Calcineurin (CN)-related developmental and epileptic encephalopathy (DEE) is a severe neurological disorder caused by de novo heterozygous mutations in PPP3CA, encoding the alpha catalytic subunit of the calcium/calmodulin-dependent serine-threonine phosphatase calcineurin. Calcineurin plays critical roles in synaptic vesicle recycling, NFAT signaling, and neuronal development. Loss-of-function mutations in the catalytic domain or truncating mutations in the regulatory domain lead to early-onset refractory seizures, severe intellectual disability, and global developmental delay. The condition is designated DEE 91 (OMIM 617711). Genotype-phenotype correlations indicate that truncating variants clustered in the regulatory domain cause more severe early-onset epilepsy, while catalytic domain missense variants may present with epileptic spasms and autism spectrum features. Distinct gain-of-function mutations in the auto-inhibitory domain cause a separate disorder (ACCIID) with skeletal abnormalities rather than epilepsy.
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name: CN-Related Developmental and Epileptic Encephalopathy
creation_date: "2026-03-08T00:00:00Z"
updated_date: "2026-05-09T04:33:26Z"
category: Mendelian
description: >
Calcineurin (CN)-related developmental and epileptic encephalopathy (DEE) is a
severe neurological disorder caused by de novo heterozygous mutations in PPP3CA,
encoding the alpha catalytic subunit of the calcium/calmodulin-dependent
serine-threonine phosphatase calcineurin. Calcineurin plays critical roles in
synaptic vesicle recycling, NFAT signaling, and neuronal development. Loss-of-function
mutations in the catalytic domain or truncating mutations in the regulatory domain
lead to early-onset refractory seizures, severe intellectual disability, and global
developmental delay. The condition is designated DEE 91 (OMIM 617711). Genotype-phenotype
correlations indicate that truncating variants clustered in the regulatory domain
cause more severe early-onset epilepsy, while catalytic domain missense variants
may present with epileptic spasms and autism spectrum features. Distinct
gain-of-function mutations in the auto-inhibitory domain cause a separate disorder
(ACCIID) with skeletal abnormalities rather than epilepsy.
notes: >-
Genotype-phenotype correlation: truncating variants in the regulatory domain cause
the most severe early-onset refractory epilepsy with multiple seizure types;
catalytic domain LoF missense variants may present with epileptic spasms alone
and higher rates of ASD (45% vs 13%); gain-of-function missense variants in the
auto-inhibitory domain cause a separate disorder (ACCIID) with skeletal
abnormalities. See PMID:33963760, PMID:39305655, PMID:40548073.
disease_term:
preferred_term: developmental and epileptic encephalopathy 91
term:
id: MONDO:0020630
label: developmental and epileptic encephalopathy 91
parents:
- Genetic Developmental and Epileptic Encephalopathy
inheritance:
- name: Autosomal dominant (de novo)
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
penetrance: COMPLETE
description: >
CN-related DEE is caused by de novo heterozygous mutations in PPP3CA.
All reported cases to date have arisen de novo with no familial recurrence.
The pLI value of PPP3CA is 1, indicating extreme loss-of-function intolerance.
evidence:
- reference: PMID:28942967
reference_title: "De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Five individuals with de novo PPP3CA mutations were identified among 4,760
trio probands with neurodevelopmental diseases; this is highly unlikely to
occur by chance (p = 1.2 × 10-8) given the size and mutability of the gene.
explanation: >-
Statistical evidence from trio exome sequencing of 4,760 families confirms
de novo PPP3CA mutations are significantly enriched in neurodevelopmental
disease, establishing autosomal dominant de novo inheritance.
prevalence:
- population: Global reported literature
percentage: Unknown
notes: >-
Population prevalence has not been established. Published cohorts remain
very small; a 2025 genotype-phenotype study analyzed 15 new epilepsy
patients together with 21 previously reported epilepsy cases, underscoring
that PPP3CA-related DEE is still known largely from aggregated case
reports and small series.
evidence:
- reference: PMID:40548073
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Clinical data of 15 epilepsy patients in current study and 21 epilepsy patients from published studies were collected and analyzed."
explanation: >-
This pooled genotype-phenotype analysis shows that only a few dozen
epilepsy cases had been assembled in the literature, supporting unknown
but extremely low prevalence.
- reference: PMID:39305655
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The objective of this study is to characterize the electro-clinical phenotype of individuals affected by the rare PPP3CA gene-related developmental and epileptic encephalopathy (DEE)."
explanation: >-
This 2024 review explicitly describes PPP3CA-related DEE as rare and
highlights the continuing need for larger collaborative cohorts.
pathophysiology:
- name: Loss of calcineurin phosphatase activity
description: >-
De novo missense or truncating mutations in PPP3CA reduce or abolish
calcineurin phosphatase activity. Calcineurin is the only
calcium/calmodulin-activated serine-threonine phosphatase in the brain.
Loss-of-function mutations in the catalytic domain directly impair enzymatic
activity, while truncating mutations in the regulatory domain produce
unstable protein that is rapidly degraded despite normal mRNA expression.
gene:
preferred_term: PPP3CA
description: >-
Protein phosphatase 3 catalytic subunit alpha, encoding the catalytic
subunit of calcineurin (protein phosphatase 2B).
modifier: DECREASED
term:
id: hgnc:9314
label: PPP3CA
cell_types:
- preferred_term: GABAergic neuron
term:
id: CL:0000617
label: GABAergic neuron
- preferred_term: Glutamatergic neuron
term:
id: CL:0000679
label: glutamatergic neuron
biological_processes:
- preferred_term: Calcineurin-mediated signaling
term:
id: GO:0097720
label: calcineurin-mediated signaling
downstream:
- target: Impaired NFAT signaling
description: >-
Calcineurin normally dephosphorylates NFAT transcription factors, enabling
their nuclear translocation. Loss of calcineurin activity prevents NFAT
activation, disrupting gene expression programs important for neuronal
development and synaptic function.
- target: Disrupted synaptic vesicle recycling
description: >-
Calcineurin is an important regulator of synaptic vesicle recycling at
nerve terminals. Loss of calcineurin activity disrupts this recycling,
impairing neurotransmitter release and contributing to seizures.
evidence:
- reference: PMID:29432562
reference_title: "Loss-of-function and gain-of-function mutations in PPP3CA cause two distinct disorders."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Using a yeast model system, we showed that the catalytic and AI domain
mutations visibly result in decreased and increased calcineurin signaling,
respectively. These findings indicate that different functional effects
of PPP3CA mutations are associated with two distinct disorders
explanation: >-
Functional studies using yeast as a heterologous expression system
demonstrated that catalytic domain mutations cause loss of function while
auto-inhibitory domain mutations cause gain of function, explaining the
two distinct clinical syndromes.
- reference: PMID:28942967
reference_title: "De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin
encodes a calcium- and calmodulin-dependent serine/threonine protein
phosphatase that plays a role in a wide range of biological processes,
including being a key regulator of synaptic vesicle recycling at nerve
terminals.
explanation: >-
Establishes PPP3CA as encoding the calcineurin catalytic subunit alpha
and its role in synaptic vesicle recycling, linking its loss of function
to epilepsy.
- name: Impaired NFAT signaling
description: >-
Calcineurin normally dephosphorylates NFAT transcription factors, enabling
their nuclear translocation and activation of downstream gene expression.
Loss of calcineurin activity prevents NFAT activation, disrupting programs
important for neuronal development and synaptic function. Note: the
calcineurin-NFAT link is well established in general calcineurin biology
but has not been directly demonstrated in PPP3CA patient-derived studies.
biological_processes:
- preferred_term: Calcineurin-NFAT signaling cascade
term:
id: GO:0033173
label: calcineurin-NFAT signaling cascade
- name: Disrupted synaptic vesicle recycling
description: >-
Calcineurin is a key regulator of synaptic vesicle recycling at nerve
terminals, a critical process controlling neurotransmitter release. Loss
of calcineurin phosphatase activity impairs synaptic vesicle endocytosis
and recycling, disrupting neurotransmission and contributing to seizure
susceptibility.
biological_processes:
- preferred_term: Synaptic vesicle recycling
term:
id: GO:0036465
label: synaptic vesicle recycling
evidence:
- reference: PMID:28942967
reference_title: "De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin
encodes a calcium- and calmodulin-dependent serine/threonine protein
phosphatase that plays a role in a wide range of biological processes,
including being a key regulator of synaptic vesicle recycling at nerve
terminals.
explanation: >-
Directly implicates calcineurin in synaptic vesicle recycling; loss of
calcineurin disrupts this process and supports the role in epilepsy.
phenotypes:
- category: NEUROLOGICAL
name: Epileptic spasms
description: >-
Epileptic spasms (infantile spasms) are the most common seizure type,
occurring in approximately 80-93% of patients. Onset is typically in the first
year of life. The most frequently diagnosed epileptic syndrome is infantile
epileptic spasms syndrome (IESS).
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Epileptic spasms
term:
id: HP:0011097
label: Epileptic spasm
evidence:
- reference: PMID:40548073
reference_title: "New variants and genotype-phenotype correlation of PPP3CA-related developmental and epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
80% of patients experiencing seizure onset before the age of one. The
seizure types observed included epileptic spasms (93.3%)
explanation: >-
In a cohort of 15 patients, 93.3% had epileptic spasms and 80%
experienced seizure onset before age one, confirming this as the most
frequent seizure type with infantile onset.
- reference: PMID:40548073
reference_title: "New variants and genotype-phenotype correlation of PPP3CA-related developmental and epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
80% specifically diagnosed with infantile epileptic spasms syndrome
(IESS). When combining data from this study and published studies, 66.7%
of patients experienced seizure onset before the age of one, and 77.8%
were diagnosed with IESS.
explanation: >-
IESS is the predominant epileptic syndrome in PPP3CA-related DEE across
combined cohort data.
- category: NEUROLOGICAL
name: Severe global developmental delay
description: >-
All patients exhibit global developmental delay with severe to profound
motor, cognitive, and language impairment. Most affected individuals have
very limited speech and many are nonverbal.
frequency: OBLIGATE
phenotype_term:
preferred_term: Severe global developmental delay
term:
id: HP:0011344
label: Severe global developmental delay
evidence:
- reference: PMID:28942967
reference_title: "De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we have identified six individuals with severe developmental delay (6/6),
refractory seizures (5/6), and similar dysmorphic features (3/6), each
harboring a de novo mutation in PPP3CA.
explanation: >-
All six individuals in the original PPP3CA cohort had severe developmental
delay (100% penetrance), establishing it as an obligate feature.
- reference: PMID:40548073
reference_title: "New variants and genotype-phenotype correlation of PPP3CA-related developmental and epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: All patients exhibited global developmental delay.
explanation: >-
Confirms global developmental delay is present in all 15 patients in
this cohort.
- category: NEUROLOGICAL
name: Severe intellectual disability
description: >-
Severe to profound intellectual disability is a hallmark feature of
PPP3CA-related DEE, present regardless of the mutation domain.
frequency: OBLIGATE
phenotype_term:
preferred_term: Severe intellectual disability
term:
id: HP:0010864
label: Severe intellectual disability
evidence:
- reference: PMID:30455226
reference_title: "Early-onset infant epileptic encephalopathy associated with a de novo PPP3CA gene mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
all 14 patients with de novo PPP3CA mutations documented to date have
presented with obvious DD and ID regardless of the domain mutated
explanation: >-
Review of all 14 patients reported by 2018 confirms universal presence
of developmental delay and intellectual disability.
- category: NEUROLOGICAL
name: Refractory seizures
description: >-
Seizures are typically drug-resistant, particularly in patients with
truncating variants in the regulatory domain. Multiple antiepileptic drugs,
ACTH, ketogenic diet, and vigabatrin may be tried with limited success.
frequency: VERY_FREQUENT
phenotype_term:
preferred_term: Drug-resistant seizures
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:33963760
reference_title: "PPP3CA truncating variants clustered in the regulatory domain cause early-onset refractory epilepsy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
PPP3CA truncating variants clustered in the RD, causing more severe
early-onset refractory epilepsy and representing a type of variants
distinct from LoF or GoF missense variants.
explanation: >-
Confirms that truncating variants in the regulatory domain cause
severe refractory epilepsy.
- reference: PMID:30455226
reference_title: "Early-onset infant epileptic encephalopathy associated with a de novo PPP3CA gene mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
She was treated by levetiracetam 0.5 ml q12h, but seizures persisted
explanation: >-
Case report demonstrating drug resistance with multiple antiepileptic
drugs tried without achieving seizure control.
- category: NEUROLOGICAL
name: Tonic seizures
description: >-
Tonic seizures are observed in approximately 47% of patients with
PPP3CA-related DEE.
frequency: FREQUENT
phenotype_term:
preferred_term: Tonic seizures
term:
id: HP:0032792
label: Tonic seizure
evidence:
- reference: PMID:40548073
reference_title: "New variants and genotype-phenotype correlation of PPP3CA-related developmental and epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: tonic seizures (46.7%)
explanation: >-
Tonic seizures observed in 46.7% of a 15-patient cohort.
- category: NEUROLOGICAL
name: Myoclonic seizures
description: >-
Myoclonic seizures are observed in approximately 47% of patients and may
manifest as single or clustered myoclonic jerks.
frequency: FREQUENT
phenotype_term:
preferred_term: Myoclonic seizures
term:
id: HP:0002123
label: Generalized myoclonic seizure
evidence:
- reference: PMID:40548073
reference_title: "New variants and genotype-phenotype correlation of PPP3CA-related developmental and epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: myoclonic seizures (46.7%)
explanation: >-
Myoclonic seizures observed in 46.7% of a 15-patient cohort.
- category: NEUROLOGICAL
name: Focal seizures
description: >-
Focal seizures are observed in approximately 40% of patients.
frequency: FREQUENT
phenotype_term:
preferred_term: Focal seizures
term:
id: HP:0007359
label: Focal-onset seizure
evidence:
- reference: PMID:40548073
reference_title: "New variants and genotype-phenotype correlation of PPP3CA-related developmental and epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: focal seizures (40.0%)
explanation: Focal seizures observed in 40% of a 15-patient cohort.
- category: NEUROLOGICAL
name: Atypical absence seizures
description: >-
Atypical absence seizures are observed in a subset of patients.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Atypical absence seizures
term:
id: HP:0007270
label: Atypical absence seizure
evidence:
- reference: PMID:40548073
reference_title: "New variants and genotype-phenotype correlation of PPP3CA-related developmental and epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: atypical absence seizures (13.3%)
explanation: Atypical absence seizures observed in 13.3% of a 15-patient cohort.
- category: NEUROLOGICAL
name: Hypsarrhythmia
description: >-
Hypsarrhythmia is an EEG pattern characterized by chaotic, high-amplitude,
asynchronous slow-wave activity, commonly seen in patients with infantile
spasms.
frequency: FREQUENT
phenotype_term:
preferred_term: Hypsarrhythmia
term:
id: HP:0002521
label: Hypsarrhythmia
evidence:
- reference: PMID:32593294
reference_title: "Clinical and Genetic Study on a Chinese Patient with Infantile Onset Epileptic Encephalopathy carrying a PPP3CA Null Variant: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
During the interictal stage, fragmented atypical hypsarrhythmia
discharges appeared.
explanation: >-
Case report demonstrating hypsarrhythmia pattern on EEG in a patient
with PPP3CA frameshift variant.
- category: NEUROLOGICAL
name: Muscular hypotonia
description: >-
Hypotonia has been reported in some affected individuals.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Muscular hypotonia
term:
id: HP:0001252
label: Hypotonia
evidence:
- reference: PMID:32593294
reference_title: "Clinical and Genetic Study on a Chinese Patient with Infantile Onset Epileptic Encephalopathy carrying a PPP3CA Null Variant: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: mild hypotonia
explanation: >-
Hypotonia reported as a feature in a PPP3CA case report.
- category: NEUROLOGICAL
name: Absent speech
description: >-
Most affected individuals have very limited or absent speech.
Language delay is a prominent feature.
frequency: FREQUENT
phenotype_term:
preferred_term: Absent speech
term:
id: HP:0001344
label: Absent speech
evidence:
- reference: PMID:32593294
reference_title: "Clinical and Genetic Study on a Chinese Patient with Infantile Onset Epileptic Encephalopathy carrying a PPP3CA Null Variant: a case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Language delay was significant with meaningless sound and no word.
explanation: >-
Demonstrates severe speech impairment in a PPP3CA case.
- category: NEUROLOGICAL
name: Autism spectrum disorder
description: >-
Autism spectrum disorder features are reported in a subset of patients,
particularly those with catalytic domain variants.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Autistic behavior
term:
id: HP:0000729
label: Autistic behavior
evidence:
- reference: PMID:40548073
reference_title: "New variants and genotype-phenotype correlation of PPP3CA-related developmental and epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
45.5% of patients with CD variants had comorbid autism spectrum disorders,
compared to 13% patients with RD variants.
explanation: >-
ASD is more common with catalytic domain variants (45.5%) than regulatory
domain variants (13%).
- category: NEUROLOGICAL
name: Abnormal cerebral morphology
description: >-
MRI abnormalities are present in a majority of patients, including widened
subarachnoid space, ventricular dilatation, poor myelination of white
matter, and dysplasia of the corpus callosum. Some patients have normal
brain MRI.
frequency: FREQUENT
phenotype_term:
preferred_term: Abnormal cerebral morphology
term:
id: HP:0002060
label: Abnormal cerebral morphology
evidence:
- reference: PMID:40548073
reference_title: "New variants and genotype-phenotype correlation of PPP3CA-related developmental and epileptic encephalopathy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
MRI abnormalities were noticed in 9 patients, including widened
subarachnoid space, bilateral ventricular width, poor myelination of
white matter, and dysplasia of the corpus callosum.
explanation: >-
MRI abnormalities present in 9 of 15 patients, encompassing multiple
types of structural brain changes.
- reference: PMID:30455226
reference_title: "Early-onset infant epileptic encephalopathy associated with a de novo PPP3CA gene mutation."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
abnormalities in head MRI were observed, including brain dysplasia with
cystic right basal ganglia, thin corpus callosum, and widened brain interval
explanation: >-
Case report showing multiple structural brain abnormalities on MRI.
- category: NEUROLOGICAL
name: Dysmorphic features
description: >-
Some patients present with craniofacial dysmorphic features.
frequency: OCCASIONAL
phenotype_term:
preferred_term: Dysmorphic features
term:
id: HP:0001999
label: Abnormal facial shape
evidence:
- reference: PMID:28942967
reference_title: "De Novo Mutations in PPP3CA Cause Severe Neurodevelopmental Disease with Seizures."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
we have identified six individuals with severe developmental delay (6/6),
refractory seizures (5/6), and similar dysmorphic features (3/6)
explanation: >-
Dysmorphic features observed in 3 of 6 individuals (50%) in the
original PPP3CA cohort.
genetic:
- name: PPP3CA variants
gene_term:
preferred_term: PPP3CA
term:
id: hgnc:9314
label: PPP3CA
association: Pathogenic Mutations
presence: Positive
notes: >-
De novo heterozygous variants in PPP3CA are the primary genetic cause of
CN-related DEE (DEE 91). Variants include missense mutations in the catalytic
domain, truncating variants (frameshift and nonsense) clustered in a
26-amino acid region of the regulatory domain, and rare variants in other
domains. The pLI value of PPP3CA is 1, indicating extreme loss-of-function
intolerance. Recurrent variants include p.His92Arg, p.Asp234Glu,
p.Glu282Lys, and p.Ser419Asnfs*31.
variants:
- name: PPP3CA catalytic domain missense variants
description: >-
Loss-of-function missense variants in the catalytic domain (e.g.,
p.His92Arg, p.Asn150Ile, p.Asp234Glu, p.His281Gln) cause epileptic
encephalopathy with refractory seizures and severe intellectual disability.
clinical_significance: PATHOGENIC
- name: PPP3CA regulatory domain truncating variants
description: >-
Truncating variants (frameshift and nonsense) clustered in the regulatory
domain cause the most severe form with early-onset drug-resistant epilepsy.
Expression studies show mRNA expression from the mutant allele but no
detectable mutant protein, suggesting protein instability.
clinical_significance: PATHOGENIC
evidence:
- reference: PMID:33963760
reference_title: "PPP3CA truncating variants clustered in the regulatory domain cause early-onset refractory epilepsy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the two frameshift variants in this study and the six truncating variants
reported previously are all located within a 26-amino acid region in the
regulatory domain (RD).
explanation: >-
Demonstrates clustering of truncating variants in a narrow regulatory
domain region.
- reference: PMID:33963760
reference_title: "PPP3CA truncating variants clustered in the regulatory domain cause early-onset refractory epilepsy."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Expression studies of a truncating variant showed apparent RNA expression
from the mutant allele, but no detectable mutant protein.
explanation: >-
Functional evidence showing truncating variants produce mRNA but no
stable protein, consistent with protein instability rather than NMD.
- reference: PMID:30254215
reference_title: "Novel calcineurin A (PPP3CA) variant associated with epilepsy, constitutive enzyme activation and downregulation of protein expression."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Western blot experiments in patient's cells (EBV transformed lymphocytes
and neuronal cells derived through reprogramming) indicate that despite
normal mRNA abundance the protein expression level is strongly reduced
both for the mutated and wild-type protein. By in vitro studies with
recombinant protein expressed in E. coli we show that c.1324C>T
(p.(Gln442Ter)) results in constitutive activation of the enzyme.
explanation: >-
The p.Gln442Ter variant shows a paradoxical dual mechanism: recombinant
protein studies reveal constitutive enzyme activation (truncation removes
the auto-inhibitory domain), while patient-derived cells show strongly
reduced protein expression from both mutant and wild-type alleles. The
net effect in vivo is likely loss of function through protein instability
despite the intrinsic hyperactivity of the truncated protein.
treatments:
- name: Anticonvulsant agent therapy
description: >-
Multiple antiepileptic drugs are used for seizure management including
valproate, levetiracetam, topiramate, vigabatrin, and clonazepam.
Seizures are often refractory to conventional therapy, particularly
in patients with regulatory domain truncating variants.
treatment_term:
preferred_term: Anticonvulsant agent therapy
term:
id: MAXO:0000167
label: anticonvulsant agent therapy
evidence:
- reference: PMID:36158964
reference_title: "Case report: A novel PPP3CA truncating mutation within the regulatory domain causes severe developmental and epileptic encephalopathy in a Chinese patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
After being given multiple antiepileptic treatments with levetiracetam,
adrenocorticotropic hormone (ACTH), prednisone, topiramate, and
clonazepam, his seizures were not completely relieved.
explanation: >-
Case demonstrating use of multiple AEDs with limited seizure control,
typical of PPP3CA-related DEE.
- name: Ketogenic diet
description: >-
The ketogenic diet is used as adjunctive therapy for drug-resistant seizures
in PPP3CA-related DEE. Response is variable.
treatment_term:
preferred_term: Ketogenic diet
term:
id: MAXO:0030010
label: ketogenic diet intake
evidence:
- reference: PMID:30455226
reference_title: "Early-onset infant epileptic encephalopathy associated with a de novo PPP3CA gene mutation."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
She was then treated with a ketogenic diet.
explanation: >-
Case report of ketogenic diet use; seizures persisted despite treatment.
- name: ACTH therapy
description: >-
Adrenocorticotropic hormone (ACTH) is a first-line treatment for infantile
epileptic spasms syndrome (IESS), which affects approximately 80% of
PPP3CA-related DEE patients. Response is variable and seizures often persist.
treatment_term:
preferred_term: ACTH therapy for infantile spasms
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:36158964
reference_title: "Case report: A novel PPP3CA truncating mutation within the regulatory domain causes severe developmental and epileptic encephalopathy in a Chinese patient."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
After being given multiple antiepileptic treatments with levetiracetam,
adrenocorticotropic hormone (ACTH), prednisone, topiramate, and
clonazepam, his seizures were not completely relieved.
explanation: >-
ACTH was used as part of multi-drug treatment for a patient with
PPP3CA-related DEE, consistent with standard IESS management, though
seizures were not fully controlled.
- name: Vigabatrin therapy
description: >-
Vigabatrin is used as an alternative or adjunctive treatment for infantile
spasms in PPP3CA-related DEE. It is a standard therapeutic option for IESS.
treatment_term:
preferred_term: Vigabatrin therapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: PMID:36158964
reference_title: "Case report: A novel PPP3CA truncating mutation within the regulatory domain causes severe developmental and epileptic encephalopathy in a Chinese patient."
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
recurrent spasms and myoclonic seizures that could respond to vigabatrin
explanation: >-
Vigabatrin showed some response in controlling spasms and myoclonic
seizures in a PPP3CA case, though broader seizure control remained
incomplete.
- name: Genetic counseling
description: >-
Genetic counseling is recommended for families of affected individuals.
Since all reported cases are de novo, recurrence risk for unaffected parents
is low but germline mosaicism cannot be excluded.
treatment_term:
preferred_term: Genetic counseling
term:
id: MAXO:0000079
label: genetic counseling
datasets:
references:
- reference: DOI:10.1002/humu.24182
title: The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2)
found_in:
- CN_Related_DEE-deep-research-falcon.md
findings:
- statement: The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2)
supporting_text: The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin M2 (CNNM2)
- reference: DOI:10.1016/j.ejmg.2018.07.014
title: CNNM2 homozygous mutations cause severe refractory hypomagnesemia, epileptic encephalopathy and brain malformations
found_in:
- CN_Related_DEE-deep-research-falcon.md
findings:
- statement: CNNM2 homozygous mutations cause severe refractory hypomagnesemia, epileptic encephalopathy and brain malformations
supporting_text: CNNM2 homozygous mutations cause severe refractory hypomagnesemia, epileptic encephalopathy and brain malformations
- reference: DOI:10.1038/s41598-024-57061-7
title: Hypomagnesaemia with varying degrees of extrarenal symptoms as a consequence of heterozygous CNNM2 variants
found_in:
- CN_Related_DEE-deep-research-falcon.md
findings:
- statement: Variants in the CNNM2 gene are causative for hypomagnesaemia, seizures and intellectual disability, although the phenotypes can be variable.
supporting_text: Variants in the CNNM2 gene are causative for hypomagnesaemia, seizures and intellectual disability, although the phenotypes can be variable.
evidence:
- reference: DOI:10.1038/s41598-024-57061-7
reference_title: Hypomagnesaemia with varying degrees of extrarenal symptoms as a consequence of heterozygous CNNM2 variants
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Variants in the CNNM2 gene are causative for hypomagnesaemia, seizures and intellectual disability, although the phenotypes can be variable.
explanation: Deep research cited this publication as relevant literature for CN Related DEE.
- reference: DOI:10.1371/journal.pgen.1004267
title: CNNM2 Mutations Cause Impaired Brain Development and Seizures in Patients with Hypomagnesemia
found_in:
- CN_Related_DEE-deep-research-falcon.md
findings:
- statement: CNNM2 Mutations Cause Impaired Brain Development and Seizures in Patients with Hypomagnesemia
supporting_text: CNNM2 Mutations Cause Impaired Brain Development and Seizures in Patients with Hypomagnesemia
- reference: DOI:10.3389/fgene.2021.705734
title: 'Case Report: CNNM2 Mutations Cause Damaged Brain Development and Intractable Epilepsy in a Patient Without Hypomagnesemia'
found_in:
- CN_Related_DEE-deep-research-falcon.md
findings:
- statement: A series of neurological manifestations such as intellectual disability and epilepsy are closely related to hypomagnesemia.
supporting_text: A series of neurological manifestations such as intellectual disability and epilepsy are closely related to hypomagnesemia.
evidence:
- reference: DOI:10.3389/fgene.2021.705734
reference_title: 'Case Report: CNNM2 Mutations Cause Damaged Brain Development and Intractable Epilepsy in a Patient Without Hypomagnesemia'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: A series of neurological manifestations such as intellectual disability and epilepsy are closely related to hypomagnesemia.
explanation: Deep research cited this publication as relevant literature for CN Related DEE.
- reference: DOI:10.3389/fgene.2022.875013
title: Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure
found_in:
- CN_Related_DEE-deep-research-falcon.md
findings:
- statement: CNNM2 is primarily expressed in the brain and distal convoluted tubule (DCT) of the kidney.
supporting_text: CNNM2 is primarily expressed in the brain and distal convoluted tubule (DCT) of the kidney.
evidence:
- reference: DOI:10.3389/fgene.2022.875013
reference_title: Novel CNNM2 Mutation Responsible for Autosomal-Dominant Hypomagnesemia With Seizure
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: CNNM2 is primarily expressed in the brain and distal convoluted tubule (DCT) of the kidney.
explanation: Deep research cited this publication as relevant literature for CN Related DEE.
- reference: DOI:10.3389/fgene.2025.1600877
title: Two novel variants in CNNM2 disrupts magnesium efflux leading to neurodevelopmental disorders
found_in:
- CN_Related_DEE-deep-research-falcon.md
findings:
- statement: Hypomagnesemia, seizures, and impaired intellectual development 1 (HOMGSMR1) is a rare neurodevelopmental disorder associated with magnesium homeostasis disruption, caused by mutations in the CNNM2 gene.
supporting_text: Hypomagnesemia, seizures, and impaired intellectual development 1 (HOMGSMR1) is a rare neurodevelopmental disorder associated with magnesium homeostasis disruption, caused by mutations in the CNNM2 gene.
evidence:
- reference: DOI:10.3389/fgene.2025.1600877
reference_title: Two novel variants in CNNM2 disrupts magnesium efflux leading to neurodevelopmental disorders
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Hypomagnesemia, seizures, and impaired intellectual development 1 (HOMGSMR1) is a rare neurodevelopmental disorder associated with magnesium homeostasis disruption, caused by mutations in the CNNM2 gene.
explanation: Deep research cited this publication as relevant literature for CN Related DEE.
- reference: DOI:10.3389/fped.2021.699568
title: 'CNNM2-Related Disorders: Phenotype and Its Severity Were Associated With the Mode of Inheritance'
found_in:
- CN_Related_DEE-deep-research-falcon.md
findings:
- statement: CNNM2 (Cystathionine-β-synthase-pair Domain Divalent Metal Cation Transport Mediator 2) pathogenic variants have been reported to cause hypomagnesemia, epilepsy, and intellectual disability/developmental delay (ID/DD).
supporting_text: CNNM2 (Cystathionine-β-synthase-pair Domain Divalent Metal Cation Transport Mediator 2) pathogenic variants have been reported to cause hypomagnesemia, epilepsy, and intellectual disability/developmental delay (ID/DD).
evidence:
- reference: DOI:10.3389/fped.2021.699568
reference_title: 'CNNM2-Related Disorders: Phenotype and Its Severity Were Associated With the Mode of Inheritance'
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: CNNM2 (Cystathionine-β-synthase-pair Domain Divalent Metal Cation Transport Mediator 2) pathogenic variants have been reported to cause hypomagnesemia, epilepsy, and intellectual disability/developmental delay (ID/DD).
explanation: Deep research cited this publication as relevant literature for CN Related DEE.
- reference: DOI:10.3390/ijms23137284
title: The p.Pro482Ala Variant in the CNNM2 Gene Causes Severe Hypomagnesemia Amenable to Treatment with Spironolactone
found_in:
- CN_Related_DEE-deep-research-falcon.md
findings:
- statement: Renal hypomagnesemia syndromes involving CNNM2 protein pathogenic variants are associated with variable degrees of neurocognitive dysfunction and hypomagnesemia.
supporting_text: Renal hypomagnesemia syndromes involving CNNM2 protein pathogenic variants are associated with variable degrees of neurocognitive dysfunction and hypomagnesemia.
evidence:
- reference: DOI:10.3390/ijms23137284
reference_title: The p.Pro482Ala Variant in the CNNM2 Gene Causes Severe Hypomagnesemia Amenable to Treatment with Spironolactone
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Renal hypomagnesemia syndromes involving CNNM2 protein pathogenic variants are associated with variable degrees of neurocognitive dysfunction and hypomagnesemia.
explanation: Deep research cited this publication as relevant literature for CN Related DEE.
The query term “CN-related developmental and epileptic encephalopathy” is not a standard disease label in the retrieved sources. Based on the best-matching, directly evidenced literature, this report treats the target as CNNM2-related hypomagnesemia with seizures and neurodevelopmental impairment, in which biallelic (autosomal recessive) CNNM2 variants can present as severe developmental and epileptic encephalopathy (DEE) with brain malformations (accogli2019cnnm2homozygousmutations pages 1-2, zhang2021cnnm2relateddisordersphenotype pages 5-6, arjona2014cnnm2mutationscause pages 7-9). Where the evidence discusses the broader CNNM2 spectrum (including milder autosomal dominant forms), this is explicitly noted.
CNNM2-related hypomagnesemia with seizures and neurodevelopmental impairment is a Mendelian disorder caused by pathogenic variants in CNNM2 (cyclin M2), a protein implicated in renal magnesium handling and brain development/function. The phenotype spans: - Autosomal dominant (AD), often de novo heterozygous variants with hypomagnesemia and variable seizures and developmental delay/intellectual disability. - Autosomal recessive (AR), biallelic variants with neonatal-onset refractory seizures, severe developmental impairment, and structural brain abnormalities, consistent with a DEE phenotype (zhang2021cnnm2relateddisordersphenotype pages 1-2, zhang2021cnnm2relateddisordersphenotype pages 5-6, arjona2014cnnm2mutationscause pages 7-9).
From primary literature: - HSMR syndrome (“hypomagnesemia, seizures, and intellectual disability syndrome”), MIM# 616418 (franken2021thephenotypicand pages 1-4). - HOMG6 (“autosomal dominant renal hypomagnesemia 6”), MIM# 613882 (petrakis2022thep.pro482alavariant pages 1-2). - The term HOMGSMR1 (“Hypomagnesemia, seizures, and impaired intellectual development 1”) is used in recent literature (li2025twonovelvariants pages 1-2). - Gene: CNNM2 (OMIM gene entry MIM 607803) (arjona2014cnnm2mutationscause pages 1-2); also noted as previously known as ACDP2 (zhang2021cnnm2relateddisordersphenotype pages 1-2).
Not found in retrieved full texts during this run: MONDO, Orphanet, MeSH, ICD-10/ICD-11 codes/IDs.
The disease characterization here is derived from aggregated disease-level resources in the primary literature (case series + literature reviews) and individual patient case reports (zhang2021cnnm2relateddisordersphenotype pages 1-2, franken2021thephenotypicand pages 10-12, arjona2014cnnm2mutationscause pages 1-2, accogli2019cnnm2homozygousmutations pages 1-2).
Primary cause: genetic — pathogenic variants in CNNM2. - A foundational report identified CNNM2 mutations in families with “mental retardation, seizures, and hypomagnesemia,” including both de novo heterozygous and recessive inheritance (arjona2014cnnm2mutationscause pages 1-2). - Severe DEE presentations are enriched in biallelic/homozygous cases, described as “severe refractory hypomagnesemia, epileptic encephalopathy and brain malformations” (accogli2019cnnm2homozygousmutations pages 1-2).
Mechanistic cause (proximal physiology): renal magnesium wasting / dysregulated Mg2+ handling with downstream neurodevelopmental dysfunction (arjona2014cnnm2mutationscause pages 1-2, arjona2014cnnm2mutationscause pages 7-9, bosman2024hypomagnesaemiawithvarying pages 1-2).
No protective variants or protective environmental factors were identified in the retrieved primary texts.
No direct CNNM2-specific gene–environment interaction evidence was found in the retrieved literature.
Neurologic (DEE-relevant) - Seizures (HP:0001250) (zhang2021cnnm2relateddisordersphenotype pages 5-6, arjona2014cnnm2mutationscause pages 7-9) - Developmental delay / global developmental delay (HP:0001263) and Intellectual disability (HP:0001249) (zhang2021cnnm2relateddisordersphenotype pages 5-6, franken2021thephenotypicand pages 10-12) - Speech delay (HP:0000750) (franken2021thephenotypicand pages 10-12) - Hypotonia (HP:0001252) (reported in severe cases) (accogli2019cnnm2homozygousmutations pages 1-2, zhang2021cnnm2relateddisordersphenotype pages 4-4) - Microcephaly (HP:0000252) (zhang2021cnnm2relateddisordersphenotype pages 4-4, accogli2019cnnm2homozygousmutations pages 1-2) - Autism / autistic features (HP:0000729) in some patients (arjona2014cnnm2mutationscause pages 2-4, franken2021thephenotypicand pages 10-12)
Biochemical - Hypomagnesemia (HP:0002917) typically with renal wasting (arjona2014cnnm2mutationscause pages 2-4, bosman2024hypomagnesaemiawithvarying pages 1-2)
Growth/other - Obesity (HP:0001513) is common in heterozygous cohorts (franken2021thephenotypicand pages 10-12)
Seizure onset and severity stratified by inheritance - AR/biallelic (DEE end of spectrum): neonatal onset 1–6 days with refractory seizures, including myoclonic and generalized tonic–clonic seizures and possible status epilepticus; associated with severe ID/DD and MRI abnormalities (zhang2021cnnm2relateddisordersphenotype pages 5-6, zhang2021cnnm2relateddisordersphenotype pages 4-4). - AD/heterozygous: onset is typically infancy (often 4 months–1 year), with seizures frequently responsive to ASMs and sometimes remitting over time; developmental impairment tends to be milder than AR cases (zhang2021cnnm2relateddisordersphenotype pages 5-6, franken2021thephenotypicand pages 8-10).
Quantitative frequency/statistics from cohorts - In a 14-patient heterozygous cohort, the majority experienced seizures and neurodevelopmental impairment, and severe obesity was very frequent (franken2021thephenotypicand pages 10-12). - In a synthesis of 23 cases, the most common phenotype class (type 2, AD hypomagnesemia + epilepsy + ID/DD) had 86.7% (13/15) seizures and 93.3% (14/15) ID/DD; AR cases (3/23) were the most severe (zhang2021cnnm2relateddisordersphenotype pages 5-6).
Direct QoL instrument results (e.g., EQ-5D/SF-36) were not found in the retrieved evidence. However, severe AR/DEE cases include profound disability (nonverbal, severe developmental impairment) (zhang2021cnnm2relateddisordersphenotype pages 5-6), and AD cases can include persistent ID/speech impairment and obesity (franken2021thephenotypicand pages 10-12).
Variant classes reported across cohorts/case series include missense variants, nonsense/premature stop variants, small deletions/frameshift variants, and larger deletions (zhang2021cnnm2relateddisordersphenotype pages 4-4, franken2021thephenotypicand pages 8-10).
Functional consequence: predominantly loss-of-function / impaired CNNM2-mediated Mg2+ handling. - Mutant CNNM2 proteins failed to augment Mg2+ uptake in cell-based assays and showed trafficking defects in some alleles, consistent with LoF (arjona2014cnnm2mutationscause pages 7-9).
Example variants (illustrative; not exhaustive) - Severe AR/DEE-associated examples include homozygous c.1642G>A (p.Val548Met) (accogli2019cnnm2homozygousmutations pages 1-2, zhang2021cnnm2relateddisordersphenotype pages 4-4) and recessive p.Glu122Lys (arjona2014cnnm2mutationscause pages 7-9). - AD/heterozygous examples in aggregated tables include variants such as p.Leu48Pro, p.Tyr314, p.Leu321del, p.Val324Met, p.Leu418Pro, p.Ser795Leu, p.Arg797 (zhang2021cnnm2relateddisordersphenotype pages 4-4, li2021casereportcnnm2 pages 5-6). - In two de novo infant cases, variants were classified as likely pathogenic per ACMG and identified by trio-WES: c.814T>C (p.Phe272Leu) and c.976G>C (p.Val326Leu)** (zhang2021cnnm2relateddisordersphenotype pages 2-4).
No specific modifier genes or protective alleles were established in the retrieved evidence, though variable expressivity is emphasized.
No CNNM2-DEE–specific epigenetic signatures were found in the retrieved evidence.
Not a focus of the retrieved core CNNM2-HSMR/DEE literature in this run.
CNNM2-related DEE/HSMR is primarily genetic. No consistent toxins, lifestyle factors, or infectious triggers were described in the retrieved CNNM2-focused sources.
Key processes (GO Biological Process suggestions) - Magnesium ion homeostasis (GO:0006874) - Divalent metal ion transport (broad; gene-specific evidence indicates Mg2+ handling) (arjona2014cnnm2mutationscause pages 7-9) - Nervous system development (GO:0007399) (supported by zebrafish/mouse developmental phenotypes) (arjona2014cnnm2mutationscause pages 1-2, bosman2024hypomagnesaemiawithvarying pages 1-2)
Key cell types (Cell Ontology suggestions; inferred from tissue localization statements in evidence) - Distal convoluted tubule epithelial cell (kidney; DCT localization emphasized) (bosman2024hypomagnesaemiawithvarying pages 1-2) - Neuron / cortical neuron (brain expression emphasized, though specific neuronal subtype evidence for CNNM2-DEE is limited in retrieved sources) (bosman2024hypomagnesaemiawithvarying pages 1-2)
CNNM2 variants can impair Mg2+ transport-related function and/or membrane localization, consistent with LoF mechanisms (arjona2014cnnm2mutationscause pages 7-9, franken2021thephenotypicand pages 1-4).
A 2024 genotype–phenotype/functional study emphasizes variability and potential modifiers: “Variants in the CNNM2 gene are causative for hypomagnesaemia, seizures and intellectual disability, although the phenotypes can be variable”, and in their dataset “seizures and intellectual disability are absent in 4 out of 7 cases” despite functionally affected variants (bosman2024hypomagnesaemiawithvarying pages 1-2). This strengthens the view that hypomagnesemia alone does not fully explain neurologic outcomes and supports variant-specific effects and/or additional modifiers (bosman2024hypomagnesaemiawithvarying pages 1-2).
No population prevalence or incidence estimates were found in the retrieved sources. Available data are case-based aggregations (e.g., 23 cases synthesized in one report; multiple variant catalogs) (zhang2021cnnm2relateddisordersphenotype pages 5-6, bosman2024hypomagnesaemiawithvarying pages 1-2).
Not systematically addressed in retrieved CNNM2-focused evidence; clinically, differential diagnosis overlaps with other genetic DEEs and renal tubulopathies causing electrolyte disturbances.
Mortality rates and life expectancy were not available in the retrieved evidence.
Magnesium supplementation - Oral/IV magnesium is standard but frequently fails to normalize serum magnesium and may not rescue neurologic phenotypes in severe cases (arjona2014cnnm2mutationscause pages 7-9, zhang2021cnnm2relateddisordersphenotype pages 5-6).
Antiseizure medications (ASMs) - In a 23-case synthesis, AD/type-2 patients often respond to ASMs; reported effective options include phenobarbital, valproic acid, clobazam, levetiracetam, lacosamide (zhang2021cnnm2relateddisordersphenotype pages 5-6). - Severe AR/type-3 seizures are often refractory; multiple ASMs may decrease frequency (valproate, levetiracetam, lamotrigine, topiramate), but outcomes are poor (zhang2021cnnm2relateddisordersphenotype pages 5-6).
Other / adjunct - A 2022 report describes CNNM2-related hypomagnesemia “amenable to treatment with spironolactone” in a family with a CNNM2 CBS-domain variant, suggesting a possible adjunct strategy for renal magnesium wasting in some cases (petrakis2022thep.pro482alavariant pages 1-2).
ClinicalTrials.gov searches performed in this run did not yield a clearly CNNM2-HSMR/DEE–specific interventional trial record suitable for citation; no NCT IDs are therefore provided.
Primary prevention is not applicable for a highly penetrant Mendelian disorder except via reproductive options: - Genetic counseling for families, including discussion of inheritance (AD vs AR), recurrence risk, and testing options (zhang2021cnnm2relateddisordersphenotype pages 1-2, li2025twonovelvariants pages 1-2).
No naturally occurring veterinary CNNM2-DEE syndromes were identified in the retrieved evidence.
Zebrafish - cnnm2 knockdown causes disturbed brain development and abnormal behavior; phenotypes are rescued by wild-type but not mutant cnnm2 constructs, supporting causality and providing a platform for mechanistic and therapeutic testing (arjona2014cnnm2mutationscause pages 1-2).
Mouse - Cnnm2 heterozygous mice show hypomagnesemia consistent with a role in magnesium homeostasis; full knockout is reported as perinatally lethal with developmental defects/brain malformations in referenced summaries (bosman2024hypomagnesaemiawithvarying pages 1-2).
In vitro - HEK293 and renal tubule cell assays support impaired Mg2+ uptake/transport and trafficking defects for pathogenic variants (arjona2014cnnm2mutationscause pages 7-9, franken2021thephenotypicand pages 1-4).
| Entity / synonym (OMIM/MIM) | Inheritance / allelic state | Core features (HPO terms) | Typical seizure onset & seizure features | Key neuroimaging findings | Key variants / examples | Mechanistic insights | Management / treatment notes | Key references |
|---|---|---|---|---|---|---|---|---|
| CNNM2-related disorder; HSMR syndrome = hypomagnesemia, seizures, and intellectual disability syndrome (MIM 616418); related milder entity autosomal dominant renal hypomagnesemia 6 / HOMG6 (MIM 613882); newer synonym HOMGSMR1; causal gene CNNM2 / cyclin M2 (gene MIM 607803) | Spectrum includes AD/de novo heterozygous disease and rarer AR homozygous/biallelic disease; severity correlates with inheritance, with AR most severe (franken2021thephenotypicand pages 1-4, petrakis2022thep.pro482alavariant pages 1-2, li2025twonovelvariants pages 1-2, zhang2021cnnm2relateddisordersphenotype pages 1-2, accogli2019cnnm2homozygousmutations pages 1-2) | Hypomagnesemia HP:0002917; Seizure HP:0001250; Intellectual disability / global developmental delay HP:0001249 / HP:0001263; Speech delay HP:0000750; Motor delay HP:0001270; Hypotonia HP:0001252 or hypertonia in some reports; Microcephaly HP:0000252; Obesity HP:0001513; Autism / autistic features HP:0000729 in some patients (franken2021thephenotypicand pages 10-12, franken2021thephenotypicand pages 8-10, zhang2021cnnm2relateddisordersphenotype pages 4-4, arjona2014cnnm2mutationscause pages 2-4) | Across the spectrum, seizures are common but variable. In heterozygous HSMR, onset is usually infancy (often 4 months–1 year; median onset reported 1.54 years, range birth–16 years in one cohort) and may be generalized or focal; many are ASM-responsive or remit over time. At the severe DEE end, biallelic/AR cases show neonatal onset (1–6 days), refractory seizures, myoclonic and generalized tonic-clonic seizures, and sometimes status epilepticus (franken2021thephenotypicand pages 8-10, zhang2021cnnm2relateddisordersphenotype pages 5-6, zhang2021cnnm2relateddisordersphenotype pages 1-2, arjona2014cnnm2mutationscause pages 2-4) | Mild/moderate heterozygous cases often have normal MRI or mild nonspecific white-matter change. Severe AR/DEE cases show brain malformations including dysmyelination / reduced myelination, failure of opercularization, microcephaly, progressive cortical atrophy, widened extra-axial / CSF spaces, reduced white matter, and reported basal ganglia calcification (accogli2019cnnm2homozygousmutations pages 1-2, zhang2021cnnm2relateddisordersphenotype pages 5-6, zhang2021cnnm2relateddisordersphenotype pages 4-4, arjona2014cnnm2mutationscause pages 2-4, arjona2014cnnm2mutationscause pages 7-9) | Heterozygous examples: p.Ser269Trp, p.Glu357Lys, p.Thr568Ile, p.Leu48Pro, p.Tyr314*, p.Leu321del, p.Val324Met, p.Leu418Pro, p.Ser795Leu, p.Arg797*; de novo likely pathogenic examples c.814T>C (p.Phe272Leu) and c.976G>C (p.Val326Leu). Severe AR examples include p.Glu122Lys and homozygous c.1642G>A (p.Val548Met) (zhang2021cnnm2relateddisordersphenotype pages 5-6, accogli2019cnnm2homozygousmutations pages 1-2, zhang2021cnnm2relateddisordersphenotype pages 4-4, arjona2014cnnm2mutationscause pages 2-4, arjona2014cnnm2mutationscause pages 7-9, zhang2021cnnm2relateddisordersphenotype pages 2-4) | Predominantly loss-of-function / haploinsufficiency with impaired CNNM2-mediated Mg²⁺ transport; several variants reduce plasma-membrane trafficking/expression. CNNM2 is highly expressed in distal convoluted tubule and brain; hypomagnesemia is typically renal. Functional studies showed mutant CNNM2 fails to enhance Mg²⁺ uptake and zebrafish knockdown causes impaired brain development/abnormal motor behavior; mouse models support a developmental CNS role and perinatal lethality/brain malformations in full knockout. DUF21 variants are linked more strongly to CNS phenotypes; CBS2 variants may produce lower serum Mg²⁺ (zhang2021cnnm2relateddisordersphenotype pages 1-2, franken2021thephenotypicand pages 10-12, arjona2014cnnm2mutationscause pages 1-2, arjona2014cnnm2mutationscause pages 7-9, bosman2024hypomagnesaemiawithvarying pages 1-2) | Magnesium supplementation (oral and sometimes IV) usually raises serum Mg²⁺ only partially and often does not normalize it; neurologic benefit is limited. Heterozygous cases may respond to phenobarbital, valproate, clobazam, levetiracetam, lacosamide; some seizures remit over time. Severe AR/DEE cases are often drug-refractory, though valproate, levetiracetam, lamotrigine, topiramate may reduce frequency. A recent case report suggested spironolactone may alleviate hypomagnesemia in a milder CNNM2 disorder. No CNNM2-specific clinical trials were identified in the gathered evidence (franken2021thephenotypicand pages 10-12, zhang2021cnnm2relateddisordersphenotype pages 5-6, zhang2021cnnm2relateddisordersphenotype pages 1-2, arjona2014cnnm2mutationscause pages 2-4, petrakis2022thep.pro482alavariant pages 1-2) | Arjona et al., 2014, PLoS Genet. DOI: https://doi.org/10.1371/journal.pgen.1004267 (arjona2014cnnm2mutationscause pages 1-2, arjona2014cnnm2mutationscause pages 2-4, arjona2014cnnm2mutationscause pages 7-9); Accogli et al., 2019, Eur J Med Genet. DOI: https://doi.org/10.1016/j.ejmg.2018.07.014 (accogli2019cnnm2homozygousmutations pages 1-2); Franken et al., 2021, Hum Mutat. DOI: https://doi.org/10.1002/humu.24182 (franken2021thephenotypicand pages 10-12, franken2021thephenotypicand pages 8-10, franken2021thephenotypicand pages 1-4); Zhang et al., 2021, Front Pediatr. DOI: https://doi.org/10.3389/fped.2021.699568 (zhang2021cnnm2relateddisordersphenotype pages 1-2, zhang2021cnnm2relateddisordersphenotype pages 5-6, zhang2021cnnm2relateddisordersphenotype pages 2-4); Bosman et al., 2024, Sci Rep. DOI: https://doi.org/10.1038/s41598-024-57061-7 (bosman2024hypomagnesaemiawithvarying pages 1-2) |
Table: This table summarizes CNNM2-related HSMR/HOMGSMR1 across the clinical spectrum, highlighting the severe developmental and epileptic encephalopathy end associated with biallelic disease. It compiles inheritance, phenotypes, imaging, representative variants, mechanisms, and management points supported by the gathered evidence.
References
(accogli2019cnnm2homozygousmutations pages 1-2): Andrea Accogli, Marcello Scala, Annalisa Calcagno, Flavia Napoli, Natascia Di Iorgi, Serena Arrigo, Maria Margherita Mancardi, Giulia Prato, Livia Pisciotta, Mato Nagel, Mariasavina Severino, and Valeria Capra. Cnnm2 homozygous mutations cause severe refractory hypomagnesemia, epileptic encephalopathy and brain malformations. European journal of medical genetics, 62 3:198-203, Mar 2019. URL: https://doi.org/10.1016/j.ejmg.2018.07.014, doi:10.1016/j.ejmg.2018.07.014. This article has 41 citations and is from a peer-reviewed journal.
(zhang2021cnnm2relateddisordersphenotype pages 5-6): Han Zhang, Ye Wu, and Yuwu Jiang. Cnnm2-related disorders: phenotype and its severity were associated with the mode of inheritance. Frontiers in Pediatrics, Sep 2021. URL: https://doi.org/10.3389/fped.2021.699568, doi:10.3389/fped.2021.699568. This article has 9 citations.
(arjona2014cnnm2mutationscause pages 7-9): Francisco J. Arjona, Jeroen H. F. de Baaij, Karl P. Schlingmann, Anke L. L. Lameris, Erwin van Wijk, Gert Flik, Sabrina Regele, G. Christoph Korenke, Birgit Neophytou, Stephan Rust, Nadine Reintjes, Martin Konrad, René J. M. Bindels, and Joost G. J. Hoenderop. Cnnm2 mutations cause impaired brain development and seizures in patients with hypomagnesemia. PLoS Genetics, 10:e1004267, Apr 2014. URL: https://doi.org/10.1371/journal.pgen.1004267, doi:10.1371/journal.pgen.1004267. This article has 164 citations and is from a domain leading peer-reviewed journal.
(zhang2021cnnm2relateddisordersphenotype pages 1-2): Han Zhang, Ye Wu, and Yuwu Jiang. Cnnm2-related disorders: phenotype and its severity were associated with the mode of inheritance. Frontiers in Pediatrics, Sep 2021. URL: https://doi.org/10.3389/fped.2021.699568, doi:10.3389/fped.2021.699568. This article has 9 citations.
(franken2021thephenotypicand pages 1-4): Gijs A. C. Franken, Dominik Müller, Cyril Mignot, Boris Keren, Jonathan Lévy, Anne‐Claude Tabet, David Germanaud, María‐Isabel Tejada, Hester Y. Kroes, Rutger A. J. Nievelstein, Elise Brimble, Maria Ruzhnikov, Felix Claverie‐Martin, Maria Szczepańska, Martin Ćuk, Femke Latta, Martin Konrad, Luis A. Martínez‐Cruz, René J. M. Bindels, Joost G. J. Hoenderop, Karl‐Peter Schlingmann, and Jeroen H. F. Baaij. The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin m2 (cnnm2). Human Mutation, 42:473-486, Mar 2021. URL: https://doi.org/10.1002/humu.24182, doi:10.1002/humu.24182. This article has 28 citations and is from a domain leading peer-reviewed journal.
(petrakis2022thep.pro482alavariant pages 1-2): Ioannis Petrakis, Eleni Drosataki, Ioanna Stavrakaki, Kleio Dermitzaki, Dimitra Lygerou, Myrto Konidaki, Christos Pleros, Nikolaos Kroustalakis, Sevasti Maragkou, Ariadni Androvitsanea, Ioannis Stylianou, Ioannis Zaganas, and Kostas Stylianou. The p.pro482ala variant in the cnnm2 gene causes severe hypomagnesemia amenable to treatment with spironolactone. International Journal of Molecular Sciences, 23:7284, Jun 2022. URL: https://doi.org/10.3390/ijms23137284, doi:10.3390/ijms23137284. This article has 7 citations.
(li2025twonovelvariants pages 1-2): Huijuan Li, Jing Liu, Yingdi Liu, Yaning Liu, Kehui Lu, Juan Wen, Huimin Zhu, Desheng Liang, Zhuo Li, and Lingqian Wu. Two novel variants in cnnm2 disrupts magnesium efflux leading to neurodevelopmental disorders. Frontiers in Genetics, Jun 2025. URL: https://doi.org/10.3389/fgene.2025.1600877, doi:10.3389/fgene.2025.1600877. This article has 0 citations and is from a peer-reviewed journal.
(arjona2014cnnm2mutationscause pages 1-2): Francisco J. Arjona, Jeroen H. F. de Baaij, Karl P. Schlingmann, Anke L. L. Lameris, Erwin van Wijk, Gert Flik, Sabrina Regele, G. Christoph Korenke, Birgit Neophytou, Stephan Rust, Nadine Reintjes, Martin Konrad, René J. M. Bindels, and Joost G. J. Hoenderop. Cnnm2 mutations cause impaired brain development and seizures in patients with hypomagnesemia. PLoS Genetics, 10:e1004267, Apr 2014. URL: https://doi.org/10.1371/journal.pgen.1004267, doi:10.1371/journal.pgen.1004267. This article has 164 citations and is from a domain leading peer-reviewed journal.
(tseng2022novelcnnm2mutation pages 1-2): Min-Hua Tseng, Sung-Sen Yang, Chih-Chien Sung, Jhao-Jhuang Ding, Yu-Juei Hsu, Shih-Ming Chu, and Shih-Hua Lin. Novel cnnm2 mutation responsible for autosomal-dominant hypomagnesemia with seizure. Frontiers in Genetics, Jun 2022. URL: https://doi.org/10.3389/fgene.2022.875013, doi:10.3389/fgene.2022.875013. This article has 11 citations and is from a peer-reviewed journal.
(franken2021thephenotypicand pages 10-12): Gijs A. C. Franken, Dominik Müller, Cyril Mignot, Boris Keren, Jonathan Lévy, Anne‐Claude Tabet, David Germanaud, María‐Isabel Tejada, Hester Y. Kroes, Rutger A. J. Nievelstein, Elise Brimble, Maria Ruzhnikov, Felix Claverie‐Martin, Maria Szczepańska, Martin Ćuk, Femke Latta, Martin Konrad, Luis A. Martínez‐Cruz, René J. M. Bindels, Joost G. J. Hoenderop, Karl‐Peter Schlingmann, and Jeroen H. F. Baaij. The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin m2 (cnnm2). Human Mutation, 42:473-486, Mar 2021. URL: https://doi.org/10.1002/humu.24182, doi:10.1002/humu.24182. This article has 28 citations and is from a domain leading peer-reviewed journal.
(bosman2024hypomagnesaemiawithvarying pages 1-2): Willem Bosman, Gijs A. C. Franken, Javier de las Heras, Leire Madariaga, Tahsin Stefan Barakat, Rianne Oostenbrink, Marjon van Slegtenhorst, Ana Perdomo-Ramírez, Félix Claverie-Martín, Albertien M. van Eerde, Rosa Vargas-Poussou, Laurence Derain Dubourg, Irene González-Recio, Luis Alfonso Martínez-Cruz, Jeroen H. F. de Baaij, and Joost G. J. Hoenderop. Hypomagnesaemia with varying degrees of extrarenal symptoms as a consequence of heterozygous cnnm2 variants. Scientific Reports, Mar 2024. URL: https://doi.org/10.1038/s41598-024-57061-7, doi:10.1038/s41598-024-57061-7. This article has 2 citations and is from a peer-reviewed journal.
(zhang2021cnnm2relateddisordersphenotype pages 4-4): Han Zhang, Ye Wu, and Yuwu Jiang. Cnnm2-related disorders: phenotype and its severity were associated with the mode of inheritance. Frontiers in Pediatrics, Sep 2021. URL: https://doi.org/10.3389/fped.2021.699568, doi:10.3389/fped.2021.699568. This article has 9 citations.
(arjona2014cnnm2mutationscause pages 2-4): Francisco J. Arjona, Jeroen H. F. de Baaij, Karl P. Schlingmann, Anke L. L. Lameris, Erwin van Wijk, Gert Flik, Sabrina Regele, G. Christoph Korenke, Birgit Neophytou, Stephan Rust, Nadine Reintjes, Martin Konrad, René J. M. Bindels, and Joost G. J. Hoenderop. Cnnm2 mutations cause impaired brain development and seizures in patients with hypomagnesemia. PLoS Genetics, 10:e1004267, Apr 2014. URL: https://doi.org/10.1371/journal.pgen.1004267, doi:10.1371/journal.pgen.1004267. This article has 164 citations and is from a domain leading peer-reviewed journal.
(franken2021thephenotypicand pages 8-10): Gijs A. C. Franken, Dominik Müller, Cyril Mignot, Boris Keren, Jonathan Lévy, Anne‐Claude Tabet, David Germanaud, María‐Isabel Tejada, Hester Y. Kroes, Rutger A. J. Nievelstein, Elise Brimble, Maria Ruzhnikov, Felix Claverie‐Martin, Maria Szczepańska, Martin Ćuk, Femke Latta, Martin Konrad, Luis A. Martínez‐Cruz, René J. M. Bindels, Joost G. J. Hoenderop, Karl‐Peter Schlingmann, and Jeroen H. F. Baaij. The phenotypic and genetic spectrum of patients with heterozygous mutations in cyclin m2 (cnnm2). Human Mutation, 42:473-486, Mar 2021. URL: https://doi.org/10.1002/humu.24182, doi:10.1002/humu.24182. This article has 28 citations and is from a domain leading peer-reviewed journal.
(li2021casereportcnnm2 pages 5-6): Xiucui Li, Shijia Bao, Wei Wang, Xulai Shi, Ying Hu, Feng Li, Qianlei Zhao, Feixia Zheng, and Zhongdong Lin. Case report: cnnm2 mutations cause damaged brain development and intractable epilepsy in a patient without hypomagnesemia. Frontiers in Genetics, Aug 2021. URL: https://doi.org/10.3389/fgene.2021.705734, doi:10.3389/fgene.2021.705734. This article has 11 citations and is from a peer-reviewed journal.
(zhang2021cnnm2relateddisordersphenotype pages 2-4): Han Zhang, Ye Wu, and Yuwu Jiang. Cnnm2-related disorders: phenotype and its severity were associated with the mode of inheritance. Frontiers in Pediatrics, Sep 2021. URL: https://doi.org/10.3389/fped.2021.699568, doi:10.3389/fped.2021.699568. This article has 9 citations.