An autosomal recessive, adult-onset, axonal sensorimotor polyneuropathy that was mapped in a large consanguineous Costa Rican family and is caused by biallelic loss of function in PNKP, the bifunctional DNA-repair enzyme polynucleotide kinase 3'-phosphatase. The gene assignment has a history that this entry puts in front rather than in a footnote, because a reader who consults an older source will find the wrong gene. The locus was mapped to 19q13.3 in 2001; in 2009 an exhaustive Sanger screen of the interval found a single homozygous missense variant, MED25 p.Ala335Val, and MED25 was proposed as causative. No second CMT family with a MED25 variant was ever reported. Re-examining the same family by exome sequencing in 2018 found a homozygous nonsense variant in PNKP, p.Gln517ter, in the last exon of an adjacent gene inside the same linkage interval - a variant that the original screen had actually seen but discarded, because the PNKP annotation then in use placed it outside the coding sequence. Five further unrelated Costa Rican CMT2 patients who had been typed as MED25 heterozygotes turned out to be compound heterozygous for that PNKP allele and a second one, p.Thr408del, already associated with ataxia with oculomotor apraxia type 4. The MED25 and PNKP variants cosegregate on one ancestral founder haplotype, which is exactly why the first screen landed on the wrong one of the two. The ClinGen Charcot-Marie-Tooth Disease Gene Curation Expert Panel classified MED25-CMT2B2 as DISPUTED in 2021, noting among other things that the MED25 allele is homozygous in four unaffected gnomAD individuals. So this is not a mapped locus without a gene. It is a mapped locus whose gene was misassigned and then corrected, and the corrected gene brings a mechanism with it. PNKP is a bifunctional end-processing enzyme: it phosphorylates 5' ends and dephosphorylates 3' ends to create the 5'-phosphate/3'-hydroxyl termini that DNA ligase requires. Loss of that activity leaves single-strand breaks unrepaired, and in cells from patients across the whole PNKP disease spectrum the measured deficit is specifically in single-strand break repair and not in double-strand break repair. The p.Gln517ter allele truncates the last five residues of a C-terminus that is buried between the kinase and phosphatase domains and contacts both, so the predicted consequence is destabilisation of the folded enzyme rather than removal of a catalytic residue. What makes CMT2B2 a distinct entity within that spectrum rather than a relabelling of it is severity and tissue distribution. PNKP variants also cause microcephaly with seizures and developmental delay (MCSZ) at the severe neurodevelopmental end, and ataxia with oculomotor apraxia type 4 (AOA4) in between. The CMT2B2 patients have neither microcephaly, seizures nor developmental delay; onset is in the third decade; and the leading problem is a severe length-dependent axonal sensorimotor neuropathy, with cerebellar involvement present but mild - slurred speech in all of them, oculomotor involvement in some, and cerebellar atrophy on MRI without brain or brainstem atrophy. The 2018 authors attribute that mildness to an allelic effect. A further observation from the biochemistry lines up with the clinical split without proving it: reduced PNKP phosphatase activity tracks with neurodevelopmental disease while reduced kinase activity tracks with neurodegeneration. This entry records that correlation as a correlation. Management is supportive and is not disease-specific; no CMT2B2 treatment study appears in the sources curated here.
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Conditions with similar clinical presentations that must be differentiated from Charcot-Marie-Tooth Disease Type 2B2:
name: Charcot-Marie-Tooth Disease Type 2B2
creation_date: "2026-09-08T19:00:00Z"
category: Mendelian
disease_term:
preferred_term: Charcot-Marie-Tooth disease type 2B2
term:
id: MONDO:0011570
label: Charcot-Marie-Tooth disease type 2B2
synonyms:
- CMT2B2
- AR-CMT2B2
- ARCMT2B
- Charcot-Marie-Tooth disease, axonal, autosomal recessive, B2
- autosomal recessive axonal CMT4C3
- PNKP-related axonal Charcot-Marie-Tooth disease
parents:
- Charcot-Marie-Tooth Disease Type 2
- Hereditary Motor and Sensory Neuropathy
description: >-
An autosomal recessive, adult-onset, axonal sensorimotor polyneuropathy that
was mapped in a large consanguineous Costa Rican family and is caused by
biallelic loss of function in PNKP, the bifunctional DNA-repair enzyme
polynucleotide kinase 3'-phosphatase.
The gene assignment has a history that this entry puts in front rather than in
a footnote, because a reader who consults an older source will find the wrong
gene. The locus was mapped to 19q13.3 in 2001; in 2009 an exhaustive Sanger
screen of the interval found a single homozygous missense variant, MED25
p.Ala335Val, and MED25 was proposed as causative. No second CMT family with a
MED25 variant was ever reported. Re-examining the same family by exome
sequencing in 2018 found a homozygous nonsense variant in PNKP, p.Gln517ter,
in the last exon of an adjacent gene inside the same linkage interval - a
variant that the original screen had actually seen but discarded, because the
PNKP annotation then in use placed it outside the coding sequence. Five further
unrelated Costa Rican CMT2 patients who had been typed as MED25 heterozygotes
turned out to be compound heterozygous for that PNKP allele and a second one,
p.Thr408del, already associated with ataxia with oculomotor apraxia type 4. The
MED25 and PNKP variants cosegregate on one ancestral founder haplotype, which
is exactly why the first screen landed on the wrong one of the two. The ClinGen
Charcot-Marie-Tooth Disease Gene Curation Expert Panel classified
MED25-CMT2B2 as DISPUTED in 2021, noting among other things that the MED25
allele is homozygous in four unaffected gnomAD individuals.
So this is not a mapped locus without a gene. It is a mapped locus whose gene
was misassigned and then corrected, and the corrected gene brings a mechanism
with it. PNKP is a bifunctional end-processing enzyme: it phosphorylates 5'
ends and dephosphorylates 3' ends to create the 5'-phosphate/3'-hydroxyl
termini that DNA ligase requires. Loss of that activity leaves single-strand
breaks unrepaired, and in cells from patients across the whole PNKP disease
spectrum the measured deficit is specifically in single-strand break repair
and not in double-strand break repair. The p.Gln517ter allele truncates the
last five residues of a C-terminus that is buried between the kinase and
phosphatase domains and contacts both, so the predicted consequence is
destabilisation of the folded enzyme rather than removal of a catalytic
residue.
What makes CMT2B2 a distinct entity within that spectrum rather than a
relabelling of it is severity and tissue distribution. PNKP variants also cause
microcephaly with seizures and developmental delay (MCSZ) at the severe
neurodevelopmental end, and ataxia with oculomotor apraxia type 4 (AOA4) in
between. The CMT2B2 patients have neither microcephaly, seizures nor
developmental delay; onset is in the third decade; and the leading problem is a
severe length-dependent axonal sensorimotor neuropathy, with cerebellar
involvement present but mild - slurred speech in all of them, oculomotor
involvement in some, and cerebellar atrophy on MRI without brain or brainstem
atrophy. The 2018 authors attribute that mildness to an allelic effect. A
further observation from the biochemistry lines up with the clinical split
without proving it: reduced PNKP phosphatase activity tracks with
neurodevelopmental disease while reduced kinase activity tracks with
neurodegeneration. This entry records that correlation as a correlation.
Management is supportive and is not disease-specific; no CMT2B2 treatment
study appears in the sources curated here.
notes: >-
Deep-research provenance, recorded because the first attempt failed in a way a
later curator should know about. The committed falcon report
(research/Charcot-Marie-Tooth_Disease_Type_2B2-deep-research-falcon.md) is a
retry. The first run, launched from the plain entry name, produced a report
that was about the right disease (CMT2B2 named 62 times) but reproduced the
superseded 2009 gene assignment throughout: MED25 was mentioned 57 times and
PNKP zero times, with no mention of Gln517ter, AOA4 or MCSZ, and its
curation conclusion was to represent CMT2B2 as a MED25 disease-gene assertion.
That report was discarded rather than committed, because research/ is consumed
as a curation input and it would have led a curator to the disputed gene. The
retry inlined the gene, the two alleles, the OMIM number and the reassigning
paper in the disease_name variable, and returned PNKP as the top gene at 89
occurrences against MED25 at 19, reaching the same conclusion this entry does
independently. Reproduce the failure with:
`just research-disorder falcon Charcot-Marie-Tooth_Disease_Type_2B2`.
Note also that `just preflight-dr` returns SKIP for this entity in both runs,
because MONDO records no causal gene for MONDO:0011570 and the gene-identity
discriminator therefore cannot run. SKIP is not a pass; the substitution and
gene-attribution checks here were done by hand.
classifications:
harrisons_chapter:
- classification_value: NEUROLOGIC
external_assertions:
- name: OMIM Charcot-Marie-Tooth disease, axonal, type 2B2
source: OMIM
assertion_type: disease_record
external_id: OMIM:605589
description: >-
OMIM phenotype entry for CMT2B2, the 19q13.3 axonal recessive CMT mapped in
the Costa Rican family.
- name: ClinGen MED25 / Charcot-Marie-Tooth disease type 2B2 (Disputed)
source: ClinGen
assertion_type: gene_disease_validity
external_id: CGGV:assertion_c0e0d66f-c68d-4df3-bab2-71afc448e4b0-2021-03-22T201527.084Z
description: >-
Charcot-Marie-Tooth Disease Gene Curation Expert Panel, 22 March 2021, SOP8:
Disputed, autosomal recessive. The panel's reasoning names PNKP as the better
supported gene.
prevalence:
- population: Costa Rica (founder haplotype)
measure_type: CASES_IN_LITERATURE
prevalence_class: NOT_YET_DOCUMENTED
notes: >-
No prevalence estimate exists. The published series is one large
consanguineous Costa Rican family plus five unrelated Costa Rican CMT2
patients, all carrying the same ancestral founder haplotype. Whether the
entity exists outside that founder population is unknown.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "suggesting that this is an ancestral founder haplotype"
explanation: >-
The reported patients all carry one ancestral haplotype, which is why the
case count is not a population estimate.
inheritance:
- name: Autosomal Recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
The original family is consanguineous and multi-generational with all
affected members homozygous for PNKP p.Gln517ter; the five later patients are
compound heterozygous for p.Gln517ter and p.Thr408del.
evidence:
- reference: CGGV:assertion_c0e0d66f-c68d-4df3-bab2-71afc448e4b0-2021-03-22T201527.084Z
reference_title: "MED25 / Charcot-Marie-Tooth disease type 2B2 (Disputed)"
supports: SUPPORT
evidence_source: OTHER
snippet: "In association with a late-onset, axonal, sensorimotor polyneuropathy, MED25 was first described in a Costa Rican family with an extended multi-generational, autosomal recessive pedigree"
explanation: >-
Records the recessive pedigree structure of the founding family, which is
unchanged by the later reassignment of the gene.
pathophysiology:
- name: Biallelic PNKP Loss-of-Function Variant
role: trigger
biological_scale: MOLECULAR
description: >-
The founding family is homozygous for PNKP c.1549C>T p.Gln517ter, a nonsense
variant in the last exon that removes the final five residues. Five further
Costa Rican patients are compound heterozygous for that allele and
c.1221_1223del p.Thr408del, an in-frame deletion previously reported in
ataxia with oculomotor apraxia type 4. Both alleles sit on the same ancestral
haplotype as the MED25 p.Ala335Val variant that was originally proposed as
causative, which is why an exhaustive Sanger screen of the interval reached
the wrong gene in 2009.
genetic_context:
allele_type: SNV
variant_origin: GERMLINE
zygosity: HOMOZYGOUS
functional_impact_category: LOSS_OF_FUNCTION
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Using exome sequencing, we now identified a homozygous nonsense variant (p.Gln517ter) in the last exon of an adjacent gene, the polynucleotide kinase 3'-phosphatase (PNKP) gene."
explanation: >-
The gene-discovery statement that reassigns CMT2B2 from MED25 to PNKP.
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "It consists of a three-base deletion in exon 14, c.1221_1223del"
explanation: >-
The second allele, carried in compound heterozygosity by the five later
patients.
- reference: CGGV:assertion_c0e0d66f-c68d-4df3-bab2-71afc448e4b0-2021-03-22T201527.084Z
reference_title: "MED25 / Charcot-Marie-Tooth disease type 2B2 (Disputed)"
supports: SUPPORT
evidence_source: OTHER
snippet: "The authors identified 5 further families carrying biallelic loss-of-function mutations in PNKP as well, pointing towards the pathogenicity of this gene over MED25."
explanation: >-
ClinGen's independent reading of the same evidence, naming PNKP as the
causative gene for this entity.
downstream:
- target: Destabilised PNKP C-Terminus and Loss of DNA End-Processing Activity
causal_link_type: DIRECT
description: >-
The truncated residues are structural, so the first consequence is on the
enzyme itself.
- name: Destabilised PNKP C-Terminus and Loss of DNA End-Processing Activity
role: central_effector
biological_scale: MOLECULAR
description: >-
PNKP is bifunctional: a 5'-kinase and a 3'-phosphatase that together convert
damaged break termini into the 5'-phosphate/3'-hydroxyl ends that ligation
requires. Its two catalytic domains both bind DNA and the C-terminus is
buried between them, contacting residues in each. The residues removed by
p.Gln517ter are exactly those contacts, so the predicted lesion is
destabilisation of the folded enzyme rather than loss of a catalytic residue.
molecular_functions:
- preferred_term: PNKP polynucleotide 5'-kinase activity
term:
id: GO:0046404
label: ATP-dependent polydeoxyribonucleotide 5'-hydroxyl-kinase activity
modifier: LOSS_OF_FUNCTION
- preferred_term: PNKP polynucleotide 3'-phosphatase activity
term:
id: GO:0046403
label: polynucleotide 3'-phosphatase activity
modifier: LOSS_OF_FUNCTION
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "PKNP catalyzes the 5-prime phosphorylation of nucleic acids and also has an associated 3-prime phosphatase activity"
explanation: >-
The two enzymatic activities of PNKP. The source spells the gene PKNP here;
the quote is reproduced as printed.
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: COMPUTATIONAL
snippet: "PNKP contains a kinase and a phosphate domain that are both involved in DNA binding."
explanation: >-
The domain architecture behind the structural-destabilisation reading. The
structural analysis in that paper is a homology model of human PNKP built on
the murine crystal structure, so it is graded as computational.
downstream:
- target: Impaired DNA Single-Strand Break Repair
causal_link_type: DIRECT
description: >-
Without correctly processed termini, the ligation step of single-strand
break repair cannot proceed.
- name: Impaired DNA Single-Strand Break Repair
role: central_effector
biological_scale: MOLECULAR
description: >-
Primary fibroblasts from PNKP patients spanning the whole disease spectrum
show a markedly reduced rate of single-strand break repair. The same study
looked for a double-strand break repair defect and did not find one, which
matters because PNKP participates in both pathways and the double-strand
route would have been the natural assumption. Restoring repair in those cells
needed both catalytic activities plus the FHA domain that binds XRCC1.
cell_types:
- preferred_term: fibroblast
term:
id: CL:0000057
label: fibroblast
biological_processes:
- preferred_term: single strand break repair
term:
id: GO:0000012
label: single strand break repair
modifier: DECREASED
evidence:
- reference: PMID:32504494
reference_title: "Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "In contrast, the rate of SSB repair (SSBR) is markedly reduced."
explanation: >-
The measured repair deficit in patient-derived fibroblasts.
- reference: PMID:32504494
reference_title: "Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair."
supports: REFUTE
evidence_source: IN_VITRO
snippet: "did not detect a significant defect in DSB repair (DSBR) in primary fibroblasts from PNKP patients spanning the spectrum of PNKP-mutated pathologies."
explanation: >-
Cited against the alternative reading of this node, that the lesion is in
double-strand break repair. It is a negative result and is curated as one.
- reference: PMID:32504494
reference_title: "Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Hereditary mutations in polynucleotide kinase-phosphatase (PNKP) result in a spectrum of neurological pathologies ranging from neurodevelopmental dysfunction in microcephaly with early onset seizures (MCSZ) to neurodegeneration in ataxia oculomotor apraxia-4 (AOA4) and Charcot-Marie-Tooth disease (CMT2B2)."
explanation: >-
Places CMT2B2 explicitly inside the PNKP allelic spectrum whose repair
biology this study measured, so the cellular result is about this disease
and not only about its severe siblings.
downstream:
- target: Accumulation of Unrepaired Single-Strand Breaks in Post-Mitotic Neurons
causal_link_type: DIRECT
description: >-
A reduced repair rate in cells that cannot dilute damage by division leaves
breaks outstanding.
- name: Accumulation of Unrepaired Single-Strand Breaks in Post-Mitotic Neurons
role: effector
biological_scale: CELLULAR
description: >-
The step from a measured repair-rate deficit in fibroblasts to break burden
in human neurons is an inference, not a measurement, and is curated as one.
What supports it is that the study's own conclusion frames reduced
single-strand break repair as the source of the neurodegenerative as well as
the neurodevelopmental pathology, and that the extent of the reduction tracks
disease severity.
cell_types:
- preferred_term: neuron
term:
id: CL:0000540
label: neuron
biological_processes:
- preferred_term: DNA repair
term:
id: GO:0006281
label: DNA repair
modifier: DECREASED
evidence:
- reference: PMID:32504494
reference_title: "Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair."
supports: SUPPORT
directness: INDIRECT
evidence_source: IN_VITRO
snippet: "these data implicate reduced rates of SSBR, not DSBR, as the source of both neurodevelopmental and neurodegenerative pathology in PNKP-mutated disease"
explanation: >-
The authors' own attribution of the neurodegenerative arm of PNKP disease to
the single-strand break repair deficit. Graded INDIRECT because the
measurement is in fibroblasts and the claim is about neurons.
downstream:
- target: Length-Dependent Peripheral Axonal Degeneration
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
No intermediate step between outstanding breaks and axonal loss is
established in the sources curated here.
- target: Cerebellar Neuronal Injury
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
The same unresolved gap applies to the cerebellar arm.
- name: Length-Dependent Peripheral Axonal Degeneration
role: effector
biological_scale: TISSUE
conforms_to: "peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination"
description: >-
Every reported patient, from the original family and from the five later
families, was diagnosed clinically and electrophysiologically with an axonal
peripheral polyneuropathy. Nerve conduction shows a severe reduction of the
compound muscle action potential with relative preservation of F-wave latency
- the axonal-loss pattern, not a demyelinating one - and in the most affected
patient the CMAP could not be recorded at all.
cell_types:
- preferred_term: sensory neuron
term:
id: CL:0000101
label: sensory neuron
- preferred_term: motor neuron
term:
id: CL:0000100
label: motor neuron
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "All patients from the large Costa Rican family and the five additional families were clinically and electrophysiologically diagnosed with axonal peripheral polyneuropathy."
explanation: >-
Establishes the axonal polyneuropathy across the whole reported series.
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the electrophysiological analysis demonstrated a severe reduction of the CMAP of affected nerves with relative preservation of F-waves latency"
explanation: >-
The electrophysiological signature of axonal loss that this node asserts.
downstream:
- target: Adult-Onset Axonal Sensorimotor Polyneuropathy
causal_link_type: DIRECT
description: >-
Progressive length-dependent fibre loss is the leading clinical problem.
- name: Cerebellar Neuronal Injury
role: effector
biological_scale: TISSUE
conforms_to: "cerebellar_purkinje_degeneration#Cerebellar Neuron Insult"
description: >-
Brain MRI showed cerebellar atrophy in every individual studied, with no
white-matter abnormality and no brain or brainstem atrophy. The
cerebellum is therefore involved but selectively and mildly compared with the
severe end of the PNKP spectrum. No neuropathology is available in this
entity, so the cellular target within the cerebellum is not identified here
and Purkinje-cell loss specifically is not asserted.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "MRI of the brain revealed cerebellar atrophy with no white matter abnormalities, brain atrophy, nor brainstem atrophy, in all studied individuals"
explanation: >-
The imaging finding, including the negatives that bound how far the
cerebellar claim extends.
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: OTHER
snippet: "Homozygous variants in this gene were previously linked to progressive cerebellar atrophy and polyneuropathy [6]"
explanation: >-
The combination of cerebellar atrophy with polyneuropathy was already on
record for PNKP before this entity was reassigned to it.
downstream:
- target: Mild Cerebellar Dysfunction
causal_link_type: DIRECT
description: >-
Cerebellar atrophy is expressed clinically as dysarthria and oculomotor
signs rather than as a disabling ataxia.
- name: Adult-Onset Axonal Sensorimotor Polyneuropathy
role: outcome
biological_scale: ORGANISM
conforms_to: "peripheral_axonal_degeneration#Peripheral Neuropathy"
description: >-
A symmetric motor and sensory neuropathy with distal muscle wasting and
impaired deep tendon reflexes, beginning between the ages of 28 and 42 in the
original family, progressing slowly, and ending in loss of independent
ambulation in the most advanced patient.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "presented with a symmetric motor and sensory neuropathy, distal muscle wasting, impaired deep tendon reflexes, and age at onset between 28 and 42 years."
explanation: >-
The clinical syndrome and its adult age of onset in the founding family.
downstream:
- target: Distal Muscle Weakness
causal_link_type: DIRECT
description: Length-dependent motor fibre loss.
- target: Distal Amyotrophy
causal_link_type: DIRECT
description: Denervation atrophy of intrinsic hand and foot muscles and calves.
- target: Areflexia
causal_link_type: DIRECT
description: Loss of the afferent and efferent limbs of the tendon reflex arc.
- target: Distal Sensory Impairment
causal_link_type: DIRECT
description: Large-fibre sensory loss, vibration and position first.
- target: Pes Cavus and Hammertoes
causal_link_type: DIRECT
description: >-
Chronic imbalance between intrinsic and extrinsic foot muscles, in the one
patient in whom it was recorded.
- target: Claw Hand Deformity
causal_link_type: DIRECT
description: >-
Wasting of the intrinsic hand muscles with unopposed long flexors and
extensors; the commonest deformity in the reassessed patients.
- target: Scoliosis
causal_link_type: DIRECT
description: >-
Mild lumbar scoliosis, recorded in all four reassessed patients alongside
the axial and proximal weakness.
- target: Loss of Ambulation
causal_link_type: DIRECT
description: The end state of progressive distal and then proximal weakness.
- name: Mild Cerebellar Dysfunction
role: outcome
biological_scale: ORGANISM
description: >-
Slurred speech in every reassessed patient and oculomotor involvement in
some, without microcephaly, seizures or developmental delay. This is the
clinical expression of the milder end of the PNKP spectrum, which the 2018
authors attribute to an allelic effect.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Detailed clinical reassessment of the initial family and the new individuals revealed in all an adult-onset slowly progressive CMT2 associated with signs of cerebellar dysfunction such as slurred speech and oculomotor involvement, but neither microcephaly, seizures, nor developmental delay."
explanation: >-
The defining clinical contrast with MCSZ and with the severe AOA4 end of the
spectrum.
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We propose that PKNP variants are the major causative variant for the CMT2 phenotype in these individuals and that the milder clinical manifestation is due to an allelic effect."
explanation: >-
The authors' proposed explanation for the mildness, quoted with its hedge
intact - it is a proposal, not a demonstration.
downstream:
- target: Dysarthria
causal_link_type: DIRECT
description: Cerebellar speech.
- target: Oculomotor Apraxia
causal_link_type: DIRECT
description: >-
Difficulty initiating voluntary saccades, in the two male patients.
- target: Cerebellar Atrophy
causal_link_type: DIRECT
description: The imaging correlate.
- target: Gait Ataxia
causal_link_type: DIRECT
description: >-
Recorded in the one patient still ambulant without support, where it is
separable from the weakness-driven gait failure of the others.
phenotypes:
- category: Neurologic
name: Distal Muscle Weakness
phenotype_term:
preferred_term: Distal muscle weakness
term:
id: HP:0002460
label: Distal muscle weakness
clinical_course: PROGRESSIVE
frequency: OBLIGATE
notes: >-
Present in all reported patients. The band is OBLIGATE because the neuropathy
is the ascertainment criterion for the entity, not because a penetrance study
exists.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "presented with a symmetric motor and sensory neuropathy, distal muscle wasting, impaired deep tendon reflexes, and age at onset between 28 and 42 years."
explanation: Distal motor involvement in the founding family.
- category: Neurologic
name: Distal Amyotrophy
phenotype_term:
preferred_term: Distal amyotrophy
term:
id: HP:0003693
label: Distal amyotrophy
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "presented with a symmetric motor and sensory neuropathy, distal muscle wasting, impaired deep tendon reflexes, and age at onset between 28 and 42 years."
explanation: Distal muscle wasting in the founding family.
- category: Neurologic
name: Areflexia
description: >-
Deep-tendon reflexes were absent in the lower extremities of the reassessed
patients and reduced in the upper limbs.
phenotype_term:
preferred_term: Areflexia
term:
id: HP:0001284
label: Areflexia
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Deep-tendon reflexes were absent in the lower extremities."
explanation: The reflex finding in the reassessed patients.
- category: Neurologic
name: Distal Sensory Impairment
description: >-
Marked loss of vibration and position sense in upper and lower limbs, with
touch and pain preserved only in the upper extremities - a large-fibre
pattern.
phenotype_term:
preferred_term: Distal sensory impairment
term:
id: HP:0002936
label: Distal sensory impairment
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "presented with a symmetric motor and sensory neuropathy, distal muscle wasting, impaired deep tendon reflexes, and age at onset between 28 and 42 years."
explanation: >-
Sensory as well as motor involvement in the founding family. The detailed
modality breakdown is in the same paper's clinical section.
- category: Musculoskeletal
name: Pes Cavus and Hammertoes
description: >-
Recorded in the youngest male of the four reassessed patients; the other
three had claw hand and mild lumbar scoliosis without pes cavus.
phenotype_term:
preferred_term: Pes cavus
term:
id: HP:0001761
label: Pes cavus
notes: >-
1/4 reassessed patients. No frequency band is given: four patients cannot
support one, and the source attributes the finding to a single individual.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "only the youngest male (CMT1190, compound heterozygous) had pes cavus and hammertoes"
explanation: >-
Attributes the foot deformity to one of the four reassessed patients, which
is why no frequency band is asserted.
- category: Neurologic
name: Loss of Ambulation
description: >-
The most advanced patient had been wheelchair-bound for five years and was
dependent for activities of daily living; two others were only intermittently
mobile.
phenotype_term:
preferred_term: Loss of ambulation
term:
id: HP:0002505
label: Loss of ambulation
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mobility 5 years in wheelchair Mobile, mild gait ataxia Intermittent mobile Intermittent mobile"
explanation: >-
The mobility row of the clinical table, which the cache renders as a flat
line. Read across the four patients it gives: five years in a wheelchair,
mobile with mild gait ataxia, and two intermittently mobile.
- category: Neurologic
name: Dysarthria
description: >-
Slurred speech was present in all four reassessed patients and was most
pronounced in the oldest.
phenotype_term:
preferred_term: Dysarthria
term:
id: HP:0001260
label: Dysarthria
frequency: OBLIGATE
notes: >-
4/4 reassessed patients. OBLIGATE is used against that denominator only; the
full reported series is larger than the four who were reassessed in person.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "None of them were affected by movement disorders, but all had slurred speech, most pronounced in the oldest male (CMT1003, compound heterozygous)."
explanation: >-
Slurred speech in all reassessed patients, and the absence of a movement
disorder alongside it.
- category: Neurologic
name: Oculomotor Apraxia
description: >-
Difficulty initiating voluntary saccades, complete in the oldest male and
partial in the youngest, with the vestibulo-ocular reflex preserved in both.
The two females had at most mild difficulty initiating saccades.
phenotype_term:
preferred_term: Oculomotor apraxia
term:
id: HP:0000657
label: Oculomotor apraxia
notes: >-
2/4 reassessed patients, and it is the feature that most clearly links this
entity to AOA4 at the other end of the PNKP spectrum. No frequency band is
given for a denominator of four.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Detailed clinical reassessment of the initial family and the new individuals revealed in all an adult-onset slowly progressive CMT2 associated with signs of cerebellar dysfunction such as slurred speech and oculomotor involvement, but neither microcephaly, seizures, nor developmental delay."
explanation: Oculomotor involvement as part of the cerebellar picture.
- category: Neurologic
name: Cerebellar Atrophy
description: >-
Cerebellar atrophy on brain MRI in every individual imaged, without
white-matter change and without brain or brainstem atrophy.
phenotype_term:
preferred_term: Cerebellar atrophy
term:
id: HP:0001272
label: Cerebellar atrophy
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "MRI of the brain revealed cerebellar atrophy with no white matter abnormalities, brain atrophy, nor brainstem atrophy, in all studied individuals"
explanation: The imaging finding in all imaged patients.
- category: Musculoskeletal
name: Claw Hand Deformity
description: >-
Claw hand was present in all four reassessed patients - three times as common
as the pes cavus curated alongside it - and follows the wasting of the
intrinsic hand muscles that the same examination records.
phenotype_term:
preferred_term: Claw hand deformity
term:
id: HP:0034337
label: Claw hand deformity
frequency: OBLIGATE
notes: >-
4/4 reassessed patients. OBLIGATE is used against that denominator only; the
full reported series is larger than the four examined in person.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Deformities Claw hand Claw hand, pes cavus and hammertoes Claw hand Claw hand"
explanation: >-
The deformities row of the clinical table, which the cache renders as a flat
line. Read across the four patients it gives claw hand in all four, with pes
cavus and hammertoes added in the second.
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "mild lumbar scoliosis and a claw hand"
explanation: >-
The narrative statement of the same finding on general examination.
- category: Musculoskeletal
name: Scoliosis
description: >-
Mild lumbar scoliosis on general examination in all four reassessed patients.
phenotype_term:
preferred_term: Scoliosis
term:
id: HP:0002650
label: Scoliosis
severity: MILD
notes: >-
4/4 reassessed patients, described as mild and lumbar. No band is asserted
beyond that denominator.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "mild lumbar scoliosis and a claw hand"
explanation: >-
General-examination finding in the reassessed patients.
- category: Neurologic
name: Gait Ataxia
description: >-
Mild gait ataxia in the one patient who remained able to walk without support.
In the others, gait failure is driven by weakness rather than by ataxia, which
is why the finding is recorded separately from Loss of Ambulation rather than
folded into it.
phenotype_term:
preferred_term: Gait ataxia
term:
id: HP:0002066
label: Gait ataxia
severity: MILD
notes: >-
1/4 reassessed patients. This is the feature that places CMT2B2 on the same
axis as AOA4 while keeping it at the mild end: ataxia is present but is not
the leading disability, which is the contrast the differential turns on. No
frequency band is asserted for a denominator of four.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Mobility 5 years in wheelchair Mobile, mild gait ataxia Intermittent mobile Intermittent mobile"
explanation: >-
The mobility row of the clinical table, which the cache renders as a flat
line. Across the four patients it gives five years in a wheelchair, mobile
with mild gait ataxia, and two intermittently mobile; the ataxia belongs to
the second.
- category: Neurologic
name: Absence of Microcephaly, Seizures and Developmental Delay
description: >-
Curated as a positive finding because it is what separates this entity from
MCSZ, the severe neurodevelopmental end of the same gene's spectrum. Neither
cognitive impairment, nor microcephaly, nor seizures was found on neurological
examination.
phenotype_term:
preferred_term: Absence of microcephaly, seizures and developmental delay
notes: >-
Deliberately carries no `term:`. The HPO has no class for the coordinated
absence of three features, and binding any one of them would assert its
presence. Deliberately left unwired to the pathograph as well: it is a
negative finding that bounds the entity against its allelic siblings, not a
consequence of any node in the causal chain.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Detailed clinical reassessment of the initial family and the new individuals revealed in all an adult-onset slowly progressive CMT2 associated with signs of cerebellar dysfunction such as slurred speech and oculomotor involvement, but neither microcephaly, seizures, nor developmental delay."
explanation: >-
The examined absence of the MCSZ features, which is what makes this a
distinct point on the PNKP spectrum.
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The neurological examination did not show evidence of cognitive impairment"
explanation: >-
Adds the absence of cognitive impairment on examination. The same sentence
goes on to exclude microcephaly and seizures, but carries a bracketed
citation marker there that the reference validator strips, so only the first
clause is quoted.
genetic:
- name: PNKP
gene_term:
preferred_term: PNKP
term:
id: hgnc:9154
label: PNKP
relationship_type: CAUSATIVE
variant_origin: GERMLINE
inheritance:
- name: Autosomal Recessive
notes: >-
PNKP encodes polynucleotide kinase 3'-phosphatase, a bifunctional DNA
end-processing enzyme. Two disease alleles are reported in this entity:
c.1549C>T p.Gln517ter, homozygous in the original Costa Rican family, and
c.1221_1223del p.Thr408del, carried in compound heterozygosity with it by five
further Costa Rican patients and previously associated with AOA4. Both lie on
the same ancestral founder haplotype as the MED25 variant that was originally
proposed. ClinGen has no curation of the PNKP-CMT2B2 relationship itself; its
PNKP record covers microcephaly, seizures and developmental delay
(MONDO:0013254, Definitive).
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Using exome sequencing, we now identified a homozygous nonsense variant (p.Gln517ter) in the last exon of an adjacent gene, the polynucleotide kinase 3'-phosphatase (PNKP) gene."
explanation: The gene assignment for this entity.
- reference: CGGV:assertion_c0e0d66f-c68d-4df3-bab2-71afc448e4b0-2021-03-22T201527.084Z
reference_title: "MED25 / Charcot-Marie-Tooth disease type 2B2 (Disputed)"
supports: SUPPORT
evidence_source: OTHER
snippet: "Re-assessing the first and only reported family by WES, Leal et al. identified a homozygous stop mutation in PNKP, a gene that is located in the same linkage region"
explanation: >-
ClinGen's account of the reassignment, from the panel that disputed the
previous gene.
- name: MED25
gene_term:
preferred_term: MED25
term:
id: hgnc:28845
label: MED25
association: Disputed ClinGen gene-disease validity; superseded by PNKP
relationship_type: DISPUTED
variant_origin: GERMLINE
notes: >-
Recorded because the 2009 assignment is still in circulation and a curator or
clinician meeting "CMT2B2, MED25" needs to find the correction here rather
than assume this entry is out of date. The MED25 p.Ala335Val variant
cosegregates with the causal PNKP alleles on one founder haplotype, no second
CMT family with a MED25 variant has been published, and the variant is
homozygous in four unaffected gnomAD individuals. MED25 does cause a separate
recessive disorder, Basel-Vanagaite-Smirin-Yosef syndrome, which is curated
separately and does not include neuropathy.
evidence:
- reference: CGGV:assertion_c0e0d66f-c68d-4df3-bab2-71afc448e4b0-2021-03-22T201527.084Z
reference_title: "MED25 / Charcot-Marie-Tooth disease type 2B2 (Disputed)"
supports: SUPPORT
evidence_source: OTHER
snippet: "MED25 | HGNC:28845 | Charcot-Marie-Tooth disease type 2B2 | MONDO:0011570 | AR | Disputed | SOP8 | Charcot-Marie-Tooth Disease Gene Curation Expert Panel"
explanation: >-
The ClinGen classification row, keyed on this entry's own MONDO identifier.
- reference: CGGV:assertion_c0e0d66f-c68d-4df3-bab2-71afc448e4b0-2021-03-22T201527.084Z
reference_title: "MED25 / Charcot-Marie-Tooth disease type 2B2 (Disputed)"
supports: REFUTE
evidence_source: OTHER
snippet: "the only reported variant has been found in a homozygous state in 4 unaffected individuals (GnomAD)"
explanation: >-
Population evidence against MED25 p.Ala335Val being sufficient to cause the
disease.
- reference: PMID:19290556
reference_title: "Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We identified a homozygous p.A335V mutation in the MED25 gene in an extended Costa Rican family with autosomal recessively inherited Charcot-Marie-Tooth neuropathy linked to the CMT2B2 locus in chromosome 19q13.3."
explanation: >-
The original 2009 assignment, cited so the superseded claim is visible in the
entry rather than only its correction.
diagnosis:
- name: Nerve Conduction Studies and Electromyography
description: >-
Electrophysiology establishes the axonal character: severely reduced compound
muscle action potentials with relative preservation of F-wave latencies,
rather than the uniform conduction slowing of a demyelinating neuropathy.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the electrophysiological analysis demonstrated a severe reduction of the CMAP of affected nerves with relative preservation of F-waves latency"
explanation: The electrophysiological pattern used to classify the neuropathy.
- name: Brain MRI
description: >-
Worth doing even when the presentation is a pure neuropathy: cerebellar
atrophy was present in every patient imaged and is the finding that points
from an isolated axonal CMT2 towards the PNKP spectrum.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "MRI of the brain revealed cerebellar atrophy with no white matter abnormalities, brain atrophy, nor brainstem atrophy, in all studied individuals"
explanation: The imaging finding that redirects the differential.
- name: PNKP Sequencing, and Reading the Whole Gene
description: >-
The cautionary detail from the original work is that the causal variant was
present in the first Sanger screen and was discarded, because the PNKP gene
annotation in use at the time contained an upstream stop codon that placed the
variant outside the coding sequence. A last-exon variant in a gene with a
contested annotation is exactly what a filtering step drops.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Using exome sequencing, we now identified a homozygous nonsense variant (p.Gln517ter) in the last exon of an adjacent gene, the polynucleotide kinase 3'-phosphatase (PNKP) gene."
explanation: >-
The variant and its position in the last exon, which is the part of the gene
the earlier analysis mishandled.
differential_diagnoses:
- name: Ataxia with oculomotor apraxia type 4 (AOA4)
description: >-
The same gene and, in five of the reported CMT2B2 patients, literally one of
the same alleles: p.Thr408del was described first in AOA4. AOA4 leads with
ataxia and oculomotor apraxia; CMT2B2 leads with the neuropathy and has
cerebellar signs that are mild by comparison. The distinction is one of
severity and emphasis within an allelic spectrum, not of gene.
evidence:
- reference: PMID:32504494
reference_title: "Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Hereditary mutations in polynucleotide kinase-phosphatase (PNKP) result in a spectrum of neurological pathologies ranging from neurodevelopmental dysfunction in microcephaly with early onset seizures (MCSZ) to neurodegeneration in ataxia oculomotor apraxia-4 (AOA4) and Charcot-Marie-Tooth disease (CMT2B2)."
explanation: Places the three PNKP entities on one spectrum.
- name: Microcephaly with seizures and developmental delay (MCSZ)
description: >-
The severe neurodevelopmental end of the PNKP spectrum. It is excluded here on
examination rather than by assumption: the reassessed CMT2B2 patients had no
cognitive impairment, no microcephaly and no seizures.
evidence:
- reference: PMID:30039206
reference_title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Detailed clinical reassessment of the initial family and the new individuals revealed in all an adult-onset slowly progressive CMT2 associated with signs of cerebellar dysfunction such as slurred speech and oculomotor involvement, but neither microcephaly, seizures, nor developmental delay."
explanation: The examined absence of the MCSZ features.
- name: PNKP neuropathy presenting before ataxia
description: >-
A separate report describes early-onset axonal sensorimotor neuropathy from
PNKP variants with ataxia appearing only years later and without oculomotor
apraxia. It matters for the differential because it means a PNKP patient can
present as a pure CMT for a long time, so the absence of cerebellar signs at
first assessment does not exclude the gene.
evidence:
- reference: PMID:27066567
reference_title: Mutation in PNKP presenting initially as axonal Charcot-Marie-Tooth disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "early-onset axonal sensory-motor neuropathy (or axonal Charcot-Marie-Tooth (CMT) disease) followed years later by ataxia without oculomotor apraxia can be caused by deleterious variants in PNKP"
explanation: >-
Establishes that PNKP disease can present as an isolated axonal neuropathy
before any cerebellar sign appears.
treatments:
- name: Physiotherapy, orthoses and rehabilitation
description: >-
Care is supportive and is extrapolated from general Charcot-Marie-Tooth
practice: individualised physiotherapy, ankle-foot orthoses and mobility aids,
and orthopaedic assessment of fixed foot deformity or scoliosis.
therapeutic_modality: BEHAVIORAL
treatment_term:
preferred_term: physical therapy and rehabilitation
term:
id: NCIT:C15302
label: Physical Therapy
target_phenotypes:
- preferred_term: Distal muscle weakness
term:
id: HP:0002460
label: Distal muscle weakness
- preferred_term: Loss of ambulation
term:
id: HP:0002505
label: Loss of ambulation
notes: >-
No treatment study specific to CMT2B2 appears in the sources curated here, so
this records what is done rather than what has been tested in this entity. It
is grounded in the general CMT2 management literature instead, and the source
used for that is a GeneReviews chapter that has been formally RETIRED by its
publisher and is flagged as possibly out of date. It is cited because it is
the general CMT2 management literature the entry's description already says
the care is extrapolated from, and leaving the extrapolation unsourced would
have been the weaker option; but a current chapter should replace it when one
exists. Note also that the retired chapter is written around the dominant CMT2
subtypes, while this entity is recessive.
evidence:
- reference: PMID:20301462
reference_title: "Charcot-Marie-Tooth Neuropathy Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: "special shoes and/or ankle/foot orthoses (AFO) to correct foot drop and aid walking; surgery as needed for severe pes cavus; forearm crutches, canes, wheelchairs as needed for mobility; exercise as tolerated"
explanation: >-
The general CMT2 management recommendations this treatment extrapolates
from. Graded INDIRECT because the chapter is about CMT2 as a group and says
nothing about CMT2B2 or PNKP, and OTHER because it is expert consensus
guidance rather than a study - and it is a retired chapter.
- name: Genetic counselling and cascade testing
description: >-
Autosomal recessive counselling for the family, with the specific point that
the founder haplotype carries both a MED25 and a PNKP variant, so a report
naming only MED25 does not settle carrier status.
therapeutic_modality: OTHER
treatment_term:
preferred_term: genetic counseling
term:
id: NCIT:C15240
label: Genetic Counseling
notes: >-
The counselling recommendation itself is general rather than
disorder-specific; the haplotype fact it turns on is cited on the prevalence
record and the MED25 genetic entry. The recurrence figure most often quoted
for CMT2 does not apply here: the retired GeneReviews CMT2 chapter is written
around the dominant subtypes and gives a 50 percent offspring risk, whereas
this entity is recessive.
evidence:
- reference: PMID:20301462
reference_title: "Charcot-Marie-Tooth Neuropathy Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: "Most subtypes of CMT2 are inherited in an autosomal dominant manner; however, some are inherited in an autosomal recessive manner."
explanation: >-
Cited for the point the counselling turns on - that CMT2 is a mixed group
and the dominant recurrence figures quoted for it do not transfer to a
recessive subtype such as this one.
- name: Avoidance of neurotoxic medications
description: >-
General CMT2 guidance is to avoid drugs known to cause nerve damage, naming
vincristine, isoniazid and nitrofurantoin. This is clinically consequential in
an axonal neuropathy with already reduced or unrecordable compound muscle
action potentials, and it is the one piece of the extrapolated management that
changes prescribing rather than adding a service.
therapeutic_modality: OTHER
treatment_term:
preferred_term: supportive care
term:
id: NCIT:C15747
label: Supportive Care
notes: >-
Extrapolated from the general CMT2 literature, not tested in this entity, and
the source chapter is retired. No neurotoxic-drug exposure is reported in any
CMT2B2 patient in the sources curated here.
evidence:
- reference: PMID:20301462
reference_title: "Charcot-Marie-Tooth Neuropathy Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
supports: SUPPORT
directness: INDIRECT
evidence_source: OTHER
snippet: "medications known to cause nerve damage (e.g., vincristine, isoniazid, nitrofurantoin)"
explanation: >-
Names the agents the general CMT2 guidance advises avoiding. Graded INDIRECT
because the advice is for CMT2 as a group rather than for this subtype.
discussions:
- discussion_id: gap_cmt2b2_med25_modifier
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Does the MED25 p.Ala335Val variant contribute anything to the CMT2B2
phenotype, or is it purely a passenger on the founder haplotype?
rationale: >-
Every reported patient carries both variants, because the two genes are
adjacent and the alleles cosegregate on a single ancestral haplotype. That
perfect linkage is what made the original assignment go wrong, and it also
means no reported patient separates the two. ClinGen's Disputed call rests on
the absence of other MED25 CMT families and on four unaffected gnomAD
homozygotes, which argues MED25 alone is not sufficient - but it does not
exclude a modifying contribution in the presence of biallelic PNKP loss. The
2009 work reported that the MED25 variant broadens SH3-domain binding
specificity and that Med25 is coordinately expressed with Pmp22, so a
modifier hypothesis is not empty. Settling it needs a PNKP-biallelic patient
who is not on this haplotype.
attaches_to:
- genetic#MED25
- pathophysiology#Biallelic PNKP Loss-of-Function Variant
- discussion_id: gap_cmt2b2_neuron_break_burden
kind: KNOWLEDGE_GAP
status: OPEN
prompt: >-
Is the single-strand break burden actually raised in the peripheral neurons
and cerebellar neurons of PNKP patients, and does it explain why those cells
and not others degenerate?
rationale: >-
The repair deficit is measured in patient fibroblasts, a dividing cell type
with no phenotype. The step to post-mitotic neurons is an inference from the
biochemistry, and it is the step that has to carry the tissue selectivity of a
ubiquitously expressed enzyme. The kinase-versus-phosphatase correlation
reported alongside it is suggestive but is a correlation across a small set of
alleles, not a demonstrated determinant.
attaches_to:
- pathophysiology#Accumulation of Unrepaired Single-Strand Breaks in Post-Mitotic Neurons
- pathophysiology#Impaired DNA Single-Strand Break Repair
references:
- reference: PMID:30039206
title: "The polynucleotide kinase 3'-phosphatase gene (PNKP) is involved in Charcot-Marie-Tooth disease (CMT2B2) previously related to MED25."
- reference: PMID:32504494
title: "Pathological mutations in PNKP trigger defects in DNA single-strand break repair but not DNA double-strand break repair."
- reference: PMID:20301462
title: "Charcot-Marie-Tooth Neuropathy Type 2 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
- reference: PMID:19290556
title: "Identification of the variant Ala335Val of MED25 as responsible for CMT2B2: molecular data, functional studies of the SH3 recognition motif and correlation between wild-type MED25 and PMP22 RNA levels in CMT1A animal models."
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.
Record notes
Deep-research provenance, recorded because the first attempt failed in a way a later curator should know about. The committed falcon report (research/Charcot-Marie-Tooth_Disease_Type_2B2-deep-research-falcon.md) is a retry. The first run, launched from the plain entry name, produced a report that was about the right disease (CMT2B2 named 62 times) but reproduced the superseded 2009 gene assignment throughout: MED25 was mentioned 57 times and PNKP zero times, with no mention of Gln517ter, AOA4 or MCSZ, and its curation conclusion was to represent CMT2B2 as a MED25 disease-gene assertion. That report was discarded rather than committed, because research/ is consumed as a curation input and it would have led a curator to the disputed gene. The retry inlined the gene, the two alleles, the OMIM number and the reassigning paper in the disease_name variable, and returned PNKP as the top gene at 89 occurrences against MED25 at 19, reaching the same conclusion this entry does independently. Reproduce the failure with: `just research-disorder falcon Charcot-Marie-Tooth_Disease_Type_2B2`. Note also that `just preflight-dr` returns SKIP for this entity in both runs, because MONDO records no causal gene for MONDO:0011570 and the gene-identity discriminator therefore cannot run. SKIP is not a pass; the substitution and gene-attribution checks here were done by hand.
Create: Charcot-Marie-Tooth Disease Type 2B2 (MONDO:0011570, PNKP) · 2026-09-08T18:52:04Z · View source
Resolved claim issue #11468 as entry_type DISEASE, not OUT_OF_SCOPE. The issue raised the possibility that CMT2B2 is a mapped locus with no identified gene, on the pattern of the three DCM loci ruled OUT_OF_SCOPE in PR #11466. It is not. The gene is PNKP, and the entity has a mechanism to build a pathograph from. Gene identity, resolved without a second MONDO query. Two sources keyed on this entry's own MONDO ID: - ClinGen's Gene-Disease Validity table (the release pinned in the committed data/clingen/MANIFEST.yaml, snapshot_date 2026-08-13; the CSV itself is gitignored and not committed) carries MED25 / HGNC:28845 / Charcot-Marie-Tooth disease type 2B2 / MONDO:0011570 / AR / Disputed, curated by the Charcot-Marie-Tooth Disease Gene Curation Expert Panel in March 2021. Its narrative names PNKP as the better supported gene and records that the MED25 allele is homozygous in four unaffected gnomAD individuals. - PMID:30039206 (Leal et al., Neurogenetics 2018) re-sequenced the original Costa Rican family by exome and found homozygous PNKP c.1549C>T p.Gln517ter in the last exon of an adjacent gene inside the same linkage interval, plus five further Costa Rican CMT2 patients compound heterozygous for that allele and p.Thr408del. I then re-checked kb/ for PNKP under its own name rather than the numbered label, which is the miss the issue warned about. PNKP appears in seven files, all as prose mentions inside other entries; there is no PNKP umbrella entry, no MCSZ entry and no AOA4 entry, so nothing already covered this concept. dismech's own Charcot-Marie-Tooth_Disease_Type_2 entry already records the MED25-to-PNKP reassignment in its inheritance description, which is what first surfaced the gene. Mechanism. Seven pathophysiology nodes from biallelic PNKP loss of function through destabilisation of the buried C-terminus, impaired DNA single-strand break repair, and accumulated breaks in post-mitotic neurons, to a length-dependent axonal degeneration arm and a cerebellar arm. Three nodes declare conforms_to: two against peripheral_axonal_degeneration and one against cerebellar_purkinje_degeneration#Cerebellar Neuron Insult. The structure deliberately mirrors Ataxia_With_Oculomotor_Apraxia_Type_1, which curates the same kind of DNA-single-strand-break-repair lesion for APTX. Two claims are graded rather than asserted. The step from a repair-rate deficit measured in patient fibroblasts to break burden in neurons is curated with directness: INDIRECT and an INDIRECT_UNKNOWN_INTERMEDIATES edge, because no intermediate is established. And PMID:32504494's negative result - no significant double-strand break repair defect across the PNKP spectrum - is curated as a REFUTE item against the alternative reading of that node rather than being dropped. The cerebellar node explicitly does not assert Purkinje cell loss. There is no neuropathology in this entity; the evidence is MRI atrophy, and the node says so. MED25 is kept in the genetic block with relationship_type: DISPUTED rather than deleted, because the 2009 assignment is still in circulation and a reader meeting 'CMT2B2, MED25' needs to find the correction here. Its evidence carries both the original 2009 claim (PMID:19290556, SUPPORT) and the gnomAD counter-evidence (CGGV, REFUTE). Things deliberately constrained. No prevalence figure: one founder haplotype, six index cases. No frequency band on pes cavus (1 of 4 reassessed) or oculomotor apraxia (2 of 4). Two OBLIGATE bands are used and both carry their denominator in notes. Both treatments are marked deliberately uncited, because no CMT2B2-specific management study appears in the sources curated here and the GeneReviews CMT overview in the cache carries only its purpose statement, not management content. The negative phenotype - absence of microcephaly, seizures and developmental delay - carries no HP term and is deliberately unwired, with the reason recorded. A snippet note. Two evidence items originally quoted a sentence containing the bracketed citation marker [11], which the reference validator strips before matching. Rather than adding a literal_bracket_patterns entry, the quotes were changed to sentences that do not depend on the bracket. Deep research, and a failure worth recording. The committed falcon report is a RETRY. The first run, launched from the plain entry name, returned a report about the right disease (CMT2B2 named 62 times) that reproduced the superseded 2009 gene assignment throughout - MED25 mentioned 57 times, PNKP zero times, no mention of Gln517ter, AOA4 or MCSZ - and whose stated curation conclusion was to represent CMT2B2 as a MED25 disease-gene assertion. It was discarded rather than committed, because research/ is consumed as a curation input and that report would have led a curator straight to the disputed gene. The retry inlined the gene, both alleles, the OMIM number and the reassigning paper in the disease_name variable and returned PNKP as the top gene at 89 occurrences against MED25 at 19, independently reaching the same conclusion as this entry. Both runs are recorded in the entry's own notes with the reproduction command. just preflight-dr returns SKIP for this entity in both runs because MONDO records no causal gene for MONDO:0011570, so the gene-identity discriminator cannot run; SKIP is unchecked, not passed, and the substitution and gene-attribution checks were done by hand. The retry's own reference validation resolved 6 of 6 citations with a 0.0 confabulation rate and no off-topic references. No ontology term was bound from either report. Orphan audit. All 16 downstream, sequelae, reports_on and target_mechanisms targets diffed against node and phenotype names: zero orphans. Items with no incoming edge are the trigger node, the two treatments, and the deliberately unwired negative phenotype. Validation. just validate (40/40 snippets verified; PMID and CGGV references only, so nothing skipped by prefix), validate-terms, validate-disorders, check-entity-refs, check-duplicate-keys, check-causal-targets, check-enum-values, check-qualifier-terms, check-stubs, plus whole-KB check-title-snippets, check-snippet-length and check-snippet-grading. Post-review changes (#11485). Three findings, all additive, all accepted. First, the molecular-function binding was three levels too general and half-missing: GO:0016301 kinase activity was replaced with GO:0046404 ATP-dependent polydeoxyribonucleotide 5'-hydroxyl-kinase activity, and a second entry was added for GO:0046403 polynucleotide 3'-phosphatase activity, because PNKP is bifunctional, the node's own description says so, and a destabilising truncation removes both activities. Both terms were verified against OLS before binding. Second, claw hand was present in 4 of 4 reassessed patients - more frequent than the pes cavus that already had a phenotype - and survived only as prose inside that phenotype's description; it is now curated against HP:0034337, quoting the deformities row of the clinical table. Mild lumbar scoliosis, 4 of 4, was added from the same sentence against HP:0002650. Third, gait ataxia was quoted in the file but never curated; it is now a phenotype against HP:0002066, reusing the mobility-table snippet already present, and wired from the cerebellar outcome node. That one matters beyond completeness: ataxia is the axis on which this entity is distinguished from AOA4, and the differential argued it in prose while the structured data omitted it. On the review's fifth point, the notes sentence claiming the general CMT management literature does not address this entity was wrong, and the cache contradicted it. PMID:20301462, the RETIRED GeneReviews CMT2 chapter, is already cached here and carries a substantive management section. Both treatments are now cited to it with directness INDIRECT and evidence_source OTHER, and a third treatment was added for the agents-to-avoid statement (vincristine, isoniazid, nitrofurantoin), which is the one piece of that guidance that changes prescribing in an axonal neuropathy. Every one of those citations records in its notes that the chapter is retired and is written around the dominant CMT2 subtypes while this entity is recessive; the chapter's own sentence acknowledging that some CMT2 subtypes are recessive is quoted on the counselling entry for exactly that reason.
Charcot–Marie–Tooth disease type 2B2 (CMT2B2; ARCMT2B; OMIM 605589) is an exceptionally rare, autosomal-recessive, predominantly axonal sensorimotor neuropathy with variably associated cerebellar and oculomotor dysfunction. The definitive disease-specific evidence comes primarily from a large consanguineous Costa Rican family and five additional Costa Rican subjects. The original assignment to homozygous MED25 p.Ala335Val should be retained only as historical: reanalysis identified homozygous PNKP c.1549C>T (p.Gln517Ter) in the extended family and compound-heterozygous p.Gln517Ter/p.Thr408del in the five additional cases. These data support PNKP, not MED25, as the causal gene; the ClinGen CMT Gene Curation Expert Panel’s disputed classification of the MED25–CMT relationship is therefore concordant with the primary evidence. The principal paper was published online July 24, 2018 (PMID 30039206; DOI 10.1007/s10048-018-0555-7). (leal2018thepolynucleotidekinase pages 1-2, leal2018thepolynucleotidekinase pages 6-8, leal2018thepolynucleotidekinase pages 4-6)
The defining clinical course is adult onset—approximately 28–42 years in the original family—followed by slowly progressive distal weakness and wasting, sensory loss, areflexia, gait impairment, and severe axonal sensorimotor abnormalities on nerve-conduction studies. Dysarthria, gait ataxia, oculomotor abnormalities, and mild cerebellar atrophy can accompany the neuropathy. Unlike severe PNKP-related microcephaly, seizures, and developmental delay (MCSZ), the reported CMT2B2 subjects did not have congenital microcephaly, seizures, or developmental delay. CMT2B2 is best curated as the adult-onset, neuropathy-predominant end of a continuous PNKP-related spectrum that also includes ataxia with oculomotor apraxia type 4 (AOA4) and MCSZ. (leal2018thepolynucleotidekinase pages 1-2, leal2018thepolynucleotidekinase pages 6-8, gatti2019fromcongenitalmicrocephaly pages 1-2)
| Entity/domain | Curated finding | Evidence type/strength | Ontology/database annotation |
|---|---|---|---|
| Disease identity | Charcot-Marie-Tooth disease type 2B2 (CMT2B2; ARCMT2B) is a very rare autosomal-recessive, predominantly axonal sensorimotor neuropathy with mild cerebellar/oculomotor involvement in the reported Costa Rican cases. | Strong for the reported kindreds; limited generalizability because evidence derives from one extended family and five additional Costa Rican subjects (leal2018thepolynucleotidekinase pages 1-2, leal2018thepolynucleotidekinase pages 6-8, leal2018thepolynucleotidekinase pages 4-6) | OMIM: 605589; MONDO: MONDO:0011570 supplied by requester—verify against the current MONDO release before ingestion; candidate class: hereditary motor and sensory neuropathy |
| Gene attribution | The best-supported cause is biallelic PNKP loss-of-function/hypomorphic variation. The earlier MED25 p.Ala335Val attribution was superseded after reanalysis found segregating biallelic PNKP variants; MED25–CMT2B2 validity is classified Disputed by the ClinGen CMT Gene Curation Expert Panel. | Strong human segregation/reanalysis evidence for PNKP; contradictory/insufficient evidence for MED25 (leal2018thepolynucleotidekinase pages 1-2, leal2018thepolynucleotidekinase pages 6-8) | PNKP; candidate relationship: biallelic loss of function → CMT2B2. MED25 should be retained only as a historical/disputed attribution |
| Homozygous genotype | The large consanguineous Costa Rican family carried PNKP c.1549C>T (p.Gln517Ter; p.Gln517*) homozygously. The premature stop lies in the last exon and truncates the conserved C-terminal region. | Strong segregation evidence in the discovery pedigree; pathogenicity supported by predicted structural destabilization, although direct allele-specific functional testing is limited (leal2018thepolynucleotidekinase pages 1-2, leal2018thepolynucleotidekinase pages 6-8) | Variant class: germline nonsense; candidate ACMG concepts: PVS1/segregation/phenotype specificity, subject to transcript-specific curation |
| Compound-heterozygous genotype | Five unrelated Costa Rican CMT2 subjects were reported with PNKP c.1549C>T (p.Gln517Ter) in trans with c.1221_1223del (p.Thr408del). | Strong case-level and segregation evidence across five additional subjects; p.Thr408del had also been associated with recessive ataxia (leal2018thepolynucleotidekinase pages 1-2, leal2018thepolynucleotidekinase pages 4-6) | Variant classes: germline nonsense plus in-frame deletion; verify HGVS against the designated clinical transcript before database loading |
| Peripheral neuropathy phenotype | Adult-onset, slowly progressive, length-dependent axonal sensorimotor polyneuropathy produced gait disturbance, falls, distal weakness and wasting, impaired/absent reflexes, and marked vibration/position-sense loss. Onset in the original family was approximately 28–42 years; additional cases generally began in the third decade. | Strong but small human case-series evidence; severe disability was variable, including wheelchair dependence in one subject after five years (leal2018thepolynucleotidekinase pages 1-2, leal2018thepolynucleotidekinase pages 6-8, leal2018thepolynucleotidekinase pages 4-6) | Candidate HPO: adult onset; progressive peripheral neuropathy; axonal sensorimotor polyneuropathy; distal muscle weakness/atrophy; areflexia; impaired proprioception; gait disturbance |
| Electrophysiology | Nerve-conduction studies showed markedly reduced or absent sensory responses and reduced compound muscle action potentials, with secondary slowing of motor conduction in severe axonal disease. | Strong objective clinical evidence in reported patients (leal2018thepolynucleotidekinase pages 6-8, leal2018thepolynucleotidekinase pages 4-6) | Candidate HPO: abnormal peripheral nerve conduction; reduced CMAP amplitude; absent sensory nerve action potentials; axonal degeneration |
| Cerebellar and oculomotor signs | Slurred speech/dysarthria, wide-based or ataxic gait, postural instability, and variable oculomotor abnormalities—including oculomotor apraxia in some subjects—accompanied the neuropathy. MRI could show mild cerebellar atrophy without brainstem or white-matter abnormalities. | Moderate-to-strong case-series evidence; expression was variable (leal2018thepolynucleotidekinase pages 6-8, leal2018thepolynucleotidekinase pages 4-6) | Candidate HPO: cerebellar ataxia; dysarthria; oculomotor apraxia; abnormality of ocular movements; cerebellar atrophy |
| Features absent in reported CMT2B2 cohort | The Costa Rican CMT2B2 subjects lacked congenital microcephaly, seizures, developmental delay, cognitive impairment, and dystonia, distinguishing their presentation from classic MCSZ. | Strong for examined subjects, but absence cannot be generalized to every future PNKP-neuropathy case (leal2018thepolynucleotidekinase pages 1-2, leal2018thepolynucleotidekinase pages 4-6) | Negated candidate HPO: microcephaly; seizure; global developmental delay; cognitive impairment; dystonia |
| PNKP protein function | PNKP is a DNA-end-processing enzyme with an N-terminal FHA interaction domain and catalytic 3′-phosphatase and 5′-kinase activities. It converts obstructive termini into ligatable 3′-OH/5′-phosphate ends. | Strong biochemical, structural, and cellular evidence (weinfeld2011tidyinguploose pages 5-7, weinfeld2011tidyinguploose pages 4-5, dumitrache2017polynucleotidekinasephosphatase(pnkp) pages 1-2) | Candidate GO: DNA 3′-phosphatase activity; polynucleotide 5′-hydroxyl-kinase activity; DNA repair; DNA single-strand-break repair; nonhomologous end joining |
| Single-strand-break repair mechanism | Oxidative or TOP1-associated damage generates noncanonical DNA ends. PARP1/PARP2 and the XRCC1 scaffold organize repair; PNKP processes 3′-phosphate and 5′-OH termini, POLB fills gaps, and LIG3 seals the strand. XRCC1 interaction stimulates PNKP recruitment and catalytic turnover. | Strong pathway-level biochemical/cellular evidence; exact recruitment order may vary by lesion and remains partly unresolved (weinfeld2011tidyinguploose pages 4-5, hulmakova2025theroleof pages 20-23, dumitrache2017polynucleotidekinasephosphatase(pnkp) pages 1-2) | Candidate GO: base-excision repair; DNA single-strand-break repair; response to oxidative stress. Candidate compartments: nucleus, chromatin, DNA-repair complex |
| Downstream pathophysiology | Reduced PNKP function is expected to cause persistent strand-break termini, impaired repair, transcriptional/genomic stress, and preferential dysfunction or loss of long-lived peripheral and cerebellar neurons. The final link from the two Costa Rican alleles to selective axonal degeneration remains inferred, not directly demonstrated in patient neurons. | Strong general PNKP/DNA-repair evidence but moderate, inferential disease-specific chain (leal2018thepolynucleotidekinase pages 6-8, jiang2022mutationsofthe pages 13-13, dumitrache2017polynucleotidekinasephosphatase(pnkp) pages 1-2) | Candidate GO: cellular response to DNA damage stimulus; maintenance of genome stability; neuron death. Candidate CL: peripheral sensory neuron, lower motor neuron, cerebellar Purkinje cell |
| Allelic relationship to AOA4 | AOA4 (OMIM 616267) is another biallelic PNKP disorder, typically emphasizing progressive cerebellar ataxia, oculomotor apraxia, and axonal polyneuropathy. CMT2B2 occupies the neuropathy-predominant, adult-onset end of an overlapping spectrum. | Strong human allelic-spectrum evidence; strict genotype–phenotype boundaries are not established (leal2018thepolynucleotidekinase pages 1-2, gatti2019fromcongenitalmicrocephaly pages 1-2, garrelfs2020eurresearchinformation pages 1-3) | Candidate disease relationship: allelic disorder; candidate HPO: cerebellar ataxia, oculomotor apraxia, axonal neuropathy |
| Allelic relationship to MCSZ | MCSZ (OMIM 613402) usually presents with congenital microcephaly, early seizures, developmental delay, and progressive cerebellar atrophy; later neuropathy/ataxia may occur. Published cohorts support a continuum from severe neurodevelopmental disease to adult neurodegeneration. | Strong human evidence for a phenotypic continuum; simple residual-activity rules remain incomplete (gatti2019fromcongenitalmicrocephaly pages 1-2, gatti2019fromcongenitalmicrocephaly pages 2-3, garrelfs2020eurresearchinformation pages 1-3) | Candidate disease relationship: allelic disorder; candidate HPO: congenital microcephaly, early-onset seizure, global developmental delay, cerebellar atrophy |
| Diagnostics | Diagnosis requires neurological examination, nerve-conduction studies/EMG, assessment for ataxia and eye-movement abnormalities, brain MRI when central signs are present, and molecular confirmation of biallelic PNKP variants by neuropathy/ataxia panel, exome, or genome sequencing with segregation analysis. | Clinically well supported, but no CMT2B2-specific consensus criteria or validated biochemical diagnostic assay exist (leal2018thepolynucleotidekinase pages 1-2, leal2018thepolynucleotidekinase pages 6-8, leal2018thepolynucleotidekinase pages 4-6) | Candidate NCIT interventions: genetic testing, whole-exome sequencing, whole-genome sequencing, electromyography, nerve-conduction study, magnetic-resonance imaging |
| Treatment status | No approved disease-modifying, gene, RNA, or PNKP-replacement therapy and no relevant CMT2B2-specific interventional trial were identified. Current care is supportive: physical/occupational therapy, orthoses and mobility aids, fall prevention, pain management, speech support, and orthopedic evaluation for deformity. | Supportive practice extrapolated from general CMT/ataxia management; no CMT2B2 treatment-response rates | Candidate NCIT interventions: physical therapy, occupational therapy, orthotic device, assistive device, pain management, speech therapy, orthopedic surgery |
| Epidemiology and evidence gaps | Disease-specific prevalence, incidence, carrier frequency, sex ratio, penetrance, life expectancy, quantitative natural history, modifiers, protective factors, pharmacogenomics, biomarkers, and quality-of-life statistics are unavailable. No exact p.Gln517Ter/p.Thr408del neuronal model or disease-specific single-cell, spatial, or multi-omics dataset was identified. | Major limitation: extremely small, geographically concentrated ascertainment; broader PNKP cohorts cannot substitute for CMT2B2-specific estimates (leal2018thepolynucleotidekinase pages 1-2, gatti2019fromcongenitalmicrocephaly pages 1-2, garrelfs2020eurresearchinformation pages 1-3, hulmakova2025theroleof pages 32-35) | Mark as unknown/not established; avoid assigning population frequencies or phenotype percentages beyond the published cohort |
Table: Compact knowledge-base table distinguishing PNKP-related CMT2B2 from the disputed MED25 attribution and summarizing its variants, phenotype, mechanism, allelic spectrum, diagnostics, treatment status, and evidence gaps.
CMT2B2 is a hereditary motor and sensory neuropathy in which axonal loss, rather than primary demyelination, is the predominant peripheral-nerve lesion. Its distinctive syndromic extension is mild or variable cerebellar and oculomotor dysfunction. The label “CMT2B2” is historically locus- and pedigree-based; molecularly, the condition is a PNKP-related DNA-strand-break-repair disorder. (leal2018thepolynucleotidekinase pages 1-2, leal2018thepolynucleotidekinase pages 6-8)
This report summarizes aggregated disease-level evidence from published pedigrees and mechanistic experiments. It is not derived from an EHR or an individual clinical record.
The original 19q13.3 locus was mapped in a large consanguineous Costa Rican family with autosomal-recessive axonal neuropathy, and homozygous MED25 p.Ala335Val was initially proposed as causal. Because no convincing independent MED25 CMT cases emerged, Leal and colleagues re-examined the family by exome sequencing. Their abstract states: “Using exome sequencing, we now identified a homozygous nonsense variant (p.Gln517ter) in the last exon of an adjacent gene, the polynucleotide kinase 3′-phosphatase (PNKP) gene.” Five additional subjects carrying one copy of the MED25 allele instead proved to have two PNKP alleles. This independent-genotype logic strongly favors PNKP and undermines MED25 causality. (leal2018thepolynucleotidekinase pages 1-2)
The primary cause is germline biallelic damaging variation in PNKP. In the extended family, p.Gln517Ter was homozygous; in five additional cases, p.Gln517Ter occurred in trans with the in-frame deletion p.Thr408del. Both genotypes are consistent with partial loss of PNKP function. The disease is not infectious, toxic, immune-mediated, or environmentally acquired. (leal2018thepolynucleotidekinase pages 1-2, leal2018thepolynucleotidekinase pages 4-6)
Having two pathogenic or likely pathogenic PNKP alleles is the necessary established risk factor. Consanguinity increased the probability of homozygosity in the original family. A first-degree family history compatible with recessive inheritance raises diagnostic probability, but absence of such history does not exclude compound heterozygosity. The MED25 p.Ala335Val allele is not an independently supported risk factor for CMT2B2 and should not be used for predictive testing by itself. (leal2018thepolynucleotidekinase pages 1-2)
Variant nomenclature should be transcript-verified before clinical loading because historical papers may use differing transcript conventions. The reported forms are:
Population frequencies, Costa Rican carrier frequencies, and ancestry-stratified frequencies were not established in the retrieved disease-specific literature. No modifier gene, protective allele, epigenetic risk state, or reproducible susceptibility locus has been demonstrated.
No environmental exposure has been shown to cause or protect against CMT2B2. Because reactive oxygen species generate substrates repaired by PNKP, oxidative burden is mechanistically relevant, but no human study shows that smoking, diet, occupation, radiation, alcohol, or exercise modifies penetrance or progression. Avoidance of neurotoxic medications and excessive alcohol is prudent in hereditary neuropathy care, but it is tertiary risk reduction rather than proven CMT2B2-specific prevention. The same distinction applies to exercise: appropriately dosed activity may preserve function, but it does not correct PNKP deficiency.
The original family had onset at approximately 28–42 years; additional subjects generally developed polyneuropathy in the third decade. Initial manifestations included gait disturbance, falls, and postural instability. Progression produced distal weakness and atrophy in feet, calves, and hands; absent or impaired tendon reflexes; severe loss of vibration and position sense; claw hands; and, in some cases, pes cavus or hammertoes. Nerve-conduction studies showed absent or markedly reduced sensory responses and low or absent compound muscle action potentials. Modest motor-conduction slowing was interpreted as secondary to severe axonal loss rather than evidence of a primary demyelinating neuropathy. (leal2018thepolynucleotidekinase pages 1-2, leal2018thepolynucleotidekinase pages 6-8, leal2018thepolynucleotidekinase pages 4-6)
Suggested HPO concepts include adult onset, progressive peripheral neuropathy, axonal sensorimotor polyneuropathy, distal muscle weakness, distal muscle atrophy, areflexia, impaired proprioception, reduced vibration sense, gait disturbance, pes cavus, hammertoes, claw hand, reduced CMAP amplitude, and absent sensory nerve action potentials.
Slurred speech/dysarthria was prominent in the additionally characterized cases. Wide-based or mildly ataxic gait, cerebellar dysfunction, and variable oculomotor abnormalities were reported; two listed subjects had oculomotor apraxia. MRI could show mild cerebellar atrophy without brainstem or cerebral white-matter abnormalities. Candidate HPO concepts are cerebellar ataxia, dysarthria, oculomotor apraxia, abnormal ocular movement, postural instability, and cerebellar atrophy. (leal2018thepolynucleotidekinase pages 6-8, leal2018thepolynucleotidekinase pages 4-6)
Expression was variable. One additional subject became wheelchair-dependent after five years, while another remained ambulatory with mild gait ataxia. Frequencies calculated from this tiny, ascertained series would not be valid population estimates. Accordingly, findings such as dysarthria “in all listed additional cases” should be stored as case-series observations, not universal penetrance. (leal2018thepolynucleotidekinase pages 4-6)
The Costa Rican CMT2B2 patients lacked microcephaly, seizures, developmental delay, cognitive impairment, and dystonia. These are important negated phenotypes for the reported cohort, not absolute exclusion criteria for every future neuropathy-predominant PNKP case. Broader PNKP cohorts demonstrate overlap: early MCSZ can later acquire neuropathy and ataxia, and adult disease can emphasize polyneuropathy and cerebellar signs. (leal2018thepolynucleotidekinase pages 1-2, gatti2019fromcongenitalmicrocephaly pages 1-2, gatti2019fromcongenitalmicrocephaly pages 2-3)
No CMT2B2-specific EQ-5D, SF-36, PROMIS, CMT Health Index, or disease-burden study was identified. Nevertheless, the documented falls, hand and foot weakness, sensory loss, speech impairment, orthopedic deformity, and wheelchair dependence indicate substantial effects on mobility, activities of daily living, communication, and independence. Quantitative utility values should be marked unavailable.
PNKP encodes polynucleotide kinase 3′-phosphatase, a bifunctional DNA-end-processing enzyme. It contains an N-terminal forkhead-associated interaction domain and catalytic phosphatase and kinase regions. PNKP operates in XRCC1-associated single-strand-break/base-excision repair and XRCC4–LIG4-associated nonhomologous end joining. (weinfeld2011tidyinguploose pages 5-7, weinfeld2011tidyinguploose pages 4-5, dumitrache2017polynucleotidekinasephosphatase(pnkp) pages 1-2)
The reported variants are constitutional/germline, not somatic. p.Gln517Ter truncates a conserved C-terminal region. Structural modeling in the disease report predicted disruption of kinase/phosphatase-domain orientation and the ADP-binding region, providing a plausible reduction-of-function mechanism. p.Thr408del is an in-frame deletion previously observed in recessive ataxia and contributes to disease when paired with p.Gln517Ter. (leal2018thepolynucleotidekinase pages 6-8, leal2018thepolynucleotidekinase pages 4-6)
For clinical curation, classification should be performed independently under current ACMG/AMP specifications using the laboratory’s selected transcript, validated population frequency, segregation, phase, and any available functional evidence. “Pathogenic” should not be inferred solely from this report’s wording without that transcript-level review.
No reproducible CMT2B2 modifier genes, methylation signature, chromatin biomarker, large structural rearrangement, somatic mosaicism, or germline mosaicism have been reported. The disease does not involve aneuploidy, repeat expansion, mitochondrial-genome variation, or a recurrent cytogenetic rearrangement. PNKP may participate in mitochondrial DNA repair, but a CMT2B2-specific mitochondrial molecular signature has not been established. (gatti2019fromcongenitalmicrocephaly pages 1-2, hulmakova2025theroleof pages 32-35)
No toxin, pollutant, radiation exposure, occupation, diet, infection, smoking behavior, or alcohol exposure has been causally associated with CMT2B2. Reactive oxygen species and ionizing radiation generate DNA termini that PNKP normally processes, establishing biochemical substrate relevance—not a demonstrated epidemiologic exposure effect. There is no zoonotic or transmissible agent.
Oxidative damage, base-excision intermediates, and trapped topoisomerase-I lesions can leave 3′-phosphate, 3′-phosphoglycolate, or 5′-OH termini that cannot be directly ligated. PARP1 or PARP2 senses damaged chromatin and promotes recruitment of XRCC1. XRCC1 acts as a scaffold for PNKP, DNA polymerase β, and DNA ligase III. PNKP removes 3′ phosphate and phosphorylates 5′ hydroxyl; polymerase fills the gap and LIG3 seals the strand. XRCC1 can stimulate PNKP turnover by displacing it from processed products. Evidence also supports lesion-dependent alternative recruitment orders in which PNKP or APE1 engages an end before stable XRCC1 accumulation; neither model should be treated as universally exclusive. (weinfeld2011tidyinguploose pages 4-5, hulmakova2025theroleof pages 20-23)
A concise functional quotation from the mechanistic literature is that PNKP participates in both “XRCC1-based single-strand break/base-excision repair” and NHEJ. The neurologic relevance arises because unrepaired oxidative SSBs can block transcription in nondividing neurons. (dumitrache2017polynucleotidekinasephosphatase(pnkp) pages 1-2)
In NHEJ, PNKP binds the CK2-phosphorylated XRCC4 tail through its FHA domain, processes abnormal DNA ends, and facilitates subsequent ligation by DNA ligase IV. PNKP kinase activity supplies 5′ phosphate, while its phosphatase activity can remove 3′ phosphate. However, lack of immunodeficiency in most PNKP-affected people implies that V(D)J-associated end joining is sufficiently preserved by residual function or redundant processing. This helps explain why PNKP disease is neurologically prominent rather than a classic radiosensitive immunodeficiency. (hulmakova2025theroleof pages 32-35, weinfeld2011tidyinguploose pages 5-7)
The 2018 authors explicitly concluded that the Costa Rican presentation represented a milder “allelic effect.” Current evidence supports a residual-function continuum but not a deterministic rule linking one domain or activity to one phenotype. The same or nearby alleles can occur across overlapping syndromes; genetic background and unknown modifiers probably contribute. (leal2018thepolynucleotidekinase pages 1-2, gatti2019fromcongenitalmicrocephaly pages 1-2, hulmakova2025theroleof pages 32-35)
No CMT2B2-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, CRISPR-screen, or integrated multi-omics dataset was identified. Recent work has nevertheless refined the wider PNKP field:
Suggested GO terms include DNA 3′-phosphatase activity, polynucleotide 5′-hydroxyl-kinase activity, DNA single-strand-break repair, base-excision repair, nonhomologous end joining, cellular response to oxidative stress, DNA-damage response, and maintenance of genome stability. Suggested cell types are peripheral sensory neuron, lower motor neuron, cerebellar Purkinje cell, and Schwann cell; neuronal involvement is primary, whereas a primary Schwann-cell defect is not demonstrated.
The primary system is the peripheral nervous system, particularly long motor and sensory axons of distal limbs. Secondary structures include distal skeletal muscle, which undergoes neurogenic wasting, and feet/hands, which develop imbalance-related deformity. Cerebellar and oculomotor pathways are variably involved. Findings are usually bilateral and length-dependent rather than focal or unilateral. (leal2018thepolynucleotidekinase pages 6-8, leal2018thepolynucleotidekinase pages 4-6)
Candidate anatomical annotations include peripheral nerve, spinal nerve, motor neuron axon, sensory neuron axon, skeletal muscle of limb, hand, foot, cerebellum, and ocular motor system. Candidate UBERON concepts should be identifier-validated locally. At the subcellular level, relevant compartments are nucleus, chromatin, DNA-repair complex, and possibly mitochondrion; only the nuclear strand-break-repair role is firmly linked to CMT2B2.
CMT2B2 onset is chronic and insidious, usually in adulthood in the known Costa Rican cases. Early disease consists of gait disturbance, falls, and distal sensorimotor symptoms. Intermediate disease adds progressive weakness, wasting, proprioceptive loss, dysarthria, and ataxia. Advanced disease may require a wheelchair, although progression is variable. No episodic attacks, relapses, or spontaneous remissions were reported. The disorder is lifelong and progressive. (leal2018thepolynucleotidekinase pages 1-2, leal2018thepolynucleotidekinase pages 6-8, leal2018thepolynucleotidekinase pages 4-6)
There is no validated staging system, annualized progression rate, or proven therapeutic window. Earlier identification is nevertheless clinically useful before fixed contractures, recurrent falls, or severe deconditioning emerge.
Inheritance is autosomal recessive. For two carrier parents, each pregnancy has a 25% probability of an affected child, 50% probability of an unaffected carrier, and 25% probability of inheriting neither familial allele. Both sexes are expected to be affected equally. Anticipation is not expected. Penetrance appears high among reported biallelic adults, but the denominator is too small and ascertained to claim complete penetrance. Expressivity is variable. (leal2018thepolynucleotidekinase pages 1-2, leal2018thepolynucleotidekinase pages 4-6)
Consanguinity was central to discovery of the homozygous extended family. The recurrence of p.Gln517Ter and p.Thr408del among Costa Rican cases suggests population enrichment or shared ancestry, but formal haplotype/founder analysis and carrier-frequency data are unavailable. No prevalence per 100,000, incidence, sex ratio, or global geographic distribution can be calculated. The known disease-specific evidence is geographically concentrated in Costa Rica; broader PNKP disease has been reported internationally, but it cannot be used as CMT2B2 epidemiology.
Evaluation should include detailed pedigree and consanguinity history; neurologic examination of distal power, atrophy, reflexes, proprioception, gait, speech, cerebellar function, and eye movements; and nerve-conduction studies/EMG. The expected electrophysiologic pattern is severe axonal sensorimotor polyneuropathy with low or absent SNAPs and CMAPs. Brain MRI is indicated when ataxia, dysarthria, or oculomotor findings are present and may show mild cerebellar atrophy. (leal2018thepolynucleotidekinase pages 6-8, leal2018thepolynucleotidekinase pages 4-6)
Serum alpha-fetoprotein, albumin, and cholesterol may be abnormal elsewhere in the PNKP spectrum, particularly AOA4/MCSZ, but no laboratory analyte is a validated CMT2B2 biomarker. A broader nine-patient PNKP cohort found increasing alpha-fetoprotein and progressive cerebellar atrophy across the spectrum; these findings should be considered supportive, not subtype-defining. (garrelfs2020eurresearchinformation pages 1-3)
Single-gene PNKP testing is efficient when the familial variants are known. CMA, karyotype, FISH, mitochondrial DNA analysis, and repeat-expansion testing are not first-line for a classic familial case, although they may be used in unresolved differential diagnosis. RNA sequencing may clarify a suspected splice variant but is not a routine validated CMT2B2 assay.
Important alternatives include other axonal CMT genes; AOA1/APTX, AOA2/SETX, and AOA4/PNKP; spinocerebellar ataxia with axonal neuropathy; Friedreich ataxia; POLG-related disease; RFC1 biallelic expansion disease; mitochondrial neuropathies; and acquired toxic, metabolic, inflammatory, or nutritional neuropathy. Adult neuropathy plus dysarthria/oculomotor findings and recessive inheritance should elevate PNKP.
Population and newborn screening are not indicated because prevalence, carrier frequency, and early intervention benefit are unknown. Cascade testing of adult relatives and targeted carrier testing of reproductive partners are appropriate after molecular confirmation.
No disease-specific survival curve, mortality rate, life-expectancy estimate, or 5-/10-year outcome is available. The principal morbidity is progressive motor and sensory disability, falls, deformity, loss of ambulation, and communication difficulty. At least one patient became wheelchair-dependent rapidly, whereas another retained mobility with mild ataxia, demonstrating substantial prognostic variability. (leal2018thepolynucleotidekinase pages 4-6)
Respiratory failure, cardiomyopathy, immunodeficiency, and systemic organ failure are not established defining complications. A broader PNKP cohort found no consistent immunodeficiency or cancer predisposition; isolated malignancies should not be interpreted as a proven syndrome-level risk. (garrelfs2020eurresearchinformation pages 1-3)
No validated prognostic biomarker exists. Baseline motor function, rate of decline, electrophysiologic axonal loss, falls, contractures, and cerebellar involvement are reasonable clinical monitoring variables but not validated prediction models.
There is no approved disease-modifying therapy, PNKP replacement, gene therapy, RNA therapy, or genome-editing treatment for CMT2B2. No relevant disease-specific interventional trial was identified in the ClinicalTrials.gov search; therefore, response rates and molecular-treatment adverse-event data do not exist.
Current real-world management is multidisciplinary and supportive:
Candidate NCIT intervention concepts are physical therapy, occupational therapy, orthotic device, assistive device, exercise therapy, pain management, speech therapy, genetic counseling, and orthopedic surgery. These interventions may preserve independence or address complications, but there are no CMT2B2-specific controlled outcome estimates.
Primary prevention through lifestyle or vaccination is not applicable to a Mendelian recessive disorder. Reproductive prevention options include genetic counseling, carrier testing of relatives and partners, prenatal diagnosis, and preimplantation genetic testing for a known familial genotype. Secondary prevention consists of molecular diagnosis before substantial disability and anticipatory assessment of gait, falls, deformity, and cerebellar symptoms. Tertiary prevention includes orthoses, exercise, contracture prevention, safe mobility, pain treatment, and avoidance of unnecessary neurotoxic exposure. There is no prophylactic drug.
No well-established naturally occurring veterinary disease equivalent to human p.Gln517Ter/p.Thr408del CMT2B2 was identified. There is no breed association, zoonotic potential, transmission, or cross-species infectious susceptibility. PNKP orthologs and DNA-end-processing functions are evolutionarily conserved, which supports comparative modeling, but database-specific NCBI Gene, Taxon, and VBO identifiers should be verified before knowledge-base insertion.
Complete PNKP loss is embryonically lethal in mice. Conditional neural deletion demonstrated that PNKP is required for neurogenesis and genome stability through multiple DNA-repair pathways, strongly supporting nervous-system dependence on PNKP. These models reproduce severe neurodevelopmental consequences more closely than adult-onset CMT2B2 and should not be described as exact CMT2B2 models. (hulmakova2025theroleof pages 32-35, jiang2022mutationsofthe pages 13-13)
Cellular systems include PNKP-deficient or complemented human cell lines, patient fibroblasts, DNA-end-processing assays, clonogenic genotoxic-sensitivity assays, and structural/biochemical reconstitution. These demonstrate impaired repair, persistent abnormal ends, and sensitivity to oxidative, radiomimetic, or topoisomerase-associated damage. Their limitations are the absence of long axons, neuron–glia interactions, and organismal aging. (weinfeld2011tidyinguploose pages 4-5, jiang2022mutationsofthe pages 13-13, jiang2022mutationsofthe pages 12-13)
No validated knock-in mouse, zebrafish, Drosophila, organoid, or patient-derived motor/sensory-neuron model carrying exactly p.Gln517Ter alone or p.Gln517Ter/p.Thr408del was identified in the evidence reviewed through 2024. Developing isogenic iPSC-derived peripheral sensory and motor neurons with these genotypes is a high-priority research need.
The PNKP reassignment is convincing because it integrates exome discovery, recessive segregation, two genotypic configurations, multiple subjects, biological plausibility, and a coherent allelic spectrum. However, nearly every quantitative disease-characteristic field remains limited by the small, geographically concentrated cohort. Prevalence, penetrance, carrier frequency, longitudinal progression, survival, quality-of-life scores, biomarkers, modifiers, treatment outcomes, and environmental interactions are unknown. Mechanistic evidence is strong for PNKP generally but only partly allele- and cell-type-specific for CMT2B2. Thus, the knowledge-base entry should clearly separate demonstrated human CMT2B2 observations, broader human PNKP-spectrum evidence, experimental PNKP mechanism, and inferred selective axonal pathophysiology.
References
(leal2018thepolynucleotidekinase pages 1-2): Alejandro Leal, Sixto Bogantes-Ledezma, Arif B. Ekici, Steffen Uebe, Christian T. Thiel, Heinrich Sticht, Martin Berghoff, Corinna Berghoff, Bernal Morera, Michael Meisterernst, and André Reis. The polynucleotide kinase 3′-phosphatase gene (pnkp) is involved in charcot-marie-tooth disease (cmt2b2) previously related to med25. Neurogenetics, 19:215-225, Jul 2018. URL: https://doi.org/10.1007/s10048-018-0555-7, doi:10.1007/s10048-018-0555-7. This article has 51 citations and is from a peer-reviewed journal.
(leal2018thepolynucleotidekinase pages 6-8): Alejandro Leal, Sixto Bogantes-Ledezma, Arif B. Ekici, Steffen Uebe, Christian T. Thiel, Heinrich Sticht, Martin Berghoff, Corinna Berghoff, Bernal Morera, Michael Meisterernst, and André Reis. The polynucleotide kinase 3′-phosphatase gene (pnkp) is involved in charcot-marie-tooth disease (cmt2b2) previously related to med25. Neurogenetics, 19:215-225, Jul 2018. URL: https://doi.org/10.1007/s10048-018-0555-7, doi:10.1007/s10048-018-0555-7. This article has 51 citations and is from a peer-reviewed journal.
(leal2018thepolynucleotidekinase pages 4-6): Alejandro Leal, Sixto Bogantes-Ledezma, Arif B. Ekici, Steffen Uebe, Christian T. Thiel, Heinrich Sticht, Martin Berghoff, Corinna Berghoff, Bernal Morera, Michael Meisterernst, and André Reis. The polynucleotide kinase 3′-phosphatase gene (pnkp) is involved in charcot-marie-tooth disease (cmt2b2) previously related to med25. Neurogenetics, 19:215-225, Jul 2018. URL: https://doi.org/10.1007/s10048-018-0555-7, doi:10.1007/s10048-018-0555-7. This article has 51 citations and is from a peer-reviewed journal.
(gatti2019fromcongenitalmicrocephaly pages 1-2): Marta Gatti, Stefania Magri, Lorenzo Nanetti, Elisa Sarto, Daniela Di Bella, Ettore Salsano, Chiara Pantaleoni, Caterina Mariotti, and Franco Taroni. From congenital microcephaly to adult onset cerebellar ataxia: distinct and overlapping phenotypes in patients with pnkp gene mutations. American Journal of Medical Genetics Part A, 179:2277-2283, Aug 2019. URL: https://doi.org/10.1002/ajmg.a.61339, doi:10.1002/ajmg.a.61339. This article has 29 citations.
(weinfeld2011tidyinguploose pages 5-7): Michael Weinfeld, Rajam S. Mani, Ismail Abdou, R. Daniel Aceytuno, and J.N. Mark Glover. Tidying up loose ends: the role of polynucleotide kinase/phosphatase in dna strand break repair. Trends in biochemical sciences, 36 5:262-71, May 2011. URL: https://doi.org/10.1016/j.tibs.2011.01.006, doi:10.1016/j.tibs.2011.01.006. This article has 247 citations and is from a domain leading peer-reviewed journal.
(weinfeld2011tidyinguploose pages 4-5): Michael Weinfeld, Rajam S. Mani, Ismail Abdou, R. Daniel Aceytuno, and J.N. Mark Glover. Tidying up loose ends: the role of polynucleotide kinase/phosphatase in dna strand break repair. Trends in biochemical sciences, 36 5:262-71, May 2011. URL: https://doi.org/10.1016/j.tibs.2011.01.006, doi:10.1016/j.tibs.2011.01.006. This article has 247 citations and is from a domain leading peer-reviewed journal.
(dumitrache2017polynucleotidekinasephosphatase(pnkp) pages 1-2): Lavinia C. Dumitrache and Peter J. McKinnon. Polynucleotide kinase-phosphatase (pnkp) mutations and neurologic disease. Mechanisms of Ageing and Development, 161:121-129, Jan 2017. URL: https://doi.org/10.1016/j.mad.2016.04.009, doi:10.1016/j.mad.2016.04.009. This article has 95 citations and is from a peer-reviewed journal.
(hulmakova2025theroleof pages 20-23): A Hulmáková. The role of polynucleotide kinase/phosphatase in dna strand break repair and its implications in human diseases. Unknown journal, 2025.
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(gatti2019fromcongenitalmicrocephaly pages 2-3): Marta Gatti, Stefania Magri, Lorenzo Nanetti, Elisa Sarto, Daniela Di Bella, Ettore Salsano, Chiara Pantaleoni, Caterina Mariotti, and Franco Taroni. From congenital microcephaly to adult onset cerebellar ataxia: distinct and overlapping phenotypes in patients with pnkp gene mutations. American Journal of Medical Genetics Part A, 179:2277-2283, Aug 2019. URL: https://doi.org/10.1002/ajmg.a.61339, doi:10.1002/ajmg.a.61339. This article has 29 citations.
(hulmakova2025theroleof pages 32-35): A Hulmáková. The role of polynucleotide kinase/phosphatase in dna strand break repair and its implications in human diseases. Unknown journal, 2025.
(jiang2022mutationsofthe pages 12-13): Bingcheng Jiang, Cameron Murray, Bonnie L. Cole, J. N. Mark Glover, Gordon K. Chan, Jean Deschenes, Rajam S. Mani, Sudip Subedi, John D. Nerva, Anthony C. Wang, Christina M. Lockwood, Heather C. Mefford, Sarah E. S. Leary, Jeffery G. Ojemann, Michael Weinfeld, and Chibawanye I. Ene. Mutations of the dna repair gene pnkp in a patient with microcephaly, seizures, and developmental delay (mcsz) presenting with a high-grade brain tumor. Scientific Reports, Mar 2022. URL: https://doi.org/10.1038/s41598-022-09097-w, doi:10.1038/s41598-022-09097-w. This article has 17 citations and is from a peer-reviewed journal.
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These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:
MONDO:0011570 (3 mentions) - the report calls it "if available"; MONDO calls it Charcot-Marie-Tooth disease type 2B2