Vertebral Malformation syndrome.
  conforms_to: "axial_segmentation_serial_homology#Vertebral and Costal Malsegmentation"
  evidence:
  - reference: PMID:28777481
    reference_title: "A human case of SLC35A3-related skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "anomalous vertebrae, including butterfly, and hemivertebrae \nthroughout the spine,"
    explanation: Documents the human vertebral malsegmentation outcome of the segmentation defect.
- name: Impaired Glycosaminoglycan Biosynthesis
  biological_scale: MOLECULAR
  description: >
    Beyond N-glycan branching, SLC35A3 loss reduces the UDP-GlcNAc supply for
    glycosaminoglycan (GAG) chain synthesis. In Slc35a3-null mice the amounts of
    heparan sulfate, keratan sulfate, and chondroitin/dermatan sulfate are all
    significantly decreased, implicating impaired GAG (and therefore proteoglycan)
    biosynthesis as a distinct arm of the skeletal pathology.
  biological_processes:
  - preferred_term: glycosaminoglycan biosynthetic process
    term:
      id: GO:0006024
      label: glycosaminoglycan biosynthetic process
    modifier: DECREASED
  downstream:
  - target: Growth Plate Cartilage ECM Deficiency
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:37053259
    reference_title: "Mice lacking nucleotide sugar transporter SLC35A3 exhibit lethal chondrodysplasia with vertebral anomalies and impaired glycosaminoglycan biosynthesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "the amounts of heparan sulfate, keratan sulfate, and chondroitin sulfate/dermatan sulfate, were significantly decreased"
    explanation: Establishes decreased glycosaminoglycan biosynthesis as a discrete downstream lesion.
- name: Growth Plate Cartilage ECM Deficiency
  biological_scale: TISSUE
  description: >
    Decreased GAG/proteoglycan biosynthesis degrades the quality of the
    growth-plate cartilage extracellular matrix. In Slc35a3-null embryos the
    growth-plate extracellular space is drastically reduced and proliferative
    chondrocytes are reshaped, with proliferation, apoptosis, and differentiation
    unaffected — indicating the chondrodysplasia arises from abnormal ECM quality
    rather than chondrocyte loss.
  cell_types:
  - preferred_term: chondrocyte
    term:
      id: CL:0000138
      label: chondrocyte
  downstream:
  - target: Skeletal and Joint Dysgenesis
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:37053259
    reference_title: "Mice lacking nucleotide sugar transporter SLC35A3 exhibit lethal chondrodysplasia with vertebral anomalies and impaired glycosaminoglycan biosynthesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "extracellular space was drastically reduced, and many flat proliferative chondrocytes were reshaped"
    explanation: Localizes the lesion to growth-plate cartilage ECM quality, the intermediate step to skeletal dysgenesis.
- name: Skeletal and Joint Dysgenesis
  biological_scale: TISSUE
  description: >
    Abnormal cartilage extracellular matrix and impaired glycosylation of
    proteins required for normal skeletal and joint development produce distal
    arthrogryposis (congenital contractures predominant in the hands), scoliosis,
    camptodactyly, chondrodysplasia, and additional skeletal defects. The bovine
    SLC35A3 disorder Complex Vertebral Malformation syndrome recapitulates the
    same arthrogryposis-with-skeletal-defects phenotype, supporting a conserved
    glycosylation-dependent mechanism of skeletal patterning.
  evidence:
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "General examination showed \ndistal arthrogryposis predominant in the hands in both siblings and severe left \ndorso-lumbar convex scoliosis in one."
    explanation: Documents distal arthrogryposis and scoliosis as the skeletal/joint consequences.
  - reference: PMID:24031089
    reference_title: "Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Spontaneous mutation in SLC35A3 has been discovered in cattle \nworldwide, recapitulating the human phenotype with arthrogryposis and additional \nskeletal defects known as Complex Vertebral Malformation syndrome."
    explanation: Bovine SLC35A3 model recapitulates the human arthrogryposis and skeletal-defect phenotype.
  - reference: PMID:37053259
    reference_title: "Mice lacking nucleotide sugar transporter SLC35A3 exhibit lethal chondrodysplasia with vertebral anomalies and impaired glycosaminoglycan biosynthesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "perinatal lethal and exhibited chondrodysplasia recapitulating CVM-like vertebral anomalies"
    explanation: Slc35a3-null mice recapitulate the CVM-like chondrodysplasia/skeletal phenotype, providing in vivo causal evidence.
phenotypes:
- name: Autism spectrum disorder
  description: >-
    Syndromic autism spectrum disorder is a defining feature, with speech delay,
    impaired social interaction, and repetitive behavior.
  phenotype_term:
    preferred_term: Autism
    term:
      id: HP:0000717
      label: Autism
  evidence:
  - reference: PMID:24031089
    reference_title: "Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "eight patients from a \nlarge kindred, who suffered from autism spectrum disorder, arthrogryposis and \nepilepsy."
    explanation: Autism spectrum disorder is a core presenting feature of the founding kindred.
- name: Epilepsy
  description: >-
    Epilepsy is a core feature of the syndrome, ranging from seizures to severe
    early-onset epileptic encephalopathy.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:24031089
    reference_title: "Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "who suffered from autism spectrum disorder, arthrogryposis and \nepilepsy."
    explanation: Epilepsy is one of the three defining features of the syndrome.
- name: Epileptic encephalopathy
  description: >-
    Some affected individuals manifest a severe early-onset epileptic
    encephalopathy with a suppression-burst EEG pattern and multifocal
    paroxysmal activity.
  phenotype_term:
    preferred_term: Epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifesting a severe epileptic encephalopathy (EE) with skeletal abnormalities,"
    explanation: Documents severe early-onset epileptic encephalopathy in affected siblings.
- name: Infantile spasms
  description: >-
    Infantile (epileptic) spasms with focal and tonic vibratory seizures from
    early infancy are reported in the epileptic encephalopathy presentation.
  phenotype_term:
    preferred_term: Infantile spasms
    term:
      id: HP:0012469
      label: Infantile spasms
  evidence:
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both siblings exhibited \ninfantile spasms, associated with focal, and tonic vibratory seizures from early \ninfancy."
    explanation: Documents infantile spasms with focal and tonic seizures from early infancy.
- name: Suppression-burst EEG pattern
  description: >-
    EEG in the epileptic-encephalopathy presentation shows a suppression-burst
    pattern with multifocal paroxysmal activity.
  phenotype_term:
    preferred_term: EEG with burst suppression
    term:
      id: HP:0010851
      label: EEG with burst suppression
  evidence:
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "EEG recordings showed a suppression-burst (SB) pattern and multifocal \nparoxysmal activity in both."
    explanation: Documents the suppression-burst EEG pattern in both affected siblings.
- name: Intellectual disability
  description: Severe intellectual disability accompanies the neurodevelopmental phenotype.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition both had quadriplegia, acquired \nmicrocephaly, and severe intellectual disability."
    explanation: Documents severe intellectual disability in affected siblings.
- name: Global developmental delay
  description: >-
    Delayed psychomotor development is a core, definitional feature of the
    syndrome, evolving to mild-to-moderate intellectual disability with age.
  phenotype_term:
    preferred_term: Delayed psychomotor development
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: ORPHA:370943
    reference_title: "Autism spectrum disorder-epilepsy-arthrogryposis syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "general muscle hypotonia, delayed psychomotor development"
    explanation: Orphanet's definition lists delayed psychomotor development among the defining features of SLC35A3-CDG.
- name: Muscle hypotonia
  description: >-
    Generalized muscle hypotonia is a core clinical feature of the syndrome,
    contributing to the early neuromotor presentation.
  phenotype_term:
    preferred_term: Muscle hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: ORPHA:370943
    reference_title: "Autism spectrum disorder-epilepsy-arthrogryposis syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "general muscle hypotonia, delayed psychomotor development"
    explanation: Orphanet's definition lists general muscle hypotonia among the defining features of SLC35A3-CDG.
- name: Distal arthrogryposis
  description: >-
    Distal arthrogryposis (congenital joint contractures) predominant in the
    hands is one of the three defining features of the syndrome.
  phenotype_term:
    preferred_term: Distal arthrogryposis
    term:
      id: HP:0005684
      label: Distal arthrogryposis
  evidence:
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "General examination showed \ndistal arthrogryposis predominant in the hands in both siblings"
    explanation: Documents distal arthrogryposis predominant in the hands.
- name: Acquired microcephaly
  description: Acquired (postnatal) microcephaly is reported in affected individuals.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition both had quadriplegia, acquired \nmicrocephaly, and severe intellectual disability."
    explanation: Documents acquired microcephaly.
- name: Scoliosis
  description: Severe scoliosis (dorso-lumbar convex) is reported as part of the skeletal phenotype.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severe left \ndorso-lumbar convex scoliosis in one."
    explanation: Documents severe scoliosis in an affected sibling.
- name: Vertebral anomalies
  description: >-
    Vertebral anomalies, including butterfly and hemivertebrae throughout the
    spine, are reported in the skeletal-dysplasia presentation and mirror the
    bovine Complex Vertebral Malformation phenotype.
  phenotype_term:
    preferred_term: Hemivertebrae
    term:
      id: HP:0002937
      label: Hemivertebrae
  evidence:
  - reference: PMID:28777481
    reference_title: "A human case of SLC35A3-related skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "anomalous vertebrae, including butterfly, and hemivertebrae \nthroughout the spine,"
    explanation: Documents butterfly vertebrae and hemivertebrae in a patient with SLC35A3-related skeletal dysplasia.
- name: Camptodactyly
  description: Camptodactyly is reported among the distal limb/skeletal anomalies.
  phenotype_term:
    preferred_term: Camptodactyly
    term:
      id: HP:0012385
      label: Camptodactyly
  evidence:
  - reference: PMID:28777481
    reference_title: "A human case of SLC35A3-related skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "short limbs, \ncamptodactyly, talipes valgus, rocker bottom feet, and facial dysmorphism"
    explanation: Documents camptodactyly and additional distal limb anomalies.
- name: Swan neck-like finger deformities
  description: >-
    The distal arthrogryposis of SLC35A3-CDG includes mild flexion contractures
    of the fingers with deviation of the distal phalanges and swan-neck
    deformity, part of the defining Orphanet characterization of the syndrome.
  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: ORPHA:370943
    reference_title: "Autism spectrum disorder-epilepsy-arthrogryposis syndrome"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "deviation of the distal phalanges, swan-neck deformity"
    explanation: Orphanet's definition of SLC35A3-CDG characterizes the distal arthrogryposis as including finger flexion contractures, distal-phalangeal deviation, and swan-neck deformity.
- name: Micrognathia
  description: Micrognathia (retromicrognathia) is a reported dysmorphic feature.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:28777481
    reference_title: "A human case of SLC35A3-related skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as well as cleft palate, micrognathia, patent foramen \novale,"
    explanation: Documents micrognathia in a patient with SLC35A3-related skeletal dysplasia.
- name: Cleft palate
  description: Cleft palate is reported in the skeletal-dysplasia presentation.
  phenotype_term:
    preferred_term: Cleft palate
    term:
      id: HP:0000175
      label: Cleft palate
  evidence:
  - reference: PMID:28777481
    reference_title: "A human case of SLC35A3-related skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as well as cleft palate, micrognathia, patent foramen \novale,"
    explanation: Documents cleft palate in an affected patient.
- name: Quadriplegia
  description: >-
    Quadriplegia (tetraplegia) was present in both affected siblings of the
    epileptic-encephalopathy family.
  phenotype_term:
    preferred_term: Tetraplegia
    term:
      id: HP:0002445
      label: Tetraplegia
  evidence:
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition both had quadriplegia, acquired \nmicrocephaly, and severe intellectual disability."
    explanation: Documents quadriplegia in both affected siblings.
- name: Facial dysmorphism
  description: Facial dysmorphism is reported in the skeletal-dysplasia presentation.
  phenotype_term:
    preferred_term: Facial dysmorphism
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:28777481
    reference_title: "A human case of SLC35A3-related skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "camptodactyly, talipes valgus, rocker bottom feet, and facial dysmorphism"
    explanation: Documents facial dysmorphism in an affected patient.
- name: Short limbs
  description: Short limbs are reported in the skeletal-dysplasia presentation.
  phenotype_term:
    preferred_term: Short limbs
    term:
      id: HP:0009826
      label: Limb undergrowth
  evidence:
  - reference: PMID:28777481
    reference_title: "A human case of SLC35A3-related skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "posterior embryotoxon, short limbs, \ncamptodactyly,"
    explanation: Documents short limbs in an affected patient.
- name: Talipes
  description: Talipes valgus is reported among the distal limb anomalies.
  phenotype_term:
    preferred_term: Talipes valgus
    term:
      id: HP:0004684
      label: Talipes valgus
  evidence:
  - reference: PMID:28777481
    reference_title: "A human case of SLC35A3-related skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "camptodactyly, talipes valgus, rocker bottom feet, and facial dysmorphism"
    explanation: Documents talipes valgus in an affected patient.
- name: Patent ductus arteriosus
  description: >-
    Patent ductus arteriosus (with patent foramen ovale) is reported in the
    skeletal-dysplasia case; cardiac anomalies also feature in the bovine CVM
    phenotype.
  phenotype_term:
    preferred_term: Patent ductus arteriosus
    term:
      id: HP:0001643
      label: Patent ductus arteriosus
  evidence:
  - reference: PMID:28777481
    reference_title: "A human case of SLC35A3-related skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patent foramen \novale, patent ductus arteriosus, posterior embryotoxon, short limbs,"
    explanation: Documents patent ductus arteriosus in an affected patient.
- name: Patent foramen ovale
  description: Patent foramen ovale is reported in the skeletal-dysplasia case.
  phenotype_term:
    preferred_term: Patent foramen ovale
    term:
      id: HP:0001655
      label: Patent foramen ovale
  evidence:
  - reference: PMID:28777481
    reference_title: "A human case of SLC35A3-related skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "as well as cleft palate, micrognathia, patent foramen \novale,"
    explanation: Documents patent foramen ovale in an affected patient.
- name: Rocker-bottom feet
  description: Rocker-bottom feet are reported among the distal limb anomalies.
  phenotype_term:
    preferred_term: Rocker bottom feet
    term:
      id: HP:0001838
      label: Rocker bottom foot
  evidence:
  - reference: PMID:28777481
    reference_title: "A human case of SLC35A3-related skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "talipes valgus, rocker bottom feet, and facial dysmorphism"
    explanation: Documents rocker-bottom feet in an affected patient.
- name: Posterior embryotoxon
  description: Posterior embryotoxon is reported as an ocular anterior-segment finding.
  phenotype_term:
    preferred_term: Posterior embryotoxon
    term:
      id: HP:0000627
      label: Posterior embryotoxon
  evidence:
  - reference: PMID:28777481
    reference_title: "A human case of SLC35A3-related skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patent ductus arteriosus, posterior embryotoxon, short limbs,"
    explanation: Documents posterior embryotoxon in an affected patient.
biochemical:
- name: Reduced highly branched N-glycans
  notes: >-
    The biochemical hallmark is a decrease in cell-surface highly branched
    (tri- and tetraantennary) N-glycans with a reciprocal increase in
    lower-branched glycoforms, reflecting the Golgi UDP-GlcNAc deficiency;
    patient biochemical testing confirms abnormal protein glycosylation
    consistent with a defective Golgi UDP-GlcNAc transporter. This is a type II
    CDG glycosylation signature. Because SLC35A3 primarily affects branching
    rather than whole-transferrin galactosylation/sialylation, routine serum
    transferrin screening may be less sensitive than direct N-glycan branching
    analysis.
  evidence:
  - reference: PMID:28777481
    reference_title: "A human case of SLC35A3-related skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biochemical analysis confirmed abnormal protein glycosylation, consistent with a \ndefective Golgi UDP-GlcNAc transporter, validating the mutations."
    explanation: Patient biochemical testing confirms abnormal glycosylation from a defective Golgi UDP-GlcNAc transporter.
genetic:
- name: SLC35A3
  association: Loss of function mutation
  variant_origin: GERMLINE
  features: >-
    Autosomal recessive gene at 1p21 encoding the major Golgi UDP-GlcNAc
    transporter. Biallelic (homozygous or compound heterozygous) pathogenic
    variants (missense and other deleterious variants) reduce UDP-GlcNAc
    transport into the Golgi, impairing N-glycan branching.
  gene_term:
    preferred_term: SLC35A3
    term:
      id: hgnc:11023
      label: SLC35A3
  evidence:
  - reference: PMID:24031089
    reference_title: "Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified \ndeleterious mutations in SLC35A3 in these patients. SLC35A3 encodes the major \nGolgi uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) transporter."
    explanation: Establishes SLC35A3 as the causal gene via linkage and exome sequencing.
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified novel compound heterozygous mutations in SLC35A3 in both children."
    explanation: Independent family confirming recessive SLC35A3 variants as causal.
treatments:
- name: Antiseizure medication therapy
  description: >-
    Symptomatic management of epilepsy and epileptic encephalopathy with
    antiseizure medications; no disease-modifying therapy is established for
    SLC35A3-CDG.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: anticonvulsant agent therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  evidence:
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manifesting a severe epileptic encephalopathy (EE) with skeletal abnormalities,"
    explanation: The severe epileptic encephalopathy phenotype is the target of symptomatic antiseizure therapy.
- name: Orthopedic and rehabilitative management
  description: >-
    Supportive orthopedic and rehabilitative care for distal arthrogryposis,
    contractures, scoliosis, and vertebral anomalies (physical therapy, bracing,
    and surgical correction as indicated).
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "General examination showed \ndistal arthrogryposis predominant in the hands in both siblings and severe left \ndorso-lumbar convex scoliosis in one."
    explanation: The arthrogryposis and scoliosis burden is the target of orthopedic and rehabilitative management.
- name: Genetic counseling
  description: >-
    Genetic counseling is indicated given the documented autosomal recessive
    inheritance, with a 25% recurrence risk for future pregnancies of carrier
    couples; carrier testing, prenatal diagnosis, and preimplantation genetic
    testing are reproductive options once the familial variants are known.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "identified novel compound heterozygous mutations in SLC35A3 in both children."
    explanation: The documented recessive (compound heterozygous) inheritance is what makes genetic counseling and recurrence-risk assessment appropriate.
diagnosis:
- name: Trio exome or genome sequencing
  description: >-
    Molecular diagnosis rests on genomic sequencing — trio whole-exome or
    whole-genome sequencing (or a CDG/arthrogryposis/epileptic-encephalopathy
    gene panel with deletion/duplication analysis) to identify biallelic SLC35A3
    variants, confirmed by parental segregation.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:28777481
    reference_title: "A human case of SLC35A3-related skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical exome \nsequencing revealed a novel missense homozygous mutation in SLC35A3."
    explanation: Clinical exome sequencing established the molecular diagnosis in an affected patient.
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WGS of the siblings-parents quartet \nidentified novel compound heterozygous mutations in SLC35A3 in both children."
    explanation: Quartet whole-genome sequencing with parental segregation identified the biallelic variants.
- name: Functional glycosylation confirmation
  description: >-
    Biochemical/functional testing supports variant interpretation: patient
    fibroblasts can be assayed for reduced Golgi UDP-GlcNAc transport and loss of
    highly branched N-glycans. Because the lesion is in N-glycan branching rather
    than whole-transferrin galactosylation/sialylation, routine serum transferrin
    screening is frequently insensitive and a normal result does not exclude the
    diagnosis.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:28777481
    reference_title: "A human case of SLC35A3-related skeletal dysplasia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "biochemical analysis confirmed abnormal protein glycosylation, consistent with a \ndefective Golgi UDP-GlcNAc transporter, validating the mutations."
    explanation: Follow-up biochemical glycosylation analysis functionally validated the SLC35A3 variants.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ultra-rare; only a small number of families/patients have been reported
    since the 2013 description (a founding kindred of eight affected individuals
    plus subsequent sibling pairs and isolated cases). No population prevalence,
    incidence, or carrier-frequency estimate is available.
discussions:
- discussion_id: slc35a3_sole_transporter_model_mismatch
  prompt: >-
    Is SLC35A3 truly the sole/primary Golgi UDP-GlcNAc transporter in humans, or
    do redundant transport routes compensate in a cell-type-dependent manner?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Golgi UDP-GlcNAc Transport
  rationale: >-
    Patient fibroblasts show reduced Golgi UDP-GlcNAc transport and loss of
    highly branched N-glycans, supporting SLC35A3 as the major transporter.
    However, CRISPR knockout of SLC35A3 in CHO, HEK293T, and HepG2 cell lines
    gives cell-context-dependent results: in CHO cells N-glycan branching was
    impaired even though vesicular UDP-GlcNAc transport was not decreased, and in
    HepG2 cells no qualitative N-glycan change was seen — implying redundant or
    alternative UDP-GlcNAc transport routes. Whether this redundancy operates in
    the human neural and skeletal tissues that drive the disease phenotype is
    unresolved, so a negative cell-line transport result should not be treated as
    disproof of the human patient-fibroblast lesion.
  evidence:
  - reference: PMID:32938718
    reference_title: "Biosynthesis of GlcNAc-rich N- and O-glycans in the Golgi apparatus does not require the nucleotide sugar transporter SLC35A3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These \nfindings suggest that SLC35A3 may not be the primary UDP-GlcNAc transporter \nand/or different mechanisms of UDP-GlcNAc transport into the Golgi apparatus may \nexist."
    explanation: Knockout cell-line data question whether SLC35A3 is the sole/primary UDP-GlcNAc transporter, defining the model-vs-human gap.
  - reference: PMID:32938718
    reference_title: "Biosynthesis of GlcNAc-rich N- and O-glycans in the Golgi apparatus does not require the nucleotide sugar transporter SLC35A3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "in SLC35A3-knockout CHO cells, only limited \nchanges were observed; GlcNAc was still incorporated into N-glycans, but complex \ntype N-glycan branching was impaired, although UDP-GlcNAc transport into Golgi \nvesicles was not decreased."
    explanation: Shows the dissociation between branching defect and measurable transport in one knockout cell model, motivating the mismatch.
- discussion_id: slc35a3_lfng_notch_segmentation_untested
  prompt: >-
    Does SLC35A3 loss disrupt somite formation specifically by starving LFNG of
    UDP-GlcNAc and thereby dysregulating Notch segmentation-clock signaling in
    the presomitic mesoderm, or through another route?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Impaired Somite Segmentation
  rationale: >-
    The SLC35A3→LFNG→Notch segmentation-clock mechanism is currently inferred
    from Slc35a3 presomitic-mesoderm expression and the CVM-like vertebral
    phenotype of Slc35a3-null mice, not from direct measurement of Notch
    signaling. The originating study explicitly frames it as a hypothesis still
    requiring test: the expression of segmentation-clock Notch molecules in
    Slc35a3-null embryos has not yet been examined.
  proposed_experiments:
  - experiment_id: exp_slc35a3_notch_clock_psm
    name: Segmentation-clock Notch profiling in Slc35a3-null presomitic mesoderm
    description: >-
      Examine the expression and cyclic oscillation of Notch segmentation-clock
      molecules (e.g., Lfng, Hes7, and cyclic Notch target genes) in the
      presomitic mesoderm of Slc35a3-null embryos during somite formation,
      compared with wild-type littermates.
    decision_criterion: >-
      Disrupted or dampened cyclic Notch/Lfng expression in the Slc35a3-null PSM
      would support the LFNG-substrate-supply model; preserved oscillation would
      point to a Notch-independent route to malsegmentation.
  evidence:
  - reference: PMID:37053259
    reference_title: "Mice lacking nucleotide sugar transporter SLC35A3 exhibit lethal chondrodysplasia with vertebral anomalies and impaired glycosaminoglycan biosynthesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "To investigate this hypothesis, the expression of Notch signaling molecules involved in the segmentation clock should be examined in detail during somite formation"
    explanation: The originating mouse study frames the SLC35A3-LFNG-Notch segmentation-clock mechanism as an untested hypothesis requiring direct examination.
- discussion_id: slc35a3_neuronal_glycoprotein_targets_unknown
  prompt: >-
    Which specific neuronal glycoproteins, hypoglycosylated as a consequence of
    SLC35A3 deficiency, drive the autism / epilepsy / intellectual-disability
    phenotype?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Neurodevelopmental Dysfunction
  rationale: >-
    The neurodevelopmental phenotype is attributed to impaired glycosylation of
    central-nervous-system proteins, but the specific responsible glycoproteins
    remain unidentified and the causal link is stated only as a possibility.
    This is why Neurodevelopmental Dysfunction is deliberately modeled as a
    single coarse node rather than a resolved molecular cascade.
  proposed_experiments:
  - experiment_id: exp_slc35a3_neural_glycoproteomics
    name: Glycoproteomics of SLC35A3-deficient patient-derived neural cells
    description: >-
      Perform site-specific N-glycoproteomics (lectin/HILIC enrichment with mass
      spectrometry) on SLC35A3-patient-derived or iPSC-derived neurons versus
      isogenic controls to identify the neuronal glycoproteins whose branched
      N-glycans are selectively lost, prioritizing candidates in
      neurodevelopmental and synaptic pathways.
    decision_criterion: >-
      Reproducible loss of highly branched N-glycans on a defined set of
      CNS-expressed glycoproteins, enriched for neurodevelopmental function,
      would nominate specific molecular effectors of the phenotype; a diffuse,
      non-selective glycosylation shift would instead support a global,
      non-target-specific mechanism.
  evidence:
  - reference: PMID:28328131
    reference_title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurological symptoms and skeletal abnormalities might result from impaired \nglycosylation of proteins involved in normal development and function of the \ncentral nervous system"
    explanation: The mechanistic link to CNS-protein glycosylation is stated only as a possibility, leaving the specific target glycoproteins undefined.
references:
- reference: PMID:24031089
  title: "Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis."
- reference: PMID:28328131
  title: "Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects."
- reference: PMID:28777481
  title: "A human case of SLC35A3-related skeletal dysplasia."
- reference: PMID:23766508
  title: "UDP-N-acetylglucosamine transporter (SLC35A3) regulates biosynthesis of highly branched N-glycans and keratan sulfate."
- reference: PMID:37053259
  title: "Mice lacking nucleotide sugar transporter SLC35A3 exhibit lethal chondrodysplasia with vertebral anomalies and impaired glycosaminoglycan biosynthesis."
- reference: PMID:32938718
  title: "Biosynthesis of GlcNAc-rich N- and O-glycans in the Golgi apparatus does not require the nucleotide sugar transporter SLC35A3."
- reference: PMID:41554664
  title: "CDG due to Defective Membrane Transporters: Update."
📚

References & Deep Research

References

7
PMID:24031089
Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis.
No top-level findings curated for this source.
PMID:28328131
Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects.
No top-level findings curated for this source.
PMID:28777481
A human case of SLC35A3-related skeletal dysplasia.
No top-level findings curated for this source.
PMID:23766508
UDP-N-acetylglucosamine transporter (SLC35A3) regulates biosynthesis of highly branched N-glycans and keratan sulfate.
No top-level findings curated for this source.
PMID:37053259
Mice lacking nucleotide sugar transporter SLC35A3 exhibit lethal chondrodysplasia with vertebral anomalies and impaired glycosaminoglycan biosynthesis.
No top-level findings curated for this source.
PMID:32938718
Biosynthesis of GlcNAc-rich N- and O-glycans in the Golgi apparatus does not require the nucleotide sugar transporter SLC35A3.
No top-level findings curated for this source.
PMID:41554664
CDG due to Defective Membrane Transporters: Update.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 11 citations 2026-07-30T23:56:24.539557

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Autism Spectrum Disorder-Epilepsy-Arthrogryposis Syndrome
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Autism Spectrum Disorder-Epilepsy-Arthrogryposis Syndrome covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Autism Spectrum Disorder–Epilepsy–Arthrogryposis Syndrome

Executive summary

Autism spectrum disorder–epilepsy–arthrogryposis syndrome is an ultra-rare, autosomal-recessive congenital disorder of glycosylation caused by biallelic pathogenic variants in SLC35A3. It is also called SLC35A3-CDG. The disorder combines congenital joint and skeletal abnormalities—particularly arthrogryposis—with developmental impairment/autistic features and epilepsy. The best current case synthesis identifies only 12 reported patients, so phenotype frequencies, penetrance, prognosis, and genotype–phenotype relationships remain poorly quantified. Two reported patients died at 21 days and 9 years, but severity ranges from mild to profound. (OpenTargets Search: Autism spectrum disorder-epilepsy-arthrogryposis syndrome, kamiyama2024solutecarrierfamily pages 11-12, quelhas2026cdgdueto pages 5-6)

The disease mechanism is impaired transport of UDP-N-acetylglucosamine (UDP-GlcNAc) into the Golgi apparatus, disturbing glycan and proteoglycan biosynthesis needed for neural, cartilage, vertebral, and joint development. Patient fibroblasts have shown reduced Golgi UDP-GlcNAc transport and reduced highly branched cell-surface N-glycans. Mouse and cattle findings provide strong orthogonal support for the skeletal mechanism. No disease-modifying treatment or syndrome-specific clinical trial was identified; management is multidisciplinary and symptomatic. (kamiyama2024solutecarrierfamily pages 11-12, szulc2020biosynthesisofglcnacrich pages 1-2, quelhas2026cdgdueto pages 5-6)

domain established finding evidence type/strength ontology/database annotation
Disease identity Ultra-rare Mendelian syndrome characterized by autism/neurodevelopmental impairment, epilepsy/seizures, and congenital arthrogryposis with skeletal abnormalities; represented in Orphanet as Autism spectrum disorder-epilepsy-arthrogryposis syndrome (Orphanet 370943) and linked to SLC35A3 (OpenTargets Search: Autism spectrum disorder-epilepsy-arthrogryposis syndrome, kamiyama2024solutecarrierfamily pages 11-12, quelhas2026cdgdueto pages 5-6) Curated disease database association plus review synthesis of primary case reports; moderate Orphanet: 370943; disease label: SLC35A3-CDG / autism spectrum disorder-epilepsy-arthrogryposis syndrome
Causal gene Causal gene is SLC35A3, encoding a Golgi nucleotide-sugar transporter with UDP-GlcNAc transport activity (OpenTargets Search: Autism spectrum disorder-epilepsy-arthrogryposis syndrome, kamiyama2024solutecarrierfamily pages 11-12) Strong molecular and disease-association evidence; human disease and transporter biology Gene: SLC35A3; protein class: solute carrier family 35; pathway theme: Golgi glycosylation
Inheritance Reported human disease is autosomal recessive due to biallelic pathogenic variants in SLC35A3 (kamiyama2024solutecarrierfamily pages 11-12, quelhas2026cdgdueto pages 5-6) Human case-based evidence summarized in reviews; moderate Inheritance: autosomal recessive
Epidemiology Twelve patients have been reported, including a large kindred with eight patients and two siblings; no reliable population prevalence or incidence estimate is available (quelhas2026cdgdueto pages 5-6) Review summary of published human cases; moderate for case count, weak for epidemiology Evidence note: ultra-rare disorder; no population registry estimate
Core congenital musculoskeletal phenotype Predominant problems involve skeleton and joints, especially congenital arthrogryposis mainly affecting hands and feet, short long bones, and broader skeletal defects including vertebral anomalies/CMV-like changes (kamiyama2024solutecarrierfamily pages 11-12, quelhas2026cdgdueto pages 5-6) Human clinical evidence with supportive animal/model concordance; moderate-strong HPO suggestions: Arthrogryposis multiplex congenita; Congenital joint contractures; Short long bones; Vertebral anomaly
Craniofacial and growth phenotype Reported associated features include microcephaly and facial dysmorphism, including retromicrognathy and cleft palate (quelhas2026cdgdueto pages 5-6) Human clinical evidence; moderate HPO suggestions: Microcephaly; Facial dysmorphism; Retrognathia/micrognathia; Cleft palate
Neurodevelopmental phenotype Patients show impaired intellectual/neurodevelopmental development; syndrome name and original disease entity include autism spectrum disorder (kamiyama2024solutecarrierfamily pages 11-12, OpenTargets Search: Autism spectrum disorder-epilepsy-arthrogryposis syndrome) Human disease reports summarized in reviews and curated database label; moderate HPO suggestions: Global developmental delay; Intellectual disability; Autism spectrum disorder / autistic behavior
Seizure phenotype Seizures/epilepsy are a recurring core feature; disease severity ranges from mild to profound (kamiyama2024solutecarrierfamily pages 11-12, quelhas2026cdgdueto pages 5-6) Human case evidence; moderate HPO suggestions: Seizure; Epilepsy
Natural history / prognosis Clinical severity ranges from mild to profound; 2 reported deaths occurred at 21 days and 9 years, indicating that severe early-life and childhood mortality can occur (quelhas2026cdgdueto pages 5-6) Small-case natural history evidence; limited-moderate Outcome annotation: variable severity; possible early mortality
Molecular mechanism SLC35A3 is a Golgi UDP-GlcNAc transporter; disease mechanism is impaired Golgi UDP-GlcNAc transport causing abnormal glycosylation, including reduced highly branched N-glycans and likely broader effects on proteoglycans/GAG-related development (kamiyama2024solutecarrierfamily pages 11-12) Strong mechanistic evidence from transporter biology, patient cells, and models GO/pathway suggestions: UDP-N-acetylglucosamine transport; Golgi apparatus; protein glycosylation; glycosaminoglycan biosynthesis
Patient-cell functional evidence Golgi vesicles isolated from patient fibroblasts showed significantly reduced UDP-GlcNAc transport activity; patient fibroblasts supported a glycosylation defect with reduced highly branched N-glycans on the cell surface (kamiyama2024solutecarrierfamily pages 11-12) Direct human functional evidence; strong Cell type: fibroblast; assay class: Golgi vesicle transport / glycosylation profiling
Comparative / animal evidence Bovine SLC35A3 missense variation causes complex vertebral malformation with vertebral defects, arthrogryposis, craniofacial anomalies, and perinatal lethality; Slc35a3-null mice show chondrodysplasia, CMV-like vertebral anomalies, reduced cartilage ECM/proteoglycans, and perinatal lethality (kamiyama2024solutecarrierfamily pages 11-12) Strong comparative/model support for skeletal-development mechanism Species/model annotation: cattle natural disease; mouse knockout; phenotype theme: vertebral malformation / chondrodysplasia
Cellular models CRISPR SLC35A3-knockout mammalian cell lines show context-dependent glycosylation effects, supporting a role in Golgi UDP-GlcNAc handling while also suggesting compensatory/alternative transport mechanisms (szulc2020biosynthesisofglcnacrich pages 18-20, szulc2020biosynthesisofglcnacrich pages 1-2) In vitro mechanistic evidence; moderate Model annotation: CRISPR knockout cell lines (CHO, HEK293T, HepG2)
Diagnosis Recommended diagnosis is direct gene or exome sequencing demonstrating biallelic SLC35A3 variants in a compatible phenotype; functional studies in fibroblasts can support pathogenicity where available (quelhas2026cdgdueto pages 5-6, kamiyama2024solutecarrierfamily pages 11-12) Review/guideline-style recommendation supported by human functional evidence; moderate Diagnostic annotation: exome sequencing; genome/gene sequencing; functional fibroblast testing
Treatment No disease-specific therapy is established; treatment is reported as purely symptomatic/supportive (quelhas2026cdgdueto pages 5-6) Review summary; moderate MAXO-style suggestions: symptomatic treatment; seizure management; orthopedic management; developmental therapies
Major evidence gaps Very small number of published patients, sparse variant-level public detail in available sources, no validated biomarkers or disease-specific therapy, no clinical trials found, and no robust prevalence, penetrance, QoL, or longitudinal natural-history datasets (quelhas2026cdgdueto pages 5-6, kamiyama2024solutecarrierfamily pages 11-12) High-confidence gap assessment based on absence/scarcity of evidence; strong for gap statement Knowledge-base flags: evidence sparse; ultra-rare; natural history unknown; no interventional trials identified

Table: This table summarizes the most actionable disease facts for Autism spectrum disorder-epilepsy-arthrogryposis syndrome, focusing on established human findings, mechanism, diagnosis, models, and current evidence gaps. It is designed as a compact knowledge-base artifact with ontology and database mapping cues.

1. Disease information

Definition and classification

This is a Mendelian neurodevelopmental–skeletal syndrome within the congenital disorders of glycosylation. Its defining clinical triad is neurodevelopmental impairment/autism, epilepsy or seizures, and congenital arthrogryposis. Skeletal dysplasia and craniofacial abnormalities broaden the recognized phenotype. The disease-level association with SLC35A3 is independently represented in Open Targets. (OpenTargets Search: Autism spectrum disorder-epilepsy-arthrogryposis syndrome, kamiyama2024solutecarrierfamily pages 11-12)

Identifiers and synonyms

  • Preferred name: Autism spectrum disorder–epilepsy–arthrogryposis syndrome.
  • Established synonyms: SLC35A3-CDG; SLC35A3-related congenital disorder of glycosylation; SLC35A3-related arthrogryposis–neurodevelopmental syndrome.
  • Orphanet: ORPHA:370943. (OpenTargets Search: Autism spectrum disorder-epilepsy-arthrogryposis syndrome)
  • Gene: SLC35A3, Ensembl ENSG00000117620, approved name “solute carrier family 35 member A3.” (OpenTargets Search: Autism spectrum disorder-epilepsy-arthrogryposis syndrome)
  • OMIM/MONDO: The exact current record numbers were not independently returned by the available tools and should be verified directly before database ingestion. The label is present in disease-ontology aggregation, but an unverified identifier should not be asserted.
  • ICD-10/ICD-11 and MeSH: No syndrome-specific code was identified. Clinical coding ordinarily requires component or broader rare-genetic-disease codes for congenital arthrogryposis, developmental disorder, epilepsy, and congenital disorder of glycosylation.

The evidence is primarily aggregated disease-level evidence derived from published individual cases and families, not an EHR-derived population cohort. The 2026 synthesis reports 12 patients, including eight members of a large kindred and a separate sibling pair. (quelhas2026cdgdueto pages 5-6)

2. Etiology

Causal factor

The primary cause is biallelic germline loss-of-function or function-impairing variation in SLC35A3, inherited in an autosomal-recessive pattern. SLC35A3 encodes a multi-pass Golgi nucleotide-sugar transporter associated with UDP-GlcNAc delivery for glycosylation. (kamiyama2024solutecarrierfamily pages 11-12)

A concise statement from the 2024 transporter review is: “In 2013, Edvardson et al. identified deleterious mutations in SLC35A3 in patients with arthrogryposis, impaired intellectual development, and seizures.” (kamiyama2024solutecarrierfamily pages 11-12)

Genetic risk factors

The decisive risk factor is inheritance of two pathogenic SLC35A3 alleles. Consanguinity is relevant because recessive alleles can become homozygous in related parents, and the original literature included a large kindred; however, a quantitative consanguinity-associated risk estimate is unavailable. No validated susceptibility loci, modifier genes, founder effect, or carrier-frequency estimate has been established. (quelhas2026cdgdueto pages 5-6)

Variant-level assertions should be taken from the original reports or current ClinVar records during curation. The retrieved evidence supports deleterious biallelic variants and subsequent missense/splice-related reports, but did not provide a complete, consistently transcript-normalized list suitable for clinical annotation.

Environmental, infectious, and lifestyle factors

No toxin, infection, diet, parental behavior, occupational exposure, or lifestyle factor is known to cause this syndrome. It is a constitutional genetic disorder. Environment can affect general health, seizure threshold, contracture complications, and access to rehabilitation, but these are modifiers of clinical status rather than causes of SLC35A3-CDG.

Protective factors and gene–environment interaction

No protective allele, diet, supplement, drug, or environmental intervention has been validated. No disease-specific gene–environment interaction has been demonstrated. Avoid extrapolating galactose supplementation used experimentally in some other transporter CDGs to SLC35A3-CDG; no corresponding therapeutic evidence was identified here.

3. Phenotypes

Because only 12 patients are summarized in the current literature, most frequencies cannot be estimated reliably. Terms below should therefore be annotated as reported, not universally present. (quelhas2026cdgdueto pages 5-6)

Congenital musculoskeletal phenotype

  • Arthrogryposis/congenital multiple-joint contractures: predominantly hands and feet; congenital, non-progressive as a malformation, although functional consequences can evolve with growth.
  • Short long bones and skeletal dysplasia: variable severity.
  • Vertebral abnormalities: may resemble complex vertebral malformation.
  • Potential associated joint limitation and orthopedic disability: likely to impair positioning, mobility, dressing, hygiene, and activities of daily living.

Suggested HPO terms include Arthrogryposis multiplex congenita, Congenital joint contracture, Abnormality of the hand, Abnormality of the foot, Short long bones, Skeletal dysplasia, and Abnormal vertebral morphology. Exact HPO identifiers should be validated against the current HPO release. (kamiyama2024solutecarrierfamily pages 11-12, quelhas2026cdgdueto pages 5-6)

Neurologic and behavioral phenotype

  • Global developmental delay/intellectual disability: severity ranges from mild to profound.
  • Autistic behavior/autism spectrum disorder: part of the original syndrome designation; detailed standardized DSM assessments are not consistently reported.
  • Epilepsy/seizures: recurrent core manifestation; available evidence does not support a reliable syndrome-specific seizure-type distribution, onset median, or treatment-response rate.
  • Microcephaly: reported in the current clinical synthesis.

Suggested HPO terms are Global developmental delay, Intellectual disability, Autistic behavior, Seizure, Epilepsy, and Microcephaly. Neurodevelopmental disability and epilepsy can substantially affect communication, education, independence, caregiver burden, and safety, but no EQ-5D, PROMIS, SF-36, or syndrome-specific quality-of-life study was found. (kamiyama2024solutecarrierfamily pages 11-12, quelhas2026cdgdueto pages 5-6)

Craniofacial phenotype

Reported abnormalities include facial dysmorphism, retromicrognathia, and cleft palate. Suggested HPO terms include Abnormal facial shape, Micrognathia/retrognathia, and Cleft palate. Feeding, airway, speech, and dental effects should be assessed individually. (quelhas2026cdgdueto pages 5-6)

Laboratory and biochemical phenotype

The most informative reported abnormality is functional rather than a routine serum result: Golgi vesicles from patient fibroblasts showed significantly reduced UDP-GlcNAc transport and markedly reduced highly branched N-glycans at the cell surface. A normal routine metabolic panel or even a nondiagnostic generic CDG screen would therefore not exclude the condition. (kamiyama2024solutecarrierfamily pages 11-12)

4. Genetic and molecular information

Gene and protein

SLC35A3 encodes a ubiquitously expressed Golgi membrane protein originally termed UGT-related protein 2. It was identified as a UDP-GlcNAc transporter through complementation experiments in Kluyveromyces lactis and subsequent mammalian studies. SLC35A3 shares sequence identity with other SLC35 nucleotide-sugar transporters, including SLC35A2 and SLC35A1. (kamiyama2024solutecarrierfamily pages 11-12)

Pathogenic variants

Human disease results from germline biallelic variants. Reported classes across the SLC35A3 disease literature include function-impairing missense and splice variants; however, the retrieved material did not provide a complete ClinVar-grade list with HGVS transcript, ACMG classification, segregation, and gnomAD frequency. Those fields should be populated only after direct review of the original reports and current ClinVar/gnomAD entries.

There is no evidence that this is a somatic disorder. No recurrent chromosomal rearrangement, aneuploidy, repeat expansion, mitochondrial variant, or epigenetic lesion defines the syndrome. Modifier genes and disease-specific episignatures have not been established.

Functional consequence

Patient fibroblast evidence supports reduced transporter activity and abnormal glycan branching. Nevertheless, modern CRISPR knockout experiments complicate a simplistic “sole UDP-GlcNAc transporter” model. In CHO cells, SLC35A3 knockout did not decrease vesicular UDP-GlcNAc transport and caused only subtle N-glycan effects; in HEK293T cells, transport decreased but was not abolished, while N-glycan branching could remain intact. These findings imply cell-type-dependent compensation, alternative transport routes, or transporter complexes. (szulc2020biosynthesisofglcnacrich pages 18-20, szulc2020biosynthesisofglcnacrich pages 1-2)

Thus, the best current interpretation is partial failure of a Golgi nucleotide-sugar transport network, with particularly important consequences in developing neural and skeletal tissues, rather than universal elimination of all GlcNAc-containing glycans.

5. Environmental information

No environmental contributor or infectious trigger has been demonstrated. Smoking, alcohol, exercise, diet, pollution, and radiation have no established etiologic role. Standard avoidance of seizure triggers and prevention of immobility-related complications are clinically sensible but do not constitute primary prevention of the genetic disorder.

6. Mechanism and pathophysiology

Causal chain

  1. Upstream genetic defect: biallelic SLC35A3 variants impair the abundance, localization, stability, or transport function of the Golgi membrane protein.
  2. Transport defect: insufficient or dysregulated UDP-GlcNAc entry into specific Golgi compartments reduces substrate availability to selected glycosyltransferases.
  3. Glycosylation defect: abnormal N-glycan branching and likely disturbed proteoglycan/glycosaminoglycan production alter cell-surface and extracellular-matrix molecules.
  4. Skeletal-development consequences: reduced or abnormal cartilage extracellular matrix disrupts chondrocyte organization, growth-plate architecture, vertebral segmentation, and joint development, producing skeletal dysplasia and arthrogryposis.
  5. Neural consequences: altered glycosylation of molecules needed for neural development, synaptic organization, excitability, and cell–matrix interactions plausibly produces developmental impairment, autism-related behavior, and epilepsy. The exact neuronal glycoproteins responsible remain unidentified. (kamiyama2024solutecarrierfamily pages 11-12)

Pathways and ontology suggestions

Suggested GO biological-process concepts include nucleotide-sugar transmembrane transport, UDP-N-acetylglucosamine transport, protein N-linked glycosylation, glycosaminoglycan biosynthetic process, proteoglycan biosynthetic process, cartilage development, skeletal-system development, and nervous-system development. Suggested GO cellular components are Golgi membrane, Golgi apparatus, and Golgi lumen. Relevant chemical concepts include UDP-N-acetyl-D-glucosamine and N-acetyl-D-glucosamine; CHEBI identifiers should be checked against the current release before ingestion.

Suggested cell types include chondrocyte (CL mapping), proliferative growth-plate chondrocyte, fibroblast, neuron, and neural progenitor cell. Of these, direct patient evidence is strongest for fibroblasts; chondrocyte involvement is strongly supported by the knockout mouse. (kamiyama2024solutecarrierfamily pages 11-12)

Immune, metabolic, and omics findings

No syndrome-specific chronic inflammation, autoimmunity, immunodeficiency, oxidative injury, mitochondrial defect, or characteristic small-molecule metabolomic signature has been established. No disease-specific patient single-cell, spatial-transcriptomic, proteomic, lipidomic, or integrated multi-omic study was identified. The available molecular profiling is principally glycan analysis and targeted transport assays.

7. Anatomical structures affected

The primary systems are:

  • Central nervous system: brain development and neuronal function; suggested UBERON concepts include brain and central nervous system.
  • Musculoskeletal system: joints of hands and feet, vertebral column, long bones, cartilage, and growth plates.
  • Craniofacial structures: mandible and palate.
  • Tissue level: nervous tissue, cartilage, connective tissue, extracellular matrix, and skeletal tissues.
  • Subcellular level: Golgi membrane/lumen.

No consistent unilateral or lateralized pattern is established. Skeletal involvement is generally multiple and often bilateral. Mouse evidence specifically demonstrates altered growth-plate cartilage extracellular matrix and abnormal proliferative chondrocyte morphology. (kamiyama2024solutecarrierfamily pages 11-12, quelhas2026cdgdueto pages 5-6)

8. Temporal development and natural history

Arthrogryposis and structural skeletal abnormalities are prenatal/congenital, indicating a critical developmental window before birth. Neurodevelopmental impairment becomes evident in infancy or childhood, while seizures may occur early, but the available case synthesis does not establish a reliable median age at seizure onset. The disorder is lifelong; congenital contractures are not intrinsically degenerative, although orthopedic consequences can change during growth. (kamiyama2024solutecarrierfamily pages 11-12, quelhas2026cdgdueto pages 5-6)

There is no validated stage system, remission pattern, or longitudinal natural-history model. Neurodevelopmental gains may occur with therapy, and epilepsy may respond variably to standard antiseizure treatment, but reversal of the underlying developmental abnormalities has not been shown.

9. Inheritance and population

Epidemiology

Only 12 patients were summarized in the latest retrieved review. This is a published-case count, not prevalence. No incidence per 100,000, geographic distribution, sex ratio, ethnic enrichment, carrier frequency, or population-registry estimate is available. Publication and ascertainment bias are substantial. (quelhas2026cdgdueto pages 5-6)

Inheritance and counseling

Inheritance is autosomal recessive. For two confirmed heterozygous parents, each pregnancy conventionally carries a 25% probability of an affected child, a 50% probability of an unaffected carrier, and a 25% probability of inheriting neither familial variant. Penetrance among individuals with clearly pathogenic biallelic genotypes appears high, but expressivity is markedly variable. No anticipation is expected. Germline mosaicism has not been specifically quantified and is less central than parental carrier status.

10. Diagnostics

Clinical recognition

Consider SLC35A3-CDG when congenital arthrogryposis or vertebral/skeletal dysplasia co-occurs with developmental delay, autistic features, microcephaly, or epilepsy. Craniofacial findings such as micrognathia or cleft palate increase suspicion but are not required. (kamiyama2024solutecarrierfamily pages 11-12, quelhas2026cdgdueto pages 5-6)

Recommended genetic approach

  1. Trio whole-exome or whole-genome sequencing is the most efficient approach for an unsolved syndromic presentation.
  2. A comprehensive developmental epileptic encephalopathy, arthrogryposis, skeletal-dysplasia, or CDG panel should include SLC35A3 and provide deletion/duplication analysis.
  3. Confirm candidate variants by orthogonal testing and parental segregation.
  4. Use RNA analysis for suspected splice variants when feasible.
  5. Patient-fibroblast UDP-GlcNAc transport and glycan-branching studies can supply functional evidence for uncertain variants, although these are specialized research assays. (kamiyama2024solutecarrierfamily pages 11-12, quelhas2026cdgdueto pages 5-6)

CMA can detect an alternative pathogenic copy-number disorder but will generally miss small biallelic SLC35A3 variants. Routine karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not first-line disease-specific tests.

Phenotype assessment

Recommended baseline evaluations include neurologic examination, EEG for suspected seizures, brain MRI when clinically indicated, developmental/autism assessment, orthopedic examination, spine and limb radiography, feeding/swallowing and airway assessment when micrognathia or cleft palate is present, and hearing/vision assessment as part of comprehensive neurodevelopmental care.

Differential diagnosis

Important alternatives include other congenital disorders of glycosylation; SCYL2-related arthrogryposis multiplex congenita 4; NALCN-related CLIFAHDD; MAGEL2-related Schaaf–Yang syndrome; CNTNAP1-related lethal congenital contracture syndrome; PIEZO2-, ECEL1-, MYH3-, TPM2-, and ZC4H2-related arthrogryposis disorders; and other developmental epileptic encephalopathies with congenital contractures. The distinguishing feature is demonstration of pathogenic biallelic SLC35A3 variants, ideally with functional support.

11. Outcome and prognosis

Severity is highly variable, from mild to profound. In the 12-patient synthesis, two deaths occurred—at 21 days and 9 years—but this cannot be converted into a valid mortality rate because of tiny sample size, incomplete follow-up, and ascertainment bias. No median survival or life-expectancy estimate exists. (quelhas2026cdgdueto pages 5-6)

Likely long-term morbidity includes intellectual and communication disability, epilepsy, impaired mobility and self-care from contractures or skeletal deformity, orthopedic pain, feeding/speech issues in patients with palatal or mandibular abnormalities, and substantial caregiver burden. No validated disease-specific prognostic biomarker or quality-of-life instrument has been studied.

12. Treatment

No approved molecular, gene, RNA, cell, or substrate-replacement therapy exists. The recent transporter-CDG review characterizes treatment as “purely symptomatic.” (quelhas2026cdgdueto pages 5-6)

A practical multidisciplinary strategy is:

  • Epilepsy: standard seizure-type-directed antiseizure medication; rescue plan; consider ketogenic diet, vagus-nerve stimulation, or epilepsy surgery only under usual drug-resistant-epilepsy criteria—not as syndrome-specific therapy.
  • Musculoskeletal disease: early physiotherapy, stretching and positioning, occupational therapy, splinting/orthoses, mobility equipment, surveillance for spine/hip/limb deformity, and individualized orthopedic surgery.
  • Development and autism-related disability: early-intervention services, speech/language therapy, augmentative communication, behavioral and educational support.
  • Cleft palate/micrognathia: craniofacial, ENT, dental, feeding, speech, and airway management.
  • Nutrition and safety: swallowing assessment, nutrition support, bone-health monitoring, and prevention of aspiration, pressure injury, and contracture complications.

Suggested MAXO concepts include genetic counseling, exome sequencing, electroencephalography, brain MRI, radiography, antiseizure pharmacotherapy, physical therapy, occupational therapy, speech therapy, orthotic treatment, orthopedic surgery, nutritional support, and developmental intervention. Exact MAXO identifiers should be validated before entry.

No disease-specific ClinicalTrials.gov study was found. There are no SLC35A3-specific response rates or pharmacogenomic recommendations.

13. Prevention

Primary lifestyle prevention is not possible. Reproductive prevention options for a family with known pathogenic variants include carrier testing of relatives, cascade screening, prenatal diagnosis, and preimplantation genetic testing for monogenic disease. Secondary prevention consists of early molecular diagnosis, seizure recognition, developmental intervention, and orthopedic surveillance. Tertiary prevention targets contracture progression, aspiration, injury from seizures, immobility, and loss of function.

There is no relevant vaccine or antimicrobial prophylaxis. Genetic counseling is the principal preventive intervention.

14. Other species and natural disease

A naturally occurring SLC35A3 disorder is well established in Holstein Friesian cattle. Homozygosity for bovine p.Val180Phe causes autosomal-recessive complex vertebral malformation, with cervical/thoracic vertebral defects, malformed ribs, craniofacial dysmorphism, lower-limb arthrogryposis, cardiac anomalies, and frequent intrauterine or perinatal death; heterozygotes are asymptomatic. This is a close comparative model of the human skeletal phenotype, although autism and epilepsy cannot be considered equivalently modeled. (kamiyama2024solutecarrierfamily pages 11-12)

The disease is not infectious and has no zoonotic or cross-species transmission risk.

15. Model organisms and experimental systems

Mouse

CRISPR-generated Slc35a3-null mice display chondrodysplasia, complex-vertebral-malformation-like anomalies, and perinatal lethality. Growth-plate cartilage has markedly reduced extracellular matrix, altered proliferative chondrocyte morphology, and reduced heparan sulfate, keratan sulfate, and chondroitin/dermatan sulfate proteoglycans. This provides strong causal evidence linking SLC35A3 loss to defective cartilage matrix and skeletal development. The model is limited by perinatal lethality and does not establish the human behavioral or epilepsy phenotype. (kamiyama2024solutecarrierfamily pages 11-12)

Cellular and yeast systems

Canine SLC35A3 complemented a K. lactis mutant lacking terminal GlcNAc, establishing transporter function. Mammalian CRISPR knockout models in CHO, HEK293T, and HepG2 cells demonstrate cell-context-dependent effects and suggest compensatory UDP-GlcNAc transport. These systems are useful for variant complementation, transport assays, glycomic analysis, and screening strategies, but they do not reproduce organism-level neurodevelopment. (kamiyama2024solutecarrierfamily pages 11-12, szulc2020biosynthesisofglcnacrich pages 18-20, szulc2020biosynthesisofglcnacrich pages 1-2)

Recent developments and expert interpretation

The most important recent source is Kamiyama and Sone’s August 2024 review, Solute Carrier Family 35 (SLC35)—An Overview and Recent Progress, DOI: https://doi.org/10.3390/biologics4030017. It integrates human fibroblast, cattle, and knockout-mouse evidence and concludes that SLC35A3 is essential for glycosylation of molecules involved in neural and skeletal development. (kamiyama2024solutecarrierfamily pages 11-12)

A key conceptual advance is that SLC35A3 is not necessarily the only route for mammalian Golgi UDP-GlcNAc delivery. The 2020 JBC knockout study found substantial cell-type dependence and residual transport, supporting redundancy or transporter cooperation: https://doi.org/10.1074/jbc.RA119.012362, published online September 16, 2020. (szulc2020biosynthesisofglcnacrich pages 18-20, szulc2020biosynthesisofglcnacrich pages 1-2)

The January 2026 membrane-transporter CDG update, DOI: https://doi.org/10.1002/jimd.70133, provides the latest retrieved clinical tally—12 patients—and emphasizes the wide severity range and absence of disease-specific treatment. Although later than the requested 2023–2024 priority window, it is currently the most useful consolidated clinical update. (quelhas2026cdgdueto pages 5-6)

Evidence limitations and curation cautions

This knowledge base entry should be marked low-count/high-uncertainty. Most clinical claims derive from case reports and related families rather than independent population cohorts. Percentages should not be assigned to individual phenotypes unless extracted patient-by-patient from the primary reports. The two deaths among 12 published patients are observations, not a 16.7% disease mortality estimate. Similarly, the syndrome name should not be interpreted to mean that every molecularly confirmed patient necessarily has formally diagnosed autism, epilepsy, and arthrogryposis.

Primary landmark citation: Edvardson S, et al. Mutations in SLC35A3 cause autism spectrum disorder, epilepsy and arthrogryposis. Journal of Medical Genetics, September 2013;50:733–739. DOI: https://doi.org/10.1136/jmedgenet-2013-101753. Subsequent key human citation: Marini C, et al. Recessive mutations in SLC35A3 cause early onset epileptic encephalopathy with skeletal defects. American Journal of Medical Genetics Part A, April 2017;173:1119–1123. DOI: https://doi.org/10.1002/ajmg.a.38112. These primary papers should be consulted directly for final HGVS variant, patient-level frequency, segregation, and PMID fields before production database release.

References

  1. (OpenTargets Search: Autism spectrum disorder-epilepsy-arthrogryposis syndrome): Open Targets Query (Autism spectrum disorder-epilepsy-arthrogryposis syndrome, 1 results). Buniello, A. et al. (2025). Open Targets Platform: facilitating therapeutic hypotheses building in drug discovery. Nucleic Acids Research.

  2. (kamiyama2024solutecarrierfamily pages 11-12): Shin Kamiyama and Hideyuki Sone. Solute carrier family 35 (slc35)—an overview and recent progress. Biologics, 4:242-279, Aug 2024. URL: https://doi.org/10.3390/biologics4030017, doi:10.3390/biologics4030017. This article has 14 citations and is from a peer-reviewed journal.

  3. (quelhas2026cdgdueto pages 5-6): D. Quelhas, C. R. Ferreira, and J. Jaeken. cdg due to defective membrane transporters: update. Journal of Inherited Metabolic Disease, Jan 2026. URL: https://doi.org/10.1002/jimd.70133, doi:10.1002/jimd.70133. This article has 0 citations and is from a peer-reviewed journal.

  4. (szulc2020biosynthesisofglcnacrich pages 1-2): Bozena Szulc, Paulina Sosicka, Dorota Maszczak-Seneczko, Edyta Skurska, Auhen Shauchuk, Teresa Olczak, Hudson H. Freeze, and Mariusz Olczak. Biosynthesis of glcnac-rich n- and o-glycans in the golgi apparatus does not require the nucleotide sugar transporter slc35a3. Journal of Biological Chemistry, 295:16445-16463, Nov 2020. URL: https://doi.org/10.1074/jbc.ra119.012362, doi:10.1074/jbc.ra119.012362. This article has 32 citations and is from a domain leading peer-reviewed journal.

  5. (szulc2020biosynthesisofglcnacrich pages 18-20): Bozena Szulc, Paulina Sosicka, Dorota Maszczak-Seneczko, Edyta Skurska, Auhen Shauchuk, Teresa Olczak, Hudson H. Freeze, and Mariusz Olczak. Biosynthesis of glcnac-rich n- and o-glycans in the golgi apparatus does not require the nucleotide sugar transporter slc35a3. Journal of Biological Chemistry, 295:16445-16463, Nov 2020. URL: https://doi.org/10.1074/jbc.ra119.012362, doi:10.1074/jbc.ra119.012362. This article has 32 citations and is from a domain leading peer-reviewed journal.

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