Distal Myopathy 7, Adult-Onset, X-Linked

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Classifications

Harrison's Part

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Mappings

MONDO

MONDO:0024771 myopathy, distal, 7, adult-onset, X-linked

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Inheritance

1

X-linked inheritance HP:0001417

All reported patients are hemizygous males. Most probands had a negative family history and presented as sporadic cases; only one family contributed two affected brothers. The generic X-linked term is bound deliberately rather than X-linked recessive or X-linked dominant: no female heterozygote has been phenotyped, so there is no basis for choosing between them, and published tabulations of this disease are inconsistent on the point.

X-linked inheritance

Show evidence (1 reference)

PMID:33974137 SUPPORT Human Clinical

"In all ten families, except the two brothers in F5, all probands reported negative family history of muscle weakness and presented as sporadic cases"

Supports the sporadic presentation typical of a late-onset X-linked disorder, which is the reason family history rarely raises the diagnosis.

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Discussions and Knowledge Gaps

2

Has anyone systematically audiogrammed a cohort of SMPX missense-variant myopathy patients, and would formal audiometry find subclinical auditory involvement that clinical history and examination missed?

KNOWLEDGE GAP OPEN gap_mpd7_subclinical_auditory_involvement

Attached to

genetic#SMPX phenotypes#Distal muscle weakness

This entry claims no auditory phenotype, and that claim rests on the defining cohort recording no hearing loss on examination into the eighth decade. What it does not rest on is a systematic audiometric study: the source reports absence of recorded hearing loss, not normal audiograms in a screened cohort. Aggregated phenotype annotations for MPD7 in third-party resources do list hearing impairment, so the annotation layer and the primary literature disagree. The question matters because a positive result would move SMPX from two allelic diseases towards one pleiotropic disease with allele-dependent emphasis, and would change how a clinician follows a myopathy patient.

Proposed experiments

Pure-tone and high-frequency audiometry in an SMPX missense-variant cohort

exp_mpd7_audiometry_in_missense_cohort

Perform standardised pure-tone audiometry, extended high-frequency audiometry and otoacoustic emissions on hemizygous carriers of the reported SMPX missense alleles, comparing against age- and sex-matched normative data, and stratifying by N-terminal versus C-terminal allele since these differ in their effect on protein solubility.

Decision criterion

A consistent, age-adjusted threshold shift relative to matched controls resolves the gap towards auditory involvement; thresholds within normative limits resolve it towards the current two-disease reading.

Would support

phenotypes#Distal muscle weakness

Supporting outcome

Age-adjusted high-frequency threshold elevation in missense carriers would show that the myopathy alleles also affect the cochlea subclinically, and would require adding an auditory phenotype to this entry.

Refuting outcome

Audiograms within age-matched normative limits across the cohort would confirm the current claim that the missense alleles spare hearing.

Show evidence (2 references)

PMID:33974137 SUPPORT Human Clinical

"Cardiac evaluations with echocardiography were normal and no hearing loss was recorded even at higher age"

The whole basis for the no-hearing-loss claim. Note the wording is that no hearing loss was recorded, which is what makes the systematic-audiometry question a real gap rather than a rhetorical one.

PMID:39017652 SUPPORT Other

"The weakness typically started in the forearms with finger extension defect and in the lower legs with ankle dorsiflexion weakness and progressed to scapular arm abduction muscles while sparing the heart and respiratory muscles."

An independent review restating the organ sparing, which is the same kind of absence claim as the hearing one and rests on the same small cohort. Evidence source is OTHER because this is a review.

Smpx-deficient zebrafish show both inner-ear and muscle defects, but the model is a knockdown and human MPD7 is caused by aggregation-prone missense alleles. Does the fish pleiotropy say anything about this disease, or only about SMPX loss of function?

HUMAN MODEL MISMATCH OPEN mismatch_smpx_zebrafish_knockdown_allele_class

Attached to

pathophysiology#SMPX missense variant with increased aggregation propensity animal_models#Zebrafish

The zebrafish result is the strongest single argument that SMPX is one pleiotropic gene rather than two diseases, because one perturbation produces both organ phenotypes. But the perturbation is loss of function, which in humans produces hearing loss without myopathy, and the fish phenotype is an embryonic developmental defect rather than an adult-onset degenerative one. No model yet expresses a human missense allele at endogenous levels in muscle, so the aggregation mechanism this entry models has no in vivo model at all. Until one exists, the fish pleiotropy cannot be used either to argue that MPD7 patients should be deaf or to argue that they should not be.

Proposed experiments

Knock-in animal model carrying a human SMPX missense allele

exp_smpx_knockin_missense_animal_model

Generate a knock-in model expressing an orthologous version of a human aggregation-prone SMPX allele at the endogenous locus, alongside a null allele and wild-type controls. Compare adult skeletal muscle for SMPX inclusions, rimmed vacuoles and progressive distal weakness, and compare the inner ear for hair-cell and auditory-threshold phenotypes.

Decision criterion

Divergence between knock-in and null in the direction of muscle pathology supports the aggregation mechanism; convergence of the two on the auditory phenotype refutes it.

Would support

pathophysiology#Sarcoplasmic SMPX inclusion body formation

Would refute

pathophysiology#SMPX-enriched stress granule persistence

Supporting outcome

Adult-onset muscle inclusions and weakness in the knock-in but not the null would confirm that the missense alleles act by a different mechanism from loss of function, and would separate the two SMPX diseases at the level of the model as well as the clinic.

Refuting outcome

An auditory phenotype in the knock-in equal to that of the null, without a muscle phenotype, would show the missense alleles are simply hypomorphic and undercut the gain-of-function reading.

Show evidence (1 reference)

PMID:34204426 SUPPORT Model Organism

"This piece of evidence highlights the need for more in-depth analyses in search for possible correlations between SMPX mutations and muscular disorders in humans, thus potentially turning this non-syndromic hearing loss-associated gene into the genetic cause of dysfunctions characterized by more..."

The zebrafish authors posing the syndromic-versus-two-diseases question themselves, which is the mismatch this discussion records.

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Pathophysiology

4

SMPX missense variant with increased aggregation propensity

Four hemizygous SMPX missense variants (p.P7T, p.A13V, p.P27A, p.S78N) have been reported. In silico aggregation prediction and cell fractionation agree that the mutant protein is less soluble than wild type, with the two N-terminal changes producing the largest effect. This is a change in the behaviour of the protein rather than its absence, which is what separates this disease from the SMPX loss-of-function alleles that cause DFNX4 hearing loss.

SMPX hgnc:11122

Genetic context allele_type: SNV variant_origin: GERMLINE zygosity: HEMIZYGOUS functional_impact_category: GAIN_OF_FUNCTION

Hemizygous germline missense alleles in affected males. GAIN_OF_FUNCTION is used because the defining report states the mechanism in those words and contrasts it explicitly with the loss-of-function alleles that cause DFNX4 hearing loss. It is a toxic gain through aggregation, not increased normal SMPX activity. NEOMORPHIC was considered and rejected: no source reports a novel activity of the mutant protein, only reduced solubility and accumulation.

Downstream

Sarcoplasmic SMPX inclusion body formation Reduced solubility of the mutant protein corresponds to its accumulation in inclusions in patient muscle fibres.

SMPX-enriched stress granule persistence A second, less established route by which mutant SMPX may act; see the node's own evidence for what the source does and does not show.

Show evidence (2 references)

PMID:33974137 SUPPORT In Vitro

"In silico predictions and subsequent cell culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein."

States the molecular consequence of the disease alleles that this node records.

PMID:33974137 SUPPORT In Vitro

"they supported clearly reduced solubility of SMPX p.P7T and p.A13V, whereas the C-terminal mutations showed a minor yet significant effect"

The biochemical measurement behind the aggregation claim, and the reason the node describes the effect as graded across the four alleles rather than uniform.

Sarcoplasmic SMPX inclusion body formation

Sarcoplasmic and subsarcolemmal protein inclusions accumulate in skeletal muscle fibres. They stain for SMPX itself along with SQSTM1/p62, ubiquitin, SMI-31 and vinculin, and are negative for TDP-43. Some inclusions bind Congo red with apple-green birefringence, so at least a subset has amyloid-like character. Equivalent SMPX-positive inclusions were not found in control myopathies with rimmed-vacuolar or myofibrillar pathology, which makes the finding specific to this disease rather than a shared end-stage change.

skeletal muscle fiber CL:0008002

inclusion body assembly GO:0070841 ↑ INCREASED

Downstream

Myofibrillar lesion formation and myofibre degeneration Protein accumulation is accompanied by myotilin-positive myofibrillar lesions containing the chaperone-assisted selective autophagy proteins BAG3 and HSPB8.

Show evidence (2 references)

PMID:33974137 SUPPORT Human Clinical

"Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics."

Establishes the inclusions in patient muscle that this node represents.

PMID:33974137 SUPPORT Human Clinical

"Neither SMPX-positive protein inclusions, nor other SMPX accumulation was observed in any other disease control myopathies with rimmed vacuolar and/or myofibrillar pathology"

Supports the specificity claim: the inclusions are not a generic feature of rimmed-vacuolar myopathy, which is what makes them mechanistically informative here.

SMPX-enriched stress granule persistence

In transfected cells, SMPX localises to a minority of stress granules, and granules enriched for SMPX recover more slowly after proteasome-inhibition stress. This node is retained because the source reports the observation, but it is deliberately not treated as an established disease mechanism: the same experiments found no major difference between wild-type and mutant SMPX, so nothing yet ties the delayed granule clearance to the disease alleles.

stress granule disassembly GO:0035617 ↓ DECREASED

Show evidence (2 references)

PMID:33974137 SUPPORT In Vitro

"In cell culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance."

Supports the granule-clearance observation itself. Note this is a statement about SMPX, not specifically about the mutant alleles.

PMID:33974137 NO_EVIDENCE In Vitro

"However, as our experiments did not reveal major differential effects on SG dynamics between wild-type and mutant SMPX, the potential role of SGs in the pathomechanism remains unclear and should be addressed in further studies in experimental systems allowing longer-term SMPX expression."

The authors' own statement that the mutant-specific stress-granule mechanism is untested rather than demonstrated. This is why the incoming edge is causal_link_type UNKNOWN and why the node makes no causal claim downstream.

Myofibrillar lesion formation and myofibre degeneration

Muscle shows general myopathic change of variable severity — fibre size variation, internal nuclei, rimmed vacuolar pathology — together with less prominent myotilin- and alphaB-crystallin-positive myofibrillar lesions. Electron microscopy found the sarcomere largely preserved, with intact M-bands and irregular Z-disc alignment, so this is protein-accumulation pathology rather than gross sarcomeric disintegration.

skeletal muscle fiber CL:0008002

Animal models

Smpx-deficient zebrafish Zebrafish partially recapitulates Establishes that SMPX is required for normal muscle fibre organisation, which is consistent with muscle being a target tissue.

Downstream

Distal muscle weakness Progressive myofibre pathology in the anterior lower leg and forearm produces the distal-predominant weakness that defines the phenotype.

Weakness of long finger extensor muscles The forearm half of the presenting deficit, from myofibre loss in the long finger extensors.

Foot dorsiflexor weakness The lower-leg half of the presenting deficit, from myofibre loss in the anterior compartment, which is also where the MRI fatty replacement appears first.

Shoulder girdle muscle weakness Later spread of the same myofibre pathology to the shoulder abductors.

Axial muscle weakness Paravertebral involvement reported in one patient with the p.S78N founder allele. Recorded as an edge of the spectrum rather than a core step.

Proximal muscle weakness Later spread of the same process to more proximal muscles.

Fatty replacement of skeletal muscle Chronic myofibre loss is replaced by fat, which is what the characteristic MRI pattern detects.

Show evidence (2 references)

PMID:33974137 SUPPORT Human Clinical

"In addition, we observed less prominent myofibrillar pathology immunoreactive for myotilin and αB-crystallin."

Establishes the myofibrillar component of the tissue pathology and its subordinate weight relative to the inclusions.

PMID:33974137 SUPPORT Human Clinical

"EM of patient muscles did not reveal major disorganization of sarcomeric structures; M-bands were intact whereas the alignment of Z-discs was irregular"

Supports the qualification that the sarcomere is largely preserved, which keeps this node from overstating structural breakdown.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

10

Limbs 3

Weakness of long finger extensor muscles HP:0009077

Show evidence (2 references)

PMID:33974137 SUPPORT Human Clinical

"In the probands of families F1–F5, onset of finger extensor/ankle dorsiflexor weakness was observed in the 3rd–4th decade."

Names finger extensor weakness specifically as a presenting deficit.

PMID:39017652 SUPPORT Other

"The weakness typically started in the forearms with finger extension defect and in the lower legs with ankle dorsiflexion weakness and progressed to scapular arm abduction muscles while sparing the heart and respiratory muscles."

Independent restatement in a review. Evidence source is OTHER because this is a review.

Foot dorsiflexor weakness HP:0009027

Show evidence (1 reference)

PMID:33974137 SUPPORT Human Clinical

"In the probands of families F1–F5, onset of finger extensor/ankle dorsiflexor weakness was observed in the 3rd–4th decade."

Names ankle dorsiflexor weakness specifically as a presenting deficit.

Shoulder girdle muscle weakness HP:0003547

Show evidence (1 reference)

PMID:39017652 SUPPORT Other

"The weakness typically started in the forearms with finger extension defect and in the lower legs with ankle dorsiflexion weakness and progressed to scapular arm abduction muscles while sparing the heart and respiratory muscles."

The sentence recording progression to the shoulder abductors, and in the same clause the sparing of heart and respiratory muscles. Evidence source is OTHER because this is a review.

Musculoskeletal 6

Distal muscle weakness HP:0002460

Course: PROGRESSIVE Onset: ADULT

Show evidence (2 references)

PMID:33974137 SUPPORT Human Clinical

"In the probands of families F1–F5, onset of finger extensor/ankle dorsiflexor weakness was observed in the 3rd–4th decade."

Gives both the distribution and the age of onset recorded on this phenotype.

PMID:33974137 SUPPORT Human Clinical

"In our study all patients presented with highly similar clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking."

Supports the distal-over-proximal gradient and the preserved ambulation that distinguishes this myopathy from faster distal myopathies.

Proximal muscle weakness HP:0003701

Show evidence (1 reference)

PMID:33974137 SUPPORT Human Clinical

"Thereafter, the symptoms slowly progressed over decades to severe distal more than proximal upper and lower limb weakness"

Records proximal involvement while preserving the ordering that makes it secondary to the distal weakness.

Fatty replacement of skeletal muscle HP:0012548

Show evidence (1 reference)

PMID:33974137 SUPPORT Human Clinical

"Muscle imaging of the patients showed a characteristic MRI pattern of muscle involvement (Fig.2) with fatty replacement in the anterior compartment muscles of the lower legs, later in the calf muscles medial gastrocnemius and soleus, and very late changes in the thigh muscles more in the hamstrings."

Gives the muscles involved and the sequence, which is the basis for the imaging finding recorded separately below.

Axial muscle weakness HP:0003327

Show evidence (1 reference)

PMID:39017652 SUPPORT Other

"Recently, Salman et al., also described an individual with the founder pathogenic variant p.S78N and prominent paravertebral muscle involvement."

A review reporting the axial finding. It is cited in place of the primary case report (PMID:38615630), which has no abstract in the reference cache and so could not be snippet-verified. Evidence source is OTHER because this is a review.

Rimmed vacuoles HP:0003805

Show evidence (1 reference)

PMID:33974137 SUPPORT Human Clinical

"showed general myopathic changes of variable severity, including fiber size variation, internal nuclei, rimmed vacuolar pathology and sarcoplasmic inclusions, which stained positive with antibodies against SMPX, SQSTM1/p62, SMI-31, ubiquitin, and the known SMPX-interacting protein vinculin"

Reports the rimmed vacuoles alongside the immunostaining profile of the accompanying inclusions.

Increased variability in muscle fibre diameter Increased variability in muscle fiber diameter HP:0003557

Show evidence (1 reference)

PMID:33974137 SUPPORT Human Clinical

"Hematoxylin & eosin (HE) staining shows fiber size variation and internal nuclei"

Direct histological description of the fibre-size variability recorded here.

Cellular 1

Muscle fibre sarcoplasmic inclusion bodies Muscle fiber inclusion bodies HP:0100299

Show evidence (1 reference)

PMID:33974137 SUPPORT Human Clinical

"The sarcoplasmic inclusions in patient F9 II.1 muscle showed Congo red fluorescence when viewed with fluorescent microscope using Texas red filter, suggesting amyloid-like aggregation"

The amyloid-like staining result. Note it is reported for one patient's biopsy, which is why the entry says "a subset" rather than treating amyloid as a defining feature.

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Genetic Associations

1

SMPX (Missense, gain-of-function)

Gene: SMPX hgnc:11122

Show evidence (2 references)

PMID:33974137 SUPPORT In Vitro

"Our findings suggest that the missense variants described here cause muscle disease through a gain-of-function mechanism of mutant SMPX, contrasting with the loss-of-function mutations associated with hearing loss."

The source of the functional_impact_category value and of the allelic-series contrast with DFNX4.

PMID:39272213 SUPPORT Human Clinical

"Variations in SMPX causing truncation of the protein product were associated with DFNX4, which resulted in typical audiological profiles before and after the age of 10 years, whereas nontruncated proteins typically led to distal myopathy."

An independent large hearing-loss cohort stating the same genotype-phenotype split from the other side of the allelic series.

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Variants

4

SMPX c.233G>A p.Ser78Asn

Gene: SMPX hgnc:11122

The recurrent allele in families F1-F5, which share Maltese ancestry and a 5.35 Mb founder haplotype estimated at about 25 generations old. Located near the SMPX C-terminus; its effect on solubility is smaller than that of the N-terminal alleles.

Show evidence (1 reference)

PMID:33974137 SUPPORT Human Clinical

"Families F1–F5 shared ancestral history tracing back to Malta. SNP genotyping of F1 and F2 revealed a common haplotype of chrX:17499443–22849591 amounting to 5.35 Mb"

Establishes the shared founder haplotype behind this recurrent allele.

SMPX c.38C>T p.Ala13Val

Gene: SMPX hgnc:11122

An N-terminal allele reported in a German family. Together with p.P7T it is one of the two changes that most increase predicted aggregation propensity and most reduce experimental solubility, which is the basis for the N-terminal versus C-terminal stratification in the proposed audiometry experiment.

Show evidence (1 reference)

PMID:33974137 SUPPORT In Vitro

"they supported clearly reduced solubility of SMPX p.P7T and p.A13V, whereas the C-terminal mutations showed a minor yet significant effect"

Places p.A13V with p.P7T in the high-solubility-effect N-terminal group.

SMPX c.79C>G p.Pro27Ala

Gene: SMPX hgnc:11122

An N-terminal allele shared by two French families with a 19.79 Mb founder haplotype estimated at about eight generations, or roughly 200 years.

Show evidence (1 reference)

PMID:33974137 SUPPORT Human Clinical

"The French families F6–F7 shared in chrX:12750254–32544555 a haplotype of 19.79 Mb (25.5 cM), going back to approximately eight generations or 200 years"

Establishes the French founder haplotype behind this allele.

SMPX c.19C>A p.Pro7Thr

Gene: SMPX hgnc:11122

An N-terminal allele reported in a Finnish family with very late onset. It is the only one of the four present in population databases, at 6/205,256 alleles in gnomAD; the authors read the carriers there as a possible further founder population rather than as evidence against pathogenicity.

Show evidence (1 reference)

PMID:33974137 SUPPORT Human Clinical

"The observed mutations were absent in public genome aggregation databases except for the very late onset c.19C>A (p.P7T), which has a population frequency of 2.92"

Records that three of the four alleles are absent from population databases and the fourth is present at very low frequency in a late-onset context.

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Medical Actions

3

Physical and occupational therapy

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

Platform: Behavioral / lifestyle

Rehabilitation directed at the distal deficits: hand function for the finger extensor weakness, gait and fall prevention for the ankle dorsiflexor weakness. No disease-specific rehabilitation protocol or outcome study exists for this myopathy; this follows general hereditary distal myopathy practice.

Ankle-foot orthosis and mobility aids

Platform: Device

Orthoses for foot drop and mobility aids as the distal lower-limb weakness progresses. Ambulation is typically retained for decades, so the aim is gait stability rather than replacement of walking.

Supportive neuromuscular care

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

No disease-modifying treatment has been reported and no trial or treatment study exists for this disease. Management is symptom-directed and is captured by the two specific entries above; this entry marks the absence of anything disease-modifying rather than adding a further intervention.

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Diagnosis

4

SMPX sequencing

Confirmation is molecular. SMPX is a small gene that was not on neuromuscular panels before 2021, and the defining cohort was found by high-throughput sequencing after conventional neuromuscular gene testing came back negative, so a prior negative panel does not exclude the diagnosis.

exome sequencing NCIT:C101295

Show evidence (1 reference)

PMID:33974137 SUPPORT Human Clinical

"We analyzed the HTS data from the probands for potential disease-causing variants that could explain their disease phenotype but did not identify causative variants in any of the known neuromuscular disease genes."

Records that the diagnosis was reached by sequencing after the known neuromuscular genes were excluded, which is the point about prior negative panels.

Lower-limb muscle MRI

Muscle imaging shows a stereotyped order of fatty replacement and is what raises the specific suspicion. It has been described in one cohort and has not been evaluated as a diagnostic test, so it is supportive rather than confirmatory.

Show evidence (1 reference)

PMID:33974137 SUPPORT Human Clinical

"Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration."

States the imaging pattern is characteristic, which is what makes it useful diagnostically.

Muscle biopsy

Biopsy is supportive rather than independently diagnostic. It shows rimmed-vacuolar and myofibrillar-like change that overlaps other myopathies; what is specific is the SMPX-immunoreactive sarcoplasmic inclusion, which was absent from every rimmed-vacuolar and myofibrillar disease control tested.

muscle biopsy NCIT:C51895

Show evidence (1 reference)

PMID:33974137 SUPPORT Human Clinical

"Neither SMPX-positive protein inclusions, nor other SMPX accumulation was observed in any other disease control myopathies with rimmed vacuolar and/or myofibrillar pathology"

The specificity result that makes the SMPX immunostain, rather than the rimmed vacuoles, the discriminating biopsy finding.

Cardiac and respiratory assessment

Echocardiography was normal in the tested patients and the heart and respiratory muscles are described as spared, which is clinically load-bearing: cardiac or respiratory involvement points away from this diagnosis and towards another distal or myofibrillar myopathy. The sparing rests on a small cross-sectional cohort, so baseline assessment remains reasonable.

Show evidence (2 references)

PMID:39017652 SUPPORT Other

"The weakness typically started in the forearms with finger extension defect and in the lower legs with ankle dorsiflexion weakness and progressed to scapular arm abduction muscles while sparing the heart and respiratory muscles."

The organ-sparing statement. Evidence source is OTHER because this is a review.

PMID:33974137 SUPPORT Human Clinical

"Cardiac evaluations with echocardiography were normal and no hearing loss was recorded even at higher age"

The primary cohort's cardiac result, which is the observation the sparing claim rests on.

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Imaging Findings

1

Anterior-compartment-first fatty degeneration on lower-limb MRI

Lower-limb MRI shows a stereotyped order of fatty replacement — anterior compartment of the lower legs, then medial gastrocnemius and soleus, then late thigh involvement predominantly in the hamstrings. The pattern is reported as characteristic of the disease, but it has been described in one cohort and has not been evaluated as a diagnostic test.

Mri

Fatty replacement of skeletal muscle HP:0012548

The primary report and a later review disagree about which thigh muscles are affected first at the late stage. The finding description follows the primary report; see the second evidence item.

Show evidence (2 references)

PMID:33974137 SUPPORT Human Clinical

"Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration."

States that the imaging pattern is characteristic, which is the claim this finding records.

PMID:39017652 SUPPORT Other

"Muscle imaging across several patients showed a pattern of muscle involvement where fatty replacement affected the anterior compartment muscles of the lower legs."

Independent restatement of the lower-leg pattern. Note this review describes the thigh stage as adductors and quadriceps more than hamstrings, which is the opposite of the primary report; the entry follows the primary report and records the discrepancy here rather than choosing silently. Evidence source is OTHER because this is a review.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Ten patients from nine families in five countries in the defining report. No population rate has been estimated and none should be inferred from the case count. Two founder haplotypes (Maltese/Italian and French) mean the allele is regionally clustered rather than uniformly rare, and the authors argue the disease is under-recognised because late-onset X-linked disease usually presents as sporadic.

Show evidence (2 references)

PMID:33974137 SUPPORT Human Clinical

"Four different missense mutations were identified in ten patients from nine families in five different countries, suggesting that this disease could be prevalent in other populations as well."

Gives the total published case count that this literature-count measure records, and the authors' own statement that it is a floor rather than an estimate.

PMID:33974137 SUPPORT Human Clinical

"Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher."

Supports the note that occurrence is regionally clustered by founder alleles, so a single worldwide rate would misdescribe it.

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Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Distal Myopathy 7, Adult-Onset, X-Linked:

Myofibrillar myopathy MONDO:0018943

Overlapping Features Myotilin-positive myofibrillar lesions containing BAG3 and HSPB8 are present in SMPX myopathy, so biopsies can be read as myofibrillar myopathy. The discriminator is the SMPX-positive sarcoplasmic inclusion, which was absent from every myofibrillar and rimmed-vacuolar control biopsy tested.

Distinguishing Features

SMPX-immunoreactive sarcoplasmic inclusions favour SMPX myopathy.
Marked desmin accumulation is absent in SMPX myopathy.
X-linked inheritance with only affected males favours SMPX myopathy.

Show evidence (1 reference)

PMID:33974137 SUPPORT Human Clinical

"In addition, resemblance to other myofibrillar myopathies was observed as myotilin-positive myofibrillar lesions also contain BAG3 and HSPB8."

States the overlap with myofibrillar myopathy that puts it in the differential.

X-linked non-syndromic hearing loss, DFNX4 Not Yet Curated MONDO:0010238

Overlapping Features The other SMPX disease, already curated in this knowledge base as a subtype of X-linked Nonsyndromic Hearing Loss. It is allelic but not overlapping in presentation: DFNX4 is childhood-onset progressive hearing loss from truncating loss-of-function alleles, with no reported skeletal myopathy, and the myopathy cohort had no hearing loss on examination into the eighth decade.

Distinguishing Features

Truncating or splice-disrupting SMPX alleles favour DFNX4; missense alleles favour the myopathy.
Progressive hearing loss beginning in the first two decades favours DFNX4.
Adult-onset distal limb weakness with normal hearing favours the myopathy.

Show evidence (1 reference)

PMID:33974137 SUPPORT Human Clinical

"In our families, in contrast, affected adult males examined in their 6th–8th decades showed no hearing loss and neither reported any hearing impairment in their relatives."

The direct statement that the two SMPX phenotypes have been observed apart from each other, which is the basis for curating them as separate entries.

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Animal Models

1

Smpx-deficient zebrafish

Morpholino knockdown of smpx in zebrafish embryos produces both an inner-ear phenotype (reduced kinocilia, altered stereocilia, impaired hair-cell mechanotransduction) and a muscle phenotype (defective myofibre organisation and function). It was built to test the loss-of-function hypothesis for DFNX4 hearing loss, not this disease.

Species

Zebrafish

Genotype

smpx morpholino knockdown

Publication

PMID:34204426

Pathograph links

Myofibrillar lesion formation and myofibre degeneration partially recapitulates fidelity: low Establishes that SMPX is required for normal muscle fibre organisation, which is consistent with muscle being a target tissue.

Limitations: Fidelity is LOW because the model is a knockdown and therefore reproduces the allele class that causes DFNX4 hearing loss, not the aggregation-prone missense alleles that cause this myopathy. It is an embryonic developmental phenotype rather than an adult-onset degenerative one, and it produces no protein inclusions or rimmed vacuoles. It is evidence that smpx matters in muscle, not evidence for the mechanism modelled in this entry.

Show evidence (1 reference)

PMID:34204426 SUPPORT Model Organism

"Additionally, we observed a clear muscular phenotype consisting of the defective organization and functioning of muscle fibers, strongly suggesting a potential role for the protein in the development of muscle fibers."

The muscle result that makes this model partially informative for the myofibre node.

Show evidence (1 reference)

PMID:34204426 SUPPORT Model Organism

"In the attempt to confirm this hypothesis we generated an Smpx-deficient zebrafish model, pointing out its crucial role in proper inner ear development."

States what the model was built to test, which is why its relevance to the myopathy is indirect.

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Source YAML

click to show

name: Distal Myopathy 7, Adult-Onset, X-Linked
creation_date: "2026-09-03T23:59:00Z"
category: Mendelian
description: >-
  An adult-onset, slowly progressive distal myopathy caused by hemizygous
  missense variants in SMPX, the small muscle protein X-linked. Weakness begins
  in the finger extensors and ankle dorsiflexors in the third to fourth decade
  and progresses over decades to distal-more-than-proximal limb weakness, with
  walking usually retained into old age. Muscle biopsy shows rimmed vacuoles and
  SMPX-positive sarcoplasmic inclusions, some with amyloid-like staining
  properties, and the mutant protein is less soluble and more aggregation-prone
  than wild type. This is an allelic but mechanistically distinct disease from
  DFNX4 X-linked non-syndromic hearing loss, which is caused by SMPX
  loss-of-function alleles; the myopathy cohort reported no hearing loss and no
  cardiac involvement.
disease_term:
  preferred_term: myopathy, distal, 7, adult-onset, X-linked
  term:
    id: MONDO:0024771
    label: "myopathy, distal, 7, adult-onset, X-linked"
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0024771
      label: "myopathy, distal, 7, adult-onset, X-linked"
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
synonyms:
- MPD7
- SMPX-related distal myopathy
- distal myopathy with protein inclusions
parents:
- distal myopathy
- hereditary disease
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Ten patients from nine families in five countries in the defining report.
    No population rate has been estimated and none should be inferred from the
    case count. Two founder haplotypes (Maltese/Italian and French) mean the
    allele is regionally clustered rather than uniformly rare, and the authors
    argue the disease is under-recognised because late-onset X-linked disease
    usually presents as sporadic.
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Four different missense mutations were identified in ten patients from nine families in five different countries, suggesting that this disease could be prevalent in other populations as well.
    explanation: >-
      Gives the total published case count that this literature-count measure
      records, and the authors' own statement that it is a floor rather than an
      estimate.
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Haplotype analysis of patients with similar ancestry revealed two different founder mutations in Southern Europe and France, indicating that the prevalence in these populations may be higher.
    explanation: >-
      Supports the note that occurrence is regionally clustered by founder
      alleles, so a single worldwide rate would misdescribe it.
inheritance:
- name: X-linked inheritance
  inheritance_term:
    preferred_term: X-linked inheritance
    term:
      id: HP:0001417
      label: X-linked inheritance
  description: >-
    All reported patients are hemizygous males. Most probands had a negative
    family history and presented as sporadic cases; only one family contributed
    two affected brothers. The generic X-linked term is bound deliberately rather
    than X-linked recessive or X-linked dominant: no female heterozygote has been
    phenotyped, so there is no basis for choosing between them, and published
    tabulations of this disease are inconsistent on the point.
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In all ten families, except the two brothers in F5, all probands reported negative family history of muscle weakness and presented as sporadic cases
    explanation: >-
      Supports the sporadic presentation typical of a late-onset X-linked
      disorder, which is the reason family history rarely raises the diagnosis.
pathophysiology:
- name: SMPX missense variant with increased aggregation propensity
  biological_scale: MOLECULAR
  description: >-
    Four hemizygous SMPX missense variants (p.P7T, p.A13V, p.P27A, p.S78N) have
    been reported. In silico aggregation prediction and cell fractionation agree
    that the mutant protein is less soluble than wild type, with the two
    N-terminal changes producing the largest effect. This is a change in the
    behaviour of the protein rather than its absence, which is what separates
    this disease from the SMPX loss-of-function alleles that cause DFNX4 hearing
    loss.
  genes:
  - preferred_term: SMPX
    term:
      id: hgnc:11122
      label: SMPX
  genetic_context:
    variant_origin: GERMLINE
    zygosity: HEMIZYGOUS
    allele_type: SNV
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Hemizygous germline missense alleles in affected males. GAIN_OF_FUNCTION is
      used because the defining report states the mechanism in those words and
      contrasts it explicitly with the loss-of-function alleles that cause DFNX4
      hearing loss. It is a toxic gain through aggregation, not increased normal
      SMPX activity. NEOMORPHIC was considered and rejected: no source reports a
      novel activity of the mutant protein, only reduced solubility and
      accumulation.
  notes: >-
    No GO or PATO term is bound to this node. "Increased aggregation propensity"
    is a physicochemical property of the mutant protein; GO has no matching
    biological-process or molecular-function term, and binding a generic protein
    folding or oligomerization term would assert an activity the source does not
    report. The consequence is captured at the next node with GO:0070841.
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In silico predictions and subsequent cell culture studies showed that the missense mutations increase aggregation propensity of the SMPX protein.
    explanation: >-
      States the molecular consequence of the disease alleles that this node
      records.
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      they supported clearly reduced solubility of SMPX p.P7T and p.A13V, whereas the C-terminal mutations showed a minor yet significant effect
    explanation: >-
      The biochemical measurement behind the aggregation claim, and the reason
      the node describes the effect as graded across the four alleles rather
      than uniform.
  downstream:
  - target: Sarcoplasmic SMPX inclusion body formation
    description: >-
      Reduced solubility of the mutant protein corresponds to its accumulation
      in inclusions in patient muscle fibres.
    causal_link_type: DIRECT
  - target: SMPX-enriched stress granule persistence
    description: >-
      A second, less established route by which mutant SMPX may act; see the
      node's own evidence for what the source does and does not show.
    causal_link_type: UNKNOWN
- name: Sarcoplasmic SMPX inclusion body formation
  biological_scale: CELLULAR
  conforms_to: "loss_of_proteostasis#Misfolded-Protein Aggregation"
  description: >-
    Sarcoplasmic and subsarcolemmal protein inclusions accumulate in skeletal
    muscle fibres. They stain for SMPX itself along with SQSTM1/p62, ubiquitin,
    SMI-31 and vinculin, and are negative for TDP-43. Some inclusions bind Congo
    red with apple-green birefringence, so at least a subset has amyloid-like
    character. Equivalent SMPX-positive inclusions were not found in control
    myopathies with rimmed-vacuolar or myofibrillar pathology, which makes the
    finding specific to this disease rather than a shared end-stage change.
  biological_processes:
  - preferred_term: inclusion body assembly
    modifier: INCREASED
    term:
      id: GO:0070841
      label: inclusion body assembly
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Histopathological and electron microscopic analysis of patient muscle biopsies revealed myopathic findings with rimmed vacuoles and the presence of sarcoplasmic inclusions, some with amyloid-like characteristics.
    explanation: >-
      Establishes the inclusions in patient muscle that this node represents.
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neither SMPX-positive protein inclusions, nor other SMPX accumulation was observed in any other disease control myopathies with rimmed vacuolar and/or myofibrillar pathology
    explanation: >-
      Supports the specificity claim: the inclusions are not a generic feature of
      rimmed-vacuolar myopathy, which is what makes them mechanistically
      informative here.
  downstream:
  - target: Myofibrillar lesion formation and myofibre degeneration
    description: >-
      Protein accumulation is accompanied by myotilin-positive myofibrillar
      lesions containing the chaperone-assisted selective autophagy proteins
      BAG3 and HSPB8.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: SMPX-enriched stress granule persistence
  biological_scale: CELLULAR
  description: >-
    In transfected cells, SMPX localises to a minority of stress granules, and
    granules enriched for SMPX recover more slowly after proteasome-inhibition
    stress. This node is retained because the source reports the observation,
    but it is deliberately not treated as an established disease mechanism: the
    same experiments found no major difference between wild-type and mutant
    SMPX, so nothing yet ties the delayed granule clearance to the disease
    alleles.
  biological_processes:
  - preferred_term: stress granule disassembly
    modifier: DECREASED
    term:
      id: GO:0035617
      label: cytoplasmic stress granule disassembly
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In cell culture studies, overexpressed SMPX localized to stress granules and slowed down their clearance.
    explanation: >-
      Supports the granule-clearance observation itself. Note this is a statement
      about SMPX, not specifically about the mutant alleles.
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: NO_EVIDENCE
    evidence_source: IN_VITRO
    snippet: >-
      However, as our experiments did not reveal major differential effects on SG dynamics between wild-type and mutant SMPX, the potential role of SGs in the pathomechanism remains unclear and should be addressed in further studies in experimental systems allowing longer-term SMPX expression.
    explanation: >-
      The authors' own statement that the mutant-specific stress-granule
      mechanism is untested rather than demonstrated. This is why the incoming
      edge is causal_link_type UNKNOWN and why the node makes no causal claim
      downstream.
- name: Myofibrillar lesion formation and myofibre degeneration
  biological_scale: TISSUE
  description: >-
    Muscle shows general myopathic change of variable severity — fibre size
    variation, internal nuclei, rimmed vacuolar pathology — together with less
    prominent myotilin- and alphaB-crystallin-positive myofibrillar lesions.
    Electron microscopy found the sarcomere largely preserved, with intact
    M-bands and irregular Z-disc alignment, so this is protein-accumulation
    pathology rather than gross sarcomeric disintegration.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, we observed less prominent myofibrillar pathology immunoreactive for myotilin and αB-crystallin.
    explanation: >-
      Establishes the myofibrillar component of the tissue pathology and its
      subordinate weight relative to the inclusions.
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      EM of patient muscles did not reveal major disorganization of sarcomeric structures; M-bands were intact whereas the alignment of Z-discs was irregular
    explanation: >-
      Supports the qualification that the sarcomere is largely preserved, which
      keeps this node from overstating structural breakdown.
  downstream:
  - target: Distal muscle weakness
    description: >-
      Progressive myofibre pathology in the anterior lower leg and forearm
      produces the distal-predominant weakness that defines the phenotype.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Weakness of long finger extensor muscles
    description: >-
      The forearm half of the presenting deficit, from myofibre loss in the long
      finger extensors.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Foot dorsiflexor weakness
    description: >-
      The lower-leg half of the presenting deficit, from myofibre loss in the
      anterior compartment, which is also where the MRI fatty replacement appears
      first.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Shoulder girdle muscle weakness
    description: >-
      Later spread of the same myofibre pathology to the shoulder abductors.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Axial muscle weakness
    description: >-
      Paravertebral involvement reported in one patient with the p.S78N founder
      allele. Recorded as an edge of the spectrum rather than a core step.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Proximal muscle weakness
    description: >-
      Later spread of the same process to more proximal muscles.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Fatty replacement of skeletal muscle
    description: >-
      Chronic myofibre loss is replaced by fat, which is what the characteristic
      MRI pattern detects.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
phenotypes:
- name: Distal muscle weakness
  category: Musculoskeletal
  description: >-
    Onset in the finger extensors and ankle dorsiflexors in the third to fourth
    decade, progressing over decades to severe distal weakness of both upper and
    lower limbs. Walking is retained late; the oldest reported patient was still
    ambulant at 80.
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
    clinical_course: PROGRESSIVE
    onset:
      onset_category: ADULT
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the probands of families F1–F5, onset of finger extensor/ankle dorsiflexor weakness was observed in the 3rd–4th decade.
    explanation: >-
      Gives both the distribution and the age of onset recorded on this
      phenotype.
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our study all patients presented with highly similar clinical features: adult-onset, usually distal more than proximal limb muscle weakness, slowly progressing over decades with preserved walking.
    explanation: >-
      Supports the distal-over-proximal gradient and the preserved ambulation
      that distinguishes this myopathy from faster distal myopathies.
- name: Weakness of long finger extensor muscles
  category: Musculoskeletal
  description: >-
    Finger extension weakness in the forearm is one of the two presenting
    deficits, appearing in the third to fourth decade alongside ankle
    dorsiflexor weakness.
  phenotype_term:
    preferred_term: Finger extensor weakness
    term:
      id: HP:0009077
      label: Weakness of long finger extensor muscles
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the probands of families F1–F5, onset of finger extensor/ankle dorsiflexor weakness was observed in the 3rd–4th decade.
    explanation: >-
      Names finger extensor weakness specifically as a presenting deficit.
  - reference: PMID:39017652
    reference_title: Current advance on distal myopathy genetics.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The weakness typically started in the forearms with finger extension defect and in the lower legs with ankle dorsiflexion weakness and progressed to scapular arm abduction muscles while sparing the heart and respiratory muscles.
    explanation: >-
      Independent restatement in a review. Evidence source is OTHER because this
      is a review.
- name: Foot dorsiflexor weakness
  category: Musculoskeletal
  description: >-
    Ankle dorsiflexor weakness in the anterior compartment of the lower leg is
    the other presenting deficit, and is the muscle group in which the
    characteristic MRI fatty replacement appears first.
  phenotype_term:
    preferred_term: Ankle dorsiflexor weakness
    term:
      id: HP:0009027
      label: Foot dorsiflexor weakness
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the probands of families F1–F5, onset of finger extensor/ankle dorsiflexor weakness was observed in the 3rd–4th decade.
    explanation: >-
      Names ankle dorsiflexor weakness specifically as a presenting deficit.
- name: Shoulder girdle muscle weakness
  category: Musculoskeletal
  description: >-
    Weakness progresses from the presenting distal muscles to the shoulder
    abductors. Recorded as shoulder girdle weakness rather than as scapular
    winging: the source describes involvement of the arm abduction muscles, and
    winging is a distinct clinical sign that no cited source reports.
  phenotype_term:
    preferred_term: Shoulder girdle muscle weakness
    term:
      id: HP:0003547
      label: Shoulder girdle muscle weakness
  evidence:
  - reference: PMID:39017652
    reference_title: Current advance on distal myopathy genetics.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The weakness typically started in the forearms with finger extension defect and in the lower legs with ankle dorsiflexion weakness and progressed to scapular arm abduction muscles while sparing the heart and respiratory muscles.
    explanation: >-
      The sentence recording progression to the shoulder abductors, and in the
      same clause the sparing of heart and respiratory muscles. Evidence source
      is OTHER because this is a review.
- name: Proximal muscle weakness
  category: Musculoskeletal
  description: >-
    Proximal limb muscles become involved after the distal muscles and remain
    less affected.
  phenotype_term:
    preferred_term: Proximal muscle weakness
    term:
      id: HP:0003701
      label: Proximal muscle weakness
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thereafter, the symptoms slowly progressed over decades to severe distal more than proximal upper and lower limb weakness
    explanation: >-
      Records proximal involvement while preserving the ordering that makes it
      secondary to the distal weakness.
- name: Fatty replacement of skeletal muscle
  category: Musculoskeletal
  description: >-
    Fatty degeneration in a characteristic order: anterior compartment of the
    lower legs first, then medial gastrocnemius and soleus, and only very late
    the thigh, predominantly the hamstrings.
  phenotype_term:
    preferred_term: Fatty replacement of skeletal muscle
    term:
      id: HP:0012548
      label: Fatty replacement of skeletal muscle
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Muscle imaging of the patients showed a characteristic MRI pattern of muscle involvement (Fig.2) with fatty replacement in the anterior compartment muscles of the lower legs, later in the calf muscles medial gastrocnemius and soleus, and very late changes in the thigh muscles more in the hamstrings.
    explanation: >-
      Gives the muscles involved and the sequence, which is the basis for the
      imaging finding recorded separately below.
- name: Axial muscle weakness
  category: Musculoskeletal
  description: >-
    Paravertebral muscle involvement has been reported as a prominent feature in
    an individual carrying the p.S78N founder allele, extending the pattern
    beyond the limb muscles described in the defining cohort. It is a single
    reported case, so it is recorded as part of the spectrum rather than as a
    core feature.
  phenotype_term:
    preferred_term: Axial muscle weakness
    term:
      id: HP:0003327
      label: Axial muscle weakness
  evidence:
  - reference: PMID:39017652
    reference_title: Current advance on distal myopathy genetics.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Recently, Salman et al., also described an individual with the founder pathogenic variant p.S78N and prominent paravertebral muscle involvement.
    explanation: >-
      A review reporting the axial finding. It is cited in place of the primary
      case report (PMID:38615630), which has no abstract in the reference cache
      and so could not be snippet-verified. Evidence source is OTHER because this
      is a review.
- name: Rimmed vacuoles
  category: Histopathology
  description: >-
    Rimmed vacuolar pathology in skeletal muscle fibres, seen on H&E and
    positive for the autophagosome marker LC3b.
  phenotype_term:
    preferred_term: Rimmed vacuoles
    term:
      id: HP:0003805
      label: Rimmed vacuoles
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      showed general myopathic changes of variable severity, including fiber size variation, internal nuclei, rimmed vacuolar pathology and sarcoplasmic inclusions, which stained positive with antibodies against SMPX, SQSTM1/p62, SMI-31, ubiquitin, and the known SMPX-interacting protein vinculin
    explanation: >-
      Reports the rimmed vacuoles alongside the immunostaining profile of the
      accompanying inclusions.
- name: Muscle fibre sarcoplasmic inclusion bodies
  category: Histopathology
  description: >-
    Sarcoplasmic and subsarcolemmal inclusions positive for SMPX, SQSTM1/p62,
    ubiquitin, SMI-31 and vinculin, and negative for TDP-43. A subset binds
    Congo red and shows apple-green birefringence under polarised light.
  phenotype_term:
    preferred_term: Muscle fiber inclusion bodies
    term:
      id: HP:0100299
      label: Muscle fiber inclusion bodies
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The sarcoplasmic inclusions in patient F9 II.1 muscle showed Congo red fluorescence when viewed with fluorescent microscope using Texas red filter, suggesting amyloid-like aggregation
    explanation: >-
      The amyloid-like staining result. Note it is reported for one patient's
      biopsy, which is why the entry says "a subset" rather than treating amyloid
      as a defining feature.
- name: Increased variability in muscle fibre diameter
  category: Histopathology
  description: >-
    Fibre size variation with internal nuclei, part of the general myopathic
    change seen across biopsies.
  phenotype_term:
    preferred_term: Increased variability in muscle fiber diameter
    term:
      id: HP:0003557
      label: Increased variability in muscle fiber diameter
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hematoxylin & eosin (HE) staining shows fiber size variation and internal nuclei
    explanation: >-
      Direct histological description of the fibre-size variability recorded
      here.
imaging_findings:
- name: Anterior-compartment-first fatty degeneration on lower-limb MRI
  modality: MRI
  description: >-
    Lower-limb MRI shows a stereotyped order of fatty replacement — anterior
    compartment of the lower legs, then medial gastrocnemius and soleus, then
    late thigh involvement predominantly in the hamstrings. The pattern is
    reported as characteristic of the disease, but it has been described in one
    cohort and has not been evaluated as a diagnostic test.
  phenotype_term:
    preferred_term: Fatty replacement of skeletal muscle
    term:
      id: HP:0012548
      label: Fatty replacement of skeletal muscle
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration.
    explanation: >-
      States that the imaging pattern is characteristic, which is the claim this
      finding records.
  - reference: PMID:39017652
    reference_title: Current advance on distal myopathy genetics.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Muscle imaging across several patients showed a pattern of muscle involvement where fatty replacement affected the anterior compartment muscles of the lower legs.
    explanation: >-
      Independent restatement of the lower-leg pattern. Note this review describes
      the thigh stage as adductors and quadriceps more than hamstrings, which is
      the opposite of the primary report; the entry follows the primary report and
      records the discrepancy here rather than choosing silently. Evidence source
      is OTHER because this is a review.
  notes: >-
    The primary report and a later review disagree about which thigh muscles are
    affected first at the late stage. The finding description follows the primary
    report; see the second evidence item.
genetic:
- name: SMPX
  association: Missense, gain-of-function
  gene_term:
    preferred_term: SMPX
    term:
      id: hgnc:11122
      label: SMPX
  notes: >-
    The controlled functional-impact value for these alleles is carried on the
    pathophysiology node's genetic_context block, which is the schema home for a
    variant's functional consequence.
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Our findings suggest that the missense variants described here cause muscle disease through a gain-of-function mechanism of mutant SMPX, contrasting with the loss-of-function mutations associated with hearing loss.
    explanation: >-
      The source of the functional_impact_category value and of the allelic-series
      contrast with DFNX4.
  - reference: PMID:39272213
    reference_title: "Genomic and phenotypic landscapes of X-linked hereditary hearing loss in the Chinese population."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Variations in SMPX causing truncation of the protein product were associated with DFNX4, which resulted in typical audiological profiles before and after the age of 10 years, whereas nontruncated proteins typically led to distal myopathy.
    explanation: >-
      An independent large hearing-loss cohort stating the same genotype-phenotype
      split from the other side of the allelic series.
variants:
- name: SMPX c.233G>A p.Ser78Asn
  description: >-
    The recurrent allele in families F1-F5, which share Maltese ancestry and a
    5.35 Mb founder haplotype estimated at about 25 generations old. Located near
    the SMPX C-terminus; its effect on solubility is smaller than that of the
    N-terminal alleles.
  gene:
    preferred_term: SMPX
    term:
      id: hgnc:11122
      label: SMPX
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Families F1–F5 shared ancestral history tracing back to Malta. SNP genotyping of F1 and F2 revealed a common haplotype of chrX:17499443–22849591 amounting to 5.35 Mb
    explanation: >-
      Establishes the shared founder haplotype behind this recurrent allele.
- name: SMPX c.38C>T p.Ala13Val
  description: >-
    An N-terminal allele reported in a German family. Together with p.P7T it is
    one of the two changes that most increase predicted aggregation propensity
    and most reduce experimental solubility, which is the basis for the
    N-terminal versus C-terminal stratification in the proposed audiometry
    experiment.
  gene:
    preferred_term: SMPX
    term:
      id: hgnc:11122
      label: SMPX
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      they supported clearly reduced solubility of SMPX p.P7T and p.A13V, whereas the C-terminal mutations showed a minor yet significant effect
    explanation: >-
      Places p.A13V with p.P7T in the high-solubility-effect N-terminal group.
- name: SMPX c.79C>G p.Pro27Ala
  description: >-
    An N-terminal allele shared by two French families with a 19.79 Mb founder
    haplotype estimated at about eight generations, or roughly 200 years.
  gene:
    preferred_term: SMPX
    term:
      id: hgnc:11122
      label: SMPX
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The French families F6–F7 shared in chrX:12750254–32544555 a haplotype of 19.79 Mb (25.5 cM), going back to approximately eight generations or 200 years
    explanation: >-
      Establishes the French founder haplotype behind this allele.
- name: SMPX c.19C>A p.Pro7Thr
  description: >-
    An N-terminal allele reported in a Finnish family with very late onset. It is
    the only one of the four present in population databases, at 6/205,256
    alleles in gnomAD; the authors read the carriers there as a possible further
    founder population rather than as evidence against pathogenicity.
  gene:
    preferred_term: SMPX
    term:
      id: hgnc:11122
      label: SMPX
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The observed mutations were absent in public genome aggregation databases except for the very late onset c.19C>A (p.P7T), which has a population frequency of 2.92
    explanation: >-
      Records that three of the four alleles are absent from population databases
      and the fourth is present at very low frequency in a late-onset context.
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
diagnosis:
- name: SMPX sequencing
  description: >-
    Confirmation is molecular. SMPX is a small gene that was not on
    neuromuscular panels before 2021, and the defining cohort was found by
    high-throughput sequencing after conventional neuromuscular gene testing came
    back negative, so a prior negative panel does not exclude the diagnosis.
  diagnosis_term:
    preferred_term: exome sequencing
    term:
      id: NCIT:C101295
      label: Whole Exome Sequencing
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We analyzed the HTS data from the probands for potential disease-causing variants that could explain their disease phenotype but did not identify causative variants in any of the known neuromuscular disease genes.
    explanation: >-
      Records that the diagnosis was reached by sequencing after the known
      neuromuscular genes were excluded, which is the point about prior negative
      panels.
- name: Lower-limb muscle MRI
  description: >-
    Muscle imaging shows a stereotyped order of fatty replacement and is what
    raises the specific suspicion. It has been described in one cohort and has
    not been evaluated as a diagnostic test, so it is supportive rather than
    confirmatory.
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Lower limb muscle imaging showed a characteristic pattern of muscle involvement and fatty degeneration.
    explanation: >-
      States the imaging pattern is characteristic, which is what makes it useful
      diagnostically.
- name: Muscle biopsy
  description: >-
    Biopsy is supportive rather than independently diagnostic. It shows
    rimmed-vacuolar and myofibrillar-like change that overlaps other myopathies;
    what is specific is the SMPX-immunoreactive sarcoplasmic inclusion, which was
    absent from every rimmed-vacuolar and myofibrillar disease control tested.
  diagnosis_term:
    preferred_term: muscle biopsy
    term:
      id: NCIT:C51895
      label: Muscle Biopsy
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Neither SMPX-positive protein inclusions, nor other SMPX accumulation was observed in any other disease control myopathies with rimmed vacuolar and/or myofibrillar pathology
    explanation: >-
      The specificity result that makes the SMPX immunostain, rather than the
      rimmed vacuoles, the discriminating biopsy finding.
- name: Cardiac and respiratory assessment
  description: >-
    Echocardiography was normal in the tested patients and the heart and
    respiratory muscles are described as spared, which is clinically
    load-bearing: cardiac or respiratory involvement points away from this
    diagnosis and towards another distal or myofibrillar myopathy. The sparing
    rests on a small cross-sectional cohort, so baseline assessment remains
    reasonable.
  evidence:
  - reference: PMID:39017652
    reference_title: Current advance on distal myopathy genetics.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The weakness typically started in the forearms with finger extension defect and in the lower legs with ankle dorsiflexion weakness and progressed to scapular arm abduction muscles while sparing the heart and respiratory muscles.
    explanation: >-
      The organ-sparing statement. Evidence source is OTHER because this is a
      review.
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac evaluations with echocardiography were normal and no hearing loss was recorded even at higher age
    explanation: >-
      The primary cohort's cardiac result, which is the observation the sparing
      claim rests on.
treatments:
- name: Physical and occupational therapy
  description: >-
    Rehabilitation directed at the distal deficits: hand function for the finger
    extensor weakness, gait and fall prevention for the ankle dorsiflexor
    weakness. No disease-specific rehabilitation protocol or outcome study exists
    for this myopathy; this follows general hereditary distal myopathy practice.
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  therapeutic_modality: BEHAVIORAL
- name: Ankle-foot orthosis and mobility aids
  description: >-
    Orthoses for foot drop and mobility aids as the distal lower-limb weakness
    progresses. Ambulation is typically retained for decades, so the aim is gait
    stability rather than replacement of walking.
  therapeutic_modality: DEVICE
  notes: >-
    No treatment_term is bound. NCIT has no clinical-action term for orthosis
    use that is reachable from Clinical Intervention or Procedure, which is the
    same gap CLAUDE.md records for device usage generally. A free-text name is
    kept rather than binding an unsuitable term.
- name: Supportive neuromuscular care
  description: >-
    No disease-modifying treatment has been reported and no trial or treatment
    study exists for this disease. Management is symptom-directed and is captured
    by the two specific entries above; this entry marks the absence of anything
    disease-modifying rather than adding a further intervention.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
animal_models:
- name: Smpx-deficient zebrafish
  species: Zebrafish
  genotype: smpx morpholino knockdown
  publication: PMID:34204426
  description: >-
    Morpholino knockdown of smpx in zebrafish embryos produces both an inner-ear
    phenotype (reduced kinocilia, altered stereocilia, impaired hair-cell
    mechanotransduction) and a muscle phenotype (defective myofibre organisation
    and function). It was built to test the loss-of-function hypothesis for
    DFNX4 hearing loss, not this disease.
  modeled_mechanisms:
  - target: Myofibrillar lesion formation and myofibre degeneration
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Establishes that SMPX is required for normal muscle fibre organisation,
      which is consistent with muscle being a target tissue.
    limitations: >-
      Fidelity is LOW because the model is a knockdown and therefore reproduces
      the allele class that causes DFNX4 hearing loss, not the aggregation-prone
      missense alleles that cause this myopathy. It is an embryonic developmental
      phenotype rather than an adult-onset degenerative one, and it produces no
      protein inclusions or rimmed vacuoles. It is evidence that smpx matters in
      muscle, not evidence for the mechanism modelled in this entry.
    evidence:
    - reference: PMID:34204426
      reference_title: "Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Additionally, we observed a clear muscular phenotype consisting of the defective organization and functioning of muscle fibers, strongly suggesting a potential role for the protein in the development of muscle fibers.
      explanation: >-
        The muscle result that makes this model partially informative for the
        myofibre node.
  evidence:
  - reference: PMID:34204426
    reference_title: "Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In the attempt to confirm this hypothesis we generated an Smpx-deficient zebrafish model, pointing out its crucial role in proper inner ear development.
    explanation: >-
      States what the model was built to test, which is why its relevance to the
      myopathy is indirect.
differential_diagnoses:
- name: Myofibrillar myopathy
  disease_term:
    preferred_term: myofibrillar myopathy
    term:
      id: MONDO:0018943
      label: myofibrillar myopathy
  description: >-
    Myotilin-positive myofibrillar lesions containing BAG3 and HSPB8 are present
    in SMPX myopathy, so biopsies can be read as myofibrillar myopathy. The
    discriminator is the SMPX-positive sarcoplasmic inclusion, which was absent
    from every myofibrillar and rimmed-vacuolar control biopsy tested.
  distinguishing_features:
  - SMPX-immunoreactive sarcoplasmic inclusions favour SMPX myopathy.
  - Marked desmin accumulation is absent in SMPX myopathy.
  - X-linked inheritance with only affected males favours SMPX myopathy.
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, resemblance to other myofibrillar myopathies was observed as myotilin-positive myofibrillar lesions also contain BAG3 and HSPB8.
    explanation: >-
      States the overlap with myofibrillar myopathy that puts it in the
      differential.
- name: X-linked non-syndromic hearing loss, DFNX4
  disease_term:
    preferred_term: hearing loss, X-linked 4
    term:
      id: MONDO:0010238
      label: hearing loss, X-linked 4
  description: >-
    The other SMPX disease, already curated in this knowledge base as a subtype
    of X-linked Nonsyndromic Hearing Loss. It is allelic but not overlapping in
    presentation: DFNX4 is childhood-onset progressive hearing loss from
    truncating loss-of-function alleles, with no reported skeletal myopathy, and
    the myopathy cohort had no hearing loss on examination into the eighth
    decade.
  distinguishing_features:
  - Truncating or splice-disrupting SMPX alleles favour DFNX4; missense alleles favour the myopathy.
  - Progressive hearing loss beginning in the first two decades favours DFNX4.
  - Adult-onset distal limb weakness with normal hearing favours the myopathy.
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In our families, in contrast, affected adult males examined in their 6th–8th decades showed no hearing loss and neither reported any hearing impairment in their relatives.
    explanation: >-
      The direct statement that the two SMPX phenotypes have been observed apart
      from each other, which is the basis for curating them as separate entries.
discussions:
- discussion_id: gap_mpd7_subclinical_auditory_involvement
  prompt: >-
    Has anyone systematically audiogrammed a cohort of SMPX missense-variant
    myopathy patients, and would formal audiometry find subclinical auditory
    involvement that clinical history and examination missed?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - genetic#SMPX
  - phenotypes#Distal muscle weakness
  rationale: >-
    This entry claims no auditory phenotype, and that claim rests on the defining
    cohort recording no hearing loss on examination into the eighth decade. What
    it does not rest on is a systematic audiometric study: the source reports
    absence of recorded hearing loss, not normal audiograms in a screened cohort.
    Aggregated phenotype annotations for MPD7 in third-party resources do list
    hearing impairment, so the annotation layer and the primary literature
    disagree. The question matters because a positive result would move SMPX from
    two allelic diseases towards one pleiotropic disease with allele-dependent
    emphasis, and would change how a clinician follows a myopathy patient.
  proposed_experiments:
  - experiment_id: exp_mpd7_audiometry_in_missense_cohort
    name: Pure-tone and high-frequency audiometry in an SMPX missense-variant cohort
    description: >-
      Perform standardised pure-tone audiometry, extended high-frequency
      audiometry and otoacoustic emissions on hemizygous carriers of the reported
      SMPX missense alleles, comparing against age- and sex-matched normative
      data, and stratifying by N-terminal versus C-terminal allele since these
      differ in their effect on protein solubility.
    would_support:
    - phenotypes#Distal muscle weakness
    supporting_outcome:
    - >-
        Age-adjusted high-frequency threshold elevation in missense carriers would
        show that the myopathy alleles also affect the cochlea subclinically, and
        would require adding an auditory phenotype to this entry.
    refuting_outcome:
    - >-
        Audiograms within age-matched normative limits across the cohort would
        confirm the current claim that the missense alleles spare hearing.
    decision_criterion: >-
      A consistent, age-adjusted threshold shift relative to matched controls
      resolves the gap towards auditory involvement; thresholds within normative
      limits resolve it towards the current two-disease reading.
  evidence:
  - reference: PMID:33974137
    reference_title: "Missense mutations in small muscle protein X-linked (SMPX) cause distal myopathy with protein inclusions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cardiac evaluations with echocardiography were normal and no hearing loss was recorded even at higher age
    explanation: >-
      The whole basis for the no-hearing-loss claim. Note the wording is that no
      hearing loss was recorded, which is what makes the systematic-audiometry
      question a real gap rather than a rhetorical one.
  - reference: PMID:39017652
    reference_title: Current advance on distal myopathy genetics.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The weakness typically started in the forearms with finger extension defect and in the lower legs with ankle dorsiflexion weakness and progressed to scapular arm abduction muscles while sparing the heart and respiratory muscles.
    explanation: >-
      An independent review restating the organ sparing, which is the same kind of
      absence claim as the hearing one and rests on the same small cohort.
      Evidence source is OTHER because this is a review.
- discussion_id: mismatch_smpx_zebrafish_knockdown_allele_class
  prompt: >-
    Smpx-deficient zebrafish show both inner-ear and muscle defects, but the
    model is a knockdown and human MPD7 is caused by aggregation-prone missense
    alleles. Does the fish pleiotropy say anything about this disease, or only
    about SMPX loss of function?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#SMPX missense variant with increased aggregation propensity
  - animal_models#Zebrafish
  rationale: >-
    The zebrafish result is the strongest single argument that SMPX is one
    pleiotropic gene rather than two diseases, because one perturbation produces
    both organ phenotypes. But the perturbation is loss of function, which in
    humans produces hearing loss without myopathy, and the fish phenotype is an
    embryonic developmental defect rather than an adult-onset degenerative one.
    No model yet expresses a human missense allele at endogenous levels in
    muscle, so the aggregation mechanism this entry models has no in vivo model
    at all. Until one exists, the fish pleiotropy cannot be used either to argue
    that MPD7 patients should be deaf or to argue that they should not be.
  proposed_experiments:
  - experiment_id: exp_smpx_knockin_missense_animal_model
    name: Knock-in animal model carrying a human SMPX missense allele
    description: >-
      Generate a knock-in model expressing an orthologous version of a human
      aggregation-prone SMPX allele at the endogenous locus, alongside a null
      allele and wild-type controls. Compare adult skeletal muscle for SMPX
      inclusions, rimmed vacuoles and progressive distal weakness, and compare
      the inner ear for hair-cell and auditory-threshold phenotypes.
    would_support:
    - pathophysiology#Sarcoplasmic SMPX inclusion body formation
    would_refute:
    - pathophysiology#SMPX-enriched stress granule persistence
    supporting_outcome:
    - >-
        Adult-onset muscle inclusions and weakness in the knock-in but not the null
        would confirm that the missense alleles act by a different mechanism from
        loss of function, and would separate the two SMPX diseases at the level of
        the model as well as the clinic.
    refuting_outcome:
    - >-
        An auditory phenotype in the knock-in equal to that of the null, without a
        muscle phenotype, would show the missense alleles are simply hypomorphic
        and undercut the gain-of-function reading.
    decision_criterion: >-
      Divergence between knock-in and null in the direction of muscle pathology
      supports the aggregation mechanism; convergence of the two on the auditory
      phenotype refutes it.
  evidence:
  - reference: PMID:34204426
    reference_title: "Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      This piece of evidence highlights the need for more in-depth analyses in search for possible correlations between SMPX mutations and muscular disorders in humans, thus potentially turning this non-syndromic hearing loss-associated gene into the genetic cause of dysfunctions characterized by more than one symptom, making SMPX a novel syndromic gene.
    explanation: >-
      The zebrafish authors posing the syndromic-versus-two-diseases question
      themselves, which is the mismatch this discussion records.
datasets: []
clinical_trials: []
notes: >-
  Boundary with the other SMPX disease. SMPX causes two clinically separate
  diseases, and this knowledge base curates them as two entries: DFNX4 hearing
  loss is a subtype of X-linked Nonsyndromic Hearing Loss, and this myopathy is
  its own entry. The split follows the literature rather than the gene: the
  variant class differs (truncating and splice-disrupting alleles for DFNX4,
  missense for the myopathy), the proposed mechanism differs (loss of function
  versus toxic aggregation), and each cohort lacks the other's phenotype. It is
  not airtight — one missense allele has been reported in hearing loss, where it
  is read as a destabilising hypomorph rather than as an aggregating allele — so
  the residual uncertainty is recorded as a KNOWLEDGE_GAP about systematic
  audiometry rather than resolved silently in either direction.

  Not curated. The chaperone-assisted selective autophagy explanation for the
  myofibrillar lesions is stated by the source as "one possibility" and is not
  modelled as a pathophysiology node. No module conformance to
  disabled_macroautophagy was declared for the same reason. Conformance to the
  amyloidogenesis module was also not declared: Congo red positivity and
  apple-green birefringence are reported for one patient's biopsy and described
  by the authors as amyloid-like, which is weaker than a conformance claim
  needs. Two later case reports that would extend the phenotype
  (PMID:38615630, axial involvement; PMID:39230604, scapuloperoneal and
  myofibrillar presentation) have no abstract indexed in the reference cache, so
  no snippet could be verified and neither is cited.

Distal Myopathy 7, Adult-Onset, X-Linked

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