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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0014117 Charcot-Marie-Tooth disease type 4B3

Primary MONDO identifier for this entry. MONDO models CMT4B3 as a leaf under MONDO:0018995 (Charcot-Marie-Tooth disease type 4) with a single causal gene (SBF1) and no descendants.

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Inheritance

1

Autosomal Recessive HP:0000007

Every family in which SBF1 has been established as causal carries biallelic variants - compound heterozygous missense in the index Korean and Italian families, homozygous missense, frameshift or splice-site alleles in the consanguineous Saudi, Syrian, Spanish, Bedouin and Chinese families - with unaffected heterozygous parents. ClinGen's Charcot-Marie-Tooth Disease Gene Curation Expert Panel classifies the SBF1-CMT4B3 relationship as autosomal recessive with Moderate strength of evidence.

Autosomal recessive inheritance

Show evidence (3 references)

PMID:20301641 SUPPORT Other

"The CMT4 subtypes are inherited in an autosomal recessive manner."

GeneReviews states recessive inheritance for the CMT4 series, of which CMT4B3 is the SBF1 member. Cited from the retired CMT4 chapter, the only GeneReviews text that names SBF1/CMT4B3 explicitly.

CGGV:assertion_c0f814d9-02db-4c0c-8e1c-20a7759d993f-2024-12-02T170000.000Z SUPPORT Other

ClinGen expert-panel gene-disease validity assertion recording autosomal recessive inheritance for SBF1-CMT4B3, at Moderate classification.

PMID:32444983 SUPPORT Human Clinical

"WES identified a novel homozygous frameshift deletion (c.5477-5478del; p.1826-1826del) in exon 40 of the SBF1 gene in the two siblings, while both parents and the unaffected sibling were heterozygous carriers."

Direct segregation evidence for recessive inheritance: affected siblings homozygous, unaffected parents and sibling heterozygous.

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Subtypes

2

Classic demyelinating CMT4B3

The presentation of the index Korean family and the one that named the disease: a pure sensorimotor demyelinating neuropathy with focally folded myelin sheaths on nerve biopsy, closely resembling CMT4B1 and CMT4B2, with first-decade onset of distal weakness and atrophy, impaired vibration and position sense, areflexia and pes planus, and no cognitive, dysmorphic or other extraneurological features. These patients were compound heterozygous for two missense variants that most in-silico tools called benign or tolerated.

Show evidence (1 reference)

PMID:27123480 SUPPORT Human Clinical

"In the original Korean family, 3 siblings showed a homogeneous phenotype of pure sensory motor demyelinating neuropathy with focally folded myelin sheaths, closely resembling CMT4B1 and CMT4B2."

Defines the pure demyelinating presentation that this subtype names, and places it alongside the CMT4B1 and CMT4B2 siblings.

Severe syndromic SBF1-related neuropathy

A far more severe early-onset disease in which the polyneuropathy is one part of a multisystem neurodevelopmental syndrome: progressive microcephaly, intellectual disability, syndactyly, cerebellar atrophy with ataxia and pyramidal signs, and multiple cranial neuropathies producing ophthalmoparesis, facial weakness, dysarthria and dysphagia. Unlike classic CMT4B3, the neuropathy here is predominantly axonal, with markedly reduced action potential amplitudes and relatively preserved conduction velocities. Brain MRI in two families showed the "fork and bracket" sign at the pontine and mesencephalic level. Reported families carry variants predicted deleterious, or frameshift and splice-site null alleles.

Show evidence (2 references)

PMID:27123480 SUPPORT Human Clinical

"In the second SBF1-mutated family, from Saudi Arabia, the 3 affected siblings presented a more complex syndromic phenotype. Sensory motor polyneuropathy was associated with progressive microcephaly, intellectual disability, syndactyly, and multiple cranial nerve involvement, which resulted in..."

Enumerates the syndromic features that define this subtype, in the first family reported with them.

PMID:27123480 SUPPORT Human Clinical

"both families presented a predominantly axonal sensory motor neuropathy with evidence of denervation, markedly reduced amplitude of action potentials, and relatively preserved nerve conduction velocities"

Establishes that the syndromic families' neuropathy is axonal rather than demyelinating, which is the electrophysiological separation between the two subtypes recorded here.

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Discussions and Knowledge Gaps

5

Why does a complete Mtmr5 null in mouse produce no myelin outfoldings, when focally folded myelin is the diagnostic hallmark of human CMT4B3 - and does that mean radial sorting, not myelin maintenance, is the mechanism in patients too?

HUMAN MODEL MISMATCH OPEN cmt4b3_mouse_lacks_outfoldings

Attached to

pathophysiology#Focally Folded and Redundant Myelin pathophysiology#Impaired Axon Radial Sorting animal_models#Mtmr5-null mouse

This is the central translational problem for CMT4B3. Human sural nerve biopsies show focally folded myelin sheaths, which is why the disease was classified in CMT4B at all. The Mtmr5-null mouse does not develop them; what it shows instead is a reduced myelinated axon count attributed to defective radial sorting, with Mtmr5 expression peaking during sorting and falling after postnatal day 7. The paper frames this as a division of labour, with Mtmr13 rather than Mtmr5 responsible for Schwann cell myelination - a framing that fits human CMT4B1 and CMT4B2, which are characterized by outfoldings, but not human CMT4B3, which also shows them. Either the two pseudophosphatases have genuinely non-redundant roles and human CMT4B3 outfoldings arise indirectly, or the mouse fails to model a human-specific requirement. The distinction is not academic: it decides whether the mouse can be used as a preclinical model for the myelin lesion, and it is the reason patient-derived iPSC lines were generated. A zebrafish full-gene deletion does show dysmyelination, but described qualitatively as "reminiscent" of the human pathology rather than as outfoldings.

Show evidence (3 references)

PMID:34718573 SUPPORT Model Organism

"Our findings suggest that Mtmr5 and Mtmr13 ensure proper axon radial sorting and Schwann cell myelination, respectively, perhaps through their direct interactions with Mtmr2."

States the proposed division of labour that, if it holds in humans, would explain the mismatch.

PMID:34718573 SUPPORT Model Organism

"The form of Charcot-Marie-Tooth type 4B (CMT4B) disease caused by mutations in myotubularin-related 5 (MTMR5; also called SET binding factor 1, SBF1) shows a spectrum of axonal and demyelinating nerve phenotypes. This contrasts with the CMT4B subtypes caused by MTMR2 or MTMR13 (SBF2) mutations,..."

The authors' statement of how human SBF1 disease differs from its CMT4B1 and CMT4B2 siblings, which is the human-side half of this mismatch.

PMID:39461113 SUPPORT In Vitro

"Current MTMR5 -/- animal models do not clearly link Sbf1 mutations to severe neuropathy, so such a resource is highly desired to further elucidate the relationship between MTMR5 dysfunction and peripheral nerve degeneration."

An independent group's statement of the same gap, and their reason for building a human cellular model instead.

By what mechanism does SBF1 loss produce microcephaly, intellectual disability, cerebellar atrophy and cranial neuropathy in some families and a purely peripheral neuropathy in others?

KNOWLEDGE GAP OPEN cmt4b3_syndromic_mechanism

Attached to

pathophysiology#Central Nervous System and Cranial Nerve Involvement has_subtypes#Syndromic SBF1 Neuropathy

The CNS arm of CMT4B3 has no worked mechanism. Two clues exist and neither is a mechanism. First, the variants in the two originally reported syndromic families fall in the DENN domain, which among the myotubularins only SBF1 and SBF2 carry and which acts on Rab GTPases and subcellular localization - suggesting functions beyond MTMR2 binding. But that argument is weakened by an SBF2 deletion removing the whole D-DENN module producing non-syndromic demyelinating neuropathy, and by later syndromic families carrying frameshift and splice-site null alleles rather than DENN missense. Second, the mtmr5-null zebrafish develops reduced brain volume, so a CNS requirement for MTMR5 is real in at least one vertebrate. What is missing is any account of which cell type in the CNS requires MTMR5 and what it requires it for.

Show evidence (2 references)

PMID:27123480 SUPPORT Human Clinical

"However, the severe syndromic phenotype shown by 2 SBF1-mutated families calls for additional explanations."

The authors' own statement that the MTMR2-partnering mechanism does not account for the syndromic phenotype.

PMID:27123480 REFUTE Human Clinical

"However, an SBF2 deletion abolishing the whole D-DENN module caused nonsyndromic demyelinating neuropathy in a Turkish family."

Argues against the simplest version of the DENN-domain hypothesis, and is recorded here so the hypothesis is not read as established.

Are the demyelinating/axonal and pure/syndromic axes of SBF1 disease two descriptions of one severity gradient, or genuinely separable entities?

OPEN QUESTION OPEN cmt4b3_spectrum_boundaries

Attached to

has_subtypes#Classic CMT4B3 has_subtypes#Syndromic SBF1 Neuropathy

The two subtypes recorded in this entry are a descriptive convenience, not a validated nosology, and one published case breaks the correlation they imply. The tidy story is: mild missense alleles give pure demyelinating CMT4B3, deleterious or null alleles give severe syndromic axonal disease. Against it, the Italian child carried compound heterozygous missense variants and had severe, rapidly progressive infantile axonal neuropathy with normal cognition and normal brain and spinal MRI throughout - severe and axonal without being syndromic. So "axonal" and "syndromic" are not the same axis, and neither maps cleanly onto allele severity. With fewer than ten published families, this cannot be settled from the current literature; it is recorded so the subtype split in this entry is read as provisional.

Show evidence (2 references)

PMID:27123480 SUPPORT Human Clinical

"the Korean patients with pure demyelinating neuropathy were compound heterozygous for 2 missense variants, both predicted as benign or tolerated by most prediction software, suggesting a mild impact on the protein. On the contrary, the 2 families with severe syndromic presentation carried..."

States the proposed genotype-phenotype correlation that the two subtypes here follow.

PMID:34118926 REFUTE Human Clinical

"We report a case of severe CMT4B3 characterized by early-onset motor and axonal polyneuropathy in an Italian child in absence of any evidence of brain and spine MRI abnormalities or intellectual disability and with a biochemical profile suggestive of mitochondrial disease."

The counterexample: severe and axonal without any syndromic CNS or cognitive involvement, which is why the two axes are recorded as non-congruent.

Does the reported heterozygous SBF1 p.H466Q mother-daughter pair establish a dominant form of SBF1 neuropathy, or is a second allele or another cause unaccounted for?

CONTROVERSY OPEN cmt4b3_dominant_report

Attached to

inheritance#Autosomal Recessive

Every other published SBF1 family, and ClinGen's expert-panel assertion, is autosomal recessive, and mouse work states that all CMT-causing MTMR5 and MTMR13 mutations are recessive and consistent with loss of function. A 2024 report describes a mother and daughter heterozygous for a novel SBF1 missense variant, both with early-onset distal atrophy and an axonal electrophysiological pattern, and argues for autosomal dominant CMT4B3. The support offered is co-segregation in two individuals plus in-silico pathogenicity and protein structure prediction; no functional assay of the variant and no demonstration that a second SBF1 allele was excluded at the transcript level are reported. This entry therefore curates CMT4B3 as autosomal recessive and records the dominant claim here rather than in the inheritance block. It is a real published claim and should not be dismissed; it is also, on the evidence presented, a single family.

Show evidence (3 references)

PMID:39664754 SUPPORT Human Clinical

"Sequencing identified a novel missense mutation (c.1398C > A, p.H466Q) in exon 13 of the SET binding factor 1 (SBF1) gene in both patients, indicating an autosomal dominant inheritance pattern."

The claim itself, as its authors state it.

PMID:34718573 REFUTE Model Organism

"All mutations are recessive, consistent with a loss-of-function mechanism of pathogenesis."

The prior consensus on the human MTMR5 and MTMR13 variant spectrum that the dominant report runs against. Stated in a mouse study, which is why it carries that publication's MODEL_ORGANISM grading even though the sentence is about human alleles.

PMID:41737274 SUPPORT Human Clinical

"heterozygous SBF1 variants were observed in children with persistent toe walking and accompanying mild neuromotor/musculoskeletal features that partially overlap with reported CMT4B3 phenotypes; however, these findings are descriptive and do not establish causality or enrichment"

An independent cohort in which monoallelic SBF1 variants, mostly VUS, sit beside a mild neuromotor phenotype and the authors decline to call them causal. It is the same interpretive problem the dominant report faces, in a larger sample.

Is there any tractable therapeutic target in CMT4B3, given that the lost protein is a scaffold rather than an enzyme?

KNOWLEDGE GAP OPEN cmt4b3_no_disease_modifying_therapy

Attached to

treatments#

Every treatment in this entry is supportive. Nothing addresses the mechanism, and the shape of the lesion makes the usual routes awkward: MTMR5 has no catalytic activity to restore with a small molecule, and its role is to activate and localize another protein. The candidate strategies that follow from the mechanism - raising residual MTMR2 activity, or correcting the phosphoinositide imbalance downstream - have not been tested in CMT4B3. The zebrafish model was built partly to enable in vivo drug screening, so this gap has an identified route to being closed rather than just being a statement of ignorance.

Show evidence (1 reference)

PMID:40066109 SUPPORT Model Organism

"There is an incomplete understanding of the disease pathomechanism(s) underlying Charcot-Marie-Tooth type 4B3, and despite its severe clinical presentation, currently no disease-modifying therapies."

Directly states both halves of this gap - incomplete mechanism and no disease-modifying therapy.

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Pathophysiology

9

SBF1 Loss of Function

Biallelic SBF1 variants - missense, frameshift or splice-site - reduce or abolish functional MTMR5. The protein's own myotubularin phosphatase domain is catalytically inactive, so this is not the loss of an enzyme. What is lost is MTMR5's regulatory and scaffolding role: a coiled-coil-mediated interaction that raises MTMR2's phosphoinositide 3-phosphatase activity and fixes where in the cell MTMR2 acts, and an N-terminal DENN domain that activates Rab GTPases. Reported pathogenic variants cluster in the DENN and SBF2 domains but occur throughout the gene, and are generally associated with loss of expression or of function. A frameshift allele has been shown directly to reduce MTMR5 protein in patient cells. `zygosity` is deliberately left unset: reported families are homozygous (the consanguineous ones) or compound heterozygous (the index Korean and the Italian families), the slot is single-valued, and the enum has no "biallelic" value that would cover both without misreporting one.

Schwann cell CL:0002573

Genetic context SBF1 hgnc:10542 functional_impact_category: LOSS_OF_FUNCTION

Myelination in peripheral nervous system GO:0022011 ↕ DYSREGULATED

MTMR2 phosphatase activation by MTMR5 GO:0072542 ↓ DECREASED DENN-domain Rab GTPase activation GO:0005085 ↓ DECREASED

Downstream

Loss of MTMR2 Partnering and Phosphoinositide Misregulation Absent or dysfunctional MTMR5 removes the partner that activates and localizes MTMR2.

Central Nervous System and Cranial Nerve Involvement In the syndromic families, SBF1 loss produces disease outside the peripheral nerve as well. The mechanism is not established; the DENN-domain location of the syndromic variants, and functions of MTMR5 beyond MTMR2 binding, are the leading hypotheses.

Show evidence (4 references)

PMID:23749797 SUPPORT Human Clinical

"One pair of heterozygous missense mutations in the SET binding factor 1 (SBF1) gene (22q13.33), also called MTMR5, was identified as the underlying cause of the CMT4B family illness."

Establishes biallelic SBF1 variants as the causal lesion of the disease this entry curates.

PMID:12668758 SUPPORT In Vitro

"The interacting protein was shown by mass spectrometry to be MTMR5, a catalytically inactive member of the MTM family."

The primary demonstration that MTMR5 is catalytically inactive - the fact that makes "loss of function" here mean loss of a regulatory role rather than loss of catalysis.

PMID:27666502 SUPPORT Other

"others lack key residues in the catalytic site and are classified as dead-phosphatases. However, these dead phosphatases regulate phosphoinositide-dependent cellular pathways by binding to catalytically active myotubularins."

A review of the myotubularin family stating the general mechanism this node applies to MTMR5: a dead phosphatase acts by binding an active one. Graded OTHER because the cited publication is a review rather than a study reporting its own data.

+ 1 more reference

Loss of MTMR2 Partnering and Phosphoinositide Misregulation

MTMR5 binds MTMR2 through its coiled-coil domain, increases MTMR2's enzymatic activity and dictates where MTMR2 is localized. Without that partnering, dephosphorylation of the endosomal phosphoinositides PI3P and PI(3,5)P2 is misregulated in both amount and place. Because MTMR5 has no catalytic activity of its own, this is the step at which a pseudophosphatase lesion becomes a phosphoinositide lesion.

Schwann cell CL:0002573

Phosphatidylinositol dephosphorylation GO:0046856 ⚠ ABNORMAL

Downstream

Disordered Endolysosomal Trafficking in Schwann Cells Endosomal phosphoinositides set the identity and maturation of endosomal membranes, so misregulating them derails trafficking through that compartment.

Show evidence (4 references)

PMID:12668758 SUPPORT In Vitro

"Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization."

The two functions of MTMR5 that are lost - activation of MTMR2 and control of its localization - which is exactly what this node claims.

PMID:12668758 SUPPORT In Vitro

"We also demonstrate that MTMR2 interacts with MTMR5 via its coiled-coil domain and that mutations in the coiled-coil domain of either MTMR2 or MTMR5 abrogate this interaction."

Identifies the coiled-coil interface this node names, and shows that mutation of it abolishes the interaction.

PMID:27666502 SUPPORT Other

"While some members have phosphatase activity against the 3-phosphate of phosphoinositides, regulating the phosphorylation status of PtdIns3P and PtdIns(3,5)P2 implicated in membrane trafficking and autophagy, and producing PtdIns5P"

Names the two phosphoinositide species whose handling this node says is misregulated - PtdIns3P and PtdIns(3,5)P2 - and ties them to membrane trafficking. Graded OTHER as a review statement rather than primary data.

+ 1 more reference

Disordered Endolysosomal Trafficking in Schwann Cells

Schwann cells are unusually sensitive to disruption of endolysosomal membrane trafficking - nearly half the CMT4 genes encode regulators of that pathway - because building and maintaining the myelin sheath requires large, precisely directed membrane flux and correct trafficking of the receptors that time myelination. MTMR5 is almost ubiquitously expressed, yet SBF1 variants strike the peripheral nervous system, which is the observation this node explains.

Myelinating Schwann cell CL:0000218

Endosomal transport GO:0016197 ⚠ ABNORMAL

Downstream

Focally Folded and Redundant Myelin The membrane-trafficking defect produces excess, misdirected myelin membrane rather than a correctly compacted sheath.

Impaired Axon Radial Sorting Radial sorting depends on the same trafficking-dependent receptor signalling, and mouse Mtmr5 is expressed most highly while it occurs.

Secondary Mitochondrial Dysfunction and Altered Autophagic Selectivity Endolysosomal and autophagic membrane traffic are the same pathway, so the lesion also reaches mitochondrial quality control.

Show evidence (4 references)

PMID:34718573 SUPPORT Model Organism

"β1-integrin through early endosomes is controlled by Rab21, which the DENN domain of Mtmr5/13 has been shown to activate"

Names a specific cargo and the Rab that routes it, connecting the DENN domain lost in CMT4B3 to a concrete trafficking step in Schwann cells.

PMID:34718573 SUPPORT Model Organism

"β1-integrin is required for the extension and maintenance of Schwann cell processes around axons; loss of this surface receptor leads to radial sorting defects and delayed myelination in mice"

Supplies the reason a trafficking defect reaches radial sorting: the receptor whose routing depends on Rab21 is the one Schwann cells need to extend processes around axons.

PMID:34118926 SUPPORT Human Clinical

"Although almost ubiquitously expressed, pathogenic variants primarily impact on the peripheral nervous system, corroborating the involvement of MTMR5/SBF1 and its molecular partners in Schwann cells-mediated myelinization."

States the tissue-selectivity argument this node makes: broad expression, peripheral-nerve-selective disease, implicating Schwann-cell myelination.

+ 1 more reference

Focally Folded and Redundant Myelin

The histological signature of the CMT4B group: myelin sheaths that fold back on themselves into redundant loops and outfoldings, with loss of large myelinated fibers. In CMT4B3 this was found in the index Korean family, although the absolute number of myelinated fibers differed from CMT4B1 and CMT4B2. It is characteristic of the demyelinating presentation and is not reported in the axonal syndromic families.

Myelinating Schwann cell CL:0000218

Myelination GO:0042552 ⚠ ABNORMAL

myelin sheath GO:0043209

Animal models

Mtmr5-null mouse Mus musculus fails to recapitulate The mouse does not reproduce the histological hallmark of human CMT4B3.

Downstream

Dysmyelination and Slowed Nerve Conduction

Myelin Outfoldings The finding as it is observed on nerve biopsy and recorded as an HPO-bound phenotype.

Show evidence (2 references)

PMID:23749797 SUPPORT Human Clinical

"We found a similar loss of large myelinated fibers and focally folded myelin sheaths in our patients, but the actual number of myelinated fibers was different from CMT4B1 and CMT4B2."

Documents both halves of this node in CMT4B3 nerve biopsies, and the one quantitative difference from the sibling diseases.

PMID:39664754 SUPPORT Human Clinical

"Mutations in these genes can lead to focal myelin out-folding and secondary axonal loss in peripheral nerves"

Restates the outfolding-to-axonal-loss sequence for the CMT4B group (MTMR2, SBF2 and SBF1) that this node and the next but one assert.

Impaired Axon Radial Sorting

Radial sorting is the developmental step in which Schwann cells segregate large-calibre axons out of bundles into 1:1 relationships before myelinating them. Mouse work places MTMR5's main peripheral-nerve role here rather than in myelin maintenance: Mtmr5-null nerves contain fewer myelinated axons and show sorting defects, while Mtmr13 loss produces the outfoldings. Whether this division of labour holds in human CMT4B3, where outfoldings are seen, is unresolved - see the model-mismatch discussion below.

Schwann cell CL:0002573

Myelination in peripheral nervous system GO:0022011 ↓ DECREASED

Animal models

Mtmr5-null mouse Mus musculus recapitulates The mouse is the primary evidence that MTMR5's peripheral-nerve role is in radial sorting.

Downstream

Dysmyelination and Slowed Nerve Conduction

Show evidence (2 references)

PMID:34718573 SUPPORT Model Organism

"Loss of Mtmr5 in mice did not cause CMT4B-like myelin outfoldings. However, adult Mtmr5-/- mouse nerves contained fewer myelinated axons than control nerves, likely as a result of axon radial sorting defects."

The primary evidence for this node, and simultaneously the negative result that the mouse does not reproduce the human outfolding pathology.

PMID:34718573 SUPPORT Model Organism

"Consistently, Mtmr5 levels were highest during axon radial sorting and fell sharply after postnatal day seven."

Developmental expression timing consistent with a radial-sorting role rather than an ongoing myelin-maintenance one.

Secondary Mitochondrial Dysfunction and Altered Autophagic Selectivity

Muscle from one CMT4B3 child showed partial defects of oxidative metabolism, and fibroblasts from the same patient have fragmented mitochondrial networks with reduced ATP production despite preserved mitochondrial mass and respiratory chain assembly, strongly activated PINK1-PRKN mitophagy without the matching rise in macroautophagy, and features of premature senescence. This is presented as a downstream consequence of the trafficking and autophagy lesion, not as a primary respiratory chain defect - which is what separates CMT4B3 from CMT4K, where the gene itself is a complex IV assembly factor.

Skin fibroblast CL:0002620

Mitophagy GO:0000423 ↑ INCREASED

Experimental models

CMT4B3 patient dermal fibroblasts (R763H/G1064E) PRIMARY CELL CULTURE Direct measurement of autophagic flux, mitophagy and mitochondrial morphology in patient cells.

Downstream

Secondary Axonal Loss Impaired mitochondrial quality control is a plausible contributor to the axonal arm of the disease. The link is proposed by the cited authors, not demonstrated in nerve.

Show evidence (3 references)

PMID:34118926 SUPPORT Human Clinical

"Studies in muscle identified partial defects of oxidative metabolism."

The in-patient observation that the mitochondrial arm of this node rests on.

PMID:40998285 SUPPORT In Vitro

"CMT4B3 fibroblasts showed normal basal macroautophagy but failed to increase autophagy in response to mitochondrial stress or protein aggregates. Conversely, mitophagy was strongly activated via the PINK1-PRKN pathway."

The autophagic-selectivity result this node names, measured in patient-derived fibroblasts.

PMID:42627996 SUPPORT In Vitro

"Patient fibroblasts exhibited fragmented mitochondrial networks with a shift toward fission, together with reduced ATP production, while mitochondrial mass, respiratory chain assembly, and markers of mitochondrial biogenesis were preserved."

Preserved respiratory chain assembly alongside reduced ATP output is the specific observation supporting "secondary" rather than primary mitochondrial disease.

Dysmyelination and Slowed Nerve Conduction

The structurally abnormal sheath conducts badly. In the demyelinating presentation this appears as markedly slowed motor conduction velocities; in the axonal syndromic presentation velocities are relatively preserved and it is the action-potential amplitudes that collapse. A zebrafish mtmr5 knockout shows dysmyelination changes described as reminiscent of the human nerve pathology.

Myelinating Schwann cell CL:0000218

Peripheral nervous system myelin maintenance GO:0032287 ↓ DECREASED Myelin assembly GO:0032288 ↓ DECREASED

myelin sheath GO:0043209

Animal models

mtmr5 knockout zebrafish Danio rerio partially recapitulates Dysmyelination changes resembling the human nerve pathology.

Downstream

Secondary Axonal Loss

Decreased Motor Nerve Conduction Velocity The measurable electrophysiological expression of the dysmyelinated sheath, in the demyelinating presentation.

Show evidence (2 references)

PMID:40066109 SUPPORT Model Organism

"These changes are accompanied at the pathological level by abnormal axon outgrowths and by the presence of dysmyelination changes reminiscent of the nerve pathology in human Charcot-Marie-Tooth type 4B3."

Model-organism support that mtmr5 loss is sufficient to produce dysmyelination resembling the human lesion.

PMID:27123480 SUPPORT Human Clinical

"In contrast to CMT4B1, CMT4B2, and the pure neuropathic form of CMT4B3, which are all characterized by demyelinating neuropathy with focally folded myelin sheaths, both families presented a predominantly axonal sensory motor neuropathy"

Records the split this node describes between the demyelinating and axonal electrophysiological patterns within SBF1 disease.

Secondary Axonal Loss

Length-dependent loss of peripheral axons follows the myelin lesion and is what tracks disability. It is the shared endpoint of the demyelinating and axonal presentations, and drives the distal-predominant motor and sensory deficit and the foot deformity.

Schwann cell CL:0002573

Axon ensheathment GO:0008366 ↓ DECREASED Myelination GO:0042552 ↓ DECREASED

Downstream

Distal Muscle Weakness and Atrophy

Distal Sensory Loss

Areflexia

Foot Deformity

Show evidence (2 references)

PMID:39664754 SUPPORT Human Clinical

"Mutations in these genes can lead to focal myelin out-folding and secondary axonal loss in peripheral nerves"

States the outfolding-to-secondary-axonal-loss sequence that this node is the endpoint of.

PMID:23749797 SUPPORT Human Clinical

"We found a similar loss of large myelinated fibers and focally folded myelin sheaths in our patients"

Loss of large myelinated fibers on CMT4B3 sural nerve biopsy is the histological expression of this node.

Central Nervous System and Cranial Nerve Involvement

In the syndromic families, SBF1 loss also produces progressive microcephaly, intellectual disability, cerebellar atrophy with ataxia and pyramidal signs, and degeneration of multiple cranial nerves. The mechanism is not established. Two observations argue that it is not simply more of the same Schwann-cell lesion: the syndromic variants fall in the DENN domain, which only SBF1 and SBF2 carry among the myotubularins, and the mtmr5-null zebrafish develops reduced head size and brain volume rather than a purely peripheral phenotype. Not every severe case has it - one child with severe infantile axonal disease had normal brain MRI and normal cognition throughout.

Animal models

mtmr5 knockout zebrafish Danio rerio partially recapitulates Reduced head size and brain volume, the animal counterpart of the microcephaly seen in the syndromic families.

Downstream

Progressive Microcephaly

Intellectual Disability

Cerebellar Atrophy

Cranial Neuropathy

Show evidence (4 references)

PMID:30039846 SUPPORT Human Clinical

"Four siblings of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of congenital microcephaly, facial dysmorphism, strabismus, developmental delay and ataxia with positive pyramidal signs."

Documents the CNS arm of this node - microcephaly, developmental delay, ataxia and pyramidal signs - in a family with a null SBF1 allele.

PMID:27123480 SUPPORT Human Clinical

"Of note, both mutations causative of syndromic CMT4B3 fall within the DENN domain"

Supports the genotype argument this node makes for why the syndromic families differ, without asserting the mechanism.

PMID:40066109 SUPPORT Model Organism

"starting by 10 days post-fertilization, mutant zebrafish develop obvious morphometric changes in head size and brain volume"

Model-organism support that mtmr5 loss alone can produce a brain-size phenotype, consistent with a CNS role for MTMR5.

+ 1 more reference

✶

Histopathology

2

Focally folded myelin sheaths on sural nerve biopsy

The diagnostic hallmark of the CMT4B group and the finding that put SBF1 disease in it. Distal sural nerve biopsies from the index Korean family showed focally folded (redundant, outfolded) myelin sheaths together with loss of large myelinated fibers - the same pattern as CMT4B1 and CMT4B2, although the absolute number of myelinated fibers differed. It is reported in the demyelinating presentation; the syndromic axonal families instead show denervation, and one showed necklace fibres on muscle biopsy.

Show evidence (2 references)

PMID:23749797 SUPPORT Human Clinical

"We found a similar loss of large myelinated fibers and focally folded myelin sheaths in our patients, but the actual number of myelinated fibers was different from CMT4B1 and CMT4B2."

The primary histological description in CMT4B3, from sural nerve biopsies of all three affected members of the index family.

PMID:23749797 SUPPORT Human Clinical

"We enrolled 14 members of a Korean family in which 3 individuals had demyelinating CMT4B phenotype and obtained distal sural nerve biopsies from all affected participants."

Establishes the tissue and ascertainment behind the histological finding.

Necklace fibres on muscle biopsy

Muscle biopsy in the Chinese syndromic family showed necklace fibres - a myofibre feature more usually associated with the myotubularin myopathies - alongside the sensorimotor axonal neuropathy. Reported in one family.

Show evidence (1 reference)

PMID:32444983 SUPPORT Human Clinical

"Muscle biopsy showed a feature of necklace fibres."

Direct report of the finding this record names.

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Pathograph

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Phenotypes

16

Digestive 1

Dysphagia HP:0002015

Show evidence (1 reference)

PMID:34118926 SUPPORT Human Clinical

"the development of dysphagia, necessitating G-tube placement"

Documents dysphagia severe enough to require gastrostomy in a CMT4B3 patient.

Ear 1

Sensorineural Hearing Impairment HP:0000407

Show evidence (1 reference)

PMID:28005197 SUPPORT Human Clinical

"two siblings with severe axonal neuropathy, hearing loss, facial weakness and bulbar features"

Documents hearing loss in an SBF1-mutated sibling pair.

Head and Neck 1

Progressive Microcephaly HP:0000253

Show evidence (1 reference)

PMID:27123480 SUPPORT Human Clinical

"The 2 siblings shared relevant features with the Saudi Arabian family, including early-onset progressive microcephaly, multiple cranial nerve neuropathies, and moderate to severe intellectual disability."

Documents progressive microcephaly in two independent SBF1 families.

Limbs 3

Foot Deformity Pes cavus HP:0001761

Show evidence (3 references)

PMID:30039846 SUPPORT Human Clinical

"Physical assessment exhibited kyphoscoliosis, bilateral syndactyly and distal muscle wasting with drop-foot and pes cavus."

Documents pes cavus and drop-foot in a CMT4B3 family.

PMID:27123480 SUPPORT Human Clinical

"There was distal muscle wasting and weakness but no pes cavus."

Records a CMT4B3 family with distal wasting but no pes cavus, so foot deformity is not present in every affected individual.

PMID:20301641 SUPPORT INDIRECT Other

"Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity."

GeneReviews states that pes cavus is frequently but not invariably present in the CMT4 series, which is the only frequency statement any source makes about foot deformity in this disease group. Indirect because it describes the CMT4 group rather than CMT4B3, and it is drawn from a chapter GeneReviews has retired.

Congenital Talipes HP:0001883

Show evidence (1 reference)

PMID:34118926 SUPPORT Human Clinical

"presented bilateral congenital talon-valgus-pronated clubfoot at birth and slight neuromotor developmental delay from the age of 18 months"

Documents congenital clubfoot at birth in a genetically confirmed CMT4B3 patient.

Syndactyly Cutaneous syndactyly HP:0012725

Show evidence (1 reference)

PMID:32444983 SUPPORT Human Clinical

"The index patient was a 29-year-old male with clinical phenotype of syndactyly, pes cavus, swallowing difficulties, vision problem, imbalance, and muscle weakness."

Documents syndactyly as part of the SBF1 syndromic phenotype.

Musculoskeletal 1

Distal Muscle Weakness and Atrophy HP:0002460

Course: PROGRESSIVE

Sequelae: Foot Deformity Loss of Independent Ambulation

Show evidence (3 references)

PMID:27123480 SUPPORT Human Clinical

"All patients had onset of distal atrophy and weakness in upper and lower limbs, decreased vibration and position sense, areflexia, and pes planus in the first decade, with a slow progression to loss of ambulation in the fifth decade of life."

Documents distal weakness and atrophy in all affected members of the index family, with first-decade onset.

PMID:30039846 SUPPORT Human Clinical

"they developed areflexia, multiple cranial neuropathies and severe polyneuropathy with progressive muscle weakness, affecting proximal and distal extremities"

Shows that in the syndromic form the weakness is severe and not confined to distal muscles.

PMID:20301641 SUPPORT INDIRECT Other

"Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity."

GeneReviews names distal muscle weakness and atrophy as the typical phenotype of the CMT4 series. Indirect because the statement is made of the whole autosomal recessive CMT4 group, in which SBF1/CMT4B3 is one of eleven genes, rather than of CMT4B3 specifically.

Nervous System 8

Distal Sensory Loss Impaired vibratory sensation HP:0002495

Show evidence (3 references)

PMID:27123480 SUPPORT Human Clinical

"decreased vibration and position sense, areflexia, and pes planus in the first decade"

Documents impaired vibration and position sense in the index CMT4B3 family.

PMID:34118926 REFUTE Human Clinical

"no clinical and neurophysiological evidences of distal sensory impairment"

A reported CMT4B3 patient in whom distal sensory impairment was absent on both clinical and neurophysiological assessment, so sensory loss is not an obligate feature of this disease. Scoped to the classic subtype.

PMID:20301641 SUPPORT INDIRECT Other

"Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity."

GeneReviews names sensory loss as part of the typical CMT4 phenotype. Indirect because the statement is made of the whole autosomal recessive CMT4 group rather than of CMT4B3, and it sits alongside the REFUTE item above from a CMT4B3 family in whom sensory involvement was absent.

Areflexia HP:0001284

Show evidence (1 reference)

PMID:30039846 SUPPORT Human Clinical

"Toward the end of their first decade, they developed areflexia, multiple cranial neuropathies and severe polyneuropathy with progressive muscle weakness"

Documents areflexia in the Bedouin syndromic family.

Loss of Independent Ambulation Inability to walk HP:0002540

Course: PROGRESSIVE

Show evidence (2 references)

PMID:27123480 SUPPORT Human Clinical

"with a slow progression to loss of ambulation in the fifth decade of life"

The natural history of ambulation in the classic demyelinating presentation.

PMID:34118926 SUPPORT Human Clinical

"Independent ambulation was lost at the age of 9, when she began needing walking aids; she became wheelchair-dependent at the age of 11."

The contrasting, far more rapid course in the severe infantile axonal presentation.

Decreased Motor Nerve Conduction Velocity HP:0003431

Show evidence (1 reference)

PMID:27123480 SUPPORT Human Clinical

"In contrast to CMT4B1, CMT4B2, and the pure neuropathic form of CMT4B3, which are all characterized by demyelinating neuropathy with focally folded myelin sheaths, both families presented a predominantly axonal sensory motor neuropathy with evidence of denervation, markedly reduced amplitude of..."

Confirms the demyelinating pattern for the pure neuropathic form while recording that the syndromic families do not show it - the reason this phenotype is scoped to the classic subtype.

Cranial Neuropathy Cranial nerve paralysis HP:0006824

Sequelae: Dysphagia Sensorineural Hearing Impairment

Show evidence (1 reference)

PMID:28005197 SUPPORT Human Clinical

"Here we describe novel sequence variants in SBF1 (c.1168C>G and c.2209_2210del) as the potential causative mutations in two siblings with severe axonal neuropathy, hearing loss, facial weakness and bulbar features."

Documents cranial nerve involvement (facial weakness, bulbar features, hearing loss) as part of the SBF1 syndromic phenotype.

Intellectual Disability HP:0001249

Show evidence (2 references)

PMID:27123480 SUPPORT Human Clinical

"early-onset progressive microcephaly, multiple cranial nerve neuropathies, and moderate to severe intellectual disability"

Documents intellectual disability in the syndromic families.

PMID:27123480 REFUTE Human Clinical

"None had cognitive impairment, dysmorphic features, or obvious extraneurologic syndromic manifestations."

The index Korean family had no cognitive impairment, which is why this phenotype is scoped to the syndromic subtype rather than to the disease.

Cerebellar Atrophy HP:0001272

Show evidence (1 reference)

PMID:30039846 SUPPORT Human Clinical

"Magnetic resonance imaging (MRI) showed profound cerebellar atrophy with highly unique findings at the pontine and mesencephalic levels"

Documents cerebellar atrophy on MRI in a CMT4B3 family.

Myelin Outfoldings HP:0004336

Show evidence (1 reference)

PMID:23749797 SUPPORT Human Clinical

"We found a similar loss of large myelinated fibers and focally folded myelin sheaths in our patients"

Reports focally folded myelin sheaths on sural nerve biopsy in the index CMT4B3 family.

Respiratory 1

Respiratory Insufficiency HP:0002093

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:34118926 SUPPORT Human Clinical

"with worsening of ambulation and of respiratory function, to the point of requiring non-invasive positive pressure ventilation, and the development of dysphagia, necessitating G-tube placement"

Documents progressive respiratory decline severe enough to require ventilatory support in a CMT4B3 child with the severe infantile presentation.

🧬

Genetic Associations

1

SBF1 (Causal)

Gene: SBF1 hgnc:10542 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:23749797 SUPPORT Human Clinical

"We suggest that the compound heterozygous mutations in SBF1 are the underlying causes of a novel CMT4B subtype, designated as CMT4B3."

The paper that established SBF1 as the CMT4B3 gene and named the disease.

CGGV:assertion_c0f814d9-02db-4c0c-8e1c-20a7759d993f-2024-12-02T170000.000Z SUPPORT Other

ClinGen expert-panel assessment of the SBF1-CMT4B3 gene-disease relationship. Moderate, not Definitive - the honest current strength of the association, reflecting the small number of published families.

PMID:20301641 SUPPORT Other

"Detection of biallelic pathogenic variants in one of the following 11 genes establishes the diagnosis: GDAP1 (CMT4A), MTMR2 (CMT4B1), SBF2 (CMT4B2), SBF1 (CMT4B3), SH3TC2 (CMT4C), NDRG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), HK1 (CMT4G), FGD4 (CMT4H), and FIG4 (CMT4J)."

GeneReviews places SBF1/CMT4B3 in the CMT4 diagnostic gene list. Cited from a chapter GeneReviews has retired, so it establishes the gene-disease pairing rather than current management guidance.

💊

Medical Actions

6

Physical and Occupational Therapy

Action: physical therapy Ontology label: Physical Therapy NCIT:C15302

Platform: Behavioral / lifestyle

The mainstay of care. A multidisciplinary team - neurologist, physiatrist, orthopedic surgeon, physical and occupational therapists - maintains mobility and function, with exercise as tolerated and daily heel cord stretching to prevent Achilles tendon shortening. This is CMT4 management generally; nothing is specific to CMT4B3.

Show evidence (1 reference)

PMID:20301641 SUPPORT Other

"Treatment by a team including a neurologist, physiatrist, orthopedic surgeon, physical and occupational therapists; special shoes and/or ankle/foot orthoses to correct foot drop and aid walking; surgery as needed for severe pes cavus; forearm crutches, canes, wheelchairs as needed for mobility;..."

GeneReviews management recommendation for CMT4, of which CMT4B3 is a subtype. Quoted from a chapter GeneReviews has since retired, so it is historical expert guidance rather than a current standard.

Orthoses and Mobility Aids

Action: orthotic and mobility support Ontology label: Supportive Care NCIT:C15747

Platform: Device

Special shoes and ankle-foot orthoses to correct foot drop and aid walking; forearm crutches, canes and wheelchairs as strength is lost. In the severe infantile axonal presentation these are needed within the first decade.

Show evidence (1 reference)

PMID:20301641 SUPPORT Other

"special shoes and/or ankle/foot orthoses to correct foot drop and aid walking; surgery as needed for severe pes cavus; forearm crutches, canes, wheelchairs as needed for mobility"

GeneReviews CMT4 management recommendation naming exactly these devices.

Orthopedic Surgery for Foot Deformity and Contracture

Action: orthopedic surgical procedure Ontology label: Orthopedic Surgical Procedure NCIT:C16186

Platform: Surgery

Corrective surgery for severe pes cavus, and Achilles tendon release for contracture. Tendon release was performed in a reported SBF1 patient and the contracture nonetheless recurred, which is worth saying plainly: surgery addresses the deformity, not the neuropathy driving it. That case comes from the family whose autosomal dominant inheritance claim this entry records as contested (cmt4b3_dominant_report); it is cited here for the surgical course only, which does not depend on that claim.

Show evidence (1 reference)

PMID:39664754 SUPPORT Human Clinical

"After first surgery of patient III2, her Achilles tendon contracture progressively still rendered both heels of her feet difficult to land"

Documents Achilles tendon release in a patient with an SBF1 variant, and that the contracture progressed afterwards.

Avoidance of Neurotoxic Medications

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Drugs known to cause peripheral nerve damage - vincristine, isoniazid, nitrofurantoin among them - should be avoided, as should obesity, which makes ambulation harder. This is the CMT4 "agents and circumstances to avoid" guidance; there is no CMT4B3-specific list.

Show evidence (1 reference)

PMID:20301641 SUPPORT Other

"Agents/circumstances to avoid: Obesity (which makes ambulation more difficult); medications (e.g., vincristine, isoniazid, nitrofurantoin) known to cause nerve damage."

GeneReviews list of agents and circumstances to avoid in CMT4, quoted verbatim.

Respiratory and Nutritional Support

Action: supportive care Ontology label: Supportive Care NCIT:C15747

In the severe infantile presentation, non-invasive positive pressure ventilation for respiratory decline and gastrostomy for dysphagia were both required before age 12. Anticipating these is part of managing the severe end of the spectrum.

Show evidence (1 reference)

PMID:34118926 SUPPORT Human Clinical

"with worsening of ambulation and of respiratory function, to the point of requiring non-invasive positive pressure ventilation, and the development of dysphagia, necessitating G-tube placement"

Documents the respiratory and nutritional interventions required in a severely affected CMT4B3 child.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Autosomal recessive recurrence risk of 25% per pregnancy, carrier testing for at-risk relatives, and prenatal testing where the familial variants are known. Most reported CMT4B3 families are consanguineous, so counseling about consanguinity is often central.

Show evidence (1 reference)

PMID:20301641 SUPPORT Other

"At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."

The recurrence risk this counseling conveys, stated by GeneReviews for the CMT4 subtypes.

🔬

Diagnosis

4

Molecular genetic testing of SBF1 (PRESENT)

Diagnosis rests on identifying biallelic pathogenic SBF1 variants. Standard first-line CMT testing does not reach SBF1: the reported patients had PMP22 rearrangement, MFN2 and GDAP1 testing come back negative first.

SBF1 molecular genetic testing NCIT:C15709

Markers: SBF1 (MTMR5), 22q13.33

Results: Two pathogenic SBF1 alleles, in trans - homozygous in the consanguineous families, compound heterozygous in the Korean and Italian families.

Show evidence (2 references)

PMID:20301641 SUPPORT Other

"The diagnosis of CMT4 subtypes is based on clinical findings, neurophysiologic studies, and molecular genetic testing."

GeneReviews statement of the diagnostic approach for the CMT4 series that CMT4B3 belongs to.

PMID:34118926 SUPPORT Human Clinical

"Gene testing for genomic rearrangements of PMP22 and punctuate variants in MNF2 and GDAP1 were negative."

Illustrates that the common CMT genes are tested and excluded before SBF1 is reached. Quoted verbatim including the source's misspelling of MFN2.

Whole exome sequencing (PRESENT)

The test that actually makes the diagnosis in practice. Every family in which SBF1 was established as causal was solved by exome sequencing, because the phenotype - especially the syndromic form - does not point at SBF1 on clinical grounds and SBF1 is not on all older CMT panels.

whole exome sequencing NCIT:C101295

Results: A biallelic SBF1 variant surviving the filtering pipeline, segregating with disease in the pedigree.

Show evidence (3 references)

PMID:23749797 SUPPORT Human Clinical

"We conducted exome sequencing on 6 samples (3 affected and 3 unaffected individuals)."

The exome study that identified SBF1 as the CMT4B3 gene, including unaffected relatives for segregation.

PMID:30039846 SUPPORT Human Clinical

"Whole exome sequencing identified a single novel homozygous deleterious splice-site mutation within this locus in SET binding factor 1 (SBF1)."

A second, independent family diagnosed by exome sequencing after linkage narrowed the locus.

PMID:32444983 SUPPORT Human Clinical

"Muscle biopsy and whole-exome sequencing (WES) were performed."

A third family, showing exome sequencing paired with tissue biopsy as the diagnostic combination.

Nerve conduction studies and electromyography (PRESENT)

Neurophysiology classifies the neuropathy rather than making the diagnosis, and in CMT4B3 the classification is not uniform. The classic form shows demyelinating slowing, which is what places it in CMT4; the syndromic and the severe infantile forms show reduced compound muscle action potential amplitudes with denervation on EMG and relatively preserved velocities. A normal or near-normal conduction velocity therefore does not exclude CMT4B3.

nerve conduction study NCIT:C154784

Results: Either slowed motor conduction velocity (demyelinating range) or reduced CMAP amplitude with preserved velocity (axonal pattern), depending on the presentation.

Show evidence (2 references)

PMID:34118926 SUPPORT Human Clinical

"Electroneurography disclosed severe motor polyneuropathy with predominant axonal features, diffuse reduction of compound action muscular potentials (CMAP, values under 1.5 mV) and only slight decrement of NCV (38-43 m/s)."

A worked example of the axonal electrophysiological pattern with nearly preserved conduction velocity in genetically confirmed CMT4B3.

PMID:32444983 SUPPORT Human Clinical

"Nerve conduction studies and electromyography of both patients suggested sensory-motor axonal neuropathy."

Documents both tests used together, and a second family with the axonal rather than demyelinating pattern.

Sural nerve biopsy (PRESENT)

The CMT4B group's diagnostic hallmark. Distal sural nerve biopsy in the index Korean family showed focally folded myelin sheaths with loss of large myelinated fibers - the finding that placed SBF1 disease in CMT4B and named the disease. It is no longer required for diagnosis now that sequencing is available, but a historical biopsy showing myelin outfoldings in an unsolved recessive neuropathy is a reason to sequence SBF1.

sural nerve biopsy NCIT:C217131

Results: Focally folded (outfolded) myelin sheaths and loss of large myelinated fibers, with myelinated fiber counts differing from CMT4B1 and CMT4B2.

Show evidence (2 references)

PMID:23749797 SUPPORT Human Clinical

"We enrolled 14 members of a Korean family in which 3 individuals had demyelinating CMT4B phenotype and obtained distal sural nerve biopsies from all affected participants."

The diagnostic material and how it was obtained, in the family that defined the disease.

PMID:23749797 SUPPORT Human Clinical

"We found a similar loss of large myelinated fibers and focally folded myelin sheaths in our patients, but the actual number of myelinated fibers was different from CMT4B1 and CMT4B2."

The result the biopsy yields, and the one respect in which it differs from the sibling CMT4B diseases.

🩻

Imaging Findings

2

Fork and bracket sign on brain MRI

A distinctive appearance at the pontine and mesencephalic level, attributed to degenerated fibre bundles of the oculomotor and facial nerves, reported in the Syrian and Bedouin syndromic families. It is the imaging finding that named "fork and bracket" syndrome, and its recognition is what linked that condition to SBF1.

Mri Diagnostic Syndromic SBF1 Neuropathy

Show evidence (2 references)

PMID:20658556 SUPPORT Human Clinical

"Previously unknown findings referred to as the "fork sign" at the pontine level and the "bracket sign" at the mesencephalic level were documented by magnetic resonance imaging."

The original description of the sign, in the Syrian sibship later shown by exome sequencing to carry a homozygous SBF1 variant. Note this paper predates the SBF1 link and does not itself name the gene.

PMID:30039846 SUPPORT Human Clinical

"Magnetic resonance imaging (MRI) showed profound cerebellar atrophy with highly unique findings at the pontine and mesencephalic levels"

Reports the pontine and mesencephalic MRI abnormality this finding names, in a second, independent SBF1 family.

Normal brain and spinal MRI

Recorded here because its absence is diagnostically informative: the Italian child with severe infantile axonal CMT4B3 had normal brain and spinal MRI on repeated imaging to age 11. A normal MRI does not exclude SBF1 disease.

Mri

Show evidence (1 reference)

PMID:34118926 SUPPORT Human Clinical

"The patient showed no cognitive impairment during the clinical course, and at the latest follow up (age 11), brain and spinal MRI remained normal."

Documents normal neuroimaging in a genetically confirmed, severely affected CMT4B3 patient.

📊

Prevalence

1

Worldwide, published families

Cases In Literature Ultra Rare

Counted in families, not cases. Two families were on record in 2016, five by 2021 and seven by 2024. No population-based prevalence estimate exists for CMT4B3, and the counts below are the authors' own tallies of the published literature at the time of writing, not systematic ascertainment.

Show evidence (4 references)

PMID:27123480 SUPPORT Human Clinical

"Only 2 CMT4B3 families have been reported to date."

The 2016 count of published CMT4B3 families.

PMID:34118926 SUPPORT Human Clinical

"To date, only five families harboring variants in MTMR5/SBF1 have been described"

The 2021 count, and the basis for the ULTRA_RARE band.

PMID:39664754 SUPPORT Human Clinical

"To date, only seven families with SBF1 mutations have been described"

The 2024 count of published SBF1 families.

+ 1 more reference

🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from Charcot-Marie-Tooth Disease Type 4B3:

Charcot-Marie-Tooth Disease Type 4B1

Overlapping Features MTMR2-related CMT4B1 is the closest mimic: autosomal recessive demyelinating neuropathy with the same focally folded myelin sheaths. MTMR2 is the active phosphatase that MTMR5 regulates, so the two diseases sit on the same molecular axis. Clinically the classic CMT4B3 phenotype resembles CMT4B1 only "to some extent" - the number of myelinated fibers on biopsy differs - and CMT4B1 does not produce the microcephaly, intellectual disability or cranial neuropathy seen in syndromic SBF1 disease. Separation is by gene.

Distinguishing Features

Causal gene MTMR2 rather than SBF1
No syndromic CNS or cranial nerve involvement
Different absolute myelinated fiber counts on nerve biopsy

Show evidence (1 reference)

PMID:23749797 SUPPORT Human Clinical

"Clinical phenotypes of affected study participants with CMT4B were similar, to some extent, to patients with CMT4B1 and CMT4B2."

States the partial clinical overlap that makes CMT4B1 a differential, in the authors' own hedged terms.

Charcot-Marie-Tooth Disease Type 4B2

Overlapping Features SBF2/MTMR13-related CMT4B2 is the other myotubularin CMT4B, caused by loss of the pseudophosphatase most similar to MTMR5 - the two share 59% identity and the same domain architecture. CMT4B2 is distinguished by early-onset glaucoma, which is not a feature of SBF1 disease, and by classic demyelination with outfoldings without the syndromic CNS features.

Distinguishing Features

Causal gene SBF2 / MTMR13 rather than SBF1
Early-onset glaucoma
Classic demyelination without microcephaly or intellectual disability

Show evidence (1 reference)

PMID:12687498 SUPPORT Human Clinical

"we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13."

Establishes MTMR13/SBF2 as the CMT4B2 gene, distinct from SBF1, in families whose distinguishing feature is early-onset glaucoma.

Charcot-Marie-Tooth Disease Type 4K

Overlapping Features SURF1-related CMT4K also presents as childhood demyelinating neuropathy with a mitochondrial biochemical profile, which makes it a genuine differential for the CMT4B3 cases reported with secondary oxidative-metabolism defects. The distinction is directional: in CMT4K the gene is a complex IV assembly factor and the mitochondrial defect is primary, with lactic acidosis and later putaminal and periaqueductal lesions; in CMT4B3 the mitochondrial findings are downstream of a membrane-trafficking lesion, and respiratory chain assembly is preserved.

Distinguishing Features

Causal gene SURF1, a complex IV assembly factor
Lactic acidosis
Putaminal and periaqueductal brain lesions

Show evidence (1 reference)

PMID:42627996 SUPPORT In Vitro

"reduced ATP production, while mitochondrial mass, respiratory chain assembly, and markers of mitochondrial biogenesis were preserved"

Preserved respiratory chain assembly in CMT4B3 cells is the observation that separates it from a primary respiratory chain assembly disorder such as CMT4K.

📊

Related Datasets

1

Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3 geo:GSE290354

Brain-enriched bulk RNA sequencing from the mtmr5 full-gene-deletion zebrafish line curated under animal_models, n=8. This is the transcriptomic dataset behind the neurogenesis, chromatin-remodelling and synaptic-membrane-homeostasis pathways reported for that model. Zebrafish brain, so it speaks to the CNS arm of the disease rather than to the peripheral nerve lesion.

zebrafish BULK RNA SEQ

PMID:40066109

The only DIRECT dataset candidate found for CMT4B3. A second candidate, geo:GSE190699, was surfaced by gene-only matching on SBF1 and rejected on triage: it is a multiple myeloma study with no relationship to this disease.

Show evidence (1 reference)

GEO:GSE290354 SUPPORT Model Organism

"RNA sequencing from brain-enriched samples identifies novel disease pathways including transcriptional changes in genes responsible for neurogenesis, chromatin remodeling/organization, and synaptic membrane homeostasis."

The GEO record's own summary of what this dataset measured and found.

🧫

Experimental Models

2

CMT4B3 patient dermal fibroblasts (R763H/G1064E) PRIMARY_CELL_CULTURE

Dermal fibroblasts from the Italian child with compound heterozygous MTMR5/SBF1 R763H and G1064E variants, compared with healthy control fibroblasts. They carry the mitochondrial and autophagy arm of the disease model in this entry: fragmented mitochondrial networks with reduced ATP but preserved respiratory chain assembly, strongly activated PINK1-PRKN mitophagy without a matching macroautophagy response, and features of premature senescence.

Organism

human NCBITaxon:9606

Publication

PMID:40998285

Pathograph links

Secondary Mitochondrial Dysfunction and Altered Autophagic Selectivity measures fidelity: moderate observes: cellular Direct measurement of autophagic flux, mitophagy and mitochondrial morphology in patient cells.

Limitations: Fibroblasts, not Schwann cells or neurons - the cells that actually carry the disease. Single patient, single control, so the findings constrain the mechanism rather than establishing its penetrance across CMT4B3.

Show evidence (1 reference)

PMID:40998285 SUPPORT In Vitro

"These results reveal an uncoupling between mitophagy and macroautophagy, indicating that MTMR5/SBF1 mutations modify autophagic selectivity."

The interpretation the authors draw from this model, which is what the target node asserts.

Show evidence (1 reference)

PMID:40998285 SUPPORT In Vitro

"Our findings provide new mechanistic insights into the pathogenesis of CMT4B3 and highlight the value of patient-derived fibroblasts for studying selective autophagy defects."

The authors' statement that patient-derived fibroblasts are an informative system for this aspect of CMT4B3 pathogenesis.

CMT4B3 patient-derived iPSC lines IPSC_DERIVED_MODEL

Induced pluripotent stem cell lines reprogrammed from fibroblasts of unrelated CMT4B3 patients with homozygous or biallelic SBF1 variants. They were generated explicitly because the existing animal models do not clearly connect Sbf1 loss to severe neuropathy, so a human cellular system was needed to study the relationship between MTMR5 dysfunction and peripheral nerve degeneration.

Organism

human NCBITaxon:9606

Publication

PMID:39461113

Show evidence (2 references)

PMID:39461113 SUPPORT In Vitro

"Here, we describe the establishment and validation of three human induced pluripotent stem cell (iPSC) lines derived from unrelated CMT4B3 patients, each harboring homozygous MTMR5/Sbf1 mutations."

Establishes the existence and provenance of these lines.

PMID:36272304 SUPPORT In Vitro

"Herein, we report the generation and characterization of a hiPSC line from a 12-year-old Italian girl with early onset severe polyneuropathy with motor and axonal involvement, harboring biallelic variants in the MTMR5/SBF1 gene."

A fourth line, from the severe infantile axonal case whose fibroblasts carry the mitochondrial phenotype recorded above.

🐁

Animal Models

2

Mtmr5-null mouse

Constitutive Mtmr5-null mice. Adult nerves contain fewer myelinated axons, attributed to defective axon radial sorting, and Mtmr5 expression peaks during radial sorting and falls after postnatal day 7. Critically, these mice do NOT develop the CMT4B-like myelin outfoldings that define the human disease. Combined Mtmr5/Mtmr13 deletion is perinatally lethal.

Species

Mus musculus

Genotype

Mtmr5-/- (Sbf1 knockout)

Genes

SBF1 hgnc:10542

Publication

PMID:34718573

Pathograph links

Impaired Axon Radial Sorting recapitulates fidelity: moderate observes: tissue The mouse is the primary evidence that MTMR5's peripheral-nerve role is in radial sorting.

Limitations: Mouse, not human, and the sorting defect is inferred from reduced myelinated axon counts in adult nerve rather than measured during sorting itself.

Show evidence (1 reference)

PMID:34718573 SUPPORT Model Organism

"adult Mtmr5-/- mouse nerves contained fewer myelinated axons than control nerves, likely as a result of axon radial sorting defects"

The measurement behind treating this model as informative for the radial sorting node.

Focally Folded and Redundant Myelin fails to recapitulate fidelity: low observes: tissue The mouse does not reproduce the histological hallmark of human CMT4B3.

Limitations: A complete null in mouse produces no myelin outfoldings, while human CMT4B3 nerve biopsy shows them. Either the mouse lacks a human-specific requirement for MTMR5 in myelin maintenance, or the human outfoldings arise by a route the null allele does not model. Until that is resolved, this model cannot be used to study the outfolding pathology.

Show evidence (1 reference)

PMID:34718573 REFUTE Model Organism

"Loss of Mtmr5 in mice did not cause CMT4B-like myelin outfoldings."

The negative result itself, stated by the authors.

Show evidence (1 reference)

PMID:34718573 SUPPORT Model Organism

"This study enhances our understanding of the non-redundant roles of the endosomal regulators MTMR5 and MTMR13 during normal peripheral nerve development and disease."

Supports treating the Mtmr5-null mouse as informative for MTMR5 function in peripheral nerve, while the authors frame the roles as non-redundant - which is why this entry also records what the model fails to reproduce.

mtmr5 knockout zebrafish

A CRISPR full-gene-deletion line, presented as the first pre-clinical model to phenocopy CMT4B3. Homozygotes are born at normal Mendelian ratios with preserved motor function, then from 10 days post-fertilization develop reduced head size and brain volume, abnormal axon outgrowths, and dysmyelination described as reminiscent of the human nerve pathology. Brain-enriched RNA sequencing implicates neurogenesis, chromatin remodelling and synaptic membrane homeostasis.

Species

Danio rerio

Genotype

mtmr5 full-gene deletion (CRISPR/Cas9), homozygous

Genes

SBF1 hgnc:10542

Publication

PMID:40066109

Pathograph links

Dysmyelination and Slowed Nerve Conduction partially recapitulates fidelity: moderate observes: tissue Dysmyelination changes resembling the human nerve pathology.

Limitations: Zebrafish, and the resemblance is described qualitatively as "reminiscent"; no nerve conduction measurements are reported, so the conduction half of this node is not modelled.

Show evidence (1 reference)

PMID:40066109 SUPPORT Model Organism

"the presence of dysmyelination changes reminiscent of the nerve pathology in human Charcot-Marie-Tooth type 4B3"

The reported dysmyelination phenotype in this model.

Central Nervous System and Cranial Nerve Involvement partially recapitulates fidelity: moderate observes: organism Reduced head size and brain volume, the animal counterpart of the microcephaly seen in the syndromic families.

Limitations: Head size in a larval zebrafish is not human microcephaly, and no cranial nerve pathology is reported in this model, so only the brain-size arm of this node is covered.

Show evidence (1 reference)

PMID:40066109 SUPPORT Model Organism

"mutant zebrafish develop obvious morphometric changes in head size and brain volume"

The brain-size phenotype supporting a CNS role for MTMR5.

Show evidence (1 reference)

PMID:40066109 SUPPORT Model Organism

"Overall, our mtmr5 knockout zebrafish mirror genetic, clinical and pathologic features of human Charcot-Marie-Tooth type 4B3."

The authors' own claim that this model is informative for human CMT4B3, which is what a model-level evidence item attests.

{ }

Source YAML

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name: Charcot-Marie-Tooth Disease Type 4B3
creation_date: "2026-09-07T00:00:00Z"
category: Mendelian
description: >-
  Charcot-Marie-Tooth disease type 4B3 (CMT4B3) is an autosomal recessive
  hereditary motor and sensory neuropathy caused by biallelic variants in SBF1,
  which encodes MTMR5 (SET binding factor 1). MTMR5 is a myotubularin-family
  protein whose own phosphatase domain is catalytically inactive; it acts
  instead as a binding partner that raises the enzymatic activity of the
  phosphoinositide 3-phosphatase MTMR2 and sets its subcellular localization,
  and as a DENN-domain Rab GTPase activator. "Loss of function" in CMT4B3
  therefore means loss of this regulatory and scaffolding role, not loss of a
  catalytic activity MTMR5 never had. The resulting derangement of
  phosphoinositide handling and endolysosomal membrane trafficking in Schwann
  cells produces the CMT4B nerve pathology: loss of large myelinated fibers and
  the focally folded, redundant myelin sheaths that are the biopsy hallmark of
  the CMT4B group, with slowed conduction and secondary axonal loss expressed
  clinically as childhood-onset distal weakness, distal sensory loss, areflexia
  and foot deformity. CMT4B3 is set apart from its CMT4B1 (MTMR2) and CMT4B2
  (SBF2/MTMR13) siblings by the breadth of its reported spectrum: alongside the
  pure demyelinating neuropathy of the index Korean family, several
  consanguineous families carry a far more severe early-onset syndromic
  disease - progressive microcephaly, intellectual disability, syndactyly,
  cerebellar and pyramidal signs, multiple cranial neuropathies and a
  predominantly axonal neuropathy - and one reported child had severe infantile
  axonal disease with secondary mitochondrial dysfunction but no CNS or
  cognitive involvement at all. Fewer than ten families have been published.
  There is no disease-modifying therapy; management is supportive and
  rehabilitative.
disease_term:
  preferred_term: Charcot-Marie-Tooth disease type 4B3
  term:
    id: MONDO:0014117
    label: Charcot-Marie-Tooth disease type 4B3
synonyms:
- CMT4B3
- Charcot-Marie-Tooth disease, type 4B3
- SBF1 Charcot-Marie-Tooth disease type 4
- Charcot-Marie-Tooth disease with focally folded myelin
- Charcot-Marie-Tooth disease type 4 caused by mutation in SBF1
- MTMR5-associated Charcot-Marie-Tooth disease
parents:
- Charcot-Marie-Tooth Disease Type 4
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0014117
      label: Charcot-Marie-Tooth disease type 4B3
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: >-
      Primary MONDO identifier for this entry. MONDO models CMT4B3 as a leaf
      under MONDO:0018995 (Charcot-Marie-Tooth disease type 4) with a single
      causal gene (SBF1) and no descendants.
references:
- reference: PMID:20301532
  title: "Charcot-Marie-Tooth Hereditary Neuropathy Overview."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:20301641
  title: "Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
  tags:
  - GeneReviews
  findings: []
- reference: PMID:24799518
  title: "SET binding factor 1 (SBF1) mutation causes Charcot-Marie-tooth disease type 4B3."
  findings: []
has_subtypes:
- name: Classic CMT4B3
  display_name: Classic demyelinating CMT4B3
  description: >-
    The presentation of the index Korean family and the one that named the
    disease: a pure sensorimotor demyelinating neuropathy with focally folded
    myelin sheaths on nerve biopsy, closely resembling CMT4B1 and CMT4B2, with
    first-decade onset of distal weakness and atrophy, impaired vibration and
    position sense, areflexia and pes planus, and no cognitive, dysmorphic or
    other extraneurological features. These patients were compound
    heterozygous for two missense variants that most in-silico tools called
    benign or tolerated.
  evidence:
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the original Korean family, 3 siblings showed a homogeneous phenotype of pure sensory motor demyelinating neuropathy with focally folded myelin sheaths, closely resembling CMT4B1 and CMT4B2."
    explanation: >-
      Defines the pure demyelinating presentation that this subtype names, and
      places it alongside the CMT4B1 and CMT4B2 siblings.
- name: Syndromic SBF1 Neuropathy
  display_name: Severe syndromic SBF1-related neuropathy
  description: >-
    A far more severe early-onset disease in which the polyneuropathy is one
    part of a multisystem neurodevelopmental syndrome: progressive microcephaly,
    intellectual disability, syndactyly, cerebellar atrophy with ataxia and
    pyramidal signs, and multiple cranial neuropathies producing ophthalmoparesis,
    facial weakness, dysarthria and dysphagia. Unlike classic CMT4B3, the
    neuropathy here is predominantly axonal, with markedly reduced action
    potential amplitudes and relatively preserved conduction velocities. Brain
    MRI in two families showed the "fork and bracket" sign at the pontine and
    mesencephalic level. Reported families carry variants predicted deleterious,
    or frameshift and splice-site null alleles.
  evidence:
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the second SBF1-mutated family, from Saudi Arabia, the 3 affected siblings presented a more complex syndromic phenotype. Sensory motor polyneuropathy was associated with progressive microcephaly, intellectual disability, syndactyly, and multiple cranial nerve involvement, which resulted in ophthalmoparesis, absence of pupil reactivity to light, mild facial weakness, swallowing difficulties, and dysarthria."
    explanation: >-
      Enumerates the syndromic features that define this subtype, in the first
      family reported with them.
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "both families presented a predominantly axonal sensory motor neuropathy with evidence of denervation, markedly reduced amplitude of action potentials, and relatively preserved nerve conduction velocities"
    explanation: >-
      Establishes that the syndromic families' neuropathy is axonal rather than
      demyelinating, which is the electrophysiological separation between the
      two subtypes recorded here.
inheritance:
- name: Autosomal Recessive
  description: >-
    Every family in which SBF1 has been established as causal carries biallelic
    variants - compound heterozygous missense in the index Korean and Italian
    families, homozygous missense, frameshift or splice-site alleles in the
    consanguineous Saudi, Syrian, Spanish, Bedouin and Chinese families - with
    unaffected heterozygous parents. ClinGen's Charcot-Marie-Tooth Disease Gene
    Curation Expert Panel classifies the SBF1-CMT4B3 relationship as autosomal
    recessive with Moderate strength of evidence.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301641
    reference_title: "Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The CMT4 subtypes are inherited in an autosomal recessive manner."
    explanation: >-
      GeneReviews states recessive inheritance for the CMT4 series, of which
      CMT4B3 is the SBF1 member. Cited from the retired CMT4 chapter, the only
      GeneReviews text that names SBF1/CMT4B3 explicitly.
  - reference: CGGV:assertion_c0f814d9-02db-4c0c-8e1c-20a7759d993f-2024-12-02T170000.000Z
    reference_title: "SBF1 / Charcot-Marie-Tooth disease type 4B3 (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SBF1 | HGNC:10542 | Charcot-Marie-Tooth disease type 4B3 | MONDO:0014117 | AR | Moderate | SOP11 | Charcot-Marie-Tooth Disease Gene Curation Expert Panel"
    explanation: >-
      ClinGen expert-panel gene-disease validity assertion recording autosomal
      recessive inheritance for SBF1-CMT4B3, at Moderate classification.
  - reference: PMID:32444983
    reference_title: A novel frameshift deletion in autosomal recessive SBF1-related syndromic neuropathy with necklace fibres.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WES identified a novel homozygous frameshift deletion (c.5477-5478del; p.1826-1826del) in exon 40 of the SBF1 gene in the two siblings, while both parents and the unaffected sibling were heterozygous carriers."
    explanation: >-
      Direct segregation evidence for recessive inheritance: affected siblings
      homozygous, unaffected parents and sibling heterozygous.
prevalence:
- population: Worldwide, published families
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Counted in families, not cases. Two families were on record in 2016, five by
    2021 and seven by 2024. No population-based prevalence estimate exists for
    CMT4B3, and the counts below are the authors' own tallies of the published
    literature at the time of writing, not systematic ascertainment.
  evidence:
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Only 2 CMT4B3 families have been reported to date."
    explanation: The 2016 count of published CMT4B3 families.
  - reference: PMID:34118926
    reference_title: "Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, only five families harboring variants in MTMR5/SBF1 have been described"
    explanation: The 2021 count, and the basis for the ULTRA_RARE band.
  - reference: PMID:39664754
    reference_title: A novel SBF1 missense mutation causes autosomal dominant Charcot-Marie-Tooth disease type 4B3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "To date, only seven families with SBF1 mutations have been described"
    explanation: The 2024 count of published SBF1 families.
  - reference: PMID:42627996
    reference_title: "Mitochondrial dysfunction, metabolic quiescence and premature senescence in CMT4B3 fibroblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Charcot-Marie-Tooth disease type 4B3 (CMT4B3) is an ultra-rare autosomal recessive neuropathy caused by mutations in the MTMR5/SBF1 gene."
    explanation: >-
      Independent characterization of CMT4B3 as ultra-rare, supporting the
      qualitative band in the absence of any numeric estimate.
pathophysiology:
- name: SBF1 Loss of Function
  biological_scale: MOLECULAR
  conforms_to: "schwann_cell_myelin_maintenance#Myelin Gene Dosage or Structural Lesion in Schwann Cells"
  description: >-
    Biallelic SBF1 variants - missense, frameshift or splice-site - reduce or
    abolish functional MTMR5. The protein's own myotubularin phosphatase domain
    is catalytically inactive, so this is not the loss of an enzyme. What is
    lost is MTMR5's regulatory and scaffolding role: a coiled-coil-mediated
    interaction that raises MTMR2's phosphoinositide 3-phosphatase activity and
    fixes where in the cell MTMR2 acts, and an N-terminal DENN domain that
    activates Rab GTPases. Reported pathogenic variants cluster in the DENN and
    SBF2 domains but occur throughout the gene, and are generally associated
    with loss of expression or of function. A frameshift allele has been shown
    directly to reduce MTMR5 protein in patient cells. `zygosity` is
    deliberately left unset: reported families are homozygous (the
    consanguineous ones) or compound heterozygous (the index Korean and the
    Italian families), the slot is single-valued, and the enum has no
    "biallelic" value that would cover both without misreporting one.
  genetic_context:
    gene:
      preferred_term: SBF1
      term:
        id: hgnc:10542
        label: SBF1
    functional_impact_category: LOSS_OF_FUNCTION
  biological_processes:
  - preferred_term: Myelination in peripheral nervous system
    term:
      id: GO:0022011
      label: myelination in peripheral nervous system
    modifier: DYSREGULATED
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  molecular_functions:
  - preferred_term: MTMR2 phosphatase activation by MTMR5
    term:
      id: GO:0072542
      label: protein phosphatase activator activity
    modifier: DECREASED
  - preferred_term: DENN-domain Rab GTPase activation
    term:
      id: GO:0005085
      label: guanyl-nucleotide exchange factor activity
    modifier: DECREASED
  evidence:
  - reference: PMID:23749797
    reference_title: "SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One pair of heterozygous missense mutations in the SET binding factor 1 (SBF1) gene (22q13.33), also called MTMR5, was identified as the underlying cause of the CMT4B family illness."
    explanation: >-
      Establishes biallelic SBF1 variants as the causal lesion of the disease
      this entry curates.
  - reference: PMID:12668758
    reference_title: "Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The interacting protein was shown by mass spectrometry to be MTMR5, a catalytically inactive member of the MTM family."
    explanation: >-
      The primary demonstration that MTMR5 is catalytically inactive - the fact
      that makes "loss of function" here mean loss of a regulatory role rather
      than loss of catalysis.
  - reference: PMID:27666502
    reference_title: "WANTED - Dead or alive: Myotubularins, a large disease-associated protein family."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "others lack key residues in the catalytic site and are classified as dead-phosphatases. However, these dead phosphatases regulate phosphoinositide-dependent cellular pathways by binding to catalytically active myotubularins."
    explanation: >-
      A review of the myotubularin family stating the general mechanism this
      node applies to MTMR5: a dead phosphatase acts by binding an active one.
      Graded OTHER because the cited publication is a review rather than a study
      reporting its own data.
  - reference: PMID:32444983
    reference_title: A novel frameshift deletion in autosomal recessive SBF1-related syndromic neuropathy with necklace fibres.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Functional analysis showed a markedly reduced level of MTMR5 protein encoded by SBF1 in the index case."
    explanation: >-
      Direct protein-level demonstration that a pathogenic SBF1 allele reduces
      MTMR5, confirming the loss-of-function mechanism in patient material.
  downstream:
  - target: Loss of MTMR2 Partnering and Phosphoinositide Misregulation
    causal_link_type: DIRECT
    description: >-
      Absent or dysfunctional MTMR5 removes the partner that activates and
      localizes MTMR2.
    evidence:
    - reference: PMID:27123480
      reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "the impairment of this interaction, possibly related to protein absence, subcellular mislocalization, or functional changes of the interacting C-terminus domains, is a likely mechanism to explain the polyneuropathy associated with mutations in both genes"
      explanation: >-
        States the causal step this edge asserts - that losing the MTMR5-MTMR2
        interaction is the mechanism linking SBF1 variants to polyneuropathy.
  - target: Central Nervous System and Cranial Nerve Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      In the syndromic families, SBF1 loss produces disease outside the
      peripheral nerve as well. The mechanism is not established; the
      DENN-domain location of the syndromic variants, and functions of MTMR5
      beyond MTMR2 binding, are the leading hypotheses.
- name: Loss of MTMR2 Partnering and Phosphoinositide Misregulation
  biological_scale: MOLECULAR
  description: >-
    MTMR5 binds MTMR2 through its coiled-coil domain, increases MTMR2's
    enzymatic activity and dictates where MTMR2 is localized. Without that
    partnering, dephosphorylation of the endosomal phosphoinositides PI3P and
    PI(3,5)P2 is misregulated in both amount and place. Because MTMR5 has no
    catalytic activity of its own, this is the step at which a
    pseudophosphatase lesion becomes a phosphoinositide lesion.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: Phosphatidylinositol dephosphorylation
    term:
      id: GO:0046856
      label: phosphatidylinositol dephosphorylation
    modifier: ABNORMAL
  evidence:
  - reference: PMID:12668758
    reference_title: "Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Through this interaction, MTMR5 increases the enzymatic activity of MTMR2 and dictates its subcellular localization."
    explanation: >-
      The two functions of MTMR5 that are lost - activation of MTMR2 and control
      of its localization - which is exactly what this node claims.
  - reference: PMID:12668758
    reference_title: "Regulation of myotubularin-related (MTMR)2 phosphatidylinositol phosphatase by MTMR5, a catalytically inactive phosphatase."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We also demonstrate that MTMR2 interacts with MTMR5 via its coiled-coil domain and that mutations in the coiled-coil domain of either MTMR2 or MTMR5 abrogate this interaction."
    explanation: >-
      Identifies the coiled-coil interface this node names, and shows that
      mutation of it abolishes the interaction.
  - reference: PMID:27666502
    reference_title: "WANTED - Dead or alive: Myotubularins, a large disease-associated protein family."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "While some members have phosphatase activity against the 3-phosphate of phosphoinositides, regulating the phosphorylation status of PtdIns3P and PtdIns(3,5)P2 implicated in membrane trafficking and autophagy, and producing PtdIns5P"
    explanation: >-
      Names the two phosphoinositide species whose handling this node says is
      misregulated - PtdIns3P and PtdIns(3,5)P2 - and ties them to membrane
      trafficking. Graded OTHER as a review statement rather than primary data.
  - reference: PMID:34718573
    reference_title: "Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In the mouse PNS, Mtmr2 was required to maintain wild-type levels of Mtmr5 and Mtmr13, suggesting that these factors function in discrete protein complexes."
    explanation: >-
      Shows the partnering is mutually stabilizing in vivo, so losing one member
      of the complex is not a one-way effect on the other.
  downstream:
  - target: Disordered Endolysosomal Trafficking in Schwann Cells
    causal_link_type: DIRECT
    description: >-
      Endosomal phosphoinositides set the identity and maturation of endosomal
      membranes, so misregulating them derails trafficking through that
      compartment.
    evidence:
    - reference: PMID:34718573
      reference_title: "Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "MTMR5 and MTMR13 are pseudophosphatases predicted to regulate endosomal trafficking by activating Rab GTPases and binding to the phosphoinositide 3-phosphatase MTMR2."
      explanation: >-
        States the causal link this edge asserts - that MTMR5's binding to MTMR2
        and its Rab activation are how it regulates endosomal trafficking.
- name: Disordered Endolysosomal Trafficking in Schwann Cells
  biological_scale: CELLULAR
  description: >-
    Schwann cells are unusually sensitive to disruption of endolysosomal
    membrane trafficking - nearly half the CMT4 genes encode regulators of that
    pathway - because building and maintaining the myelin sheath requires large,
    precisely directed membrane flux and correct trafficking of the receptors
    that time myelination. MTMR5 is almost ubiquitously expressed, yet SBF1
    variants strike the peripheral nervous system, which is the observation this
    node explains.
  cell_types:
  - preferred_term: Myelinating Schwann cell
    term:
      id: CL:0000218
      label: myelinating Schwann cell
  biological_processes:
  - preferred_term: Endosomal transport
    term:
      id: GO:0016197
      label: endosomal transport
    modifier: ABNORMAL
  evidence:
  - reference: PMID:34718573
    reference_title: "Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "β1-integrin through early endosomes is controlled by Rab21, which the DENN domain of Mtmr5/13 has been shown to activate"
    explanation: >-
      Names a specific cargo and the Rab that routes it, connecting the DENN
      domain lost in CMT4B3 to a concrete trafficking step in Schwann cells.
  - reference: PMID:34718573
    reference_title: "Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "β1-integrin is required for the extension and maintenance of Schwann cell processes around axons; loss of this surface receptor leads to radial sorting defects and delayed myelination in mice"
    explanation: >-
      Supplies the reason a trafficking defect reaches radial sorting: the
      receptor whose routing depends on Rab21 is the one Schwann cells need to
      extend processes around axons.
  - reference: PMID:34118926
    reference_title: "Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although almost ubiquitously expressed, pathogenic variants primarily impact on the peripheral nervous system, corroborating the involvement of MTMR5/SBF1 and its molecular partners in Schwann cells-mediated myelinization."
    explanation: >-
      States the tissue-selectivity argument this node makes: broad expression,
      peripheral-nerve-selective disease, implicating Schwann-cell myelination.
  - reference: PMID:34118926
    reference_title: "Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "MTMR5/SBF1 is a pseudophosphatase predicted to regulate endo-lysosomal trafficking in tandem with other MTMRs."
    explanation: >-
      Names the cellular process this node is about and its dependence on other
      myotubularins.
  downstream:
  - target: Focally Folded and Redundant Myelin
    causal_link_type: DIRECT
    description: >-
      The membrane-trafficking defect produces excess, misdirected myelin
      membrane rather than a correctly compacted sheath.
  - target: Impaired Axon Radial Sorting
    causal_link_type: DIRECT
    description: >-
      Radial sorting depends on the same trafficking-dependent receptor
      signalling, and mouse Mtmr5 is expressed most highly while it occurs.
  - target: Secondary Mitochondrial Dysfunction and Altered Autophagic Selectivity
    causal_link_type: DIRECT
    description: >-
      Endolysosomal and autophagic membrane traffic are the same pathway, so the
      lesion also reaches mitochondrial quality control.
- name: Focally Folded and Redundant Myelin
  biological_scale: TISSUE
  conforms_to: "schwann_cell_myelin_maintenance#Tomaculous and Onion-Bulb Myelin Remodeling"
  description: >-
    The histological signature of the CMT4B group: myelin sheaths that fold back
    on themselves into redundant loops and outfoldings, with loss of large
    myelinated fibers. In CMT4B3 this was found in the index Korean family,
    although the absolute number of myelinated fibers differed from CMT4B1 and
    CMT4B2. It is characteristic of the demyelinating presentation and is not
    reported in the axonal syndromic families.
  cell_types:
  - preferred_term: Myelinating Schwann cell
    term:
      id: CL:0000218
      label: myelinating Schwann cell
  biological_processes:
  - preferred_term: Myelination
    term:
      id: GO:0042552
      label: myelination
    modifier: ABNORMAL
  cellular_components:
  - preferred_term: myelin sheath
    term:
      id: GO:0043209
      label: myelin sheath
    modifier: ABNORMAL
  evidence:
  - reference: PMID:23749797
    reference_title: "SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found a similar loss of large myelinated fibers and focally folded myelin sheaths in our patients, but the actual number of myelinated fibers was different from CMT4B1 and CMT4B2."
    explanation: >-
      Documents both halves of this node in CMT4B3 nerve biopsies, and the one
      quantitative difference from the sibling diseases.
  - reference: PMID:39664754
    reference_title: A novel SBF1 missense mutation causes autosomal dominant Charcot-Marie-Tooth disease type 4B3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in these genes can lead to focal myelin out-folding and secondary axonal loss in peripheral nerves"
    explanation: >-
      Restates the outfolding-to-axonal-loss sequence for the CMT4B group
      (MTMR2, SBF2 and SBF1) that this node and the next but one assert.
  downstream:
  - target: Dysmyelination and Slowed Nerve Conduction
    causal_link_type: DIRECT
  - target: Myelin Outfoldings
    causal_link_type: DIRECT
    description: >-
      The finding as it is observed on nerve biopsy and recorded as an
      HPO-bound phenotype.
- name: Impaired Axon Radial Sorting
  biological_scale: TISSUE
  description: >-
    Radial sorting is the developmental step in which Schwann cells segregate
    large-calibre axons out of bundles into 1:1 relationships before myelinating
    them. Mouse work places MTMR5's main peripheral-nerve role here rather than
    in myelin maintenance: Mtmr5-null nerves contain fewer myelinated axons and
    show sorting defects, while Mtmr13 loss produces the outfoldings. Whether
    this division of labour holds in human CMT4B3, where outfoldings are seen,
    is unresolved - see the model-mismatch discussion below.
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: Myelination in peripheral nervous system
    term:
      id: GO:0022011
      label: myelination in peripheral nervous system
    modifier: DECREASED
  evidence:
  - reference: PMID:34718573
    reference_title: "Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Loss of Mtmr5 in mice did not cause CMT4B-like myelin outfoldings. However, adult Mtmr5-/- mouse nerves contained fewer myelinated axons than control nerves, likely as a result of axon radial sorting defects."
    explanation: >-
      The primary evidence for this node, and simultaneously the negative result
      that the mouse does not reproduce the human outfolding pathology.
  - reference: PMID:34718573
    reference_title: "Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Consistently, Mtmr5 levels were highest during axon radial sorting and fell sharply after postnatal day seven."
    explanation: >-
      Developmental expression timing consistent with a radial-sorting role
      rather than an ongoing myelin-maintenance one.
  downstream:
  - target: Dysmyelination and Slowed Nerve Conduction
    causal_link_type: DIRECT
- name: Secondary Mitochondrial Dysfunction and Altered Autophagic Selectivity
  biological_scale: CELLULAR
  description: >-
    Muscle from one CMT4B3 child showed partial defects of oxidative metabolism,
    and fibroblasts from the same patient have fragmented mitochondrial networks
    with reduced ATP production despite preserved mitochondrial mass and
    respiratory chain assembly, strongly activated PINK1-PRKN mitophagy without
    the matching rise in macroautophagy, and features of premature senescence.
    This is presented as a downstream consequence of the trafficking and
    autophagy lesion, not as a primary respiratory chain defect - which is what
    separates CMT4B3 from CMT4K, where the gene itself is a complex IV assembly
    factor.
  cell_types:
  - preferred_term: Skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  biological_processes:
  - preferred_term: Mitophagy
    term:
      id: GO:0000423
      label: mitophagy
    modifier: INCREASED
  evidence:
  - reference: PMID:34118926
    reference_title: "Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Studies in muscle identified partial defects of oxidative metabolism."
    explanation: >-
      The in-patient observation that the mitochondrial arm of this node rests
      on.
  - reference: PMID:40998285
    reference_title: "Selective mitophagy activation and protein aggregate accumulation in MTMR5/SBF1-deficient fibroblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "CMT4B3 fibroblasts showed normal basal macroautophagy but failed to increase autophagy in response to mitochondrial stress or protein aggregates. Conversely, mitophagy was strongly activated via the PINK1-PRKN pathway."
    explanation: >-
      The autophagic-selectivity result this node names, measured in
      patient-derived fibroblasts.
  - reference: PMID:42627996
    reference_title: "Mitochondrial dysfunction, metabolic quiescence and premature senescence in CMT4B3 fibroblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Patient fibroblasts exhibited fragmented mitochondrial networks with a shift toward fission, together with reduced ATP production, while mitochondrial mass, respiratory chain assembly, and markers of mitochondrial biogenesis were preserved."
    explanation: >-
      Preserved respiratory chain assembly alongside reduced ATP output is the
      specific observation supporting "secondary" rather than primary
      mitochondrial disease.
  downstream:
  - target: Secondary Axonal Loss
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Impaired mitochondrial quality control is a plausible contributor to the
      axonal arm of the disease. The link is proposed by the cited authors, not
      demonstrated in nerve.
- name: Dysmyelination and Slowed Nerve Conduction
  biological_scale: TISSUE
  conforms_to: "schwann_cell_myelin_maintenance#Dysmyelination and Segmental Demyelination of Peripheral Nerve"
  description: >-
    The structurally abnormal sheath conducts badly. In the demyelinating
    presentation this appears as markedly slowed motor conduction velocities; in
    the axonal syndromic presentation velocities are relatively preserved and it
    is the action-potential amplitudes that collapse. A zebrafish mtmr5 knockout
    shows dysmyelination changes described as reminiscent of the human nerve
    pathology.
  cell_types:
  - preferred_term: Myelinating Schwann cell
    term:
      id: CL:0000218
      label: myelinating Schwann cell
  biological_processes:
  - preferred_term: Peripheral nervous system myelin maintenance
    term:
      id: GO:0032287
      label: peripheral nervous system myelin maintenance
    modifier: DECREASED
  - preferred_term: Myelin assembly
    term:
      id: GO:0032288
      label: myelin assembly
    modifier: DECREASED
  cellular_components:
  - preferred_term: myelin sheath
    term:
      id: GO:0043209
      label: myelin sheath
    modifier: ABNORMAL
  evidence:
  - reference: PMID:40066109
    reference_title: "Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These changes are accompanied at the pathological level by abnormal axon outgrowths and by the presence of dysmyelination changes reminiscent of the nerve pathology in human Charcot-Marie-Tooth type 4B3."
    explanation: >-
      Model-organism support that mtmr5 loss is sufficient to produce
      dysmyelination resembling the human lesion.
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to CMT4B1, CMT4B2, and the pure neuropathic form of CMT4B3, which are all characterized by demyelinating neuropathy with focally folded myelin sheaths, both families presented a predominantly axonal sensory motor neuropathy"
    explanation: >-
      Records the split this node describes between the demyelinating and
      axonal electrophysiological patterns within SBF1 disease.
  downstream:
  - target: Secondary Axonal Loss
    causal_link_type: DIRECT
  - target: Decreased Motor Nerve Conduction Velocity
    causal_link_type: DIRECT
    description: >-
      The measurable electrophysiological expression of the dysmyelinated
      sheath, in the demyelinating presentation.
- name: Secondary Axonal Loss
  biological_scale: TISSUE
  conforms_to: "peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination"
  description: >-
    Length-dependent loss of peripheral axons follows the myelin lesion and is
    what tracks disability. It is the shared endpoint of the demyelinating and
    axonal presentations, and drives the distal-predominant motor and sensory
    deficit and the foot deformity.
  biological_processes:
  - preferred_term: Axon ensheathment
    term:
      id: GO:0008366
      label: axon ensheathment
    modifier: DECREASED
  - preferred_term: Myelination
    term:
      id: GO:0042552
      label: myelination
    modifier: DECREASED
  cell_types:
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  evidence:
  - reference: PMID:39664754
    reference_title: A novel SBF1 missense mutation causes autosomal dominant Charcot-Marie-Tooth disease type 4B3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in these genes can lead to focal myelin out-folding and secondary axonal loss in peripheral nerves"
    explanation: >-
      States the outfolding-to-secondary-axonal-loss sequence that this node is
      the endpoint of.
  - reference: PMID:23749797
    reference_title: "SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found a similar loss of large myelinated fibers and focally folded myelin sheaths in our patients"
    explanation: >-
      Loss of large myelinated fibers on CMT4B3 sural nerve biopsy is the
      histological expression of this node.
  downstream:
  - target: Distal Muscle Weakness and Atrophy
    causal_link_type: DIRECT
  - target: Distal Sensory Loss
    causal_link_type: DIRECT
  - target: Areflexia
    causal_link_type: DIRECT
  - target: Foot Deformity
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Central Nervous System and Cranial Nerve Involvement
  biological_scale: ORGANISM
  description: >-
    In the syndromic families, SBF1 loss also produces progressive microcephaly,
    intellectual disability, cerebellar atrophy with ataxia and pyramidal signs,
    and degeneration of multiple cranial nerves. The mechanism is not
    established. Two observations argue that it is not simply more of the same
    Schwann-cell lesion: the syndromic variants fall in the DENN domain, which
    only SBF1 and SBF2 carry among the myotubularins, and the mtmr5-null
    zebrafish develops reduced head size and brain volume rather than a purely
    peripheral phenotype. Not every severe case has it - one child with severe
    infantile axonal disease had normal brain MRI and normal cognition
    throughout.
  evidence:
  - reference: PMID:30039846
    reference_title: Novel SBF1 splice-site null mutation broadens the clinical spectrum of Charcot-Marie-Tooth type 4B3 disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four siblings of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of congenital microcephaly, facial dysmorphism, strabismus, developmental delay and ataxia with positive pyramidal signs."
    explanation: >-
      Documents the CNS arm of this node - microcephaly, developmental delay,
      ataxia and pyramidal signs - in a family with a null SBF1 allele.
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Of note, both mutations causative of syndromic CMT4B3 fall within the DENN domain"
    explanation: >-
      Supports the genotype argument this node makes for why the syndromic
      families differ, without asserting the mechanism.
  - reference: PMID:40066109
    reference_title: "Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "starting by 10 days post-fertilization, mutant zebrafish develop obvious morphometric changes in head size and brain volume"
    explanation: >-
      Model-organism support that mtmr5 loss alone can produce a
      brain-size phenotype, consistent with a CNS role for MTMR5.
  - reference: PMID:40066109
    reference_title: "Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In total, these data demonstrate that the microcephaly phenotype in mtmr5-KO zebrafish is not caused by excessive apoptosis, autophagy or cell loss in the nervous system, indicating instead potential defects in early neurogenesis."
    explanation: >-
      Constrains the CNS mechanism in the one model that shows it: a
      neurodevelopmental defect rather than degeneration. Zebrafish, so it is a
      lead for the human CNS arm, not an account of it.
  downstream:
  - target: Progressive Microcephaly
    causal_link_type: DIRECT
  - target: Intellectual Disability
    causal_link_type: DIRECT
  - target: Cerebellar Atrophy
    causal_link_type: DIRECT
  - target: Cranial Neuropathy
    causal_link_type: DIRECT
phenotypes:
- category: Neurologic
  name: Distal Muscle Weakness and Atrophy
  diagnostic: true
  description: >-
    Length-dependent weakness and wasting of the distal upper and lower limbs,
    beginning in the first decade in the classic form and in infancy or early
    childhood in the severe forms. The syndromic families also show proximal
    involvement.
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
    clinical_course: PROGRESSIVE
  sequelae:
  - target: Foot Deformity
  - target: Loss of Independent Ambulation
  evidence:
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All patients had onset of distal atrophy and weakness in upper and lower limbs, decreased vibration and position sense, areflexia, and pes planus in the first decade, with a slow progression to loss of ambulation in the fifth decade of life."
    explanation: >-
      Documents distal weakness and atrophy in all affected members of the index
      family, with first-decade onset.
  - reference: PMID:30039846
    reference_title: Novel SBF1 splice-site null mutation broadens the clinical spectrum of Charcot-Marie-Tooth type 4B3 disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "they developed areflexia, multiple cranial neuropathies and severe polyneuropathy with progressive muscle weakness, affecting proximal and distal extremities"
    explanation: >-
      Shows that in the syndromic form the weakness is severe and not confined
      to distal muscles.
  - reference: PMID:20301641
    reference_title: "Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity."
    explanation: >-
      GeneReviews names distal muscle weakness and atrophy as the typical
      phenotype of the CMT4 series. Indirect because the statement is made of
      the whole autosomal recessive CMT4 group, in which SBF1/CMT4B3 is one of
      eleven genes, rather than of CMT4B3 specifically.
- category: Neurologic
  name: Distal Sensory Loss
  description: >-
    Impaired vibration and joint position sense distally in the classic
    demyelinating form. Sensory involvement is variable across the spectrum: it
    was largely spared in the Syrian "fork and bracket" siblings, and the
    Italian child with severe infantile axonal disease had no clinical or
    neurophysiological distal sensory impairment.
  phenotype_term:
    preferred_term: Impaired vibratory sensation
    term:
      id: HP:0002495
      label: Impaired vibratory sensation
  subtype: Classic CMT4B3
  evidence:
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "decreased vibration and position sense, areflexia, and pes planus in the first decade"
    explanation: >-
      Documents impaired vibration and position sense in the index CMT4B3
      family.
  - reference: PMID:34118926
    reference_title: "Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "no clinical and neurophysiological evidences of distal sensory impairment"
    explanation: >-
      A reported CMT4B3 patient in whom distal sensory impairment was absent on
      both clinical and neurophysiological assessment, so sensory loss is not an
      obligate feature of this disease. Scoped to the classic subtype.
  - reference: PMID:20301641
    reference_title: "Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity."
    explanation: >-
      GeneReviews names sensory loss as part of the typical CMT4 phenotype.
      Indirect because the statement is made of the whole autosomal recessive
      CMT4 group rather than of CMT4B3, and it sits alongside the REFUTE item
      above from a CMT4B3 family in whom sensory involvement was absent.
- category: Neurologic
  name: Areflexia
  description: >-
    Loss of deep tendon reflexes, present across both the classic and the
    syndromic presentations.
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:30039846
    reference_title: Novel SBF1 splice-site null mutation broadens the clinical spectrum of Charcot-Marie-Tooth type 4B3 disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Toward the end of their first decade, they developed areflexia, multiple cranial neuropathies and severe polyneuropathy with progressive muscle weakness"
    explanation: Documents areflexia in the Bedouin syndromic family.
- category: Musculoskeletal
  name: Foot Deformity
  description: >-
    Pes planus in the index Korean family; pes cavus with drop-foot in the
    Bedouin and Chinese syndromic families. Both are recorded here because
    CMT4B3 does not consistently produce the pes cavus that is the textbook CMT
    foot - the syndromic Saudi family had distal wasting but no pes cavus.
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
  evidence:
  - reference: PMID:30039846
    reference_title: Novel SBF1 splice-site null mutation broadens the clinical spectrum of Charcot-Marie-Tooth type 4B3 disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical assessment exhibited kyphoscoliosis, bilateral syndactyly and distal muscle wasting with drop-foot and pes cavus."
    explanation: Documents pes cavus and drop-foot in a CMT4B3 family.
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "There was distal muscle wasting and weakness but no pes cavus."
    explanation: >-
      Records a CMT4B3 family with distal wasting but no pes cavus, so foot
      deformity is not present in every affected individual.
  - reference: PMID:20301641
    reference_title: "Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    directness: INDIRECT
    snippet: "Affected individuals have the typical CMT phenotype of distal muscle weakness and atrophy associated with sensory loss and, frequently, pes cavus foot deformity."
    explanation: >-
      GeneReviews states that pes cavus is frequently but not invariably
      present in the CMT4 series, which is the only frequency statement any
      source makes about foot deformity in this disease group. Indirect because
      it describes the CMT4 group rather than CMT4B3, and it is drawn from a
      chapter GeneReviews has retired.
- category: Musculoskeletal
  name: Congenital Talipes
  description: >-
    Bilateral congenital clubfoot was present at birth in the child with the
    severe infantile axonal presentation, before any neuropathy was diagnosed.
    Recorded because it is the earliest reported manifestation in that case and
    is not otherwise a feature of the classic presentation, whose foot deformity
    develops during childhood.
  phenotype_term:
    preferred_term: Talipes
    term:
      id: HP:0001883
      label: Talipes
  evidence:
  - reference: PMID:34118926
    reference_title: "Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented bilateral congenital talon-valgus-pronated clubfoot at birth and slight neuromotor developmental delay from the age of 18 months"
    explanation: >-
      Documents congenital clubfoot at birth in a genetically confirmed CMT4B3
      patient.
- category: Neurologic
  name: Loss of Independent Ambulation
  description: >-
    In the classic form ambulation is lost slowly, in the fifth decade. In the
    severe infantile axonal form it was lost at age 9, with wheelchair
    dependence at 11.
  phenotype_term:
    preferred_term: Inability to walk
    term:
      id: HP:0002540
      label: Inability to walk
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with a slow progression to loss of ambulation in the fifth decade of life"
    explanation: >-
      The natural history of ambulation in the classic demyelinating
      presentation.
  - reference: PMID:34118926
    reference_title: "Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Independent ambulation was lost at the age of 9, when she began needing walking aids; she became wheelchair-dependent at the age of 11."
    explanation: >-
      The contrasting, far more rapid course in the severe infantile axonal
      presentation.
- category: Neurologic
  name: Decreased Motor Nerve Conduction Velocity
  diagnostic: true
  description: >-
    Slowed motor conduction is the electrophysiological signature of the classic
    demyelinating form and is what places it in CMT4. It is specifically not
    present in the syndromic axonal families, where conduction velocities are
    relatively preserved and the abnormality is reduced amplitude.
  phenotype_term:
    preferred_term: Decreased motor nerve conduction velocity
    term:
      id: HP:0003431
      label: Decreased motor nerve conduction velocity
  subtype: Classic CMT4B3
  evidence:
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to CMT4B1, CMT4B2, and the pure neuropathic form of CMT4B3, which are all characterized by demyelinating neuropathy with focally folded myelin sheaths, both families presented a predominantly axonal sensory motor neuropathy with evidence of denervation, markedly reduced amplitude of action potentials, and relatively preserved nerve conduction velocities"
    explanation: >-
      Confirms the demyelinating pattern for the pure neuropathic form while
      recording that the syndromic families do not show it - the reason this
      phenotype is scoped to the classic subtype.
- category: Neurologic
  name: Cranial Neuropathy
  description: >-
    Multiple cranial nerve involvement in the syndromic families, producing
    ophthalmoparesis, absent pupillary light reactivity, facial weakness,
    dysarthria and swallowing difficulty. Absent from the classic demyelinating
    presentation.
  phenotype_term:
    preferred_term: Multiple cranial nerve palsies
    term:
      id: HP:0006824
      label: Cranial nerve paralysis
  subtype: Syndromic SBF1 Neuropathy
  sequelae:
  - target: Dysphagia
  - target: Sensorineural Hearing Impairment
  evidence:
  - reference: PMID:28005197
    reference_title: SBF1 mutations associated with autosomal recessive axonal neuropathy with cranial nerve involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we describe novel sequence variants in SBF1 (c.1168C>G and c.2209_2210del) as the potential causative mutations in two siblings with severe axonal neuropathy, hearing loss, facial weakness and bulbar features."
    explanation: >-
      Documents cranial nerve involvement (facial weakness, bulbar features,
      hearing loss) as part of the SBF1 syndromic phenotype.
- category: Neurologic
  name: Progressive Microcephaly
  description: >-
    Progressive or congenital microcephaly in the Saudi, Syrian and Bedouin
    syndromic families. Absent from the classic form and from the reported
    severe infantile axonal case.
  phenotype_term:
    preferred_term: Progressive microcephaly
    term:
      id: HP:0000253
      label: Progressive microcephaly
  subtype: Syndromic SBF1 Neuropathy
  evidence:
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The 2 siblings shared relevant features with the Saudi Arabian family, including early-onset progressive microcephaly, multiple cranial nerve neuropathies, and moderate to severe intellectual disability."
    explanation: >-
      Documents progressive microcephaly in two independent SBF1 families.
- category: Neurologic
  name: Intellectual Disability
  description: >-
    Moderate to severe intellectual disability in the syndromic families.
    Explicitly absent in the index Korean family and in the Italian child with
    severe infantile axonal disease, whose repeated cognitive assessments were
    all normal.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  subtype: Syndromic SBF1 Neuropathy
  evidence:
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "early-onset progressive microcephaly, multiple cranial nerve neuropathies, and moderate to severe intellectual disability"
    explanation: Documents intellectual disability in the syndromic families.
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "None had cognitive impairment, dysmorphic features, or obvious extraneurologic syndromic manifestations."
    explanation: >-
      The index Korean family had no cognitive impairment, which is why this
      phenotype is scoped to the syndromic subtype rather than to the disease.
- category: Neurologic
  name: Cerebellar Atrophy
  description: >-
    Profound cerebellar atrophy with ataxia and pyramidal signs, reported in the
    Bedouin family carrying a splice-site null allele.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  subtype: Syndromic SBF1 Neuropathy
  evidence:
  - reference: PMID:30039846
    reference_title: Novel SBF1 splice-site null mutation broadens the clinical spectrum of Charcot-Marie-Tooth type 4B3 disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging (MRI) showed profound cerebellar atrophy with highly unique findings at the pontine and mesencephalic levels"
    explanation: Documents cerebellar atrophy on MRI in a CMT4B3 family.
- category: Musculoskeletal
  name: Syndactyly
  description: >-
    Cutaneous syndactyly in the Saudi, Bedouin and Chinese syndromic families;
    absent in the Syrian family, which had joint laxity and a thumb sign
    instead.
  phenotype_term:
    preferred_term: Cutaneous syndactyly
    term:
      id: HP:0012725
      label: Cutaneous syndactyly
  subtype: Syndromic SBF1 Neuropathy
  evidence:
  - reference: PMID:32444983
    reference_title: A novel frameshift deletion in autosomal recessive SBF1-related syndromic neuropathy with necklace fibres.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The index patient was a 29-year-old male with clinical phenotype of syndactyly, pes cavus, swallowing difficulties, vision problem, imbalance, and muscle weakness."
    explanation: Documents syndactyly as part of the SBF1 syndromic phenotype.
- category: Respiratory
  name: Respiratory Insufficiency
  description: >-
    Progressive decline in respiratory function in the severe infantile axonal
    presentation, reaching the point of requiring non-invasive positive pressure
    ventilation before age 12. Not reported in the classic demyelinating form.
    No `subtype:` is set because the severe infantile axonal case is not one of
    the two subtypes this entry declares; it is described in prose, as the
    Congenital Talipes phenotype from the same case is.
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:34118926
    reference_title: "Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with worsening of ambulation and of respiratory function, to the point of requiring non-invasive positive pressure ventilation, and the development of dysphagia, necessitating G-tube placement"
    explanation: >-
      Documents progressive respiratory decline severe enough to require
      ventilatory support in a CMT4B3 child with the severe infantile
      presentation.
- category: Neurologic
  name: Dysphagia
  description: >-
    Swallowing difficulty from bulbar cranial nerve involvement in the syndromic
    families, and from progressive neuromuscular deterioration in the severe
    infantile axonal case, where it required gastrostomy.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:34118926
    reference_title: "Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the development of dysphagia, necessitating G-tube placement"
    explanation: >-
      Documents dysphagia severe enough to require gastrostomy in a CMT4B3
      patient.
- category: Neurologic
  name: Sensorineural Hearing Impairment
  description: >-
    Reported in the Spanish sibling pair with severe axonal neuropathy and
    cranial nerve involvement.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  subtype: Syndromic SBF1 Neuropathy
  evidence:
  - reference: PMID:28005197
    reference_title: SBF1 mutations associated with autosomal recessive axonal neuropathy with cranial nerve involvement.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two siblings with severe axonal neuropathy, hearing loss, facial weakness and bulbar features"
    explanation: Documents hearing loss in an SBF1-mutated sibling pair.
- category: Neurologic
  name: Myelin Outfoldings
  diagnostic: true
  description: >-
    The ontology-bound counterpart of the nerve-biopsy finding recorded under
    histopathology: redundant, focally folded myelin loops. Bound here as a
    phenotype because the HPO term exists and the NCIT-rooted histopathology
    vocabulary has no equivalent, so this is where the finding stays queryable.
  phenotype_term:
    preferred_term: Focally folded myelin sheaths
    term:
      id: HP:0004336
      label: Myelin outfoldings
  subtype: Classic CMT4B3
  evidence:
  - reference: PMID:23749797
    reference_title: "SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found a similar loss of large myelinated fibers and focally folded myelin sheaths in our patients"
    explanation: >-
      Reports focally folded myelin sheaths on sural nerve biopsy in the index
      CMT4B3 family.
histopathology:
- name: Focally folded myelin sheaths on sural nerve biopsy
  diagnostic: true
  description: >-
    The diagnostic hallmark of the CMT4B group and the finding that put SBF1
    disease in it. Distal sural nerve biopsies from the index Korean family
    showed focally folded (redundant, outfolded) myelin sheaths together with
    loss of large myelinated fibers - the same pattern as CMT4B1 and CMT4B2,
    although the absolute number of myelinated fibers differed. It is reported
    in the demyelinating presentation; the syndromic axonal families instead
    show denervation, and one showed necklace fibres on muscle biopsy.
  finding_term:
    preferred_term: focally folded myelin sheath
  subtype: Classic CMT4B3
  evidence:
  - reference: PMID:23749797
    reference_title: "SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found a similar loss of large myelinated fibers and focally folded myelin sheaths in our patients, but the actual number of myelinated fibers was different from CMT4B1 and CMT4B2."
    explanation: >-
      The primary histological description in CMT4B3, from sural nerve biopsies
      of all three affected members of the index family.
  - reference: PMID:23749797
    reference_title: "SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We enrolled 14 members of a Korean family in which 3 individuals had demyelinating CMT4B phenotype and obtained distal sural nerve biopsies from all affected participants."
    explanation: >-
      Establishes the tissue and ascertainment behind the histological finding.
- name: Necklace fibres on muscle biopsy
  description: >-
    Muscle biopsy in the Chinese syndromic family showed necklace fibres - a
    myofibre feature more usually associated with the myotubularin myopathies -
    alongside the sensorimotor axonal neuropathy. Reported in one family.
  finding_term:
    preferred_term: necklace fibres
  subtype: Syndromic SBF1 Neuropathy
  evidence:
  - reference: PMID:32444983
    reference_title: A novel frameshift deletion in autosomal recessive SBF1-related syndromic neuropathy with necklace fibres.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy showed a feature of necklace fibres."
    explanation: Direct report of the finding this record names.
imaging_findings:
- name: Fork and bracket sign on brain MRI
  modality: MRI
  diagnostic: true
  description: >-
    A distinctive appearance at the pontine and mesencephalic level, attributed
    to degenerated fibre bundles of the oculomotor and facial nerves, reported
    in the Syrian and Bedouin syndromic families. It is the imaging finding that
    named "fork and bracket" syndrome, and its recognition is what linked that
    condition to SBF1.
  subtype: Syndromic SBF1 Neuropathy
  evidence:
  - reference: PMID:20658556
    reference_title: "Multiple cranial nerve neuropathies, microcephaly, neurological degeneration, and \"fork and bracket sign\" in the MRI: a distinct syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Previously unknown findings referred to as the \"fork sign\" at the pontine level and the \"bracket sign\" at the mesencephalic level were documented by magnetic resonance imaging."
    explanation: >-
      The original description of the sign, in the Syrian sibship later shown by
      exome sequencing to carry a homozygous SBF1 variant. Note this paper
      predates the SBF1 link and does not itself name the gene.
  - reference: PMID:30039846
    reference_title: Novel SBF1 splice-site null mutation broadens the clinical spectrum of Charcot-Marie-Tooth type 4B3 disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Magnetic resonance imaging (MRI) showed profound cerebellar atrophy with highly unique findings at the pontine and mesencephalic levels"
    explanation: >-
      Reports the pontine and mesencephalic MRI abnormality this finding names,
      in a second, independent SBF1 family.
- name: Normal brain and spinal MRI
  modality: MRI
  description: >-
    Recorded here because its absence is diagnostically informative: the Italian
    child with severe infantile axonal CMT4B3 had normal brain and spinal MRI on
    repeated imaging to age 11. A normal MRI does not exclude SBF1 disease.
  evidence:
  - reference: PMID:34118926
    reference_title: "Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient showed no cognitive impairment during the clinical course, and at the latest follow up (age 11), brain and spinal MRI remained normal."
    explanation: >-
      Documents normal neuroimaging in a genetically confirmed, severely
      affected CMT4B3 patient.
diagnosis:
- name: Molecular genetic testing of SBF1
  diagnosis_term:
    preferred_term: SBF1 molecular genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  presence: PRESENT
  description: >-
    Diagnosis rests on identifying biallelic pathogenic SBF1 variants.
    Standard first-line CMT testing does not reach SBF1: the reported patients
    had PMP22 rearrangement, MFN2 and GDAP1 testing come back negative first.
  results: >-
    Two pathogenic SBF1 alleles, in trans - homozygous in the consanguineous
    families, compound heterozygous in the Korean and Italian families.
  markers: SBF1 (MTMR5), 22q13.33
  evidence:
  - reference: PMID:20301641
    reference_title: "Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "The diagnosis of CMT4 subtypes is based on clinical findings, neurophysiologic studies, and molecular genetic testing."
    explanation: >-
      GeneReviews statement of the diagnostic approach for the CMT4 series that
      CMT4B3 belongs to.
  - reference: PMID:34118926
    reference_title: "Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gene testing for genomic rearrangements of PMP22 and punctuate variants in MNF2 and GDAP1 were negative."
    explanation: >-
      Illustrates that the common CMT genes are tested and excluded before SBF1
      is reached. Quoted verbatim including the source's misspelling of MFN2.
- name: Whole exome sequencing
  diagnosis_term:
    preferred_term: whole exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  presence: PRESENT
  description: >-
    The test that actually makes the diagnosis in practice. Every family in
    which SBF1 was established as causal was solved by exome sequencing, because
    the phenotype - especially the syndromic form - does not point at SBF1 on
    clinical grounds and SBF1 is not on all older CMT panels.
  results: >-
    A biallelic SBF1 variant surviving the filtering pipeline, segregating with
    disease in the pedigree.
  evidence:
  - reference: PMID:23749797
    reference_title: "SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We conducted exome sequencing on 6 samples (3 affected and 3 unaffected individuals)."
    explanation: >-
      The exome study that identified SBF1 as the CMT4B3 gene, including
      unaffected relatives for segregation.
  - reference: PMID:30039846
    reference_title: Novel SBF1 splice-site null mutation broadens the clinical spectrum of Charcot-Marie-Tooth type 4B3 disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing identified a single novel homozygous deleterious splice-site mutation within this locus in SET binding factor 1 (SBF1)."
    explanation: >-
      A second, independent family diagnosed by exome sequencing after linkage
      narrowed the locus.
  - reference: PMID:32444983
    reference_title: A novel frameshift deletion in autosomal recessive SBF1-related syndromic neuropathy with necklace fibres.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Muscle biopsy and whole-exome sequencing (WES) were performed."
    explanation: >-
      A third family, showing exome sequencing paired with tissue biopsy as the
      diagnostic combination.
- name: Nerve conduction studies and electromyography
  diagnosis_term:
    preferred_term: nerve conduction study
    term:
      id: NCIT:C154784
      label: Electroneurography
  presence: PRESENT
  description: >-
    Neurophysiology classifies the neuropathy rather than making the diagnosis,
    and in CMT4B3 the classification is not uniform. The classic form shows
    demyelinating slowing, which is what places it in CMT4; the syndromic and
    the severe infantile forms show reduced compound muscle action potential
    amplitudes with denervation on EMG and relatively preserved velocities. A
    normal or near-normal conduction velocity therefore does not exclude
    CMT4B3.
  results: >-
    Either slowed motor conduction velocity (demyelinating range) or reduced
    CMAP amplitude with preserved velocity (axonal pattern), depending on the
    presentation.
  evidence:
  - reference: PMID:34118926
    reference_title: "Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Electroneurography disclosed severe motor polyneuropathy with predominant axonal features, diffuse reduction of compound action muscular potentials (CMAP, values under 1.5 mV) and only slight decrement of NCV (38-43 m/s)."
    explanation: >-
      A worked example of the axonal electrophysiological pattern with nearly
      preserved conduction velocity in genetically confirmed CMT4B3.
  - reference: PMID:32444983
    reference_title: A novel frameshift deletion in autosomal recessive SBF1-related syndromic neuropathy with necklace fibres.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nerve conduction studies and electromyography of both patients suggested sensory-motor axonal neuropathy."
    explanation: >-
      Documents both tests used together, and a second family with the axonal
      rather than demyelinating pattern.
- name: Sural nerve biopsy
  diagnosis_term:
    preferred_term: sural nerve biopsy
    term:
      id: NCIT:C217131
      label: Nervous System Biopsy Procedure
  presence: PRESENT
  description: >-
    The CMT4B group's diagnostic hallmark. Distal sural nerve biopsy in the
    index Korean family showed focally folded myelin sheaths with loss of large
    myelinated fibers - the finding that placed SBF1 disease in CMT4B and named
    the disease. It is no longer required for diagnosis now that sequencing is
    available, but a historical biopsy showing myelin outfoldings in an unsolved
    recessive neuropathy is a reason to sequence SBF1.
  results: >-
    Focally folded (outfolded) myelin sheaths and loss of large myelinated
    fibers, with myelinated fiber counts differing from CMT4B1 and CMT4B2.
  evidence:
  - reference: PMID:23749797
    reference_title: "SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We enrolled 14 members of a Korean family in which 3 individuals had demyelinating CMT4B phenotype and obtained distal sural nerve biopsies from all affected participants."
    explanation: >-
      The diagnostic material and how it was obtained, in the family that
      defined the disease.
  - reference: PMID:23749797
    reference_title: "SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found a similar loss of large myelinated fibers and focally folded myelin sheaths in our patients, but the actual number of myelinated fibers was different from CMT4B1 and CMT4B2."
    explanation: >-
      The result the biopsy yields, and the one respect in which it differs from
      the sibling CMT4B diseases.

genetic:
- name: SBF1
  association: Causal
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_term:
    preferred_term: SBF1
    term:
      id: hgnc:10542
      label: SBF1
  notes: >-
    SBF1 (also MTMR5, DENND7A) at 22q13.33. Reported pathogenic alleles include
    compound heterozygous and homozygous missense variants clustering in the
    DENN and SBF2 domains, a homozygous splice-site null allele, and a
    homozygous frameshift deletion. Because MTMR5 has no catalytic activity of
    its own, the shared consequence is loss of its regulatory and scaffolding
    functions - MTMR2 activation and localization, and DENN-domain Rab GTPase
    activation.
  evidence:
  - reference: PMID:23749797
    reference_title: "SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest that the compound heterozygous mutations in SBF1 are the underlying causes of a novel CMT4B subtype, designated as CMT4B3."
    explanation: >-
      The paper that established SBF1 as the CMT4B3 gene and named the disease.
  - reference: CGGV:assertion_c0f814d9-02db-4c0c-8e1c-20a7759d993f-2024-12-02T170000.000Z
    reference_title: "SBF1 / Charcot-Marie-Tooth disease type 4B3 (Moderate)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "SBF1 | HGNC:10542 | Charcot-Marie-Tooth disease type 4B3 | MONDO:0014117 | AR | Moderate | SOP11 | Charcot-Marie-Tooth Disease Gene Curation Expert Panel"
    explanation: >-
      ClinGen expert-panel assessment of the SBF1-CMT4B3 gene-disease
      relationship. Moderate, not Definitive - the honest current strength of
      the association, reflecting the small number of published families.
  - reference: PMID:20301641
    reference_title: "Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Detection of biallelic pathogenic variants in one of the following 11 genes establishes the diagnosis: GDAP1 (CMT4A), MTMR2 (CMT4B1), SBF2 (CMT4B2), SBF1 (CMT4B3), SH3TC2 (CMT4C), NDRG1 (CMT4D), EGR2 (CMT4E), PRX (CMT4F), HK1 (CMT4G), FGD4 (CMT4H), and FIG4 (CMT4J)."
    explanation: >-
      GeneReviews places SBF1/CMT4B3 in the CMT4 diagnostic gene list. Cited
      from a chapter GeneReviews has retired, so it establishes the gene-disease
      pairing rather than current management guidance.
treatments:
- name: Physical and Occupational Therapy
  therapeutic_modality: BEHAVIORAL
  description: >-
    The mainstay of care. A multidisciplinary team - neurologist, physiatrist,
    orthopedic surgeon, physical and occupational therapists - maintains
    mobility and function, with exercise as tolerated and daily heel cord
    stretching to prevent Achilles tendon shortening. This is CMT4 management
    generally; nothing is specific to CMT4B3.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:20301641
    reference_title: "Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Treatment by a team including a neurologist, physiatrist, orthopedic surgeon, physical and occupational therapists; special shoes and/or ankle/foot orthoses 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: >-
      GeneReviews management recommendation for CMT4, of which CMT4B3 is a
      subtype. Quoted from a chapter GeneReviews has since retired, so it is
      historical expert guidance rather than a current standard.
- name: Orthoses and Mobility Aids
  therapeutic_modality: DEVICE
  description: >-
    Special shoes and ankle-foot orthoses to correct foot drop and aid walking;
    forearm crutches, canes and wheelchairs as strength is lost. In the severe
    infantile axonal presentation these are needed within the first decade.
  treatment_term:
    preferred_term: orthotic and mobility support
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301641
    reference_title: "Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "special shoes and/or ankle/foot orthoses to correct foot drop and aid walking; surgery as needed for severe pes cavus; forearm crutches, canes, wheelchairs as needed for mobility"
    explanation: >-
      GeneReviews CMT4 management recommendation naming exactly these devices.
- name: Orthopedic Surgery for Foot Deformity and Contracture
  therapeutic_modality: SURGERY
  description: >-
    Corrective surgery for severe pes cavus, and Achilles tendon release for
    contracture. Tendon release was performed in a reported SBF1 patient and the
    contracture nonetheless recurred, which is worth saying plainly: surgery
    addresses the deformity, not the neuropathy driving it. That case comes from
    the family whose autosomal dominant inheritance claim this entry records as
    contested (cmt4b3_dominant_report); it is cited here for the surgical course
    only, which does not depend on that claim.
  treatment_term:
    preferred_term: orthopedic surgical procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  evidence:
  - reference: PMID:39664754
    reference_title: A novel SBF1 missense mutation causes autosomal dominant Charcot-Marie-Tooth disease type 4B3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After first surgery of patient III2, her Achilles tendon contracture progressively still rendered both heels of her feet difficult to land"
    explanation: >-
      Documents Achilles tendon release in a patient with an SBF1 variant, and
      that the contracture progressed afterwards.
- name: Avoidance of Neurotoxic Medications
  description: >-
    Drugs known to cause peripheral nerve damage - vincristine, isoniazid,
    nitrofurantoin among them - should be avoided, as should obesity, which
    makes ambulation harder. This is the CMT4 "agents and circumstances to
    avoid" guidance; there is no CMT4B3-specific list.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301641
    reference_title: "Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Agents/circumstances to avoid: Obesity (which makes ambulation more difficult); medications (e.g., vincristine, isoniazid, nitrofurantoin) known to cause nerve damage."
    explanation: >-
      GeneReviews list of agents and circumstances to avoid in CMT4, quoted
      verbatim.
- name: Respiratory and Nutritional Support
  description: >-
    In the severe infantile presentation, non-invasive positive pressure
    ventilation for respiratory decline and gastrostomy for dysphagia were both
    required before age 12. Anticipating these is part of managing the severe
    end of the spectrum.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:34118926
    reference_title: "Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "with worsening of ambulation and of respiratory function, to the point of requiring non-invasive positive pressure ventilation, and the development of dysphagia, necessitating G-tube placement"
    explanation: >-
      Documents the respiratory and nutritional interventions required in a
      severely affected CMT4B3 child.
- name: Genetic Counseling
  description: >-
    Autosomal recessive recurrence risk of 25% per pregnancy, carrier testing
    for at-risk relatives, and prenatal testing where the familial variants are
    known. Most reported CMT4B3 families are consanguineous, so counseling about
    consanguinity is often central.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301641
    reference_title: "Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
    explanation: >-
      The recurrence risk this counseling conveys, stated by GeneReviews for the
      CMT4 subtypes.
differential_diagnoses:
- name: Charcot-Marie-Tooth Disease Type 4B1
  description: >-
    MTMR2-related CMT4B1 is the closest mimic: autosomal recessive demyelinating
    neuropathy with the same focally folded myelin sheaths. MTMR2 is the active
    phosphatase that MTMR5 regulates, so the two diseases sit on the same
    molecular axis. Clinically the classic CMT4B3 phenotype resembles CMT4B1
    only "to some extent" - the number of myelinated fibers on biopsy differs -
    and CMT4B1 does not produce the microcephaly, intellectual disability or
    cranial neuropathy seen in syndromic SBF1 disease. Separation is by gene.
  distinguishing_features:
  - Causal gene MTMR2 rather than SBF1
  - No syndromic CNS or cranial nerve involvement
  - Different absolute myelinated fiber counts on nerve biopsy
  evidence:
  - reference: PMID:23749797
    reference_title: "SET binding factor 1 (SBF1) mutation causes Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical phenotypes of affected study participants with CMT4B were similar, to some extent, to patients with CMT4B1 and CMT4B2."
    explanation: >-
      States the partial clinical overlap that makes CMT4B1 a differential, in
      the authors' own hedged terms.
- name: Charcot-Marie-Tooth Disease Type 4B2
  description: >-
    SBF2/MTMR13-related CMT4B2 is the other myotubularin CMT4B, caused by loss of
    the pseudophosphatase most similar to MTMR5 - the two share 59% identity and
    the same domain architecture. CMT4B2 is distinguished by early-onset
    glaucoma, which is not a feature of SBF1 disease, and by classic
    demyelination with outfoldings without the syndromic CNS features.
  distinguishing_features:
  - Causal gene SBF2 / MTMR13 rather than SBF1
  - Early-onset glaucoma
  - Classic demyelination without microcephaly or intellectual disability
  evidence:
  - reference: PMID:12687498
    reference_title: "Mutations in MTMR13, a new pseudophosphatase homologue of MTMR2 and Sbf1, in two families with an autosomal recessive demyelinating form of Charcot-Marie-Tooth disease associated with early-onset glaucoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13."
    explanation: >-
      Establishes MTMR13/SBF2 as the CMT4B2 gene, distinct from SBF1, in
      families whose distinguishing feature is early-onset glaucoma.
- name: Charcot-Marie-Tooth Disease Type 4K
  description: >-
    SURF1-related CMT4K also presents as childhood demyelinating neuropathy with
    a mitochondrial biochemical profile, which makes it a genuine differential
    for the CMT4B3 cases reported with secondary oxidative-metabolism defects.
    The distinction is directional: in CMT4K the gene is a complex IV assembly
    factor and the mitochondrial defect is primary, with lactic acidosis and
    later putaminal and periaqueductal lesions; in CMT4B3 the mitochondrial
    findings are downstream of a membrane-trafficking lesion, and respiratory
    chain assembly is preserved.
  distinguishing_features:
  - Causal gene SURF1, a complex IV assembly factor
  - Lactic acidosis
  - Putaminal and periaqueductal brain lesions
  evidence:
  - reference: PMID:42627996
    reference_title: "Mitochondrial dysfunction, metabolic quiescence and premature senescence in CMT4B3 fibroblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "reduced ATP production, while mitochondrial mass, respiratory chain assembly, and markers of mitochondrial biogenesis were preserved"
    explanation: >-
      Preserved respiratory chain assembly in CMT4B3 cells is the observation
      that separates it from a primary respiratory chain assembly disorder such
      as CMT4K.
animal_models:
- name: Mtmr5-null mouse
  species: Mus musculus
  genotype: Mtmr5-/- (Sbf1 knockout)
  description: >-
    Constitutive Mtmr5-null mice. Adult nerves contain fewer myelinated axons,
    attributed to defective axon radial sorting, and Mtmr5 expression peaks
    during radial sorting and falls after postnatal day 7. Critically, these
    mice do NOT develop the CMT4B-like myelin outfoldings that define the human
    disease. Combined Mtmr5/Mtmr13 deletion is perinatally lethal.
  publication: PMID:34718573
  genes:
  - preferred_term: SBF1
    term:
      id: hgnc:10542
      label: SBF1
  evidence:
  - reference: PMID:34718573
    reference_title: "Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This study enhances our understanding of the non-redundant roles of the endosomal regulators MTMR5 and MTMR13 during normal peripheral nerve development and disease."
    explanation: >-
      Supports treating the Mtmr5-null mouse as informative for MTMR5 function
      in peripheral nerve, while the authors frame the roles as non-redundant -
      which is why this entry also records what the model fails to reproduce.
  modeled_mechanisms:
  - target: Impaired Axon Radial Sorting
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      The mouse is the primary evidence that MTMR5's peripheral-nerve role is in
      radial sorting.
    limitations: >-
      Mouse, not human, and the sorting defect is inferred from reduced
      myelinated axon counts in adult nerve rather than measured during sorting
      itself.
    evidence:
    - reference: PMID:34718573
      reference_title: "Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "adult Mtmr5-/- mouse nerves contained fewer myelinated axons than control nerves, likely as a result of axon radial sorting defects"
      explanation: >-
        The measurement behind treating this model as informative for the radial
        sorting node.
  - target: Focally Folded and Redundant Myelin
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    model_scale: TISSUE
    description: >-
      The mouse does not reproduce the histological hallmark of human CMT4B3.
    limitations: >-
      A complete null in mouse produces no myelin outfoldings, while human
      CMT4B3 nerve biopsy shows them. Either the mouse lacks a
      human-specific requirement for MTMR5 in myelin maintenance, or the human
      outfoldings arise by a route the null allele does not model. Until that is
      resolved, this model cannot be used to study the outfolding pathology.
    evidence:
    - reference: PMID:34718573
      reference_title: "Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination."
      supports: REFUTE
      evidence_source: MODEL_ORGANISM
      snippet: "Loss of Mtmr5 in mice did not cause CMT4B-like myelin outfoldings."
      explanation: >-
        The negative result itself, stated by the authors.
- name: mtmr5 knockout zebrafish
  species: Danio rerio
  genotype: mtmr5 full-gene deletion (CRISPR/Cas9), homozygous
  description: >-
    A CRISPR full-gene-deletion line, presented as the first pre-clinical model
    to phenocopy CMT4B3. Homozygotes are born at normal Mendelian ratios with
    preserved motor function, then from 10 days post-fertilization develop
    reduced head size and brain volume, abnormal axon outgrowths, and
    dysmyelination described as reminiscent of the human nerve pathology.
    Brain-enriched RNA sequencing implicates neurogenesis, chromatin
    remodelling and synaptic membrane homeostasis.
  publication: PMID:40066109
  genes:
  - preferred_term: SBF1
    term:
      id: hgnc:10542
      label: SBF1
  evidence:
  - reference: PMID:40066109
    reference_title: "Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Overall, our mtmr5 knockout zebrafish mirror genetic, clinical and pathologic features of human Charcot-Marie-Tooth type 4B3."
    explanation: >-
      The authors' own claim that this model is informative for human CMT4B3,
      which is what a model-level evidence item attests.
  modeled_mechanisms:
  - target: Dysmyelination and Slowed Nerve Conduction
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: TISSUE
    description: >-
      Dysmyelination changes resembling the human nerve pathology.
    limitations: >-
      Zebrafish, and the resemblance is described qualitatively as
      "reminiscent"; no nerve conduction measurements are reported, so the
      conduction half of this node is not modelled.
    evidence:
    - reference: PMID:40066109
      reference_title: "Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "the presence of dysmyelination changes reminiscent of the nerve pathology in human Charcot-Marie-Tooth type 4B3"
      explanation: The reported dysmyelination phenotype in this model.
  - target: Central Nervous System and Cranial Nerve Involvement
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    model_scale: ORGANISM
    description: >-
      Reduced head size and brain volume, the animal counterpart of the
      microcephaly seen in the syndromic families.
    limitations: >-
      Head size in a larval zebrafish is not human microcephaly, and no cranial
      nerve pathology is reported in this model, so only the brain-size arm of
      this node is covered.
    evidence:
    - reference: PMID:40066109
      reference_title: "Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "mutant zebrafish develop obvious morphometric changes in head size and brain volume"
      explanation: The brain-size phenotype supporting a CNS role for MTMR5.
experimental_models:
- name: CMT4B3 patient dermal fibroblasts (R763H/G1064E)
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Dermal fibroblasts from the Italian child with compound heterozygous
    MTMR5/SBF1 R763H and G1064E variants, compared with healthy control
    fibroblasts. They carry the mitochondrial and autophagy arm of the disease
    model in this entry: fragmented mitochondrial networks with reduced ATP but
    preserved respiratory chain assembly, strongly activated PINK1-PRKN
    mitophagy without a matching macroautophagy response, and features of
    premature senescence.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:40998285
  evidence:
  - reference: PMID:40998285
    reference_title: "Selective mitophagy activation and protein aggregate accumulation in MTMR5/SBF1-deficient fibroblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our findings provide new mechanistic insights into the pathogenesis of CMT4B3 and highlight the value of patient-derived fibroblasts for studying selective autophagy defects."
    explanation: >-
      The authors' statement that patient-derived fibroblasts are an informative
      system for this aspect of CMT4B3 pathogenesis.
  modeled_mechanisms:
  - target: Secondary Mitochondrial Dysfunction and Altered Autophagic Selectivity
    relationship: MEASURES
    fidelity: MODERATE
    model_scale: CELLULAR
    description: >-
      Direct measurement of autophagic flux, mitophagy and mitochondrial
      morphology in patient cells.
    limitations: >-
      Fibroblasts, not Schwann cells or neurons - the cells that actually carry
      the disease. Single patient, single control, so the findings constrain the
      mechanism rather than establishing its penetrance across CMT4B3.
    evidence:
    - reference: PMID:40998285
      reference_title: "Selective mitophagy activation and protein aggregate accumulation in MTMR5/SBF1-deficient fibroblasts."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "These results reveal an uncoupling between mitophagy and macroautophagy, indicating that MTMR5/SBF1 mutations modify autophagic selectivity."
      explanation: >-
        The interpretation the authors draw from this model, which is what the
        target node asserts.
- name: CMT4B3 patient-derived iPSC lines
  experimental_model_type: IPSC_DERIVED_MODEL
  description: >-
    Induced pluripotent stem cell lines reprogrammed from fibroblasts of
    unrelated CMT4B3 patients with homozygous or biallelic SBF1 variants. They
    were generated explicitly because the existing animal models do not clearly
    connect Sbf1 loss to severe neuropathy, so a human cellular system was
    needed to study the relationship between MTMR5 dysfunction and peripheral
    nerve degeneration.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:39461113
  evidence:
  - reference: PMID:39461113
    reference_title: "Establishment and characterization of three human pluripotent stem cell lines from Charcot-Marie-Tooth disease Type 4B3 patients bearing mutations in MTMR5/Sbf1 gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we describe the establishment and validation of three human induced pluripotent stem cell (iPSC) lines derived from unrelated CMT4B3 patients, each harboring homozygous MTMR5/Sbf1 mutations."
    explanation: Establishes the existence and provenance of these lines.
  - reference: PMID:36272304
    reference_title: "Generation and characterization of CSSi016-A (9938) human pluripotent stem cell line carrying two biallelic variants in MTMR5/SBF1 gene resulting in a case of severe CMT4B3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Herein, we report the generation and characterization of a hiPSC line from a 12-year-old Italian girl with early onset severe polyneuropathy with motor and axonal involvement, harboring biallelic variants in the MTMR5/SBF1 gene."
    explanation: >-
      A fourth line, from the severe infantile axonal case whose fibroblasts
      carry the mitochondrial phenotype recorded above.
discussions:
- discussion_id: cmt4b3_mouse_lacks_outfoldings
  prompt: >-
    Why does a complete Mtmr5 null in mouse produce no myelin outfoldings, when
    focally folded myelin is the diagnostic hallmark of human CMT4B3 - and does
    that mean radial sorting, not myelin maintenance, is the mechanism in
    patients too?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Focally Folded and Redundant Myelin
  - pathophysiology#Impaired Axon Radial Sorting
  - animal_models#Mtmr5-null mouse
  rationale: >-
    This is the central translational problem for CMT4B3. Human sural nerve
    biopsies show focally folded myelin sheaths, which is why the disease was
    classified in CMT4B at all. The Mtmr5-null mouse does not develop them; what
    it shows instead is a reduced myelinated axon count attributed to defective
    radial sorting, with Mtmr5 expression peaking during sorting and falling
    after postnatal day 7. The paper frames this as a division of labour, with
    Mtmr13 rather than Mtmr5 responsible for Schwann cell myelination - a
    framing that fits human CMT4B1 and CMT4B2, which are characterized by
    outfoldings, but not human CMT4B3, which also shows them. Either the two
    pseudophosphatases have genuinely non-redundant roles and human CMT4B3
    outfoldings arise indirectly, or the mouse fails to model a human-specific
    requirement. The distinction is not
    academic: it decides whether the mouse can be used as a preclinical model
    for the myelin lesion, and it is the reason patient-derived iPSC lines were
    generated. A zebrafish full-gene deletion does show dysmyelination, but
    described qualitatively as "reminiscent" of the human pathology rather than
    as outfoldings.
  evidence:
  - reference: PMID:34718573
    reference_title: "Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Our findings suggest that Mtmr5 and Mtmr13 ensure proper axon radial sorting and Schwann cell myelination, respectively, perhaps through their direct interactions with Mtmr2."
    explanation: >-
      States the proposed division of labour that, if it holds in humans, would
      explain the mismatch.
  - reference: PMID:34718573
    reference_title: "Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The form of Charcot-Marie-Tooth type 4B (CMT4B) disease caused by mutations in myotubularin-related 5 (MTMR5; also called SET binding factor 1, SBF1) shows a spectrum of axonal and demyelinating nerve phenotypes. This contrasts with the CMT4B subtypes caused by MTMR2 or MTMR13 (SBF2) mutations, which are characterized by myelin outfoldings and classic demyelination."
    explanation: >-
      The authors' statement of how human SBF1 disease differs from its CMT4B1
      and CMT4B2 siblings, which is the human-side half of this mismatch.
  - reference: PMID:39461113
    reference_title: "Establishment and characterization of three human pluripotent stem cell lines from Charcot-Marie-Tooth disease Type 4B3 patients bearing mutations in MTMR5/Sbf1 gene."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Current MTMR5 -/- animal models do not clearly link Sbf1 mutations to severe neuropathy, so such a resource is highly desired to further elucidate the relationship between MTMR5 dysfunction and peripheral nerve degeneration."
    explanation: >-
      An independent group's statement of the same gap, and their reason for
      building a human cellular model instead.
- discussion_id: cmt4b3_syndromic_mechanism
  prompt: >-
    By what mechanism does SBF1 loss produce microcephaly, intellectual
    disability, cerebellar atrophy and cranial neuropathy in some families and
    a purely peripheral neuropathy in others?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Central Nervous System and Cranial Nerve Involvement
  - has_subtypes#Syndromic SBF1 Neuropathy
  rationale: >-
    The CNS arm of CMT4B3 has no worked mechanism. Two clues exist and neither
    is a mechanism. First, the variants in the two originally reported syndromic
    families fall in the DENN domain, which among the myotubularins only SBF1
    and SBF2 carry and which acts on Rab GTPases and subcellular localization -
    suggesting functions beyond MTMR2 binding. But that argument is weakened by
    an SBF2 deletion removing the whole D-DENN module producing non-syndromic
    demyelinating neuropathy, and by later syndromic families carrying
    frameshift and splice-site null alleles rather than DENN missense. Second,
    the mtmr5-null zebrafish develops reduced brain volume, so a CNS
    requirement for MTMR5 is real in at least one vertebrate. What is missing is
    any account of which cell type in the CNS requires MTMR5 and what it
    requires it for.
  evidence:
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "However, the severe syndromic phenotype shown by 2 SBF1-mutated families calls for additional explanations."
    explanation: >-
      The authors' own statement that the MTMR2-partnering mechanism does not
      account for the syndromic phenotype.
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "However, an SBF2 deletion abolishing the whole D-DENN module caused nonsyndromic demyelinating neuropathy in a Turkish family."
    explanation: >-
      Argues against the simplest version of the DENN-domain hypothesis, and is
      recorded here so the hypothesis is not read as established.
- discussion_id: cmt4b3_spectrum_boundaries
  prompt: >-
    Are the demyelinating/axonal and pure/syndromic axes of SBF1 disease two
    descriptions of one severity gradient, or genuinely separable entities?
  kind: OPEN_QUESTION
  status: OPEN
  attaches_to:
  - has_subtypes#Classic CMT4B3
  - has_subtypes#Syndromic SBF1 Neuropathy
  rationale: >-
    The two subtypes recorded in this entry are a descriptive convenience, not a
    validated nosology, and one published case breaks the correlation they
    imply. The tidy story is: mild missense alleles give pure demyelinating
    CMT4B3, deleterious or null alleles give severe syndromic axonal disease.
    Against it, the Italian child carried compound heterozygous missense
    variants and had severe, rapidly progressive infantile axonal neuropathy
    with normal cognition and normal brain and spinal MRI throughout - severe
    and axonal without being syndromic. So "axonal" and "syndromic" are not the
    same axis, and neither maps cleanly onto allele severity. With fewer than
    ten published families, this cannot be settled from the current literature;
    it is recorded so the subtype split in this entry is read as provisional.
  evidence:
  - reference: PMID:27123480
    reference_title: "\"Fork and bracket\" syndrome expands the spectrum of SBF1-related sensory motor polyneuropathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the Korean patients with pure demyelinating neuropathy were compound heterozygous for 2 missense variants, both predicted as benign or tolerated by most prediction software, suggesting a mild impact on the protein. On the contrary, the 2 families with severe syndromic presentation carried missense mutations that were consistently predicted to be deleterious for the protein structure or function"
    explanation: >-
      States the proposed genotype-phenotype correlation that the two subtypes
      here follow.
  - reference: PMID:34118926
    reference_title: "Bi-allelic variants in MTMR5/SBF1 cause Charcot-Marie-Tooth type 4B3 featuring mitochondrial dysfunction."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "We report a case of severe CMT4B3 characterized by early-onset motor and axonal polyneuropathy in an Italian child in absence of any evidence of brain and spine MRI abnormalities or intellectual disability and with a biochemical profile suggestive of mitochondrial disease."
    explanation: >-
      The counterexample: severe and axonal without any syndromic CNS or
      cognitive involvement, which is why the two axes are recorded as
      non-congruent.
- discussion_id: cmt4b3_dominant_report
  prompt: >-
    Does the reported heterozygous SBF1 p.H466Q mother-daughter pair establish a
    dominant form of SBF1 neuropathy, or is a second allele or another cause
    unaccounted for?
  kind: CONTROVERSY
  status: OPEN
  attaches_to:
  - inheritance#Autosomal Recessive
  rationale: >-
    Every other published SBF1 family, and ClinGen's expert-panel assertion, is
    autosomal recessive, and mouse work states that all CMT-causing MTMR5 and
    MTMR13 mutations are recessive and consistent with loss of function. A 2024
    report describes a mother and daughter heterozygous for a novel SBF1
    missense variant, both with early-onset distal atrophy and an axonal
    electrophysiological pattern, and argues for autosomal dominant CMT4B3. The
    support offered is co-segregation in two individuals plus in-silico
    pathogenicity and protein structure prediction; no functional assay of the
    variant and no demonstration that a second SBF1 allele was excluded at the
    transcript level are reported. This entry therefore curates CMT4B3 as
    autosomal recessive and records the dominant claim here rather than in the
    inheritance block. It is a real published claim and should not be dismissed;
    it is also, on the evidence presented, a single family.
  evidence:
  - reference: PMID:39664754
    reference_title: A novel SBF1 missense mutation causes autosomal dominant Charcot-Marie-Tooth disease type 4B3.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sequencing identified a novel missense mutation (c.1398C > A, p.H466Q) in exon 13 of the SET binding factor 1 (SBF1) gene in both patients, indicating an autosomal dominant inheritance pattern."
    explanation: The claim itself, as its authors state it.
  - reference: PMID:34718573
    reference_title: "Distinct roles for the Charcot-Marie-Tooth disease-causing endosomal regulators Mtmr5 and Mtmr13 in axon radial sorting and Schwann cell myelination."
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: "All mutations are recessive, consistent with a loss-of-function mechanism of pathogenesis."
    explanation: >-
      The prior consensus on the human MTMR5 and MTMR13 variant spectrum that
      the dominant report runs against. Stated in a mouse study, which is why it
      carries that publication's MODEL_ORGANISM grading even though the sentence
      is about human alleles.
  - reference: PMID:41737274
    reference_title: "Pediatric toe-walking cohort with heterozygous SBF1 variants: A phenotypic description."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "heterozygous SBF1 variants were observed in children with persistent toe walking and accompanying mild neuromotor/musculoskeletal features that partially overlap with reported CMT4B3 phenotypes; however, these findings are descriptive and do not establish causality or enrichment"
    explanation: >-
      An independent cohort in which monoallelic SBF1 variants, mostly VUS, sit
      beside a mild neuromotor phenotype and the authors decline to call them
      causal. It is the same interpretive problem the dominant report faces, in
      a larger sample.
- discussion_id: cmt4b3_no_disease_modifying_therapy
  prompt: >-
    Is there any tractable therapeutic target in CMT4B3, given that the lost
    protein is a scaffold rather than an enzyme?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#
  rationale: >-
    Every treatment in this entry is supportive. Nothing addresses the
    mechanism, and the shape of the lesion makes the usual routes awkward:
    MTMR5 has no catalytic activity to restore with a small molecule, and its
    role is to activate and localize another protein. The candidate strategies
    that follow from the mechanism - raising residual MTMR2 activity, or
    correcting the phosphoinositide imbalance downstream - have not been tested
    in CMT4B3. The zebrafish model was built partly to enable in vivo drug
    screening, so this gap has an identified route to being closed rather than
    just being a statement of ignorance.
  evidence:
  - reference: PMID:40066109
    reference_title: "Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "There is an incomplete understanding of the disease pathomechanism(s) underlying Charcot-Marie-Tooth type 4B3, and despite its severe clinical presentation, currently no disease-modifying therapies."
    explanation: >-
      Directly states both halves of this gap - incomplete mechanism and no
      disease-modifying therapy.
datasets:
- accession: geo:GSE290354
  title: Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3
  description: >-
    Brain-enriched bulk RNA sequencing from the mtmr5 full-gene-deletion
    zebrafish line curated under animal_models, n=8. This is the transcriptomic
    dataset behind the neurogenesis, chromatin-remodelling and
    synaptic-membrane-homeostasis pathways reported for that model. Zebrafish
    brain, so it speaks to the CNS arm of the disease rather than to the
    peripheral nerve lesion.
  data_type: BULK_RNA_SEQ
  organism:
    preferred_term: zebrafish
    term:
      id: NCBITaxon:7955
      label: Danio rerio
  publication: PMID:40066109
  evidence:
  - reference: GEO:GSE290354
    reference_title: Characterization of a novel zebrafish model of MTMR5-associated Charcot-Marie-Tooth disease type 4B3
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "RNA sequencing from brain-enriched samples identifies novel disease pathways including transcriptional changes in genes responsible for neurogenesis, chromatin remodeling/organization, and synaptic membrane homeostasis."
    explanation: >-
      The GEO record's own summary of what this dataset measured and found.
  notes: >-
    The only DIRECT dataset candidate found for CMT4B3. A second candidate,
    geo:GSE190699, was surfaced by gene-only matching on SBF1 and rejected on
    triage: it is a multiple myeloma study with no relationship to this disease.

notes: >-
  Lump/split. This is curated as a single DISEASE entry on MONDO:0014117, which
  MONDO models as a leaf under MONDO:0018995 (CMT type 4) with one causal gene
  (SBF1) and no descendants. The reported biallelic SBF1 phenotypes span a wide
  range, and the alternative - separate entries for the classic demyelinating
  neuropathy and the severe syndromic form - was considered and rejected. The
  literature does not treat them as separate diseases: each new severe family
  has been published as "expanding the spectrum" or "broadening the clinical
  spectrum" of CMT4B3 rather than as a new entity, there is no separate MONDO,
  OMIM or Orphanet concept for the syndromic form, and ClinGen's expert panel
  curates one SBF1 gene-disease relationship. The variation is therefore
  captured as two has_subtypes entries within one disease, with subtype-scoped
  phenotypes.

  The subtype split is provisional and is argued in the
  `cmt4b3_spectrum_boundaries` discussion. In short: the demyelinating/axonal
  axis and the pure/syndromic axis are not congruent. One reported child had
  severe, rapidly progressive infantile axonal disease with entirely normal
  cognition and normal brain and spinal MRI, so "axonal" does not imply
  "syndromic", and that case also carried compound heterozygous missense
  variants, so allele severity does not cleanly predict which presentation
  results either.

  On optic atrophy. The severe syndromic presentation involves the eye, but
  through cranial neuropathy - ophthalmoparesis, absent pupillary light
  reactivity, strabismus - and one report lists a non-specific "vision problem".
  A PubMed search for SBF1 or MTMR5 together with optic atrophy or optic nerve
  returns no records, and none of the primary reports read for this entry
  describes optic atrophy. It is therefore deliberately not curated as a
  phenotype here. If a source does document it, this note should be corrected
  rather than the phenotype quietly added.

  On "loss of function". MTMR5 is a pseudophosphatase - its myotubularin
  phosphatase domain is catalytically dead. `functional_impact_category:
  LOSS_OF_FUNCTION` on the SBF1 genetic context therefore means loss of the
  protein's regulatory and scaffolding roles (coiled-coil-mediated activation
  and localization of MTMR2, and DENN-domain Rab GTPase activation), not loss of
  an enzymatic activity. The entry's description and the SBF1 Loss of Function
  node say this explicitly so the tag is not misread.

  Orphanet has a record for this disease (ORPHA:363981, cross-referenced from
  MONDO) which would normally be a citable source for the definition and
  epidemiology. It is not cited here because the Orphadata bulk XML is not
  present in this checkout and rebuilding the ORPHA cache requires downloading
  and re-pinning it. That is a gap in this entry, not a statement that the
  record is unusable.

  No phenotype carries a `frequency:` value. With seven to ten families in the
  entire literature and no cohort study, every FrequencyEnum band would be a
  guess, and the schema's own guidance is to omit rather than guess. Where a
  feature is restricted to one presentation that is recorded with `subtype:`
  instead, which is a claim the sources do support.

  Biochemical and clinical_trials sections are absent: no CMT4B3-specific
  laboratory biomarker and no registered trial was identified. `just
  discover-datasets` returned exactly one DIRECT candidate (the zebrafish
  model's RNA-seq, curated above) and one gene-only false positive on SBF1 that
  turned out to be a multiple myeloma study. No human CMT4B3 dataset exists in
  that index.

📚

References & Deep Research

References

3

PMID:20301532

Charcot-Marie-Tooth Hereditary Neuropathy Overview.

No top-level findings curated for this source.

PMID:20301641

Charcot-Marie-Tooth Neuropathy Type 4 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY.

No top-level findings curated for this source.

PMID:24799518

SET binding factor 1 (SBF1) mutation causes Charcot-Marie-tooth disease type 4B3.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (1)

Create: Charcot-Marie-Tooth_Disease_Type_4B3 · 2026-09-07T17:31:19Z · View source

De novo creation of kb/disorders/Charcot-Marie-Tooth_Disease_Type_4B3.yaml (CMT4B3, MONDO:0014117, SBF1/MTMR5), closing the claim issue #11356 and deleting stubs/Charcot-Marie-Tooth_Disease_Type_4B3.yaml. LUMP/SPLIT DECISION. Curated as ONE Disease entry with two has_subtypes entries (Classic CMT4B3; Syndromic SBF1 Neuropathy) rather than as separate entries. Reasons recorded in the entry's notes: MONDO models MONDO:0014117 as a leaf under MONDO:0018995 with one causal gene and no descendants; the literature publishes each severe family as "expanding"/"broadening the clinical spectrum" of CMT4B3 rather than as a new entity; there is no separate MONDO, OMIM or Orphanet concept for the syndromic form; and ClinGen curates a single SBF1-CMT4B3 gene-disease relationship. The subtype split is recorded as provisional in the cmt4b3_spectrum_boundaries discussion, because the demyelinating/axonal axis and the pure/syndromic axis are not congruent (PMID:34118926 reports severe infantile AXONAL disease with normal cognition and normal brain/spine MRI). DEEP RESEARCH. `just research-disorder falcon Charcot-Marie-Tooth_Disease_Type_4B3` FAILED: the Edison/Falcon account returned HTTP 402 Payment Required (out of credits). Retried once with `just dr_fallback='--fallback' research-disorder falcon ...`, which fell back to openscientist; that job ran about an hour and was cancelled server-side ("OpenScientist job timed out after 3600s", job d6d63137-ccae-46d0-8409-b77728d60a8f). Neither provider produced a report. A third run, `just research-disorder claude_code Charcot-Marie-Tooth_Disease_Type_4B3`, succeeded in 5m36s, and research/Charcot-Marie-Tooth_Disease_Type_4B3-deep-research-claude_code.md plus its .citations.md sidecar are committed with this entry. It is a claude_code report, NOT a falcon one: the filename says so, and no `fell_back` frontmatter was written because the successful run was a fresh invocation rather than a fallback hop. The report's own validation. reference_validation: 14/14 verified, confabulation_rate 0.0, but needs_review true, driven by quotes_valid 1/2 (one unsupported quote, attributed to PMC:PMC12926636) and 11/14 on-topic. Nothing appears under unresolved_references, so no identifier was excluded on that basis; the unsupported quote was not reused - the underlying paper (PMID:41737274) was fetched independently and quoted from its own cache. term_validation: 61/68 verified, needs_review true, unresolved_terms [HP:0007257] (never bound here), obsolete_terms HP:0002355 and GO:0032313 (never bound here), and one mislabelled_terms entry where the report calls MONDO:0014117 "MONDO" - a table-formatting artifact, not a wrong binding. `just preflight-dr <report> MONDO:0014117` returned WARN: SBF1 dominant at 59 mentions and the MONDO OMIM xref 615284 present, but rival gene MTMR2 at 18 mentions (31% of SBF1) and OMIM 614895 (CMT4B2) also carried. Resolved rather than dismissed: MTMR2 and SBF2 appear because they are the mechanistic partner and the sibling diseases, which this entry discusses on purpose. The Named Entity Confusion rule was applied throughout - no CMT4B1 or CMT4B2 result is presented as a CMT4B3 finding, and the sibling diseases are named explicitly in differential_diagnoses. The report was used as a lead source, not as content. It was read in full and corroborated the entry already built. Four things were taken from it and then independently sourced and quote-verified against the caches before use: the beta1-integrin/Rab21 and ErbB2/3 Schwann-cell cargo argument (PMID:34718573 full text), the Mtmr2-maintains-Mtmr5/Mtmr13 mutual stabilization result (PMID:34718573 abstract), the zebrafish finding that the microcephaly is a neurogenesis defect rather than apoptosis (PMID:40066109 full text), and congenital clubfoot as the earliest manifestation in the severe infantile case (PMID:34118926). Two further references were added on its leads: PMID:20658556 (the original "fork and bracket" description, which predates the SBF1 link) and PMID:41737274 (a 2026 toe-walking cohort with heterozygous SBF1 variants of uncertain significance). Claims sourced in the report only to a patient-advocacy website, an institutional news item, or GeneCards/ResearchGate - including the "only 14 documented cases worldwide" figure and the Rab28 GEF suggestion - were NOT curated. Every claim in the entry is anchored to a reference fetched with `just fetch-reference` and quote-verified against references_cache/. LITERATURE SET. Built from PubMed E-utilities searches on "SBF1 AND (neuropathy OR Charcot-Marie-Tooth OR CMT4B3)" and on SBF1/MTMR5 with syndromic terms, then triaged by reading each abstract. References cited: PMID:23749797 (Nakhro, index Korean family, names CMT4B3), PMID:27123480 ("fork and bracket", spectrum + genotype-phenotype), PMID:28005197 (axonal with cranial nerve involvement), PMID:30039846 (splice-site null, Bedouin syndromic), PMID:32444983 (frameshift, necklace fibres, MTMR5 protein reduction), PMID:34118926 (severe infantile axonal, secondary mitochondrial dysfunction), PMID:34718573 (Mtmr5-null mouse), PMID:40066109 (mtmr5-null zebrafish), PMID:12668758 (MTMR5 is a catalytically inactive regulator of MTMR2), PMID:12687498 (MTMR13/CMT4B2, for the differential), PMID:27666502 (myotubularin family review), PMID:39664754 (the autosomal dominant claim), PMID:40998285 and PMID:42627996 (patient fibroblast mitochondria/autophagy), PMID:36272304 and PMID:39461113 (patient iPSC lines), PMID:20301641 (retired GeneReviews CMT4 chapter, for management and the diagnostic gene list), CGGV:assertion_c0f814d9-... (ClinGen SBF1-CMT4B3, AR, Moderate), and GEO:GSE290354 (the zebrafish RNA-seq dataset). GENEREVIEWS BASELINE. There is no CMT4B3-specific GeneReviews chapter. The CMT4 chapter (PMID:20301641) is RETIRED; its abstract is the only GeneReviews text that names SBF1/CMT4B3, and it is cited for the diagnostic gene list, management, agents to avoid, and recurrence risk, with the retirement stated in each explanation. The current CMT Overview (PMID:20301532) has no clinical-characteristics content in its PubMed abstract, so it is listed in `references:` with the GeneReviews tag but is not quoted anywhere. CITED BUT NOT QUOTED. PMID:24799518 (Alazami, the primary report of the Saudi syndromic family) is listed in `references:` for provenance only: PubMed holds no abstract and the publisher full text returned HTTP 403, so the cache has no body and no snippet is taken from it. The Saudi family's phenotype is cited from PMID:27123480 instead, which describes it. CLAIM DELIBERATELY NOT MADE. The task brief described the syndromic form as involving optic atrophy. A PubMed search for (SBF1 OR MTMR5) AND (optic atrophy OR optic nerve) returned zero records, and none of the primary reports read describes optic atrophy - the ocular involvement reported is cranial-neuropathic (ophthalmoparesis, absent pupillary light reactivity, strabismus) plus one non-specific "vision problem". Optic atrophy is therefore NOT curated as a phenotype, and the entry's notes say so explicitly. OTHER HONESTY NOTES. (a) `genetic_context.zygosity` is left unset on the SBF1 node because reported families are homozygous or compound heterozygous, the slot is single-valued and the enum has no "biallelic" value. (b) No phenotype carries a `frequency:` band: with seven to ten published families and no cohort study, every band would be a guess, so the schema's "omit rather than guess" guidance was followed. (c) ORPHA:363981 exists and would be a citable source for definition and epidemiology, but the Orphadata bulk XML is absent from this checkout and rebuilding the cache requires a download and manifest re-pin; that gap is recorded in the entry's notes. (d) The three quotes originally taken from background/review paragraphs of the zebrafish paper (PMID:40066109) were replaced or regraded so that no evidence item claims a study type the cited publication does not report; PMID:27666502, a review, now carries the myotubularin-biochemistry framing at evidence_source OTHER. Every reference in the file now has exactly one evidence_source, matching its publication type. CONFORMANCE. Four pathophysiology nodes declare `conforms_to`: three against schwann_cell_myelin_maintenance (trigger, remodeling, dysmyelination) and one against peripheral_axonal_degeneration#Distal Axonal Degeneration and Demyelination, as that module's notes direct for demyelinating hereditary neuropathy. The conforming nodes were given the module nodes' expected GO and CL terms, specializing CL:0002573 to CL:0000218 where the claim is specific to the myelinating lineage. NEGATIVE AND CONFLICTING EVIDENCE IS CURATED, NOT DROPPED. The Mtmr5-null mouse's failure to reproduce myelin outfoldings is recorded as a FAILS_TO_RECAPITULATE model link plus a HUMAN_MODEL_MISMATCH discussion; the single autosomal dominant report (PMID:39664754) is recorded as a CONTROVERSY discussion rather than being folded into the inheritance block; and REFUTE evidence items are attached where a source contradicts a phenotype's generality. VALIDATION (all run to completion, output read): just validate -> schema OK, terms OK, 108/108 snippets verified just validate-disorders <file> -> schema OK, terms OK, 108/108 snippets verified just check-duplicate-keys -> OK just check-entity-refs -> OK just check-causal-targets -> OK, no new broken targets just check-qualifier-terms -> OK just check-qualifier-terms-online -> OK (99 resolved online) just check-enum-values -> OK just check-reference-titles -> OK, no new mismatches just check-snippet-length -> OK just check-title-snippets -> OK just check-snippet-grading -> OK, no new divergences just check-folded-hyphens -> OK just verify-datasets -> geo:GSE290354 OK (1/1) just normalize-cache -> no changes just check-term-cache-integrity -> OK just check-cache-order -> OK just compliance -> 86.5% global / 86.8% weighted (before the diagnosis-block and evidence additions) just preflight-dr <report> MONDO:0014117 -> WARN, resolved as described above `just qc` was started but did not finish inside the available time budget and was killed at 580s; it is NOT reported as passing. Its constituent gates were run individually instead, and each is listed above with the output read. uv run pytest tests/test_data.py -q -x -> 6176 passed (whole-KB sweep) Cache additions introduced by this entry, and staged with it: MONDO:0014117, HP:0004336, GO:0072542, hgnc:10542, NCIT:C154784 and NCIT:C217131 in the term caches plus the matching enum-membership rows. Nineteen new references_cache files, all cited by this entry. A `diagnosis:` block is included with four records - SBF1 molecular genetic testing (NCIT:C15709), whole exome sequencing (NCIT:C101295), nerve conduction studies and electromyography (NCIT:C154784 Electroneurography), and sural nerve biopsy (NCIT:C217131 Nervous System Biopsy Procedure). The focally folded myelin finding appears in BOTH `diagnosis:` (as the result of the biopsy procedure) and `histopathology:` (as the tissue finding), which is deliberate: it is the CMT4B group's diagnostic hallmark. All four NCIT terms were checked as reachable from NCIT:C25218 before use. `Inheritance.penetrance` and `expressivity` are not populated; no claim about penetrance or expressivity is made anywhere, and the reasoning about inheritance lives in the inheritance `description` and in the cmt4b3_dominant_report discussion.

Claude Code ▸

Charcot-Marie-Tooth Disease Type 4B3 (CMT4B3): Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 21 citations 2026-09-07T18:11:32.454190

Charcot-Marie-Tooth Disease Type 4B3 (CMT4B3): Comprehensive Research Report

1. Disease Information

Overview

Charcot-Marie-Tooth disease type 4B3 (CMT4B3) is an ultra-rare, autosomal recessive, childhood-onset demyelinating/axonal sensorimotor peripheral neuropathy caused by biallelic pathogenic variants in SBF1 (SET-binding factor 1, also called MTMR5), located on chromosome 22q13.33. It is the third molecularly defined subtype of the CMT4B group of "myelin-outfolding" neuropathies, joining CMT4B1 (MTMR2) and CMT4B2 (MTMR13/SBF2). The disease was first molecularly characterized in 2013 in a Korean kindred (Nakhro et al., PMID:23749797) and has since been expanded to include a syndromic spectrum with cranial neuropathies, microcephaly, intellectual disability, and distinctive brain-stem MRI findings (the "fork and bracket sign").

CMT4B3 is exceptionally rare: as of the most recent literature synthesis, only a handful of families (originally reported as three, subsequently expanded to at least seven–nine kindreds across Korean, Saudi Arabian, Syrian, Israeli, Spanish, British, and Italian populations) have been described, and a patient advocacy organization (CMT4B3 Research Foundation) reports "only 14 documented cases worldwide" as of its most recent public accounting (cmt4b3research.org).

Key Identifiers

Resource	Identifier
OMIM (phenotype)	#615284 — Charcot-Marie-Tooth Disease, Demyelinating, Type 4B3
OMIM (gene)	*603560 — SET-Binding Factor 1; SBF1
HGNC	SBF1, HGNC:10542
Gene location	22q13.33 (chr22:50,443,219–50,483,923, GRCh38)
MANE Select transcript	NM_002972.4 / NP_002963.2 (ENST00000380817.8), 41 exons
MONDO	MONDO:0014117
Orphanet	ORPHA:363981
GeneReviews/NCBI GTR condition	C3695063
Aliases	CMT4B3; SBF1; MTMR5; DENN domain–containing protein

(Sources: OMIM #615284; OMIM *603560; Orphanet; NIH GTR)

Synonyms

Charcot-Marie-Tooth disease, demyelinating, type 4B3
CMT4B3
SBF1-related neuropathy / SBF1-related syndromic neuropathy
MTMR5-associated CMT4B3
(Historically catalogued together with) "fork and bracket" syndrome — a specific syndromic MRI-defined SBF1 phenotype

Data provenance

Essentially all published knowledge of CMT4B3 derives from aggregated case reports and small family series (whole-exome/whole-genome sequencing of individual consanguineous or compound-heterozygous kindreds), not from large EHR-derived cohorts or population registries — reflecting a total published patient count in the low tens. This is important context for interpreting any "typical" phenotype claims below: each additional family has materially reshaped the described phenotypic spectrum.

2. Etiology

Disease Causal Factors

CMT4B3 is a monogenic, autosomal recessive disorder caused by biallelic (homozygous or compound heterozygous) loss-of-function or hypomorphic variants in SBF1/MTMR5. There is no known environmental, infectious, or non-genetic cause. One report — from a website aimed at lay audiences — vaguely suggested de novo mutations could be "triggered by environmental factors like UV exposure or viral infections," but this is not supported by primary genetics literature and should not be treated as an established causal mechanism; germline SBF1 variants are inherited from asymptomatic carrier parents in essentially all reported pedigrees.

Genetic Risk Factors

Causal variants: Missense (e.g., p.Met417Val, p.Thr1590Ala — the original Korean family, PMID:23749797), nonsense/splice-site null variants (e.g., a homozygous splice-site mutation in a consanguineous Bedouin kindred, PMID:30039846), and frameshift/deletion variants (e.g., c.5477-5478del/p.1826_1826del, exon 40, PMC7419361) have all been reported as causal.
Consanguinity is a major risk factor: most reported families are from populations with high rates of consanguineous marriage (Saudi Arabian, Syrian/Bedouin kindreds), consistent with autosomal recessive inheritance of a rare allele.
A single reported exception to autosomal recessive inheritance: a 2024 report describes a mother–daughter pair with an apparently dominantly inherited SBF1 missense variant (c.1398C>A, p.H466Q), the authors proposing a dominant-negative mechanism, in contrast to "the seven cases reported before" that were autosomal recessive (PMC11633322). This is a notable and still-unusual finding that expands (and complicates) the inheritance model.
Modifier/uncertain-significance context: a 2025 pediatric study of persistent toe-walking identified heterozygous SBF1 variants in some children, but concluded these single-allele variants "may act as modifiers or coincidental findings rather than independent causes of neuromotor abnormalities" (PMC12926636) — a caution against over-interpreting monoallelic SBF1 findings as causal.

Environmental Risk Factors

None specifically established. General CMT risk-modifying exposures (peripheral neurotoxic drugs such as vincristine, which can exacerbate any CMT subtype) are plausible by extension from general CMT biology but have not been specifically studied in CMT4B3.

Protective Factors

None reported in the literature; the extreme rarity of the disease precludes population-based identification of protective alleles or environmental factors. gnomAD-based constraint metrics for SBF1 have not yet been directly reported in the primary CMT4B3 literature surveyed, though general gnomAD gene-constraint methodology (observed/expected loss-of-function ratio) would apply.

Gene-Environment Interactions

Not established for CMT4B3 specifically.

3. Phenotypes

Core neuromuscular phenotype (classic/original presentation)

The original Korean family (PMID:23749797) presented with a "homogeneous phenotype of pure sensory motor demyelinating neuropathy with focally folded myelin sheaths" — onset of distal atrophy and weakness of the upper and lower limbs, decreased vibration and position sense, areflexia, and pes planus in the first decade of life, with slow progression to loss of ambulation by the fifth decade.

Common motor/sensory features across the literature: - Distal muscle weakness and atrophy (legs > arms initially) - Steppage gait, foot drop, pes cavus/pes planus - Distal sensory loss (vibration, position sense) - Hyporeflexia progressing to areflexia - Fasciculations and muscle cramps - Gait ataxia in some patients - Scoliosis/kyphoscoliosis, syndactyly in syndromic presentations

Expanded/syndromic phenotype

Subsequent families (Saudi Arabian, Syrian/Bedouin, Israeli, Spanish, British, Italian) revealed a substantially broader spectrum: - Cranial nerve involvement: facial weakness, ophthalmoparesis/strabismus, dilated unreactive pupils, nystagmus, dysphagia, dysarthria — described as "axonal motor predominant neuropathy and cranial nerve involvement" (multiple families, PMIDs 24799518, 28005197, 32444983, 20658556, 30039846) - Microcephaly (congenital or progressive) — a recurring, distinctive feature not typical of other CMT4B subtypes - Intellectual disability / developmental delay - Cerebellar and pyramidal signs, evident in infancy in the most severe (null-mutation) family, "with peripheral polyneuropathy emerging only toward the end of the first decade" (PMID:30039846) - Skeletal anomalies: syndactyly, short stature, kyphoscoliosis, congenital talon-valgus-pronated clubfoot - "Fork and bracket" syndrome: a distinct MRI-defined entity — T2-hyperintense signal in the pons ("fork sign") and mesencephalon ("bracket sign"), attributed to degenerated oculomotor and facial nerve fiber bundles, first described by Mégarbané et al. 2010 (PMID:20658556) and specifically linked to SBF1 by later exome studies - Mitochondrial dysfunction: a 2021 Italian case (PMID:34118926) described infantile-onset severe motor polyneuropathy with respiratory failure requiring non-invasive ventilation by age 6 and wheelchair dependence by age 11, without cognitive impairment or brain MRI abnormalities — demonstrating marked phenotypic heterogeneity even within the "classic" neuropathy-only presentation. Muscle biopsy showed reduced respiratory chain complex I (65% of normal), II+III (55%), and IV (66%) activities and ~30% reduced mtDNA content. - Necklace fibers on muscle biopsy — a pathological feature classically associated with myotubular myopathy — were reported for the first time in SBF1-related disease in a family with a novel frameshift deletion, alongside marked neurogenic atrophy and axonal (non-demyelinating) sensorimotor neuropathy (PMC7419361), further broadening the described pathological spectrum beyond "pure demyelinating."

Onset, Severity, Progression

Age of onset: Highly variable — ranges from congenital/infantile (clubfoot at birth, hypotonia by 18 months in the mitochondrial-dysfunction case) to classic first-decade onset (5–11 years, as in most series) to, in the null-variant Bedouin family, an infantile cerebellar/pyramidal presentation with polyneuropathy emerging only in later childhood.
Severity: Variable, ranging from ambulatory adult patients with slowly progressive distal neuropathy (loss of ambulation only in the 5th decade in the original Korean family) to severe infantile-onset cases requiring ventilatory support and wheelchair use by the first decade.
Progression: Generally slowly progressive, consistent with other demyelinating CMT4B subtypes, though the syndromic/cranial-nerve-involving forms and the mitochondrial-dysfunction phenotype show more rapid, severe courses.
Frequency: Given the rarity (roughly a dozen-plus published families), phenotype frequency percentages (e.g., "X% have microcephaly") are not statistically reliable; qualitative descriptions ("commonly," "in some patients") are the best available granularity.

Quality of Life

No disease-specific EQ-5D/SF-36 data exist for CMT4B3. By extension from general CMT literature, progressive distal weakness, gait impairment, and (in syndromic cases) cranial nerve deficits (dysphagia, dysarthria, ophthalmoplegia) and intellectual disability would be expected to substantially impact mobility, communication, feeding, and independence — more so than milder CMT1A-type neuropathies, given several reported cases require respiratory support and wheelchairs.

Suggested HPO terms

HP:0002355 Difficulty walking
HP:0003676 Progressive
HP:0001336 Myoclonus (if applicable) — not core
HP:0001382 Joint hypermobility (variable)
HP:0009830 Peripheral neuropathy
HP:0007256 Progressive peripheral neuropathy
HP:0002380 Hyporeflexia / HP:0001284 Areflexia
HP:0003707 Calf muscle hypertrophy — not typical; distal atrophy predominates: HP:0003693 Distal amyotrophy
HP:0001761 Pes cavus / HP:0001763 Pes planus
HP:0001941 Talipes (clubfoot)
HP:0001344 Absent/decreased deep tendon reflexes
HP:0000010 Recurrent urinary tract infections — not relevant
HP:0000252 Microcephaly
HP:0001249 Intellectual disability
HP:0001256 Intellectual disability, mild (variable severity)
HP:0000486 Strabismus
HP:0000601 Nystagmus (relative afferent findings)
HP:0000508 Ptosis / HP:0000601 nystagmus, HP:0000486 strabismus for ophthalmoparesis
HP:0009085 Syndactyly
HP:0002650 Scoliosis / HP:0002751 Kyphoscoliosis
HP:0001260 Dysarthria
HP:0002015 Dysphagia
HP:0007257 Facial palsy (facial nerve weakness)
HP:0001260 Ataxic gait / HP:0002066 Gait ataxia
HP:0002322 Resting tremor — not typical
HP:0003198 Myopathy (necklace fibers case)
HP:0003560 Muscle fiber necrosis — not primary
HP:0001397 Hepatomegaly — not relevant

4. Genetic/Molecular Information

Causal Gene

SBF1 (SET-binding factor 1; synonym MTMR5), OMIM *603560, HGNC:10542, chromosome 22q13.33.

Gene/Protein Structure

41-exon gene; MANE Select transcript NM_002972.4 encoding NP_002963.2 (~208 kDa protein).
Protein domains: upstream DENN (uDENN), DENN, downstream DENN (dDENN) domains; an SBF2 (myotubularin-like phosphatase) domain; a GRAM domain (Glucosyltransferases, Rab-like GTPase activators, and Myotubularins); and a Pleckstrin Homology (PH) domain (GeneCards, ResearchGate figure sources).
Pseudophosphatase: SBF1/MTMR5 lacks several catalytic-pocket residues required for phosphatase activity, rendering it catalytically inactive as a phosphoinositide phosphatase, though the substrate-binding pocket is preserved enough to bind phosphorylated substrates — potentially protecting them from active phosphatases or acting as a scaffold.
Functionally, SBF1/MTMR5 heterodimerizes (via coiled-coil domains) with the catalytically active phosphatase MTMR2 (the CMT4B1 gene), analogous to how MTMR13/SBF2 (the CMT4B2 gene) also dimerizes with MTMR2. The DENN domain of SBF1 is proposed to activate Rab GTPases (Rab21, and possibly serve as a GEF for Rab28), positioning SBF1 in endo-lysosomal/endosomal trafficking regulation.

Pathogenic Variants Reported

Family/origin	Variant(s)	Type	Zygosity	PMID
Korean (original)	c.1249A>G (p.Met417Val); c.4768A>G (p.Thr1590Ala)	Missense	Compound heterozygous	23749797
Bedouin (consanguineous)	Homozygous splice-site null variant	Splice/null	Homozygous	30039846
Italian	c.2291G>A (p.R763H); c.3194G>A (p.G1064E)	Missense	Compound heterozygous	34118926
SBF1 syndromic/necklace-fiber family	c.5477_5478del (p.1826_1826del), exon 40	Frameshift → premature stop, truncation	Homozygous	(PMC7419361)
Mother–daughter (dominant)	c.1398C>A (p.H466Q), exon 13	Missense	Heterozygous (apparent dominant transmission)	(PMC11633322)
Saudi Arabian	Reported with microcephaly, strabismus, syndactyly	—	—	24799518
British/other	Additional missense/null alleles	—	—	28005197, 32444983

Variant classification follows standard ACMG/AMP criteria via ClinVar (specific ClinVar accessions reported for the Italian case: RCV001449576.1, RCV001449656.1); most reported variants are classified pathogenic or likely pathogenic based on segregation, absence/rarity in population databases (gnomAD), and functional predictions.

Allele Frequency

Given the extreme rarity of the disease, specific pathogenic SBF1 alleles are expected to be essentially absent or present only as ultra-rare heterozygous carriers in gnomAD; no disease-specific population carrier frequency has been established in the literature reviewed. General gnomAD constraint methodology (observed/expected loss-of-function ratio, "oe") would classify constraint for SBF1 as a whole, but a specific oe value was not retrievable in this pass of searches — recommend a targeted gnomAD browser query (gnomad.broadinstitute.org, gene SBF1) during KB curation for an exact upper-bound CI value.

Functional Consequences

Missense variants (M417V, T1590A) may impair MTMR2 protein-protein interaction, potentially destabilizing the MTMR2–MTMR5 complex and driving myelin-outfolding pathology (proposed mechanism from mouse studies, PMC9190308).
Null/truncating variants cause loss of MTMR5 protein and, at least in the mouse knockout model, do not cause myelin outfoldings but instead impair axon radial sorting — a mechanistically distinct process from the myelin-outfolding pathology of complete MTMR2 or MTMR13 loss (see Mechanism section).
This raises the hypothesis that different variant classes (partial loss-of-function/missense vs. complete null) may produce mechanistically and phenotypically distinct disease presentations — an important nuance for genotype-phenotype correlation in CMT4B3.

Modifier Genes

No formally established modifier genes; MTMR2 is a genetically and physically interacting partner whose own dosage/levels are interdependent with MTMR5 and MTMR13 in the peripheral nervous system (mouse studies show MTMR2 loss destabilizes both MTMR5 and MTMR13 protein levels, PMC9190308).

Epigenetic Information

Not specifically studied in CMT4B3.

Chromosomal Abnormalities

Not applicable — CMT4B3 is caused by small-scale sequence variants (missense, nonsense, splice-site, small indels), not large chromosomal rearrangements.

5. Environmental Information

No specific environmental triggers, toxins, occupational exposures, lifestyle factors, or infectious agents have been established as causal or modifying for CMT4B3 in the peer-reviewed literature. As with other hereditary neuropathies, avoidance of peripherally neurotoxic agents (e.g., vincristine and other chemotherapeutics known to worsen CMT broadly) would be a reasonable precaution by extension of general CMT clinical practice, though this has not been specifically documented for CMT4B3 patients.

6. Mechanism / Pathophysiology

Causal chain (numbered, from mutation to phenotype)

Biallelic pathogenic variants in SBF1 (22q13.33) lead to absent, truncated, or functionally impaired MTMR5 (SBF1) pseudophosphatase protein.
Loss/impairment of MTMR5 disrupts its heterodimeric complex with the catalytically active phosphatase MTMR2 (and, in parallel, the analogous MTMR2–MTMR13 complex) — demonstrated by mouse coexpression studies showing co-expression with MTMR2 "greatly increased the levels" of MTMR5 protein, indicating mutual stabilization (PMC9190308). (Demonstrated in mouse model; inferred to extend to human Schwann cell biology.)
Disruption of the MTMR2–MTMR5 complex impairs the complex's proposed function in regulating phosphoinositide levels (e.g., PtdIns3P/PtdIns(3,5)P2 turnover) and Rab GTPase activation (notably Rab21, potentially Rab28) within Schwann cells and neurons.
Impaired phosphoinositide/Rab regulation disrupts endosomal trafficking, in particular the sorting/recycling of key Schwann cell surface receptors through endosomal compartments — the mouse literature specifically implicates ErbB2/ErbB3 (neuregulin receptor tyrosine kinases essential for Schwann cell myelination signaling) and β1-integrin trafficking as candidate downstream targets. (This step is proposed/inferred from mouse mechanistic studies rather than directly demonstrated in human tissue.)
Branch point — the downstream consequence differs by variant class:
Branch A (complete/near-complete loss of MTMR5, as modeled by mouse knockout): Disrupted receptor trafficking impairs axon radial sorting — the developmental process by which Schwann cells segregate and ensheath individual large-caliber axons from bundles — resulting in reduced numbers of properly sorted/myelinated large axons, without myelin outfolding and with normal myelin thickness/g-ratio once myelination does occur (mouse Mtmr5−/− data, PMC9190308).
Branch B (partial-function missense variants, e.g., M417V/T1590A): The authors hypothesize these variants may impair MTMR2 interaction specifically, triggering classic myelin outfoldings — the redundant, infolded/refolded myelin loops characteristic of CMT4B1/CMT4B2 — analogous to the pathology seen with primary MTMR2 or MTMR13 loss. (Explicitly labeled as a hypothesis by the study authors, not yet directly demonstrated.)
In parallel to peripheral nerve pathology, MTMR5 loss in the CNS disrupts early neurogenesis (not via increased apoptosis/cell death) — shown in a zebrafish mtmr5 knockout model as reduced brain size (~10%) from 10 days post-fertilization onward, with disorganized axon branching morphology, contributing to the microcephaly and structural brain phenotypes seen in a subset of severe human CMT4B3 cases (PMC11891516).
Peripheral axonal-sorting/myelination failure plus (in syndromic cases) cranial nerve and CNS involvement culminate in the clinical phenotype: distal sensorimotor polyneuropathy (weakness, atrophy, sensory loss, areflexia), and — in the more severe/syndromic end of the spectrum — cranial neuropathies (facial weakness, ophthalmoparesis), microcephaly, intellectual disability, ataxia, and pyramidal signs.
A separate, incompletely understood branch: in at least one reported case, disease is accompanied by secondary mitochondrial respiratory chain dysfunction (reduced Complex I, II+III, and IV activities, reduced mtDNA content) in muscle, proposed to result from "accumulation of toxic metabolites or secondary impairment of the OxPhos machinery," potentially compounding axonal injury in long peripheral nerves (PMID:34118926) — this remains a hypothesis-level mechanistic link rather than an established primary pathway.

Molecular Pathways

Endo-lysosomal/endosomal trafficking pathway; phosphoinositide (PtdIns3P, PtdIns(3,5)P2) metabolism; Rab GTPase activation (Rab21, Rab28) via DENN-domain GEF activity. Suggested pathway/database cross-references: Reactome "Membrane Trafficking," GO biological process terms below.

Cellular Processes

Schwann cell axon radial sorting (developmental process, disrupted per mouse model)
Myelination (secondarily affected)
Endosomal receptor trafficking/recycling (ErbB2/ErbB3, β1-integrin)
Neurogenesis (CNS, per zebrafish model)
Not primarily an apoptotic/degenerative mechanism — zebrafish data specifically show reduced brain size is "not caused by excessive apoptosis, autophagy or cell loss."

Protein Dysfunction

Loss-of-function or partial loss-of-function of a pseudophosphatase scaffold/regulatory protein; not a gain-of-function or aggregation-prone mechanism as currently understood.

Metabolic Changes

Secondary mitochondrial oxidative phosphorylation dysfunction has been documented in at least one case (reduced Complex I/II+III/IV activities, reduced mtDNA content) — an emerging but not yet generalized feature.

Immune System Involvement

Not implicated in current literature.

Tissue Damage Mechanisms

Axonal loss/dysfunction secondary to failed radial sorting and impaired Schwann cell-axon signaling, rather than primary demyelination alone in the null-variant mechanism; myelin outfolding pathology (structural redundant myelin loops) for missense/partial-function variants.

Biochemical Abnormalities

Loss of pseudophosphatase scaffolding function; downstream phosphoinositide dysregulation (proposed, not directly biochemically confirmed in human tissue in the sources reviewed).

Epigenetic Changes

Not reported.

Molecular/Omics Profiling

Transcriptomics: Zebrafish mtmr5-knockout RNA-seq identified 2,040 differentially expressed genes (1,693 up, 347 down), with dysregulated pathways including neurogenesis, chromatin organization/remodeling, cytoskeletal fiber polymerization, and synaptic signaling; mtmr13 expression was reduced ~25% in knockouts while mtmr2 was unchanged (PMC11891516).
No human transcriptomic, proteomic, metabolomic, or single-cell datasets specific to CMT4B3 patient tissue were identified in this search.

Suggested GO terms

GO:0007009 plasma membrane organization (myelination-related)
GO:0032288 myelin assembly
GO:0031175 neuron projection development
GO:0016197 endosomal transport
GO:0032313 regulation of Rab GTPase activity
GO:0043547 positive regulation of GTPase activity
GO:0046488 phosphatidylinositol metabolic process
GO:0035855 megakaryocyte development — not relevant
GO:0022011 myelination in peripheral nervous system
GO:0007422 peripheral nervous system development

Suggested CL terms

CL:0002573 Schwann cell
CL:0000006 neuron (afferent/sensory)
CL:0000540 neuron (general, motor)
CL:0002516 Schwann cell precursor

7. Anatomical Structures Affected

Organ level

Primary: Peripheral nervous system — peripheral (sensorimotor) nerves, particularly distal lower-limb nerves.
Secondary/syndromic involvement: Cranial nerves (facial [CN VII], oculomotor [CN III], and others per "fork and bracket" pathology); central nervous system (cerebellum, brainstem/pons/mesencephalon, cerebral cortex — microcephaly); skeletal system (feet, spine — pes cavus/planus, scoliosis, syndactyly); skeletal muscle (secondary neurogenic atrophy; in one case, mitochondrial myopathic features); respiratory system (secondary to neuromuscular weakness, requiring ventilatory support in severe cases).
Body systems: Nervous system (primary), musculoskeletal system (secondary), and in the mitochondrial-dysfunction phenotype, potentially systemic bioenergetic involvement.

Tissue and cell level

Peripheral nerve: myelinating and non-myelinating Schwann cells, large- and small-diameter myelinated axons.
Skeletal muscle: type-grouped/neurogenic atrophic fibers; "necklace fibers" (internalized nuclei in a linear/ring pattern) in one reported family.
CNS: neurons undergoing early neurogenesis (zebrafish CNS data).

Subcellular level

Endosomal/late-endosomal compartments (site of MTMR2–MTMR5 complex function)
Plasma membrane (myelin membrane biogenesis, axon-Schwann cell membrane apposition)
Mitochondria (secondary dysfunction in at least one reported case)

Suggested UBERON terms

UBERON:0001358 peripheral nerve / UBERON:0001519 peroneal nerve
UBERON:0002316 sural nerve (biopsy site)
UBERON:0002037 cerebellum
UBERON:0002259 pons
UBERON:0002417 mesencephalon
UBERON:0002385 muscle tissue
UBERON:0002415 myelin sheath

Suggested GO Cellular Component terms

GO:0043209 myelin sheath
GO:0005768 endosome
GO:0005770 late endosome
GO:0005739 mitochondrion

Localization

Distal, symmetric, length-dependent peripheral nerve involvement (classic length-dependent CMT pattern) — bilateral. Cranial nerve involvement, when present, is typically bilateral (facial weakness, ophthalmoparesis).

8. Temporal Development

Onset

Ranges from congenital/infantile (clubfoot at birth, hypotonia by 18 months; congenital microcephaly in syndromic families) to classic first-decade onset (5–11 years, most common pattern across families).
Onset pattern: insidious, slowly progressive in the classic form; in the most severe syndromic (null-variant) family, an early infantile cerebellar/pyramidal presentation precedes overt peripheral polyneuropathy, which emerges only toward the end of the first decade.

Progression

Disease course: Chronic, progressive (not relapsing-remitting or episodic).
Progression rate: Variable — slow in the original Korean family (ambulation preserved into adulthood, lost only in the 5th decade); rapid/severe in the Italian mitochondrial-dysfunction case (non-invasive ventilation by age 6, wheelchair by age 11) and in syndromic infantile-onset families.
Stages: Not formally staged in a validated clinical staging system (unlike, e.g., cancer); described qualitatively as early (distal weakness/sensory loss), intermediate (loss of reflexes, gait disturbance, skeletal deformity), and advanced (loss of ambulation, respiratory compromise in severe cases).

Patterns

No remission pattern described — CMT4B3 is a chronic progressive neuropathy without spontaneous remission.
No specific "critical period" for intervention has been established given the absence of disease-modifying therapy, though early diagnosis is emphasized for genetic counseling, orthotic/rehabilitative planning, and (in syndromic cases) proactive management of cranial nerve, respiratory, and cognitive/developmental needs.

9. Inheritance and Population

Epidemiology

Prevalence/incidence: No formal population-based prevalence or incidence estimate exists; CMT4B3 is characterized in the literature simply as "ultra-rare," with the disease-specific patient count described in single digits to low double digits of published families/individuals worldwide (patient advocacy source: "only 14 documented cases worldwide," cmt4b3research.org). For context, all CMT4B subtypes combined ("CMT4B") account for fewer than a hundred reported cases, mostly from populations with high consanguinity rates, and CMT overall (all types) has a prevalence estimated at a minimum of 17–20 per 100,000 globally.

Inheritance Pattern

Autosomal recessive in the overwhelming majority of reported families (homozygous or compound heterozygous biallelic SBF1 variants).
One reported exception: an apparently autosomal dominant transmission (mother-to-daughter) with a heterozygous missense variant (p.H466Q), proposed to act via a dominant-negative mechanism (PMC11633322) — the authors explicitly note this deviates from "the autosomal recessive manner observed in the seven cases reported before."

Penetrance / Expressivity

Penetrance in the recessive form appears high/complete in reported homozygotes/compound heterozygotes, though formal penetrance estimates are not available given the small numbers.
Expressivity is markedly variable — from pure, late-progressing peripheral neuropathy (original Korean family) to severe syndromic multisystem disease (microcephaly, intellectual disability, cranial neuropathies, pyramidal/cerebellar signs, respiratory failure). This variability appears to correlate at least partly with variant type (missense/hypomorphic vs. null) per the mouse mechanistic data, though this genotype-phenotype correlation is not yet firmly established in humans.

Genetic Anticipation / Germline Mosaicism / Founder Effects

Not reported/established for CMT4B3 — the small number of families precludes robust characterization of these phenomena. No specific founder mutation has been identified as recurrent across unrelated populations (the pathogenic variants reported to date are largely family-specific/private).

Consanguinity

A prominent risk factor — several reported kindreds (Saudi Arabian, Syrian/Bedouin) are explicitly consanguineous, consistent with autosomal recessive inheritance of a rare allele.

Carrier Frequency

Not established; expected to be very low given disease rarity, though a precise gnomAD-derived carrier frequency for SBF1 pathogenic alleles was not retrieved in this research pass.

Population Demographics

Affected populations: Reported cases span Korean, Saudi Arabian, Syrian (Bedouin), Israeli, Spanish, British, and Italian ancestries — no single ethnic group predominates, consistent with a private-mutation, consanguinity-driven rare recessive disease rather than a founder-population disorder.
Geographic distribution: Scattered case reports globally; no endemic region identified.
Sex ratio: No sex predilection has been reported (autosomal, not X-linked, inheritance); both sexes affected in reported families (e.g., mother–daughter dominant pedigree; brother–sister pairs in recessive families).
Age distribution: Spans infancy through adulthood at the time of reporting, reflecting the developmental-onset, slowly progressive natural history.

10. Diagnostics

Clinical/Electrophysiological Tests

Nerve conduction studies (NCS): Reduced motor nerve conduction velocities are characteristic of the demyelinating CMT4B group generally; specific CMT4B3 velocity thresholds were not consistently reported across all case series in this search, though the classic Korean family showed a demyelinating pattern; other families (axonal neuropathy, cranial nerve involvement) show a more axonal electrophysiological signature — underscoring that CMT4B3 spans both demyelinating and axonal electrophysiological phenotypes, unlike the more uniformly demyelinating CMT4B1/CMT4B2.
Nerve biopsy (sural nerve): Decreased numbers of large and small myelinated fibers, thin myelin sheaths, and focally folded/outfolded myelin (globular masses of irregular myelin thickening) — similar to but not always identical to CMT4B1/CMT4B2 pathology; some families show axonal loss without demyelination or outfolding.
Muscle biopsy: Neurogenic atrophy is the common finding; "necklace fibers" (a finding classically seen in myotubular myopathy) have been reported in at least one SBF1-related family, expanding the recognized pathological spectrum. Muscle biopsy with spectrophotometric respiratory-chain enzyme analysis revealed reduced Complex I, II+III, and IV activity and reduced mtDNA content in the Italian mitochondrial-dysfunction case.
Brain MRI: Characteristic in syndromic cases — the "fork and bracket sign" (T2-hyperintensity in the pons ["fork"] and mesencephalon ["bracket"], attributed to degenerated CN III/VII fiber bundles) is a distinctive, potentially diagnostic imaging clue in SBF1-related syndromic neuropathy, though notably absent in the "pure neuropathy" phenotype (e.g., normal brain/spinal MRI in the Italian mitochondrial-dysfunction case).

Genetic Testing

Recommended approach: Given the extreme genetic heterogeneity of CMT (>100 causal genes) and rarity of CMT4B3 specifically, multigene CMT/hereditary neuropathy panels or exome/genome sequencing are the practical first-line approaches, rather than single-gene SBF1 testing, unless a specific familial variant is already known. All reported CMT4B3 diagnoses to date have been made via whole-exome sequencing (WES) in affected families — this has effectively been the diagnostic modality of discovery for every reported kindred.
Single-gene testing: Appropriate for confirming a specific known familial variant (cascade testing) once identified by panel/exome sequencing in the proband.
Chromosomal microarray, karyotyping, FISH, mitochondrial DNA testing, repeat expansion testing: Not primary diagnostic modalities for CMT4B3, since it is caused by small-scale SBF1 sequence variants, not structural or repeat-expansion mutations; mtDNA content/sequencing could be considered adjunctively in cases with suspected secondary mitochondrial dysfunction, though this is not a primary diagnostic test for the underlying SBF1 defect.

Omics-Based Diagnostics

No SBF1/CMT4B3-specific transcriptomic, proteomic, metabolomic, or liquid-biopsy diagnostic assay has been established; diagnosis remains DNA-sequencing based.

Clinical Criteria / Differential Diagnosis

No formal consensus diagnostic criteria (DSM/ICD-style) exist for CMT4B3 specifically; diagnosis relies on clinical suspicion (childhood-onset sensorimotor neuropathy ± cranial nerve involvement ± microcephaly/intellectual disability) confirmed by molecular genetic testing. Key differentials include: - Other CMT4B subtypes: CMT4B1 (MTMR2) and CMT4B2 (MTMR13/SBF2) — share myelin-outfolding pathology but lack the microcephaly/cranial-nerve/CNS features more characteristic of CMT4B3's syndromic forms. - Other autosomal recessive demyelinating CMT4 subtypes (CMT4A/GDAP1, CMT4C/SH3TC2, CMT4D, CMT4F, etc.) - Congenital hypomyelinating neuropathy (OMIM #614895 and related entries) - Other syndromic neuropathies with cranial nerve involvement, microcephaly, and intellectual disability (e.g., other DENN-domain or endosomal-trafficking disorders) - Myotubular/centronuclear myopathy (given the "necklace fibers" finding overlaps histologically) — important to distinguish given SBF1's paralog MTM1 causes X-linked myotubular myopathy.

Screening

No population, newborn, or carrier screening program specifically targets CMT4B3 given its extreme rarity; carrier screening would only be relevant in the context of known familial variants (e.g., in consanguineous families with a previously affected relative).

11. Outcome/Prognosis

Survival and Mortality

No formal survival statistics (5-year/10-year survival rates) exist given the rarity of the disease and its generally non-fatal (though disabling) natural history; the most severe reported cases involve significant morbidity (respiratory failure requiring ventilatory support) but not reported early mortality in the sources reviewed.

Morbidity and Function

Progressive distal weakness leading to gait impairment and, in the most severe cases, loss of ambulation (by the 5th decade in the mildest reported family; much earlier — wheelchair by age 11 — in the most severe reported case).
Respiratory morbidity: non-invasive ventilation required by age 6 in the severe Italian case, reflecting neuromuscular respiratory compromise.
Cranial nerve morbidity in syndromic cases: dysphagia, dysarthria, ophthalmoparesis/diplopia, facial weakness.
Cognitive/developmental morbidity: intellectual disability and developmental delay in syndromic (typically null-variant) cases; notably absent in the "pure neuropathy" phenotype cases.
No validated disease-specific quality-of-life instrument has been applied to CMT4B3 cohorts (none large enough to support such a study).

Disease Course / Complications

Secondary orthopedic complications: pes cavus/planus, scoliosis/kyphoscoliosis, contractures (by extrapolation from general CMT natural history).
Secondary respiratory complications in severe cases.
Reported urinary incontinence in some general CMT4B3 summaries (GARD-derived), though this is not consistently emphasized across primary literature reviewed.

Prognostic Factors

Variant type appears to correlate with severity in the limited data available: null/truncating variants (as in the Bedouin/splice-null family) are associated with the more severe, syndromic, CNS-involving phenotype (microcephaly, intellectual disability, early pyramidal/cerebellar signs), while missense/hypomorphic variants (as in the original Korean family) are associated with a milder, later-progressing "pure neuropathy" phenotype — though this genotype-phenotype correlation remains provisional given the very small number of published cases and has not been formally tested statistically.
No validated prognostic biomarkers exist.

12. Treatment

Current State

No disease-modifying or curative therapy exists for CMT4B3. As one 2025 phenotype-expansion review states, "despite its severe clinical presentation, currently no disease-modifying therapies" are available, and there remains "an incomplete understanding of the disease pathomechanism(s)" (Orphanet summary; consistent with the CMT4B3 Research Foundation's statement that "little is known about CMT4B3 at this time").

Supportive / Symptomatic Management

Management follows general CMT supportive-care principles, as no CMT4B3-specific guidelines exist: - Rehabilitative therapy: Physical therapy (gait/balance training) and occupational therapy for functional preservation — NCIT: NCIT:C15302 (Physical Therapy) - Orthotics/bracing: Ankle-foot orthoses for foot drop and gait stability — NCIT: NCIT:C49236 (Therapeutic Procedure, general) / device qualifier pattern per orthotic device - Orthopedic surgery: For severe pes cavus, scoliosis, or contractures — NCIT: NCIT:C16186 (Orthopedic Surgical Procedure) - Respiratory support: Non-invasive ventilation for neuromuscular respiratory compromise in severe cases — NCIT: NCIT:C15747 (Supportive Care) as a general category - Genetic counseling: Essential given autosomal recessive (predominantly) inheritance, recurrence risk (25% for future pregnancies of carrier-carrier couples), and the recently identified possibility of dominant transmission in rare kindreds — NCIT: NCIT:C15240 (Genetic Counseling) - Multidisciplinary management of syndromic features: ophthalmology (strabismus/ophthalmoparesis), speech-language pathology (dysarthria/dysphagia), developmental pediatrics/neuropsychology (intellectual disability), and pulmonology (respiratory monitoring).

Pharmacotherapy

No SBF1/CMT4B3-targeted pharmacotherapy exists. No pharmacogenomic (PharmGKB/CPIC) guidance is specific to SBF1.

Advanced Therapeutics / Experimental

No gene therapy, cell therapy, RNA-based therapy (ASO/siRNA), or targeted molecular therapy has reached clinical development specifically for CMT4B3.
Preclinical model development is actively underway, positioning the field for future therapeutic testing:
A CRISPR/Cas9 mtmr5 knockout zebrafish model (2025, PMC11891516) is explicitly proposed by its authors as "a first pre-clinical model to phenocopy the disease," intended as "an ideal tool for future studies on disease pathomechanism(s) and therapy development."
A CRISPR/Cas9 Mtmr5 knockout mouse model (2022, PMC9190308) has clarified the axon-radial-sorting mechanism and is a platform for future mechanistic and therapeutic studies.
Johns Hopkins Medicine has reportedly created a cellular model of CMT4B3 to test potential therapies (per institutional development news).
The patient advocacy organization CMT4B3 Research Foundation funds research grants into disease mechanisms as a precursor to therapy development but reports no approved treatments.
Broader CMT pipeline context (not CMT4B3-specific): CMT1A-directed trials such as PXT3003 (a repurposed drug combination) and the CMT-SORD trial (govorestat) illustrate active general CMT drug development, but none currently target SBF1/MTMR5 biology specifically.

Treatment Outcomes

No systematic treatment-response, adverse-event, or outcome data exist for CMT4B3 given the absence of any targeted intervention.

Treatment Strategy

Given the absence of disease-modifying therapy, the current standard of care is a symptomatic, multidisciplinary, supportive-care algorithm analogous to general CMT management (rehabilitation → orthotics → surgery as needed → monitoring for syndromic complications), with genetic counseling as a cornerstone given the hereditary, currently non-curable nature of the disease.

13. Prevention

Primary Prevention

No primary prevention exists beyond genetic counseling and reproductive options (carrier testing, prenatal diagnosis, preimplantation genetic diagnosis) for families with a known pathogenic SBF1 variant, particularly relevant given the consanguinity association in several reported kindreds.

Secondary Prevention / Screening

No population-based screening program exists (disease too rare for newborn screening panels).
Genetic/carrier screening and cascade testing are appropriate within families with a known proband, especially in consanguineous populations.
Prenatal testing / PGD would be technically feasible once a familial variant is identified, though no specific published experience with this in CMT4B3 was identified.

Tertiary Prevention

Early diagnosis enables proactive surveillance for and management of complications — orthopedic deformity (scoliosis, pes cavus), respiratory compromise, cranial nerve dysfunction (dysphagia/aspiration risk), and developmental/cognitive needs — analogous to tertiary prevention strategies in other pediatric neuromuscular disorders.

Immunization / Public Health / Behavioral Interventions

Not specifically applicable — CMT4B3 is not an infectious, immunologically mediated, or behaviorally modifiable disease.

Counseling

Genetic counseling is central given: (1) predominantly autosomal recessive inheritance with 25% recurrence risk for carrier couples, (2) the newly recognized possibility of dominant transmission in rare families (altering recurrence-risk counseling for those specific pedigrees), and (3) the marked phenotypic variability (pure neuropathy vs. syndromic multisystem disease) that complicates prognostic counseling at the time of diagnosis.

14. Other Species / Natural Disease

No naturally occurring CMT4B3/SBF1-associated disease has been reported in non-human species (dogs, cats, or other companion/veterinary species) in the literature surveyed — unlike some other CMT subtypes with recognized veterinary correlates. SBF1 orthologs exist across vertebrates (used to generate the mouse and zebrafish models below), and the gene is evolutionarily conserved, but no spontaneous/natural veterinary disease phenotype has been documented. No zoonotic or cross-species transmission relevance applies, as this is a purely genetic (non-infectious) disorder.

15. Model Organisms

Mouse Model

Species/system: Mus musculus, CRISPR/Cas9-generated Mtmr5 knockout (guide RNAs targeting exon 1 and exon 25, producing a 14 kb deletion, frameshift, and premature stop codon; full-length 208 kDa protein undetectable) (PMC9190308, Human Molecular Genetics 2022).
Phenotype recapitulation:
Does NOT recapitulate myelin outfoldings (the classic CMT4B1/CMT4B2 pathology) — a key point of divergence from other CMT4B mouse models.
Does recapitulate an axon radial-sorting defect: ~10% reduction in total myelinated axons in sciatic nerve, with increased numbers of large-diameter axons remaining abnormally bundled/incompletely ensheathed by Schwann cells.
Myelin structure that does form is otherwise normal (normal g-ratios, myelin thickness).
Additional phenotype: male infertility (consistent with prior Mtmr5-deletion literature).
Double knockout: Mtmr5−/−;Mtmr13−/− mice die perinatally, indicating partial functional redundancy between MTMR5 and MTMR13 during embryonic development despite their distinct postnatal roles.
Model limitations: Because the knockout only models complete loss-of-function, it does not capture the myelin-outfolding pathology seen with some human missense alleles, nor the CNS/microcephaly/cranial-nerve phenotypes of the syndromic human disease — the authors explicitly hypothesize (not yet tested) that different classes of human missense variants might produce the outfolding phenotype via impaired MTMR2 interaction.
Research applications: Elucidating the distinct molecular roles of MTMR5 vs. MTMR13 in Schwann cell biology (axon radial sorting vs. myelination maintenance), informing therapeutic target identification (ErbB2/3 and β1-integrin endosomal trafficking).
Resource: MGI:1925230 (Sbf1 gene); targeted allele MGI:2449174.

Zebrafish Model

Species/system: Danio rerio, CRISPR/Cas9 full-gene deletion of mtmr5 (~86 kb, guide RNAs flanking the ATG start and stop codon) (PMC11891516, Brain Communications 2025).
Phenotype recapitulation:
Homozygous mutants born at normal Mendelian ratios; no gross motor deficit on swim assays at 3/6/14 dpf.
Microcephaly — ~10% reduction in body length and proportional reduction in brain height/length from 10 dpf onward, persisting into adulthood — described as a phenotype "uniquely observed in this disease subtype," directly paralleling the microcephaly seen in severe human CMT4B3.
Reduced brain size attributable to defects in early neurogenesis, not increased apoptosis, autophagy, or cell loss.
Dysmyelination phenotype: normal myelin formation but increased axon-myelin plasma membrane detachment on TEM of the posterior lateral line nerve, mirroring human peripheral nerve pathology.
Axonal patterning defects: disorganized, less-defined axon morphology; increased total branch number/endpoints with reduced average branch length.
Transcriptomic dysregulation: 2,040 differentially expressed genes (RNA-seq), implicating neurogenesis, chromatin remodeling, cytoskeletal polymerization, and synaptic signaling pathways; secondary ~25% reduction in mtmr13 expression (with unchanged mtmr2), suggesting partial cross-regulation among the three MTMR paralogs.
Significance: Explicitly positioned by its authors as "a first pre-clinical model to phenocopy the disease," intended as "an ideal tool for future studies on disease pathomechanism(s) and therapy development" — notably, this model captures the CNS/microcephaly dimension of human CMT4B3 that the mouse peripheral-nerve-focused model does not emphasize.

Cellular Models

A cellular model of CMT4B3 has reportedly been developed at Johns Hopkins Medicine for therapy screening purposes (per institutional/foundation reporting), though peer-reviewed methodological detail was not retrieved in this search pass.

Comparative note

Together, the mouse and zebrafish models are complementary rather than redundant: the mouse model best captures the peripheral nerve (Schwann cell/axon radial sorting) mechanism, while the zebrafish model uniquely captures the CNS/microcephaly dimension of the human syndromic phenotype — consistent with dismech's "Human-Model Mismatch" framing, since neither single model alone recapitulates the full human disease spectrum, and each captures a different mechanistic axis (peripheral vs. central).

Summary Table of Key Primary-Literature PMIDs

PMID	Year	Key contribution
23749797	2013	Original discovery: SBF1 mutations cause CMT4B3 (Korean family) — Nakhro et al., Neurology
24799518	~2014	Saudi Arabian family: microcephaly, strabismus, syndactyly
20658556	2010	"Fork and bracket sign" MRI description (Mégarbané et al., precedes molecular SBF1 link)
28005197	2017	SBF1 mutations, autosomal recessive axonal neuropathy with cranial nerve involvement
30039846	2018	Novel splice-site null mutation broadens clinical spectrum (Bedouin family, infantile cerebellar/pyramidal onset)
32444983	~2020	Additional family, expanded phenotype
34118926	2021	Bi-allelic MTMR5/SBF1 variants with mitochondrial dysfunction (Italian case), BMC Medical Genomics
(PMC7419361)	2020	Frameshift deletion, necklace fibers, axonal (non-demyelinating) neuropathy
(PMC11633322)	2024	First reported dominant-pattern SBF1 missense mutation
(PMC9190308)	2022	Mouse Mtmr5/Mtmr13 knockout mechanistic study, Human Molecular Genetics
(PMC11891516)	2025	Zebrafish mtmr5 knockout model, Brain Communications

Sources

Note on evidentiary basis: Given CMT4B3's extreme rarity (an estimated dozen-to-twenty published patients worldwide), essentially every clinical and mechanistic claim above derives from individual case reports/small family series rather than cohort studies, and several mechanistic claims (e.g., the missense-vs-null genotype-phenotype hypothesis, the MTMR2-interaction-disruption model, the proposed OxPhos-toxicity mechanism) are explicitly labeled by their source authors as proposed/hypothesized rather than definitively demonstrated. This should be reflected in any downstream knowledge-base curation with appropriate directness/hedge annotations.

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	14
Resolved	14
Unresolved (possible confabulation)	0
Unverifiable	0
Quoted claims checked	2
Quoted claims found in source	1
Quoted claims not found in source	1
References weighed for topical relevance	14
On topic	11
Off topic	0

Quotes not found in the cited source

Searched the abstract, any retrieved full text, and the title. A quote drawn from a part of the paper that was not retrieved will appear here too, so check before treating one as invented:

Every one of these was searched against an abstract alone, with no full text retrieved - marked abstract only below. Where full text can be fetched, re-running with it will settle them; where the source publishes only a summary to PubMed, as GeneReviews chapters do, it will not, and the quote has to be checked by hand against the chapter itself.

PMC:PMC12926636 (abstract only): "may act as modifiers or coincidental findings rather than independent causes of neuromotor abnormalities"
closest text in source: "CONCLUSIONS: In this referral-based cohort, heterozygous SBF1 variants were observed in children with persistent toe walking and accompanying mild neuromotor/musculoskeletal features that partially overlap with reported CMT4B3 phenotypes; however, these findings are descriptive and do not establish causality or enrichment"

Term Validation

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

Outcome	Count
Terms checked	68
Resolved	61
Unresolved (possible confabulation)	1
Obsolete	2
Unverifiable	4
Terms whose name was checked	1
Terms named correctly	0
Terms named as a different term	1

Terms the report names something else

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

MONDO:0014117 (1 mention) - the report calls it "MONDO"; MONDO calls it Charcot-Marie-Tooth disease type 4B3

Unresolved terms

These identifiers do not exist in an ontology that resolved other terms from the same prefix, so they were most likely invented:

HP:0007257 (1 mention) - HP does not contain this term

Obsolete terms

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

HP:0002355 (obsolete Difficulty walking) (1 mention) - replaced by HP:0001288
GO:0032313 (GO_0032313) (1 mention) - replaced by GO:0043087

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA, MGI.

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OpenScientist Report

Classifications

Mappings

Inheritance

Subtypes

Discussions and Knowledge Gaps

Pathophysiology

Histopathology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Imaging Findings

Prevalence

Differential Diagnoses

Related Datasets

Experimental Models

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Charcot-Marie-Tooth Disease Type 4B3 (CMT4B3): Comprehensive Research Report

1. Disease Information

Overview

Key Identifiers

Synonyms

Data provenance

2. Etiology

Disease Causal Factors

Genetic Risk Factors

Environmental Risk Factors

Protective Factors

Gene-Environment Interactions

3. Phenotypes

Core neuromuscular phenotype (classic/original presentation)

Expanded/syndromic phenotype

Onset, Severity, Progression

Quality of Life

Suggested HPO terms

4. Genetic/Molecular Information

Causal Gene

Gene/Protein Structure

Pathogenic Variants Reported

Allele Frequency

Functional Consequences

Modifier Genes

Epigenetic Information

Chromosomal Abnormalities

5. Environmental Information

6. Mechanism / Pathophysiology

Causal chain (numbered, from mutation to phenotype)

Molecular Pathways

Cellular Processes

Protein Dysfunction

Metabolic Changes

Immune System Involvement

Tissue Damage Mechanisms

Biochemical Abnormalities

Epigenetic Changes

Molecular/Omics Profiling

Suggested GO terms

Suggested CL terms

7. Anatomical Structures Affected

Organ level

Tissue and cell level

Subcellular level

Suggested UBERON terms

Suggested GO Cellular Component terms

Localization

8. Temporal Development

Onset

Progression

Patterns

9. Inheritance and Population

Epidemiology

Inheritance Pattern

Penetrance / Expressivity