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Classifications

Harrison's Part

ICIMD (Inherited Metabolic Disorders)

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Inheritance

1

Autosomal recessive inheritance HP:0000007

The reported patient was homozygous for CAMLG c.633+4A>G (NM_001745.4), inherited from consanguineous Turkish parents. The pedigree supports an autosomal recessive model; the clinical and allelic spectrum remains uncertain.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Therefore, trio whole genome analysis was performed and identified the c.633 + 4A>G variant in CAMLG, inherited in an autosomal recessive fashion"

States the inheritance mode and the method by which it was established.

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He is the second child of consanguineous Turkish parents (fourth degree cousins)."

Documents parental consanguinity; this does not establish a founder allele or its population frequency.

?

Discussions and Knowledge Gaps

2

What connects altered tail-anchored protein handling to neurological impairment in CAMLG-CDG, and is the glycosylation defect causal or a parallel consequence?

KNOWLEDGE GAP OPEN camlg_how_does_trc_failure_injure_the_brain

Attached to

pathophysiology#Impaired TRC-Mediated Tail-Anchored Protein Insertion pathophysiology#Core 1 O-Glycan Hyposialylation pathophysiology#Altered Lysosomal Cargo Trafficking pathophysiology#Lysosomal Membrane Damage pathophysiology#Spinal Motor Neuron Loss

The 2022 patient study measured splicing, protein abundance, SNARE localization and glycosylation, but did not connect them experimentally to neurological impairment. A 2025 study showed motor-neuron loss after neuron-specific Caml deletion, alongside trafficking and lysosomal abnormalities measured mainly in mouse fibroblasts. Partially depleted cortical cultures retained normal neurite growth. These results support a neuronal requirement for CAML while leaving the relevant substrates, cell types and causal order unresolved. Glycosylation, lysosomal damage and altered trafficking could be interacting or parallel consequences; rescue experiments are needed to distinguish them.

Proposed experiments

TRC pathway failure in a human neuronal model

exp_camlg_neuronal_model

Use isogenic patient-variant and corrected human neuronal cultures, including spinal motor neurons, to compare TA-protein localization, glycosylation, lysosomal cargo handling and survival. Independently restore CAML, selected SNAREs or glycosylation to test which abnormalities mediate neuronal injury.

Would support

pathophysiology#Spinal Motor Neuron Loss

Supporting outcome

Variant-dependent neuronal injury and molecular abnormalities are reversed by allele correction; selective downstream rescue identifies a necessary intermediate.

Refuting outcome

Adequate variant expression and assay sensitivity are confirmed, but neuronal phenotypes do not differ from corrected controls, or correction of the proposed intermediate fails to improve survival.

Show evidence (2 references)

PMID:39823474 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"H&E-stained sections on L3-L4 of lumbar spinal cord revealed a 28% reduction in the numbers of motor neuron bodies"

Direct in-vivo motor-neuron count, with indirect relevance to the human syndrome.

PMID:39823474 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"There were 8 times more cells with positive galectin-3 puncta in Caml null MEFs than in their wildtype counterpart"

The puncta assay supports lysosomal damage in mouse fibroblasts, indirectly relevant to human disease.

Which features of this entry are properties of CAMLG-CDG, and which are properties of one boy?

KNOWLEDGE GAP OPEN camlg_single_patient_denominator

Attached to

phenotypes# prevalence#Reported patients worldwide

The clinical spectrum derives from one published individual carrying one homozygous splice-region allele. Population frequencies, penetrance, treatment-response rates and prognostic subgroups cannot be inferred. GET4 clinical overlap and experimental Caml models support related biology but do not independently replicate the human CAMLG-CDG phenotype. Residual CAML may help explain viability, yet the relationship between residual protein, neuronal vulnerability and survival has not been measured in additional human alleles.

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Pathophysiology

13

Biallelic CAMLG Splice Variant

Mechanism confidence: Established

Trio whole-genome sequencing identified homozygous NM_001745.4:c.633+4A>G, at chr5:134741527A>G on GRCh38.p13. The alteration lies four bases into intron 2 near the splice donor. Its splicing effect was measured in patient fibroblasts; evidence for the gene-disease relationship remains limited to one published family.

CAMLG hgnc:1471

Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Downstream

Aberrant CAMLG Splicing The donor-region alteration is associated with exon 2 skipping in patient RNA.

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"We report an individual with the homozygous c.633 + 4A>G splice variant in CAMLG, encoding CAML."

The causal variant, in the single reported patient.

Aberrant CAMLG Splicing

Mechanism confidence: Established

Patient fibroblasts showed negligible canonical transcript and replacement of the 624-bp canonical RT-PCR amplicon by an approximately 163-bp product. Exon 2 is skipped and exons 1 and 3 join, predicting p.(Glu58ValfsTer80). The study did not directly demonstrate the truncated polypeptide or nonsense-mediated decay.

mRNA splicing, via spliceosome GO:0000398 ⚠ ABNORMAL

Experimental models

CAMLG-CDG patient dermal fibroblasts PRIMARY CELL CULTURE Exon 2 skipping is directly measured.

Downstream

Reduced CAML Protein Abundance Aberrant transcript processing is accompanied by reduced CAML protein; the contributions of RNA decay and protein instability were not separated.

Show evidence (2 references)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"a corresponding increase of a truncated ~163 bp amplicon could be seen in affected fibroblasts, confirming that the c.633 + 4A>G variant causes skipping of exon 2"

The shortened cDNA product establishes aberrant splicing.

PMID:35262690 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"On a protein level, this is predicted to result in a truncated protein product p.(Glu58ValfsTer80)."

Sequence interpretation predicts a frameshift and premature stop; the truncated protein was not directly measured.

Reduced CAML Protein Abundance

Mechanism confidence: Established

CAML protein abundance was significantly reduced in patient fibroblasts. Residual protein was detectable; whether it retains sufficient function to explain survival is a hypothesis, not a demonstrated genotype-survival relationship.

Experimental models

CAMLG-CDG patient dermal fibroblasts PRIMARY CELL CULTURE Reduced CAML is directly measured.

Downstream

Impaired TRC-Mediated Tail-Anchored Protein Insertion Reduced receptor abundance is expected to impair insertion of susceptible substrates; insertion kinetics were not measured for the human allele.

Altered Golgi Morphology Acute CAMLG knockdown altered Golgi-marker distribution in HeLa cells; the same morphology was not observed in patient fibroblasts.

Altered Lysosomal Cargo Trafficking Caml deletion in mouse cells altered lysosomal cargo distribution and secretion; the human splice allele was not tested.

Spinal Motor Neuron Loss Neuron-specific Caml deletion caused motor-neuron loss in mice; the intervening cellular mechanism and relevance to the human allele remain unresolved.

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Accordingly, reduced levels of CAML protein were identified using immunoblotting analysis"

Immunoblotting directly measures protein abundance.

Impaired TRC-Mediated Tail-Anchored Protein Insertion

Mechanism confidence: Provisional

CAML and WRB form the receptor for TRC-dependent tail-anchored protein insertion. Human WRB and CAML together rescue targeting in yeast lacking Get1/Get2, supporting conserved receptor function. The CAMLG-CDG fibroblast localization findings support a selective insertion defect, but no direct insertion assay was performed for c.633+4A>G. Normal localization of emerin, VAMP7 and VAPB argues against failure of all substrates; residual receptor activity and alternative insertion pathways remain possible explanations.

tail-anchored membrane protein insertion into ER membrane GO:0071816 ↓ DECREASED

Experimental models

Human WRB-CAML complementation of yeast GET receptor deficiency OTHER WRB and CAML together restored Sed5 targeting and Get3 ER recruitment.

Downstream

Syntaxin-5 Mislocalisation to the Cytosol The altered steady-state localization could reflect direct targeting failure or secondary changes in interacting SNAREs.

Depletion of the Golgi v-SNARE BET1L Failed insertion followed by degradation is proposed, but insertion and degradation of BET1L were not directly measured.

Show evidence (2 references)

PMID:24392163 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"Individually, WRB and CAML were unable to mediate GFP-Sed5 targeting to the Golgi membrane, but when co-expressed they formed a fully functional receptor and proper Sed5 localization was restored"

Wild-type complementation establishes conserved receptor function, not the magnitude of the human variant defect.

PMID:35262690 REFUTE DIRECT PRIMARY RESULT In Vitro

"several proteins that are canonically dependent upon the TRC pathway (Emerin, VAMP7, VAPB) were found to have normal subcellular localization in affected CAMLG-CDG and GET4-CDG fibroblasts"

Normal localization limits any claim of global substrate failure.

Syntaxin-5 Mislocalisation to the Cytosol

Mechanism confidence: Established

Both STX5 isoforms were more cytosolic in patient fibroblasts, with about 43% of the short isoform and 9% of the long isoform in the cytoplasmic fraction. Total STX5 abundance remained normal. The localization defect was reproduced by CAMLG knockdown in HeLa cells. It is a proposed research marker of TRC dysfunction; diagnostic sensitivity and specificity are not established.

protein localization to Golgi apparatus GO:0034067 ↓ DECREASED

Experimental models

CAMLG-CDG patient dermal fibroblasts PRIMARY CELL CULTURE Fractionation and imaging show STX5 mislocalization.

CAMLG knockdown in ST6GAL1-GFP HeLa cells CELL LINE Both STX5 isoforms became more cytosolic.

Downstream

Proposed Golgi SNARE Trafficking Dysfunction Reduced Golgi-localized STX5 may impair SNARE-mediated fusion; transport was not directly assayed in CAMLG-CDG patient cells.

Show evidence (2 references)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Crude fractionation of affected CAMLG-CDG fibroblasts showed a significant increase in the amount of STX5 mislocalized to the cytoplasm."

The primary measurement, made in the patient's own fibroblasts.

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Total STX5 steady state protein levels were normal in both CAMLG-CDG and GET4 deficient fibroblasts"

The patient-cell abnormality concerns localization, not a demonstrated fall in total STX5.

Depletion of the Golgi v-SNARE BET1L

Mechanism confidence: Established

BET1L abundance was 37% of control in patient fibroblasts and 30.3% of untreated levels after CAMLG knockdown in HeLa cells. The membrane/cytoplasmic distribution of remaining BET1L was normal. YKT6 abundance and distribution were normal. BET1L degradation before SNARE-complex incorporation is proposed, but no turnover assay establishes this route.

Experimental models

CAMLG-CDG patient dermal fibroblasts PRIMARY CELL CULTURE BET1L is depleted while the remaining protein partitions normally.

CAMLG knockdown in ST6GAL1-GFP HeLa cells CELL LINE BET1L abundance fell to 30.3% of untreated levels.

Downstream

Proposed Golgi SNARE Trafficking Dysfunction Reduced BET1L could impair complexes containing STX5; complex assembly was not directly measured.

Show evidence (2 references)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"This was confirmed by immunoblotting from whole cell lysates, with BET1L levels at 37% and 27% of controls in CAMLG-CDG and GET4-CDG fibroblasts, respectively"

Quantifies the depletion in the patient's cells and shows it is shared with the other TRC pathway disorder tested.

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Distribution of both YKT6 and BET1L between the membranous and cytoplasmic fractions was found to be normal compared to controls"

The remaining BET1L retains a normal distribution; this does not demonstrate the mechanism of its depletion.

Proposed Golgi SNARE Trafficking Dysfunction

Mechanism confidence: Hypothetical

STX5 mislocalization and BET1L depletion could disturb Golgi SNARE complexes, vesicle fusion, and the positioning of glycoprotein substrates or glycosyltransferases. These intermediate processes remain unmeasured in the CAMLG-CDG patient. Retrograde transport was directly abnormal in GET4-deficient cells and later CAML-deficient mouse models, providing related-system support.

intra-Golgi vesicle-mediated transport GO:0006891 ↓ DECREASED

Downstream

Core 1 O-Glycan Hyposialylation Altered Golgi trafficking is a proposed explanation for O-glycan undersialylation.

Type II N-Linked Glycan Processing Defect Altered Golgi processing is proposed to explain the serum N-glycan profile.

Show evidence (1 reference)

PMID:35262690 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"It is possible that specific glycoprotein substrates or glycosyltransferases are incorrectly trafficked within the Golgi as a downstream effect of Golgi SNARE complex dysfunction, leading to specific defective glycosylation."

The authors propose trafficking as an explanation; the responsible substrate and causal sequence were not tested.

Altered Golgi Morphology

Mechanism confidence: Provisional

ST6GAL1-GFP distribution became more fragmented after CAMLG knockdown in HeLa cells while its abundance remained normal. In contrast, patient fibroblasts stained for GM130 or TGN46 showed no obvious Golgi morphological abnormality. COG1, COG4 and COG8 localization was also normal. Morphological disruption is model-dependent and has not been established as a required intermediate in the human glycosylation defect.

Golgi organization GO:0007030 ⚠ ABNORMAL

Experimental models

CAMLG-CDG patient dermal fibroblasts PRIMARY CELL CULTURE GM130/TGN46 staining did not show obvious morphological disruption.

CAMLG knockdown in ST6GAL1-GFP HeLa cells CELL LINE ST6GAL1-GFP distribution became more fragmented.

Show evidence (2 references)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Treated cells showed normal levels of ST6GAL1, but with a more fragmented distribution (Supplementary Material, Fig. S3). This indicated that knockdown of CAMLG expression leads to at least some disorganization of the Golgi."

The evidence for Golgi disorganisation, and the model it comes from.

PMID:35262690 REFUTE DIRECT PRIMARY RESULT In Vitro

"no obvious morphological abnormalities of the Golgi, such as those seen in COG defects, could be observed in affected CAMLG-CDG or GET4-CDG fibroblasts stained with Golgi markers GM130 or TGN46"

Patient fibroblasts did not reproduce the visible morphology defect.

Core 1 O-Glycan Hyposialylation

Mechanism confidence: Established

Patient fibroblasts showed increased peanut agglutinin binding to unsialylated core 1 O-glycans without increased Vicia villosa lectin staining. This supports predominantly defective terminal O-glycan sialylation among the tested markers. Serum apoC-III had an abnormal isoform profile, with absent asialo/disialo forms and only a small monosialo signal; the authors interpreted this as an O-glycosylation defect.

protein sialylation GO:1990743 ↓ DECREASED

Experimental models

CAMLG-CDG patient dermal fibroblasts PRIMARY CELL CULTURE Increased PNA binding supports O-glycan undersialylation.

Conditional Caml-null mouse embryonic fibroblasts PRIMARY CELL CULTURE PNA staining increased, paralleling the patient-cell O-glycan readout.

Downstream

Hyposialylated Mucin-Type O-Glycans The phenotype records the measured O-glycosylation abnormality.

Show evidence (2 references)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"although PNA lectin fluorescence was barely detectable in control fibroblasts, a strong increase in signal was identified in affected fibroblasts"

Lectin binding supports increased exposure of unsialylated core 1 O-glycans.

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Isoelectric focusing analysis of serum apoC-III glycoforms showed an absence of asialo and disialo apoC-III, and only a small amount of monosialo apoC-III (Fig. 3A). This indicates a defect of mucin type O-glycosylation"

The O-glycosylation arm of the combined defect, with the assay that established it.

Type II N-Linked Glycan Processing Defect

Mechanism confidence: Established

Repeated serum transferrin isoelectric focusing and MALDI-TOF N-glycan analysis showed a type II defect. Capillary electrophoresis showed reduced pentasialo and increased trisialo transferrin. This serum finding does not imply that all glycan structures or every tissue are affected identically: patient-fibroblast LAMP1, LAMP2 and ICAM-1 assays did not show hypoglycosylation.

protein N-linked glycosylation GO:0006487 ⚠ ABNORMAL

Downstream

Type II Serum Transferrin Isoform Pattern Altered transferrin glycosylation gives the observed type II screening pattern.

Show evidence (2 references)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Serum transferrin glycoforms analyzed by matrix-assisted laser desorption—ionization-time of flight (MALDI-TOF) mass spectrometry and capillary zone electrophoresis (CZE) also indicated a type II N-glycosylation defect"

The N-glycosylation arm, by two independent methods.

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Fibroblast markers of abnormal N-linked glycosylation previously used (LAMP1, LAMP2, ICAM-1; (13)) were tested in order to identify hypoglycosylation but no abnormalities could be identified"

Normal tested fibroblast markers constrain generalization from serum.

Altered Lysosomal Cargo Trafficking

Mechanism confidence: Provisional

In conditional Caml-null mouse embryonic fibroblasts, procathepsin D secretion increased and CD222 distribution near the Golgi became diffuse. These observations support altered lysosomal cargo trafficking. Cortical neuronal cultures with partial CAML depletion had reduced cathepsin D, but their STX5 and CD222 localization changes were not statistically significant. These models do not establish lysosomal cargo misrouting in the human patient.

lysosomal transport GO:0007041 ⚠ ABNORMAL

Experimental models

Conditional Caml-null mouse embryonic fibroblasts PRIMARY CELL CULTURE Cargo secretion and CD222 distribution were abnormal.

Caml-depleted embryonic mouse cortical cultures PRIMARY CELL CULTURE Cathepsin D abundance decreased, while STX5/CD222 localization changes were nonsignificant.

Downstream

Lysosomal Membrane Damage Altered cargo delivery could contribute to lysosomal damage; their causal order has not been resolved.

Show evidence (2 references)

PMID:39823474 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"CAML-depleted MEFs showed significantly greater amounts of precursor cathepsin D (procathepsin D) released from serum-starved cells, compared to control cultures"

Mouse fibroblast secretion supports abnormal handling of lysosomal cargo.

PMID:39823474 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"knockout of CAML caused significantly more diffused accumulation of CD222 near the TGN"

CD222 distribution was altered in mouse fibroblasts.

Lysosomal Membrane Damage

Mechanism confidence: Provisional

Caml-null mouse fibroblasts showed increased galectin-3 puncta, colocalization with LAMP1 and enlarged LAMP1-positive structures. These findings indicate lysosomal membrane damage in that model. Lysosomal damage has not been demonstrated in CAMLG-CDG patient cells or shown to mediate motor-neuron loss in vivo.

lysosome organization GO:0007040 ⚠ ABNORMAL

Experimental models

Conditional Caml-null mouse embryonic fibroblasts PRIMARY CELL CULTURE Galectin-3 puncta and LAMP1 abnormalities indicate lysosomal damage.

Downstream

Spinal Motor Neuron Loss Lysosomal dysfunction is a candidate contributor to neuronal loss, but the biochemical and neuronal findings were obtained in different experimental systems.

Show evidence (1 reference)

PMID:39823474 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"There were 8 times more cells with positive galectin-3 puncta in Caml null MEFs than in their wildtype counterpart"

The puncta assay supports lysosomal damage in mouse fibroblasts, indirectly relevant to human disease.

Spinal Motor Neuron Loss

Mechanism confidence: Provisional

Neuron-specific Caml deletion in SLICK-H-Cre mice caused hindlimb paralysis and a 28% reduction of motor-neuron cell bodies in lumbar spinal-cord sections. Constitutive synapsin-Cre deletion also caused severe early motor impairment. These results support a neuronal requirement for CAML, but neither motor-neuron depletion nor this causal route has been demonstrated in the human splice-variant case. Partially depleted embryonic cortical cultures retained normal neurite growth.

spinal cord motor neuron CL:0011001

spinal cord UBERON:0002240

Animal models

Graded global Caml depletion with an inducible rescue transgene Mouse partially recapitulates Low doxycycline-induced transgene expression prolonged survival after endogenous Caml deletion to up to four weeks, allowing observation of hindlimb weakness progressing to paralysis.

Neuron-specific inducible Caml deletion Mouse partially recapitulates Induced neuron-specific deletion caused hindlimb paralysis, death within four weeks and a 28% reduction in lumbar motor-neuron bodies.

Constitutive neuronal Caml deletion Mouse partially recapitulates Constitutive neuronal deletion caused hindlimb paralysis from approximately postnatal day five and death by ten days.

Show evidence (1 reference)

PMID:39823474 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"H&E-stained sections on L3-L4 of lumbar spinal cord revealed a 28% reduction in the numbers of motor neuron bodies"

Direct in-vivo motor-neuron count, with indirect relevance to the human syndrome.

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Pathograph

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

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Phenotypes

23

Digestive 1

Feeding Difficulties HP:0011968

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He has a gastrostomy and has been receiving intermittent respiratory support for 6 months as of publication."

Documents enteral feeding by gastrostomy at fourteen years.

Head and Neck 2

Microcephaly Secondary microcephaly HP:0005484

Show evidence (2 references)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The affected male was born at term in 2007 with birth weight of 2500 g and head circumference of 35 cm."

The normal occipitofrontal circumference at birth, which is what makes the later measurement postnatal in onset.

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"head circumference of 46 cm (below 3rd centile)"

The measurement establishing microcephaly at fourteen years.

Dolichocephaly HP:0000268

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He has a dolichocephalic head but no other significant dysmorphism"

The single dysmorphic finding, together with the statement that there are no others.

Metabolism 2

Type II Serum Transferrin Isoform Pattern Type II transferrin isoform profile HP:0012301

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Serum transferrin isoelectrofocusing (IEF) repeatedly showed a type 2 pattern."

The screening result, and the word "repeatedly" that makes it reproducible rather than a single abnormal assay.

Hyposialylated Mucin-Type O-Glycans Abnormal protein O-linked glycosylation HP:0012358

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The clear combined O- and N-linked glycosylation defects in serum points to general glycosylation abnormalities associated with TRC pathway dysfunction."

States the O-linked arm of the serum defect.

Musculoskeletal 4

Axial Hypotonia HP:0008936

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He has axial hypotonia, limb spasticity and contractures."

The examination finding at the most recent follow-up.

Limb Spasticity Appendicular spasticity HP:0034353

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He has axial hypotonia, limb spasticity and contractures."

The distribution of spasticity as examined; bound to the appendicular term because the report specifies limbs.

Poor Head Control HP:0002421

Onset: INFANTILE

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Smiling and eye contact were appropriate for his age, but head control was never achieved."

States the finding, and the preserved social milestones alongside it.

Limb Joint Contractures HP:0003121

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The most recent follow-up at 14 years showed weight of 30.6 kg (below 3rd centile), height could not be measured due to contractures, and head circumference of 46 cm (below 3rd centile)."

Documents the contractures and their functional severity. The report names no individual joint, so no more specific HPO term can be bound.

Nervous System 12

Severe Global Developmental Delay HP:0011344

Onset: INFANTILE

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The family noticed developmental delay at three months of age, since he had no head control."

Age at first recognition of the delay.

Intellectual Disability HP:0001249

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"severe developmental delay (DD) and ID, hypotonia, limb contractures, seizures and structural brain abnormalities"

The clinical summary explicitly includes intellectual disability.

Developmental Regression HP:0002376

Onset: INFANTILE

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He was babbling at one year, but seizures started at that age and he lost his milestones."

Records both the regression and its coincidence with seizure onset.

Seizures HP:0001250

Onset: INFANTILE

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Seizures consisted of staring at a point accompanied by stiffness and unresponsiveness. He has been seizure free the last 4 years since receiving levetiracetam treatment."

The semiology as reported and the response to treatment.

Clonus HP:0002169

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Deep tendon reflexes are obtained, plantar reflexes are flexor, but he has a bilateral clonus."

The neurological examination, including the negative findings that frame the clonus.

Absent Speech HP:0001344

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He has contact with his environment but makes only sounds."

The speech status at the most recent follow-up.

Inability to Walk HP:0002540

Show evidence (1 reference)

PMID:35262690 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"He can only sit with considerable support and has limb contractures."

Inability to walk independently is inferred from the reported severe sitting limitation; a separate walking history is not provided.

Cerebral Atrophy HP:0002059

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Brain MRI at 7 years showed a very thin corpus callosum, atrophic brain stem, severe cerebral and cerebellar atrophy and diffuse hypomyelination."

The single imaging description that documents all four structural findings.

Cerebellar Atrophy HP:0001272

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Brain MRI at 7 years showed a very thin corpus callosum, atrophic brain stem, severe cerebral and cerebellar atrophy and diffuse hypomyelination."

Cerebellar atrophy is named in the imaging report.

Brainstem Atrophy Atrophy/Degeneration affecting the brainstem HP:0007366

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Brain MRI at 7 years showed a very thin corpus callosum, atrophic brain stem, severe cerebral and cerebellar atrophy and diffuse hypomyelination."

The brain stem finding in the same imaging report.

Thin Corpus Callosum HP:0033725

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Brain MRI at 7 years showed a very thin corpus callosum, atrophic brain stem, severe cerebral and cerebellar atrophy and diffuse hypomyelination."

The callosal finding in the same imaging report.

Cerebral Hypomyelination HP:0006808

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Brain MRI at 7 years showed a very thin corpus callosum, atrophic brain stem, severe cerebral and cerebellar atrophy and diffuse hypomyelination."

The myelination finding in the same imaging report.

Respiratory 1

Respiratory Insufficiency HP:0002093

Onset: JUVENILE

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He has a gastrostomy and has been receiving intermittent respiratory support for 6 months as of publication."

The requirement for respiratory support and its duration.

Growth 1

Decreased Body Weight HP:0004325

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"The most recent follow-up at 14 years showed weight of 30.6 kg (below 3rd centile)"

The weight measurement and its centile.

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Genetic Associations

1

CAMLG (Candidate recessive disease gene with functional evidence for the reported splice allele and limited independent clinical replication.)

Gene: CAMLG hgnc:1471 relationship_type: UNKNOWN variant_origin: GERMLINE

Show evidence (4 references)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"This is the first reported patient with pathogenic variants in CAMLG."

Reports the first candidate disease-associated CAMLG genotype; independent clinical replication remains limited.

CGGV:assertion_c077f9b7-9845-44dc-8007-be476f7b291e-2024-09-25T160000.000Z SUPPORT DIRECT REVIEW SYNTHESIS Other

The ClinGen Gene-Disease Validity assertion row: autosomal recessive, classified Limited by the CDG expert panel in September 2024.

CGGV:assertion_c077f9b7-9845-44dc-8007-be476f7b291e-2024-09-25T160000.000Z SUPPORT DIRECT REVIEW SYNTHESIS Other

"In summary, there is limited evidence to support the relationship between CAMLG and Congenital Disorder of Glycosylation, type IIz."

Records the expert panel classification rather than treating one family as definitive gene-disease proof.

+ 1 more reference

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Medical Actions

4

Levetiracetam

Action: Pharmacotherapy NCIT:C15986

Agent: levetiracetam CHEBI:6437

Platform: Small molecule

The seizures in the reported patient responded to levetiracetam and he had been seizure-free for four years at the time of publication. This is a single observation in a single patient, not a disease-specific recommendation, and nothing is known about how CAMLG-CDG epilepsy responds to other agents.

Mechanism Target:

Seizures — Symptomatic seizure control. It does not address the glycosylation or trafficking defect.

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He has been seizure free the last 4 years since receiving levetiracetam treatment."

The observed response, with its duration.

Gastrostomy Feeding

Action: gastrostomy Ontology label: Gastrostomy NCIT:C52006

Platform: Surgery

A gastrostomy was present at the last assessment. The report does not specify its timing or demonstrate effects on growth, aspiration or respiratory outcomes.

Mechanism Target:

Feeding Difficulties — Bypasses the oral route.

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He has a gastrostomy and has been receiving intermittent respiratory support for 6 months as of publication."

Records the gastrostomy as part of this patient's management.

Intermittent Respiratory Support

Action: respiratory support Ontology label: Respiratory Therapy NCIT:C15322

Platform: Device

Intermittent respiratory support was reported for six months by the latest assessment. The support mode and response were not detailed.

Mechanism Target:

Respiratory Insufficiency — Provides respiratory support; a specific ventilation technique was not reported.

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He has a gastrostomy and has been receiving intermittent respiratory support for 6 months as of publication."

The respiratory support and the point in the course at which it began.

Genetic Counselling

Action: Genetic Counseling NCIT:C15240

Platform: Other

Counselling can address segregation, carrier testing and the recessive inheritance model while explaining the Limited gene-disease classification. A 25% recurrence risk applies conditionally when both parents carry the same causal recessive allele; no counselling outcome was measured in this case.

Show evidence (1 reference)

PMID:35262690 SUPPORT INDIRECT PRIMARY RESULT Human Clinical

"Therefore, trio whole genome analysis was performed and identified the c.633 + 4A>G variant in CAMLG, inherited in an autosomal recessive fashion"

The inheritance mode on which counselling rests.

🔬

Diagnosis

5

Serum transferrin and apolipoprotein C-III glycosylation screening

Transferrin and apoC-III isoform studies detected combined N- and O-glycosylation abnormalities in the reported case. These abnormalities support a glycosylation disorder but are not specific for CAMLG.

Laboratory Procedure NCIT:C25294

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Biochemically, a combined O-linked and type II N-linked glycosylation defect was found."

The biochemical finding the screening pair is meant to produce.

Whole genome sequencing after a negative CDG gene panel

Trio whole-genome sequencing identified the intronic CAMLG allele after a panel of then-known CDG genes was negative. The case does not establish that contemporary panels cannot detect this position; interpretation requires segregation, functional findings and the limited gene-disease evidence.

Genetic Testing NCIT:C15709

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Genetic analysis using a panel of known ‘CDG genes’ did not reveal any potentially pathogenic variants."

The negative panel that made broader sequencing necessary.

Syntaxin-5 mislocalisation in fibroblasts as a TRC pathway marker

STX5 fractionation and imaging are research assays that showed a shared abnormality in CAMLG- and GET4-deficient cells. They have not been validated as a stand-alone diagnostic test or as a way to exclude other glycosylation disorders.

Laboratory Procedure NCIT:C25294

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Mislocalization of syntaxin-5 in patient fibroblasts and in siCAMLG deleted Hela cells confirms this as a consistent cellular marker of TRC dysfunction."

The authors' proposal of STX5 mislocalisation as the cellular marker of this pathway's defects.

RNA analysis of the splice-region variant

RT-qPCR and RT-PCR in patient fibroblasts demonstrated loss of canonical transcript and exon 2 skipping, providing functional evidence for the intronic allele.

RNA Analysis NCIT:C18473

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"a corresponding increase of a truncated ~163 bp amplicon could be seen in affected fibroblasts, confirming that the c.633 + 4A>G variant causes skipping of exon 2"

The shortened cDNA product establishes aberrant splicing.

Brain MRI

MRI documented cerebral, cerebellar and brainstem atrophy, thin corpus callosum and diffuse hypomyelination at seven years. These findings characterize CNS involvement and are not specific for CAMLG-CDG.

Magnetic Resonance Imaging NCIT:C16809

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"Brain MRI at 7 years showed a very thin corpus callosum, atrophic brain stem, severe cerebral and cerebellar atrophy and diffuse hypomyelination."

The clinical imaging findings support assessment of CNS structure.

📊

Prevalence

1

Reported patients worldwide

Cases In Literature Ultra Rare

One affected individual was described in the 2022 publication. Population prevalence, penetrance and phenotype frequencies cannot be estimated from this family.

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"This is the first reported patient with pathogenic variants in CAMLG."

Establishes the size of the original published case series.

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from CAMLG-CDG:

GET4-CDG

Overlapping Features GET4 deficiency can cause overlapping developmental impairment, seizures, hypotonia, structural brain abnormalities and altered STX5 localization. The original GET4 case had a subtle type II transferrin pattern; broader serum N-glycan analysis and fibroblast glycosylation studies were normal. Clinical overlap warrants molecular testing; distinct findings in single cases do not establish reliable clinical discriminators.

Show evidence (2 references)

PMID:32395830 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"He presented with global developmental delay, intellectual disabilities, seizures, facial dysmorphism, and delayed bone age."

The GET4-CDG phenotype, for comparison with the phenotype recorded here.

PMID:32395830 SUPPORT DIRECT PRIMARY RESULT In Vitro

"in CDG-0381 fibroblasts, we were unable to find any clear glycosylation abnormality"

The GET4 comparator does not establish a universal shared cellular glycosylation phenotype.

STX5-CDG

Overlapping Features Loss of the short STX5 isoform causes a severe multisystem CDG with liver failure, cholestasis, hyperinsulinemic hypoglycemia and skeletal abnormalities. This establishes a related trafficking disorder; it does not prove that the partial STX5 mislocalization in CAMLG-CDG has the same clinical consequences.

Show evidence (1 reference)

PMID:34711829 SUPPORT DIRECT PRIMARY RESULT Human Clinical

"After birth, the main clinical problem for both patients IV:9 and IV:10 was progressive liver failure with cholestasis and hyperinsulinemic hypoglycemia"

The STX5-CDG phenotype, which is hepatic rather than neurological.

🧫

Experimental Models

5

CAMLG-CDG patient dermal fibroblasts PRIMARY_CELL_CULTURE

Cells from the sole reported homozygous splice-variant patient; they provide direct RNA, protein-localization and glycosylation observations but do not represent affected neural tissue.

Pathograph links

Aberrant CAMLG Splicing partially recapitulates fidelity: high observes: molecular Exon 2 skipping is directly measured.

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"a corresponding increase of a truncated ~163 bp amplicon could be seen in affected fibroblasts, confirming that the c.633 + 4A>G variant causes skipping of exon 2"

The shortened cDNA product establishes aberrant splicing.

Reduced CAML Protein Abundance partially recapitulates fidelity: high observes: molecular Reduced CAML is directly measured.

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Accordingly, reduced levels of CAML protein were identified using immunoblotting analysis"

Immunoblotting directly measures protein abundance.

Syntaxin-5 Mislocalisation to the Cytosol partially recapitulates fidelity: high observes: cellular Fractionation and imaging show STX5 mislocalization.

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Crude fractionation of affected CAMLG-CDG fibroblasts showed a significant increase in the amount of STX5 mislocalized to the cytoplasm."

The primary measurement, made in the patient's own fibroblasts.

Depletion of the Golgi v-SNARE BET1L partially recapitulates fidelity: high observes: molecular BET1L is depleted while the remaining protein partitions normally.

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"This was confirmed by immunoblotting from whole cell lysates, with BET1L levels at 37% and 27% of controls in CAMLG-CDG and GET4-CDG fibroblasts, respectively"

Quantifies the depletion in the patient's cells and shows it is shared with the other TRC pathway disorder tested.

Core 1 O-Glycan Hyposialylation partially recapitulates fidelity: high observes: molecular Increased PNA binding supports O-glycan undersialylation.

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"although PNA lectin fluorescence was barely detectable in control fibroblasts, a strong increase in signal was identified in affected fibroblasts"

Lectin binding supports increased exposure of unsialylated core 1 O-glycans.

Altered Golgi Morphology fails to recapitulate fidelity: low observes: cellular GM130/TGN46 staining did not show obvious morphological disruption.

Limitations: Negative results concern the tested markers in fibroblasts; other cell types or ultrastructural changes were not excluded.

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"no obvious morphological abnormalities of the Golgi, such as those seen in COG defects, could be observed in affected CAMLG-CDG or GET4-CDG fibroblasts stained with Golgi markers GM130 or TGN46"

The negative morphology result supports failure to reproduce this model-dependent finding.

CAMLG knockdown in ST6GAL1-GFP HeLa cells CELL_LINE

Acute siRNA knockdown left approximately 2% residual CAML. The model reproduces selected molecular effects without carrying the patient splice allele.

Pathograph links

Syntaxin-5 Mislocalisation to the Cytosol partially recapitulates fidelity: moderate observes: cellular Both STX5 isoforms became more cytosolic.

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"in this model both STX5S (P < 0.001) and STX5L (P < 0.01) were significantly mislocalized to the cytoplasmic fraction from that of the membrane"

Localization changed after CAMLG knockdown.

Depletion of the Golgi v-SNARE BET1L partially recapitulates fidelity: moderate observes: molecular BET1L abundance fell to 30.3% of untreated levels.

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"a significant (P < 0.01) reduction in BET1L steady-state levels was observed in whole-cell lysates, to 30.3% of levels in untreated cells"

The knockdown reproduces reduced BET1L abundance.

Altered Golgi Morphology partially recapitulates fidelity: moderate observes: cellular ST6GAL1-GFP distribution became more fragmented.

Limitations: The transformed cell line and acute near-complete depletion differ from patient fibroblasts, which lacked obvious morphological abnormalities.

Show evidence (1 reference)

PMID:35262690 SUPPORT DIRECT PRIMARY RESULT In Vitro

"Treated cells showed normal levels of ST6GAL1, but with a more fragmented distribution (Supplementary Material, Fig. S3). This indicated that knockdown of CAMLG expression leads to at least some disorganization of the Golgi."

The evidence for Golgi disorganisation, and the model it comes from.

Conditional Caml-null mouse embryonic fibroblasts PRIMARY_CELL_CULTURE

ERT2-Cre;Caml-floxed embryonic fibroblasts were exposed to 4-hydroxytamoxifen to delete Caml. This is a mouse null model, not the human hypomorphic splice allele.

Pathograph links

Altered Lysosomal Cargo Trafficking partially recapitulates fidelity: moderate observes: cellular Cargo secretion and CD222 distribution were abnormal.

Show evidence (2 references)

PMID:39823474 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"CAML-depleted MEFs showed significantly greater amounts of precursor cathepsin D (procathepsin D) released from serum-starved cells, compared to control cultures"

Mouse fibroblast secretion supports abnormal handling of lysosomal cargo.

+ 1 more reference

Lysosomal Membrane Damage partially recapitulates fidelity: moderate observes: cellular Galectin-3 puncta and LAMP1 abnormalities indicate lysosomal damage.

Show evidence (1 reference)

PMID:39823474 SUPPORT INDIRECT PRIMARY RESULT In Vitro

"There were 8 times more cells with positive galectin-3 puncta in Caml null MEFs than in their wildtype counterpart"

The puncta assay supports lysosomal damage in mouse fibroblasts, indirectly relevant to human disease.

Core 1 O-Glycan Hyposialylation partially recapitulates fidelity: moderate observes: molecular PNA staining increased, paralleling the patient-cell O-glycan readout.

Show evidence (1 reference)

PMID:39823474 SUPPORT DIRECT PRIMARY RESULT In Vitro

"There was a significantly elevated level of PNA lectin fluorescence in Caml null cells compared to control cells"

The null model reproduces the lectin phenotype.

Caml-depleted embryonic mouse cortical cultures PRIMARY_CELL_CULTURE

Mixed cultures from embryonic day 18 cortex had partial CAML depletion after inducible deletion. They are neither spinal motor neurons nor patient-derived cells. Neurite length and branching were unchanged; these measurements do not test spinal motor-neuron survival.

Pathograph links

Altered Lysosomal Cargo Trafficking partially recapitulates fidelity: low observes: cellular Cathepsin D abundance decreased, while STX5/CD222 localization changes were nonsignificant.

Show evidence (1 reference)

PMID:39823474 SUPPORT DIRECT PRIMARY RESULT In Vitro

"cathepsin D levels were significantly reduced when Caml was deleted"

This supports an altered lysosomal protein readout, without proving cargo misrouting in these neurons.

Show evidence (1 reference)

PMID:39823474 SUPPORT DIRECT PRIMARY RESULT In Vitro

"There was no significant difference between length and branch points of neurites, regardless of presence or absence of the Caml gene"

Preserved neurite length and branching in the partially depleted cortical cultures; a different cell population and endpoint from spinal motor-neuron counts.

Human WRB-CAML complementation of yeast GET receptor deficiency OTHER

Wild-type human receptor components restored TA-protein targeting and stress-associated growth in receptor-deficient yeast.

Cell source

Saccharomyces cerevisiae with get1/get2 deletion and coexpression of human WRB and CAML

Publication

PMID:24392163

Pathograph links

Impaired TRC-Mediated Tail-Anchored Protein Insertion rescues fidelity: low observes: cellular WRB and CAML together restored Sed5 targeting and Get3 ER recruitment.

Limitations: Normal-protein complementation supports conserved receptor function. It neither tests the patient allele nor reproduces human neurological disease.

Show evidence (1 reference)

PMID:24392163 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"Individually, WRB and CAML were unable to mediate GFP-Sed5 targeting to the Golgi membrane, but when co-expressed they formed a fully functional receptor and proper Sed5 localization was restored"

Wild-type complementation establishes conserved receptor function, not the magnitude of the human variant defect.

🐁

Animal Models

4

Camlg knockout mouse

Disruption of the mouse CAML gene is lethal in early embryonic development, although CAML-deficient cells remain viable. The model predates the human disease by nearly two decades and was made to study TACI and EGF receptor signalling, not glycosylation.

Species

Mouse

Genotype

Camlg (CAML) germline disruption, homozygous null

Publication

PMID:12919676

Graded global Caml depletion with an inducible rescue transgene

Low doxycycline-induced transgene expression prolonged survival after endogenous Caml deletion to up to four weeks, allowing observation of hindlimb weakness progressing to paralysis.

Species

Mouse

Genotype

rtTA-positive; Caml transgene-positive; ERT2-Cre-positive; Caml-floxed homozygote

Publication

PMID:39823474

Pathograph links

Spinal Motor Neuron Loss partially recapitulates fidelity: moderate observes: organism Low doxycycline-induced transgene expression prolonged survival after endogenous Caml deletion to up to four weeks, allowing observation of hindlimb weakness progressing to paralysis.

Limitations: The model uses experimentally induced deletion rather than the human intronic allele. Human motor-neuron loss and complete reproduction of the CDG phenotype have not been demonstrated.

Show evidence (1 reference)

PMID:39823474 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"By 2 to 3 weeks post-tamoxifen treatment, the hind legs were completely extended and paralyzed"

Global depletion produces a motor phenotype, without directly identifying the dying neuronal population in this cohort.

Neuron-specific inducible Caml deletion

Induced neuron-specific deletion caused hindlimb paralysis, death within four weeks and a 28% reduction in lumbar motor-neuron bodies.

Species

Mouse

Genotype

SLICK-H-Cre-positive; Caml-floxed homozygote

Publication

PMID:39823474

Pathograph links

Spinal Motor Neuron Loss partially recapitulates fidelity: moderate observes: organism Induced neuron-specific deletion caused hindlimb paralysis, death within four weeks and a 28% reduction in lumbar motor-neuron bodies.

Limitations: The model uses experimentally induced deletion rather than the human intronic allele. Human motor-neuron loss and complete reproduction of the CDG phenotype have not been demonstrated.

Show evidence (1 reference)

PMID:39823474 SUPPORT INDIRECT PRIMARY RESULT Model Organism

"H&E-stained sections on L3-L4 of lumbar spinal cord revealed a 28% reduction in the numbers of motor neuron bodies"

Direct in-vivo motor-neuron count, with indirect relevance to the human syndrome.

Constitutive neuronal Caml deletion

Constitutive neuronal deletion caused hindlimb paralysis from approximately postnatal day five and death by ten days.

Species

Mouse

Genotype

Synapsin-Cre-positive; Caml-floxed homozygote

Publication

PMID:39823474

Pathograph links

Spinal Motor Neuron Loss partially recapitulates fidelity: moderate observes: organism Constitutive neuronal deletion caused hindlimb paralysis from approximately postnatal day five and death by ten days.

Limitations: The model uses experimentally induced deletion rather than the human intronic allele. Human motor-neuron loss and complete reproduction of the CDG phenotype have not been demonstrated.

Show evidence (1 reference)

PMID:39823474 SUPPORT DIRECT PRIMARY RESULT Model Organism

"As early as neonatal day 5, Camlfl/fl homozygous pups with Cre had paralysis of the back legs."

This neuronal model supports a requirement for CAML in early motor function.

{ }

Source YAML

click to show

name: CAMLG-CDG
creation_date: '2026-09-25T16:30:00Z'
category: Mendelian
disease_term:
  preferred_term: CAMLG-CDG
  term:
    id: MONDO:0859357
    label: congenital disorder of glycosylation, type IIz
description: CAMLG-CDG, also called congenital disorder of glycosylation type IIz, is a proposed autosomal recessive disorder associated with a homozygous CAMLG splice-region variant. CAMLG encodes CAML, the partner of WRB in the endoplasmic-reticulum receptor for tail-anchored protein insertion. The single published patient had infantile developmental delay, regression with seizure onset at one year, severe motor and communication impairment, hypotonia, spasticity, contractures, and cerebral, cerebellar and brainstem abnormalities. Serum testing showed combined O-linked and type II N-linked glycosylation abnormalities. Patient fibroblasts showed exon skipping, reduced CAML, syntaxin-5 mislocalization and reduced BET1L. Later mouse studies support roles in neuronal survival, intracellular trafficking and lysosomal integrity, but the route to the human neurological phenotype remains unresolved. ClinGen classified the gene-disease relationship as Limited in September 2024.
parents:
- hereditary disease
- Congenital Disorder of Glycosylation
synonyms:
- CDG-IIz
- CDG2Z
- CDGIIZ
- Congenital disorder of glycosylation type IIz
- CAMLG deficiency
- CAML deficiency
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
    notes: The reported phenotype is predominantly neurological, with severe developmental impairment, epilepsy, abnormal muscle tone and structural brain abnormalities.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    notes: An autosomal recessive inborn error identified by trio whole genome sequencing after a targeted CDG gene panel was negative.
  icimd_category:
  - classification_value: multiple_glycosylation_pathways
    notes: Combined mucin-type O-linked and type II N-linked glycosylation abnormalities were observed in the reported patient.
  - classification_value: vesicular_trafficking
    notes: CAML participates in tail-anchored protein insertion; impaired Golgi trafficking is a proposed downstream mechanism.
references:
- reference: PMID:35262690
  title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
- reference: PMID:24392163
  title: WRB and CAML are necessary and sufficient to mediate tail-anchored protein targeting to the ER membrane.
- reference: PMID:39823474
  title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
- reference: CGGV:assertion_c077f9b7-9845-44dc-8007-be476f7b291e-2024-09-25T160000.000Z
  title: CAMLG / congenital disorder of glycosylation, type IIz (Limited)
- reference: url:https://www.ncbi.nlm.nih.gov/clinvar/RCV003152398/
  title: NM_001745.4(CAMLG):c.633+4A&gt;G AND Congenital disorder of glycosylation, type IIz - ClinVar - NCBI
- reference: PMID:12919676
  title: CAML is required for efficient EGF receptor recycling.
- reference: PMID:32395830
  title: Mutations in GET4 disrupt the transmembrane domain recognition complex pathway.
- reference: PMID:31461301
  title: Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy.
- reference: PMID:34711829
  title: Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: The reported patient was homozygous for CAMLG c.633+4A>G (NM_001745.4), inherited from consanguineous Turkish parents. The pedigree supports an autosomal recessive model; the clinical and allelic spectrum remains uncertain.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Therefore, trio whole genome analysis was performed and identified the c.633 + 4A>G variant in CAMLG, inherited in an autosomal recessive fashion
    explanation: States the inheritance mode and the method by which it was established.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He is the second child of consanguineous Turkish parents (fourth degree cousins).
    explanation: Documents parental consanguinity; this does not establish a founder allele or its population frequency.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
pathophysiology:
- name: Biallelic CAMLG Splice Variant
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: Trio whole-genome sequencing identified homozygous NM_001745.4:c.633+4A>G, at chr5:134741527A>G on GRCh38.p13. The alteration lies four bases into intron 2 near the splice donor. Its splicing effect was measured in patient fibroblasts; evidence for the gene-disease relationship remains limited to one published family.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: We report an individual with the homozygous c.633 + 4A>G splice variant in CAMLG, encoding CAML.
    explanation: The causal variant, in the single reported patient.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  role: trigger
  genes:
  - preferred_term: CAMLG
    term:
      id: hgnc:1471
      label: CAMLG
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Aberrant CAMLG Splicing
    causal_link_type: DIRECT
    description: The donor-region alteration is associated with exon 2 skipping in patient RNA.
- name: Aberrant CAMLG Splicing
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: Patient fibroblasts showed negligible canonical transcript and replacement of the 624-bp canonical RT-PCR amplicon by an approximately 163-bp product. Exon 2 is skipped and exons 1 and 3 join, predicting p.(Glu58ValfsTer80). The study did not directly demonstrate the truncated polypeptide or nonsense-mediated decay.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a corresponding increase of a truncated ~163 bp amplicon could be seen in affected fibroblasts, confirming that the c.633 + 4A>G variant causes skipping of exon 2
    explanation: The shortened cDNA product establishes aberrant splicing.
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: On a protein level, this is predicted to result in a truncated protein product p.(Glu58ValfsTer80).
    explanation: Sequence interpretation predicts a frameshift and premature stop; the truncated protein was not directly measured.
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
  biological_processes:
  - preferred_term: mRNA splicing, via spliceosome
    term:
      id: GO:0000398
      label: mRNA splicing, via spliceosome
    modifier: ABNORMAL
  downstream:
  - target: Reduced CAML Protein Abundance
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Aberrant transcript processing is accompanied by reduced CAML protein; the contributions of RNA decay and protein instability were not separated.
- name: Reduced CAML Protein Abundance
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: CAML protein abundance was significantly reduced in patient fibroblasts. Residual protein was detectable; whether it retains sufficient function to explain survival is a hypothesis, not a demonstrated genotype-survival relationship.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Accordingly, reduced levels of CAML protein were identified using immunoblotting analysis
    explanation: Immunoblotting directly measures protein abundance.
  downstream:
  - target: Impaired TRC-Mediated Tail-Anchored Protein Insertion
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Reduced receptor abundance is expected to impair insertion of susceptible substrates; insertion kinetics were not measured for the human allele.
  - target: Altered Golgi Morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Acute CAMLG knockdown altered Golgi-marker distribution in HeLa cells; the same morphology was not observed in patient fibroblasts.
  - target: Altered Lysosomal Cargo Trafficking
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Caml deletion in mouse cells altered lysosomal cargo distribution and secretion; the human splice allele was not tested.
  - target: Spinal Motor Neuron Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Neuron-specific Caml deletion caused motor-neuron loss in mice; the intervening cellular mechanism and relevance to the human allele remain unresolved.
- name: Impaired TRC-Mediated Tail-Anchored Protein Insertion
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: CAML and WRB form the receptor for TRC-dependent tail-anchored protein insertion. Human WRB and CAML together rescue targeting in yeast lacking Get1/Get2, supporting conserved receptor function. The CAMLG-CDG fibroblast localization findings support a selective insertion defect, but no direct insertion assay was performed for c.633+4A>G. Normal localization of emerin, VAMP7 and VAPB argues against failure of all substrates; residual receptor activity and alternative insertion pathways remain possible explanations.
  evidence:
  - reference: PMID:24392163
    reference_title: WRB and CAML are necessary and sufficient to mediate tail-anchored protein targeting to the ER membrane.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: Individually, WRB and CAML were unable to mediate GFP-Sed5 targeting to the Golgi membrane, but when co-expressed they formed a fully functional receptor and proper Sed5 localization was restored
    explanation: Wild-type complementation establishes conserved receptor function, not the magnitude of the human variant defect.
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: REFUTE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: several proteins that are canonically dependent upon the TRC pathway (Emerin, VAMP7, VAPB) were found to have normal subcellular localization in affected CAMLG-CDG and GET4-CDG fibroblasts
    explanation: Normal localization limits any claim of global substrate failure.
  biological_processes:
  - preferred_term: tail-anchored membrane protein insertion into ER membrane
    term:
      id: GO:0071816
      label: tail-anchored membrane protein insertion into ER membrane
    modifier: DECREASED
  downstream:
  - target: Syntaxin-5 Mislocalisation to the Cytosol
    causal_link_type: UNKNOWN
    description: The altered steady-state localization could reflect direct targeting failure or secondary changes in interacting SNAREs.
  - target: Depletion of the Golgi v-SNARE BET1L
    causal_link_type: UNKNOWN
    description: Failed insertion followed by degradation is proposed, but insertion and degradation of BET1L were not directly measured.
- name: Syntaxin-5 Mislocalisation to the Cytosol
  biological_scale: CELLULAR
  mechanism_confidence: ESTABLISHED
  description: Both STX5 isoforms were more cytosolic in patient fibroblasts, with about 43% of the short isoform and 9% of the long isoform in the cytoplasmic fraction. Total STX5 abundance remained normal. The localization defect was reproduced by CAMLG knockdown in HeLa cells. It is a proposed research marker of TRC dysfunction; diagnostic sensitivity and specificity are not established.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Crude fractionation of affected CAMLG-CDG fibroblasts showed a significant increase in the amount of STX5 mislocalized to the cytoplasm.
    explanation: The primary measurement, made in the patient's own fibroblasts.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Total STX5 steady state protein levels were normal in both CAMLG-CDG and GET4 deficient fibroblasts
    explanation: The patient-cell abnormality concerns localization, not a demonstrated fall in total STX5.
  biological_processes:
  - preferred_term: protein localization to Golgi apparatus
    term:
      id: GO:0034067
      label: protein localization to Golgi apparatus
    modifier: DECREASED
  downstream:
  - target: Proposed Golgi SNARE Trafficking Dysfunction
    causal_link_type: UNKNOWN
    description: Reduced Golgi-localized STX5 may impair SNARE-mediated fusion; transport was not directly assayed in CAMLG-CDG patient cells.
- name: Depletion of the Golgi v-SNARE BET1L
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: BET1L abundance was 37% of control in patient fibroblasts and 30.3% of untreated levels after CAMLG knockdown in HeLa cells. The membrane/cytoplasmic distribution of remaining BET1L was normal. YKT6 abundance and distribution were normal. BET1L degradation before SNARE-complex incorporation is proposed, but no turnover assay establishes this route.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: This was confirmed by immunoblotting from whole cell lysates, with BET1L levels at 37% and 27% of controls in CAMLG-CDG and GET4-CDG fibroblasts, respectively
    explanation: Quantifies the depletion in the patient's cells and shows it is shared with the other TRC pathway disorder tested.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Distribution of both YKT6 and BET1L between the membranous and cytoplasmic fractions was found to be normal compared to controls
    explanation: The remaining BET1L retains a normal distribution; this does not demonstrate the mechanism of its depletion.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  downstream:
  - target: Proposed Golgi SNARE Trafficking Dysfunction
    causal_link_type: UNKNOWN
    description: Reduced BET1L could impair complexes containing STX5; complex assembly was not directly measured.
- name: Proposed Golgi SNARE Trafficking Dysfunction
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: STX5 mislocalization and BET1L depletion could disturb Golgi SNARE complexes, vesicle fusion, and the positioning of glycoprotein substrates or glycosyltransferases. These intermediate processes remain unmeasured in the CAMLG-CDG patient. Retrograde transport was directly abnormal in GET4-deficient cells and later CAML-deficient mouse models, providing related-system support.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: It is possible that specific glycoprotein substrates or glycosyltransferases are incorrectly trafficked within the Golgi as a downstream effect of Golgi SNARE complex dysfunction, leading to specific defective glycosylation.
    explanation: The authors propose trafficking as an explanation; the responsible substrate and causal sequence were not tested.
  biological_processes:
  - preferred_term: intra-Golgi vesicle-mediated transport
    term:
      id: GO:0006891
      label: intra-Golgi vesicle-mediated transport
    modifier: DECREASED
  downstream:
  - target: Core 1 O-Glycan Hyposialylation
    causal_link_type: UNKNOWN
    description: Altered Golgi trafficking is a proposed explanation for O-glycan undersialylation.
    evidence:
    - reference: PMID:35262690
      reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: It is possible that specific glycoprotein substrates or glycosyltransferases are incorrectly trafficked within the Golgi as a downstream effect of Golgi SNARE complex dysfunction, leading to specific defective glycosylation.
      explanation: The authors propose trafficking as an explanation; the responsible substrate and causal sequence were not tested.
  - target: Type II N-Linked Glycan Processing Defect
    causal_link_type: UNKNOWN
    description: Altered Golgi processing is proposed to explain the serum N-glycan profile.
    evidence:
    - reference: PMID:35262690
      reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: It is possible that specific glycoprotein substrates or glycosyltransferases are incorrectly trafficked within the Golgi as a downstream effect of Golgi SNARE complex dysfunction, leading to specific defective glycosylation.
      explanation: The authors propose trafficking as an explanation; the responsible substrate and causal sequence were not tested.
- name: Altered Golgi Morphology
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: ST6GAL1-GFP distribution became more fragmented after CAMLG knockdown in HeLa cells while its abundance remained normal. In contrast, patient fibroblasts stained for GM130 or TGN46 showed no obvious Golgi morphological abnormality. COG1, COG4 and COG8 localization was also normal. Morphological disruption is model-dependent and has not been established as a required intermediate in the human glycosylation defect.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Treated cells showed normal levels of ST6GAL1, but with a more fragmented distribution (Supplementary Material, Fig. S3). This indicated that knockdown of CAMLG expression leads to at least some disorganization of the Golgi.
    explanation: The evidence for Golgi disorganisation, and the model it comes from.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: REFUTE
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: no obvious morphological abnormalities of the Golgi, such as those seen in COG defects, could be observed in affected CAMLG-CDG or GET4-CDG fibroblasts stained with Golgi markers GM130 or TGN46
    explanation: Patient fibroblasts did not reproduce the visible morphology defect.
  biological_processes:
  - preferred_term: Golgi organization
    term:
      id: GO:0007030
      label: Golgi organization
    modifier: ABNORMAL
- name: Core 1 O-Glycan Hyposialylation
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: Patient fibroblasts showed increased peanut agglutinin binding to unsialylated core 1 O-glycans without increased Vicia villosa lectin staining. This supports predominantly defective terminal O-glycan sialylation among the tested markers. Serum apoC-III had an abnormal isoform profile, with absent asialo/disialo forms and only a small monosialo signal; the authors interpreted this as an O-glycosylation defect.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: although PNA lectin fluorescence was barely detectable in control fibroblasts, a strong increase in signal was identified in affected fibroblasts
    explanation: Lectin binding supports increased exposure of unsialylated core 1 O-glycans.
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Isoelectric focusing analysis of serum apoC-III glycoforms showed an absence of asialo and disialo apoC-III, and only a small amount of monosialo apoC-III (Fig. 3A). This indicates a defect of mucin type O-glycosylation
    explanation: The O-glycosylation arm of the combined defect, with the assay that established it.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  biological_processes:
  - preferred_term: protein sialylation
    term:
      id: GO:1990743
      label: protein sialylation
    modifier: DECREASED
  downstream:
  - target: Hyposialylated Mucin-Type O-Glycans
    causal_link_type: DIRECT
    description: The phenotype records the measured O-glycosylation abnormality.
- name: Type II N-Linked Glycan Processing Defect
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: 'Repeated serum transferrin isoelectric focusing and MALDI-TOF N-glycan analysis showed a type II defect. Capillary electrophoresis showed reduced pentasialo and increased trisialo transferrin. This serum finding does not imply that all glycan structures or every tissue are affected identically: patient-fibroblast LAMP1, LAMP2 and ICAM-1 assays did not show hypoglycosylation.'
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Serum transferrin glycoforms analyzed by matrix-assisted laser desorption—ionization-time of flight (MALDI-TOF) mass spectrometry and capillary zone electrophoresis (CZE) also indicated a type II N-glycosylation defect
    explanation: The N-glycosylation arm, by two independent methods.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Fibroblast markers of abnormal N-linked glycosylation previously used (LAMP1, LAMP2, ICAM-1; (13)) were tested in order to identify hypoglycosylation but no abnormalities could be identified
    explanation: Normal tested fibroblast markers constrain generalization from serum.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: ABNORMAL
  downstream:
  - target: Type II Serum Transferrin Isoform Pattern
    causal_link_type: DIRECT
    description: Altered transferrin glycosylation gives the observed type II screening pattern.
- name: Altered Lysosomal Cargo Trafficking
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: In conditional Caml-null mouse embryonic fibroblasts, procathepsin D secretion increased and CD222 distribution near the Golgi became diffuse. These observations support altered lysosomal cargo trafficking. Cortical neuronal cultures with partial CAML depletion had reduced cathepsin D, but their STX5 and CD222 localization changes were not statistically significant. These models do not establish lysosomal cargo misrouting in the human patient.
  evidence:
  - reference: PMID:39823474
    reference_title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: CAML-depleted MEFs showed significantly greater amounts of precursor cathepsin D (procathepsin D) released from serum-starved cells, compared to control cultures
    explanation: Mouse fibroblast secretion supports abnormal handling of lysosomal cargo.
  - reference: PMID:39823474
    reference_title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: knockout of CAML caused significantly more diffused accumulation of CD222 near the TGN
    explanation: CD222 distribution was altered in mouse fibroblasts.
  biological_processes:
  - preferred_term: lysosomal transport
    term:
      id: GO:0007041
      label: lysosomal transport
    modifier: ABNORMAL
  downstream:
  - target: Lysosomal Membrane Damage
    causal_link_type: UNKNOWN
    description: Altered cargo delivery could contribute to lysosomal damage; their causal order has not been resolved.
- name: Lysosomal Membrane Damage
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: Caml-null mouse fibroblasts showed increased galectin-3 puncta, colocalization with LAMP1 and enlarged LAMP1-positive structures. These findings indicate lysosomal membrane damage in that model. Lysosomal damage has not been demonstrated in CAMLG-CDG patient cells or shown to mediate motor-neuron loss in vivo.
  evidence:
  - reference: PMID:39823474
    reference_title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: There were 8 times more cells with positive galectin-3 puncta in Caml null MEFs than in their wildtype counterpart
    explanation: The puncta assay supports lysosomal damage in mouse fibroblasts, indirectly relevant to human disease.
  biological_processes:
  - preferred_term: lysosome organization
    term:
      id: GO:0007040
      label: lysosome organization
    modifier: ABNORMAL
  downstream:
  - target: Spinal Motor Neuron Loss
    causal_link_type: UNKNOWN
    description: Lysosomal dysfunction is a candidate contributor to neuronal loss, but the biochemical and neuronal findings were obtained in different experimental systems.
- name: Spinal Motor Neuron Loss
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: Neuron-specific Caml deletion in SLICK-H-Cre mice caused hindlimb paralysis and a 28% reduction of motor-neuron cell bodies in lumbar spinal-cord sections. Constitutive synapsin-Cre deletion also caused severe early motor impairment. These results support a neuronal requirement for CAML, but neither motor-neuron depletion nor this causal route has been demonstrated in the human splice-variant case. Partially depleted embryonic cortical cultures retained normal neurite growth.
  evidence:
  - reference: PMID:39823474
    reference_title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: H&E-stained sections on L3-L4 of lumbar spinal cord revealed a 28% reduction in the numbers of motor neuron bodies
    explanation: Direct in-vivo motor-neuron count, with indirect relevance to the human syndrome.
  cell_types:
  - preferred_term: spinal cord motor neuron
    term:
      id: CL:0011001
      label: spinal cord motor neuron
  locations:
  - preferred_term: spinal cord
    term:
      id: UBERON:0002240
      label: spinal cord
phenotypes:
- category: Neurologic
  name: Severe Global Developmental Delay
  description: Delay was noticed at three months of age because head control had not been achieved, and it never was. At fourteen years he has contact with his environment but no speech, and can sit only with considerable support.
  phenotype_term:
    preferred_term: Severe global developmental delay
    term:
      id: HP:0011344
      label: Severe global developmental delay
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The family noticed developmental delay at three months of age, since he had no head control.
    explanation: Age at first recognition of the delay.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Neurologic
  name: Intellectual Disability
  description: The defining study described intellectual disability in addition to severe developmental delay. Formal cognitive test scores were not reported.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: severe developmental delay (DD) and ID, hypotonia, limb contractures, seizures and structural brain abnormalities
    explanation: The clinical summary explicitly includes intellectual disability.
- category: Neurologic
  name: Developmental Regression
  description: He was babbling at one year, and lost the milestones he had reached as seizures began at the same age. Regression coinciding with seizure onset is the point in the history where the course changes from delay to loss.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He was babbling at one year, but seizures started at that age and he lost his milestones.
    explanation: Records both the regression and its coincidence with seizure onset.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Neurologic
  name: Seizures
  description: Seizures began at one year and consisted of staring, stiffness and unresponsiveness; the report did not assign a formal seizure type. Four years of seizure freedom were reported during levetiracetam treatment.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Seizures consisted of staring at a point accompanied by stiffness and unresponsiveness. He has been seizure free the last 4 years since receiving levetiracetam treatment.
    explanation: The semiology as reported and the response to treatment.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Neurologic
  name: Axial Hypotonia
  description: Axial hypotonia was present alongside limb spasticity and contractures at the most recent examination.
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He has axial hypotonia, limb spasticity and contractures.
    explanation: The examination finding at the most recent follow-up.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Neurologic
  name: Limb Spasticity
  description: Spasticity confined to the limbs, alongside axial hypotonia and with bilateral clonus on examination.
  phenotype_term:
    preferred_term: Limb spasticity
    term:
      id: HP:0034353
      label: Appendicular spasticity
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He has axial hypotonia, limb spasticity and contractures.
    explanation: The distribution of spasticity as examined; bound to the appendicular term because the report specifies limbs.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Neurologic
  name: Clonus
  description: Bilateral, with preserved deep tendon reflexes and flexor plantar responses.
  phenotype_term:
    preferred_term: Clonus
    term:
      id: HP:0002169
      label: Clonus
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Deep tendon reflexes are obtained, plantar reflexes are flexor, but he has a bilateral clonus.
    explanation: The neurological examination, including the negative findings that frame the clonus.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Neurologic
  name: Poor Head Control
  description: Head control had not been achieved when delay was first recognized at three months, and was never subsequently achieved.
  phenotype_term:
    preferred_term: Poor head control
    term:
      id: HP:0002421
      label: Poor head control
    onset:
      onset_category: INFANTILE
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Smiling and eye contact were appropriate for his age, but head control was never achieved.
    explanation: States the finding, and the preserved social milestones alongside it.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Neurologic
  name: Absent Speech
  description: Babbling at one year was lost with the regression; at fourteen he makes only sounds while remaining in contact with his environment.
  phenotype_term:
    preferred_term: Absent speech
    term:
      id: HP:0001344
      label: Absent speech
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He has contact with his environment but makes only sounds.
    explanation: The speech status at the most recent follow-up.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Neurologic
  name: Inability to Walk
  description: At the reported assessment, the patient could sit only with considerable support, indicating severe motor limitation and inability to walk independently. The report does not provide a separate walking milestone history.
  phenotype_term:
    preferred_term: Inability to walk
    term:
      id: HP:0002540
      label: Inability to walk
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He can only sit with considerable support and has limb contractures.
    explanation: Inability to walk independently is inferred from the reported severe sitting limitation; a separate walking history is not provided.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
- category: Musculoskeletal
  name: Limb Joint Contractures
  description: Contractures of the limbs, present by the time of the most recent assessment and severe enough that height could not be measured.
  phenotype_term:
    preferred_term: Limb joint contracture
    term:
      id: HP:0003121
      label: Limb joint contracture
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The most recent follow-up at 14 years showed weight of 30.6 kg (below 3rd centile), height could not be measured due to contractures, and head circumference of 46 cm (below 3rd centile).
    explanation: Documents the contractures and their functional severity. The report names no individual joint, so no more specific HPO term can be bound.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Nervous System Imaging
  name: Cerebral Atrophy
  description: Severe, on brain MRI at seven years.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI at 7 years showed a very thin corpus callosum, atrophic brain stem, severe cerebral and cerebellar atrophy and diffuse hypomyelination.
    explanation: The single imaging description that documents all four structural findings.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Nervous System Imaging
  name: Cerebellar Atrophy
  description: Severe, on the same MRI as the cerebral atrophy.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI at 7 years showed a very thin corpus callosum, atrophic brain stem, severe cerebral and cerebellar atrophy and diffuse hypomyelination.
    explanation: Cerebellar atrophy is named in the imaging report.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Nervous System Imaging
  name: Brainstem Atrophy
  description: An atrophic brain stem on MRI at seven years, alongside the supratentorial and cerebellar atrophy.
  phenotype_term:
    preferred_term: Brainstem atrophy
    term:
      id: HP:0007366
      label: Atrophy/Degeneration affecting the brainstem
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI at 7 years showed a very thin corpus callosum, atrophic brain stem, severe cerebral and cerebellar atrophy and diffuse hypomyelination.
    explanation: The brain stem finding in the same imaging report.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Nervous System Imaging
  name: Thin Corpus Callosum
  description: Very thin on MRI at seven years.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI at 7 years showed a very thin corpus callosum, atrophic brain stem, severe cerebral and cerebellar atrophy and diffuse hypomyelination.
    explanation: The callosal finding in the same imaging report.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Nervous System Imaging
  name: Cerebral Hypomyelination
  description: Diffuse hypomyelination was reported on MRI at seven years; a longitudinal imaging trajectory was not provided.
  phenotype_term:
    preferred_term: Cerebral hypomyelination
    term:
      id: HP:0006808
      label: Cerebral hypomyelination
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Brain MRI at 7 years showed a very thin corpus callosum, atrophic brain stem, severe cerebral and cerebellar atrophy and diffuse hypomyelination.
    explanation: The myelination finding in the same imaging report.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Craniofacial
  name: Microcephaly
  description: Head circumference was 35 cm at term birth and 46 cm, below the third centile, at fourteen years, consistent with postnatal development of microcephaly.
  phenotype_term:
    preferred_term: Secondary microcephaly
    term:
      id: HP:0005484
      label: Secondary microcephaly
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The affected male was born at term in 2007 with birth weight of 2500 g and head circumference of 35 cm.
    explanation: The normal occipitofrontal circumference at birth, which is what makes the later measurement postnatal in onset.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: head circumference of 46 cm (below 3rd centile)
    explanation: The measurement establishing microcephaly at fourteen years.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Craniofacial
  name: Dolichocephaly
  description: Dolichocephaly was noted at fourteen years, with no other significant dysmorphism reported in this individual.
  phenotype_term:
    preferred_term: Dolichocephaly
    term:
      id: HP:0000268
      label: Dolichocephaly
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He has a dolichocephalic head but no other significant dysmorphism
    explanation: The single dysmorphic finding, together with the statement that there are no others.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Growth
  name: Decreased Body Weight
  description: Weight was 30.6 kg, below the third centile, at fourteen years. The report does not quantify weight change after gastrostomy.
  phenotype_term:
    preferred_term: Decreased body weight
    term:
      id: HP:0004325
      label: Decreased body weight
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The most recent follow-up at 14 years showed weight of 30.6 kg (below 3rd centile)
    explanation: The weight measurement and its centile.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Gastrointestinal
  name: Feeding Difficulties
  description: Feeding is by gastrostomy. The report states the gastrostomy rather than the swallowing assessment behind it, so this phenotype is recorded at the level the source supports.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He has a gastrostomy and has been receiving intermittent respiratory support for 6 months as of publication.
    explanation: Documents enteral feeding by gastrostomy at fourteen years.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Respiratory
  name: Respiratory Insufficiency
  description: Intermittent respiratory support had been used for six months by the reported follow-up at fourteen years. The mode of support and underlying respiratory mechanism were not specified.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
    onset:
      onset_category: JUVENILE
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He has a gastrostomy and has been receiving intermittent respiratory support for 6 months as of publication.
    explanation: The requirement for respiratory support and its duration.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Laboratory
  name: Type II Serum Transferrin Isoform Pattern
  description: Serum transferrin isoelectric focusing repeatedly showed a type II pattern. Capillary electrophoresis showed reduced pentasialo and increased trisialo transferrin.
  phenotype_term:
    preferred_term: Type II transferrin isoform profile
    term:
      id: HP:0012301
      label: Type II transferrin isoform profile
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Serum transferrin isoelectrofocusing (IEF) repeatedly showed a type 2 pattern.
    explanation: The screening result, and the word "repeatedly" that makes it reproducible rather than a single abnormal assay.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- category: Laboratory
  name: Hyposialylated Mucin-Type O-Glycans
  description: Serum apoC-III isoelectric focusing showed absent asialo/disialo forms and a small monosialo signal. Patient fibroblasts showed increased peanut agglutinin binding, supporting core 1 O-glycan undersialylation.
  phenotype_term:
    preferred_term: Abnormal protein O-linked glycosylation
    term:
      id: HP:0012358
      label: Abnormal protein O-linked glycosylation
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The clear combined O- and N-linked glycosylation defects in serum points to general glycosylation abnormalities associated with TRC pathway dysfunction.
    explanation: States the O-linked arm of the serum defect.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
genetic:
- name: CAMLG
  gene_term:
    preferred_term: CAMLG
    term:
      id: hgnc:1471
      label: CAMLG
  relationship_type: UNKNOWN
  variant_origin: GERMLINE
  presence: PRESENT
  notes: CAMLG encodes CAML, also called GET2, a partner of WRB in tail-anchored protein insertion. The reported homozygous c.633+4A>G allele causes aberrant splicing and reduced protein in fibroblasts. ClinGen classifies the recessive gene-disease relationship as Limited. ClinVar RCV003152398.2 flags the literature-only OMIM pathogenic submission because supporting gene-disease evidence is insufficient; this is not a benign classification or proof against the functional result.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This is the first reported patient with pathogenic variants in CAMLG.
    explanation: Reports the first candidate disease-associated CAMLG genotype; independent clinical replication remains limited.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: CGGV:assertion_c077f9b7-9845-44dc-8007-be476f7b291e-2024-09-25T160000.000Z
    reference_title: CAMLG / congenital disorder of glycosylation, type IIz (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: CAMLG | HGNC:1471 | congenital disorder of glycosylation, type IIz | MONDO:0859357 | AR | Limited | SOP11 | Congenital Disorders of Glycosylation Gene Curation Expert Panel | 2024-09-25T16:00:00.000Z
    explanation: 'The ClinGen Gene-Disease Validity assertion row: autosomal recessive, classified Limited by the CDG expert panel in September 2024.'
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: CGGV:assertion_c077f9b7-9845-44dc-8007-be476f7b291e-2024-09-25T160000.000Z
    reference_title: CAMLG / congenital disorder of glycosylation, type IIz (Limited)
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In summary, there is limited evidence to support the relationship between CAMLG and Congenital Disorder of Glycosylation, type IIz.
    explanation: Records the expert panel classification rather than treating one family as definitive gene-disease proof.
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
  - reference: url:https://www.ncbi.nlm.nih.gov/clinvar/RCV003152398/
    reference_title: NM_001745.4(CAMLG):c.633+4A&gt;G AND Congenital disorder of glycosylation, type IIz - ClinVar - NCBI
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    directness: DIRECT
    snippet: P/LP classification for a variant in a gene with insufficient evidence for a gene-disease relationship
    explanation: ClinVar flags the pathogenic submission at the gene-disease evidence level; this does not reclassify the variant as benign.
  gene_disease_validity:
  - validity_classification: LIMITED
    classified_by: CLINGEN
    external_id: CGGV:assertion_c077f9b7-9845-44dc-8007-be476f7b291e-2024-09-25T160000.000Z
    evidence:
    - reference: CGGV:assertion_c077f9b7-9845-44dc-8007-be476f7b291e-2024-09-25T160000.000Z
      reference_title: CAMLG / congenital disorder of glycosylation, type IIz (Limited)
      supports: SUPPORT
      evidence_source: OTHER
      snippet: In summary, there is limited evidence to support the relationship between CAMLG and Congenital Disorder of Glycosylation, type IIz.
      explanation: Records the expert panel classification rather than treating one family as definitive gene-disease proof.
      quote_role: REVIEW_SYNTHESIS
      directness: DIRECT
    notes: Congenital Disorders of Glycosylation Gene Curation Expert Panel; classification dated 25 September 2024.
  association: Candidate recessive disease gene with functional evidence for the reported splice allele and limited independent clinical replication.
prevalence:
- population: Reported patients worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: One affected individual was described in the 2022 publication. Population prevalence, penetrance and phenotype frequencies cannot be estimated from this family.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: This is the first reported patient with pathogenic variants in CAMLG.
    explanation: Establishes the size of the original published case series.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
diagnosis:
- name: Serum transferrin and apolipoprotein C-III glycosylation screening
  description: Transferrin and apoC-III isoform studies detected combined N- and O-glycosylation abnormalities in the reported case. These abnormalities support a glycosylation disorder but are not specific for CAMLG.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Biochemically, a combined O-linked and type II N-linked glycosylation defect was found.
    explanation: The biochemical finding the screening pair is meant to produce.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  diagnosis_term:
    preferred_term: Laboratory Procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
- name: Whole genome sequencing after a negative CDG gene panel
  description: Trio whole-genome sequencing identified the intronic CAMLG allele after a panel of then-known CDG genes was negative. The case does not establish that contemporary panels cannot detect this position; interpretation requires segregation, functional findings and the limited gene-disease evidence.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Genetic analysis using a panel of known ‘CDG genes’ did not reveal any potentially pathogenic variants.
    explanation: The negative panel that made broader sequencing necessary.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
- name: Syntaxin-5 mislocalisation in fibroblasts as a TRC pathway marker
  description: STX5 fractionation and imaging are research assays that showed a shared abnormality in CAMLG- and GET4-deficient cells. They have not been validated as a stand-alone diagnostic test or as a way to exclude other glycosylation disorders.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: Mislocalization of syntaxin-5 in patient fibroblasts and in siCAMLG deleted Hela cells confirms this as a consistent cellular marker of TRC dysfunction.
    explanation: The authors' proposal of STX5 mislocalisation as the cellular marker of this pathway's defects.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  diagnosis_term:
    preferred_term: Laboratory Procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
- name: RNA analysis of the splice-region variant
  description: RT-qPCR and RT-PCR in patient fibroblasts demonstrated loss of canonical transcript and exon 2 skipping, providing functional evidence for the intronic allele.
  diagnosis_term:
    preferred_term: RNA Analysis
    term:
      id: NCIT:C18473
      label: RNA Analysis
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: a corresponding increase of a truncated ~163 bp amplicon could be seen in affected fibroblasts, confirming that the c.633 + 4A>G variant causes skipping of exon 2
    explanation: The shortened cDNA product establishes aberrant splicing.
- name: Brain MRI
  description: MRI documented cerebral, cerebellar and brainstem atrophy, thin corpus callosum and diffuse hypomyelination at seven years. These findings characterize CNS involvement and are not specific for CAMLG-CDG.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Brain MRI at 7 years showed a very thin corpus callosum, atrophic brain stem, severe cerebral and cerebellar atrophy and diffuse hypomyelination.
    explanation: The clinical imaging findings support assessment of CNS structure.
treatments:
- name: Levetiracetam
  description: The seizures in the reported patient responded to levetiracetam and he had been seizure-free for four years at the time of publication. This is a single observation in a single patient, not a disease-specific recommendation, and nothing is known about how CAMLG-CDG epilepsy responds to other agents.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: levetiracetam
      term:
        id: CHEBI:6437
        label: levetiracetam
  target_mechanisms:
  - target: Seizures
    description: Symptomatic seizure control. It does not address the glycosylation or trafficking defect.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He has been seizure free the last 4 years since receiving levetiracetam treatment.
    explanation: The observed response, with its duration.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Gastrostomy Feeding
  description: A gastrostomy was present at the last assessment. The report does not specify its timing or demonstrate effects on growth, aspiration or respiratory outcomes.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: gastrostomy
    term:
      id: NCIT:C52006
      label: Gastrostomy
  target_mechanisms:
  - target: Feeding Difficulties
    description: Bypasses the oral route.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He has a gastrostomy and has been receiving intermittent respiratory support for 6 months as of publication.
    explanation: Records the gastrostomy as part of this patient's management.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Intermittent Respiratory Support
  description: Intermittent respiratory support was reported for six months by the latest assessment. The support mode and response were not detailed.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: respiratory support
    term:
      id: NCIT:C15322
      label: Respiratory Therapy
  target_mechanisms:
  - target: Respiratory Insufficiency
    description: Provides respiratory support; a specific ventilation technique was not reported.
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He has a gastrostomy and has been receiving intermittent respiratory support for 6 months as of publication.
    explanation: The respiratory support and the point in the course at which it began.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
- name: Genetic Counselling
  description: Counselling can address segregation, carrier testing and the recessive inheritance model while explaining the Limited gene-disease classification. A 25% recurrence risk applies conditionally when both parents carry the same causal recessive allele; no counselling outcome was measured in this case.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:35262690
    reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Therefore, trio whole genome analysis was performed and identified the c.633 + 4A>G variant in CAMLG, inherited in an autosomal recessive fashion
    explanation: The inheritance mode on which counselling rests.
    directness: INDIRECT
    quote_role: PRIMARY_RESULT
experimental_models:
- name: CAMLG-CDG patient dermal fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: Cells from the sole reported homozygous splice-variant patient; they provide direct RNA, protein-localization and glycosylation observations but do not represent affected neural tissue.
  modeled_mechanisms:
  - target: Aberrant CAMLG Splicing
    relationship: PARTIALLY_RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: Exon 2 skipping is directly measured.
    evidence:
    - reference: PMID:35262690
      reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: a corresponding increase of a truncated ~163 bp amplicon could be seen in affected fibroblasts, confirming that the c.633 + 4A>G variant causes skipping of exon 2
      explanation: The shortened cDNA product establishes aberrant splicing.
  - target: Reduced CAML Protein Abundance
    relationship: PARTIALLY_RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: Reduced CAML is directly measured.
    evidence:
    - reference: PMID:35262690
      reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: Accordingly, reduced levels of CAML protein were identified using immunoblotting analysis
      explanation: Immunoblotting directly measures protein abundance.
  - target: Syntaxin-5 Mislocalisation to the Cytosol
    relationship: PARTIALLY_RECAPITULATES
    fidelity: HIGH
    model_scale: CELLULAR
    description: Fractionation and imaging show STX5 mislocalization.
    evidence:
    - reference: PMID:35262690
      reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Crude fractionation of affected CAMLG-CDG fibroblasts showed a significant increase in the amount of STX5 mislocalized to the cytoplasm.
      explanation: The primary measurement, made in the patient's own fibroblasts.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Depletion of the Golgi v-SNARE BET1L
    relationship: PARTIALLY_RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: BET1L is depleted while the remaining protein partitions normally.
    evidence:
    - reference: PMID:35262690
      reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: This was confirmed by immunoblotting from whole cell lysates, with BET1L levels at 37% and 27% of controls in CAMLG-CDG and GET4-CDG fibroblasts, respectively
      explanation: Quantifies the depletion in the patient's cells and shows it is shared with the other TRC pathway disorder tested.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
  - target: Core 1 O-Glycan Hyposialylation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: HIGH
    model_scale: MOLECULAR
    description: Increased PNA binding supports O-glycan undersialylation.
    evidence:
    - reference: PMID:35262690
      reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: although PNA lectin fluorescence was barely detectable in control fibroblasts, a strong increase in signal was identified in affected fibroblasts
      explanation: Lectin binding supports increased exposure of unsialylated core 1 O-glycans.
  - target: Altered Golgi Morphology
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: CELLULAR
    description: GM130/TGN46 staining did not show obvious morphological disruption.
    evidence:
    - reference: PMID:35262690
      reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: no obvious morphological abnormalities of the Golgi, such as those seen in COG defects, could be observed in affected CAMLG-CDG or GET4-CDG fibroblasts stained with Golgi markers GM130 or TGN46
      explanation: The negative morphology result supports failure to reproduce this model-dependent finding.
    limitations: Negative results concern the tested markers in fibroblasts; other cell types or ultrastructural changes were not excluded.
- name: CAMLG knockdown in ST6GAL1-GFP HeLa cells
  experimental_model_type: CELL_LINE
  description: Acute siRNA knockdown left approximately 2% residual CAML. The model reproduces selected molecular effects without carrying the patient splice allele.
  modeled_mechanisms:
  - target: Syntaxin-5 Mislocalisation to the Cytosol
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Both STX5 isoforms became more cytosolic.
    evidence:
    - reference: PMID:35262690
      reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: in this model both STX5S (P < 0.001) and STX5L (P < 0.01) were significantly mislocalized to the cytoplasmic fraction from that of the membrane
      explanation: Localization changed after CAMLG knockdown.
  - target: Depletion of the Golgi v-SNARE BET1L
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: BET1L abundance fell to 30.3% of untreated levels.
    evidence:
    - reference: PMID:35262690
      reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: a significant (P < 0.01) reduction in BET1L steady-state levels was observed in whole-cell lysates, to 30.3% of levels in untreated cells
      explanation: The knockdown reproduces reduced BET1L abundance.
  - target: Altered Golgi Morphology
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: ST6GAL1-GFP distribution became more fragmented.
    evidence:
    - reference: PMID:35262690
      reference_title: 'CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Treated cells showed normal levels of ST6GAL1, but with a more fragmented distribution (Supplementary Material, Fig. S3). This indicated that knockdown of CAMLG expression leads to at least some disorganization of the Golgi.
      explanation: The evidence for Golgi disorganisation, and the model it comes from.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
    limitations: The transformed cell line and acute near-complete depletion differ from patient fibroblasts, which lacked obvious morphological abnormalities.
- name: Conditional Caml-null mouse embryonic fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: ERT2-Cre;Caml-floxed embryonic fibroblasts were exposed to 4-hydroxytamoxifen to delete Caml. This is a mouse null model, not the human hypomorphic splice allele.
  modeled_mechanisms:
  - target: Altered Lysosomal Cargo Trafficking
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Cargo secretion and CD222 distribution were abnormal.
    evidence:
    - reference: PMID:39823474
      reference_title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: CAML-depleted MEFs showed significantly greater amounts of precursor cathepsin D (procathepsin D) released from serum-starved cells, compared to control cultures
      explanation: Mouse fibroblast secretion supports abnormal handling of lysosomal cargo.
    - reference: PMID:39823474
      reference_title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: knockout of CAML caused significantly more diffused accumulation of CD222 near the TGN
      explanation: CD222 distribution was altered in mouse fibroblasts.
  - target: Lysosomal Membrane Damage
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: Galectin-3 puncta and LAMP1 abnormalities indicate lysosomal damage.
    evidence:
    - reference: PMID:39823474
      reference_title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: There were 8 times more cells with positive galectin-3 puncta in Caml null MEFs than in their wildtype counterpart
      explanation: The puncta assay supports lysosomal damage in mouse fibroblasts, indirectly relevant to human disease.
  - target: Core 1 O-Glycan Hyposialylation
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: PNA staining increased, paralleling the patient-cell O-glycan readout.
    evidence:
    - reference: PMID:39823474
      reference_title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: There was a significantly elevated level of PNA lectin fluorescence in Caml null cells compared to control cells
      explanation: The null model reproduces the lectin phenotype.
- name: Caml-depleted embryonic mouse cortical cultures
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: Mixed cultures from embryonic day 18 cortex had partial CAML depletion after inducible deletion. They are neither spinal motor neurons nor patient-derived cells. Neurite length and branching were unchanged; these measurements do not test spinal motor-neuron survival.
  modeled_mechanisms:
  - target: Altered Lysosomal Cargo Trafficking
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    model_scale: CELLULAR
    description: Cathepsin D abundance decreased, while STX5/CD222 localization changes were nonsignificant.
    evidence:
    - reference: PMID:39823474
      reference_title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: cathepsin D levels were significantly reduced when Caml was deleted
      explanation: This supports an altered lysosomal protein readout, without proving cargo misrouting in these neurons.
  evidence:
  - reference: PMID:39823474
    reference_title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: There was no significant difference between length and branch points of neurites, regardless of presence or absence of the Caml gene
    explanation: Preserved neurite length and branching in the partially depleted cortical cultures; a different cell population and endpoint from spinal motor-neuron counts.
- name: Human WRB-CAML complementation of yeast GET receptor deficiency
  experimental_model_type: OTHER
  description: Wild-type human receptor components restored TA-protein targeting and stress-associated growth in receptor-deficient yeast.
  cell_source: Saccharomyces cerevisiae with get1/get2 deletion and coexpression of human WRB and CAML
  publication: PMID:24392163
  modeled_mechanisms:
  - target: Impaired TRC-Mediated Tail-Anchored Protein Insertion
    relationship: RESCUES
    fidelity: LOW
    model_scale: CELLULAR
    description: WRB and CAML together restored Sed5 targeting and Get3 ER recruitment.
    evidence:
    - reference: PMID:24392163
      reference_title: WRB and CAML are necessary and sufficient to mediate tail-anchored protein targeting to the ER membrane.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: Individually, WRB and CAML were unable to mediate GFP-Sed5 targeting to the Golgi membrane, but when co-expressed they formed a fully functional receptor and proper Sed5 localization was restored
      explanation: Wild-type complementation establishes conserved receptor function, not the magnitude of the human variant defect.
    limitations: Normal-protein complementation supports conserved receptor function. It neither tests the patient allele nor reproduces human neurological disease.
animal_models:
- name: Camlg knockout mouse
  species: Mouse
  genotype: Camlg (CAML) germline disruption, homozygous null
  publication: PMID:12919676
  description: Disruption of the mouse CAML gene is lethal in early embryonic development, although CAML-deficient cells remain viable. The model predates the human disease by nearly two decades and was made to study TACI and EGF receptor signalling, not glycosylation.
  modeled_mechanisms:
  - target: Severe Global Developmental Delay
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: ORGANISM
    description: The complete null does not produce a viable animal with a neurological phenotype, so it cannot model the human developmental course.
    limitations: Complete germline deletion is embryonically lethal and cannot reproduce the postnatal course of the surviving human splice-variant case. Residual activity as an explanation for human survival remains hypothetical.
    evidence:
    - reference: PMID:12919676
      reference_title: CAML is required for efficient EGF receptor recycling.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: To study its function in the mouse, we disrupted the CAML gene and found it to be required for early embryonic development, but not for cellular viability.
      explanation: The embryonic lethality that prevents this model from reporting on a postnatal neurodevelopmental phenotype.
      quote_role: PRIMARY_RESULT
      directness: DIRECT
- name: Graded global Caml depletion with an inducible rescue transgene
  species: Mouse
  genotype: rtTA-positive; Caml transgene-positive; ERT2-Cre-positive; Caml-floxed homozygote
  publication: PMID:39823474
  description: Low doxycycline-induced transgene expression prolonged survival after endogenous Caml deletion to up to four weeks, allowing observation of hindlimb weakness progressing to paralysis.
  modeled_mechanisms:
  - target: Spinal Motor Neuron Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Low doxycycline-induced transgene expression prolonged survival after endogenous Caml deletion to up to four weeks, allowing observation of hindlimb weakness progressing to paralysis.
    evidence:
    - reference: PMID:39823474
      reference_title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: By 2 to 3 weeks post-tamoxifen treatment, the hind legs were completely extended and paralyzed
      explanation: Global depletion produces a motor phenotype, without directly identifying the dying neuronal population in this cohort.
    limitations: The model uses experimentally induced deletion rather than the human intronic allele. Human motor-neuron loss and complete reproduction of the CDG phenotype have not been demonstrated.
- name: Neuron-specific inducible Caml deletion
  species: Mouse
  genotype: SLICK-H-Cre-positive; Caml-floxed homozygote
  publication: PMID:39823474
  description: Induced neuron-specific deletion caused hindlimb paralysis, death within four weeks and a 28% reduction in lumbar motor-neuron bodies.
  modeled_mechanisms:
  - target: Spinal Motor Neuron Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Induced neuron-specific deletion caused hindlimb paralysis, death within four weeks and a 28% reduction in lumbar motor-neuron bodies.
    evidence:
    - reference: PMID:39823474
      reference_title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: INDIRECT
      snippet: H&E-stained sections on L3-L4 of lumbar spinal cord revealed a 28% reduction in the numbers of motor neuron bodies
      explanation: Direct in-vivo motor-neuron count, with indirect relevance to the human syndrome.
    limitations: The model uses experimentally induced deletion rather than the human intronic allele. Human motor-neuron loss and complete reproduction of the CDG phenotype have not been demonstrated.
- name: Constitutive neuronal Caml deletion
  species: Mouse
  genotype: Synapsin-Cre-positive; Caml-floxed homozygote
  publication: PMID:39823474
  description: Constitutive neuronal deletion caused hindlimb paralysis from approximately postnatal day five and death by ten days.
  modeled_mechanisms:
  - target: Spinal Motor Neuron Loss
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: Constitutive neuronal deletion caused hindlimb paralysis from approximately postnatal day five and death by ten days.
    evidence:
    - reference: PMID:39823474
      reference_title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      quote_role: PRIMARY_RESULT
      directness: DIRECT
      snippet: As early as neonatal day 5, Camlfl/fl homozygous pups with Cre had paralysis of the back legs.
      explanation: This neuronal model supports a requirement for CAML in early motor function.
    limitations: The model uses experimentally induced deletion rather than the human intronic allele. Human motor-neuron loss and complete reproduction of the CDG phenotype have not been demonstrated.
differential_diagnoses:
- name: GET4-CDG
  description: GET4 deficiency can cause overlapping developmental impairment, seizures, hypotonia, structural brain abnormalities and altered STX5 localization. The original GET4 case had a subtle type II transferrin pattern; broader serum N-glycan analysis and fibroblast glycosylation studies were normal. Clinical overlap warrants molecular testing; distinct findings in single cases do not establish reliable clinical discriminators.
  evidence:
  - reference: PMID:32395830
    reference_title: Mutations in GET4 disrupt the transmembrane domain recognition complex pathway.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: He presented with global developmental delay, intellectual disabilities, seizures, facial dysmorphism, and delayed bone age.
    explanation: The GET4-CDG phenotype, for comparison with the phenotype recorded here.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
  - reference: PMID:32395830
    reference_title: Mutations in GET4 disrupt the transmembrane domain recognition complex pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: in CDG-0381 fibroblasts, we were unable to find any clear glycosylation abnormality
    explanation: The GET4 comparator does not establish a universal shared cellular glycosylation phenotype.
- name: GET3-CDG (ASNA1-related cardiomyopathy)
  description: Biallelic ASNA1 variants caused rapidly progressive neonatal dilated cardiomyopathy and death in two siblings. Slight transferrin and apoC-III abnormalities were observed, but the authors cautioned that these might be secondary. This phenotype differs from the predominantly neurological CAMLG case, without defining an absolute organ-specific rule for either gene.
  evidence:
  - reference: PMID:31461301
    reference_title: Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    directness: DIRECT
    snippet: Exome sequencing was used to screen for the causative genetic defect in a pair of siblings with rapidly progressive dilated cardiomyopathy and death in early infancy.
    explanation: The primary ASNA1 study directly describes the cardiac presentation in two siblings.
- name: STX5-CDG
  description: Loss of the short STX5 isoform causes a severe multisystem CDG with liver failure, cholestasis, hyperinsulinemic hypoglycemia and skeletal abnormalities. This establishes a related trafficking disorder; it does not prove that the partial STX5 mislocalization in CAMLG-CDG has the same clinical consequences.
  evidence:
  - reference: PMID:34711829
    reference_title: Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: After birth, the main clinical problem for both patients IV:9 and IV:10 was progressive liver failure with cholestasis and hyperinsulinemic hypoglycemia
    explanation: The STX5-CDG phenotype, which is hepatic rather than neurological.
    quote_role: PRIMARY_RESULT
    directness: DIRECT
discussions:
- discussion_id: camlg_how_does_trc_failure_injure_the_brain
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: What connects altered tail-anchored protein handling to neurological impairment in CAMLG-CDG, and is the glycosylation defect causal or a parallel consequence?
  attaches_to:
  - pathophysiology#Impaired TRC-Mediated Tail-Anchored Protein Insertion
  - pathophysiology#Core 1 O-Glycan Hyposialylation
  - pathophysiology#Altered Lysosomal Cargo Trafficking
  - pathophysiology#Lysosomal Membrane Damage
  - pathophysiology#Spinal Motor Neuron Loss
  rationale: The 2022 patient study measured splicing, protein abundance, SNARE localization and glycosylation, but did not connect them experimentally to neurological impairment. A 2025 study showed motor-neuron loss after neuron-specific Caml deletion, alongside trafficking and lysosomal abnormalities measured mainly in mouse fibroblasts. Partially depleted cortical cultures retained normal neurite growth. These results support a neuronal requirement for CAML while leaving the relevant substrates, cell types and causal order unresolved. Glycosylation, lysosomal damage and altered trafficking could be interacting or parallel consequences; rescue experiments are needed to distinguish them.
  proposed_experiments:
  - experiment_id: exp_camlg_neuronal_model
    name: TRC pathway failure in a human neuronal model
    description: Use isogenic patient-variant and corrected human neuronal cultures, including spinal motor neurons, to compare TA-protein localization, glycosylation, lysosomal cargo handling and survival. Independently restore CAML, selected SNAREs or glycosylation to test which abnormalities mediate neuronal injury.
    would_support:
    - pathophysiology#Spinal Motor Neuron Loss
    supporting_outcome:
    - Variant-dependent neuronal injury and molecular abnormalities are reversed by allele correction; selective downstream rescue identifies a necessary intermediate.
    refuting_outcome:
    - Adequate variant expression and assay sensitivity are confirmed, but neuronal phenotypes do not differ from corrected controls, or correction of the proposed intermediate fails to improve survival.
  evidence:
  - reference: PMID:39823474
    reference_title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: H&E-stained sections on L3-L4 of lumbar spinal cord revealed a 28% reduction in the numbers of motor neuron bodies
    explanation: Direct in-vivo motor-neuron count, with indirect relevance to the human syndrome.
  - reference: PMID:39823474
    reference_title: Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    directness: INDIRECT
    snippet: There were 8 times more cells with positive galectin-3 puncta in Caml null MEFs than in their wildtype counterpart
    explanation: The puncta assay supports lysosomal damage in mouse fibroblasts, indirectly relevant to human disease.
- discussion_id: camlg_single_patient_denominator
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which features of this entry are properties of CAMLG-CDG, and which are properties of one boy?
  attaches_to:
  - phenotypes#
  - prevalence#Reported patients worldwide
  rationale: The clinical spectrum derives from one published individual carrying one homozygous splice-region allele. Population frequencies, penetrance, treatment-response rates and prognostic subgroups cannot be inferred. GET4 clinical overlap and experimental Caml models support related biology but do not independently replicate the human CAMLG-CDG phenotype. Residual CAML may help explain viability, yet the relationship between residual protein, neuronal vulnerability and survival has not been measured in additional human alleles.
notes: The CAML protein is also called GET2 in trafficking literature. Clinical observations in this entry concern the published recessive CAMLG-CDG case; common CAMLG variants studied in adult neurodegenerative-disease risk and unrelated immune-cell functions do not define this syndrome.

📚

References & Deep Research

References

9

PMID:35262690

CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking.

No top-level findings curated for this source.

PMID:24392163

WRB and CAML are necessary and sufficient to mediate tail-anchored protein targeting to the ER membrane.

No top-level findings curated for this source.

PMID:39823474

Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.

No top-level findings curated for this source.

CGGV:assertion_c077f9b7-9845-44dc-8007-be476f7b291e-2024-09-25T160000.000Z

CAMLG / congenital disorder of glycosylation, type IIz (Limited)

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/clinvar/RCV003152398/

NM_001745.4(CAMLG):c.633+4A>G AND Congenital disorder of glycosylation, type IIz - ClinVar - NCBI

No top-level findings curated for this source.

PMID:12919676

CAML is required for efficient EGF receptor recycling.

No top-level findings curated for this source.

PMID:32395830

Mutations in GET4 disrupt the transmembrane domain recognition complex pathway.

No top-level findings curated for this source.

PMID:31461301

Biallelic Variants in ASNA1, Encoding a Cytosolic Targeting Factor of Tail-Anchored Proteins, Cause Rapidly Progressive Pediatric Cardiomyopathy.

No top-level findings curated for this source.

PMID:34711829

Congenital disorder of glycosylation caused by starting site-specific variant in syntaxin-5.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (2)

Review CAMLG-CDG mechanisms, limited clinical evidence and neuronal models · 2026-10-01T14:36:25Z · View source

Review the complete CAMLG-CDG entry, its CREATE history, the matching deep-research report and citation list, and the cached primary literature. Eligibility was checked against origin/main 5ece56453d85ddb3c99778917fb7011ab2a43c14 and the refreshed paginated open-PR file census: no previous REVIEW and no open KB/history overlap. Automated research preflight returned SKIP because MONDO has no causal-gene edge; manual OMIM 620201 / MONDO:0859357 / CAMLG identity checks agree with the primary report and current ClinGen record. Retain the established gene-named disease and synonyms. Read the complete 2022 clinical/functional paper (PMID35262690), including methods, results, figure legends and discussion. Separate physical intronic alteration, observed exon skipping, predicted protein truncation and measured reduced CAML. A +4 donor-region variant is not a canonical splice-dinucleotide substitution. Preserve the normal localization of several tail-anchored substrates and distinguish measured STX5 mislocalization/BET1L abundance from proposed insertion, degradation and SNARE-trafficking steps. Separate Golgi morphology, O-glycan undersialylation and the serum type II N-glycan defect. Record the normal patient-fibroblast Golgi morphology alongside the HeLa result, and avoid assuming otherwise-normal glycan structure from a limited marker panel. Add substantive 2025 evidence omitted from the entry and research report: PMID39823474 was read in full, including all scientific text, methods and figure legends. Graded global depletion and neuron-specific Caml deletion models survive long enough to show severe motor phenotypes, and the SLICK-H model has measured lumbar motor-neuron loss. Mouse fibroblasts show altered lysosomal cargo handling, galectin/LAMP1 abnormalities and increased PNA staining. Keep these findings distinct from the partially depleted cortical cultures, whose STX5/CD222 localization changes and neurite growth differences were nonsignificant. Represent the new cellular/organism models and proposed lysosomal route without asserting that mouse motor-neuron pathology explains every human clinical feature. Read the 2014 WRB/CAML yeast-complementation paper (PMID24392163) and add a limited normal-function rescue model. The 2003 mouse-null source remains abstract-only after refetch and DOI fallback; no inaccessible full-text details are asserted. Preserve one-family uncertainty without assigning phenotype frequencies. Add explicitly reported intellectual disability, use the limb-joint contracture term, and bind postnatal microcephaly to Secondary microcephaly. Remove unsupported claims of progressive radiographic loss, a fixed versus progressive course, unreported walking milestone history, precise respiratory-support starting age, gastrostomy airway protection and treatment failure inferred from a single low weight. Remove unsupported sequela edges. Connect all 23 clinical findings with appropriately qualified mechanisms or unresolved clinical associations. Retain the levetiracetam response as a single-patient observation. Refresh diagnostic interpretation with RNA confirmation and brain MRI; classify STX5 localization as a research marker rather than a validated discriminatory clinical test. Preserve observed supportive treatments and make genetic counselling explicitly indirect. Read GET4 and ASNA1 comparator papers in full and the relevant STX5 clinical/functional results. Do not import GET4 bortezomib rescue or ASNA1 cardiac outcomes as CAMLG therapies or phenotypes. The GET4 serum/cellular glycosylation findings and slight ASNA1 glycoform abnormalities do not establish an identical glycosylation defect across all TRC disorders. Current ClinGen CCID008383 remains Limited (September 2024). Add a structured gene_disease_validity assertion and replace the schema's Strong/Definitive CAUSATIVE relationship label with UNKNOWN plus an explicit candidate-causation association. Preserve the experimentally demonstrated variant effects while avoiding a definitive gene-disease claim. ClinVar RCV003152398.2 flags the literature-only OMIM pathogenic submission for insufficient gene-disease evidence; this is not a benign classification. ClinGen's live summary swaps author names for two model papers and lists MRI age as onset/exome sequencing; use the primary publications for those facts. The immutable structured CGGV source remains the cited classification record. Search current Europe PMC/PubMed gene literature and ClinicalTrials.gov. The search identified the 2025 mouse paper but no independent second CAMLG-CDG case report. A Parkinson disease common-variant study (PMID40053464) was read for its relevant results and limitations; it does not establish another recessive CDG allele or phenotype and is not cited. The sole trial-registry match is an unrelated lupus telitacicept study with a CAML background mention. Fresh GeneReviews and StatPearls checks both return NO_CHAPTER. No disease-specific intervention trial is added. Retain both scientific discussions, updating the neurological mechanism question for the new mouse evidence and remaining human neuronal/allele-specific uncertainty. Remove curation-process prose from disease notes. Regenerate every new reference cache through just fetch-reference; unused DOI, live ClinGen HTML and Parkinson-study caches are excluded from the PR. Validate all 91 exact quotations and 100 titles, schema and ontology bindings, history, complete phenotype connectivity, structured gene validity and repository evidence-hygiene gates.

Create: CAMLG-CDG (congenital disorder of glycosylation type IIz, MONDO:0859357) · 2026-09-25T16:58:59Z · View source

De novo curation of MONDO:0859357 (congenital disorder of glycosylation, type IIz). Gene identification. The stub recorded no gene. CDG-IIz was resolved to CAMLG from MONDO:0859357 -> OMIM:620201 / MedGen C5774295 (NCBI E-utilities esummary), then MedGen -> NCBI Gene 819 (elink), which returns CAMLG at 5q31.1 with CDG2Z and GET2 among its aliases. HGNC:1471 was read from the HGNC REST API in the same step. The primary literature search (PubMed 'CAMLG-CDG', 'CDG2Z', 'CAMLG AND (glycosylation OR CDG)') returns exactly one patient report, Wilson et al. 2022 (PMID:35262690), whose title names the disease CAMLG-CDG. Naming / lump-split. Curated as a Disease under the gene-named form CAMLG-CDG. The automated second opinion on issue #12798 pointed out that the two most recently curated type-II CDG entries (IIr, IIw) kept the roman-numeral name, and suggested the collision with a separately curated non-CDG disease of the same gene as the likely reason for IIr (ATP6AP2). That check was run here: 'grep -ril CAMLG kb/' returns no disorder entry, so there is no collision and the dominant gene-named convention applies. Roman-numeral and OMIM forms are carried as synonyms. The stub was updated to entry_type: DISEASE in a separate commit before the entry was written, then deleted with the curation commit. Deep research. Requested provider falcon returned HTTP 402 (account out of credits); the run fell back to claude_code, as configured. The report is committed as research/CAMLG-CDG-deep-research-claude_code.md with its citations sidecar. 'just preflight-dr' returned SKIP, not FAIL: MONDO records no RO:0004003 causal gene for MONDO:0859357 so the automated gene-identity check cannot discriminate. The manual fallback confirms the report is on-topic - top gene CAMLG (21 mentions), OMIM 620201 matching MONDO's own xref. The report's own term validation flagged four suspect HPO/GO CURIEs (HP:0002451, HP:0007266, HP:0007305, GO:0006486); none of them was used. Every binding in the entry was looked up independently through the OLS REST API. The report also mis-states the age of seizure onset as ~3 months; the primary source says one year, and the entry follows the primary source. The report's suggestion to trace the mouse knockout claim to its own source was taken - PMID:12919676 is cited directly for the Camlg null rather than Wilson et al.'s background sentence, which is cited alongside it for the hypomorph/null contrast. Evidence. 64 snippets, all exact-quote verified against cached references (references_cache/PMID_35262690.md is full_text_xml, so the full-text quotes are CI-reproducible under linkml-reference-validator 0.3.0rc1). Six references are cited: the defining paper, the GET4, ASNA1/GET3, STX5 and mouse-knockout papers used for the differential and the animal model, and the ClinGen assertion below. Structured sources, and a corrected negative claim. An earlier draft of the entry's notes asserted that ClinGen had published no gene-disease validity assertion for CAMLG. Re-running the search against the source rather than trusting the draft refuted it: the ClinGen CSV carries CGGV:assertion_c077f9b7-9845-44dc-8007-be476f7b291e-2024-09-25T160000.000Z, CAMLG / congenital disorder of glycosylation, type IIz, AR, classification Limited, CDG Gene Curation Expert Panel, 2024-09-25. It is now cited in the genetic section and stated in the description, since a Limited classification bears directly on how a CAMLG variant should be read on a diagnostic panel. The cache file was built with `clingen-rebuild --id ... --cache-dir references_cache` from a fresh download of the unversioned ClinGen URL; data/clingen/MANIFEST.yaml was deliberately not repinned, as that is a repo-wide change outside this entry's scope, and the assertion has not changed since 2024 so the pinned release should yield the same bytes. Orphanet has no corresponding concept: OLS ORDO searches for "CAMLG", "glycosylation type IIz" and "CDG-IIz" each returned 0, against 99 for "glycosylation" as a control. Deliberate omissions. No phenotype carries a frequency band: with one reported patient any band would be an assertion about a denominator of one. No GeneReviews or StatPearls chapter covers the disease (`just check-genereviews`, offline and --online, reports NO_CHAPTER for both). gnomAD was not consulted for the intronic variant and no population-frequency claim is made. The T-cell biology of CAML was left out as a non-disease-linked gene function. The two downstream pathograph steps - Golgi SNARE disorder to hyposialylation, and the biochemical defect to the neurological phenotype - are marked PROVISIONAL and HYPOTHETICAL because the defining study offers both as proposals and states that the pathomechanism is not established. Environment. Disk on the curation machine was at 97%, so no private rc venv was built; an existing linkml-reference-validator 0.3.0rc1 environment was reused and its version re-read immediately before each gate. No ontology SQLite build was downloaded - all term lookups went through the OLS REST API.

Claude Code ▸

CAMLG-CDG (Congenital Disorder of Glycosylation, Type IIz) — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 14 citations 2026-09-25T16:47:03.500337

CAMLG-CDG (Congenital Disorder of Glycosylation, Type IIz) — Comprehensive Research Report

Summary

CAMLG-CDG is an ultra-rare, autosomal recessive congenital disorder of glycosylation (CDG) caused by biallelic loss-of-function variants in CAMLG (calcium-modulating ligand, encoding the CAML protein). It was first reported in a single 14-year-old male patient in 2022 by Wilson, Durin, Unal, and colleagues (Human Molecular Genetics) and is designated CDG2Z in OMIM (#620201; gene: CAMLG, OMIM 601118). CAMLG-CDG is the third* described human disorder of the TRC ("transmembrane domain recognition complex," also called the GET pathway) — following GET4-CDG (OMIM #618751, CATP4/UBL4A-family disorder) and GET3/ASNA1-related disease — establishing "TRC pathway disorders" as an emerging disease category distinct from the classical CDG mechanisms (glycan assembly/transfer enzymes, nucleotide-sugar transporters, or COG/vesicular-tethering defects) (Wilson et al. 2022, PMID:35262690).

Primary source for nearly all clinical/molecular/mechanistic content below: Wilson MP, Durin Z, Unal Ö, et al. "CAMLG-CDG: a novel congenital disorder of glycosylation linked to defective membrane trafficking." Hum Mol Genet. 2022;31(15):2571-2581. doi:10.1093/hmg/ddac055. PMID:35262690; PMCID:PMC9396942. This is the sole primary literature report to date; no independent second family has yet been published (searched September 2026).

1. Disease Information

What it is. CAMLG-CDG is a Type II CDG (glycan-processing/trafficking defect rather than assembly defect) presenting with a predominantly severe neurological phenotype — global developmental delay, hypotonia, spasticity, epilepsy, and structural brain abnormalities — arising from combined defects in N-linked and mucin-type O-linked glycan sialylation, secondary to disrupted membrane insertion of tail-anchored (TA) SNARE proteins in the Golgi.

Key identifiers: - MONDO: MONDO:0859357 (per the dismech curation stub for this disease, issue #12798 — a lead, not independently re-verified against the MONDO release in this session) - OMIM phenotype: #620201 — Congenital Disorder of Glycosylation, Type IIz (CDG2Z) - OMIM gene: 601118 — CALCIUM-MODULATING LIGAND; CAMLG - Gene identifiers: HGNC:1471; NCBI Gene ID 819; approved name "calcium modulating ligand"; chromosome 5q31.1 (hg38 ~chr5:134,737,608–134,752,705) - Reference transcript used in the report: NM_001745.4 - Inheritance: Autosomal recessive - Synonyms/aliases for the gene: CAML (protein), calcium-modulating cyclophilin ligand - Orphanet/ICD-10/ICD-11: No dedicated Orphanet or ICD codes were identified in this search — consistent with the condition's extreme rarity and single-patient status; it would fall under the general CDG-II ICD-10 code (E77.8, other disorders of glycoprotein metabolism) if coded clinically. - Data provenance:* All disease-level information is derived from a single published index case (a structured case report / mechanistic study), i.e., individual-patient-level data aggregated into one peer-reviewed report — not a registry or large cohort.

2. Etiology

Disease causal factor: Purely genetic/monogenic. Biallelic (here, homozygous) loss-of-function variation in CAMLG abrogates CAML protein expression, disrupting the TRC/GET tail-anchored protein insertion pathway.

Genetic risk factors: - The reported variant, c.633+4A>G (chr5:134,741,527A>G, GRCh38.p13), is a canonical splice-donor-region variant in intron 2 causing exon 2 skipping. - Consanguinity is the dominant risk factor identified: the patient is "the second child of consanguineous Turkish parents (fourth degree cousins)," with an unaffected older sibling and no other family history of metabolic disease (Wilson et al. 2022). This is the classic epidemiologic signature of an autosomal recessive founder/private variant surfacing through consanguineous mating. - No population allele-frequency data for this specific variant were retrievable in this session (gnomAD query not performed); given a single reported homozygote in a consanguineous pedigree, the variant is presumptively very rare/private. - No modifier genes have been reported (single case; no genotype-phenotype correlation possible yet).

Environmental/other risk factors: None reported or plausible — this is a purely monogenic ER/Golgi membrane-insertion disorder.

Protective factors: None reported. The report speculates (see mechanism/model-organism section below) that residual leaky splicing producing a small amount of functional CAML is what allows human survival, given that complete Camlg knockout is embryonic lethal in mice — this is an inferred within-patient mechanism of attenuation, not a population-level protective genetic variant.

Gene-environment interactions: None described; not applicable to this single-gene ER trafficking disorder.

3. Phenotypes

All phenotype data below derive from the one published patient (male, born 2007 at term; most recent evaluation at age 14) (Wilson et al. 2022, PMID:35262690). Frequencies are necessarily "1/1" (n=1); no population frequency data exist.

Phenotype	Onset / Detail	Suggested HPO term
Global developmental delay	Noted from 3 months of age — "no head control"	HP:0001263 Global developmental delay
Loss of developmental milestones	Onset ~3 months, coincident with seizure onset	HP:0032199 Regression (or HP:0002376 Developmental regression)
Seizures	Onset ~3 months; described as "staring at a point accompanied by stiffness and unresponsiveness" (semiology consistent with tonic/absence-type seizures)	HP:0001250 Seizure; consider HP:0002373 Febrile seizure — not stated; better HP:0032794 (focal-onset seizure) or generic HP:0001250
Drug-responsive epilepsy	Seizure-free ×4 years on levetiracetam at last follow-up	HP:0011182 Levetiracetam-responsive (not a real HPO term — record as treatment response in `notes`, not HPO); use HP:0001250 for the seizure phenotype itself
Axial hypotonia	Present at exam	HP:0008936 Axial hypotonia
Limb spasticity	Present	HP:0001257 Spasticity
Limb contractures	Present	HP:0001371 Flexion contracture (or HP:0034392 generic contractures)
Bilateral clonus	Present on exam	HP:0100659 Clonus (verify exact term)
Severe global motor impairment	"can only sit with considerable support"	HP:0002510 Spastic tetraparesis / HP:0002keeping generic HP:0001344 not appropriate — best mapped to HP:0002020 or functional-status descriptors; recommend HP:0001272 (Cerebellar atrophy) separately for imaging, and a general severe motor impairment term
Severe expressive language impairment	"makes only sounds" (nonverbal)	HP:0002465 or HP:0000750 Delayed speech and language development (severe/absent)
Growth failure — weight	30.6 kg at 14 y, below 3rd centile	HP:0004325 Decreased body weight
Microcephaly (acquired/postnatal)	Head circumference 46 cm at 14 y, below 3rd centile	HP:0000252 Microcephaly
Dolichocephaly	Noted on exam; "no other significant dysmorphism"	HP:0000268 Dolichocephaly
Feeding difficulty requiring gastrostomy	Chronic, ongoing	HP:0002020 Gastrostomy / feeding difficulties → HP:0011968
Respiratory insufficiency	Requires intermittent respiratory support	HP:0002093 Respiratory insufficiency
Normal eye movements	Explicitly noted as normal (negative finding, worth recording)	—
No organomegaly	Explicitly negative	—

Neuroimaging (brain MRI, age 7 years): "very thin corpus callosum, atrophic brain stem, severe cerebral and cerebellar atrophy and diffuse hypomyelination" — HPO candidates: HP:0033725/HP:0002079 (Hypoplasia of the corpus callosum / Thin corpus callosum — HP:0002079 or HP:0033725), HP:0002099 or HP:0001272 (Cerebellar atrophy), HP:0002451 (Limb ataxia — not stated), HP:0007266 (Diffuse cerebral atrophy), HP:0002194 (Delayed gross motor development), HP:0002087/HP:0002012 (brainstem atrophy — map to HP:0007366 Cerebellar vermis atrophy / HP:0002080 or a generic "Abnormality of brainstem morphology"), and HP:0007305 (Abnormality of the cerebral white matter) / HP:0012448 (Delayed myelination) for diffuse hypomyelination.

Severity/progression: The phenotype is characterized as a static, severe encephalopathy after an early regression — not clearly progressive after the seizure-onset period, though long-term natural history is unknown from a single case followed to age 14. Seizures became well-controlled (4 years seizure-free on levetiracetam at last report), which is a meaningful treatment-response data point.

Quality of life impact: Not formally measured (no EQ-5D/SF-36/PROMIS data); qualitatively, the patient has profound functional dependency (gastrostomy-fed, intermittent respiratory support, nonverbal, needs support to sit), consistent with a severe pediatric neurodevelopmental CDG phenotype.

Pediatric framing: This is a congenital/infantile-onset disorder by definition (symptom onset at 3 months); there is no adult-onset or adult-recognized phenotype reported, and the disorder should not be conflated with adult presentations of unrelated Golgi trafficking disorders.

4. Genetic/Molecular Information

Causal gene: CAMLG (HGNC:1471; NCBI Gene 819; OMIM *601118), chromosome 5q31.1.

The reported pathogenic variant (single family, homozygous): - Genomic: chr5:134,741,527A>G (GRCh38.p13) - Transcript (NM_001745.4): c.633+4A>G — an intron 2 splice-donor-region variant, 4 bp into the intron - Predicted protein consequence: p.(Glu58ValfsTer80) via aberrant splicing - Splicing mechanism (functionally confirmed in patient fibroblasts): the variant causes skipping of exon 2 (461 nucleotides, 154 codons) with fusion of exons 1 and 3, producing a frameshift and premature termination. - RT-qPCR: "expression of the canonical CAMLG transcript was negligible" in patient fibroblasts vs. controls. - cDNA PCR: the normal full-length 624 bp amplicon was absent in patient fibroblasts, replaced by a truncated ~163 bp amplicon, "confirming that the c.633+4A>G variant causes skipping of exon 2." - Protein level: immunoblotting showed significantly reduced CAML protein in patient fibroblasts (P<0.05) — i.e., not a complete null at the protein level, consistent with leaky/residual normal splicing (see Mechanism section).

Variant classification: Not explicitly stated as an ACMG/AMP tier in the retrieved abstract/full-text excerpts; functionally it behaves as a hypomorphic loss-of-function allele (severe reduction, not complete absence, of protein) — this functional hypomorphism is proposed by the authors as the reason the patient is viable despite Camlg being an embryonic-lethal gene in mouse knockouts.

Zygosity/origin: Homozygous germline variant, inherited from consanguineous heterozygous-carrier parents (autosomal recessive).

Population frequency: Not retrieved in this session (gnomAD lookup not performed for this specific intronic variant); given a single reported homozygote from a consanguineous union, expect it to be absent or present at very low allele count in gnomAD — this should be independently verified via gnomAD/ClinVar before curation, not assumed from this report.

Modifier genes: None identified (n=1 case; no comparative genetics possible).

Epigenetics / chromosomal abnormalities: Not applicable/not reported for this disorder — it is a single-nucleotide splice variant, not a structural or epigenetic lesion.

Gene product function (CAML protein): - CAML (calcium-modulating cyclophilin ligand) is an ER-resident, widely expressed multipass transmembrane protein. - TRC/GET pathway role (disease-relevant mechanism): Together with GET1/WRB, CAML forms the ER membrane receptor component of the TRC (transmembrane domain recognition complex) pathway, which inserts C-terminal tail-anchored (TA) proteins into the ER membrane. Per the primary paper: "the recognition complex (composed of BAG6, GET4 and UBL4A)…binds to TA proteins and then to GET3 (TRC40, ASNA1)…GET3 chaperones the TA protein to the ER membrane where GET1 (WRB) and CAML form a receptor which enables its integration within the lipid bilayer." - Independent, non-CDG-related function (background/older literature, distinct from the 2022 disease report): CAML was originally characterized as a calcium-signaling protein downstream of the T-cell receptor and upstream of calcineurin/NFAT, binding cyclophilin B (Bram & Crabtree, Nature 1994, not independently re-verified in this session — flagged as background knowledge, not a primary-source citation obtained here). Later functional work (PMID:26561552, J Immunol 2015) showed CAML is required for survival of TCR-activated peripheral T cells — tamoxifen-inducible CAML-knockout T cells expressed normal early activation markers (CD25, CD69) and produced IL-2 normally but proliferated less and died, implicating CAML in a late post-activation T-cell survival step rather than early signaling. A separate paper (PMID:16111633, not independently verified this session) reported CAML is required for thymocyte development, with CAML inactivation reducing double-positive/single-positive thymocyte numbers and altering positive/negative selection. - Note for dismech curation (§3a-type lump/split consideration): these T-cell/immune functions of CAML are a separate, non-disease-linked biological role of the same gene — the one reported patient's phenotype is neurological, not immunological (no immunodeficiency features described), so this T-cell biology should be treated as background gene function rather than imported as a clinical feature of CAMLG-CDG absent direct patient evidence.

5. Environmental Information

No environmental factors, lifestyle factors, or infectious triggers are described or plausible for this monogenic ER-trafficking disorder. Not applicable.

6. Mechanism / Pathophysiology

Ordered causal chain (as established in Wilson et al. 2022, PMID:35262690)

Homozygous c.633+4A>G splice variant in CAMLG → causes skipping of exon 2 (RT-PCR/cDNA-confirmed) → frameshift/premature termination (p.Glu58ValfsTer80) → near-loss of canonical CAMLG transcript and markedly reduced CAML protein (immunoblot-confirmed, P<0.05) in patient fibroblasts.
Reduced/absent functional CAML → loss of the CAML/GET1(WRB) ER-membrane receptor component of the TRC (GET) pathway → impaired insertion of a subset of tail-anchored (TA) proteins into ER/Golgi membranes, specifically Golgi SNARE machinery.
Specifically, short-form syntaxin-5 (STX5S) and, to a lesser extent, long-form (STX5L) are mislocalized from Golgi membrane to cytosol — crude subcellular fractionation showed significantly increased cytoplasmic STX5 in both forms (P<0.05 long form, P<0.001 short form), with the short form more affected (43% mislocalized in CAMLG-CDG vs. 9% for the long form); immunofluorescence confirmed reduced STX5 colocalization with the Golgi marker giantin (P<0.0001). This was reproduced by siRNA knockdown of CAMLG in HeLa cells (residual CAML ~2%), reproducing STX5S (P<0.001) and STX5L (P<0.01) mislocalization — establishing STX5 mislocalization as a consistent cellular biomarker of TRC pathway dysfunction across two independent cell systems.
Downstream v-SNARE BET1L (GS15) — which the authors note is "more associated with the short form than the long form of STX5, and is required for retrograde trafficking within the Golgi" — is drastically reduced at the protein level: 37% of control levels in CAMLG-CDG fibroblasts and 27% of control in GET4-CDG fibroblasts (P<0.01; comparator disorder, see below), and reduced to 30.3% of control in CAMLG-siRNA-knockdown HeLa cells (P<0.01). BET1L/YKT6 localization (membrane vs. cytoplasm fractionation) was normal — the defect is in overall steady-state protein level, not mislocalization, distinguishing this from the STX5 mechanism.
Loss of correctly assembled/positioned Golgi SNARE complexes (STX5-BET1L axis) → impaired Golgi trafficking machinery → disorganized Golgi — indirectly supported by ST6GAL1 (a sialyltransferase) showing normal total protein levels but "a more fragmented distribution" upon CAMLG knockdown, "indicating at least some disorganization of the Golgi."
Golgi disorganization / impaired SNARE-dependent trafficking of glycosylation enzymes → hyposialylation of both N-linked and mucin-type O-linked glycans, producing the combined Type II CDG biochemical signature:
Serum transferrin isoelectric focusing: "repeatedly showed a type 2 pattern."
Transferrin N-glycan MALDI-TOF: CDG-II pattern with reduced pentasialotransferrin and raised trisialotransferrin (undersialylated species).
ApoC-III (mucin-type O-glycosylation marker): "absence of asialo and disialo apoC-III, and only a small amount of monosialo apoC-III," indicating a defect of mucin-type O-glycosylation.
Lectin studies in patient fibroblasts: peanut agglutinin (PNA) fluorescence (binds desialylated core-1 O-glycan/Gal-GalNAc) was "barely detectable in control fibroblasts" but showed "a strong increase in signal…in affected fibroblasts" — direct evidence of O-glycan hyposialylation. In contrast, vicia villosa lectin (VVL) (binds the unmodified GalNAc/Tn antigen, marking O-glycan initiation) "showed no increased signal in affected fibroblasts" — demonstrating the defect is specifically in the terminal sialylation step, not in O-glycan chain initiation.
Combined N- and O-glycan hyposialylation → the multisystem CDG phenotype, dominated here by severe CNS involvement (hypomyelination, cerebral/cerebellar atrophy, thin corpus callosum), consistent with the general CDG pattern in which the developing brain is exquisitely sensitive to glycosylation defects (general CDG biology; this generalization is background knowledge, not a specific claim from the cited paper about mechanism of CNS vulnerability, and should be flagged as inferred/general in KB curation rather than disease-specific evidence).

Branch/negative control — TRC pathway selectivity is incomplete: Not all canonical TRC-dependent TA proteins are affected. The authors explicitly tested and found normal subcellular localization of Emerin, VAMP7, and VAPB — TA proteins canonically dependent on the TRC pathway — in both CAMLG-CDG and GET4-CDG fibroblasts, indicating the pathway defect in this disease selectively/preferentially disrupts Golgi SNARE proteins (STX5, BET1L) rather than causing indiscriminate failure of all TA protein insertion. This is an important qualifying/branching point in the causal chain: reduced CAML causes a selective TA-protein trafficking defect, not global ER insertion failure, which the authors propose explains why glycosylation (a Golgi-dependent process) is specifically hit.

COG complex (a separate Golgi-tethering machinery) is not involved: steady-state levels and subcellular localization of COG1, COG4, and COG8 were normal in both CAMLG-CDG and GET4-CDG fibroblasts — ruling out a COG-complex-mediated mechanism (distinguishing this from the COG-CDG subgroup, CDG-IIa/IIc/IIe/etc.) and supporting that the TRC/SNARE-insertion defect is a mechanistically distinct route to hyposialylated CDG-II glycosylation.

Comparative mechanism — GET4-CDG (the closest prior TRC disorder)

The paper studied a previously reported GET4-deficient patient's fibroblasts in parallel: - "In fibroblasts from the previously identified individual with pathogenic variants in GET4, CAML steady state levels were normal." Interestingly, GET4 levels were also decreased in the CAMLG-CDG patient (~71% reduction versus controls), suggesting some interdependence/cross-stabilization between TRC pathway components even though CAML and GET4 act at different pathway steps. - STX5 mislocalization was reproduced in GET4-deficient fibroblasts in parallel with CAMLG-CDG, and clinical features of the CAMLG patient were noted to be "similar to those in one of the two other described TRC pathway disorders (GET4 deficiency)" — supporting a shared clinical/mechanistic disease class ("TRC pathway disorders").

Mouse model context (interpretive, not a primary-model experiment in this paper)

The authors note that complete Camlg knockout is embryonic lethal in mice, and interpret patient survival as evidence that "the small amount of remaining CAML protein…[is] sufficient to provide enough insertion of TA proteins that the phenotype is attenuated" — i.e., the human splice variant is a hypomorph, not a true null, and this residual function is proposed as necessary for viability. This is a model-organism-informed inference about human genotype-phenotype correlation (HUMAN_MODEL_MISMATCH-flavored reasoning: the mouse null is embryonic lethal, but the human hypomorphic allele produces a viable, severely affected phenotype) rather than a direct functional experiment performed in this paper on a mouse model.

Suggested ontology terms for the mechanism

GO Biological Process: GO:0071816 (tail-anchored membrane protein insertion into ER membrane); GO:0006890 (retrograde vesicle-mediated transport, Golgi to ER — for BET1L's role); GO:0006486 (protein glycosylation); GO:0006493 (protein O-linked glycosylation); GO:0006487 (protein N-linked glycosylation)
GO Molecular Function: consider GO terms for SNARE binding/protein-membrane receptor activity of CAML/GET1
GO Cellular Component: GO:0005794 (Golgi apparatus); GO:0000139 (Golgi membrane); GO:0005783 (endoplasmic reticulum)
Cell types (CL): primary evidence is from patient dermal fibroblasts (CL:0000057, fibroblast) and HeLa cells (an epithelial-derived cell line, less directly CL-mappable as a disease-relevant cell type but used for the siRNA mechanistic confirmation) — no direct neuronal/CNS cell-type-specific experiment was performed; the CNS phenotype is inferred from general CDG biology, not from a CNS-specific cell model in this paper.

7. Anatomical Structures Affected

Organ level (primary): Central nervous system — cerebrum, cerebellum, brainstem, corpus callosum (structural MRI abnormalities: cerebral/cerebellar atrophy, thin corpus callosum, brainstem atrophy, diffuse hypomyelination). UBERON: UBERON:0000955 (brain), UBERON:0002037 (cerebellum), UBERON:0002771 (falx cerebri/corpus callosum — use UBERON:0002336 corpus callosum), UBERON:0002298 (brainstem).
Secondary/systemic involvement: Growth (failure to thrive — below 3rd centile weight/OFC), musculoskeletal (contractures, spasticity), respiratory system (requiring intermittent support), gastrointestinal (gastrostomy-dependent feeding).
Not involved / explicitly normal: No organomegaly noted; eye movements normal (no overt ophthalmologic/oculomotor involvement reported, unlike some other CDGs).
Tissue/cell level: Dermal fibroblasts (patient-derived, primary experimental system) — CL:0000057. Golgi apparatus and ER of these cells are the direct subcellular site of the trafficking defect.
Subcellular level (GO Cellular Component): Golgi membrane (GO:0000139) and ER membrane (GO:0005789) are the two organelle membranes directly implicated — CAML/GET1 receptor acts at the ER membrane for TA protein insertion, while the functional consequence (STX5/BET1L dysfunction) manifests at the Golgi.
Laterality: Not applicable/not described (a systemic biochemical-trafficking disorder, not a lateralized structural anomaly).

8. Temporal Development

Onset: Infantile — developmental delay and seizure onset both noted at 3 months of age. This is congenital-to-early-infantile onset by the standard CDG onset categories.
Onset pattern: Insidious/subacute — a normal-appearing early infancy followed by loss of milestones concurrent with seizure onset at 3 months ("developmental delay at three months of age...seizures started at that age and he lost his milestones").
Progression: The published natural history covers birth to age 14 (single longitudinal case, not a cohort). The picture is one of an early regression followed by a static but severe encephalopathy — seizures came under control (seizure-free 4 years on levetiracetam by last report), while the motor/functional profile (spasticity, contractures, need for gastrostomy and respiratory support) appears to represent a fixed, severe deficit state rather than a described progressive/degenerative course after the initial regression, though this cannot be fully distinguished from slow progression given only two time points (age 7 MRI, age 14 exam) were reported.
Disease stage/duration: Chronic, lifelong — no data on adult survival beyond age 14 (patient's age at last follow-up in the report).
Remission patterns: Partial — seizures achieved sustained remission with levetiracetam (treatment-induced, not spontaneous); no remission of the underlying developmental/motor phenotype is described (nor biologically expected, given the fixed genetic and structural brain basis).
Critical periods: Not explicitly studied, but the infantile onset with regression suggests the first months of life are a period of particular vulnerability, consistent with general CDG biology (rapid CNS myelination and glycosylation-dependent processes in infancy) — this is a general inference, not paper-specific data.

9. Inheritance and Population

Epidemiology: n = 1 reported patient worldwide (as of the 2022 publication and as of this September 2026 search, no additional cases were located in the literature). No prevalence or incidence estimate exists or is calculable; this is an ultra-rare, essentially "cases-in-literature" epidemiology (CASES_IN_LITERATURE measure type, in dismech schema terms).
Inheritance pattern: Autosomal recessive, confirmed by parental consanguinity and homozygosity of the proband.
Penetrance: Cannot be assessed from a single case (parents, presumed obligate heterozygous carriers, were not reported to have any phenotype — consistent with typical AR carrier status, but this is not explicitly discussed in the retrieved text).
Expressivity: Cannot be assessed (n=1; no comparator patients).
Genetic anticipation: Not applicable (no repeat-expansion mechanism; not a multi-generational report).
Germline mosaicism: Not discussed/not applicable (single conventional homozygous transmission from two heterozygous consanguineous parents).
Founder effects: Not established — a single Turkish consanguineous family; whether this specific variant represents a Turkish founder allele or a private familial mutation cannot be determined from one report. This would need gnomAD/regional-cohort data to assess (not retrieved in this session).
Consanguinity role: Central to this case — parents are fourth-degree cousins of Turkish origin; this is the mechanism by which a presumably rare recessive allele became homozygous.
Carrier frequency: Unknown/not reported.
Population demographics: Only known ethnicity is Turkish (single family); no broader geographic or ethnic distribution data exist. Sex: only a male patient has been reported (n=1, cannot establish a sex ratio). Age distribution: single pediatric/adolescent patient (followed birth–14 years).

10. Diagnostics

Biochemical/laboratory tests (primary diagnostic route, as used in this case): - Serum transferrin isoelectric focusing (IEF): showed a repeatable Type 2 pattern — the standard first-tier CDG screening test, here indicating a Golgi-processing (Type II) rather than ER-assembly (Type I) defect. - Transferrin N-glycan analysis by MALDI-TOF mass spectrometry: confirmed the CDG-II pattern with reduced pentasialotransferrin and increased trisialotransferrin — quantitative confirmation of undersialylation. - Serum Apolipoprotein C-III (apoC-III) isoform analysis: used as the O-glycosylation marker; showed absence of asialo-/disialo-apoC-III and only trace monosialo-apoC-III, diagnostic of a mucin-type O-glycosylation defect — important because this combined N+O defect pattern is itself a diagnostic clue pointing away from classical single-pathway CDGs toward a Golgi-trafficking-level defect. - Lectin fluorescence microscopy in cultured fibroblasts (PNA vs. VVL): a research-level cellular assay (not a routine clinical diagnostic test) used here to localize the defect specifically to the sialylation step of O-glycosylation rather than initiation.

Genetic testing: The diagnosis was reached via genome/exome-level sequencing identifying the homozygous CAMLG splice variant (specific sequencing modality — WES vs. WGS vs. panel — not specified in the retrieved excerpts); given the phenotype's severity and the era (patient evaluated to age 14, report published 2022), exome sequencing in a consanguineous family with a "CDG-II biochemical signature + neurological phenotype" gene panel/WES approach is the most likely diagnostic route. Functional/RNA-level confirmation (RT-qPCR, RT-PCR of cDNA showing exon 2 skipping, and immunoblot showing reduced CAML protein) was essential to establish pathogenicity of this intronic splice variant — illustrating that for CDG genes with unclear-significance intronic/splice variants, RNA and protein studies in patient fibroblasts are the diagnostic gold standard beyond DNA sequencing alone.

Imaging: Brain MRI (structural) — thin corpus callosum, brainstem atrophy, cerebral/cerebellar atrophy, diffuse hypomyelination — performed at age 7.

Electrophysiology: Seizure semiology described clinically; specific EEG findings were not detailed in the retrieved excerpts.

Differential diagnosis: Broadly, other Type II CDGs presenting with severe neurological phenotype and combined N-/O-glycosylation defects (e.g., COG-CDGs, other Golgi-trafficking CDGs) and, specifically within the emerging TRC-disorder class, GET4-CDG — clinically the closest comparator per the authors. Standard CDG diagnostic algorithms (transferrin IEF/MALDI-TOF as first-tier, followed by gene-specific or panel/exome sequencing) apply.

Screening: No population or newborn screening applicable (single case, no established screening program for CDGs of this type generally, let alone this ultra-rare subtype).

11. Outcome/Prognosis

Survival: The patient was alive at last follow-up (age 14), demonstrating this genotype is compatible with survival to adolescence despite the corresponding mouse knockout being embryonic lethal — a key prognostic and mechanistic data point (interpreted by the authors as reflecting residual/hypomorphic CAML function from incomplete splice disruption).
Life expectancy: Not established beyond the reported follow-up age; no long-term mortality data exist for this single-patient disorder.
Morbidity/functional outcome: Severe and static-to-slowly evolving — profound motor impairment (sits only with support), nonverbal communication, gastrostomy-dependent nutrition, intermittent respiratory support — indicating a high burden of chronic disability typical of severe pediatric CDGs with CNS involvement.
Complications: Feeding/nutritional compromise (requiring gastrostomy), respiratory insufficiency (requiring intermittent support), contractures/spasticity as secondary musculoskeletal complications of chronic hypertonia/immobility.
Recovery potential: Seizures show good treatment response (sustained remission on levetiracetam); the structural brain abnormalities and motor/developmental impairments are not described as reversible.
Prognostic factors: None can be statistically derived from n=1; qualitatively, early seizure onset and severe MRI abnormalities correlate with the severe overall phenotype in this patient, consistent with (but not independently proving) a general CDG pattern that early-onset epilepsy plus significant structural brain disease predicts poor functional outcome.

12. Treatment

No disease-specific or mechanism-targeted therapy exists for CAMLG-CDG; management reported is purely supportive/symptomatic:

Antiepileptic pharmacotherapy: Levetiracetam — patient became and remained seizure-free for 4 years at last report. (NCIT treatment-action term: NCIT:C15986 Pharmacotherapy, with therapeutic_agent bound to the specific drug — CHEBI ID for levetiracetam would need independent lookup/verification, not retrieved in this session.)
Nutritional support: Gastrostomy tube feeding for chronic feeding difficulty (NCIT candidate: a gastrostomy/enteral feeding procedure term — exact NCIT code not verified in this session).
Respiratory support: Intermittent respiratory support (ventilatory/respiratory assistance — NCIT candidate term not verified in this session).
No gene therapy, enzyme replacement, cell therapy, RNA-based therapy, or disease-modifying treatment has been reported or trialled for this disorder (consistent with its status as a single-case, very recently described condition; unlike PMM2-CDG, there is no dedicated clinical trial infrastructure).
No clinical trials (ClinicalTrials.gov / WHO ICTRP) specific to CAMLG-CDG were identified.

Treatment strategy: Purely symptomatic/multidisciplinary supportive care (neurology for seizure management, nutrition/GI for gastrostomy feeding, pulmonology for respiratory support) — the standard approach for a severe, non-treatable Type II CDG with predominant CNS involvement.

13. Prevention

Primary prevention: None specific to this disorder beyond general genetic counseling; given the demonstrated role of consanguinity in this case, standard genetic counseling regarding consanguineous unions and recessive disease risk is the only "prevention" lever identifiable from the available data.
Secondary prevention/screening: No population or targeted carrier-screening program exists (ultra-rare, single-family-described variant); prenatal or preimplantation genetic testing would be theoretically possible for this specific family once the causal variant is known (standard for a molecularly characterized AR disorder), but this was not reported as having occurred or being offered in the paper.
Genetic counseling: Applicable for the affected family (recurrence risk 25% for future pregnancies of the same parents; carrier risk for the unaffected sibling) — general AR genetics principles, not disease-specific data from the paper.
Public health/prophylaxis: Not applicable to this ultra-rare monogenic disorder.

14. Other Species / Natural Disease

Taxonomy: No naturally occurring CAMLG-deficient disease has been reported in any non-human species (companion animal, livestock, or wildlife) in the literature searched. Camlg orthologs exist across mammals (the original CAMLG gene-mapping paper noted synteny with mouse chromosome 13; NCBITaxon:10090 for Mus musculus ortholog Camlg, MGI-mapped — exact MGI ID not independently verified in this session).
Comparative biology: CAML/the TRC-GET pathway is evolutionarily conserved from yeast (where the pathway was first characterized: Get1/Get2/Get3/Get4/Get5 in Saccharomyces cerevisiae) to humans, underlying the pathway's alternate name "GET pathway" (Guided Entry of Tail-anchored proteins). This conservation is the basis for the yeast nomenclature (GET1=WRB, GET3=ASNA1/TRC40, GET4) used interchangeably with the mammalian TRC pathway naming in the primary paper.
Zoonotic potential: Not applicable (not an infectious disease).

15. Model Organisms

Mouse (Mus musculus): The primary paper cites that complete germline Camlg knockout is embryonic lethal in mice (cited as prior literature within Wilson et al. 2022, exact original mouse-knockout citation not independently retrieved/verified in this session — flag as a claim requiring its own primary-source PMID before KB citation). This model demonstrates CAML is essential for viability at the whole-organism level in a way that overlaps only partially with the human hypomorphic-allele phenotype — a human-model mismatch worth flagging explicitly in curation (HUMAN_MODEL_MISMATCH): the mouse null is incompatible with life, while the human splice-hypomorph is compatible with survival to at least adolescence, which the authors attribute to residual protein rather than to any species-specific difference in CAML's essentiality.
Conditional/inducible mouse models (immune-function studies, mechanistically related but not disease models per se): Tamoxifen-inducible CAML-knockout mice (tCAML−/−) were used in unrelated immunology work (PMID:26561552) to study T-cell survival post-TCR activation, and thymocyte-specific CAML inactivation was studied in PMID:16111633 for T-cell development — these are functional/mechanistic models of CAML biology in the immune system, not models of the CDG phenotype, and should not be conflated with CAMLG-CDG animal-model evidence in KB curation; they establish gene function generally but were not designed or used to recapitulate the glycosylation/neurological disease phenotype.
Cellular models used directly for CAMLG-CDG mechanism (the actual disease models in the primary paper):
Patient-derived primary dermal fibroblasts — the principal disease model, used for RT-PCR/RT-qPCR splicing confirmation, immunoblotting (CAML, GET4, STX5, BET1L, YKT6, COG1/4/8, ST6GAL1), subcellular fractionation, and immunofluorescence (STX5/giantin colocalization; PNA/VVL lectin staining).
HeLa cells with siRNA-mediated CAMLG knockdown (residual CAML ~2%) — used as an independent, non-patient-derived cellular system to confirm STX5 mislocalization and BET1L reduction, establishing reproducibility of the mechanism outside the patient's own genetic background — this fidelity/reproducibility is a strength of the mechanistic evidence (RECAPITULATES-type relationship in dismech modeled_mechanisms terms).
GET4-deficient patient fibroblasts (from a previously published, separate patient) — used as a comparator TRC-pathway-disorder cell line, not a model of CAMLG-CDG itself, but establishing shared downstream mechanism (STX5 mislocalization, BET1L reduction) across two distinct TRC pathway gene defects.
No zebrafish, Drosophila, C. elegans, or yeast disease-modeling experiments were performed in this paper (the yeast GET pathway is referenced only as evolutionary/mechanistic background, not as an experimental model in this study).
No organoid, iPSC-derived, or CNS-specific (neuronal) model system was used — this is a notable gap: despite the phenotype being predominantly neurological (hypomyelination, brain atrophy), all functional/mechanistic work was performed in fibroblasts and HeLa cells, not neural cell types. This is worth flagging as a limitation/gap for any HUMAN_MODEL_MISMATCH or knowledge-gap discussion in KB curation — the CNS-specific pathophysiology (why hypomyelination and cerebellar/cerebral atrophy specifically result from this Golgi-SNARE/sialylation defect) is inferred by analogy to general CDG neurobiology rather than directly demonstrated in a neural model in this paper.

Notes on Evidence Quality and Gaps for Curation

Single-source, single-patient disease. Essentially all clinical and molecular content in this report traces to one peer-reviewed paper (PMID:35262690) describing one family/one patient. This should be reflected in dismech curation as CASES_IN_LITERATURE for prevalence, and every phenotype should carry a frequency understood as "1/1," not a population percentage.
OMIM (#620201, *601118) and GeneCards/NCBI/HGNC identifiers were retrieved via web search/API (mygene.info, OMIM search snippets) rather than fully fetched primary pages (OMIM blocked direct fetch with 403 in this session) — the OMIM clinical synopsis full text was not independently verified; treat the OMIM-sourced phrasing above as a lead requiring direct confirmation against omim.org before citing OMIM as a reference: in KB YAML.
MONDO:0859357 is carried over from the dismech repository's own open curation-stub issue (#12798) referencing this exact disease — this is a strong internal signal of correctness for this specific dismech instance, but was not independently re-derived from a live MONDO ontology query in this session and should still be confirmed via just fetch-reference / term-cache lookup per repository ontology-term-contract rules before binding.
HGNC:1471 for CAMLG was cross-verified via the mygene.info API (an independent source from the initial GeneCards-derived search snippet, which had first reported a slightly different number) — treat HGNC:1471 as the better-supported value, but re-confirm via just validate-terms / the HGNC cache per the repository's "never write a CURIE from memory" rule.
The mouse Camlg embryonic-lethality claim is cited within the primary paper but its ultimate original source (the specific mouse knockout study) was not independently traced/verified in this session — if used in KB curation as an animal_models entry, the original PMID for that mouse knockout paper should be located and cited directly rather than citing Wilson et al. 2022 as if it were the source of the mouse data.
No independent second case report, natural-history study, registry entry, or treatment trial exists as of this search (September 2026) — this is consistent with the disease's very recent (2022) first description and extreme rarity.

Sources

Reference Validation

Checked with linkml-reference-validator 0.3.0rc1.

Outcome	Count
References checked	6
Resolved	6
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	6
On topic	3
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	54
Resolved	52
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	1
Terms whose name was checked	17
Terms named correctly	12
Terms named as a different term	1
Terms whose name is worth a second look	4

Terms the report names something else

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

HP:0002451 (1 mention) - the report calls it "Limb ataxia — not stated"; HP calls it Limb dystonia

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

GO:0006486 (obsolete protein glycosylation) (1 mention) - replaced by GO:0009101

Terms whose name is worth a second look

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

HP:0007266 (1 mention) - the report calls it "Diffuse cerebral atrophy"; HP calls it Cerebral dysmyelination
HP:0007305 (1 mention) - the report calls it "Abnormality of the cerebral white matter"; HP calls it CNS demyelination, and lists "Demyelination in central white matter" among its other names
GO:0006890 (1 mention) - the report calls it "retrograde vesicle-mediated transport, Golgi to ER — for BET1L's role"; GO calls it retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum, and lists "retrograde vesicle-mediated transport, Golgi to ER" among its other names
GO:0006486 (1 mention) - the report calls it "protein glycosylation"; GO calls it obsolete protein glycosylation

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Prevalence

Differential Diagnoses

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

CAMLG-CDG (Congenital Disorder of Glycosylation, Type IIz) — Comprehensive Research Report

Summary

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

Ordered causal chain (as established in Wilson et al. 2022, PMID:35262690)

Comparative mechanism — GET4-CDG (the closest prior TRC disorder)

Mouse model context (interpretive, not a primary-model experiment in this paper)

Suggested ontology terms for the mechanism

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Notes on Evidence Quality and Gaps for Curation

Sources

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look