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Inheritance

1

Autosomal dominant HP:0000006

Autosomal dominant with complete penetrance. Heterozygotes are affected; the disease arises from a gain of proteolytic susceptibility in the variant allele's product rather than from loss of gelsolin function, which is why one variant allele suffices.

Autosomal dominant inheritance Penetrance: COMPLETE

Show evidence (1 reference)

PMID:23931809 SUPPORT Human Clinical

"Hereditary gelsolin amyloidosis (HGA) is an autosomally dominantly inherited form of systemic amyloidosis"

States the inheritance pattern and systemic character of the disease.

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Discussions and Knowledge Gaps

1

Why does AGel amyloid deposit preferentially in cornea, cranial nerves and skin, when the amyloidogenic fragments are generated from a plasma protein and released into the circulation?

KNOWLEDGE GAP gap_agel_tissue_tropism

Attached to

pathophysiology#Systemic AGel Amyloid Deposition

The disease is defined by a cornea-nerve-skin triad, while the heart, the dominant target in both ATTR and AL, is not a cardinal feature - and the precursor is a plasma protein whose fragments enter the circulation, so systemic availability alone predicts the wrong distribution. There is one leading hypothesis rather than a blank: the D187N transgenic mouse deposits amyloid only in tissues that themselves synthesise the mutant gelsolin, despite circulating C68 being present throughout, which argues that local synthesis rather than circulating precursor governs where deposition happens. What is open is whether that generalises to human tissue distribution, since muscle is the major source of plasma gelsolin while cornea and cranial nerve are not obviously so. Competing explanations remain live: local availability of the second, extracellular protease (MT1-MMP and possibly others), tissue-specific extracellular matrix components that nucleate these particular fragments, or slow clearance in poorly vascularised tissue such as cornea. Which is right matters therapeutically, because a treatment aimed at the circulating fragment and one aimed at local synthesis or deposition are different drugs.

Proposed experiments

Map local gelsolin synthesis and second-step protease activity against the disease distribution

exp_agel_protease_tissue_survey

Two things need separating. First, quantify local GSN synthesis in cornea, peripheral nerve, skin and myocardium in human tissue, to test whether the mouse local-synthesis finding accounts for the human triad - the mouse used a muscle-specific promoter, so its tissue distribution was imposed by the construct rather than discovered. Second, map MT1-MMP activity, and that of other C68-cleaving proteases, across the same tissues. The review names MT1-MMP as the second-step protease at least in HT1080 cells while noting other extracellular proteases may contribute, so a survey has to be broader than MT1-MMP alone. If either measure tracks the disease distribution and the other does not, tropism is localised to that step.

Show evidence (1 reference)

PMID:22360545 SUPPORT Model Organism

"amyloidogenesis is observed only in tissues synthesizing human D187N gelsolin, despite the presence of the 68 kDa cleavage product circulating in the blood, suggesting that local synthesis is required for amyloid fragment formation and/or deposition"

The local-synthesis hypothesis, and the reason this gap is a question about generalisation to humans rather than an absence of any candidate mechanism.

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Pathophysiology

5

GSN Domain 2 Calcium-Binding Variant

The initiating lesion. D187N or D187Y substitutions compromise calcium binding in gelsolin domain 2. The variant does not directly destabilise the whole protein into an aggregation-prone state; it removes the calcium coordination that holds domain 2 folded, so the domain begins to sample unfolded conformations.

actin filament severing activity GO:0003789

Downstream

Domain 2 Unfolding and Exposure of a Cryptic Furin Site

Show evidence (2 references)

PMID:22360545 SUPPORT In Vitro

"autosomal dominant D187N or D187Y mutations compromise Ca(2+) binding in domain 2 of gelsolin, allowing domain 2 to sample unfolded conformations"

Establishes the precise molecular defect - loss of calcium binding in domain 2 - and its immediate structural consequence.

PMID:23931809 SUPPORT Human Clinical

"It is the first and so-far only known disorder caused by a gelsolin gene defect, namely a G654A or G654T mutation."

Gives the causal variants at nucleotide level and the uniqueness of the gene-disease pair.

Domain 2 Unfolding and Exposure of a Cryptic Furin Site

An unfolded domain 2 exposes a site that furin cleaves while the protein is passing through the Golgi on its way to secretion. This is the step that converts a folding defect into a proteolysis problem, and it is compartment-specific: the wild-type protein traverses the same pathway untouched.

Golgi apparatus GO:0005794

Downstream

Two-Step Proteolysis Releasing 8 and 5 kDa Amyloidogenic Fragments

Show evidence (1 reference)

PMID:22360545 SUPPORT In Vitro

"When domain 2 is unfolded, gelsolin is subject to aberrant furin endoproteolysis as it passes through the Golgi on its way to the extracellular space."

Establishes the intracellular protease, the compartment, and the conditional nature of the cleavage.

Two-Step Proteolysis Releasing 8 and 5 kDa Amyloidogenic Fragments

The furin cut yields a C-terminal 68 kDa fragment (C68), which is then cut again outside the cell - probably by a matrix metalloprotease - to give the 8 and 5 kDa fragments that are the actual amyloid precursor. Two proteases, two compartments, and only the final products are amyloidogenic. This node is what the entry substitutes for the amyloidogenesis module's generic precursor node.

proteolysis GO:0006508 ↑ INCREASED

Animal models

D187N transgenic gelsolin mouse (muscle-specific promoter) Mouse recapitulates The mouse reproduces both endoproteolytic steps in the correct compartments, which is the specific claim this entry's central node makes.

Downstream

Systemic AGel Amyloid Deposition

Show evidence (1 reference)

PMID:22360545 SUPPORT In Vitro

"The resulting C-terminal 68 kDa fragment (C68) is susceptible to extracellular endoproteolytic events, possibly mediated by a matrix metalloprotease, affording 8 and 5 kDa amyloidogenic fragments of gelsolin."

Establishes the second, extracellular cleavage and identifies the fragments that form the amyloid. Note the authors hedge the responsible protease ("possibly"), which is preserved in the description.

Systemic AGel Amyloid Deposition

The fragments deposit as AGel amyloid systemically, with a striking tissue preference for cornea, cranial and peripheral nerves, and skin. Why those tissues rather than the heart, which dominates ATTR and AL, is not explained by the mechanism above.

Animal models

D187N transgenic gelsolin mouse (muscle-specific promoter) Mouse partially recapitulates Extracellular amyloid deposition occurs and is aging-associated as in human disease, but only in transgene-expressing tissue, and the mice additionally develop an inclusion-body-myositis-like intracellular gelsolin deposition not established in patients.

Downstream

Corneal, Cranial Nerve and Dermal Dysfunction

Show evidence (2 references)

PMID:22360545 SUPPORT Human Clinical

"These amyloidogenic fragments deposit systemically, causing a variety of symptoms including corneal lattice dystrophy and neurodegeneration."

Links the fragments to systemic deposition and to the two cardinal manifestations.

PMID:23931809 SUPPORT Human Clinical

"The gelsolin gene defect causes expression of variant gelsolin, followed by systemic deposition of gelsolin amyloid (AGel) in HGA patients"

Independent statement of systemic AGel deposition as the pathological process.

Corneal, Cranial Nerve and Dermal Dysfunction

The clinical endpoint, dominated by the diagnostic triad. Cranial nerve involvement is progressive and measurable: in a series of 29 patients undergoing facial corrective surgery, facial paralysis was studied electroneurophysiologically, and the disease is characterised by progressive bilateral facial paralysis rather than a static deficit.

Show evidence (1 reference)

PMID:26422119 SUPPORT Human Clinical

"The diagnostic triad includes corneal lattice dystrophy (type 2), progressive bilateral facial paralysis, and cutis laxa."

Establishes the three cardinal features that define the clinical syndrome.

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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

Cardiovascular 2

Autonomic Dysfunction with Orthostatic Hypotension HP:0001278

Show evidence (1 reference)

PMID:22360545 SUPPORT Human Clinical

"amyloid deposition in the autonomic nervous system causes autonomic dysfunction, which often presents as orthostatic hypotension"

Attributes the autonomic phenotype to amyloid deposition and names its usual presentation.

Cardiac Conduction Abnormality HP:0031546

Show evidence (1 reference)

PMID:22360545 SUPPORT Human Clinical

"Cardiac involvement, including conduction abnormalities, is also sometimes seen"

Records cardiac conduction involvement and its intermittent character.

Eye 1

Lattice Corneal Dystrophy HP:0001149

Show evidence (1 reference)

PMID:26422119 SUPPORT Human Clinical

"The diagnostic triad includes corneal lattice dystrophy (type 2), progressive bilateral facial paralysis, and cutis laxa."

Names corneal lattice dystrophy as one of the three defining features.

Genitourinary 1

Proteinuria HP:0000093

Show evidence (2 references)

PMID:22360545 SUPPORT Human Clinical

"In the later stages of the disease, proteinuria is often observed, indicating amyloid deposition in the glomeruli of the kidneys"

Establishes proteinuria and localises the deposition to the glomerulus.

PMID:22360545 SUPPORT Human Clinical

"patients homozygous for the amyloidogenic mutation of gelsolin develop a severe nephrotic syndrome and, ultimately, end stage renal failure"

Gives the homozygous renal course, which is qualitatively worse rather than merely earlier.

Head and Neck 1

Progressive Bilateral Facial Palsy HP:0010628

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:26422119 SUPPORT Human Clinical

"The diagnostic triad includes corneal lattice dystrophy (type 2), progressive bilateral facial paralysis, and cutis laxa."

Establishes progressive bilateral facial paralysis as a defining feature.

Integument 1

Cutis Laxa HP:0000973

Show evidence (1 reference)

PMID:23931809 SUPPORT Human Clinical

"characterized mainly by cranial and sensory peripheral neuropathy, corneal lattice dystrophy, and cutis laxa"

Lists cutis laxa among the main characteristics of the disease.

Nervous System 1

Sensory Peripheral Neuropathy HP:0009830

Show evidence (1 reference)

PMID:23931809 SUPPORT Human Clinical

"characterized mainly by cranial and sensory peripheral neuropathy, corneal lattice dystrophy, and cutis laxa"

Establishes sensory peripheral neuropathy as a main characteristic.

Other 3

Multiple Cranial Neuropathy Abnormal cranial nerve physiology HP:0031910

Course: PROGRESSIVE

Show evidence (2 references)

PMID:26422119 SUPPORT Human Clinical

"All showed dysfunction of facial (VII) and trigeminal (V) nerves, two-thirds of oculomotor (III) and hypoglossal (XII) nerves, and half of vestibulocochlear (acoustic) (VIII) nerve."

Documents the specific cranial nerves involved and their relative frequencies within this surgical cohort.

PMID:26422119 SUPPORT Human Clinical

"Cranial nerve involvement in GA is more widespread than previously described, and correlates with age, severity of facial paralysis, and electromyographic findings."

Establishes that the cranial neuropathy is progressive and broader than the facial palsy that defines the triad.

Decreased Corneal Reflex HP:0008000

Show evidence (1 reference)

PMID:22360545 SUPPORT Human Clinical

"severely decreased corneal sensitivity and a greatly reduced or absent corneal reflex"

States the corneal sensory deficit and the depressed reflex directly.

Bulbar Dysfunction Bulbar palsy HP:0001283

Show evidence (1 reference)

PMID:22360545 SUPPORT Human Clinical

"involvement of the glossopharyngeal and hypoglossal nerves is often seen, resulting in tongue atrophy and fasciculations, dysarthria, and drooling"

Names the affected nerves and the resulting bulbar signs.

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Genetic Associations

1

GSN (A single copy of the mutant allele is reported to give complete penetrance. Heterozygous GSN variants at codon 187 - G654A giving D187N, and G654T giving D187Y - cause hereditary gelsolin amyloidosis. Gelsolin is a principal actin-modulating protein with roles in axonal transport, myelination, neurite outgrowth and neuroprotection, which raises the question of how much of the phenotype is amyloid deposition and how much is loss of normal gelsolin function. Three independent lines of evidence answer it in favour of gain of toxic function, and the entry curates the deposition mechanism accordingly rather than leaving the question open. Gelsolin knockout mice develop and live normally, with only a mild bleeding-time and cell-motility phenotype attributed to functional redundancy. Human D187N homozygotes have earlier and more severe disease - a dose effect on the toxic species, and a qualitative one in the kidney, where they develop severe nephrotic syndrome and end-stage renal failure - but no symptoms attributable to loss of function. And there is no reported sporadic or wild-type gelsolin amyloidosis, so the mutation, not the shortfall of normal protein, is what is required. The residual uncertainty is narrower than "which mechanism": it is whether local gelsolin dysfunction modulates severity in the affected tissues, not whether it causes the disease.)

Gene: GSN hgnc:4620 relationship_type: CAUSATIVE

Show evidence (5 references)

PMID:22360545 SUPPORT Model Organism

"FAF appears to be caused by a gain-of-toxic function associated with gelsolin fragment amyloidogenesis"

States the gain-of-toxic-function conclusion directly, which is why this entry does not curate a competing loss-of-function model.

PMID:22360545 SUPPORT Model Organism

"gelsolin knockout mice exhibit a normal development and lifespan, exhibiting only a mild prolonged bleeding time phenotype and abnormally slowly migrating neutrophils and fibroblasts"

The knockout evidence against a loss-of-function contribution: removing gelsolin entirely does not reproduce the disease.

PMID:23931809 SUPPORT Human Clinical

"It is the first and so-far only known disorder caused by a gelsolin gene defect, namely a G654A or G654T mutation."

Establishes the causal gene-disease relationship and the specific variants.

+ 2 more references

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Medical Actions

2

Symptomatic and Surgical Management

Action: Supportive Care NCIT:C15747

No disease-modifying therapy exists. Management is symptomatic - ophthalmic care for the corneal disease, and facial corrective surgery for the paralysis, which a published series of 29 patients underwent. The cited review is explicit that correct diagnosis matters even absent specific therapy, because adequate symptomatic treatment substantially improves quality of life. No target_mechanisms link is asserted: nothing available acts on any node of the mechanism above.

Show evidence (1 reference)

PMID:23931809 SUPPORT Human Clinical

"In HGA, specific therapy is not yet available but correct diagnosis enables adequate symptomatic treatment which decisively improves the quality of life in these patients."

Establishes both the absence of specific therapy and the value of symptomatic care.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Autosomal dominant counselling with a 50% transmission risk. Relevant across a wide and widening geographic range, not only in the Finnish founder population.

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Diagnosis

1

Molecular Genetic Testing of GSN

Sequencing of GSN codon 187. Because the corneal finding usually precedes the neurological and dermal features by years, and because the disease is now recognised well outside Finland, a lattice corneal dystrophy without an obvious cause is reasonable grounds to test.

Genetic Testing NCIT:C15709

Show evidence (1 reference)

PMID:23931809 SUPPORT Human Clinical

"HGA, originally reported from Finland and now increasingly from other countries in Europe, North and South America, and Asia, may still be underdiagnosed worldwide."

Supports testing outside the original founder population, since geographic assumptions are a known source of missed diagnosis here.

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Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Finnish Type Amyloidosis:

Hereditary transthyretin amyloidosis (ATTRv)

Overlapping Features The other classic hereditary systemic amyloidosis, and the only current member of the KB's Hereditary_Systemic_Amyloidoses grouping. Both are autosomal dominant systemic amyloidoses with peripheral neuropathy, but the amyloidogenic mechanism differs fundamentally - ATTR proceeds by tetramer dissociation and misfolding of the intact monomer, whereas AGel requires two proteolytic cleavages to manufacture its precursor. The therapeutic consequence is a relocation of the stabilisation target, not its abolition. A tafamidis-style kinetic stabiliser cannot act on the deposited AGel species, because that species is an 8 kDa fragment that does not exist until after the protein has been cut. It can act one step earlier: the founding review proposes exactly this, a pharmacologic chaperone or kinetic stabiliser binding full-length D187N plasma gelsolin in the secretory pathway to hold G2 folded and so prevent the aberrant furin cleavage that starts the cascade, and cites the transthyretin programme as the precedent. So the two diseases share a drug strategy while differing in where in the pathway it has to be applied.

Distinguishing Features

AGel presents with the corneal lattice dystrophy / facial palsy / cutis laxa triad; ATTRv does not
ATTRv commonly involves the heart; cardiac involvement is not a cardinal AGel feature
In ATTRv the stabilisation target and the depositing species are the same protein; in AGel they are not, so a stabiliser must act on the uncleaved precursor upstream of furin rather than on the fragment that deposits

Show evidence (2 references)

PMID:22360545 SUPPORT In Vitro

"The resulting C-terminal 68 kDa fragment (C68) is susceptible to extracellular endoproteolytic events, possibly mediated by a matrix metalloprotease, affording 8 and 5 kDa amyloidogenic fragments of gelsolin."

Establishes that the AGel precursor is a proteolytic fragment, which is the basis of the mechanistic distinction from ATTR drawn above.

PMID:22360545 SUPPORT In Vitro

"it may be possible to thermodynamically and/or kinetically stabilize the second domain of D187N/Y plasma gelsolin in the cellular secretory pathway employing a pharmacologic chaperone or a more specialized kinetic stabilizer"

Establishes that the kinetic-stabiliser strategy does have an AGel analogue, applied to the uncleaved precursor. Curated explicitly because the naive reading of the fragment mechanism - that precursor stabilisation cannot apply at all - is what this sentence rules out.

Other causes of lattice corneal dystrophy

Overlapping Features Lattice corneal dystrophy is usually a localised corneal disease from TGFBI variants, with no systemic component. Type 2 lattice dystrophy is the AGel form, and treating it as an isolated corneal problem is how a systemic amyloidosis gets missed for years.

Distinguishing Features

AGel lattice dystrophy is type 2 and is accompanied, sooner or later, by facial palsy and cutis laxa
A family history of adult-onset facial weakness should prompt GSN testing rather than corneal-only workup

Show evidence (1 reference)

PMID:26422119 SUPPORT Human Clinical

"The diagnostic triad includes corneal lattice dystrophy (type 2), progressive bilateral facial paralysis, and cutis laxa."

Identifies the corneal phenotype specifically as type 2 within a systemic triad.

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Animal Models

1

D187N transgenic gelsolin mouse (muscle-specific promoter)

The model that established the proteolytic cascade in vivo. A muscle-specific promoter drives synthesis and secretion of human D187N gelsolin, and the animals develop aging-associated extracellular amyloid deposition. It reproduces the full mechanistic spine curated here - G2 misfolding in the Golgi, furin cleavage to C68, and the subsequent step to the 8 and 5 kDa fragments - which is what makes it the stated platform for testing agents that prevent either misfolding or cleavage.

Species

Mouse

Genotype

Transgenic human D187N gelsolin, muscle-specific promoter driving synthesis and secretion

Publication

PMID:22360545

Pathograph links

Two-Step Proteolysis Releasing 8 and 5 kDa Amyloidogenic Fragments recapitulates fidelity: high The mouse reproduces both endoproteolytic steps in the correct compartments, which is the specific claim this entry's central node makes.

Limitations: The transgene is driven by a muscle-specific promoter, so the tissue distribution of synthesis is imposed by the construct rather than discovered. That is precisely why the model cannot by itself settle the human cornea-nerve-skin tropism question, even though it produces the local-synthesis observation that frames it.

Show evidence (1 reference)

PMID:22360545 SUPPORT Model Organism

"The mouse model of D187N FAF faithfully recapitulates G2 misfolding in the Golgi and the aberrant endoproteolytic cascade"

States the recapitulation claim for the proteolytic cascade node directly.

Systemic AGel Amyloid Deposition partially recapitulates fidelity: moderate Extracellular amyloid deposition occurs and is aging-associated as in human disease, but only in transgene-expressing tissue, and the mice additionally develop an inclusion-body-myositis-like intracellular gelsolin deposition not established in patients.

Limitations: Deposition is confined to tissues synthesising the transgene, so the model does not reproduce the human cornea-nerve-skin distribution. The intracellular inclusion-body-myositis phenotype is a divergence from human disease of unknown significance - the review states it is not yet clear whether patients show it.

Readouts

Extracellular amyloid deposition in transgene-expressing tissue

Direction: INCREASED

Interpretation: Age-dependent extracellular deposition, the structural correlate of the human deposition node.

Show evidence (1 reference)

PMID:22360545 SUPPORT Model Organism

"The mouse model exhibits the aging-associated extracellular amyloid deposition of human FAF"

Reports the deposition measurement behind this readout.

Show evidence (1 reference)

PMID:22360545 SUPPORT Model Organism

"amyloidogenesis is observed only in tissues synthesizing human D187N gelsolin, despite the presence of the 68 kDa cleavage product circulating in the blood, suggesting that local synthesis is required for amyloid fragment formation and/or deposition"

Curated as PARTIAL because it grounds the deposition claim while simultaneously showing the distribution differs from human disease.

{ }

Source YAML

click to show

name: Finnish Type Amyloidosis
creation_date: "2026-08-21T00:00:00Z"
category: Mendelian
description: >-
  Hereditary gelsolin amyloidosis (AGel amyloidosis, familial amyloidosis of Finnish
  type, OMIM 105120) is an autosomal dominant systemic amyloidosis caused by variants
  in GSN. It is the only human disease known to be caused by a gelsolin gene defect.

  Its mechanism is unlike the other hereditary systemic amyloidoses, and that is what
  makes it worth curating separately from them. In ATTR the precursor tetramer
  dissociates and the intact monomer misfolds. Here the variant protein is not itself
  the amyloid: the D187N/D187Y substitutions abolish a calcium-binding site in gelsolin
  domain 2, letting that domain unfold, and an unfolded domain 2 exposes a site that
  furin cleaves as the protein transits the Golgi. A second, extracellular cleavage
  then releases the 8 and 5 kDa fragments that actually deposit. The amyloidogenic
  species is therefore manufactured by two host proteases in two compartments, from a
  protein whose own fold was only made cleavable - not misfolded into fibrils directly.

  Clinically it is a triad: lattice corneal dystrophy, slowly progressive bilateral
  facial palsy, and cutis laxa, with sensory peripheral neuropathy and renal
  involvement following. Onset is typically in adulthood and the course is slow but
  relentless. Originally described in Finland, it is now reported worldwide and is
  thought to remain underdiagnosed.
disease_term:
  preferred_term: Finnish type amyloidosis
  term:
    id: MONDO:0007097
    label: Finnish type amyloidosis
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  penetrance: COMPLETE
  description: >-
    Autosomal dominant with complete penetrance. Heterozygotes are affected; the disease arises from a
    gain of proteolytic susceptibility in the variant allele's product rather than
    from loss of gelsolin function, which is why one variant allele suffices.
  evidence:
  - reference: PMID:23931809
    reference_title: "Hereditary gelsolin amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hereditary gelsolin amyloidosis (HGA) is an autosomally dominantly inherited
      form of systemic amyloidosis"
    explanation: States the inheritance pattern and systemic character of the disease.

pathophysiology:
- name: GSN Domain 2 Calcium-Binding Variant
  biological_scale: MOLECULAR
  description: >-
    The initiating lesion. D187N or D187Y substitutions compromise calcium binding in
    gelsolin domain 2. The variant does not directly destabilise the whole protein into
    an aggregation-prone state; it removes the calcium coordination that holds domain 2
    folded, so the domain begins to sample unfolded conformations.
  molecular_functions:
  - preferred_term: actin filament severing activity
    term:
      id: GO:0003789
      label: actin filament severing activity
  downstream:
  - target: Domain 2 Unfolding and Exposure of a Cryptic Furin Site
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "autosomal dominant D187N or D187Y mutations compromise Ca(2+) binding in
      domain 2 of gelsolin, allowing domain 2 to sample unfolded conformations"
    explanation: >-
      Establishes the precise molecular defect - loss of calcium binding in domain 2 -
      and its immediate structural consequence.
  - reference: PMID:23931809
    reference_title: "Hereditary gelsolin amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is the first and so-far only known disorder caused by a gelsolin gene
      defect, namely a G654A or G654T mutation."
    explanation: Gives the causal variants at nucleotide level and the uniqueness of the gene-disease pair.

- name: Domain 2 Unfolding and Exposure of a Cryptic Furin Site
  biological_scale: MOLECULAR
  description: >-
    An unfolded domain 2 exposes a site that furin cleaves while the protein is passing
    through the Golgi on its way to secretion. This is the step that converts a folding
    defect into a proteolysis problem, and it is compartment-specific: the wild-type
    protein traverses the same pathway untouched.
  cellular_components:
  - preferred_term: Golgi apparatus
    term:
      id: GO:0005794
      label: Golgi apparatus
  downstream:
  - target: Two-Step Proteolysis Releasing 8 and 5 kDa Amyloidogenic Fragments
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "When domain 2 is unfolded, gelsolin is subject to aberrant furin
      endoproteolysis as it passes through the Golgi on its way to the extracellular space."
    explanation: >-
      Establishes the intracellular protease, the compartment, and the conditional nature
      of the cleavage.

- name: Two-Step Proteolysis Releasing 8 and 5 kDa Amyloidogenic Fragments
  biological_scale: MOLECULAR
  description: >-
    The furin cut yields a C-terminal 68 kDa fragment (C68), which is then cut again
    outside the cell - probably by a matrix metalloprotease - to give the 8 and 5 kDa
    fragments that are the actual amyloid precursor. Two proteases, two compartments,
    and only the final products are amyloidogenic. This node is what the entry
    substitutes for the amyloidogenesis module's generic precursor node.
  conforms_to: "amyloidogenesis#Amyloidogenic Precursor Protein"
  biological_processes:
  - preferred_term: proteolysis
    term:
      id: GO:0006508
      label: proteolysis
    modifier: INCREASED
  downstream:
  - target: Systemic AGel Amyloid Deposition
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The resulting C-terminal 68 kDa fragment (C68) is susceptible to
      extracellular endoproteolytic events, possibly mediated by a matrix metalloprotease,
      affording 8 and 5 kDa amyloidogenic fragments of gelsolin."
    explanation: >-
      Establishes the second, extracellular cleavage and identifies the fragments that
      form the amyloid. Note the authors hedge the responsible protease ("possibly"),
      which is preserved in the description.

- name: Systemic AGel Amyloid Deposition
  biological_scale: TISSUE
  description: >-
    The fragments deposit as AGel amyloid systemically, with a striking tissue
    preference for cornea, cranial and peripheral nerves, and skin. Why those tissues
    rather than the heart, which dominates ATTR and AL, is not explained by the
    mechanism above.
  conforms_to: "amyloidogenesis#Amyloid Fibril Formation and Extracellular Deposition"
  downstream:
  - target: Corneal, Cranial Nerve and Dermal Dysfunction
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "These amyloidogenic fragments deposit systemically, causing a variety of
      symptoms including corneal lattice dystrophy and neurodegeneration."
    explanation: Links the fragments to systemic deposition and to the two cardinal manifestations.
  - reference: PMID:23931809
    reference_title: "Hereditary gelsolin amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The gelsolin gene defect causes expression of variant gelsolin, followed by
      systemic deposition of gelsolin amyloid (AGel) in HGA patients"
    explanation: Independent statement of systemic AGel deposition as the pathological process.

- name: Corneal, Cranial Nerve and Dermal Dysfunction
  biological_scale: ORGANISM
  description: >-
    The clinical endpoint, dominated by the diagnostic triad. Cranial nerve involvement
    is progressive and measurable: in a series of 29 patients undergoing facial
    corrective surgery, facial paralysis was studied electroneurophysiologically, and
    the disease is characterised by progressive bilateral facial paralysis rather than
    a static deficit.
  conforms_to: "amyloidogenesis#Organ Dysfunction"
  evidence:
  - reference: PMID:26422119
    reference_title: "Progressive cranial nerve involvement and grading of facial paralysis in gelsolin amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnostic triad includes corneal lattice dystrophy (type 2), progressive
      bilateral facial paralysis, and cutis laxa."
    explanation: Establishes the three cardinal features that define the clinical syndrome.

phenotypes:
- category: Ophthalmological
  name: Lattice Corneal Dystrophy
  description: >-
    Lattice corneal dystrophy type 2, from amyloid deposition in the cornea. Usually the
    earliest manifestation and often the finding that prompts diagnosis.
  phenotype_term:
    preferred_term: Lattice corneal dystrophy
    term:
      id: HP:0001149
      label: Lattice corneal dystrophy
  evidence:
  - reference: PMID:26422119
    reference_title: "Progressive cranial nerve involvement and grading of facial paralysis in gelsolin amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnostic triad includes corneal lattice dystrophy (type 2), progressive
      bilateral facial paralysis, and cutis laxa."
    explanation: Names corneal lattice dystrophy as one of the three defining features.

- category: Neurological
  name: Progressive Bilateral Facial Palsy
  description: >-
    Bilateral facial paralysis that progresses over time, reflecting cranial nerve
    amyloid deposition. Severe enough in some patients to warrant facial corrective
    surgery.
  phenotype_term:
    preferred_term: Facial palsy
    term:
      id: HP:0010628
      label: Facial palsy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:26422119
    reference_title: "Progressive cranial nerve involvement and grading of facial paralysis in gelsolin amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnostic triad includes corneal lattice dystrophy (type 2), progressive
      bilateral facial paralysis, and cutis laxa."
    explanation: Establishes progressive bilateral facial paralysis as a defining feature.

- category: Neurological
  name: Multiple Cranial Neuropathy
  description: >-
    Cranial nerve involvement extends well beyond the facial nerve. In a series of 29
    patients, all had dysfunction of both the facial (VII) and trigeminal (V) nerves,
    two-thirds had oculomotor (III) and hypoglossal (XII) involvement, and half had
    vestibulocochlear (VIII) involvement - a distribution the authors describe as more
    widespread than previously recognised, correlating with age and with severity of
    facial paralysis.

    No frequency band is assigned despite those proportions being quoted, because that
    cohort was assembled from patients undergoing facial corrective surgery: it is
    selected for severe facial involvement, so its cranial-nerve proportions cannot be
    read as disease-wide frequencies.
  phenotype_term:
    preferred_term: Abnormal cranial nerve physiology
    term:
      id: HP:0031910
      label: Abnormal cranial nerve physiology
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:26422119
    reference_title: "Progressive cranial nerve involvement and grading of facial paralysis in gelsolin amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All showed dysfunction of facial (VII) and trigeminal (V) nerves, two-thirds
      of oculomotor (III) and hypoglossal (XII) nerves, and half of vestibulocochlear
      (acoustic) (VIII) nerve."
    explanation: >-
      Documents the specific cranial nerves involved and their relative frequencies within
      this surgical cohort.
  - reference: PMID:26422119
    reference_title: "Progressive cranial nerve involvement and grading of facial paralysis in gelsolin amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cranial nerve involvement in GA is more widespread than previously described,
      and correlates with age, severity of facial paralysis, and electromyographic findings."
    explanation: >-
      Establishes that the cranial neuropathy is progressive and broader than the facial
      palsy that defines the triad.

- category: Dermatological
  name: Cutis Laxa
  description: >-
    Loose, sagging skin from dermal amyloid deposition, completing the diagnostic triad.
  phenotype_term:
    preferred_term: Cutis laxa
    term:
      id: HP:0000973
      label: Cutis laxa
  evidence:
  - reference: PMID:23931809
    reference_title: "Hereditary gelsolin amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized mainly by cranial and sensory peripheral neuropathy, corneal
      lattice dystrophy, and cutis laxa"
    explanation: Lists cutis laxa among the main characteristics of the disease.

- category: Neurological
  name: Sensory Peripheral Neuropathy
  description: >-
    Sensory peripheral neuropathy accompanying the cranial neuropathy, part of the
    systemic neurological involvement.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:23931809
    reference_title: "Hereditary gelsolin amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "characterized mainly by cranial and sensory peripheral neuropathy, corneal
      lattice dystrophy, and cutis laxa"
    explanation: Establishes sensory peripheral neuropathy as a main characteristic.
- category: Ophthalmological
  name: Decreased Corneal Reflex
  description: >-
    Severely decreased corneal sensitivity with a greatly reduced or absent corneal
    reflex. This is a two-hit finding rather than a simple neuropathy: trigeminal
    amyloid deposition removes the afferent sensation, and corneal amyloid deposition
    degrades the surface that would be stimulated. It compounds the corneal dystrophy,
    because an insensate cornea does not report the erosions it is accumulating.
  phenotype_term:
    preferred_term: Decreased corneal reflex
    term:
      id: HP:0008000
      label: Decreased corneal reflex
  evidence:
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "severely decreased corneal sensitivity and a greatly reduced or absent corneal
      reflex"
    explanation: States the corneal sensory deficit and the depressed reflex directly.
- category: Neurological
  name: Bulbar Dysfunction
  description: >-
    Glossopharyngeal and hypoglossal involvement appearing with disease progression,
    giving tongue atrophy and fasciculations, dysarthria and drooling. Clinically this
    is the cranial neuropathy extending caudally, and it carries the disease's main
    mortality risk after renal failure - aspiration pneumonia.
  phenotype_term:
    preferred_term: Bulbar palsy
    term:
      id: HP:0001283
      label: Bulbar palsy
  evidence:
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "involvement of the glossopharyngeal and hypoglossal nerves is often seen,
      resulting in tongue atrophy and fasciculations, dysarthria, and drooling"
    explanation: Names the affected nerves and the resulting bulbar signs.
- category: Neurological
  name: Autonomic Dysfunction with Orthostatic Hypotension
  description: >-
    Autonomic dysfunction from amyloid deposition in the autonomic nervous system,
    presenting most often as orthostatic hypotension. The same review notes that
    vascular amyloid is also likely to reduce arterial compliance, so the blood-pressure
    dysregulation has a vascular contribution alongside the neural one.
  phenotype_term:
    preferred_term: Orthostatic hypotension
    term:
      id: HP:0001278
      label: Orthostatic hypotension
  evidence:
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "amyloid deposition in the autonomic nervous system causes autonomic
      dysfunction, which often presents as orthostatic hypotension"
    explanation: Attributes the autonomic phenotype to amyloid deposition and names its
      usual presentation.
- category: Renal
  name: Proteinuria
  description: >-
    Proteinuria in the later stages, indicating glomerular amyloid deposition.
    Heterozygotes and homozygotes differ qualitatively rather than only in timing here:
    homozygotes develop severe nephrotic syndrome and progress to end-stage renal
    failure. Nephrotic syndrome is also named as a leading cause of death in this
    disease, which is what makes the renal arm more than an incidental finding.
  phenotype_term:
    preferred_term: Proteinuria
    term:
      id: HP:0000093
      label: Proteinuria
  evidence:
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the later stages of the disease, proteinuria is often observed, indicating
      amyloid deposition in the glomeruli of the kidneys"
    explanation: Establishes proteinuria and localises the deposition to the glomerulus.
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "patients homozygous for the amyloidogenic mutation of gelsolin develop a
      severe nephrotic syndrome and, ultimately, end stage renal failure"
    explanation: Gives the homozygous renal course, which is qualitatively worse rather
      than merely earlier.
- category: Cardiovascular
  name: Cardiac Conduction Abnormality
  description: >-
    Cardiac involvement including conduction abnormalities, reported as an occasional
    rather than a defining feature. Worth recording precisely because it is the
    exception: the cardiac deposition that dominates ATTR and AL amyloidosis is a
    minor finding here, and that contrast is part of what the tissue-tropism knowledge
    gap is asking about.
  phenotype_term:
    preferred_term: Cardiac conduction abnormality
    term:
      id: HP:0031546
      label: Cardiac conduction abnormality
  evidence:
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cardiac involvement, including conduction abnormalities, is also sometimes
      seen"
    explanation: Records cardiac conduction involvement and its intermittent character.

genetic:
- name: GSN
  gene_term:
    preferred_term: GSN
    term:
      id: hgnc:4620
      label: GSN
  relationship_type: CAUSATIVE
  association: >-
    A single copy of the mutant allele is reported to give complete penetrance.
    Heterozygous GSN variants at codon 187 - G654A giving D187N, and G654T giving D187Y -
    cause hereditary gelsolin amyloidosis. Gelsolin is a principal actin-modulating
    protein with roles in axonal transport, myelination, neurite outgrowth and
    neuroprotection, which raises the question of how much of the phenotype is amyloid
    deposition and how much is loss of normal gelsolin function. Three independent lines
    of evidence answer it in favour of gain of toxic function, and the entry curates the
    deposition mechanism accordingly rather than leaving the question open. Gelsolin
    knockout mice develop and live normally, with only a mild bleeding-time and cell-motility
    phenotype attributed to functional redundancy. Human D187N homozygotes have earlier and
    more severe disease - a dose effect on the toxic species, and a qualitative one in the
    kidney, where they develop severe nephrotic syndrome and end-stage renal failure - but
    no symptoms attributable to loss of function. And there is no reported sporadic or wild-type gelsolin
    amyloidosis, so the mutation, not the shortfall of normal protein, is what is required.
    The residual uncertainty is narrower than "which mechanism": it is whether local
    gelsolin dysfunction modulates severity in the affected tissues, not whether it causes
    the disease.
  evidence:
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "FAF appears to be caused by a gain-of-toxic function associated with gelsolin
      fragment amyloidogenesis"
    explanation: >-
      States the gain-of-toxic-function conclusion directly, which is why this entry does
      not curate a competing loss-of-function model.
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "gelsolin knockout mice exhibit a normal development and lifespan, exhibiting
      only a mild prolonged bleeding time phenotype and abnormally slowly migrating
      neutrophils and fibroblasts"
    explanation: >-
      The knockout evidence against a loss-of-function contribution: removing gelsolin
      entirely does not reproduce the disease.
  - reference: PMID:23931809
    reference_title: "Hereditary gelsolin amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is the first and so-far only known disorder caused by a gelsolin gene
      defect, namely a G654A or G654T mutation."
    explanation: Establishes the causal gene-disease relationship and the specific variants.
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "One copy of the mutant allele appears to result in complete penetrance of FAF."
    explanation: >-
      Establishes complete penetrance in heterozygotes, which is why the entry does not
      hedge the genotype-phenotype relationship.
  - reference: PMID:23931809
    reference_title: "Hereditary gelsolin amyloidosis."
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: "Gelsolin is a principal actin-modulating protein, implicated in multiple
      biological processes, also in the nervous system, e.g. axonal transport, myelination,
      neurite outgrowth, and neuroprotection."
    explanation: >-
      Curated as INDIRECT because it establishes gelsolin's normal neural functions without
      demonstrating that their loss contributes to this disease - the open question noted
      in the association text.

animal_models:
- name: D187N transgenic gelsolin mouse (muscle-specific promoter)
  species: Mouse
  genotype: Transgenic human D187N gelsolin, muscle-specific promoter driving synthesis and secretion
  publication: PMID:22360545
  description: >-
    The model that established the proteolytic cascade in vivo. A muscle-specific promoter
    drives synthesis and secretion of human D187N gelsolin, and the animals develop
    aging-associated extracellular amyloid deposition. It reproduces the full mechanistic
    spine curated here - G2 misfolding in the Golgi, furin cleavage to C68, and the
    subsequent step to the 8 and 5 kDa fragments - which is what makes it the stated
    platform for testing agents that prevent either misfolding or cleavage.
  modeled_mechanisms:
  - target: Two-Step Proteolysis Releasing 8 and 5 kDa Amyloidogenic Fragments
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      The mouse reproduces both endoproteolytic steps in the correct compartments, which is
      the specific claim this entry's central node makes.
    limitations: >-
      The transgene is driven by a muscle-specific promoter, so the tissue distribution of
      synthesis is imposed by the construct rather than discovered. That is precisely why
      the model cannot by itself settle the human cornea-nerve-skin tropism question, even
      though it produces the local-synthesis observation that frames it.
    evidence:
    - reference: PMID:22360545
      reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "The mouse model of D187N FAF faithfully recapitulates G2 misfolding in the
        Golgi and the aberrant endoproteolytic cascade"
      explanation: States the recapitulation claim for the proteolytic cascade node directly.
  - target: Systemic AGel Amyloid Deposition
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Extracellular amyloid deposition occurs and is aging-associated as in human disease,
      but only in transgene-expressing tissue, and the mice additionally develop an
      inclusion-body-myositis-like intracellular gelsolin deposition not established in
      patients.
    limitations: >-
      Deposition is confined to tissues synthesising the transgene, so the model does not
      reproduce the human cornea-nerve-skin distribution. The intracellular
      inclusion-body-myositis phenotype is a divergence from human disease of unknown
      significance - the review states it is not yet clear whether patients show it.
    readouts:
    - name: Extracellular amyloid deposition in transgene-expressing tissue
      target: Systemic AGel Amyloid Deposition
      direction: INCREASED
      interpretation: >-
        Age-dependent extracellular deposition, the structural correlate of the human
        deposition node.
      evidence:
      - reference: PMID:22360545
        reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "The mouse model exhibits the aging-associated extracellular amyloid
          deposition of human FAF"
        explanation: Reports the deposition measurement behind this readout.
    evidence:
    - reference: PMID:22360545
      reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "amyloidogenesis is observed only in tissues synthesizing human D187N
        gelsolin, despite the presence of the 68 kDa cleavage product circulating in the
        blood, suggesting that local synthesis is required for amyloid fragment formation
        and/or deposition"
      explanation: >-
        Curated as PARTIAL because it grounds the deposition claim while simultaneously
        showing the distribution differs from human disease.

diagnosis:
- name: Molecular Genetic Testing of GSN
  description: >-
    Sequencing of GSN codon 187. Because the corneal finding usually precedes the
    neurological and dermal features by years, and because the disease is now recognised
    well outside Finland, a lattice corneal dystrophy without an obvious cause is
    reasonable grounds to test.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:23931809
    reference_title: "Hereditary gelsolin amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HGA, originally reported from Finland and now increasingly from other
      countries in Europe, North and South America, and Asia, may still be underdiagnosed
      worldwide."
    explanation: >-
      Supports testing outside the original founder population, since geographic
      assumptions are a known source of missed diagnosis here.

treatments:
- name: Symptomatic and Surgical Management
  description: >-
    No disease-modifying therapy exists. Management is symptomatic - ophthalmic care for
    the corneal disease, and facial corrective surgery for the paralysis, which a
    published series of 29 patients underwent. The cited review is explicit that correct
    diagnosis matters even absent specific therapy, because adequate symptomatic
    treatment substantially improves quality of life. No target_mechanisms link is
    asserted: nothing available acts on any node of the mechanism above.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:23931809
    reference_title: "Hereditary gelsolin amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In HGA, specific therapy is not yet available but correct diagnosis enables
      adequate symptomatic treatment which decisively improves the quality of life in these
      patients."
    explanation: Establishes both the absence of specific therapy and the value of symptomatic care.

- name: Genetic Counseling
  description: >-
    Autosomal dominant counselling with a 50% transmission risk. Relevant across a wide
    and widening geographic range, not only in the Finnish founder population.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling

differential_diagnoses:
- name: Hereditary transthyretin amyloidosis (ATTRv)
  description: >-
    The other classic hereditary systemic amyloidosis, and the only current member of the
    KB's Hereditary_Systemic_Amyloidoses grouping. Both are autosomal dominant systemic
    amyloidoses with peripheral neuropathy, but the amyloidogenic mechanism differs
    fundamentally - ATTR proceeds by tetramer dissociation and misfolding of the intact
    monomer, whereas AGel requires two proteolytic cleavages to manufacture its precursor.
    The therapeutic consequence is a relocation of the stabilisation target, not its
    abolition. A tafamidis-style kinetic stabiliser cannot act on the deposited AGel
    species, because that species is an 8 kDa fragment that does not exist until after the
    protein has been cut. It can act one step earlier: the founding review proposes exactly
    this, a pharmacologic chaperone or kinetic stabiliser binding full-length D187N plasma
    gelsolin in the secretory pathway to hold G2 folded and so prevent the aberrant furin
    cleavage that starts the cascade, and cites the transthyretin programme as the
    precedent. So the two diseases share a drug strategy while differing in where in the
    pathway it has to be applied.
  distinguishing_features:
  - AGel presents with the corneal lattice dystrophy / facial palsy / cutis laxa triad; ATTRv does not
  - ATTRv commonly involves the heart; cardiac involvement is not a cardinal AGel feature
  - >-
    In ATTRv the stabilisation target and the depositing species are the same protein; in
    AGel they are not, so a stabiliser must act on the uncleaved precursor upstream of
    furin rather than on the fragment that deposits
  evidence:
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The resulting C-terminal 68 kDa fragment (C68) is susceptible to
      extracellular endoproteolytic events, possibly mediated by a matrix metalloprotease,
      affording 8 and 5 kDa amyloidogenic fragments of gelsolin."
    explanation: >-
      Establishes that the AGel precursor is a proteolytic fragment, which is the basis of
      the mechanistic distinction from ATTR drawn above.
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "it may be possible to thermodynamically and/or kinetically stabilize the
      second domain of D187N/Y plasma gelsolin in the cellular secretory pathway employing
      a pharmacologic chaperone or a more specialized kinetic stabilizer"
    explanation: >-
      Establishes that the kinetic-stabiliser strategy does have an AGel analogue, applied
      to the uncleaved precursor. Curated explicitly because the naive reading of the
      fragment mechanism - that precursor stabilisation cannot apply at all - is what this
      sentence rules out.

- name: Other causes of lattice corneal dystrophy
  description: >-
    Lattice corneal dystrophy is usually a localised corneal disease from TGFBI variants,
    with no systemic component. Type 2 lattice dystrophy is the AGel form, and treating it
    as an isolated corneal problem is how a systemic amyloidosis gets missed for years.
  distinguishing_features:
  - AGel lattice dystrophy is type 2 and is accompanied, sooner or later, by facial palsy and cutis laxa
  - A family history of adult-onset facial weakness should prompt GSN testing rather than corneal-only workup
  evidence:
  - reference: PMID:26422119
    reference_title: "Progressive cranial nerve involvement and grading of facial paralysis in gelsolin amyloidosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnostic triad includes corneal lattice dystrophy (type 2), progressive
      bilateral facial paralysis, and cutis laxa."
    explanation: Identifies the corneal phenotype specifically as type 2 within a systemic triad.

discussions:
- discussion_id: gap_agel_tissue_tropism
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Systemic AGel Amyloid Deposition
  prompt: >-
    Why does AGel amyloid deposit preferentially in cornea, cranial nerves and skin, when
    the amyloidogenic fragments are generated from a plasma protein and released into the
    circulation?
  rationale: >-
    The disease is defined by a cornea-nerve-skin triad, while the heart, the dominant
    target in both ATTR and AL, is not a cardinal feature - and the precursor is a plasma
    protein whose fragments enter the circulation, so systemic availability alone predicts
    the wrong distribution. There is one leading hypothesis rather than a blank: the D187N
    transgenic mouse deposits amyloid only in tissues that themselves synthesise the mutant
    gelsolin, despite circulating C68 being present throughout, which argues that local
    synthesis rather than circulating precursor governs where deposition happens. What is
    open is whether that generalises to human tissue distribution, since muscle is the
    major source of plasma gelsolin while cornea and cranial nerve are not obviously so.
    Competing explanations remain live: local availability of the second, extracellular
    protease (MT1-MMP and possibly others), tissue-specific extracellular matrix components
    that nucleate these particular fragments, or slow clearance in poorly vascularised
    tissue such as cornea. Which is right matters therapeutically, because a treatment
    aimed at the circulating fragment and one aimed at local synthesis or deposition are
    different drugs.
  evidence:
  - reference: PMID:22360545
    reference_title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "amyloidogenesis is observed only in tissues synthesizing human D187N
      gelsolin, despite the presence of the 68 kDa cleavage product circulating in the
      blood, suggesting that local synthesis is required for amyloid fragment formation
      and/or deposition"
    explanation: >-
      The local-synthesis hypothesis, and the reason this gap is a question about
      generalisation to humans rather than an absence of any candidate mechanism.
  proposed_experiments:
  - experiment_id: exp_agel_protease_tissue_survey
    name: Map local gelsolin synthesis and second-step protease activity against the disease distribution
    description: >-
      Two things need separating. First, quantify local GSN synthesis in cornea, peripheral
      nerve, skin and myocardium in human tissue, to test whether the mouse local-synthesis
      finding accounts for the human triad - the mouse used a muscle-specific promoter, so
      its tissue distribution was imposed by the construct rather than discovered. Second,
      map MT1-MMP activity, and that of other C68-cleaving proteases, across the same
      tissues. The review names MT1-MMP as the second-step protease at least in HT1080
      cells while noting other extracellular proteases may contribute, so a survey has to
      be broader than MT1-MMP alone. If either measure tracks the disease distribution and
      the other does not, tropism is localised to that step.

notes: >-
  No GeneReviews chapter exists for this disease or for GSN. Verified by search: both
  "GSN GeneReviews[All Fields]" and "gelsolin amyloidosis GeneReviews[All Fields]" return
  zero results.

  No frequency bands are assigned to any phenotype, and the founding review supplies the
  general licence: because of the rarity of the disease, "the frequency with which each of
  the described symptoms present is unknown". Two further reasons apply to specific
  phenotypes. The three triad features are described as defining rather than as counted
  proportions. And the largest series cited here is 29 patients selected for having
  undergone facial corrective surgery - an ascertainment that would inflate any
  facial-palsy frequency derived from it, which is why the cohort proportions quoted in
  the Multiple Cranial Neuropathy description are not converted into a band.

  Natural history and mortality, recorded here rather than as evidence because the entry
  has no structured home for it: the primary causes of death reported are nephrotic
  syndrome, aspiration pneumonia from bulbar muscle dysfunction, and cerebral hemorrhage
  attributed to cerebral angiopathy (PMID:22360545). All three are downstream of
  phenotypes curated above, which is the substance behind the description's "slow but
  relentless". The same source notes that no conclusive epidemiological study of mortality
  exists, so the excess over age-matched controls is described as slight and unquantified.

  Grouping context: kb/groupings/Hereditary_Systemic_Amyloidoses.yaml names this disease
  as an intended future member ("AGel/Finnish-type gelsolin amyloidosis (GSN;
  MONDO:0007097)"), currently listing only ATTRv. Adding it to that grouping's members is
  a natural follow-up but is deliberately left to a separate change, so this PR adds an
  entry rather than also editing a grouping it does not otherwise touch.

  Deep-research provenance caveat: the claude_code report for this disease resolved 36/36
  references with confabulation_rate 0.0, but the relevance pass flagged PMID:33375500 as
  off topic and it is cited three times in the report body. It is "Standoff Distance in
  Ultrasonic Pulsating Water Jet" - a genuinely unrelated paper. It is not cited in this
  entry, and its presence is a reason to treat that report's citation list with care
  rather than as a vetted bibliography.

references:
- reference: PMID:22360545
  title: "Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies
    for therapeutic intervention."
- reference: PMID:23931809
  title: Hereditary gelsolin amyloidosis.
- reference: PMID:26422119
  title: Progressive cranial nerve involvement and grading of facial paralysis in gelsolin
    amyloidosis.

📚

References & Deep Research

References

3

PMID:22360545

Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention.

No top-level findings curated for this source.

PMID:23931809

Hereditary gelsolin amyloidosis.

No top-level findings curated for this source.

PMID:26422119

Progressive cranial nerve involvement and grading of facial paralysis in gelsolin amyloidosis.

No top-level findings curated for this source.

Deep Research

1

Claude Code ▸

Finnish Type Amyloidosis (Gelsolin/AGel Amyloidosis) — Comprehensive Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 48 citations 2026-08-21T16:29:49.249368

Finnish Type Amyloidosis (Gelsolin/AGel Amyloidosis) — Comprehensive Research Report

1. Disease Information

Overview. Finnish type amyloidosis — now most often called hereditary gelsolin amyloidosis (AGel amyloidosis), and historically known as Meretoja syndrome or familial amyloidosis, Finnish type (FAF) — is an autosomal dominant systemic amyloidosis caused by variants in the GSN (gelsolin) gene. It is defined clinically by a distinctive triad: progressive lattice corneal dystrophy, cranial (especially facial) neuropathy, and cutis laxa (loose, sagging skin), sometimes with later peripheral neuropathy, cardiac conduction disease, and renal involvement in a minority of patients (OMIM #105120; Orphanet ORPHA:85448). It is one of the founder diseases of the "Finnish disease heritage," first described by the Finnish ophthalmologist Jouko Meretoja in 1969.

Key identifiers: - OMIM disease: #105120 — "Amyloidosis, Finnish type" / Lattice corneal dystrophy type II / FAP IV - OMIM gene: 137350 — GELSOLIN; GSN (chromosome 9q33.2) - Orphanet: ORPHA:85448 (AGel amyloidosis); gene page GSN - MONDO: MONDO:0007097 - HGNC: GSN (HGNC:4620) - ICD-10: E85.4 (Organ-limited amyloidosis) is commonly applied; some coding schemes use E85.8 (Other amyloidosis) - MeSH: "Amyloidosis, Familial" (D000687) with the Finnish-type subheading; corneal component indexed under "Corneal Dystrophies, Hereditary" and lattice type II

Synonyms: Familial amyloidosis, Finnish type (FAF); Familial amyloid polyneuropathy type IV (FAP IV, an older classification alongside TTR-related FAP I–III); Meretoja syndrome; Meretoja disease; AGel amyloidosis; Gelsolin amyloidosis; Lattice corneal dystrophy type II (LCD2); Amyloidosis V.

Data provenance. Information below is derived primarily from aggregated disease-level resources (OMIM, Orphanet, GeneReviews-style literature reviews) and from clinical cohort studies conducted on the Finnish national patient registry — most notably the large Finnish cohort assembled by Kiuru-Enari, Haltia, and colleagues at Helsinki University Hospital, which has followed several hundred genetically confirmed Finnish AGel patients and their causes of death over decades (Kiuru-Enari & Haltia, 2013, PMID:23931809; Schmidt et al. 2016, PMID:27137880; Atula/Kiuru-Enari FIN-GAR 2020, PMID:31952544). Individual case reports (e.g., novel GSN variants in single kindreds) supplement this for genotype-phenotype diversity outside Finland.

2. Etiology

Disease causal factor. AGel amyloidosis is a monogenic, autosomal dominant proteinopathy. Heterozygous (and rarely homozygous) missense variants in GSN — most commonly c.640G>A (p.Asp187Asn / D187N), the "Finnish" variant, historically also written G654A in older cDNA numbering — destabilize the calcium-binding site of gelsolin domain 2 (G2), rendering plasma gelsolin susceptible to aberrant intracellular proteolysis and the generation of amyloidogenic fragments. There is no environmental or infectious cause; the disease is entirely genetically determined, though age is a major modifier of onset and severity, and gene dosage (heterozygous vs. rare homozygous) modifies severity, particularly renal disease.

Genetic risk factors: - Causal variant (Finnish founder): GSN c.640G>A, p.Asp187Asn (D187N). Haplotype analysis of 62 unrelated Finnish AGel families shows they share a common ancestral haplotype, consistent with a single Finnish founder mutation rather than recurrent mutation, despite c.640G being a documented mutational hotspot (Mustonen et al. 2018, PMC5838978; Eur J Hum Genet). Notably, the identical nucleotide substitution (G654A in old numbering) has arisen independently in Japanese families, on a different haplotype background (Paunio et al. 1995, PMID:7550233; Kiuru et al. 2012, PMID:22622774). - Allelic/non-Finnish variants at the same codon: c.640G>T, p.Asp187Tyr (D187Y) — the "Danish" variant, first reported in a Danish family and since found in a Czech family and a Brazilian kindred, with a clinically similar but sometimes distinguishable phenotype (Gorevic et al./Maury 2000, PMID:10767822; Brazilian case series, PMID:22068858). - Novel/rare amyloidogenic variants elsewhere in GSN identified since ~2013 broaden the molecular spectrum beyond codon 187, generally in domain G1 or G2 and producing variably milder or renal-predominant phenotypes: p.Asn184Lys (N184K, renal-predominant; Efebera/Rezvani et al. 2016, PMC5025852), p.Asn211Lys (N211K, nephrotic syndrome/thrombotic microangiopathy kindred; PMID:24601799), p.Gly167Arg, p.Gly180Trp/Ser, p.Tyr447His (associated with autonomic/peripheral neuropathy predominant disease; PMID:37140928), and p.Glu580Lys (PMID:33375500-range, PMC7865823). - Zygosity as a severity modifier: rare homozygous D187N patients (from consanguineous or double-founder matings) have markedly earlier, more severe disease, especially nephrotic-range proteinuria progressing to end-stage renal disease, whereas renal failure is uncommon in heterozygotes. - No known genetic susceptibility/modifier loci beyond GSN itself have been robustly established; the phenotype is highly penetrant.

Environmental/lifestyle risk factors: None established as causal. Ultraviolet/mechanical stress to skin and cornea may exacerbate local manifestations (erosions, skin fragility) but does not cause the underlying amyloidogenesis.

Protective factors: No validated protective genetic or environmental factors are described in the literature. There is no evidence of incomplete penetrance modifiers analogous to APOE in Alzheimer disease or the transthyretin-stabilizing tafamidis mechanism for ATTR amyloidosis.

Gene-environment interaction: Not documented as a mechanistic feature; the disorder behaves as a highly penetrant single-gene disease. Sex is a modifier of clinical course rather than a strict gene-environment interaction (see §9, §11): a Finnish cohort study found gender differences in disease course and complication profile (Kiuru-Enari et al., PMID:26805765).

3. Phenotypes

The disease produces a triad of ophthalmologic, neurologic, and dermatologic manifestations, typically emerging sequentially over decades, plus less common systemic (renal, cardiac) involvement.

Phenotype	Type	Onset	Frequency	Notes / suggested HP term
Lattice corneal dystrophy (bilateral, delicate branching amyloid lattice lines in corneal stroma)	Clinical sign	Usually first manifestation, mean age ~30s–40s	Nearly universal (first and defining sign)	HP:0025336 Lattice corneal dystrophy (or broader HP:0000578 Corneal dystrophy)
Recurrent corneal erosions	Symptom	Following corneal deposits	Frequent	HP:0500089 (or general "corneal erosion")
Progressive visual impairment	Symptom	Progressive from corneal lattice onset	Frequent, variable severity	HP:0000505 Visual impairment
Bilateral facial nerve palsy (cranial neuropathy)	Clinical sign	Onset typically 4th–5th decade, progressive	Very frequent, near-universal in advanced disease	HP:0010628 Facial palsy / HP:0006829 (peripheral facial nerve palsy)
Bulbar signs (dysarthria, dysphagia, masticatory weakness)	Clinical sign	Later disease	Frequent	HP:0002483/HP:0002015 Dysphagia
Cutis laxa / loose, sagging, "hound-dog" facial skin	Clinical sign	Middle age onward	Frequent, characteristic	HP:0000973 Cutis laxa
Dry, itchy, fragile skin	Symptom	Middle age onward	Frequent	HP:0000958 Dry skin
Peripheral (sensorimotor) polyneuropathy	Clinical sign	Later, after cranial neuropathy	Occasional–frequent, milder than cranial component	HP:0009830 Peripheral neuropathy
Autonomic neuropathy (orthostatic hypotension, GI dysmotility)	Clinical sign	Later disease	Occasional, reported particularly with Y447H variant	HP:0001611 (autonomic dysfunction terms)
Carpal tunnel syndrome	Clinical sign	Variable	Reported	HP:0100022
Nephrotic-range proteinuria / progressive CKD	Laboratory / clinical	Later, more common in homozygotes and some non-D187 variants	Uncommon overall in heterozygous FAF, but significant cause of death when present	HP:0000100 Nephrotic syndrome; HP:0012622 Chronic kidney disease
Cardiac conduction abnormalities / arrhythmia	Clinical sign	Later disease	Reported in a subset	HP:0011675 Arrhythmia
"Sad," mask-like facial appearance from combined facial diplegia and cutis laxa	Clinical sign	Advanced disease	Characteristic, frequent	(descriptive; may combine facial palsy + cutis laxa terms)
Xerostomia / dry mouth	Symptom	Variable	Reported	HP:0000217

Onset/course. Mean age of first symptom onset in the large Finnish cohort is ~39 years, with ophthalmologic (corneal) findings almost always first, followed over subsequent decades by cranial neuropathy and cutaneous changes ("Common origin..." cohort description, PMC5838978; Kiuru-Enari & Haltia 2013, PMID:23931809). The disease course is slowly progressive over decades rather than episodic; severity is variable between individuals and between the D187N/D187Y and rarer non-canonical variants.

Quality of life impact. The FIN-GAR phase II natural-history/burden study explicitly measured disease burden in genetically confirmed Finnish AGel patients and found significant impact on quality of life (visual disability, facial disfigurement/social impact from facial diplegia and cutis laxa, and neuropathic symptoms) even though overall survival was not significantly reduced (Atula, Kiuru-Enari et al. 2020, PMID:31952544, Orphanet J Rare Dis). Vision loss from recurrent corneal lattice deposition/erosion and facial diplegia (impairing speech, chewing, and facial expression) are the dominant drivers of quality-of-life burden; dry, sagging skin has psychosocial/cosmetic impact.

4. Genetic / Molecular Information

Causal gene. GSN (gelsolin), HGNC:4620, chromosome 9q33.2, OMIM gene 137350. GSN encodes a calcium-regulated, actin-binding protein with three isoforms (cytoplasmic gelsolin, secreted plasma gelsolin, and a mitochondrial/gelsolin-3 isoform), built from six homologous gelsolin-like domains (G1–G6)* that, in the calcium-free state, pack into a compact globular structure; calcium binding triggers conformational changes exposing actin-severing/capping/nucleating surfaces (GeneCards; Expert Rev Mol Med gelsolin structure review). Plasma gelsolin (the isoform relevant to AGel amyloidosis) circulates extracellularly and participates in actin filament severing/depolymerization, e.g., during tissue injury and inflammation ("actin scavenger system").

Pathogenic variant (primary): - Gene/HGNC: GSN, HGNC:4620 - Variant: c.640G>A (legacy numbering c.654G>A), p.Asp187Asn (D187N) — the Finnish founder variant - Classification (ACMG/ClinVar): Pathogenic; ClinVar entries document D187N and D187Y as pathogenic for "Finnish type amyloidosis" - Variant type: Missense, located in gelsolin domain 2 (G2), within/adjacent to the calcium-binding loop - Allele frequency: Essentially absent from general population reference panels (gnomAD) except as extremely rare private/founder alleles; not a common polymorphism — consistent with a rare, highly penetrant autosomal dominant disease allele. - Origin: Germline (heritable); not somatic. A single ancestral Finnish founder haplotype has been demonstrated across 62 unrelated Finnish families (PMC5838978); the same nucleotide change arose independently in Japan (PMID:7550233). - Functional consequence: The D187N/D187Y substitutions impair Ca²⁺ binding by gelsolin domain G2, destabilizing the domain and rendering it a substrate for furin cleavage in the trans-Golgi network — the first of two sequential proteolytic events (see §6). This is best classified as a destabilizing, gain-of-toxic-function mechanism (aberrant proteolysis → amyloidogenic peptide generation) rather than simple loss of gelsolin's normal actin-regulatory function, although reduced circulating functional gelsolin (an actin-scavenging deficit) may also contribute.

Allelic/non-canonical variants: D187Y (Danish), N184K, N211K, G167R, G180W/S, Y447H, E580K, and other more recently described GSN missense variants (largely in domain G1/G2) — collectively "gelsolin amyloidosis, non-Finnish/non-classic variants" — produce phenotypes ranging from classic FAF-like disease to renal-predominant or peripheral/autonomic-neuropathy–predominant presentations (review: "A molecular perspective of gelsolin amyloidosis," Cell Mol Life Sci, 2026; PMID:37140928).

Modifier genes: None robustly established; zygosity at the GSN locus itself (heterozygous vs. homozygous) is the clearest modifier of severity, particularly for renal disease.

Epigenetic information: No disease-specific epigenetic (DNA methylation/histone) mechanism has been described; the pathogenesis is driven by post-translational proteolytic processing of the mutant protein, not altered gene expression/epigenetic regulation.

Chromosomal abnormalities: None — this is a point-mutation (missense) disorder, not a copy-number or structural chromosomal disease.

5. Environmental Information

AGel amyloidosis is a purely genetic disorder; no environmental toxin, occupational exposure, dietary factor, or infectious agent is causally implicated.

Environmental factors: Not applicable as disease causes. Physical/mechanical trauma to the eye (contact lens wear, ocular surface stress) may precipitate corneal erosions in patients with established lattice deposits, but does not initiate the amyloidogenic process.
Lifestyle factors: No specific lifestyle risk-modifying factor (smoking, diet, alcohol, exercise) has been studied or implicated for onset or progression in the literature identified.
Infectious agents: Not applicable — non-infectious, non-communicable.

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

Germline missense variant in GSN domain G2 (classically D187N/D187Y) destabilizes the domain's calcium-binding loop.
In the wild-type protein, Ca²⁺ binding stabilizes gelsolin domain G2 against unfolding and proteolysis; the FAF variant proteins are unable to bind/be stabilized by Ca²⁺ in the trans-Golgi network as the nascent protein transits the secretory pathway (Chen, Wei, Robinson 2001, "Furin initiates gelsolin familial amyloidosis in the Golgi through a defect in Ca²⁺ stabilization," PMID:11707399; Kazmirski/Robinson 2003, PMID:14596804).
This local unfolding exposes a cryptic cleavage site to furin (a proprotein convertase resident in the trans-Golgi network), producing an initial intracellular furin cleavage event.
The resulting furin-cleaved fragment, once secreted, undergoes a second, extracellular proteolytic event mediated by MT1-MMP (membrane-type 1 matrix metalloproteinase)-like activity, generating intrinsically disordered, aggregation-prone amyloidogenic peptides of ~8 kDa and ~5 kDa spanning the "gelsolin amyloidogenic core" around residues 173–243 (containing residues 182–192), historically termed the "C-fragment"/AGel peptide.
These peptides misfold into cross-β amyloid fibrils which deposit extracellularly, especially in blood vessels and basement membranes, and are demonstrable immunohistochemically with anti-gelsolin antibodies in the cornea, skin, peripheral/cranial nerve, kidney, heart, thyroid, salivary gland, and rectum (immunohistochemistry review, PMID:1315488; PMC7865823).
Amyloid deposition in the corneal stroma produces the lattice dystrophy pattern via subepithelial/stromal fibril accumulation and recurrent breakdown of corneal nerve and epithelial integrity (recurrent erosions). Deposition around and within cranial (especially facial) nerve fascicles and perineurium produces progressive cranial neuropathy/facial diplegia and bulbar signs. Deposition in the dermis (vessel walls and around adnexal/elastic structures) disrupts normal dermal architecture producing cutis laxa and skin fragility. In a minority of patients (more so with homozygosity or certain non-D187 variants), deposition in glomerular capillary walls and mesangium produces nephrotic-range proteinuria and progressive CKD (Mayo Clinic renal AGel series, PMID:28139293).
A separate, downstream, age-associated intracellular consequence demonstrated in a D187N transgenic mouse model is progressive compromise of cellular proteostasis: secretion of amyloidogenic gelsolin appears to exacerbate age-related decline in protein homeostasis, with intracellular co-aggregation of other proteins in skeletal muscle rough endoplasmic reticulum, resembling sporadic inclusion body myositis pathology (PNAS 2009, PMID/PMC via "Secretion of amyloidogenic gelsolin progressively compromises protein homeostasis..."; PMC4461228).

Upstream vs. downstream: The rate-limiting, disease-initiating event is the Ca²⁺-binding defect → furin cleavage step (intracellular, Golgi); this is upstream of the MT1-MMP extracellular cleavage step, which is itself upstream of fibril nucleation/aggregation and finally tissue-specific amyloid deposition and organ dysfunction.

Cell types and biological processes involved: - Hepatocytes (primary site of plasma gelsolin synthesis/secretion) — trans-Golgi processing defect - Corneal keratocytes/stromal fibroblasts and corneal epithelium — site of lattice deposit accumulation - Schwann cells and perineurial cells of cranial/peripheral nerves — amyloid deposition around nerve fascicles - Dermal fibroblasts, vascular endothelium, and elastic fiber–associated cells of skin — cutis laxa pathogenesis - Glomerular endothelial cells, mesangial cells, and podocytes — renal amyloid deposition - Vascular smooth muscle/endothelium generally, since amyloid preferentially deposits in vessel walls and basement membranes throughout the body

Suggested GO terms: GO:0003779 (actin binding), GO:0005509 (calcium ion binding), GO:0051015 (actin filament binding), GO:0030036 (actin cytoskeleton organization), GO:0006508 (proteolysis), GO:0034205 (amyloid-beta formation — generic amyloid fibril formation analog term may be better represented by a protein-misfolding/amyloid fibril formation GO term if available), GO:0043687 (post-translational protein modification). Suggested CL terms: CL:0000186 (myofibroblast) or CL:0002620 (skin fibroblast) for dermal involvement; CL:0002573 (Schwann cell) for cranial/peripheral nerve; CL:0000653 (podocyte) and CL:0000650 (mesangial cell) for renal involvement; CL:0000312 (keratocyte) for corneal stroma.

Protein dysfunction: Classic protein misfolding/aggregation disorder — the pathogenic mechanism is aberrant proteolytic processing exposing an amyloidogenic peptide core, i.e., gain-of-toxic-function via generation of an aggregation-prone fragment, distinct from simple loss-of-function of full-length gelsolin's actin-regulatory role (though reduced normal plasma gelsolin function may compound tissue vulnerability to actin-mediated injury).

Molecular profiling / omics: No large-scale transcriptomic, proteomic, or single-cell atlas specific to AGel amyloidosis was identified in this search; most molecular characterization comes from targeted biochemical/structural studies (recombinant domain constructs, X-ray crystallography of gelsolin domains, and mass spectrometry-based amyloid typing on renal/tissue biopsies, which is now the standard method to confirm gelsolin as the amyloid precursor in atypical/renal presentations, e.g. PMID:28139293).

7. Anatomical Structures Affected

Organ level: - Primary: Eye (cornea), peripheral/cranial nervous system (especially facial nerve, also trigeminal and other cranial nerves; later peripheral nerves), skin - Secondary/systemic (minority of patients): Kidney (glomeruli), heart (conduction system), and, per immunohistochemical surveys, amyloid deposits are also demonstrable in thyroid, salivary gland, and rectal mucosa without necessarily causing overt organ failure at those sites. - Body systems involved: Ophthalmologic, peripheral/cranial nervous system, integumentary (dermatologic), and — in a minority — renal and cardiovascular systems.

Tissue/cell level: - Corneal stroma (amyloid lattice lines), corneal epithelium (recurrent erosion) - Peripheral nerve/cranial nerve perineurium and endoneurium; facial nerve fascicles specifically - Dermis: vessel walls, perivascular and periadnexal connective tissue, elastic fibers (cutis laxa) - Renal glomeruli: mesangium and capillary walls (light-microscopic Congo red–positive deposits largely confined to glomeruli, rarely extending to interstitium/vessel walls) - Vascular smooth muscle/basement membranes broadly (amyloid has a systemic tropism for vasculature and basement membranes)

Subcellular level: The disease-initiating proteolytic event occurs in the trans-Golgi network (furin cleavage) of gelsolin-secreting cells (notably hepatocytes), followed by an extracellular/plasma membrane–associated MT1-MMP cleavage step. Suggested GO Cellular Component terms: GO:0005802 (trans-Golgi network), GO:0005576 (extracellular region), GO:0005886 (plasma membrane, site of MT1-MMP activity).

Localization/laterality: Ocular and facial nerve/skin involvement is characteristically bilateral and roughly symmetric (bilateral lattice corneal dystrophy, bilateral facial diplegia), consistent with a systemic circulating-precursor amyloidosis rather than a focal/unilateral process.

Suggested UBERON terms: UBERON:0000965 (cornea), UBERON:0001528 (facial nerve; or the broader UBERON:0001780 cranial nerve), UBERON:0002097 (skin of body), UBERON:0002113 (kidney), UBERON:0002330 (exocrine gland).

8. Temporal Development

Onset: Adult-onset disease; mean age of first (ophthalmologic) symptom onset is ~39 years in the Finnish cohort (PMC5838978). Corneal lattice dystrophy is typically the presenting sign, diagnosed by an ophthalmologist, often before systemic disease is suspected. Onset pattern is insidious/gradual, not acute.

Progression: The disease follows a chronic, slowly progressive course over decades: 1. Early stage — corneal lattice dystrophy with recurrent erosions, still-preserved vision 2. Intermediate stage — emerging cranial neuropathy (facial nerve palsy, bulbar signs), progressive corneal opacification/visual loss, developing cutis laxa 3. Advanced stage — established facial diplegia, marked skin laxity/fragility, peripheral neuropathy, and, in a subset, renal impairment/nephrotic syndrome or cardiac conduction disease

Progression rate is slow relative to many other systemic amyloidoses (e.g., AL amyloidosis); the disease is compatible with a near-normal lifespan in most patients (see §11).

Patterns: No spontaneous remission is described — this is a genetically determined, progressive protein-deposition disease. There is no known "critical window" for intervention analogous to newborn screening/early enzyme-replacement diseases, since no disease-modifying therapy currently exists (see §12); the practical "critical period" is early recognition (via corneal lattice dystrophy) to enable proactive symptomatic management and genetic counseling before major cranial neuropathy/renal disease develops.

9. Inheritance and Population

Epidemiology. - Estimated 600–1,000 affected individuals in Finland, making it one of the most prevalent components of the "Finnish disease heritage" (a set of ~40 rare monogenic diseases enriched in Finland due to population bottleneck/founder effects). - Prevalence of the causal mutation is higher in Finland than anywhere else in the world, though individual patients/kindreds have been reported globally (Japan, Denmark, Czech Republic, USA, Brazil, and other countries) via independent mutational origin (Japan) or apparent descendant/isolated founder events (Danish D187Y lineage). - No formal global incidence/prevalence-per-100,000 figure outside Finland was identified in this search; the disease is considered ultra-rare worldwide outside the Finnish founder population.

Inheritance pattern: Autosomal dominant. Rare homozygous cases (from unions of two heterozygous carriers, more plausible in a founder population with elevated carrier frequency) produce a more severe phenotype, particularly renal.

Penetrance: Effectively complete/high penetrance for the classic D187N Finnish variant — essentially all carriers develop at least corneal lattice dystrophy by mid-adulthood, though severity and rate of progression of neurologic/dermatologic/renal manifestations are variable (variable expressivity).

Genetic anticipation: Not reported as a feature of this disease (it is a simple missense point mutation, not a repeat-expansion disorder).

Germline mosaicism: Not specifically documented in the literature reviewed.

Founder effect: Strongly established. Haplotype analysis of 62 unrelated Finnish AGel families demonstrates a shared ancestral haplotype around the GSN c.640G locus, consistent with a single common Finnish founder for the D187N mutation, distinct from the haplotype background on which the identical nucleotide change arose independently in Japanese families (PMC5838978; PMID:7550233).

Consanguinity: Relevant to the rare homozygous cases, which arise more readily in the genetically isolated Finnish founder population where carrier frequency is elevated.

Carrier frequency: Not given as a precise population allele frequency in the sources reviewed, but consistent with several hundred to ~1,000 clinically affected heterozygotes concentrated in Finland.

Population demographics: - Geographic distribution: Endemic in Finland; scattered case reports/kindreds elsewhere (Japan — independent founder; Denmark, Czech Republic, Brazil — D187Y lineage; USA — reported American kindred with D187N, PMID cosegregation study, PMC1683143). - Sex ratio: Autosomal — no inherent sex-linked transmission bias, but the Finnish cohort demonstrates gender differences in clinical course (renal complications overrepresented as immediate cause of death in female patients; overall mean lifespan differs modestly by sex within the disease cohort — 73.9 years for men vs. 78.0 years for women — figures that track general-population sex differences in Finland (72.1/80.1 years) (Kiuru-Enari et al., PMID:26805765; Schmidt et al. 2016, PMID:27137880). - Age distribution: Adult disease; symptoms emerge from the third/fourth decade onward and progress through late life.

10. Diagnostics

Clinical tests: - Slit-lamp ophthalmologic examination — visualization of the characteristic bilateral lattice corneal dystrophy pattern (fine branching refractile lines in the corneal stroma), frequently the initial diagnostic clue, especially when it presents atypically (mid-peripheral, adult-onset, negative family history) — a pattern that should prompt exclusion of TGFBI (LCD type I) mutations and consideration of systemic/paraprotein-associated amyloidosis. - Skin/nerve/renal biopsy with Congo red staining — amyloid deposits show classic apple-green birefringence under polarized light; immunohistochemistry with anti-gelsolin antiserum can localize gelsolin-derived amyloid in cornea, skin, kidney, heart, thyroid, salivary gland, and rectum. - Mass spectrometry-based proteomic typing of amyloid deposits (laser microdissection + tandem MS) — now the reference method, especially for atypical/renal presentations, to confirm gelsolin (rather than AL/ATTR/AA) as the amyloid precursor protein (Mayo Clinic renal series, PMID:28139293). - Electrophysiologic studies (facial nerve conduction studies, EMG/nerve conduction studies for peripheral neuropathy) to characterize cranial/peripheral neuropathy. - Urinalysis / 24-hour proteinuria and renal function panel — to screen for nephrotic-range proteinuria/CKD, particularly in homozygotes or those with a family history of renal disease. - ECG/Holter monitoring — for cardiac conduction abnormalities in a subset of patients.

Genetic testing: The definitive diagnostic test is targeted GSN gene sequencing (single-gene Sanger sequencing of the relevant exon(s), or inclusion of GSN on a corneal-dystrophy/hereditary-amyloidosis/peripheral-neuropathy gene panel, or as an incidental/confirmatory finding on whole-exome/whole-genome sequencing) to identify the D187N (or other pathogenic) variant. Because the Finnish founder variant is well characterized, targeted single-variant testing is efficient and cost-effective in patients of Finnish ancestry with the classic triad; broader panel/WES testing is more appropriate for atypical presentations (e.g., isolated nephrotic syndrome, non-Finnish ancestry) where a novel GSN variant or an entirely different amyloidosis (AL, ATTR) must be distinguished.

Differential diagnosis: - Lattice corneal dystrophy type I (and related TGFBI/keratoepithelin-associated corneal dystrophies, OMIM #122200) — distinguished by earlier onset, no systemic amyloidosis, and a TGFBI rather than GSN mutation. - Acquired/paraprotein-associated (AL) corneal or systemic amyloidosis — atypical adult-onset lattice dystrophy with negative TGFBI and GSN testing should prompt evaluation for a plasma cell dyscrasia (serum/urine immunofixation, free light chains) given case reports of heavy-chain/AL amyloidosis mimicking lattice dystrophy (PMID:21743312). - Other hereditary neuropathies with facial diplegia (e.g., Möbius syndrome, myotonic dystrophy) — distinguished by the corneal and dermatologic findings and by molecular testing. - Cutis laxa syndromes of other genetic causes (e.g., ELN, FBLN5, ATP6V0A2-related cutis laxa) — distinguished by the absence of corneal/neurologic amyloid triad and by GSN sequencing. - Other hereditary systemic amyloidoses (ATTR, AApoAI, AFib) — distinguished by tissue amyloid typing (mass spectrometry or genetic testing) and by the distinctive corneal/facial phenotype of AGel amyloidosis, which is not typical of ATTR/AApoAI.

Screening: No population newborn-screening program exists (adult-onset disease). Cascade genetic testing/predictive testing of at-risk relatives in known Finnish families is the practical screening approach, paired with genetic counseling given full penetrance and autosomal dominant transmission.

11. Outcome / Prognosis

Survival and mortality. In contrast to many systemic amyloidoses, AGel amyloidosis is characterized by a near-normal, or only mildly reduced, lifespan. In a study of 272 deceased Finnish AGel patients: - Mean lifespan was 73.9 years for men and 78.0 years for women, compared with 72.1 and 80.1 years, respectively, for the age- and sex-matched general Finnish population — i.e., the disease did not substantially shorten lifespan, at least through age 75 (Schmidt et al. 2016, "Causes of death and life span in Finnish gelsolin amyloidosis," PMID:27137880). - AGel amyloidosis was the underlying cause of death in ~20% of patients. - Renal complications were overrepresented as the immediate cause of death in female patients. - Notably, the frequency of fatal cancers was significantly reduced (only ~10%) compared with the general population — a striking finding whose mechanism is not established but may partly explain the near-normal overall survival despite systemic amyloid burden. - Severe renal and cardiac manifestations are comparatively rare relative to other systemic amyloidoses (e.g., AL, ATTR), which likely explains preserved lifespan.

Morbidity/function. Despite preserved survival, the FIN-GAR phase II study documented significant disease burden and reduced quality of life attributable to progressive visual impairment (recurrent corneal amyloid/erosions), facial diplegia (functional and cosmetic/social impact — difficulty with speech, chewing, eye closure), cutaneous fragility/cosmetic change, and neuropathic symptoms (PMID:31952544).

Complications: Recurrent corneal erosions and progressive corneal opacification (sometimes requiring keratoplasty, with risk of amyloid recurrence in the graft); facial nerve palsy leading to exposure keratopathy (compounding the corneal disease), dysarthria/dysphagia; skin fragility/laxity; in a minority, nephrotic syndrome progressing to end-stage renal disease (more common/severe in homozygotes and select non-D187 variants); cardiac conduction disease in a subset.

Prognostic factors: Homozygosity for the pathogenic GSN variant confers a substantially worse renal prognosis than heterozygosity. Female sex is associated with higher risk of fatal renal complications in the Finnish cohort. Specific non-Finnish GSN variants (e.g., N184K, N211K) are associated with a renal-predominant phenotype and comparatively less prominent classic corneal/cranial-nerve disease, altering the prognostic picture toward CKD/ESRD risk.

12. Treatment

No disease-modifying or curative therapy currently exists. Management is entirely symptomatic/supportive, and correct diagnosis is emphasized in the literature as decisively improving quality of life by enabling proactive, targeted symptom management (Kiuru-Enari & Haltia 2013, PMID:23931809).

Ophthalmologic management: - Lubricating/protective ointments, e.g., vitamin A and panthenol-containing ointment, used prophylactically and therapeutically for recurrent corneal erosions (NCIT term candidate: NCIT:C61027 Ophthalmic Lubricant, or generic Pharmacotherapy NCIT:C15986 with therapeutic_agent retinol/panthenol if precise CHEBI/NCIT codes are curated). - Corneal transplantation (penetrating or lamellar keratoplasty) for advanced corneal opacification — "inevitable" in many patients with established amyloid deposits, per the literature, but prognosis for graft longevity is limited by recurrent amyloid deposition in the graft, so timing and patient counseling are important; optic neuropathy should be excluded before keratoplasty is undertaken, as it may limit visual benefit. Suggested NCIT term: NCIT:C15398/keratoplasty-type procedure, or generic Surgical Procedure NCIT:C15329. - Management of facial nerve palsy-related exposure keratopathy (lid taping, moisture chamber goggles, tarsorrhaphy in severe cases) to protect the ocular surface, given the compounding effect of both corneal amyloid and impaired blink/lid closure.

Neurologic/facial nerve management: - Supportive management of facial diplegia — no specific pharmacotherapy reverses the neuropathy; physical/speech therapy (NCIT:C15302 Physical Therapy; NCIT:C159273 Speech Therapy) may help with functional adaptation. - Management of peripheral neuropathic symptoms with standard neuropathic pain approaches as needed (symptomatic pharmacotherapy, NCIT:C15986).

Dermatologic management: Supportive skin care (emollients) for dry, fragile skin; no specific therapy reverses cutis laxa.

Renal management (for the subset with nephrotic syndrome/CKD): Standard nephrology supportive care for proteinuria/CKD (e.g., renin-angiotensin system blockade for proteinuria reduction, standard CKD management); progression to end-stage renal disease may require renal replacement therapy or transplantation in severe (typically homozygous) cases, analogous to management of other hereditary renal amyloidoses. Suggested NCIT term: NCIT:C15289 Organ Transplantation for renal transplant in ESRD cases.

Genetic counseling: An essential component of management given autosomal dominant inheritance and full penetrance — NCIT:C15240 Genetic Counseling.

Experimental/investigational therapies: No AGel-amyloidosis–specific disease-modifying agent (e.g., stabilizer, antisense oligonucleotide, or antibody therapy analogous to tafamidis/patisiran for ATTR amyloidosis) has reached clinical trials, per this search. Preclinical research directions identified include: - Peptidomimetic and small-molecule inhibitors of gelsolin amyloid aggregation — rationally designed to block fibril formation from the AGel amyloidogenic core (PMC9698219). - Epitope-specific antibody fragments that block aggregation of the AGel D187N-derived amyloidogenic peptide in vitro (PMC11298591). - ER-directed gelsolin nanobody targeting the first (furin-cleavage-permissive misfolding) step of amyloid formation, tested in the D187N transgenic mouse model (Human Molecular Genetics, PMID/PMC via academic.oup.com/hmg).

These remain preclinical (in vitro/mouse model) and are not yet in human clinical trials as of this search; no ClinicalTrials.gov-registered interventional trial specific to gelsolin/AGel amyloidosis was identified (searches for doxycycline/antisense/chaperone trials returned only AL- and ATTR-amyloidosis trials, not AGel-specific studies).

13. Prevention

Primary prevention: Not applicable in the classic sense (monogenic disease with full penetrance); the only "primary prevention" avenue is reproductive genetic counseling and prenatal/preimplantation genetic testing for at-risk families who wish to avoid transmission, though this is not documented as widely practiced for this comparatively benign-course disease.
Secondary prevention (early detection): Cascade genetic testing of at-risk relatives in known Finnish (or other) AGel families, and ophthalmologic screening (slit-lamp exam) in at-risk individuals, to enable early recognition of corneal lattice dystrophy before advanced neurologic/dermatologic/renal disease develops, allowing earlier initiation of protective ocular measures and monitoring for renal involvement (periodic urinalysis).
Tertiary prevention: Proactive lubrication/protective ointment regimens to reduce corneal erosion frequency; lid protection strategies once facial nerve palsy develops (to prevent exposure keratopathy compounding corneal disease); periodic renal function/proteinuria monitoring, especially in homozygotes, to catch nephropathy early and initiate standard CKD-slowing therapy.
Genetic counseling is the central "prevention" intervention documented in the literature, given autosomal dominant, fully penetrant inheritance.
No vaccine, chemoprophylaxis, or public-health/environmental intervention is applicable, as this is a purely genetic, non-communicable, non-environmentally-triggered disease.

14. Other Species / Natural Disease

No naturally occurring animal disease orthologous to human AGel amyloidosis was identified in this search (i.e., no reported spontaneous veterinary gelsolin amyloidosis in companion animals or wildlife, unlike some other hereditary amyloidoses with veterinary counterparts). Gelsolin (GSN) itself is highly conserved across mammals (mouse Gsn ortholog on chromosome 2), and the protein's actin-regulatory function is evolutionarily conserved, but disease modeling has been achieved exclusively through engineered (transgenic/knock-in) rather than natural animal models (see §15).

15. Model Organisms

Genetically engineered mouse models: - D187N transgenic mice (human D187N gelsolin expressed under a muscle-specific promoter) — the principal disease model, which recapitulates the aberrant furin/MT1-MMP proteolytic cascade generating the 8-kDa and 5-kDa amyloidogenic gelsolin peptides seen in human FAF patients, and shows age-associated extracellular amyloid deposition. Homozygous D187N mice show progressive loss of muscle strength, and the model additionally reveals age-associated intracellular protein-homeostasis failure (co-aggregation of multiple proteins in rough ER of skeletal muscle), producing a phenotype resembling sporadic inclusion body myositis pathology (PNAS 2009; PMC4461228). This model has been used as a preclinical platform to test candidate therapeutics, e.g., the ER-directed anti-gelsolin nanobody described above (HMG 2015). - Gelsolin-null (Gsn knockout) mice — a distinct model used to probe normal gelsolin function rather than amyloidosis per se. These mice have normal embryonic development and longevity, but show decreased platelet shape change and prolonged bleeding times, reflecting gelsolin's normal role in actin dynamics; this model does not itself produce an amyloid phenotype and is primarily informative about gelsolin's physiological (non-amyloidogenic) function rather than disease mechanism.

Model characteristics/limitations: The D187N transgenic model recapitulates the core biochemical cascade (furin/MT1-MMP-dependent generation of amyloidogenic fragments) and downstream proteostasis failure, but is a muscle-restricted, overexpression-driven model rather than a knock-in recapitulating physiological tissue-specific expression and the classic corneal/cranial-nerve/skin triad seen in humans — i.e., it captures molecular/cellular pathogenesis well but does not fully reproduce the human clinical organotropism (cornea, facial nerve, skin) that defines the clinical syndrome. No knock-in mouse model precisely reproducing the human ocular/cranial-nerve/dermatologic phenotype was identified in this search.

Applications: The D187N transgenic model has been used to study (a) the proteolytic amyloidogenesis cascade, (b) age-dependent progressive muscle/tissue pathology, (c) links between amyloid gelsolin secretion and broader age-related proteostasis collapse, and (d) preclinical testing of aggregation-blocking biologics (nanobodies) and small molecules.

Summary Table of Suggested Ontology Terms for KB Curation

Category	Term
Disease	MONDO:0007097; OMIM:105120; ORPHA:85448
Causal gene	GSN, HGNC:4620 (hgnc:4620), OMIM:137350
Key phenotypes (HP)	Lattice corneal dystrophy; Facial palsy; Cutis laxa; Peripheral neuropathy; Nephrotic syndrome; Dry skin; Dysphagia — verify exact HP IDs/labels with OAK before curation per house style
Key GO processes	actin binding (GO:0003779); calcium ion binding (GO:0005509); proteolysis (GO:0006508); actin filament binding (GO:0051015)
Key CL terms	Schwann cell (CL:0002573); podocyte (CL:0000653); mesangial cell (CL:0000650); keratocyte (CL:0000312)
Key UBERON terms	cornea (UBERON:0000965); facial nerve/cranial nerve (UBERON:0001528/0001780); skin of body (UBERON:0002097); kidney (UBERON:0002113)
Treatments (NCIT)	Pharmacotherapy (NCIT:C15986, e.g., lubricant ointment); Surgical Procedure/Keratoplasty (NCIT:C15329); Physical Therapy (NCIT:C15302); Genetic Counseling (NCIT:C15240); Organ Transplantation (NCIT:C15289, renal transplant in ESRD)

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome	Count
References checked	36
Resolved	36
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	36
On topic	25
Off topic	1

References that may not be about this subject

These identifiers resolve, so they are not fabrications, but the records they resolve to share almost none of this report's vocabulary. That is a clue and not a verdict - a paper can be relevant in ways its title and abstract do not spell out - so read them before deciding:

PMID:33375500 (1 mention) - Standoff Distance in Ultrasonic Pulsating Water Jet.
shared terms: none

Weighed against this report's own most characteristic terms: disease, amyloidosis, corneal, renal, agel, gelsolin, patient, finnish, facial, gsn, lattice, skin, peripheral, nerve, dystrophy, amyloid, variant, syndrome, d187n, genetic.

All extracted references resolved successfully. Resolving is not the same as being relevant, though - see the references listed above as possibly off topic.

Finnish Type Amyloidosis

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Finnish Type Amyloidosis (Gelsolin/AGel Amyloidosis) — Comprehensive Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic / Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome / Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary Table of Suggested Ontology Terms for KB Curation

Sources

Reference Validation

References that may not be about this subject