Congenital Myasthenic Syndrome 15

Mendelian MONDO:0014542 Pathograph 12 Show in embeddings browser Congenital Myasthenic Syndrome

Congenital myasthenic syndrome 15 (CMS15) is an autosomal recessive disorder of neuromuscular transmission caused by biallelic variants in ALG14. It belongs to the small group of congenital myasthenic syndromes that are also congenital disorders of glycosylation: the defective protein is not a component of the neuromuscular junction at all, but a subunit of the multiglycosyltransferase complex that, with ALG13 and DPAGT1, catalyses the first committed steps of asparagine-linked (N-linked) protein glycosylation in the endoplasmic reticulum. The mechanism is therefore indirect, and that is the point of the entry. The acetylcholine receptor is structurally normal and its genes are intact; what fails is the post-translational modification the receptor subunits need in order to fold, assemble and reach the postsynaptic membrane in adequate numbers. Endplate acetylcholine receptor deficiency is the consequence of a housekeeping biosynthetic defect, not of a receptor lesion, which is why the disease can be a myasthenia at one end of its allelic spectrum and a multisystem neurodegenerative disorder at the other. That spectrum is wide and worth stating explicitly. The founding cohort had an inherited limb-girdle pattern of fatigable weakness with no central nervous system involvement. Subsequent reports described a severe infantile form with congenital contractures, therapy-refractory epilepsy, progressive cerebral atrophy and death within the first year, described by its authors as a new congenital disorder of glycosylation rather than as a myasthenia. Both ends carry biallelic ALG14 variants and both sit under this MONDO term, so the entry curates the whole spectrum and marks which pole each phenotype and each piece of evidence comes from.

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1
Inheritance
5
Pathophys.
8
Phenotypes
2
Gaps
12
Pathograph
1
Genes
5
Variants
2
Medical Actions
2
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Patients carry biallelic ALG14 variants, homozygous or compound heterozygous, with unaffected heterozygous carrier parents. Reported genotypes are predominantly missense; a complete null on both alleles has not been described, which is consistent with ALG14's essential housekeeping role.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:28733338 SUPPORT Human Clinical
"In all cases, parents were found to be heterozygous carriers."
Establishes recessive segregation with unaffected heterozygous parents across three families.
PMID:34971077 SUPPORT Human Clinical
"Exome sequencing indicated that the siblings had novel compound heterozygous missense variants, c.590T>G (p.Val197Gly) and c.433G>A (p.Gly145Arg), in exon 4 of ALG14."
Documents a compound heterozygous genotype, the other biallelic configuration seen in this disease.
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Discussions and Knowledge Gaps

2
Should the limb-girdle myasthenic form and the lethal infantile neurodegenerative form of ALG14 deficiency be one dismech entry or two?
OPEN QUESTION OPEN alg14_spectrum_one_entity
Attached to
pathophysiology#Impaired Glycosylation in Neural Tissue
They share a gene, a biochemical lesion and a MONDO term, which is the argument for one entry, and this entry takes that position. But they differ in nearly everything a clinician would use to recognise them: age of onset, whether the central nervous system is involved at all, survival, and whether the presenting problem looks myasthenic. The authors of the severe cohort described their patients as a new congenital disorder of glycosylation rather than as a congenital myasthenic syndrome, and MONDO places this term under both congenital myasthenic syndrome and ALG14-congenital disorder of glycosylation. If the KB later adopts a convention of splitting allelic series whose poles differ in organ involvement, this entry is a candidate for splitting into a myasthenic entry and a CDG entry linked by gene.
Which hypoglycosylated proteins mediate the cerebral atrophy and epilepsy of severe ALG14 deficiency?
KNOWLEDGE GAP OPEN neurodegeneration_intermediate_steps_unknown
Attached to
pathophysiology#Impaired Glycosylation in Neural Tissue
The endplate arm of this disease has a named target: acetylcholine receptor surface expression falls when ALG14 is silenced, shown directly. The central nervous system arm has no equivalent. Cerebral atrophy, delayed myelination and refractory epilepsy are well documented, but no specific neural glycoprotein has been shown to be hypoglycosylated and no intermediate step between the biosynthetic defect and the neurodegeneration has been established. The pathophysiology node therefore asserts an association at tissue scale rather than a mechanism, and should not be read as more than that.
⚙

Pathophysiology

5
Biallelic ALG14 Loss of Function
Biallelic ALG14 variants reduce the function of the ALG13-ALG14-DPAGT1 multiglycosyltransferase complex, which catalyses the first two committed steps of asparagine-linked protein glycosylation on the cytoplasmic face of the endoplasmic reticulum. Reported alleles are predominantly missense, so residual activity is retained; the amount retained appears to set where a patient falls on the phenotypic spectrum.
Genetic context ALG14 hgnc:28287 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns ALG14 (hgnc:28287). hgnc:28287 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Homozygous or compound heterozygous germline missense variants, including the recurrent p.Asp74Asn allele of the severe form and the p.Val197Gly / p.Gly145Arg compound heterozygous pair reported in long-surviving siblings.
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ↓ DECREASED dolichol-linked oligosaccharide biosynthetic process GO:0006488 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dolichol-linked oligosaccharide biosynthetic process (GO:0006488). GO:0006488 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Hypoglycosylation of Endplate Proteins Reduced flux through the first committed steps of N-linked glycosylation leaves proteins that depend on that pathway incompletely glycosylated.
Show evidence (1 reference)
PMID:23404334 SUPPORT Human Clinical
"ALG14 is thought to form a multiglycosyltransferase complex with ALG13 and DPAGT1 that catalyses the first two committed steps of asparagine-linked protein glycosylation."
Identifies the biochemical complex and pathway step that ALG14 loss of function impairs.
Hypoglycosylation of Endplate Proteins
ALG14 is concentrated at the muscle motor endplate, so the postsynaptic membrane is a site where reduced N-glycosylation capacity is felt disproportionately. Acetylcholine receptor subunits require N-linked glycans for correct folding, pentameric assembly and export; when the glycan supply is limited, fewer complete receptors reach the surface. The receptor genes themselves are intact, so this is a failure of post-translational processing rather than a receptor lesion.
Skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ↓ DECREASED
Neuromuscular junction GO:0031594 Gene Ontology (GO) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Neuromuscular junction (GO:0031594). GO:0031594 is an anatomical location from the Gene Ontology.
Downstream
Endplate Acetylcholine Receptor Deficiency
Impaired Glycosylation in Neural Tissue The same biosynthetic deficit acts outside muscle. Whether it becomes clinically apparent depends on how much residual ALG14 activity an allele leaves, which is why this branch is silent in the limb-girdle form and dominant in the severe infantile form.
Show evidence (1 reference)
PMID:23404334 SUPPORT In Vitro
"We show that ALG14 is concentrated at the muscle motor endplates and small interfering RNA silencing of ALG14 results in reduced cell-surface expression of muscle acetylcholine receptor expressed in human embryonic kidney 293 cells."
Localises ALG14 to the endplate and shows experimentally that reducing it lowers surface acetylcholine receptor, which is the step this node asserts.
Endplate Acetylcholine Receptor Deficiency
The postsynaptic membrane carries too few acetylcholine receptors to guarantee that each nerve impulse depolarises the muscle fibre to threshold. Transmission consequently fails intermittently and use-dependently, which is measured electrophysiologically as a decremental response of the compound muscle action potential to repetitive nerve stimulation.
Skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
neuromuscular synaptic transmission GO:0007274 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased neuromuscular synaptic transmission (GO:0007274). GO:0007274 is a biological process from the Gene Ontology. ↓ DECREASED
acetylcholine receptor activity GO:0015464 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased acetylcholine receptor activity (GO:0015464). GO:0015464 is a molecular function from the Gene Ontology. ↓ DECREASED
Neuromuscular junction GO:0031594 Gene Ontology (GO) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Neuromuscular junction (GO:0031594). GO:0031594 is an anatomical location from the Gene Ontology.
Downstream
Fatigable Skeletal Muscle Weakness
Show evidence (2 references)
PMID:34971077 SUPPORT Human Clinical
"The pathogenic variant in ALG14 results in a severe pathological form of CMS causing end-plate acetylcholine receptor deficiency."
States endplate acetylcholine receptor deficiency as the neuromuscular lesion in ALG14-related CMS.
PMID:34971077 SUPPORT Human Clinical
"Repetitive nerve stimulation test showed an abnormal decrease in compound muscle action potential."
Electrophysiological confirmation that neuromuscular transmission fails on repetitive stimulation.
Fatigable Skeletal Muscle Weakness
Clinically the transmission failure appears as weakness that worsens with sustained activity. In the founding cohort the distribution was limb-girdle, sparing the ocular and bulbar muscles that dominate many other congenital myasthenic syndromes. In the severe infantile form the weakness is present from birth as profound hypotonia with respiratory and swallowing failure.
Skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Show evidence (1 reference)
PMID:23404334 SUPPORT Human Clinical
"patients with an inherited limb-girdle pattern of myasthenic weakness"
Describes the limb-girdle distribution of fatigable weakness in the cohort in which ALG14 was identified.
Impaired Glycosylation in Neural Tissue
In severely affected patients the glycosylation deficit is not confined to the endplate. Progressive cerebral atrophy, delayed myelination and therapy-refractory epilepsy accompany the neuromuscular disease, and the authors of that cohort classified the condition as a new congenital disorder of glycosylation rather than as a myasthenia. The specific glycoproteins whose hypoglycosylation drives the neurodegeneration have not been identified, so this node records an established association whose intermediate steps are not resolved.
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (2 references)
PMID:28733338 SUPPORT Human Clinical
"All 5 patients showed severe muscular hypotonia, progressive cerebral atrophy, and therapy-refractory epilepsy."
Documents the central nervous system involvement that defines the severe pole of the spectrum.
PMID:28733338 SUPPORT Human Clinical
"These cases broaden the phenotypic spectrum associated with ALG14 congenital disorders of glycosylation as previously only isolated myasthenia has been described."
States that the central nervous system phenotype extends the previously myasthenia-only ALG14 spectrum.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Congenital Myasthenic Syndrome 15 Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Musculoskeletal 2
Fatigable weakness HP:0003473 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fatigable weakness (HP:0003473). HP:0003473 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23404334 SUPPORT Human Clinical
"patients with an inherited limb-girdle pattern of myasthenic weakness"
Characterises the weakness as myasthenic, that is fatigable.
Hypotonia HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28733338 SUPPORT Human Clinical
"All 5 patients showed severe muscular hypotonia, progressive cerebral atrophy, and therapy-refractory epilepsy."
Reports severe hypotonia in all patients of the severe cohort.
Nervous System 2
Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28733338 SUPPORT Human Clinical
"All 5 patients showed severe muscular hypotonia, progressive cerebral atrophy, and therapy-refractory epilepsy."
Reports therapy-refractory epilepsy in the severe cohort.
Cerebral atrophy HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral atrophy (HP:0002059), qualified as course progressive. HP:0002059 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:28733338 SUPPORT Human Clinical
"All 5 patients showed severe muscular hypotonia, progressive cerebral atrophy, and therapy-refractory epilepsy."
Reports progressive cerebral atrophy in the severe cohort.
Other 4
Limb-girdle muscle weakness HP:0003325 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Limb-girdle muscle weakness (HP:0003325). HP:0003325 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23404334 SUPPORT Human Clinical
"patients with an inherited limb-girdle pattern of myasthenic weakness"
Reports the limb-girdle distribution in the founding cohort.
EMG decremental response EMG: decremental response of compound muscle action potential to repetitive nerve stimulation HP:0003403 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EMG: decremental response of compound muscle action potential to repetitive nerve stimulation (HP:0003403). HP:0003403 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34971077 SUPPORT Human Clinical
"Repetitive nerve stimulation test showed an abnormal decrease in compound muscle action potential."
Reports the decremental response in ALG14-related CMS siblings.
Delayed CNS myelination HP:0002188 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed CNS myelination (HP:0002188). HP:0002188 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:34971077 SUPPORT Human Clinical
"Cranial magnetic resonance imaging scans revealed delayed myelination and cerebral atrophy."
Reports delayed myelination on imaging in ALG14-related CMS.
Arthrogryposis multiplex congenita HP:0002804 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthrogryposis multiplex congenita (HP:0002804). HP:0002804 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:34971077 SUPPORT Human Clinical
"Immediately after birth, they showed hypotonia and multiple joint contractures with low Apgar scores."
Reports multiple congenital joint contractures at birth.
PMID:28733338 SUPPORT Human Clinical
"Three patients had congenital contractures. All patients died during their first year of life."
Reports congenital contractures in three of five patients in the severe cohort.
🧬

Genetic Associations

1
ALG14 (ALG14 encodes a subunit of the UDP-N-acetylglucosamine transferase complex that it forms with ALG13 and DPAGT1 on the cytoplasmic face of the endoplasmic reticulum. The complex catalyses the first two committed steps of the dolichol-linked oligosaccharide pathway that supplies N-linked glycans. Because the gene is a general component of that pathway rather than a synapse-specific protein, the neuromuscular phenotype reflects the particular sensitivity of the endplate to reduced glycosylation capacity, and the severity of an allele determines how far beyond the endplate the disease extends. Two of the other subunits of the same pathway, DPAGT1 and ALG2, are themselves congenital myasthenic syndrome genes.)
Gene: ALG14 hgnc:28287 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ALG14 (hgnc:28287). hgnc:28287 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:23404334 SUPPORT Human Clinical
"We identify ALG14 and ALG2 as novel genes in which mutations cause a congenital myasthenic syndrome."
Establishes ALG14 as a congenital myasthenic syndrome gene, the finding that defines this disease entity.
PMID:40533459 SUPPORT Other
"A total of 40 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT,"
A 2025 review confirming ALG14 as an established CMS gene alongside ALG2 and DPAGT1, the other two glycosylation-pathway members named in this block. Graded OTHER because the source is a review rather than a primary study.
Variants (5)
ALG14 c.220G>A (p.Asp74Asn) Pathogenic
The recurrent allele in the severe infantile neurodegenerative form, found homozygously in two patients and heterozygously in three others across three families.
Show evidence (1 reference)
PMID:28733338 SUPPORT Human Clinical
"Causative mutations in ALG14 were identified in all patients."
Attributes the severe phenotype in this cohort to ALG14 variants.
ALG14 c.422T>G (p.Val141Gly) Pathogenic
A second allele in the severe infantile cohort, carried heterozygously in trans with p.Asp74Asn.
Show evidence (1 reference)
PMID:28733338 SUPPORT Human Clinical
"Additional heterozygous mutations were c.422T>G (p.Val141Gly) and c.326G>A (p.Arg109Gln)."
Names the two additional heterozygous alleles found in the severe cohort.
ALG14 c.326G>A (p.Arg109Gln) Pathogenic
A third allele in the severe infantile cohort, likewise carried heterozygously in trans with p.Asp74Asn.
Show evidence (1 reference)
PMID:28733338 SUPPORT Human Clinical
"Additional heterozygous mutations were c.422T>G (p.Val141Gly) and c.326G>A (p.Arg109Gln)."
Names the two additional heterozygous alleles found in the severe cohort.
ALG14 c.590T>G (p.Val197Gly) Pathogenic
One half of the compound heterozygous genotype in the long-surviving siblings, whose course was markedly milder than the lethal infantile cohort despite a comparably severe neonatal presentation.
Show evidence (1 reference)
PMID:34971077 SUPPORT Human Clinical
"Exome sequencing indicated that the siblings had novel compound heterozygous missense variants, c.590T>G (p.Val197Gly) and c.433G>A (p.Gly145Arg), in exon 4 of ALG14."
Names both alleles of the long-surviving siblings' genotype.
ALG14 c.433G>A (p.Gly145Arg) Pathogenic
The other half of the compound heterozygous genotype in the long-surviving siblings.
Show evidence (1 reference)
PMID:34971077 SUPPORT Human Clinical
"Exome sequencing indicated that the siblings had novel compound heterozygous missense variants, c.590T>G (p.Val197Gly) and c.433G>A (p.Gly145Arg), in exon 4 of ALG14."
Names both alleles of the long-surviving siblings' genotype.
💊

Medical Actions

2
Pyridostigmine
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: pyridostigmine CHEBI:8665 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pyridostigmine (CHEBI:8665). CHEBI:8665 is a therapeutic agent from Chemical Entities of Biological Interest.
An acetylcholinesterase inhibitor, the standard first-line treatment for postsynaptic congenital myasthenic syndromes. By slowing the hydrolysis of acetylcholine it prolongs transmitter dwell time in the cleft, partially compensating for the reduced number of endplate receptors. It does not address the glycosylation defect, which is why the response tracks the severity of the underlying allele: benefit was only temporary in the lethal infantile cohort, while long-surviving siblings gained respirator-free time.
Mechanism Target:
MODULATES Endplate Acetylcholine Receptor Deficiency — Inhibiting acetylcholinesterase prolongs acetylcholine dwell time in the synaptic cleft, so the receptors that did reach the surface are engaged more often. It compensates for the reduced receptor number without restoring it, and does nothing about the upstream glycosylation defect.
Show evidence (2 references)
PMID:34971077 SUPPORT Human Clinical
"After treatment with pyridostigmine, the time off the respirator increased."
Reports a measurable functional benefit of pyridostigmine in ALG14-related CMS.
PMID:28733338 SUPPORT Human Clinical
"In 2 of our patients, electrophysiologic testing showed abnormal decrement, but treatment with pyridostigmine led only to temporary improvement."
Records that the benefit was temporary in the severe form, which is why this evidence is graded partial rather than supporting.
Cholinesterase inhibition across the glycosylation CMS group
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
The founding study proposed that cholinesterase inhibition may help more broadly across congenital disorders of glycosylation affecting the neuromuscular junction. This is a suggestion made by the authors rather than a trial result, and is recorded as such.
Show evidence (1 reference)
PMID:23404334 SUPPORT Human Clinical
"Our findings suggest that treatment with cholinesterase inhibitors may improve muscle function in many of the congenital disorders of glycosylation."
An authors' suggestion extrapolated from their findings, not a treatment study; graded partial for that reason.
🔬

Diagnosis

2
Repetitive nerve stimulation
A decremental compound muscle action potential response localises the defect to the neuromuscular junction. It does not distinguish CMS15 from other congenital myasthenic syndromes, and in the severe infantile form the profound hypotonia and encephalopathy can make the myasthenic component easy to miss altogether.
Show evidence (1 reference)
PMID:34971077 SUPPORT Human Clinical
"Repetitive nerve stimulation test showed an abnormal decrease in compound muscle action potential."
Demonstrates the diagnostic electrophysiological finding.
Exome or genome sequencing of ALG14
Definitive diagnosis rests on identifying biallelic ALG14 variants. Because the severe form presents as an encephalopathy with contractures rather than as a myasthenia, it is frequently reached by broad sequencing rather than by a targeted neuromuscular panel.
Show evidence (1 reference)
PMID:34971077 SUPPORT Human Clinical
"Exome sequencing indicated that the siblings had novel compound heterozygous missense variants, c.590T>G (p.Val197Gly) and c.433G>A (p.Gly145Arg), in exon 4 of ALG14."
Illustrates exome sequencing as the route to diagnosis.
📈

Progression

1
Lethal infantile course
Age: birth to 12 months
In the severe form, onset is at or before birth with hypotonia and contractures, followed by refractory epilepsy and progressive cerebral atrophy, with death during the first year of life. This is not the universal course: siblings with a different compound heterozygous genotype were clinically stable at ages five and two, which is the observation behind treating allele severity as the main determinant of outcome.
Show evidence (1 reference)
PMID:28733338 SUPPORT Human Clinical
"Three patients had congenital contractures. All patients died during their first year of life."
Documents the fatal first-year course of the severe form.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Reported in small numbers since the gene was identified in 2013. The severe infantile cohort comprised five patients from three families; individual later reports have added single families. No population prevalence estimate has been published.
Show evidence (1 reference)
PMID:28733338 SUPPORT Human Clinical
"This case study of 5 patients from 3 families includes clinical phenotype, serial MRI, electrophysiologic testing, muscle biopsy, and full autopsy."
Gives the size of the largest reported cohort of the severe form.
{ }

Source YAML

click to show 
name: Congenital Myasthenic Syndrome 15
creation_date: "2026-08-28T00:00:00Z"
category: Mendelian
disease_term:
  preferred_term: Congenital myasthenic syndrome 15
  term:
    id: MONDO:0014542
    label: congenital myasthenic syndrome 15
parents:
- Congenital Myasthenic Syndrome
synonyms:
- CMS15
- ALG14 congenital myasthenic syndrome
- congenital myasthenic syndrome caused by mutation in ALG14
- myasthenic syndrome, congenital, 15, without tubular aggregates
- ALG14-CDG
description: >-
  Congenital myasthenic syndrome 15 (CMS15) is an autosomal recessive disorder
  of neuromuscular transmission caused by biallelic variants in ALG14. It
  belongs to the small group of congenital myasthenic syndromes that are also
  congenital disorders of glycosylation: the defective protein is not a
  component of the neuromuscular junction at all, but a subunit of the
  multiglycosyltransferase complex that, with ALG13 and DPAGT1, catalyses the
  first committed steps of asparagine-linked (N-linked) protein glycosylation
  in the endoplasmic reticulum.

  The mechanism is therefore indirect, and that is the point of the entry. The
  acetylcholine receptor is structurally normal and its genes are intact; what
  fails is the post-translational modification the receptor subunits need in
  order to fold, assemble and reach the postsynaptic membrane in adequate
  numbers. Endplate acetylcholine receptor deficiency is the consequence of a
  housekeeping biosynthetic defect, not of a receptor lesion, which is why the
  disease can be a myasthenia at one end of its allelic spectrum and a
  multisystem neurodegenerative disorder at the other.

  That spectrum is wide and worth stating explicitly. The founding cohort had
  an inherited limb-girdle pattern of fatigable weakness with no central
  nervous system involvement. Subsequent reports described a severe infantile
  form with congenital contractures, therapy-refractory epilepsy, progressive
  cerebral atrophy and death within the first year, described by its authors as
  a new congenital disorder of glycosylation rather than as a myasthenia. Both
  ends carry biallelic ALG14 variants and both sit under this MONDO term, so
  the entry curates the whole spectrum and marks which pole each phenotype and
  each piece of evidence comes from.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Patients carry biallelic ALG14 variants, homozygous or compound
    heterozygous, with unaffected heterozygous carrier parents. Reported
    genotypes are predominantly missense; a complete null on both alleles has
    not been described, which is consistent with ALG14's essential
    housekeeping role.
  evidence:
  - reference: PMID:28733338
    reference_title: "Early and lethal neurodegeneration with myasthenic and myopathic
      features: A new ALG14-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In all cases, parents were found to be heterozygous carriers."
    explanation: Establishes recessive segregation with unaffected heterozygous parents
      across three families.
  - reference: PMID:34971077
    reference_title: "The longest reported sibling survivors of a severe form of congenital
      myasthenic syndrome with the ALG14 pathogenic variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing indicated that the siblings had novel compound heterozygous
      missense variants, c.590T>G (p.Val197Gly) and c.433G>A (p.Gly145Arg), in exon
      4 of ALG14."
    explanation: Documents a compound heterozygous genotype, the other biallelic configuration
      seen in this disease.
genetic:
- name: ALG14
  gene_term:
    preferred_term: ALG14
    term:
      id: hgnc:28287
      label: ALG14
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    ALG14 encodes a subunit of the UDP-N-acetylglucosamine transferase complex
    that it forms with ALG13 and DPAGT1 on the cytoplasmic face of the
    endoplasmic reticulum. The complex catalyses the first two committed steps
    of the dolichol-linked oligosaccharide pathway that supplies N-linked
    glycans. Because the gene is a general component of that pathway rather
    than a synapse-specific protein, the neuromuscular phenotype reflects the
    particular sensitivity of the endplate to reduced glycosylation capacity,
    and the severity of an allele determines how far beyond the endplate the
    disease extends. Two of the other subunits of the same pathway, DPAGT1 and
    ALG2, are themselves congenital myasthenic syndrome genes.
  variants:
  - name: "ALG14 c.220G>A (p.Asp74Asn)"
    description: >-
      The recurrent allele in the severe infantile neurodegenerative form,
      found homozygously in two patients and heterozygously in three others
      across three families.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:28733338
      reference_title: "Early and lethal neurodegeneration with myasthenic and myopathic
        features: A new ALG14-CDG."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Causative mutations in ALG14 were identified in all patients."
      explanation: Attributes the severe phenotype in this cohort to ALG14 variants.
  - name: "ALG14 c.422T>G (p.Val141Gly)"
    description: >-
      A second allele in the severe infantile cohort, carried heterozygously in
      trans with p.Asp74Asn.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:28733338
      reference_title: "Early and lethal neurodegeneration with myasthenic and myopathic
        features: A new ALG14-CDG."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Additional heterozygous mutations were c.422T>G (p.Val141Gly) and c.326G>A
        (p.Arg109Gln)."
      explanation: Names the two additional heterozygous alleles found in the severe
        cohort.
  - name: "ALG14 c.326G>A (p.Arg109Gln)"
    description: >-
      A third allele in the severe infantile cohort, likewise carried
      heterozygously in trans with p.Asp74Asn.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:28733338
      reference_title: "Early and lethal neurodegeneration with myasthenic and myopathic
        features: A new ALG14-CDG."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Additional heterozygous mutations were c.422T>G (p.Val141Gly) and c.326G>A
        (p.Arg109Gln)."
      explanation: Names the two additional heterozygous alleles found in the severe
        cohort.
  - name: "ALG14 c.590T>G (p.Val197Gly)"
    description: >-
      One half of the compound heterozygous genotype in the long-surviving
      siblings, whose course was markedly milder than the lethal infantile
      cohort despite a comparably severe neonatal presentation.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:34971077
      reference_title: "The longest reported sibling survivors of a severe form of
        congenital myasthenic syndrome with the ALG14 pathogenic variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Exome sequencing indicated that the siblings had novel compound heterozygous
        missense variants, c.590T>G (p.Val197Gly) and c.433G>A (p.Gly145Arg), in exon
        4 of ALG14."
      explanation: Names both alleles of the long-surviving siblings' genotype.
  - name: "ALG14 c.433G>A (p.Gly145Arg)"
    description: >-
      The other half of the compound heterozygous genotype in the long-surviving
      siblings.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:34971077
      reference_title: "The longest reported sibling survivors of a severe form of
        congenital myasthenic syndrome with the ALG14 pathogenic variant."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Exome sequencing indicated that the siblings had novel compound heterozygous
        missense variants, c.590T>G (p.Val197Gly) and c.433G>A (p.Gly145Arg), in exon
        4 of ALG14."
      explanation: Names both alleles of the long-surviving siblings' genotype.
  evidence:
  - reference: PMID:23404334
    reference_title: "Congenital myasthenic syndromes due to mutations in ALG2 and
      ALG14."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identify ALG14 and ALG2 as novel genes in which mutations cause a
      congenital myasthenic syndrome."
    explanation: Establishes ALG14 as a congenital myasthenic syndrome gene, the finding
      that defines this disease entity.
  - reference: PMID:40533459
    reference_title: "Review of 40 genes causing congenital myasthenic syndromes."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "A total of 40 genes have been reported in CMS (AGRN, ALG14, ALG2, CHAT,"
    explanation: A 2025 review confirming ALG14 as an established CMS gene alongside
      ALG2 and DPAGT1, the other two glycosylation-pathway members named in this block.
      Graded OTHER because the source is a review rather than a primary study.
pathophysiology:
- name: Biallelic ALG14 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Biallelic ALG14 variants reduce the function of the ALG13-ALG14-DPAGT1
    multiglycosyltransferase complex, which catalyses the first two committed
    steps of asparagine-linked protein glycosylation on the cytoplasmic face of
    the endoplasmic reticulum. Reported alleles are predominantly missense, so
    residual activity is retained; the amount retained appears to set where a
    patient falls on the phenotypic spectrum.
  genetic_context:
    genes:
    - preferred_term: ALG14
      term:
        id: hgnc:28287
        label: ALG14
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Homozygous or compound heterozygous germline missense variants, including
      the recurrent p.Asp74Asn allele of the severe form and the p.Val197Gly /
      p.Gly145Arg compound heterozygous pair reported in long-surviving
      siblings.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: DECREASED
  - preferred_term: dolichol-linked oligosaccharide biosynthetic process
    term:
      id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
    modifier: DECREASED
  evidence:
  - reference: PMID:23404334
    reference_title: "Congenital myasthenic syndromes due to mutations in ALG2 and
      ALG14."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ALG14 is thought to form a multiglycosyltransferase complex with ALG13
      and DPAGT1 that catalyses the first two committed steps of asparagine-linked
      protein glycosylation."
    explanation: Identifies the biochemical complex and pathway step that ALG14 loss
      of function impairs.
  downstream:
  - target: Hypoglycosylation of Endplate Proteins
    causal_link_type: DIRECT
    description: >-
      Reduced flux through the first committed steps of N-linked glycosylation
      leaves proteins that depend on that pathway incompletely glycosylated.

- name: Hypoglycosylation of Endplate Proteins
  biological_scale: MOLECULAR
  description: >-
    ALG14 is concentrated at the muscle motor endplate, so the postsynaptic
    membrane is a site where reduced N-glycosylation capacity is felt
    disproportionately. Acetylcholine receptor subunits require N-linked
    glycans for correct folding, pentameric assembly and export; when the
    glycan supply is limited, fewer complete receptors reach the surface. The
    receptor genes themselves are intact, so this is a failure of
    post-translational processing rather than a receptor lesion.
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: Neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: DECREASED
  evidence:
  - reference: PMID:23404334
    reference_title: "Congenital myasthenic syndromes due to mutations in ALG2 and
      ALG14."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We show that ALG14 is concentrated at the muscle motor endplates and
      small interfering RNA silencing of ALG14 results in reduced cell-surface expression
      of muscle acetylcholine receptor expressed in human embryonic kidney 293 cells."
    explanation: Localises ALG14 to the endplate and shows experimentally that reducing
      it lowers surface acetylcholine receptor, which is the step this node asserts.
  downstream:
  - target: Endplate Acetylcholine Receptor Deficiency
    causal_link_type: DIRECT
  - target: Impaired Glycosylation in Neural Tissue
    causal_link_type: DIRECT
    description: >-
      The same biosynthetic deficit acts outside muscle. Whether it becomes
      clinically apparent depends on how much residual ALG14 activity an
      allele leaves, which is why this branch is silent in the limb-girdle
      form and dominant in the severe infantile form.

- name: Endplate Acetylcholine Receptor Deficiency
  biological_scale: TISSUE
  description: >-
    The postsynaptic membrane carries too few acetylcholine receptors to
    guarantee that each nerve impulse depolarises the muscle fibre to
    threshold. Transmission consequently fails intermittently and
    use-dependently, which is measured electrophysiologically as a decremental
    response of the compound muscle action potential to repetitive nerve
    stimulation.
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  locations:
  - preferred_term: Neuromuscular junction
    term:
      id: GO:0031594
      label: neuromuscular junction
  molecular_functions:
  - preferred_term: acetylcholine receptor activity
    term:
      id: GO:0015464
      label: acetylcholine receptor activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: neuromuscular synaptic transmission
    term:
      id: GO:0007274
      label: neuromuscular synaptic transmission
    modifier: DECREASED
  evidence:
  - reference: PMID:34971077
    reference_title: "The longest reported sibling survivors of a severe form of congenital
      myasthenic syndrome with the ALG14 pathogenic variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The pathogenic variant in ALG14 results in a severe pathological form
      of CMS causing end-plate acetylcholine receptor deficiency."
    explanation: States endplate acetylcholine receptor deficiency as the neuromuscular
      lesion in ALG14-related CMS.
  - reference: PMID:34971077
    reference_title: "The longest reported sibling survivors of a severe form of congenital
      myasthenic syndrome with the ALG14 pathogenic variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Repetitive nerve stimulation test showed an abnormal decrease in compound
      muscle action potential."
    explanation: Electrophysiological confirmation that neuromuscular transmission
      fails on repetitive stimulation.
  downstream:
  - target: Fatigable Skeletal Muscle Weakness
    causal_link_type: DIRECT

- name: Fatigable Skeletal Muscle Weakness
  biological_scale: ORGANISM
  description: >-
    Clinically the transmission failure appears as weakness that worsens with
    sustained activity. In the founding cohort the distribution was
    limb-girdle, sparing the ocular and bulbar muscles that dominate many other
    congenital myasthenic syndromes. In the severe infantile form the weakness
    is present from birth as profound hypotonia with respiratory and swallowing
    failure.
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:23404334
    reference_title: "Congenital myasthenic syndromes due to mutations in ALG2 and
      ALG14."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with an inherited limb-girdle pattern of myasthenic weakness"
    explanation: Describes the limb-girdle distribution of fatigable weakness in the
      cohort in which ALG14 was identified.

- name: Impaired Glycosylation in Neural Tissue
  biological_scale: TISSUE
  description: >-
    In severely affected patients the glycosylation deficit is not confined to
    the endplate. Progressive cerebral atrophy, delayed myelination and
    therapy-refractory epilepsy accompany the neuromuscular disease, and the
    authors of that cohort classified the condition as a new congenital
    disorder of glycosylation rather than as a myasthenia. The specific
    glycoproteins whose hypoglycosylation drives the neurodegeneration have not
    been identified, so this node records an established association whose
    intermediate steps are not resolved.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: DECREASED
  evidence:
  - reference: PMID:28733338
    reference_title: "Early and lethal neurodegeneration with myasthenic and myopathic
      features: A new ALG14-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 5 patients showed severe muscular hypotonia, progressive cerebral
      atrophy, and therapy-refractory epilepsy."
    explanation: Documents the central nervous system involvement that defines the
      severe pole of the spectrum.
  - reference: PMID:28733338
    reference_title: "Early and lethal neurodegeneration with myasthenic and myopathic
      features: A new ALG14-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These cases broaden the phenotypic spectrum associated with ALG14 congenital
      disorders of glycosylation as previously only isolated myasthenia has been described."
    explanation: States that the central nervous system phenotype extends the previously
      myasthenia-only ALG14 spectrum.
phenotypes:
- category: Neuromuscular
  name: Limb-girdle muscle weakness
  description: >-
    The presenting pattern in the cohort in which ALG14 was identified as a
    congenital myasthenic syndrome gene.
  phenotype_term:
    preferred_term: Limb-girdle muscle weakness
    term:
      id: HP:0003325
      label: Limb-girdle muscle weakness
  evidence:
  - reference: PMID:23404334
    reference_title: "Congenital myasthenic syndromes due to mutations in ALG2 and
      ALG14."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with an inherited limb-girdle pattern of myasthenic weakness"
    explanation: Reports the limb-girdle distribution in the founding cohort.
- category: Neuromuscular
  name: Fatigable weakness
  description: >-
    Weakness worsening with sustained or repeated activity, the defining
    functional signature of a defect in neuromuscular transmission.
  phenotype_term:
    preferred_term: Fatigable weakness
    term:
      id: HP:0003473
      label: Fatigable weakness
  evidence:
  - reference: PMID:23404334
    reference_title: "Congenital myasthenic syndromes due to mutations in ALG2 and
      ALG14."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients with an inherited limb-girdle pattern of myasthenic weakness"
    explanation: Characterises the weakness as myasthenic, that is fatigable.
- category: Neuromuscular
  name: EMG decremental response
  description: >-
    A decremental compound muscle action potential response to repetitive nerve
    stimulation, demonstrating that the lesion is at the neuromuscular junction
    rather than in the muscle fibre or the nerve.
  phenotype_term:
    preferred_term: "EMG: decremental response of compound muscle action potential
      to repetitive nerve stimulation"
    term:
      id: HP:0003403
      label: "EMG: decremental response of compound muscle action potential to repetitive
        nerve stimulation"
  evidence:
  - reference: PMID:34971077
    reference_title: "The longest reported sibling survivors of a severe form of congenital
      myasthenic syndrome with the ALG14 pathogenic variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Repetitive nerve stimulation test showed an abnormal decrease in compound
      muscle action potential."
    explanation: Reports the decremental response in ALG14-related CMS siblings.
- category: Neuromuscular
  name: Hypotonia
  description: >-
    Severe muscular hypotonia is the presenting sign in the infantile-onset
    form, present from birth.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:28733338
    reference_title: "Early and lethal neurodegeneration with myasthenic and myopathic
      features: A new ALG14-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 5 patients showed severe muscular hypotonia, progressive cerebral
      atrophy, and therapy-refractory epilepsy."
    explanation: Reports severe hypotonia in all patients of the severe cohort.
- category: Neurological
  name: Seizure
  description: >-
    Therapy-refractory epilepsy in the severe infantile form. Notably, in the
    long-surviving siblings the seizures were controlled with anti-epileptic
    drugs, so refractoriness is not invariable.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:28733338
    reference_title: "Early and lethal neurodegeneration with myasthenic and myopathic
      features: A new ALG14-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 5 patients showed severe muscular hypotonia, progressive cerebral
      atrophy, and therapy-refractory epilepsy."
    explanation: Reports therapy-refractory epilepsy in the severe cohort.
- category: Neurological
  name: Cerebral atrophy
  description: >-
    Progressive cerebral atrophy on serial imaging in the severe form,
    distinguishing it from a pure disorder of neuromuscular transmission.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:28733338
    reference_title: "Early and lethal neurodegeneration with myasthenic and myopathic
      features: A new ALG14-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All 5 patients showed severe muscular hypotonia, progressive cerebral
      atrophy, and therapy-refractory epilepsy."
    explanation: Reports progressive cerebral atrophy in the severe cohort.
- category: Neurological
  name: Delayed CNS myelination
  description: >-
    Delayed myelination on cranial magnetic resonance imaging, reported
    alongside cerebral atrophy in severely affected siblings.
  phenotype_term:
    preferred_term: Delayed CNS myelination
    term:
      id: HP:0002188
      label: Delayed CNS myelination
  evidence:
  - reference: PMID:34971077
    reference_title: "The longest reported sibling survivors of a severe form of congenital
      myasthenic syndrome with the ALG14 pathogenic variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cranial magnetic resonance imaging scans revealed delayed myelination
      and cerebral atrophy."
    explanation: Reports delayed myelination on imaging in ALG14-related CMS.
- category: Musculoskeletal
  name: Arthrogryposis multiplex congenita
  description: >-
    Congenital joint contractures, reflecting reduced fetal movement, seen in
    the severe infantile form.
  phenotype_term:
    preferred_term: Arthrogryposis multiplex congenita
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  evidence:
  - reference: PMID:34971077
    reference_title: "The longest reported sibling survivors of a severe form of congenital
      myasthenic syndrome with the ALG14 pathogenic variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Immediately after birth, they showed hypotonia and multiple joint contractures
      with low Apgar scores."
    explanation: Reports multiple congenital joint contractures at birth.
  - reference: PMID:28733338
    reference_title: "Early and lethal neurodegeneration with myasthenic and myopathic
      features: A new ALG14-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients had congenital contractures. All patients died during
      their first year of life."
    explanation: Reports congenital contractures in three of five patients in the severe
      cohort.
diagnosis:
- name: Repetitive nerve stimulation
  description: >-
    A decremental compound muscle action potential response localises the
    defect to the neuromuscular junction. It does not distinguish CMS15 from
    other congenital myasthenic syndromes, and in the severe infantile form the
    profound hypotonia and encephalopathy can make the myasthenic component
    easy to miss altogether.
  evidence:
  - reference: PMID:34971077
    reference_title: "The longest reported sibling survivors of a severe form of congenital
      myasthenic syndrome with the ALG14 pathogenic variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Repetitive nerve stimulation test showed an abnormal decrease in compound
      muscle action potential."
    explanation: Demonstrates the diagnostic electrophysiological finding.
- name: Exome or genome sequencing of ALG14
  description: >-
    Definitive diagnosis rests on identifying biallelic ALG14 variants. Because
    the severe form presents as an encephalopathy with contractures rather than
    as a myasthenia, it is frequently reached by broad sequencing rather than
    by a targeted neuromuscular panel.
  evidence:
  - reference: PMID:34971077
    reference_title: "The longest reported sibling survivors of a severe form of congenital
      myasthenic syndrome with the ALG14 pathogenic variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing indicated that the siblings had novel compound heterozygous
      missense variants, c.590T>G (p.Val197Gly) and c.433G>A (p.Gly145Arg), in exon
      4 of ALG14."
    explanation: Illustrates exome sequencing as the route to diagnosis.
treatments:
- name: Pyridostigmine
  description: >-
    An acetylcholinesterase inhibitor, the standard first-line treatment for
    postsynaptic congenital myasthenic syndromes. By slowing the hydrolysis of
    acetylcholine it prolongs transmitter dwell time in the cleft, partially
    compensating for the reduced number of endplate receptors. It does not
    address the glycosylation defect, which is why the response tracks the
    severity of the underlying allele: benefit was only temporary in the
    lethal infantile cohort, while long-surviving siblings gained
    respirator-free time.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pyridostigmine
      term:
        id: CHEBI:8665
        label: Pyridostigmine
  target_mechanisms:
  - target: Endplate Acetylcholine Receptor Deficiency
    treatment_effect: MODULATES
    description: >-
      Inhibiting acetylcholinesterase prolongs acetylcholine dwell time in the
      synaptic cleft, so the receptors that did reach the surface are engaged
      more often. It compensates for the reduced receptor number without
      restoring it, and does nothing about the upstream glycosylation defect.
  evidence:
  - reference: PMID:34971077
    reference_title: "The longest reported sibling survivors of a severe form of congenital
      myasthenic syndrome with the ALG14 pathogenic variant."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After treatment with pyridostigmine, the time off the respirator increased."
    explanation: Reports a measurable functional benefit of pyridostigmine in ALG14-related
      CMS.
  - reference: PMID:28733338
    reference_title: "Early and lethal neurodegeneration with myasthenic and myopathic
      features: A new ALG14-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 2 of our patients, electrophysiologic testing showed abnormal decrement,
      but treatment with pyridostigmine led only to temporary improvement."
    explanation: Records that the benefit was temporary in the severe form, which is
      why this evidence is graded partial rather than supporting.
- name: Cholinesterase inhibition across the glycosylation CMS group
  description: >-
    The founding study proposed that cholinesterase inhibition may help more
    broadly across congenital disorders of glycosylation affecting the
    neuromuscular junction. This is a suggestion made by the authors rather
    than a trial result, and is recorded as such.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:23404334
    reference_title: "Congenital myasthenic syndromes due to mutations in ALG2 and
      ALG14."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our findings suggest that treatment with cholinesterase inhibitors may
      improve muscle function in many of the congenital disorders of glycosylation."
    explanation: An authors' suggestion extrapolated from their findings, not a treatment
      study; graded partial for that reason.
discussions:
- discussion_id: alg14_spectrum_one_entity
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Should the limb-girdle myasthenic form and the lethal infantile
    neurodegenerative form of ALG14 deficiency be one dismech entry or two?
  attaches_to:
  - pathophysiology#Impaired Glycosylation in Neural Tissue
  rationale: >-
    They share a gene, a biochemical lesion and a MONDO term, which is the
    argument for one entry, and this entry takes that position. But they
    differ in nearly everything a clinician would use to recognise them: age
    of onset, whether the central nervous system is involved at all, survival,
    and whether the presenting problem looks myasthenic. The authors of the
    severe cohort described their patients as a new congenital disorder of
    glycosylation rather than as a congenital myasthenic syndrome, and MONDO
    places this term under both congenital myasthenic syndrome and
    ALG14-congenital disorder of glycosylation. If the KB later adopts a
    convention of splitting allelic series whose poles differ in organ
    involvement, this entry is a candidate for splitting into a myasthenic
    entry and a CDG entry linked by gene.
- discussion_id: neurodegeneration_intermediate_steps_unknown
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which hypoglycosylated proteins mediate the cerebral atrophy and epilepsy
    of severe ALG14 deficiency?
  attaches_to:
  - pathophysiology#Impaired Glycosylation in Neural Tissue
  rationale: >-
    The endplate arm of this disease has a named target: acetylcholine
    receptor surface expression falls when ALG14 is silenced, shown directly.
    The central nervous system arm has no equivalent. Cerebral atrophy,
    delayed myelination and refractory epilepsy are well documented, but no
    specific neural glycoprotein has been shown to be hypoglycosylated and no
    intermediate step between the biosynthetic defect and the neurodegeneration
    has been established. The pathophysiology node therefore asserts an
    association at tissue scale rather than a mechanism, and should not be read
    as more than that.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Reported in small numbers since the gene was identified in 2013. The severe
    infantile cohort comprised five patients from three families; individual
    later reports have added single families. No population prevalence estimate
    has been published.
  evidence:
  - reference: PMID:28733338
    reference_title: "Early and lethal neurodegeneration with myasthenic and myopathic
      features: A new ALG14-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This case study of 5 patients from 3 families includes clinical phenotype,
      serial MRI, electrophysiologic testing, muscle biopsy, and full autopsy."
    explanation: Gives the size of the largest reported cohort of the severe form.
progression:
- phase: Lethal infantile course
  age_range: birth to 12 months
  notes: >-
    In the severe form, onset is at or before birth with hypotonia and
    contractures, followed by refractory epilepsy and progressive cerebral
    atrophy, with death during the first year of life. This is not the
    universal course: siblings with a different compound heterozygous genotype
    were clinically stable at ages five and two, which is the observation
    behind treating allele severity as the main determinant of outcome.
  evidence:
  - reference: PMID:28733338
    reference_title: "Early and lethal neurodegeneration with myasthenic and myopathic
      features: A new ALG14-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three patients had congenital contractures. All patients died during
      their first year of life."
    explanation: Documents the fatal first-year course of the severe form.
references:
- reference: PMID:20301347
  title: "Congenital Myasthenic Syndromes Overview."
  tags:
  - GeneReviews
- reference: PMID:40533459
  title: "Review of 40 genes causing congenital myasthenic syndromes."
notes: >-
  Entity identity. CMS15 is the ALG14 congenital myasthenic syndrome. MONDO
  defines MONDO:0014542 as "Any congenital myasthenic syndrome in which the
  cause of the disease is a mutation in the ALG14 gene", with exact synonym
  "ALG14 congenital myasthenic syndrome" and cross-reference OMIM:616227. It
  was described together with CMS14 (ALG2, with tubular aggregates) in a single
  2013 study, and the MONDO synonym "without tubular aggregates" preserves that
  pairing. It is not the SLC18A3/VAChT congenital myasthenic syndrome, which is
  a separate entity with its own gene and OMIM entry.

  This matters because an openscientist deep-research report generated for this
  entry during curation was entirely about SLC18A3/VAChT while citing
  OMIM:616227, and none of its content was usable. The report was discarded
  rather than curated from, and the two tooling gaps it exposed are filed as
  issues #9888 (deep-research runs are dispatched with an empty mondo_id, so
  the provider has no ontology grounding) and #9889 (preflight-dr skips its
  gene-identity check when MONDO records no RO:0004003 gene, even where the
  MONDO definition names the gene in plain text).

  Scope. The entry covers the full ALG14 allelic spectrum under one MONDO term
  and marks which pole each phenotype comes from, rather than curating only the
  myasthenic end. The case for splitting it is recorded under discussions
  instead of being settled unilaterally here.
📚

References & Deep Research

References

2
PMID:20301347
Congenital Myasthenic Syndromes Overview.
No top-level findings curated for this source.
PMID:40533459
Review of 40 genes causing congenital myasthenic syndromes.
No top-level findings curated for this source.

Deep Research

1
Congenital Myasthenic Syndrome 15 Deep Research Fallback ▸

Congenital Myasthenic Syndrome 15 Deep Research Fallback

Provider Attempts

  • openscientist: just research-disorder openscientist Congenital_Myasthenic_Syndrome_15 completed successfully in 1287 s and returned an 832-line, 9-citation report. The report was discarded without being curated from, because it is about the wrong disease.

Why the report was discarded

The report's central claim is:

Finding 1 — CMS15 is a presynaptic CMS caused by biallelic SLC18A3/VAChT variants

CMS15 (MONDO:0014542) is the ALG14 congenital myasthenic syndrome. MONDO defines the term as "Any congenital myasthenic syndrome in which the cause of the disease is a mutation in the ALG14 gene", with exact synonym ALG14 congenital myasthenic syndrome and cross-reference OMIM:616227. It was described alongside CMS14 (ALG2, with tubular aggregates) in a single 2013 study, PMID:23404334, and the MONDO synonym "without tubular aggregates" preserves that pairing. SLC18A3/VAChT congenital myasthenic syndrome is a separate entity; the 2025 review of CMS genes (PMID:40533459) lists ALG14 and SLC18A3 as distinct entries in the same gene list.

The report is internally coherent, well-cited science about a real disease. It is simply not this one, which makes it more dangerous than an obviously broken report — nothing in it looks wrong. It also asserts OMIM:616227, the correct OMIM number for CMS15, next to the wrong gene, so a curator spot-checking the identifier would find it matching.

just preflight-dr <report> MONDO:0014542 scored the report's gene mentions as SLC18A3=35, CHAT=10, DAP=4, CHRNE=3, RAPSN=3. ALG14 does not appear in the top five. The preflight nonetheless resolved to SKIP rather than a failure, because MONDO records no RO:0004003 causal gene for this term.

The report itself is deliberately not committed. research/ outputs are consumed as first-class curation inputs and indexed by disease name, so a wrong-disease report filed under the CMS15 name would mislead the next curator and the artifact index. This fallback record replaces it.

Two tooling gaps were filed:

  • dismech#9888 — just research-disorder passes a hardcoded empty mondo_id, so every deep-research run for every disease and provider is dispatched with no ontology grounding. That is the upstream cause of this misidentification.
  • dismech#9889 — preflight-dr silently skips its gene-identity check when MONDO has no RO:0004003 assertion, even where the MONDO definition and exact synonyms name the gene in plain text, as they do here.

Literature Scope Used Instead

Curation was anchored on generated PubMed reference caches:

  • PMID:23404334 — Cossins et al. 2013, Brain. The founding study identifying ALG14 and ALG2 as CMS genes; source for the limb-girdle phenotype, the ALG13/ALG14/DPAGT1 complex, endplate localisation of ALG14, and the siRNA experiment showing reduced surface acetylcholine receptor.
  • PMID:28733338 — Schorling et al. 2017, Neurology. Five patients from three families with the severe infantile form; source for the neurodegenerative pole of the spectrum, the recurrent p.Asp74Asn allele, recessive segregation, and the temporary-only pyridostigmine response.
  • PMID:34971077 — Long-surviving siblings with compound heterozygous ALG14 variants; source for endplate acetylcholine receptor deficiency, the decremental response, imaging findings, and the pyridostigmine benefit.
  • PMID:40533459 — 2025 review of the 40 genes causing CMS; used to confirm that ALG14 and SLC18A3 are separately recognised CMS genes.