Hereditary Hyperekplexia

Mendelian MONDO:0021022 Pathograph 25 Show in embeddings browser Hereditary Neurological Disease Movement Disorder Channelopathy

Hereditary hyperekplexia is an ultra-rare Mendelian neuromotor disorder of inhibitory glycinergic neurotransmission. Affected neonates and infants have excessive startle responses with stiffness, hypertonia, myoclonus, and gait disturbance; some patients have recurrent apnea, developmental delay, speech delay, seizures, or gastrointestinal complications. Pathogenic variants in GLRA1, GLRB, and SLC6A5 are the best-established causes, with additional disease-causing genes including GPHN and ATAD1.

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2
Inheritance
4
Pathophys.
25
Phenotypes
25
Pathograph
5
Genes
1
Medical Actions
4
Subtypes
1
References
1
Deep Research
👪

Inheritance

2
Autosomal dominant HP:0000006
Autosomal dominant inheritance
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"Autosomal dominant"
Orphanet lists autosomal dominant inheritance for hereditary hyperekplexia.
Autosomal recessive HP:0000007
Autosomal recessive inheritance
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"Autosomal recessive"
Orphanet lists autosomal recessive inheritance for hereditary hyperekplexia.
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Subtypes

4
Hyperekplexia 1 (GLRA1) MONDO:0007868
GLRA1 hgnc:4326 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in GLRA1 (hgnc:4326). hgnc:4326 is a gene from the HUGO Gene Nomenclature Committee. Autosomal dominant inheritance Autosomal recessive inheritance
The commonest genetic form, caused by variants in GLRA1, which encodes the alpha 1 subunit of the postsynaptic inhibitory glycine receptor. Dominant missense alleles and recessive loss-of-function alleles both occur.
Show evidence (2 references)
PMID:20407582 SUPPORT REVIEW SYNTHESIS Human Clinical
"Genetic screening studies have demonstrated that hyperekplexia is genetically heterogeneous with several missense and nonsense mutations in the postsynaptic glycine receptor (GlyR) alpha1 subunit gene (GLRA1) as the primary cause."
Establishes GLRA1 as the primary cause of hereditary hyperekplexia, which is the concept MONDO numbers as hyperekplexia 1.
PMID:8651283 SUPPORT Human Clinical
"Dominant missense mutations in the human glycine receptor (GlyR) alpha 1 subunit gene (GLRA1) give rise to hereditary hyperekplexia."
Supports the dominant GLRA1 allele class recorded in this subtype.
Hyperekplexia 2 (GLRB) MONDO:0013828
GLRB hgnc:4329 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in GLRB (hgnc:4329). hgnc:4329 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance Autosomal dominant inheritance
Hyperekplexia caused by variants in GLRB, which encodes the beta subunit of the same postsynaptic glycine receptor pentamer. Both recessive and dominant alleles are reported.
Show evidence (1 reference)
PMID:23184146 SUPPORT Human Clinical
"The screening identified recessive and dominant GLRB variants in 12 unrelated hyperekplexia probands."
Multi-proband screening study establishing GLRB as a hyperekplexia gene in both recessive and dominant form.
Hyperekplexia 3 (SLC6A5) MONDO:0013827
SLC6A5 hgnc:11051 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in SLC6A5 (hgnc:11051). hgnc:11051 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance Autosomal dominant inheritance
The presynaptic form, caused by variants in SLC6A5, which encodes the presynaptic glycine transporter GlyT2. Mostly recessive, with rare dominant alleles.
Show evidence (1 reference)
PMID:16751771 SUPPORT Human Clinical
"Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia."
Establishes SLC6A5 as a hyperekplexia gene acting presynaptically, the concept MONDO numbers as hyperekplexia 3.
Hyperekplexia 4 (ATAD1) MONDO:0044330
ATAD1 hgnc:25903 HUGO Gene Nomenclature Committee (hgnc) Relation: this subtype is caused by variation in this gene This subtype is caused by variation in ATAD1 (hgnc:25903). hgnc:25903 is a gene from the HUGO Gene Nomenclature Committee. Autosomal recessive inheritance
Biallelic ATAD1 variants cause a congenital syndrome of limb stiffness, absent spontaneous movement and hypoventilation that OMIM and MONDO number as hyperekplexia 4. Its molecular lesion is not glycinergic: ATAD1 encodes Thorase, an AAA+ ATPase that disassembles GRIP1-GluA2 complexes and so controls internalisation of excitatory AMPA receptors. The clinical delineation study that assembled all eight reported patients concludes that the entity is a distinct congenital encephalopathy rather than a form of hyperekplexia, so the subtype is carried here under the ontology's numbering with that divergence recorded rather than asserted as settled.
Show evidence (3 references)
PMID:33134516 SUPPORT Human Clinical
"Patients 1 and 2 had a similar distinctive phenotype comprising congenital stiffness of limbs, absent spontaneous movements, weak sucking, and hypoventilation."
Supports biallelic ATAD1 variants as the cause of this congenital stiffness syndrome, and describes the phenotype recorded in this row.
PMID:33134516 REFUTE Human Clinical
"Analysis of the phenotypes of these 2 patients and of the 6 previous cases showed that biallelic ATAD1 mutations are responsible for a unique congenital encephalopathy likely comprising absent BEAR, different from hyperekplexia and other conditions with neonatal hypertonia."
Refutes the placement of this entity under hereditary hyperekplexia. The authors reviewed all eight reported patients and concluded the disorder is distinct from hyperekplexia, against the OMIM and MONDO numbering this row follows.
PMID:29390050 SUPPORT BACKGROUND Other
"Postsynaptically, Thorase controls the internalization of excitatory, glutamatergic AMPA receptors by disassembling complexes between the AMPA receptor-binding protein, GRIP1, and the AMPA receptor subunit GluA2."
States the molecular role of the ATAD1 product, which is at the excitatory synapse rather than the glycinergic one, and so is why this subtype is wired to its own pathophysiology node.
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Pathophysiology

4
Postsynaptic Glycine Receptor Chloride Channel Dysfunction
GLRA1 and GLRB variants impair the postsynaptic inhibitory glycine receptor, a ligand-gated chloride channel that normally mediates rapid inhibitory signaling in the brainstem and spinal cord.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
GLRA1 hgnc:4326 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GLRA1 (hgnc:4326). hgnc:4326 is a gene from the HUGO Gene Nomenclature Committee. GLRB hgnc:4329 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves GLRB (hgnc:4329). hgnc:4329 is a gene from the HUGO Gene Nomenclature Committee.
chemical synaptic transmission GO:0007268 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves chemical synaptic transmission (GO:0007268). GO:0007268 is a biological process from the Gene Ontology.
extracellularly glycine-gated chloride channel activity GO:0016934 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves extracellularly glycine-gated chloride channel activity (GO:0016934). GO:0016934 is a molecular function from the Gene Ontology.
Downstream
Glycinergic Inhibitory Neurotransmission Failure Glycine receptor channel dysfunction reduces rapid inhibitory glycinergic signaling.
Show evidence (3 references)
PMID:8651283 SUPPORT Human Clinical
"Dominant missense mutations in the human glycine receptor (GlyR) alpha 1 subunit gene (GLRA1) give rise to hereditary hyperekplexia."
This establishes GLRA1 glycine receptor variants as a cause of hereditary hyperekplexia.
PMID:8651283 SUPPORT In Vitro
"These mutations impair agonist affinities and change conductance states of expressed mutant channels, resulting in a partial loss of function."
Functional channel evidence supports reduced glycine receptor activity.
PMID:11929858 SUPPORT Human Clinical
"Following mutation analysis of the human beta-subunit of hGlyR (GLRB) in a cohort of 22 hyperekplexia patients, we provide evidence to confirm that GLRB mutations can cause human hyperekplexia."
Human mutation analysis supports GLRB as a causal glycine receptor subunit gene.
Presynaptic Glycine Transporter Dysfunction
SLC6A5 encodes the presynaptic glycine transporter GlyT2. Pathogenic variants reduce transporter localization or glycine uptake, limiting presynaptic glycine recycling needed for inhibitory synaptic transmission.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
SLC6A5 hgnc:11051 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves SLC6A5 (hgnc:11051). hgnc:11051 is a gene from the HUGO Gene Nomenclature Committee.
chemical synaptic transmission GO:0007268 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves chemical synaptic transmission (GO:0007268). GO:0007268 is a biological process from the Gene Ontology.
glycine transmembrane transporter activity GO:0015187 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves glycine transmembrane transporter activity (GO:0015187). GO:0015187 is a molecular function from the Gene Ontology.
Downstream
Glycinergic Inhibitory Neurotransmission Failure Reduced GlyT2 function disrupts presynaptic glycine availability for inhibitory signaling.
Show evidence (3 references)
PMID:16751771 SUPPORT Human Clinical
"Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia."
This directly supports SLC6A5 as a presynaptic cause of hyperekplexia.
PMID:16751771 SUPPORT In Vitro
"SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites."
Functional data support impaired GlyT2 localization and glycine uptake as the mechanism.
PMID:22753417 SUPPORT In Vitro
"This interaction impairs transporter maturation through the secretory pathway, reduces surface expression, and inhibits transport function."
Functional GlyT2 evidence supports impaired trafficking and transport as a presynaptic mechanism.
Glycinergic Inhibitory Neurotransmission Failure
Failure of glycinergic inhibition in brainstem and spinal startle circuits leaves excitatory startle reflex pathways insufficiently suppressed, producing excessive startle, stiffness, and related neuromotor features.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
chemical synaptic transmission GO:0007268 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves chemical synaptic transmission (GO:0007268). GO:0007268 is a biological process from the Gene Ontology.
Downstream
Exaggerated Startle Response
Hypertonia
Muscle Stiffness
Rigidity
Abnormality of Movement
Myoclonus
Fasciculations
Hyperreflexia
Spasticity
Neonatal Apnea Episodes
Gait Disturbance
Ataxia
Sleep Abnormality
Developmental Delay
Speech and Language Delay
Intellectual Disability
Show evidence (2 references)
PMID:23184146 SUPPORT Human Clinical
"Glycinergic neurotransmission is a major inhibitory influence in the CNS and its disruption triggers a paediatric and adult startle disorder, hyperekplexia."
The abstract directly links disrupted glycinergic neurotransmission to hyperekplexia.
PMID:8651283 SUPPORT Human Clinical
"The child displayed exaggerated startle responses and pronounced head-retraction jerks reflecting a disinhibition of vestigial brain-stem reflexes."
This supports brainstem-reflex disinhibition as the clinical circuit consequence.
Thorase-Dependent AMPA Receptor Trafficking Failure
The one route into this entry that does not pass through the glycinergic synapse. ATAD1 encodes Thorase, an AAA+ ATPase that disassembles the complex between the AMPA-receptor-binding protein GRIP1 and the AMPA receptor subunit GluA2 and thereby controls postsynaptic internalisation of excitatory AMPA receptors. The reported biallelic allele locks Thorase in its oligomeric state, disassembly of the GluA2 complex is impaired, and knockout neurons expressing the mutant carry less GluA2 at the cell surface. The node is kept separate from the glycine receptor and glycine transporter nodes because the lesion is at the excitatory synapse, which is also why the clinical delineation study reads the resulting disorder as distinct from hyperekplexia.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
ATAD1 hgnc:25903 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ATAD1 (hgnc:25903). hgnc:25903 is a gene from the HUGO Gene Nomenclature Committee.
regulation of postsynaptic AMPA receptor internalisation GO:0099149 ⚠ ABNORMAL Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal regulation of postsynaptic AMPA receptor internalisation, annotated with regulation of postsynaptic neurotransmitter receptor internalization (GO:0099149). GO:0099149 is a biological process from the Gene Ontology. disassembly of the GRIP1-GluA2 complex GO:0032984 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased disassembly of the GRIP1-GluA2 complex, annotated with protein-containing complex disassembly (GO:0032984). GO:0032984 is a biological process from the Gene Ontology.
Downstream
Muscle Stiffness The reported patients present with congenital limb stiffness, but no step between the AMPA-receptor trafficking defect and the motor phenotype has been shown, so the edge is carried as indirect with the intermediates unknown.
Show evidence (3 references)
PMID:29390050 SUPPORT BACKGROUND Other
"Postsynaptically, Thorase controls the internalization of excitatory, glutamatergic AMPA receptors by disassembling complexes between the AMPA receptor-binding protein, GRIP1, and the AMPA receptor subunit GluA2."
States the normal function this node records as failing, and locates it at the excitatory rather than the glycinergic synapse.
PMID:29390050 SUPPORT In Vitro
"Biochemical and cellular analyses show that the C-terminal end of Thorase mutant gained a novel function that strongly impacts its oligomeric state, reduces stability or expression of a set of Golgi, peroxisomal and mitochondrial proteins and affects disassembly of GluA2 and Thorase oligomer complexes."
The measurement behind the impaired complex disassembly recorded on this node.
PMID:29390050 SUPPORT In Vitro
"reduced amount of GluA2 at the cell surface suggesting that the Thorase mutant may inhibit the recycling back and/or reinsertion of AMPA receptors to the plasma membrane"
Neuronal readout of the trafficking failure, and the authors' own reading of which step is blocked.
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Pathograph

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

25
Digestive 4
Umbilical Hernia FREQUENT HP:0001537 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Umbilical hernia (HP:0001537). HP:0001537 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0001537 | Umbilical hernia | Frequent (79-30%)"
Orphanet lists umbilical hernia as frequent.
Gastroesophageal Reflux VERY_FREQUENT HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0002020 | Gastroesophageal reflux | Very frequent (99-80%)"
Orphanet lists gastroesophageal reflux as very frequent.
Hiatus Hernia VERY_FREQUENT HP:0002036 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hiatus hernia (HP:0002036). HP:0002036 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0002036 | Hiatus hernia | Very frequent (99-80%)"
Orphanet lists hiatus hernia as very frequent.
Esophagitis VERY_FREQUENT HP:0100633 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Esophagitis (HP:0100633). HP:0100633 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0100633 | Esophagitis | Very frequent (99-80%)"
Orphanet lists esophagitis as very frequent.
Limbs 1
Hip Dislocation OCCASIONAL HP:0002827 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hip dislocation (HP:0002827). HP:0002827 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0002827 | Hip dislocation | Occasional (29-5%)"
Orphanet lists hip dislocation as occasional.
Musculoskeletal 7
Spasticity VERY_FREQUENT HP:0001257 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Spasticity (HP:0001257). HP:0001257 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0001257 | Spasticity | Very frequent (99-80%)"
Orphanet lists spasticity as very frequent.
Hypertonia VERY_FREQUENT HP:0001276 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertonia (HP:0001276). HP:0001276 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:3197 SUPPORT
"HP:0001276 | Hypertonia | Very frequent (99-80%)"
Orphanet lists hypertonia as very frequent.
PMID:16751771 SUPPORT Human Clinical
"Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes."
Human SLC6A5 cases directly support hypertonia.
Joint Dislocation OCCASIONAL HP:0001373 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint dislocation (HP:0001373). HP:0001373 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0001373 | Joint dislocation | Occasional (29-5%)"
Orphanet lists joint dislocation as occasional.
Joint Stiffness VERY_FREQUENT HP:0001387 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint stiffness (HP:0001387). HP:0001387 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0001387 | Joint stiffness | Very frequent (99-80%)"
Orphanet lists joint stiffness as very frequent.
Rigidity VERY_FREQUENT HP:0002063 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rigidity (HP:0002063). HP:0002063 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0002063 | Rigidity | Very frequent (99-80%)"
Orphanet lists rigidity as very frequent.
Muscle Stiffness VERY_FREQUENT HP:0003552 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle stiffness (HP:0003552). HP:0003552 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:3197 SUPPORT
"HP:0003552 | Muscle stiffness | Very frequent (99-80%)"
Orphanet lists muscle stiffness as very frequent.
PMID:24030948 SUPPORT Human Clinical
"In addition to the characteristic 'stiffness, startles and stumbles' of hyperekplexia"
The genetically confirmed cohort identifies stiffness as a characteristic feature.
Hernia FREQUENT HP:0100790 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hernia (HP:0100790). HP:0100790 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0100790 | Hernia | Frequent (79-30%)"
Orphanet lists hernia as frequent.
Nervous System 12
Exaggerated Startle Response HP:0002267 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exaggerated startle response (HP:0002267). HP:0002267 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
ORPHA:3197 SUPPORT
"Hereditary hyperekplexia is a hereditary neurological disorder characterized by excessive startle responses."
Orphanet defines hereditary hyperekplexia by excessive startle responses.
PMID:16751771 SUPPORT Human Clinical
"Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes."
Human SLC6A5 cases directly support exaggerated tactile or acoustic startle.
Ataxia VERY_FREQUENT HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0001251 | Ataxia | Very frequent (99-80%)"
Orphanet lists ataxia as very frequent in hereditary hyperekplexia.
Gait Disturbance FREQUENT HP:0001288 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gait disturbance (HP:0001288). HP:0001288 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0001288 | Gait disturbance | Frequent (79-30%)"
Orphanet lists gait disturbance as frequent.
Myoclonus VERY_FREQUENT HP:0001336 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoclonus (HP:0001336). HP:0001336 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0001336 | Myoclonus | Very frequent (99-80%)"
Orphanet lists myoclonus as very frequent.
Hyperreflexia VERY_FREQUENT HP:0001347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperreflexia (HP:0001347). HP:0001347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0001347 | Hyperreflexia | Very frequent (99-80%)"
Orphanet lists hyperreflexia as very frequent.
Sleep Abnormality FREQUENT Sleep disturbance HP:0002360 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sleep abnormality, annotated with Sleep disturbance (HP:0002360). HP:0002360 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0002360 | Sleep abnormality | Frequent (79-30%)"
Orphanet lists sleep abnormality as frequent.
Fasciculations VERY_FREQUENT HP:0002380 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Fasciculations (HP:0002380). HP:0002380 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0002380 | Fasciculations | Very frequent (99-80%)"
Orphanet lists fasciculations as very frequent.
Abnormality of Movement VERY_FREQUENT HP:0100022 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of movement (HP:0100022). HP:0100022 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0100022 | Abnormality of movement | Very frequent (99-80%)"
Orphanet lists abnormality of movement as very frequent.
Developmental Delay FREQUENT Global developmental delay HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:24030948 SUPPORT Human Clinical
"apnoea attacks (50 of 89) and delayed development (47 of 92) were frequently reported."
The cohort reports delayed development in 47 of 92 individuals, supporting a frequent band.
PMID:24030948 SUPPORT Human Clinical
"Patients with GLRB and SLC6A5 mutations were more likely to have developmental delay"
Genotype-phenotype data support developmental delay particularly in GLRB and SLC6A5 disease.
PMID:22753417 SUPPORT Human Clinical
"In addition to classical hyperekplexia symptoms, some individuals had abnormal respiration, facial dysmorphism, delayed motor development, or intellectual disability."
The dominant GlyT2 family report supports delayed motor development among SLC6A5-associated presentations.
Speech and Language Delay OCCASIONAL Delayed speech and language development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:24030948 SUPPORT Human Clinical
"61 cases had mutations in GLRA1, 24 cases in SLC6A5 and 12 in GLRB."
The cohort denominator supports interpreting GLRB-specific speech delay as a minority overall phenotype.
PMID:24030948 SUPPORT Human Clinical
"92% of GLRB cases reported a mild to severe delay in speech acquisition."
Genotype-phenotype data directly support delayed speech acquisition in GLRB-associated hyperekplexia.
Seizure OCCASIONAL 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)
ORPHA:3197 SUPPORT
"HP:0001250 | Seizure | Occasional (29-5%)"
Orphanet lists seizure as occasional.
Intellectual Disability OCCASIONAL HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"HP:0001249 | Intellectual disability | Occasional (29-5%)"
Orphanet lists intellectual disability as occasional.
Respiratory 1
Neonatal Apnea Episodes FREQUENT HP:0002104 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Apnea (HP:0002104), qualified as neonatal onset. HP:0002104 is a phenotype from the Human Phenotype Ontology.
Onset: NEONATAL
Show evidence (2 references)
PMID:24030948 SUPPORT Human Clinical
"apnoea attacks (50 of 89) and delayed development (47 of 92) were frequently reported."
The cohort reports apnea attacks in 50 of 89 individuals, supporting a frequent band.
PMID:16751771 SUPPORT Human Clinical
"Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes."
SLC6A5 cases directly support neonatal apnea episodes.
🧬

Genetic Associations

5
GLRA1 Pathogenic Variants (Pathogenic Variants)
Gene: GLRA1 hgnc:4326 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GLRA1 (hgnc:4326). hgnc:4326 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal dominant Autosomal recessive
Show evidence (3 references)
ORPHA:3197 SUPPORT
"GLRA1 | glycine receptor alpha 1 | hgnc:4326 | Disease-causing germline mutation(s) in"
Orphanet lists GLRA1 as a disease-causing gene for hereditary hyperekplexia.
PMID:8651283 SUPPORT Human Clinical
"Dominant missense mutations in the human glycine receptor (GlyR) alpha 1 subunit gene (GLRA1) give rise to hereditary hyperekplexia."
Human genetic evidence supports dominant GLRA1-associated disease.
PMID:8651283 SUPPORT Human Clinical
"In a recessive case of hyperekplexia, we found a deletion of exons 1-6 of the GLRA1 gene."
This supports recessive GLRA1-associated hyperekplexia.
GLRB Pathogenic Variants (Pathogenic Variants)
Gene: GLRB hgnc:4329 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GLRB (hgnc:4329). hgnc:4329 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal dominant Autosomal recessive
Show evidence (2 references)
ORPHA:3197 SUPPORT
"GLRB | glycine receptor beta | hgnc:4329 | Disease-causing germline mutation(s) in"
Orphanet lists GLRB as a disease-causing gene for hereditary hyperekplexia.
PMID:23184146 SUPPORT Human Clinical
"The screening identified recessive and dominant GLRB variants in 12 unrelated hyperekplexia probands."
Human cohort data support both recessive and dominant GLRB-associated disease.
SLC6A5 Pathogenic Variants (Pathogenic Variants)
Gene: SLC6A5 hgnc:11051 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is SLC6A5 (hgnc:11051). hgnc:11051 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive Autosomal dominant
Show evidence (3 references)
ORPHA:3197 SUPPORT
"SLC6A5 | solute carrier family 6 member 5 | hgnc:11051 | Disease-causing germline mutation(s) in"
Orphanet lists SLC6A5 as a disease-causing gene for hereditary hyperekplexia.
PMID:16751771 SUPPORT Human Clinical
"Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia."
Human genetic evidence supports SLC6A5 as a presynaptic disease gene.
PMID:22753417 SUPPORT Human Clinical
"In this study, systematic DNA sequencing of SLC6A5 revealed a new dominant GlyT2 mutation"
This family study supports rare dominant SLC6A5-associated hyperekplexia.
GPHN Pathogenic Variants (Pathogenic Variants)
Gene: GPHN hgnc:15465 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GPHN (hgnc:15465). hgnc:15465 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (3 references)
ORPHA:3197 SUPPORT
"GPHN | gephyrin | hgnc:15465 | Disease-causing germline mutation(s) in"
Orphanet lists GPHN as a disease-causing gene for hereditary hyperekplexia.
PMID:12684523 SUPPORT Human Clinical
"Mutation analysis of GPHN exons in hyperekplexia patients revealed a missense mutation (A28T) in one patient causing an amino acid substitution (N10Y)."
The only reported GPHN candidate allele in a hyperekplexia patient, and the basis of the gene's listing. A single patient is the whole genetic evidence.
PMID:12684523 REFUTE In Vitro
"Functional testing demonstrated that GPHNN10Y does not disrupt GlyR-gephyrin interactions or collybistininduced cell-surface clustering."
Refutes pathogenicity of that one allele by the mechanism it would have to act through. Quoted verbatim, including the two word-joins the cached text carries where the source set GPHN-N10Y and collybistin-induced with formatting this extraction dropped.
ATAD1 Pathogenic Variants (Pathogenic Variants)
Gene: ATAD1 hgnc:25903 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ATAD1 (hgnc:25903). hgnc:25903 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"ATAD1 | ATPase family AAA domain containing 1 | hgnc:25903 | Disease-causing germline mutation(s) in"
Orphanet lists ATAD1 as a disease-causing gene for hereditary hyperekplexia.
💊

Medical Actions

1
Clonazepam
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: clonazepam CHEBI:3756 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses clonazepam (CHEBI:3756). CHEBI:3756 is a therapeutic agent from Chemical Entities of Biological Interest.
Clonazepam is the standard symptomatic pharmacotherapy for hyperekplexia, reducing excessive startle and stiffness in most treated genetically confirmed patients.
Mechanism Target:
MODULATES Glycinergic Inhibitory Neurotransmission Failure — Clonazepam increases inhibitory tone symptomatically rather than correcting the causal gene defect.
Show evidence (1 reference)
PMID:24030948 SUPPORT Human Clinical
"clonazepam is the treatment of choice (95% found it to be efficacious)."
The genetically confirmed cohort reports clonazepam efficacy in nearly all treated patients.
🔬

Diagnosis

1
Molecular Genetic Testing
Molecular genetic testing confirms the diagnosis in symptomatic neonates and supports counseling for families at risk, especially where GLRB or SLC6A5 variants are suspected.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:24030948 SUPPORT Human Clinical
"Ninety-seven individuals had a clinical diagnosis of hyperekplexia confirmed by genetic testing"
The cohort used genetic testing to confirm clinical hyperekplexia diagnoses.
PMID:24030948 SUPPORT Human Clinical
"We recommend early genetic testing for symptomatic neonates and possibly preconception counselling for those at risk for GLRB and SLC6A5 mutations"
The authors recommend early genetic testing for symptomatic neonates.
📈

Progression

1
Neonatal or infantile onset
Age: Neonatal period to infancy
Symptoms typically begin in the neonatal period or infancy, and gene-positive cohorts can have recurrent apnea and developmental delay.
Show evidence (3 references)
ORPHA:3197 SUPPORT
"Age of onset: Neonatal"
Orphanet records neonatal onset.
ORPHA:3197 SUPPORT
"Age of onset: Infancy"
Orphanet records infantile onset.
PMID:24030948 SUPPORT Human Clinical
"all gene-positive cases present in the neonatal period (occasionally prenatally)"
The 97-person genetically confirmed cohort supports neonatal presentation.
📊

Prevalence

1
Worldwide
Point Prevalence ≤0.1 per 100,000 <1 in 1,000,000
Orphanet reports hereditary hyperekplexia as an ultra-rare disorder.
Show evidence (1 reference)
ORPHA:3197 SUPPORT
"<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
Orphanet provides a worldwide point-prevalence estimate below one per million.
{ }

Source YAML

click to show 
name: Hereditary Hyperekplexia
creation_date: "2026-05-10T19:24:25Z"
description: >-
  Hereditary hyperekplexia is an ultra-rare Mendelian neuromotor disorder of
  inhibitory glycinergic neurotransmission. Affected neonates and infants have
  excessive startle responses with stiffness, hypertonia, myoclonus, and gait
  disturbance; some patients have recurrent apnea, developmental delay, speech
  delay, seizures, or gastrointestinal complications. Pathogenic variants in
  GLRA1, GLRB, and SLC6A5 are the best-established causes, with additional
  disease-causing genes including GPHN and ATAD1.
category: Mendelian
parents:
- Hereditary Neurological Disease
- Movement Disorder
- Channelopathy
synonyms:
- Congenital stiff man syndrome
- Familial startle disease
- Hereditary hyperexplexia
- Kok disease
- Stiff baby syndrome
disease_term:
  preferred_term: hereditary hyperekplexia
  term:
    id: MONDO:0021022
    label: hereditary hyperekplexia
prevalence:
- population: Worldwide
  measure_type: POINT_PREVALENCE
  prevalence_class: BELOW_1_IN_1000000
  rate_high: 0.1
  percentage: <1 per 1,000,000
  notes: Orphanet reports hereditary hyperekplexia as an ultra-rare disorder.
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "<1 / 1 000 000 | Worldwide | Point prevalence | ORPHANET"
    explanation: Orphanet provides a worldwide point-prevalence estimate below one per million.
has_subtypes:
- name: HPX1
  display_name: Hyperekplexia 1 (GLRA1)
  subtype_term:
    preferred_term: hyperekplexia 1
    term:
      id: MONDO:0007868
      label: hyperekplexia 1
  genes:
  - preferred_term: GLRA1
    term:
      id: hgnc:4326
      label: GLRA1
  description: >-
    The commonest genetic form, caused by variants in GLRA1, which encodes the
    alpha 1 subunit of the postsynaptic inhibitory glycine receptor. Dominant
    missense alleles and recessive loss-of-function alleles both occur.
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20407582
    reference_title: "The glycinergic system in human startle disease: a genetic screening approach."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: "Genetic screening studies have demonstrated that hyperekplexia is genetically heterogeneous with several missense and nonsense mutations in the postsynaptic glycine receptor (GlyR) alpha1 subunit gene (GLRA1) as the primary cause."
    explanation: >-
      Establishes GLRA1 as the primary cause of hereditary hyperekplexia, which
      is the concept MONDO numbers as hyperekplexia 1.
  - reference: PMID:8651283
    reference_title: A GLRA1 null mutation in recessive hyperekplexia challenges the functional role of glycine receptors.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dominant missense mutations in the human glycine receptor (GlyR) alpha 1 subunit gene (GLRA1) give rise to hereditary hyperekplexia."
    explanation: Supports the dominant GLRA1 allele class recorded in this subtype.
- name: HPX2
  display_name: Hyperekplexia 2 (GLRB)
  subtype_term:
    preferred_term: hyperekplexia 2
    term:
      id: MONDO:0013828
      label: hyperekplexia 2
  genes:
  - preferred_term: GLRB
    term:
      id: hgnc:4329
      label: GLRB
  description: >-
    Hyperekplexia caused by variants in GLRB, which encodes the beta subunit of
    the same postsynaptic glycine receptor pentamer. Both recessive and dominant
    alleles are reported.
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:23184146
    reference_title: GLRB is the third major gene of effect in hyperekplexia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The screening identified recessive and dominant GLRB variants in 12 unrelated hyperekplexia probands."
    explanation: >-
      Multi-proband screening study establishing GLRB as a hyperekplexia gene in
      both recessive and dominant form.
- name: HPX3
  display_name: Hyperekplexia 3 (SLC6A5)
  subtype_term:
    preferred_term: hyperekplexia 3
    term:
      id: MONDO:0013827
      label: hyperekplexia 3
  genes:
  - preferred_term: SLC6A5
    term:
      id: hgnc:11051
      label: SLC6A5
  description: >-
    The presynaptic form, caused by variants in SLC6A5, which encodes the
    presynaptic glycine transporter GlyT2. Mostly recessive, with rare dominant
    alleles.
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  evidence:
  - reference: PMID:16751771
    reference_title: Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia."
    explanation: >-
      Establishes SLC6A5 as a hyperekplexia gene acting presynaptically, the
      concept MONDO numbers as hyperekplexia 3.
- name: HPX4
  display_name: Hyperekplexia 4 (ATAD1)
  subtype_term:
    preferred_term: hyperekplexia 4
    term:
      id: MONDO:0044330
      label: hyperekplexia 4
  genes:
  - preferred_term: ATAD1
    term:
      id: hgnc:25903
      label: ATAD1
  description: >-
    Biallelic ATAD1 variants cause a congenital syndrome of limb stiffness,
    absent spontaneous movement and hypoventilation that OMIM and MONDO number
    as hyperekplexia 4. Its molecular lesion is not glycinergic: ATAD1 encodes
    Thorase, an AAA+ ATPase that disassembles GRIP1-GluA2 complexes and so
    controls internalisation of excitatory AMPA receptors. The clinical
    delineation study that assembled all eight reported patients concludes that
    the entity is a distinct congenital encephalopathy rather than a form of
    hyperekplexia, so the subtype is carried here under the ontology's numbering
    with that divergence recorded rather than asserted as settled.
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:33134516
    reference_title: Congenital immobility and stiffness related to biallelic ATAD1 variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients 1 and 2 had a similar distinctive phenotype comprising congenital stiffness of limbs, absent spontaneous movements, weak sucking, and hypoventilation."
    explanation: >-
      Supports biallelic ATAD1 variants as the cause of this congenital
      stiffness syndrome, and describes the phenotype recorded in this row.
  - reference: PMID:33134516
    reference_title: Congenital immobility and stiffness related to biallelic ATAD1 variants.
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "Analysis of the phenotypes of these 2 patients and of the 6 previous cases showed that biallelic ATAD1 mutations are responsible for a unique congenital encephalopathy likely comprising absent BEAR, different from hyperekplexia and other conditions with neonatal hypertonia."
    explanation: >-
      Refutes the placement of this entity under hereditary hyperekplexia. The
      authors reviewed all eight reported patients and concluded the disorder is
      distinct from hyperekplexia, against the OMIM and MONDO numbering this row
      follows.
  - reference: PMID:29390050
    reference_title: A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Postsynaptically, Thorase controls the internalization of excitatory, glutamatergic AMPA receptors by disassembling complexes between the AMPA receptor-binding protein, GRIP1, and the AMPA receptor subunit GluA2."
    explanation: >-
      States the molecular role of the ATAD1 product, which is at the excitatory
      synapse rather than the glycinergic one, and so is why this subtype is
      wired to its own pathophysiology node.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "Autosomal dominant"
    explanation: Orphanet lists autosomal dominant inheritance for hereditary hyperekplexia.
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "Autosomal recessive"
    explanation: Orphanet lists autosomal recessive inheritance for hereditary hyperekplexia.
progression:
- phase: Neonatal or infantile onset
  age_range: Neonatal period to infancy
  notes: >-
    Symptoms typically begin in the neonatal period or infancy, and gene-positive
    cohorts can have recurrent apnea and developmental delay.
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "Age of onset: Neonatal"
    explanation: Orphanet records neonatal onset.
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "Age of onset: Infancy"
    explanation: Orphanet records infantile onset.
  - reference: PMID:24030948
    reference_title: "Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "all gene-positive cases present in the neonatal period (occasionally prenatally)"
    explanation: The 97-person genetically confirmed cohort supports neonatal presentation.
pathophysiology:
- name: Postsynaptic Glycine Receptor Chloride Channel Dysfunction
  description: >-
    GLRA1 and GLRB variants impair the postsynaptic inhibitory glycine receptor,
    a ligand-gated chloride channel that normally mediates rapid inhibitory
    signaling in the brainstem and spinal cord.
  genes:
  - preferred_term: GLRA1
    term:
      id: hgnc:4326
      label: GLRA1
  - preferred_term: GLRB
    term:
      id: hgnc:4329
      label: GLRB
  molecular_functions:
  - preferred_term: extracellularly glycine-gated chloride channel activity
    term:
      id: GO:0016934
      label: extracellularly glycine-gated chloride channel activity
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:8651283
    reference_title: "A GLRA1 null mutation in recessive hyperekplexia challenges the functional role of glycine receptors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dominant missense mutations in the human glycine receptor (GlyR) alpha 1 subunit gene (GLRA1) give rise to hereditary hyperekplexia."
    explanation: This establishes GLRA1 glycine receptor variants as a cause of hereditary hyperekplexia.
  - reference: PMID:8651283
    reference_title: "A GLRA1 null mutation in recessive hyperekplexia challenges the functional role of glycine receptors."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "These mutations impair agonist affinities and change conductance states of expressed mutant channels, resulting in a partial loss of function."
    explanation: Functional channel evidence supports reduced glycine receptor activity.
  - reference: PMID:11929858
    reference_title: "Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Following mutation analysis of the human beta-subunit of hGlyR (GLRB) in a cohort of 22 hyperekplexia patients, we provide evidence to confirm that GLRB mutations can cause human hyperekplexia."
    explanation: Human mutation analysis supports GLRB as a causal glycine receptor subunit gene.
  downstream:
  - target: Glycinergic Inhibitory Neurotransmission Failure
    causal_link_type: DIRECT
    description: Glycine receptor channel dysfunction reduces rapid inhibitory glycinergic signaling.
    evidence:
    - reference: PMID:11929858
      reference_title: "Hyperekplexia associated with compound heterozygote mutations in the beta-subunit of the human inhibitory glycine receptor (GLRB)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "These receptors facilitate fast-response, inhibitory glycinergic neurotransmission in the brainstem and spinal cord leading to a rapid modification and reduction of the excitatory startle response."
      explanation: The cited abstract directly links glycine receptor activity to inhibitory signaling that suppresses startle.
- name: Presynaptic Glycine Transporter Dysfunction
  description: >-
    SLC6A5 encodes the presynaptic glycine transporter GlyT2. Pathogenic variants
    reduce transporter localization or glycine uptake, limiting presynaptic
    glycine recycling needed for inhibitory synaptic transmission.
  genes:
  - preferred_term: SLC6A5
    term:
      id: hgnc:11051
      label: SLC6A5
  molecular_functions:
  - preferred_term: glycine transmembrane transporter activity
    term:
      id: GO:0015187
      label: glycine transmembrane transporter activity
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:16751771
    reference_title: "Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia."
    explanation: This directly supports SLC6A5 as a presynaptic cause of hyperekplexia.
  - reference: PMID:16751771
    reference_title: "Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites."
    explanation: Functional data support impaired GlyT2 localization and glycine uptake as the mechanism.
  - reference: PMID:22753417
    reference_title: "A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "This interaction impairs transporter maturation through the secretory pathway, reduces surface expression, and inhibits transport function."
    explanation: Functional GlyT2 evidence supports impaired trafficking and transport as a presynaptic mechanism.
  downstream:
  - target: Glycinergic Inhibitory Neurotransmission Failure
    causal_link_type: DIRECT
    description: Reduced GlyT2 function disrupts presynaptic glycine availability for inhibitory signaling.
    evidence:
    - reference: PMID:16751771
      reference_title: "Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "SLC6A5 mutations result in defective subcellular GlyT2 localization, decreased glycine uptake or both, with selected mutations affecting predicted glycine and Na+ binding sites."
      explanation: Reduced glycine uptake provides the presynaptic link to impaired glycinergic neurotransmission.
- name: Glycinergic Inhibitory Neurotransmission Failure
  description: >-
    Failure of glycinergic inhibition in brainstem and spinal startle circuits
    leaves excitatory startle reflex pathways insufficiently suppressed,
    producing excessive startle, stiffness, and related neuromotor features.
  biological_processes:
  - preferred_term: chemical synaptic transmission
    term:
      id: GO:0007268
      label: chemical synaptic transmission
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:23184146
    reference_title: "GLRB is the third major gene of effect in hyperekplexia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glycinergic neurotransmission is a major inhibitory influence in the CNS and its disruption triggers a paediatric and adult startle disorder, hyperekplexia."
    explanation: The abstract directly links disrupted glycinergic neurotransmission to hyperekplexia.
  - reference: PMID:8651283
    reference_title: "A GLRA1 null mutation in recessive hyperekplexia challenges the functional role of glycine receptors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The child displayed exaggerated startle responses and pronounced head-retraction jerks reflecting a disinhibition of vestigial brain-stem reflexes."
    explanation: This supports brainstem-reflex disinhibition as the clinical circuit consequence.
  downstream:
  - target: Exaggerated Startle Response
    causal_link_type: DIRECT
  - target: Hypertonia
    causal_link_type: DIRECT
  - target: Muscle Stiffness
    causal_link_type: DIRECT
  - target: Rigidity
    causal_link_type: DIRECT
  - target: Abnormality of Movement
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Myoclonus
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Fasciculations
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Hyperreflexia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Spasticity
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Neonatal Apnea Episodes
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Gait Disturbance
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Ataxia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Sleep Abnormality
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Developmental Delay
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Speech and Language Delay
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
  - target: Intellectual Disability
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
- name: Thorase-Dependent AMPA Receptor Trafficking Failure
  description: >-
    The one route into this entry that does not pass through the glycinergic
    synapse. ATAD1 encodes Thorase, an AAA+ ATPase that disassembles the complex
    between the AMPA-receptor-binding protein GRIP1 and the AMPA receptor subunit
    GluA2 and thereby controls postsynaptic internalisation of excitatory AMPA
    receptors. The reported biallelic allele locks Thorase in its oligomeric
    state, disassembly of the GluA2 complex is impaired, and knockout neurons
    expressing the mutant carry less GluA2 at the cell surface. The node is kept
    separate from the glycine receptor and glycine transporter nodes because the
    lesion is at the excitatory synapse, which is also why the clinical
    delineation study reads the resulting disorder as distinct from hyperekplexia.
  biological_scale: MOLECULAR
  genes:
  - preferred_term: ATAD1
    term:
      id: hgnc:25903
      label: ATAD1
  biological_processes:
  - preferred_term: regulation of postsynaptic AMPA receptor internalisation
    term:
      id: GO:0099149
      label: regulation of postsynaptic neurotransmitter receptor internalization
    modifier: ABNORMAL
  - preferred_term: disassembly of the GRIP1-GluA2 complex
    term:
      id: GO:0032984
      label: protein-containing complex disassembly
    modifier: DECREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:29390050
    reference_title: A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy.
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: BACKGROUND
    snippet: "Postsynaptically, Thorase controls the internalization of excitatory, glutamatergic AMPA receptors by disassembling complexes between the AMPA receptor-binding protein, GRIP1, and the AMPA receptor subunit GluA2."
    explanation: >-
      States the normal function this node records as failing, and locates it at
      the excitatory rather than the glycinergic synapse.
  - reference: PMID:29390050
    reference_title: A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Biochemical and cellular analyses show that the C-terminal end of Thorase mutant gained a novel function that strongly impacts its oligomeric state, reduces stability or expression of a set of Golgi, peroxisomal and mitochondrial proteins and affects disassembly of GluA2 and Thorase oligomer complexes."
    explanation: >-
      The measurement behind the impaired complex disassembly recorded on this
      node.
  - reference: PMID:29390050
    reference_title: A homozygous ATAD1 mutation impairs postsynaptic AMPA receptor trafficking and causes a lethal encephalopathy.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "reduced amount of GluA2 at the cell surface suggesting that the Thorase mutant may inhibit the recycling back and/or reinsertion of AMPA receptors to the plasma membrane"
    explanation: >-
      Neuronal readout of the trafficking failure, and the authors' own reading of
      which step is blocked.
  downstream:
  - target: Muscle Stiffness
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The reported patients present with congenital limb stiffness, but no step
      between the AMPA-receptor trafficking defect and the motor phenotype has
      been shown, so the edge is carried as indirect with the intermediates
      unknown.
    evidence:
    - reference: PMID:33134516
      reference_title: Congenital immobility and stiffness related to biallelic ATAD1 variants.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients 1 and 2 had a similar distinctive phenotype comprising congenital stiffness of limbs, absent spontaneous movements, weak sucking, and hypoventilation."
      explanation: >-
        Reports the stiffness phenotype in biallelic ATAD1 patients that this edge
        connects to the trafficking defect.
phenotypes:
- category: Neurological
  name: Exaggerated Startle Response
  description: Excessive startle responses are the defining neurologic manifestation.
  phenotype_term:
    preferred_term: Exaggerated startle response
    term:
      id: HP:0002267
      label: Exaggerated startle response
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "Hereditary hyperekplexia is a hereditary neurological disorder characterized by excessive startle responses."
    explanation: Orphanet defines hereditary hyperekplexia by excessive startle responses.
  - reference: PMID:16751771
    reference_title: "Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes."
    explanation: Human SLC6A5 cases directly support exaggerated tactile or acoustic startle.
- category: Neurological
  name: Ataxia
  frequency: VERY_FREQUENT
  description: Ataxia is listed by Orphanet as a very frequent neurologic manifestation.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0001251 | Ataxia | Very frequent (99-80%)"
    explanation: Orphanet lists ataxia as very frequent in hereditary hyperekplexia.
- category: Neurological
  name: Spasticity
  frequency: VERY_FREQUENT
  description: Spasticity is a very frequent motor feature.
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0001257 | Spasticity | Very frequent (99-80%)"
    explanation: Orphanet lists spasticity as very frequent.
- category: Neurological
  name: Hypertonia
  frequency: VERY_FREQUENT
  description: Hypertonia is part of the stiff-neonate presentation.
  phenotype_term:
    preferred_term: Hypertonia
    term:
      id: HP:0001276
      label: Hypertonia
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0001276 | Hypertonia | Very frequent (99-80%)"
    explanation: Orphanet lists hypertonia as very frequent.
  - reference: PMID:16751771
    reference_title: "Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes."
    explanation: Human SLC6A5 cases directly support hypertonia.
- category: Neurological
  name: Gait Disturbance
  frequency: FREQUENT
  description: Startle-related stiffness and stumbles can produce gait disturbance.
  phenotype_term:
    preferred_term: Gait disturbance
    term:
      id: HP:0001288
      label: Gait disturbance
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0001288 | Gait disturbance | Frequent (79-30%)"
    explanation: Orphanet lists gait disturbance as frequent.
- category: Neurological
  name: Myoclonus
  frequency: VERY_FREQUENT
  description: Myoclonus is a very frequent movement manifestation.
  phenotype_term:
    preferred_term: Myoclonus
    term:
      id: HP:0001336
      label: Myoclonus
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0001336 | Myoclonus | Very frequent (99-80%)"
    explanation: Orphanet lists myoclonus as very frequent.
- category: Neurological
  name: Hyperreflexia
  frequency: VERY_FREQUENT
  description: Hyperreflexia is a very frequent neurologic finding.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0001347 | Hyperreflexia | Very frequent (99-80%)"
    explanation: Orphanet lists hyperreflexia as very frequent.
- category: Musculoskeletal
  name: Joint Dislocation
  frequency: OCCASIONAL
  description: Joint dislocation is an occasional complication, likely related to severe stiffness or startle.
  phenotype_term:
    preferred_term: Joint dislocation
    term:
      id: HP:0001373
      label: Joint dislocation
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0001373 | Joint dislocation | Occasional (29-5%)"
    explanation: Orphanet lists joint dislocation as occasional.
- category: Musculoskeletal
  name: Joint Stiffness
  frequency: VERY_FREQUENT
  description: Joint stiffness accompanies the generalized stiff phenotype.
  phenotype_term:
    preferred_term: Joint stiffness
    term:
      id: HP:0001387
      label: Joint stiffness
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0001387 | Joint stiffness | Very frequent (99-80%)"
    explanation: Orphanet lists joint stiffness as very frequent.
- category: Gastrointestinal
  name: Umbilical Hernia
  frequency: FREQUENT
  description: Umbilical hernia is a frequent associated manifestation.
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0001537 | Umbilical hernia | Frequent (79-30%)"
    explanation: Orphanet lists umbilical hernia as frequent.
- category: Gastrointestinal
  name: Gastroesophageal Reflux
  frequency: VERY_FREQUENT
  description: Gastroesophageal reflux is a very frequent gastrointestinal manifestation.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0002020 | Gastroesophageal reflux | Very frequent (99-80%)"
    explanation: Orphanet lists gastroesophageal reflux as very frequent.
- category: Gastrointestinal
  name: Hiatus Hernia
  frequency: VERY_FREQUENT
  description: Hiatus hernia is a very frequent gastrointestinal-associated feature.
  phenotype_term:
    preferred_term: Hiatus hernia
    term:
      id: HP:0002036
      label: Hiatus hernia
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0002036 | Hiatus hernia | Very frequent (99-80%)"
    explanation: Orphanet lists hiatus hernia as very frequent.
- category: Neurological
  name: Rigidity
  frequency: VERY_FREQUENT
  description: Rigidity contributes to the stiff-baby presentation.
  phenotype_term:
    preferred_term: Rigidity
    term:
      id: HP:0002063
      label: Rigidity
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0002063 | Rigidity | Very frequent (99-80%)"
    explanation: Orphanet lists rigidity as very frequent.
- category: Sleep
  name: Sleep Abnormality
  frequency: FREQUENT
  description: Sleep abnormalities are frequent in Orphanet's phenotype table.
  phenotype_term:
    preferred_term: Sleep abnormality
    term:
      id: HP:0002360
      label: Sleep disturbance
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0002360 | Sleep abnormality | Frequent (79-30%)"
    explanation: Orphanet lists sleep abnormality as frequent.
- category: Neurological
  name: Fasciculations
  frequency: VERY_FREQUENT
  description: Fasciculations are listed as a very frequent neuromotor manifestation.
  phenotype_term:
    preferred_term: Fasciculations
    term:
      id: HP:0002380
      label: Fasciculations
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0002380 | Fasciculations | Very frequent (99-80%)"
    explanation: Orphanet lists fasciculations as very frequent.
- category: Musculoskeletal
  name: Hip Dislocation
  frequency: OCCASIONAL
  description: Hip dislocation is an occasional musculoskeletal complication.
  phenotype_term:
    preferred_term: Hip dislocation
    term:
      id: HP:0002827
      label: Hip dislocation
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0002827 | Hip dislocation | Occasional (29-5%)"
    explanation: Orphanet lists hip dislocation as occasional.
- category: Neurological
  name: Muscle Stiffness
  frequency: VERY_FREQUENT
  description: Muscle stiffness is a core component of the classic stiffness-startles-stumbles triad.
  phenotype_term:
    preferred_term: Muscle stiffness
    term:
      id: HP:0003552
      label: Muscle stiffness
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0003552 | Muscle stiffness | Very frequent (99-80%)"
    explanation: Orphanet lists muscle stiffness as very frequent.
  - reference: PMID:24030948
    reference_title: "Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to the characteristic 'stiffness, startles and stumbles' of hyperekplexia"
    explanation: The genetically confirmed cohort identifies stiffness as a characteristic feature.
- category: Neurological
  name: Abnormality of Movement
  frequency: VERY_FREQUENT
  description: Abnormal movement is a broad very frequent Orphanet phenotype category.
  phenotype_term:
    preferred_term: Abnormality of movement
    term:
      id: HP:0100022
      label: Abnormality of movement
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0100022 | Abnormality of movement | Very frequent (99-80%)"
    explanation: Orphanet lists abnormality of movement as very frequent.
- category: Gastrointestinal
  name: Esophagitis
  frequency: VERY_FREQUENT
  description: Esophagitis is a very frequent gastrointestinal manifestation.
  phenotype_term:
    preferred_term: Esophagitis
    term:
      id: HP:0100633
      label: Esophagitis
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0100633 | Esophagitis | Very frequent (99-80%)"
    explanation: Orphanet lists esophagitis as very frequent.
- category: Gastrointestinal
  name: Hernia
  frequency: FREQUENT
  description: Hernia is a frequent associated finding in Orphanet.
  phenotype_term:
    preferred_term: Hernia
    term:
      id: HP:0100790
      label: Hernia
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0100790 | Hernia | Frequent (79-30%)"
    explanation: Orphanet lists hernia as frequent.
- category: Respiratory
  name: Neonatal Apnea Episodes
  frequency: FREQUENT
  description: Recurrent apnea attacks are common, especially in SLC6A5-associated disease.
  phenotype_term:
    preferred_term: Apnea
    term:
      id: HP:0002104
      label: Apnea
    onset:
      onset_category: NEONATAL
  evidence:
  - reference: PMID:24030948
    reference_title: "Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "apnoea attacks (50 of 89) and delayed development (47 of 92) were frequently reported."
    explanation: The cohort reports apnea attacks in 50 of 89 individuals, supporting a frequent band.
  - reference: PMID:16751771
    reference_title: "Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Individuals with mutations in SLC6A5 present with hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life-threatening neonatal apnea episodes."
    explanation: SLC6A5 cases directly support neonatal apnea episodes.
- category: Neurodevelopmental
  name: Developmental Delay
  frequency: FREQUENT
  description: Developmental delay is frequent in gene-positive cohorts and enriched in GLRB and SLC6A5 cases.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:24030948
    reference_title: "Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "apnoea attacks (50 of 89) and delayed development (47 of 92) were frequently reported."
    explanation: The cohort reports delayed development in 47 of 92 individuals, supporting a frequent band.
  - reference: PMID:24030948
    reference_title: "Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with GLRB and SLC6A5 mutations were more likely to have developmental delay"
    explanation: Genotype-phenotype data support developmental delay particularly in GLRB and SLC6A5 disease.
  - reference: PMID:22753417
    reference_title: "A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In addition to classical hyperekplexia symptoms, some individuals had abnormal respiration, facial dysmorphism, delayed motor development, or intellectual disability."
    explanation: The dominant GlyT2 family report supports delayed motor development among SLC6A5-associated presentations.
- category: Neurodevelopmental
  name: Speech and Language Delay
  frequency: OCCASIONAL
  description: >-
    Delayed speech acquisition is a genotype-enriched neurodevelopmental feature,
    particularly in GLRB-associated hyperekplexia.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:24030948
    reference_title: "Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "61 cases had mutations in GLRA1, 24 cases in SLC6A5 and 12 in GLRB."
    explanation: The cohort denominator supports interpreting GLRB-specific speech delay as a minority overall phenotype.
  - reference: PMID:24030948
    reference_title: "Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "92% of GLRB cases reported a mild to severe delay in speech acquisition."
    explanation: Genotype-phenotype data directly support delayed speech acquisition in GLRB-associated hyperekplexia.
- category: Neurological
  name: Seizure
  frequency: OCCASIONAL
  description: Seizures are an occasional neurologic manifestation.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0001250 | Seizure | Occasional (29-5%)"
    explanation: Orphanet lists seizure as occasional.
- category: Neurodevelopmental
  name: Intellectual Disability
  frequency: OCCASIONAL
  description: Intellectual disability is an occasional associated neurodevelopmental feature.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "HP:0001249 | Intellectual disability | Occasional (29-5%)"
    explanation: Orphanet lists intellectual disability as occasional.
genetic:
- name: GLRA1 Pathogenic Variants
  association: Pathogenic Variants
  subtype: HPX1
  case_fractions:
  - population: Swansea international hyperekplexia referral series, gene-confirmed cases
    case_fraction_percent: 62.9
    cohort_size: 97
    notes: >-
      61 of the 97 gene-confirmed cases in this series. The series reports counts
      rather than percentages; the percentage here is that count over 97.
    evidence:
    - reference: PMID:24030948
      reference_title: "Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "61 cases had mutations in GLRA1, 24 cases in SLC6A5 and 12 in GLRB."
      explanation: Reports the per-gene case counts behind this share.
  gene_term:
    preferred_term: GLRA1
    term:
      id: hgnc:4326
      label: GLRA1
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  features: >-
    GLRA1 encodes the alpha 1 subunit of the inhibitory glycine receptor.
    Dominant missense variants and recessive loss-of-function alleles have been
    reported in hereditary hyperekplexia.
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "GLRA1 | glycine receptor alpha 1 | hgnc:4326 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists GLRA1 as a disease-causing gene for hereditary hyperekplexia.
  - reference: PMID:8651283
    reference_title: "A GLRA1 null mutation in recessive hyperekplexia challenges the functional role of glycine receptors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dominant missense mutations in the human glycine receptor (GlyR) alpha 1 subunit gene (GLRA1) give rise to hereditary hyperekplexia."
    explanation: Human genetic evidence supports dominant GLRA1-associated disease.
  - reference: PMID:8651283
    reference_title: "A GLRA1 null mutation in recessive hyperekplexia challenges the functional role of glycine receptors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In a recessive case of hyperekplexia, we found a deletion of exons 1-6 of the GLRA1 gene."
    explanation: This supports recessive GLRA1-associated hyperekplexia.
- name: GLRB Pathogenic Variants
  association: Pathogenic Variants
  subtype: HPX2
  case_fractions:
  - population: Swansea international hyperekplexia referral series, gene-confirmed cases
    case_fraction_percent: 12.4
    cohort_size: 97
    notes: >-
      12 of the 97 gene-confirmed cases in this series. The series reports counts
      rather than percentages; the percentage here is that count over 97.
    evidence:
    - reference: PMID:24030948
      reference_title: "Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "61 cases had mutations in GLRA1, 24 cases in SLC6A5 and 12 in GLRB."
      explanation: Reports the per-gene case counts behind this share.
  gene_term:
    preferred_term: GLRB
    term:
      id: hgnc:4329
      label: GLRB
  inheritance:
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  features: >-
    GLRB encodes the beta subunit of the inhibitory glycine receptor. Both
    recessive and dominant GLRB variants are reported in hyperekplexia, with
    long-term additive outcomes including apnea and developmental delay.
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "GLRB | glycine receptor beta | hgnc:4329 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists GLRB as a disease-causing gene for hereditary hyperekplexia.
  - reference: PMID:23184146
    reference_title: "GLRB is the third major gene of effect in hyperekplexia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The screening identified recessive and dominant GLRB variants in 12 unrelated hyperekplexia probands."
    explanation: Human cohort data support both recessive and dominant GLRB-associated disease.
- name: SLC6A5 Pathogenic Variants
  association: Pathogenic Variants
  subtype: HPX3
  case_fractions:
  - population: Swansea international hyperekplexia referral series, gene-confirmed cases
    case_fraction_percent: 24.7
    cohort_size: 97
    notes: >-
      24 of the 97 gene-confirmed cases in this series. The series reports counts
      rather than percentages; the percentage here is that count over 97.
    evidence:
    - reference: PMID:24030948
      reference_title: "Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "61 cases had mutations in GLRA1, 24 cases in SLC6A5 and 12 in GLRB."
      explanation: Reports the per-gene case counts behind this share.
  gene_term:
    preferred_term: SLC6A5
    term:
      id: hgnc:11051
      label: SLC6A5
  inheritance:
  - name: Autosomal recessive
    inheritance_term:
      preferred_term: Autosomal recessive inheritance
      term:
        id: HP:0000007
        label: Autosomal recessive inheritance
  - name: Autosomal dominant
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
  features: >-
    SLC6A5 encodes GlyT2, the presynaptic glycine transporter. Pathogenic
    variants reduce transporter function and are associated with recessive and
    rare dominant disease with a challenging phenotype that can include
    recurrent neonatal apnea and developmental delay.
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "SLC6A5 | solute carrier family 6 member 5 | hgnc:11051 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists SLC6A5 as a disease-causing gene for hereditary hyperekplexia.
  - reference: PMID:16751771
    reference_title: "Mutations in the gene encoding GlyT2 (SLC6A5) define a presynaptic component of human startle disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we show that missense, nonsense and frameshift mutations in SLC6A5 (ref. 8), encoding the presynaptic glycine transporter 2 (GlyT2), also cause hyperekplexia."
    explanation: Human genetic evidence supports SLC6A5 as a presynaptic disease gene.
  - reference: PMID:22753417
    reference_title: "A novel dominant hyperekplexia mutation Y705C alters trafficking and biochemical properties of the presynaptic glycine transporter GlyT2."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, systematic DNA sequencing of SLC6A5 revealed a new dominant GlyT2 mutation"
    explanation: This family study supports rare dominant SLC6A5-associated hyperekplexia.
- name: GPHN Pathogenic Variants
  association: Pathogenic Variants
  gene_term:
    preferred_term: GPHN
    term:
      id: hgnc:15465
      label: GPHN
  features: >-
    GPHN encodes gephyrin, the postsynaptic scaffolding protein that clusters
    inhibitory glycine and GABA-A receptors, so the gene sits squarely in the
    pathway this disease disrupts. Its status as a hyperekplexia gene is weak
    rather than established: the one mutation screen to report a candidate found
    a single missense allele in a single patient, and the accompanying functional
    test showed that allele did not disrupt glycine-receptor binding to gephyrin
    or collybistin-induced surface clustering. The row is retained as a
    gene-level association because Orphanet lists it, with the contradicting
    functional result recorded beside it.
  notes: >-
    No MONDO class denotes a GPHN form of hyperekplexia. Searched
    synonym-inclusive with `runoak -i ols:mondo search "GPHN"` (one hit,
    MONDO:0044792 large congenital melanocytic nevus, unrelated) and
    `runoak -i ols:mondo search "gephyrin"` (no hits), so this gene has no
    subtype row and no `subtype_term` to bind.
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "GPHN | gephyrin | hgnc:15465 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists GPHN as a disease-causing gene for hereditary hyperekplexia.
  - reference: PMID:12684523
    reference_title: "Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor, and mutation analysis in hyperekplexia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation analysis of GPHN exons in hyperekplexia patients revealed a missense mutation (A28T) in one patient causing an amino acid substitution (N10Y)."
    explanation: >-
      The only reported GPHN candidate allele in a hyperekplexia patient, and the
      basis of the gene's listing. A single patient is the whole genetic evidence.
  - reference: PMID:12684523
    reference_title: "Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor, and mutation analysis in hyperekplexia."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "Functional testing demonstrated that GPHNN10Y does not disrupt GlyR-gephyrin interactions or collybistininduced cell-surface clustering."
    explanation: >-
      Refutes pathogenicity of that one allele by the mechanism it would have to
      act through. Quoted verbatim, including the two word-joins the cached text
      carries where the source set GPHN-N10Y and collybistin-induced with
      formatting this extraction dropped.
- name: ATAD1 Pathogenic Variants
  association: Pathogenic Variants
  subtype: HPX4
  gene_term:
    preferred_term: ATAD1
    term:
      id: hgnc:25903
      label: ATAD1
  features: >-
    ATAD1 encodes Thorase, an AAA+ ATPase that disassembles GRIP1-GluA2 complexes
    and so controls internalisation of excitatory AMPA receptors. Biallelic
    variants cause the congenital stiffness and immobility syndrome numbered
    hyperekplexia 4, which is the one gene in this entry whose lesion is not in
    the glycinergic synapse; the delineation study of all eight reported patients
    concludes the entity is distinct from hyperekplexia.
  evidence:
  - reference: ORPHA:3197
    reference_title: "Hereditary hyperekplexia"
    supports: SUPPORT
    snippet: "ATAD1 | ATPase family AAA domain containing 1 | hgnc:25903 | Disease-causing germline mutation(s) in"
    explanation: Orphanet lists ATAD1 as a disease-causing gene for hereditary hyperekplexia.
diagnosis:
- name: Molecular Genetic Testing
  description: >-
    Molecular genetic testing confirms the diagnosis in symptomatic neonates and
    supports counseling for families at risk, especially where GLRB or SLC6A5
    variants are suspected.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:24030948
    reference_title: "Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ninety-seven individuals had a clinical diagnosis of hyperekplexia confirmed by genetic testing"
    explanation: The cohort used genetic testing to confirm clinical hyperekplexia diagnoses.
  - reference: PMID:24030948
    reference_title: "Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We recommend early genetic testing for symptomatic neonates and possibly preconception counselling for those at risk for GLRB and SLC6A5 mutations"
    explanation: The authors recommend early genetic testing for symptomatic neonates.
treatments:
- name: Clonazepam
  description: >-
    Clonazepam is the standard symptomatic pharmacotherapy for hyperekplexia,
    reducing excessive startle and stiffness in most treated genetically
    confirmed patients.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: clonazepam
      term:
        id: CHEBI:3756
        label: clonazepam
  target_mechanisms:
  - target: Glycinergic Inhibitory Neurotransmission Failure
    treatment_effect: MODULATES
    description: Clonazepam increases inhibitory tone symptomatically rather than correcting the causal gene defect.
  evidence:
  - reference: PMID:24030948
    reference_title: "Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "clonazepam is the treatment of choice (95% found it to be efficacious)."
    explanation: The genetically confirmed cohort reports clonazepam efficacy in nearly all treated patients.
references:
- reference: PMID:20301437
  title: Hereditary Hyperekplexia Overview.
  tags:
  - GeneReviews
  findings: []
📚

References & Deep Research

References

1
PMID:20301437
Hereditary Hyperekplexia Overview.
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.

Asta ▸
Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Hereditary Hyperekplexia. Core disease mechanisms, molecular and cellular...
Asta Scientific Corpus Retrieval 20 citations 2026-05-10T12:28:49.216990

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Hereditary Hyperekplexia. Core disease mechanisms, molecular and cellular...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] A Novel Dominant Hyperekplexia Mutation Y705C Alters Trafficking and Biochemical Properties of the Presynaptic Glycine Transporter GlyT2*

  • Authors: C. Giménez, G. Perez-siles, Jaime Martínez-Villarreal, Esther Arribas-González, E. Jiménez et al.
  • Year: 2012
  • Venue: The Journal of Biological Chemistry
  • URL: https://www.semanticscholar.org/paper/f78196744b4d80d8b28460c2906665029f69ccc9
  • DOI: 10.1074/jbc.M111.319244
  • PMID: 22753417
  • Citations: 41
  • Influential citations: 1
  • Summary: This study revealed a new dominant GlyT2 mutation pY705C (c.2114A→G) in transmembrane domain 11, in eight individuals from Spain and the United Kingdom, and functionally characterized this mutation using molecular modeling, electrophysiology, [3H]glycine transport, cell surface expression, and cysteine labeling assays.
  • Evidence snippets:
  • Snippet 1 (score: 0.432) > Background: Hyperekplexia or startle disease is caused by defects in glycinergic transmission. Results: A new mutation pY705C in the glycine transporter GlyT2 alters protein trafficking and H+ and Zn2+ transport modulation. Conclusion: Multiple pathogenic mechanisms may contribute to the complex phenotype of individuals with the Y705C mutation. Significance: This is the first common dominant mutation associated with hyperekplexia affecting the presynaptic glycine transporter GlyT2. Hyperekplexia or startle disease is characterized by an exaggerated startle response, evoked by tactile or auditory stimuli, producing hypertonia and apnea episodes. Although rare, this orphan disorder can have serious consequences, including sudden infant death. Dominant and recessive mutations in the human glycine receptor (GlyR) α1 gene (GLRA1) are the major cause of this disorder. However, recessive mutations in the presynaptic Na+/Cl−-dependent glycine transporter GlyT2 gene (SLC6A5) are rapidly emerging as a second major cause of startle disease. In this study, systematic DNA sequencing of SLC6A5 revealed a new dominant GlyT2 mutation: pY705C (c.2114A→G) in transmembrane domain 11, in eight individuals from Spain and the United Kingdom. Curiously, individuals harboring this mutation show significant variation in clinical presentation. In addition to classical hyperekplexia symptoms, some individuals had abnormal respiration, facial dysmorphism, delayed motor development, or intellectual disability. We functionally characterized this mutation using molecular modeling, electrophysiology, [3H]glycine transport, cell surface expression, and cysteine labeling assays. We found that the introduced cysteine interacts with the cysteine pair Cys-311–Cys-320 in the second external loop of GlyT2. This interaction impairs transporter maturation through the secretory pathway, reduces surface expression, and inhibits transport function. Additionally, Y705C presents altered H+ and Zn2+ dependence of glycine transport that may affect the function of glycinergic neurotrans

[2] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

  • Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
  • Year: 2025
  • Venue: Journal of Veterinary Internal Medicine
  • URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
  • DOI: 10.1111/jvim.70139
  • PMID: 40492724
  • PMCID: 12150350
  • Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.419) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[3] A Journey through Huntington's Disease: Exploring Genetics, Neurobiology, and Therapeutic Advances

  • Authors: Sandeep Dey, Shreyas Katta, S. Suresh, Janhvi Mishra
  • Year: 2024
  • Venue: International Journal For Multidisciplinary Research
  • URL: https://www.semanticscholar.org/paper/735574648bec278cf15dc25fd5f1d735afaf6ae6
  • DOI: 10.36948/ijfmr.2024.v06i03.19194
  • Summary: The clinical features, ethics, and neurobiology of HD are discussed and the exciting approaches being employed today to advance understanding of underlying mechanisms in an effort to develop therapies that would delay the onset and slow progression of this disease are reviewed.
  • Evidence snippets:
  • Snippet 1 (score: 0.417) > Also, we present a modern view on the molecular biology of HD as a representative of the group of polyglutamine diseases, with an emphasis on conformational changes of mutant huntingtin, disturbances in its cellular processing, and proteolytic stress in degenerating neurons. > The main pathogenetic mechanisms of neurodegeneration in HD are discussed in detail, such as autophagy, impaired mitochondrial biogenesis, lysosomal dysfunction, organelle and protein transport, inflammation, oxidative stress, and transcription factor modulation. However, other unravelling mechanisms are still unknown. This practical and brief review summarises some of the currently known functions of the wild-type huntingtin protein and the recent findings related to the mechanisms involved in HD pathogenesis. Cellular mechanisms implicated in HD pathogenesis: The major mechanisms associated with HD pathogenesis are depicted here. The schematic shows a presynaptic neuron and a postsynaptic neuron flanked by two astrocytes. Huntingtin gene(HTT) itself is depicted as a "solenoid," based on the presumed folding due to its HEAT repeats. The mechanisms depicted are multimerization of mHtt-containing complexes, transcriptional modulation, ER-Golgi stress pathways, mitochondria and energy homeostasis, microtubular dynamics, endocytic and vesicular trafficking dynamics, autophagy, and synaptic signalling mechanisms. mHTT(mutant HTT protein). Traditionally, therapeutic approaches to HD have included compounds developed for psychiatric indications based on the affected neuronal circuitry: the frontal and motor corticostriatal circuits. None of these were initially developed for the treatment of HD. In this review we focus on the cellular and biological pathways affected by mutant HTT (mHTT) and the current status of associated drug discovery efforts. We also emphasise the need for further clinical research to validate existing hypotheses, which are mostly derived from animal studies and postmortem human tissues. It is generally accepted that most candidate therapeutics fail due to lack of efficacy in pivotal clinical studies.

[4] Direct Sarcomere Modulators Are Promising New Treatments for Cardiomyopathies

  • Authors: O. Tsukamoto
  • Year: 2019
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/07467943fe92ce135b52ded5e5dea2bfc2ddf179
  • DOI: 10.3390/ijms21010226
  • PMID: 31905684
  • PMCID: 6982115
  • Citations: 16
  • Summary: The direct inhibition of sarcomere contractility may be able to suppress the development and progression of HCM with hypercontractile mutations and improve clinical parameters in patients with HCM, and direct activation of sar COMs modulators that can positively influence the natural history of cardiomyopathies represent promising treatment options.
  • Evidence snippets:
  • Snippet 1 (score: 0.414) > Hereditary DCM can be caused by single point mutations in sarcomere proteins. However, the link between point mutations and clinical phenotypes in DCM is not thoroughly understood in most cases. Recent advances in biochemical, biophysical, stem cell, and gene editing technologies have provided a better understanding of the molecular mechanisms through which the initial insult in DCM (i.e., mutations in a sarcomere protein) induces alterations in cellular organization and contractility, resulting in disease phenotypes. In particular, hiPSC-CMs and genetically modified animals are excellent models because they can capture the initial molecular phenotype that occurs before major compensatory mechanisms mask it.

[5] Excessive Startle with Novel GLRA1 Mutations in 4 Chinese Patients and a Literature Review of GLRA1-Related Hyperekplexia

  • Authors: Fei-xia Zhan, Chaoyan Zhang, Shige Wang, Zeyu Zhu, Guang Chen et al.
  • Year: 2020
  • Venue: Journal of Clinical Neurology (Seoul, Korea)
  • URL: https://www.semanticscholar.org/paper/a8d84d4ba70e71f44456d7da28f847e0464f2f7a
  • DOI: 10.3988/jcn.2020.16.2.230
  • PMID: 32319239
  • PMCID: 7174104
  • Citations: 9
  • Summary: Hyperekplexia is a treatable disease, and clonazepam is the drug of choice, and the possible pathogenic mechanisms are discussed to enhance the understanding and recognition of the disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.413) > Background and Purpose Hyperekplexia (HPX), a rare neurogenetic disorder, is classically characterized by neonatal hypertonia, exaggerated startle response provoked by the sudden external stimuli and followed by a shortly general stiffness. Glycine receptor alpha 1 (GLRA1) is the major pathogenic gene of the disease. We described the clinical manifestations of genetically confirmed HPX patients and made a literature review of GLRA1-related HPX to improve the early recognition and prompt the management of the disorder. Methods Extensive clinical evaluations were analyzed in 4 Chinese HPX patients from two unrelated families. Next generation sequencing was conducted in the probands. Sanger sequence and segregation analysis were applied to confirm the findings. Results All four patients including 3 males and 1 female presented with excessive startle reflex, a cautious gait and recurrent falls. Moreover, startle episodes were dramatically improved with the treatment of clonazepam in all cases. Exome sequencing revealed 2 homozygous GLRA1 mutations in the patients. The mutation c.1286T>A p.I429N has been previously reported, while c.754delC p.L252* is novel. Conclusions HPX is a treatable disease, and clonazepam is the drug of choice. By studying and reviewing the disorder, we summarized the phenotype, expanded the genotype spectrum, and discussed the possible pathogenic mechanisms to enhance the understanding and recognition of the disease. Early awareness of the disease is crucial to the prompt and proper administration, as well as the genetic counseling.

[6] 18O-assisted dynamic metabolomics for individualized diagnostics and treatment of human diseases

  • Authors: E. Nemutlu, Song Zhang, N. Juranic, A. Terzic, S. Macura et al.
  • Year: 2012
  • Venue: Croatian Medical Journal
  • URL: https://www.semanticscholar.org/paper/880f053c7f060db4b990e447d0a22c4b69372ddb
  • DOI: 10.3325/cmj.2012.53.529
  • PMID: 23275318
  • PMCID: 3541579
  • Citations: 28
  • Summary: The potential use of dynamic phosphometabolomic platform for disease diagnostics currently under development at Mayo Clinic is described and discussed briefly.
  • Evidence snippets:
  • Snippet 1 (score: 0.410) > Living cells represent an integrated and interacting network of genes, transcripts, proteins, small signaling molecules, and metabolites that define cellular phenotype and function. Traditionally the focus of biomedical research was on individual genes, single protein targets, single metabolites, and metabolic or signaling pathways. This "molecular reductionist" paradigm was based on the assumption that identifying genetic variations and molecular components would lead to discovery of cures for human diseases. However, most of diseases are complex and multi-factorial and the disease phenotype is determined by the alterations of multiple genes, pathways, proteins and metabolites (at cellular, tissue, and organismal levels). Therefore, an integrated "omics" approach is more viable direction for uncovering alterations in metabolic networks, disease mechanisms, and mechanisms of drug effects. > Recent advent of large-scale metabolomics and fluxomic (metabolite dynamics and metabolic flux analysis) completed the "omics revolution" (Figure 1), where genomics, transcriptomics, proteomics, metabolomics, and fluxomics all together complement phenotype determination of living organism. Such integrated "omics" cascades provide a framework for advances in system and network biology, integrative physiology, and system medicine as well as system pharmacology and regenerative medicine. Noteworthy is the "reverse omic" approach or "metabolomicsinformed pharmacogenomics, " where discovery of specific metabolite changes have led to discovery of genetic alterations (2). Therefore, bringing new "omics" technologies to clinical practice will improve disease diagnostics and treatment by targeting drugs and procedures for each unique transcriptomic and metabolomic profiles.

[7] Therapies for Mitochondrial Disease: Past, Present, and Future

  • Authors: Megan Ball, Nicole J. Van Bergen, A. Compton, David R. Thorburn, S. Rahman et al.
  • Year: 2025
  • Venue: Journal of Inherited Metabolic Disease
  • URL: https://www.semanticscholar.org/paper/196ee50a950f29bc4134cfb8fe6bdfa9a3a1468b
  • DOI: 10.1002/jimd.70065
  • PMID: 40714961
  • PMCID: 12301291
  • Citations: 4
  • Summary: The latest developments in the pursuit to identify effective treatments for mitochondrial disease are examined and the barriers impeding their success in translation to clinical practice are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.408) > Mitochondrial disease is a diverse group of clinically and genetically complex disorders caused by pathogenic variants in nuclear or mitochondrial DNA‐encoded genes that disrupt mitochondrial energy production or other important mitochondrial pathways. Mitochondrial disease can present with a wide spectrum of clinical features and can often be difficult to recognize. These conditions can be devastating; however, for the majority, there is no targeted treatment. In the last 60 years, mitochondrial medicine has experienced significant evolution, moving from the pre‐molecular era to the Age of Genomics in which considerable gene discovery and advancement in our understanding of the pathophysiology of mitochondrial disease have been made. In the last decade, in response to the urgent need for effective treatments, a wide range of emerging therapies have been developed, driven by innovative approaches addressing both the genetic and cellular mechanisms underpinning the diseases. Emerging therapies include dietary intervention, small molecule therapies aimed to restore mitochondrial function, stem cell or liver transplantation, and gene or RNA‐based therapies. However, despite these advances, translation to clinical practice is complicated by the sheer genetic and clinical complexity of mitochondrial disease, difficulty in efficient and precise delivery of therapies to affected tissues, rarity of individual genetic conditions, lack of reliable biomarkers and clinically relevant outcome measures, and the dearth of natural history data. This review examines the latest developments in the pursuit to identify effective treatments for mitochondrial disease and discusses the barriers impeding their success in translation to clinical practice. While treatment for mitochondrial disease may be on the horizon, many challenges must be addressed before it can become a reality.

[8] Exome sequencing and metabolomic analysis of a chronic kidney disease and hearing loss patient family revealed RMND1 mutation induced sphingolipid metabolism defects

  • Authors: Nagwa Gaboon, B. Banaganapalli, K. Nasser, M. Razeeth, Mosab S. Alsaedi et al.
  • Year: 2019
  • Venue: Saudi Journal of Biological Sciences
  • URL: https://www.semanticscholar.org/paper/f1f1341fd61e31f39a5129e7c80ff67cd0b6fb0f
  • DOI: 10.1016/j.sjbs.2019.10.001
  • PMID: 31889854
  • PMCID: 6933272
  • Citations: 17
  • Influential citations: 1
  • Summary: Genetic defects in RMND1 gene alters the mitochondrial energy metabolism leading to the accumulation of ceramide, and subsequently promote dysregulated apoptosis and tissue necrosis in kidneys, this study suggests.
  • Evidence snippets:
  • Snippet 1 (score: 0.407) > One of the recently identified nuclear genes involved in mitochondrial respiratory chain deficiencies is RMND1 (Required for Meiotic Nuclear Division protein 1) (Garcia-Diaz et al., 2012;Janer et al., 2012). It has been demonstrated that various novel and common recessive mutations in RMND1 are associated with multiple phenotypes characterized by delayed maturation of vision, developmental delay, dilated cardiomyopathy, deafness and neurological defects (Gupta et al., 2016), renal tubular acidosis type 4 presented as hyponatraemia and hyperkalaemia and cystic/hypoplastic kidneys (Ng et al., 2016). Likewise, complex clinical spectrum of patients with RMND1 mutations is emerging with infantile encephalomyopathy with lactic acidosis (Garcia-Diaz et al., 2012;Casey et al., 2016) to a less severe form of developmental delay, hypotonia, renal disease and congenital sensorineural deafness (Janer et al., 2015). Therefore, molecular screening of RMND1 gene will help identify the inheritance mode of causative genetic mutations in patients with renal and or neurological defects. > MIDs have complex etiologies with underlying cross talk of inter and intra molecular signaling. Hence, metabolomic studies on these patients could provide a better understanding of the interconnectivity between genetic and molecular networks (Davies, 2018). Metabolomic profiling examines the metabolic changes in body fluids driven from cellular processes to understand the onset and pathogenesis of disease phenotype (Abbiss et al., 2019). Metabolomics analyzes metabolites by either targeted or untargeted approaches. The untargeted approach involves hypothesis free surveying of hundreds of thousands of small molecule metabolites for discovering novel mechanisms or pathways, whereas the targeted one refers to measuring predefined sets of metabolites, typically focusing on a few pathways of interest (Kalim and Rhee, 2017). The specific relationship between inherited mutations in mitochondrial proteins and their functional impacts in terms of metabolic defects in chronic kidney disease (CKD) is not yet well characterized.

[9] Rare Monogenic Diseases: Molecular Pathophysiology and Novel Therapies

  • Authors: I. Condò
  • Year: 2022
  • Venue: International Journal of Molecular Sciences
  • URL: https://www.semanticscholar.org/paper/6aece75e6947f102b657851b74e8b96df5e654c1
  • DOI: 10.3390/ijms23126525
  • PMID: 35742964
  • PMCID: 9223693
  • Citations: 18
  • Influential citations: 2
  • Summary: A rare disease is defined by its low prevalence in the general population and its presence in a very small number of people.
  • Evidence snippets:
  • Snippet 1 (score: 0.402) > The selective expression or the particular role of specific genes in a single tissue explains the appearance of organ-specific inherited diseases. This is the case of genetic disorders of the kidney, which include dominant and recessive forms of cystic diseases, and renal tubulopathies. Mutations in polycystin-1 (PKD1) or -2 (PKD2) genes lead to autosomaldominant polycystic kidney disease (ADPKD), whose gender-dependent phenotype was analyzed in the study by Talbi et al. [9]. These results, obtained in mice lacking PKD1 expression, show the involvement of intracellular Ca2+ levels in the more severe phenotype affecting male ADPKD animals. Altogether, identification of the molecular mechanisms underlying enhanced Ca2+ signaling and proliferation in cells from male kidneys may contribute to develop novel therapeutics for ADPKD [9]. The autosomal-recessive form of polycystic kidney disease (ARPKD) mostly arises from defects in the gene named polycystic kidney and hepatic disease 1 (PKHD1), whereas a minority of cases is linked to a second causative gene DZIP1L. To examine the still unclear molecular pathophysiology of ARPKD, Cordido et al. recapitulate known molecular disease mechanisms and possible therapeutic approaches, from cellular and animal models to clinical trials [10]. The knowledge of ARPKD pathogenic pathways, involving the epidermal growth factor receptor (EGFR) axis, the production of adenylyl cyclase adenosine 3 ,5 -cyclic monophosphate (cAMP) and the activation of several protein kinases, begins to stimulate possible pharmacological interventions [10]. Inherited loss of function in various electrolyte transport proteins located along the nephron leads to two types of kidney tubulopathy with overlapping clinical symptoms: Gitelman and Bartter syndromes. The review by Nuñez-Gonzalez et al. aims to explain the different molecular basis of these difficult to diagnose monogenic syndromes. Moreover, the authors provide an overview of current therapeutic approaches and highlight the presence of common and specific options for Gitelman and Bartter patients [11].

[10] Precision Therapeutics in Lennox–Gastaut Syndrome: Targeting Molecular Pathophysiology in a Developmental and Epileptic Encephalopathy

  • Authors: Debopam Samanta
  • Year: 2025
  • Venue: Children
  • URL: https://www.semanticscholar.org/paper/455479c1bfbea7b90b73c109228f67c813d13888
  • DOI: 10.3390/children12040481
  • PMID: 40310132
  • PMCID: 12025602
  • Citations: 19
  • Influential citations: 1
  • Summary: A narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies, receptor and ligand dysfunction, receptor and ligand dysfunction, cell signaling abnormalities, cell signaling abnormalities, synaptopathies, and the repurposing of existing medications with mechanism-specific effects.
  • Evidence snippets:
  • Snippet 1 (score: 0.401) > Lennox–Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by multiple drug-resistant seizure types, cognitive impairment, and distinctive electroencephalographic patterns. Current treatments primarily focus on symptom management through antiseizure medications (ASMs), dietary therapy, epilepsy surgery, and neuromodulation, but often fail to address the underlying pathophysiology or improve cognitive outcomes. As genetic causes are identified in 30–40% of LGS cases, precision therapeutics targeting specific molecular mechanisms are emerging as promising disease-modifying approaches. This narrative review explores precision therapeutic strategies for LGS based on molecular pathophysiology, including channelopathies (SCN2A, SCN8A, KCNQ2, KCNA2, KCNT1, CACNA1A), receptor and ligand dysfunction (GABA/glutamate systems), cell signaling abnormalities (mTOR pathway), synaptopathies (STXBP1, IQSEC2, DNM1), epigenetic dysregulation (CHD2), and CDKL5 deficiency disorder. Treatment modalities discussed include traditional ASMs, dietary therapy, targeted pharmacotherapy, antisense oligonucleotides, gene therapy, and the repurposing of existing medications with mechanism-specific effects. Early intervention with precision therapeutics may not only improve seizure control but could also potentially prevent progression to LGS in susceptible populations. Future directions include developing computable phenotypes for accurate diagnosis, refining molecular subgrouping, enhancing drug development, advancing gene-based therapies, personalizing neuromodulation, implementing adaptive clinical trial designs, and ensuring equitable access to precision therapeutic approaches. While significant challenges remain, integrating biological insights with innovative clinical strategies offers new hope for transforming LGS treatment from symptomatic management to targeted disease modification.

[11] The contribution of genetic determinants of blood gene expression and splicing to molecular phenotypes and health outcomes

  • Authors: A. Tokolyi, E. Persyn, A. Nath, K. Burnham, J. Marten et al.
  • Year: 2025
  • Venue: Nature Genetics
  • URL: https://www.semanticscholar.org/paper/5435e12fd796fca6db2c0ce1844b6fc252d2d73e
  • DOI: 10.1038/s41588-025-02096-3
  • PMID: 40038547
  • PMCID: 11906350
  • Citations: 14
  • Summary: This study mapped blood gene expression and splicing quantitative trait loci and uncovered gene-regulatory mechanisms at disease loci with therapeutic implications, such as WARS1 in hypertension, IL7R in dermatitis and IFNAR2 in COVID-19.
  • Evidence snippets:
  • Snippet 1 (score: 0.400) > The biological mechanisms through which most nonprotein-coding genetic variants affect disease risk are unknown. To investigate gene-regulatory mechanisms, we mapped blood gene expression and splicing quantitative trait loci (QTLs) through bulk RNA sequencing in 4,732 participants and integrated protein, metabolite and lipid data from the same individuals. We identified cis-QTLs for the expression of 17,233 genes and 29,514 splicing events (in 6,853 genes). Colocalization analyses revealed 3,430 proteomic and metabolomic traits with a shared association signal with either gene expression or splicing. We quantified the relative contribution of the genetic effects at loci with shared etiology, observing 222 molecular phenotypes significantly mediated by gene expression or splicing. We uncovered gene-regulatory mechanisms at disease loci with therapeutic implications, such as WARS1 in hypertension, IL7R in dermatitis and IFNAR2 in COVID-19. Our study provides an open-access resource on the shared genetic etiology across transcriptional phenotypes, molecular traits and health outcomes in humans (https://IntervalRNA.org.uk). > The majority of genetic variants associated with common diseases and other complex traits identified through genome-wide association studies (GWAS) lie in nonprotein-coding sequences 1 . Consequently, the molecular mechanisms that underpin many of these genotype-phenotype associations are unclear. Molecular quantitative trait locus (QTL) mapping studies, which identify genetic determinants of transcript, protein or metabolite abundance, can address this knowledge gap by identifying the molecular intermediaries that mediate genetically driven disease risk. These studies can provide specific hypotheses for functional validation experiments 2,3 . > Molecular QTL data can be used for a range of biomedical applications. For example, they have the potential to identify and validate new therapeutic targets and pathways, inform about the biological mechanisms of drug action and safety, highlight new therapeutic indications and reveal clinically relevant biomarkers [4][5][6] . > Many previous studies have carried out QTL mapping within a single molecular domain such as gene or protein expression [7][8][9][10][11][12] .

[12] Insights into Muscle Degeneration from Heritable Inclusion Body Myopathies

  • Authors: S. Krause
  • Year: 2015
  • Venue: Frontiers in Aging Neuroscience
  • URL: https://www.semanticscholar.org/paper/89a3262d2815a7a07284bcb48d9a39f76ce0e582
  • DOI: 10.3389/fnagi.2015.00013
  • PMID: 25729363
  • PMCID: 4325924
  • Citations: 14
  • Influential citations: 1
  • Summary: Several intriguing clues from monogenic defects in heritable IBMs contributing to the molecular basis of muscle loss will be discussed with special emphasis on inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia (IBMPFD) and GNE myopathy.
  • Evidence snippets:
  • Snippet 1 (score: 0.398) > In conclusion, it will be essential to continue studying fundamental cellular pathways underlying muscular hypertrophy and atrophy to advance the discovery of promising targets for the development of causative and safe therapies for skeletal muscle disorders. > An encouraging approach is a novel strategy to promote muscle maintenance and delay muscular atrophy by utilizing an antibody, which modulates the activin type II receptor (ActRII) response (Lach-Trifilieff et al., 2014). The wide therapeutic spectrum holds promise to treat a variety of progressive neuromuscular conditions regardless of the underlying molecular defect. Another example of a non-disease specific treatment option is the molecular chaperone 4-phenylbutyrate (4-PBA), an FDA-approved substance to treat children suffering from urea cycle disorders. 4-PBA acts as an ER stress inhibitor by aiding in protein folding and preventing misfolded protein accumulation and aggregation. Recently, convincing evidence was provided that 4-PBA might be also functional to resolve protein aggregates in vitro and in vivo and to improve grip strength in a mouse model for plectinopathy, a hereditary protein aggregate myopathy (Winter et al., 2014). > In summary, recent history of gene identification in hereditary inclusion body myopathies has fostered enthusiasm to facilitate detailed understanding of molecular disease mechanisms in these familial disorders. However, the involved genes show an unprecedented functional diversity. > Therefore, a plethora of key mechanisms underlying disease onset in hereditary IBMs remain to be elucidated at the molecular and physiological level, some of which may be also relevant for the etiology of sarcopenia. Neglected aspects that may be specific to the discussed hIBMs include regulation of RNA transcription and processing, cellular senescence, angiogenesis, and Z -disk architecture. > Understanding the deleterious combination of disease mechanisms in detail will be an important goal for future research to establish targeted intervention strategies and to prevent sarcopenia in those at risk to develop disease-associated or age-related muscle loss. Additionally and regardless of the underlying defect, it will be important for affected patients to immediately translate current broad understanding of muscle wasting and general advances to improve muscle function into safe, approved therapy.

[13] From Data to Cure: A Comprehensive Exploration of Multi-omics Data Analysis for Targeted Therapies

  • Authors: Arnab Mukherjee, S. Abraham, Akshita Singh, S. Balaji, K. Mukunthan
  • Year: 2024
  • Venue: Molecular Biotechnology
  • URL: https://www.semanticscholar.org/paper/04593d2268ccd7c26b5296d8342b468ca84ae7b1
  • DOI: 10.1007/s12033-024-01133-6
  • PMID: 38565775
  • PMCID: 11928429
  • Citations: 74
  • Influential citations: 2
  • Summary: This review navigates the expansive omics landscape, showcasing tailored assays for each molecular layer through genomes to metabolomes, and aims to illuminate the transformative impact of multi-omics in the big data era, shaping the future of biological research.
  • Evidence snippets:
  • Snippet 1 (score: 0.392) > Biological processes and molecular functions arise from intricate interactions among thousands of molecules, constituting inherent complexity. Integration of metabolomics data with other omics data holds significant promise for achieving a holistic understanding of disease mechanisms. Metabolomics, which focuses on the comprehensive analysis of small molecule metabolites within biological systems, provides unique insights into the functional status and metabolic phenotypes associated with various physiological and pathological conditions [160,161]. The integration of omics datasets with computational models and network analysis tools elucidates the complex interplay between genes, proteins, metabolites, and cellular processes underlying disease phenotypes. > Despite recent progress in omics technologies, the underlying genetic factors contributing to numerous metabolic phenotypes remain elusive. Metabolite biomarkers can be integrated with genomics and clinical parameters to enhance diagnostic accuracy or refine disease risk prediction models. Metabolites can also serve as intermediate phenotypes for genetic investigations, offering insights into underlying genetic mechanisms [162]. The integration of metabolomics data with either whole-exome sequencing or WGS-data presents a promising systematic strategy for pinpointing disease-causing variants and holds potential utility within the framework of a specific pathway under investigation [163]. Furthermore, at a more intricate biological and analytical level, metabolomics can be combined with various omic platforms, facilitating a comprehensive understanding of complex biological systems and interactions (Fig. 4). > The alterations in metabolite levels, perturbations in metabolic pathways, and the onset of disease states can be elucidated by assessing the epigenetic alterations. This approach offers molecular insights into the intricate interplay among genetic, epigenetic, and metabolic factors during the disease progression. Through the integration of epigenomic Fig. 4 The workflow for integration of metabolomics with other omics for a holistic understanding of disease progression and metabolomic data, the intricate relationships between epigenetic alterations and metabolic pathways in disease pathogenesis can be uncovered. In recent years, metabolomics and epigenomics have experienced notable advancement as prominent molecular and analytical methodologies for biomarker identification [164,165].

[14] Common immunopathogenesis of central nervous system diseases: the protein-homeostasis-system hypothesis

  • Authors: Kyung-Yil Lee
  • Year: 2022
  • Venue: Cell & Bioscience
  • URL: https://www.semanticscholar.org/paper/2984270ae67451b93007040848d9694d19714c9f
  • DOI: 10.1186/s13578-022-00920-5
  • PMID: 36384812
  • PMCID: 9668226
  • Citations: 9
  • Influential citations: 1
  • Summary: This article proposes a common immunopathogenesis of CNS diseases, including prion diseases, Alzheimer’s disease, and genetic diseases, through the PHS hypothesis, which proposes that the immune systems in the host control those substances according to the size and biochemical properties of the substances.
  • Evidence snippets:
  • Snippet 1 (score: 0.390) > There are hundreds of genetic diseases of the CNS. The defective proteins in genetic disorders include structural proteins for neurotransmitter receptors and other receptors or ion channels on CNS cells, and proteins involved in enzymatic process, metabolism (transport), or signal transduction pathways in various communication systems [98]. Because a discussion of each genetic disease is beyond the scope of this review, only crucial points about the pathogenesis of genetic diseases are discussed. Singlegene defect diseases of the CNS can be caused by a defective product from a gene, i.e., a protein deficiency or a malfunctioning protein. In general, autosomal dominant genetic diseases are caused by structural protein defects, and autosomal recessive diseases are caused by defects in enzymatic proteins. However, certain genetic diseases that involve an enzymatic or multifunctional protein defect can induce structural cell injury during the natural course of the illness. > Patients with genetic diseases, including HD, familial JCD, GSS, and the genetic forms of AD and PD, show different clinical manifestations from other affected people in their family, including the time of onset of neurological symptoms, speed of progression of the disease, and prognosis, suggesting that phenotypes can vary even when the genotypes are identical. Likewise, similar phenotypes of CNS symptoms can be found in different genetic diseases. In genetic animal models, the phenotypes of single gene knockout can vary by strain in mice, and the clinical manifestations of a gene defect can differ between mice and humans, and mice null for some genes have also no observable phenotypic abnormalities compared with controls [99]. These findings suggest that default of a protein might be at least partly controlled by individual's control systems and that there might exist a similar immune/repair system against cell injury in genetic diseases. > The pathophysiology of most genetic diseases in the CNS is complex because any affected gene is associated with numerous proteins and their corresponding activations of genes and epigenetic changes that occur during disease processes. Thus, the use of a genetic marker for diagnosing or predicting a prognosis remains impractical in clinical settings [100].

[15] Novel Approaches to Studying SLC13A5 Disease

  • Authors: Adriana S. Beltran
  • Year: 2024
  • Venue: Metabolites
  • URL: https://www.semanticscholar.org/paper/8469c534cd81d96f84b61e2d963dead12088feb7
  • DOI: 10.3390/metabo14020084
  • PMID: 38392976
  • PMCID: 10890222
  • Citations: 2
  • Summary: Current technologies for generating patient-specific induced pluripotent stem cells (iPSCs) and their inherent advantages and limitations are discussed, followed by a summary of the methods for differentiating iPSCs into neurons, hepatocytes, and organoids.
  • Evidence snippets:
  • Snippet 1 (score: 0.390) > The precise pathophysiology underlying how SLC13A5 loss-of-function results in epilepsy refractory to treatment is a subject of open and ongoing research. Several hypotheses suggest SLC13A5 alters metabolic pathways, leading to neuronal dysfunction. Conversely, therapeutic inhibition of NaCT in the liver is a target to improve metabolic diseases, including non-alcoholic fatty liver disease, obesity, and insulin resistance. Thus, functionally accurate modeling and characterization of the mechanisms involved in citrate transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes. They can also be used to define the spectrum of the disease and how different mutations might lead to various disease severities, screen for potential therapeutic compounds that can restore the transporter function or ameliorate the symptoms, and enable personalized medicine approaches that can tailor treatments to individual patients based on their genetic background and disease severity. > transport disruption are critical for understanding its role in human disease. > IPSC-derived cellular systems are a powerful tool for modeling rare human genetic diseases, such as SLC13A5 (Figure 5). IPSCs derived from patients containing the genetic information of the disease can overcome the limitations of animal models, providing access to relevant human cell types that recapitulate the disease phenotype. For instance, patient-derived iPSCs differentiated into neurons or hepatocytes can be used to investigate molecular and cellular mechanisms, including citrate transport and accumulation, energy metabolism, oxidative stress, and other cellular processes.

[16] Homocysteine thiolactone and N-homocysteinylated protein induce pro-atherogenic changes in gene expression in human vascular endothelial cells

  • Authors: D. Gurda, L. Handschuh, Weronika Kotkowiak, H. Jakubowski
  • Year: 2015
  • Venue: Amino Acids
  • URL: https://www.semanticscholar.org/paper/0e9ac31119ab67e72fdaa6e9cc442fa7ed2f4642
  • DOI: 10.1007/s00726-015-1956-7
  • PMID: 25802182
  • PMCID: 4458266
  • Citations: 93
  • Influential citations: 3
  • Summary: It is found that each Hcy metabolite uniquely modulates gene expression in pathways important for vascular homeostasis and identify new genes and pathways that are linked to HHcy-induced endothelial dysfunction and vascular disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > lead to the accumulation of Hcy and its metabolites in the blood-hyperhomocysteinemia (HHcy)-which is an independent risk factor for cardiovascular disease (CVD) and causes endothelial dysfunction, a hallmark of atherosclerosis (Dayal and Lentz 2008). However, molecular mechanisms underlying the pathophysiology of HHcy are not fully understood (Jakubowski 2011(Jakubowski , 2013;;Perla-Kajan et al. 2007). One hypothesis states that metabolic conversion of Hcy to Hcythiolactone initiates a pathway that leads to pathologies associated with HHcy (Jakubowski 1997a(Jakubowski , 1999(Jakubowski , 2007)). Hcy-thiolactone is chemically reactive and modifies ε-amino groups of protein lysine residues, which generates immunogenic and toxic N-homocysteinylated protein (N-Hcy-protein) (Jakubowski 2008(Jakubowski , 2013;;Jakubowski et al. 2000). > In humans and mice, HHcy leads to the accumulation of Hcy-thiolactone and N-Hcy-protein, in addition to Hcy (Chwatko et al. 2007;Jakubowski et al. 2008Jakubowski et al. , 2009)). We and other investigators have shown that HHcy induces changes in gene expression in mouse models that are associated with atherothrombotic disease (Devlin et al. 2005;DiBello et al. 2010;Ingrosso et al. 2003;Kim et al. 2011;Pogribny et al. 2008;Sharma et al. 2006;Suszynska-Zajczyk et al. 2014a, b, c, d). However, it is not known what mechanism(s) are involved and which metabolite-Hcy itself, Hcy-thiolactone, or N-Hcy-protein-is responsible for changes in gene expression. > The key to understanding mechanisms by which HHcy disrupts normal cellular function and ultimately causes disease is to identify genes whose expression is affected by individual Hcy metabolites.

[17] Recent advances in modelling of cerebellar ataxia using induced pluripotent stem cells

  • Authors: M. M. Wong, L. Watson, Esther B. E. Becker
  • Year: 2017
  • Venue: Journal of neurology & neuromedicine
  • URL: https://www.semanticscholar.org/paper/0d962652305116e383ab260b9e82d3a5ffe1722f
  • DOI: 10.29245/2572.942X/2017/7.1134
  • PMID: 28825058
  • PMCID: 5558869
  • Citations: 10
  • Summary: This review focuses on recent breakthroughs in generating human iPSC-derived Purkinje cells and highlights the future challenges that will need to be addressed in order to fully exploit these models for the modelling of the molecular mechanisms underlying cerebellar ataxias and the development of effective therapeutics.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > dominant polyglutamine spinocerebellar ataxias (SCAs) are the most studied forms of ataxias. Despite significant clinical and genetic heterogeneity, emerging evidence points to the existence of common pathogenic mechanisms that may be shared by several genetically distinct forms of cerebellar ataxias (reviewed in5-8). However, it is still unclear how the proposed pathological pathways ultimately result in cerebellar dysfunction and degeneration, predominantly affecting Purkinje cells. > Understanding disease mechanisms is key to treating neurodegenerative disorders. The heterogeneous nature of the cerebellar ataxias combined with the unavailability of human brain tissue and the lack of reliable disease models have, however, hampered our understanding of the molecular disease mechanisms underlying cerebellar ataxias and thus, the development of effective therapies. Although mouse models of several cerebellar ataxias, including FRDA and SCAs, have provided valuable insights into the pathophysiology of these disorders (reviewed in9), many questions remain about the observed species differences in disease phenotypes and the effectiveness of potential drugs in clinical trials. > To help translate research from animal models into novel treatments for ataxia patients, it is essential to validate findings in the relevant affected human cell types, particularly in cerebellar Purkinje cells. The current obstacles might be overcome by exploiting recently developed human induced pluripotent stem cell (iPSC) technology and neuronal differentiation protocols.

[18] Novel variants in KAT6B spectrum of disorders expand our knowledge of clinical manifestations and molecular mechanisms

  • Authors: M. Yabumoto, Jessica Kianmahd, Meghna Singh, Maria F. Palafox, Angela Wei et al.
  • Year: 2021
  • Venue: Molecular Genetics & Genomic Medicine
  • URL: https://www.semanticscholar.org/paper/3a47a1b1208ba7420900b090d3d7d712ed391719
  • DOI: 10.1002/mgg3.1809
  • PMID: 34519438
  • PMCID: 8580094
  • Citations: 12
  • Influential citations: 2
  • Summary: A range of features previously described for KAT6B‐related syndromes are identified, including concern for keratoconus, sensitivity to light or noise, recurring infections, and fractures in greater numbers than previously reported.
  • Evidence snippets:
  • Snippet 1 (score: 0.384) > Finally, as gene-centric models of disease have started to take hold, understanding the underlying functional mechanisms that are affected can help us elucidate the effect on molecular and cellular phenotypes that are regulated by KAT6B (Klein et al., 2019;Sheikh et al., 2012). We developed a model of KAT6B truncating variants in a human cell line to explore how these variants result in differential regulation of key transcripts. These types of approaches have been performed in a high throughput manner for tumor suppressor genes like BRCA1 (Findlay et al., 2018) and TP53 (Kotler et al., 2018) and can help identify key pathways that are dysregulated by KAT6B-related disorders and could be future targets for translational research. > Here, we analyze 20 clinical cases representing a KAT6B-related clinical spectrum across three domains: their genotype, phenotype, and experience with genetic counseling resources. Furthermore, we developed an in vitro model of KAT6B mutations using CRISPR technology to explore the effect of protein truncation on global transcriptional regulation. Here we demonstrate that the genes that drive core clinical phenotypes are enriched in our in vitro model system. Together, we show that our clinical observations parallel the transcriptional processes in our cell model systems which allow for a further understanding of the mechanisms underlying the KAT6Brelated clinical spectrum.

[19] Chromatin modifiers in neurodevelopment

  • Authors: Sarallah Rezazadeh, H. Ji, Cecilia Giulivi
  • Year: 2025
  • Venue: Frontiers in Molecular Neuroscience
  • URL: https://www.semanticscholar.org/paper/7a4d8c063c2b3a908a65bcb637cd818edad8db92
  • DOI: 10.3389/fnmol.2025.1551107
  • PMID: 40469903
  • PMCID: 12133960
  • Citations: 2
  • Summary: This mini review delves into key chromatin modifiers, including the histone methyl transferases NSD1 and ASH1L, the methyl-CpG-binding repressor MeCP2, and the enzymatic repressor EZH2, and spotlight their pivotal roles in early brain development and neurological disorders.
  • Evidence snippets:
  • Snippet 1 (score: 0.383) > Therefore, while epigenetic changes are essential for understanding specific aspects of neurodevelopmental disorders, it is crucial to view these mechanisms as part of a larger, more complex system that encompasses genetic, proteomic, and metabolic factors. Few examples underscore that while epigenetic mechanisms-such as DNA methylation and histone modificationsare essential in regulating gene expression and contribute to neurodevelopmental disorders, they do not fully explain the complex pathophysiology of these diseases. In many cases, the genetic mutations, absence of or dysfunction of protein, or toxic protein aggregation (e.g., Fragile X syndrome, HD) that occur in these disorders play a central role in the clinical phenotypes. Therefore, a comprehensive understanding of neurodevelopmental disorders must integrate epigenetic mechanisms and the broader genetic, proteomic, and cellular pathways that contribute to disease. An integrative approach that considers not only the regulation of gene expression but also the functional consequences of these changes at the protein, metabolic and cellular pathway levels will be essential for advancing our understanding of these intricate disorders and developing effective interventions and treatments. . B., Villate, O., Llano, I., Ocio, I., Martí, I., et al. (2020). Targeted next-generation sequencing in patients with suggestive X-linked intellectual disability. Genes 11:51. doi: 10.3390/genes11010051

[20] Clinical metabolomics in type 2 diabetes mellitus: from pathogenesis to biomarkers

  • Authors: Chuanxin Liu, Hetao Chen, Yujin Ma, Lei Zhang, Lulu Chen et al.
  • Year: 2025
  • Venue: Frontiers in Endocrinology
  • URL: https://www.semanticscholar.org/paper/36f8d26a208b7b96763df2e9aa3211e440031c0e
  • DOI: 10.3389/fendo.2025.1501305
  • PMID: 40070584
  • PMCID: 11893406
  • Citations: 11
  • Summary: The results facilitate understanding the pathophysiology and mechanism of type 2 diabetes mellitus and supports research in accurate diagnosis, risk prediction, curative effect, distinct stages, and prognosis judgment of T2DM.
  • Evidence snippets:
  • Snippet 1 (score: 0.383) > The metabolome is sensitive to a variety of genetic and environmental stimuli and susceptible to genetic, environmental, and gut microbiome pressures, so subtle differences between individuals can lead to large perturbations in metabolite concentrations and fluxes (15, 24). At present, cystatin C has become an ideal endogenous marker for evaluating glomerular filtration function because it is not affected by sex, age or muscle mass (25). In addition, more and more evidence shows that serum CysC is involved in the pathological process of vascular remodeling and neovascularization, which is closely related to the occurrence and development of diabetic microangiopathy (26). > Eighty-four papers were included in this review and obtained through database searches, namely, PubMed, Cochrane Library, China national knowledge internet(CNKI), General Purpose, and VIP Database. The keywords for the searches were "metabolomics" and "type 2 diabetes mellitus" and its complications. The papers were incorporated by reading and summarizing the literature according to the classification standards (27). The profound analysis of clinical differential metabolites identified in type 2 diabetes and its complications were conducted concerning composition, frequency of category, sample type, and pathways to explore the pathological mechanism of type 2 diabetes and its complications to provide a systematic basis for clinical diagnosis, risk stratification, comprehending disease progression, prognosis assessment, and drug efficacy. Our goal is to apply metabolomics to clinical diagnostic biomarkers, metabolic mechanisms, and prognostic observations, and early diagnosis can be made through metabolites to avoid progression to more serious complications.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.