👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

Autosomal recessive inheritance

Show evidence (3 references)

PMID:20301737 SUPPORT Human Clinical

"HCC is inherited in an autosomal recessive manner."

GeneReviews states the recessive mode of inheritance.

PMID:16951682 SUPPORT Human Clinical

"We describe a new autosomal recessive white matter disorder ('hypomyelination and congenital cataract') characterized by hypomyelination of the central and peripheral nervous system, progressive neurological impairment and congenital cataract."

The original description of the disorder as autosomal recessive.

PMID:20301737 SUPPORT Human Clinical

"If both parents are known to be heterozygous for a HYCC1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."

GeneReviews recurrence risks for siblings.

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Pathophysiology

7

Biallelic HYCC1 Loss-of-Function Variants

Biallelic splice-site (the recurrent IVS5+1G>T), frameshift, deletion and missense variants in HYCC1 cause complete or severe hyccin deficiency. Truncating and splice alleles give the full phenotype with peripheral neuropathy; missense alleles such as p.Leu53Pro leave some protein and a milder course.

Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION

Downstream

Destabilised Plasma-Membrane PI4KIIIalpha Complex

Misfolded Hyccin Accumulation in the Endoplasmic Reticulum

Show evidence (3 references)

PMID:16951682 SUPPORT Human Clinical

"We identified mutations in five affected families, resulting in a deficiency of hyccin, a newly identified 521-amino acid membrane protein."

Identifies hyccin deficiency as the cause in the first five families.

PMID:23998934 SUPPORT Human Clinical

"A residual amount of hyccin protein in primary fibroblasts was demonstrated by functional studies indicating that missense mutations are likely to have less detrimental effects if compared with splice-site mutations or deletions that cause the full-blown HCC phenotype, including peripheral..."

Genotype-phenotype relationship between missense and null alleles.

PMID:42382508 SUPPORT Human Clinical

"WES identified a novel homozygous mutation (NM_032581: c.636_639del p.C213Dfs*7) in the FAM126A gene."

A homozygous frameshift allele in an Iranian family.

Misfolded Hyccin Accumulation in the Endoplasmic Reticulum

The missense hyccin p.Leu53Pro aggregates in the endoplasmic reticulum and activates unfolded-protein-response kinases in cultured cells. This is a proposed additional toxic mechanism for some missense alleles, not a demonstrated cause of the human phenotype.

endoplasmic reticulum unfolded protein response GO:0030968 ↑ INCREASED

Show evidence (2 references)

PMID:24417797 SUPPORT In Vitro

"Here, we show that the L53P mutant aggregates in cells, accumulating primarily in the ER."

Aggregation of the missense protein in the ER.

PMID:24417797 SUPPORT In Vitro

"In addition, the L53P mutant expression promotes the activities of kinases involved in unfolded protein response."

UPR activation by the missense protein.

Destabilised Plasma-Membrane PI4KIIIalpha Complex

Hyccin is an intrinsic component of the plasma-membrane phosphatidylinositol 4-kinase complex with PI4KIIIalpha, TTC7 and EFR3, binding TTC7 through a large interface. Its absence lowers the levels of the other subunits and so of plasma-membrane PI4-kinase activity. Hyccin itself has no catalytic activity (GO annotates it only with protein binding), so the gene is placed on this node, whose molecular function is the activity of the complex it stabilises.

HYCC1 (FAM126A) hgnc:24587

1-phosphatidylinositol 4-kinase activity GO:0004430 ↓ DECREASED

Animal models

Drosophila glial Hyccin knockdown Drosophila melanogaster recapitulates Hyccin is required for expression of the other complex components in fly glia.

Downstream

Reduced Plasma-Membrane PtdIns(4)P Synthesis

Show evidence (2 references)

PMID:26571211 SUPPORT In Vitro

"FAM126A is an intrinsic component of the plasma membrane phosphatidylinositol 4-kinase complex that comprises PI4KIIIα and its adaptors TTC7 and EFR3 (refs 5,7)."

Places hyccin in the PI4KIIIalpha complex.

PMID:34894559 SUPPORT Model Organism

"This study shows Hyccin/FAM126A expression was necessary for the expression of other components of the PI4KIIIα complex in Drosophila."

In flies, hyccin is required for the other complex components to be expressed.

Reduced Plasma-Membrane PtdIns(4)P Synthesis

Less PtdIns(4)P, a determinant of plasma-membrane identity and the precursor of PtdIns(4,5)P2, is made at the plasma membrane. The proposed pathogenic site is the oligodendrocyte, whose myelinating function requires massive plasma-membrane expansion; this cell-type link is proposed from the protein's expression pattern and the fly model rather than measured in human oligodendrocytes.

oligodendrocyte CL:0000128

phosphatidylinositol 4-phosphate biosynthetic process GO:0180048 ↓ DECREASED

Downstream

CNS and PNS Hypomyelination

Show evidence (1 reference)

PMID:26571211 SUPPORT In Vitro

"We propose that HCC pathogenesis involves defects in PtdIns(4)P production in oligodendrocytes, whose specialized function requires massive plasma membrane expansion and thus generation of PtdIns(4)P and downstream phosphoinositides."

States the oligodendrocyte PtdIns(4)P hypothesis.

CNS and PNS Hypomyelination

Myelin is never adequately laid down in the central nervous system, and peripheral nerves show reduced myelinated-fibre density with thin or absent myelin sheaths. MRI shows diffuse supratentorial hypomyelination, often deep cerebellar white-matter hypomyelination, increased periventricular white-matter water content and brainstem pyramidal tract involvement; older patients add white-matter loss and gliosis.

oligodendrocyte CL:0000128 Schwann cell CL:0002573

central nervous system myelination GO:0022010 ↓ DECREASED

Animal models

Drosophila glial Hyccin knockdown Drosophila melanogaster partially recapitulates Glial axonal sheaths are disrupted.

Downstream

CNS hypomyelination

Peripheral demyelinating neuropathy

Lower limb weakness and wasting

Truncal hypotonia

Motor regression

Spasticity

Cerebellar ataxia

Intellectual disability

Global developmental delay

Dysarthria

Intention tremor

Seizures

Periventricular white matter abnormality

Secondary White-Matter Loss and Gliosis

Show evidence (3 references)

PMID:17974614 SUPPORT Human Clinical

"Supratentorial white matter hypomyelination was detected in all patients; 7 patients also had evidence of variably extensive areas of increased white matter water content."

Hypomyelination on MRI in every patient of a ten-patient series.

PMID:17683097 SUPPORT Human Clinical

"Sural nerve biopsy showed a slight-to-severe reduction in myelinated fiber density, with several axons surrounded by a thin myelin sheath or devoid of myelin."

Peripheral nerve hypomyelination on biopsy.

PMID:16951682 SUPPORT Human Clinical

"Our study highlights the essential role of hyccin in central and peripheral myelination."

Links hyccin deficiency to central and peripheral myelination.

Secondary White-Matter Loss and Gliosis

Older patients show white-matter bulk loss and gliosis on MRI, a secondary neurodegenerative change superimposed on the primary myelin deficiency.

Downstream

Cerebral white matter atrophy

Show evidence (2 references)

PMID:17974614 SUPPORT Human Clinical

"HCC is characterized by a combined pattern of primary myelin deficiency and secondary neurodegenerative changes."

Describes secondary neurodegeneration on top of primary hypomyelination.

PMID:17974614 SUPPORT Human Clinical

"Older patients had evidence of white matter bulk loss and gliosis."

White-matter loss and gliosis in older patients.

Lens Opacification

Bilateral congenital cataract is the feature that distinguishes this leukodystrophy from its relatives. How hyccin loss affects the lens has not been studied, so this node is not linked upstream.

Downstream

Congenital cataract

Show evidence (1 reference)

PMID:17683097 SUPPORT Human Clinical

"Hypomyelination and congenital cataract is a novel autosomal recessive white matter disorder characterized by the unique association of congenital cataract and hypomyelination of the central and peripheral nervous system."

Congenital cataract is a defining feature alongside hypomyelination.

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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

16

Eye 2

Congenital cataract VERY_FREQUENT Developmental cataract HP:0000519

Show evidence (2 references)

PMID:20301737 SUPPORT Human Clinical

"Hypomyelination and congenital cataract (HCC) is usually characterized by bilateral congenital cataracts and normal psychomotor or only mildly delayed development in the first year of life"

GeneReviews describes bilateral congenital cataracts as typical.

PMID:21911699 SUPPORT Human Clinical

"Cataract was congenital in 5 patients; it was found at 4, 5, and 7 months in 3 patients, and only a mild lens opacity was noted at age 3 years in the remaining patient."

Cataract in all nine patients of a series, with variable age at detection.

Strabismus HP:0000486

Show evidence (1 reference)

PMID:42382508 SUPPORT Human Clinical

"Additionally, we reported a novel variant and some rare clinical features, such as exophthalmos and strabismus, in our proband for the first time."

Strabismus and exophthalmos in a single proband.

Limbs 1

Lower limb weakness and wasting Lower limb muscle weakness HP:0007340

Show evidence (1 reference)

PMID:20301737 SUPPORT Human Clinical

"Cerebellar signs (truncal titubation and intention tremor) and peripheral neuropathy (muscle weakness and wasting of the legs) are present in the majority of affected individuals."

GeneReviews describes leg weakness and wasting.

Musculoskeletal 2

Spasticity HP:0001257

Show evidence (1 reference)

PMID:17683097 SUPPORT Human Clinical

"The clinical picture was characterized by bilateral congenital cataract, developmental delay, and slowly progressive neurological impairment with spasticity, cerebellar ataxia, and mild-to-moderate mental retardation."

Progressive spasticity is part of the core phenotype.

Truncal hypotonia Axial hypotonia HP:0008936

Show evidence (1 reference)

PMID:20301737 SUPPORT Human Clinical

"Dysarthria and truncal hypotonia are observed."

GeneReviews lists truncal hypotonia.

Nervous System 11

CNS hypomyelination VERY_FREQUENT HP:0003429

Show evidence (1 reference)

PMID:17974614 SUPPORT Human Clinical

"Supratentorial white matter hypomyelination was detected in all patients; 7 patients also had evidence of variably extensive areas of increased white matter water content."

Hypomyelination in all ten imaged patients.

Periventricular white matter abnormality Abnormal periventricular white matter morphology HP:0002518

Show evidence (1 reference)

PMID:21911699 SUPPORT Human Clinical

"In contrast to this clinical variability, the peculiar magnetic resonance pattern of hypomyelination combined with increased periventricular white matter water content allows distinction of HCC from other forms of hypomyelinating leukoencephalopathies."

The distinguishing MRI pattern.

Cerebral white matter atrophy HP:0012762

Show evidence (1 reference)

PMID:17974614 SUPPORT Human Clinical

"Older patients had evidence of white matter bulk loss and gliosis."

White-matter volume loss in older patients.

Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:17683097 SUPPORT Human Clinical

"The clinical picture was characterized by bilateral congenital cataract, developmental delay, and slowly progressive neurological impairment with spasticity, cerebellar ataxia, and mild-to-moderate mental retardation."

Developmental delay in a ten-patient series.

Intellectual disability VERY_FREQUENT HP:0001249

Show evidence (1 reference)

PMID:21911699 SUPPORT Human Clinical

"Mental retardation was present in all patients."

Intellectual disability in all nine patients.

Cerebellar ataxia Progressive cerebellar ataxia HP:0002073

Show evidence (1 reference)

PMID:17683097 SUPPORT Human Clinical

"The clinical picture was characterized by bilateral congenital cataract, developmental delay, and slowly progressive neurological impairment with spasticity, cerebellar ataxia, and mild-to-moderate mental retardation."

Slowly progressive cerebellar ataxia is part of the core phenotype.

Dysarthria HP:0001260

Show evidence (1 reference)

PMID:20301737 SUPPORT Human Clinical

"Dysarthria and truncal hypotonia are observed."

GeneReviews lists dysarthria.

Intention tremor HP:0002080

Show evidence (1 reference)

PMID:20301737 SUPPORT Human Clinical

"Cerebellar signs (truncal titubation and intention tremor) and peripheral neuropathy (muscle weakness and wasting of the legs) are present in the majority of affected individuals."

GeneReviews reports intention tremor in most patients.

Motor regression HP:0033044

Show evidence (1 reference)

PMID:21911699 SUPPORT Human Clinical

"Neurologic presentation was at birth in 1 child, was characterized by developmental delay at the end of the first year of life in 7 patients, and was characterized by sudden motor regression in the second year of life in the remaining patient."

One patient presented with motor regression.

Peripheral demyelinating neuropathy VERY_FREQUENT Demyelinating peripheral neuropathy HP:0007108

Show evidence (2 references)

PMID:17683097 SUPPORT Human Clinical

"Neurophysiological studies showed a slightly to markedly slowed motor nerve conduction velocity in 9 of 10 patients, and multimodal evoked potentials indicated increased central conduction times."

Slowed motor conduction in 9 of 10 patients.

PMID:21911699 SUPPORT Human Clinical

"Peripheral neuropathy was present in the 8 patients who underwent neurophysiological investigations."

Neuropathy in every patient tested in a second series.

Seizures HP:0001250

Show evidence (1 reference)

PMID:20301737 SUPPORT Human Clinical

"peripheral neuropathy (muscle weakness and wasting of the legs) are present in the majority of affected individuals. Seizures can occur."

GeneReviews states that seizures can occur; the quote includes the preceding sentence because a three-word snippet fails the snippet-length gate.

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Genetic Associations

1

HYCC1

Gene: HYCC1 (FAM126A) hgnc:24587 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

CGGV:assertion_1717e62b-6b1e-47fd-a335-de3fd597f7a4-2025-03-13T160000.000Z SUPPORT Other

ClinGen Definitive gene-disease validity for this pair.

PMID:16951682 SUPPORT Human Clinical

"We identified mutations in five affected families, resulting in a deficiency of hyccin, a newly identified 521-amino acid membrane protein."

Original identification of the causal gene.

Variants (4)

IVS5+1G>T (splice donor)

A recurrent splice-donor allele reported in the original families and again in later patients.

Show evidence (1 reference)

PMID:21911699 SUPPORT Human Clinical

"Molecular analysis depicted 3 novel mutations and the previously reported IVS5 + 1G>T mutation."

Recurrence of the splice allele.

c.636_639del (p.Cys213AspfsTer7)

A homozygous frameshift in an Iranian proband.

Show evidence (1 reference)

PMID:42382508 SUPPORT Human Clinical

"WES identified a novel homozygous mutation (NM_032581: c.636_639del p.C213Dfs*7) in the FAM126A gene."

Identifies the frameshift allele.

Microdeletion causing a premature stop

A microdeletion found in two siblings with the classic phenotype.

Show evidence (1 reference)

PMID:23998934 SUPPORT Human Clinical

"Two sibs harbouring a microdeletion causing a premature stop in the protein showed the classical clinical and neuroradiologic HCC picture."

Deletion allele with full phenotype.

p.Leu53Pro

A hypomorphic missense allele that leaves some protein, which aggregates in the endoplasmic reticulum.

Show evidence (1 reference)

PMID:24417797 SUPPORT In Vitro

"While the gene mutations often cause FAM126A protein deficiency, one known missense mutation, Leu-53-to-Pro (L53P), allows some protein to be produced."

Residual protein from the missense allele.

💊

Medical Actions

3

Cataract extraction

Action: cataract extraction Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Cataract extraction, usually in the first months of life, to protect visual development.

Show evidence (1 reference)

PMID:20301737 SUPPORT Human Clinical

"Cataract extraction usually in the first months of life."

GeneReviews management recommendation.

Rehabilitation and spasticity management

Action: physical medicine and rehabilitation for spasticity and ataxia Ontology label: Rehabilitation NCIT:C15315

Platform: Behavioral / lifestyle

Developmental therapies, special education, and physical medicine and rehabilitation for spasticity and ataxia, with pharmacological agents for spasticity and anti-seizure medication as needed.

Show evidence (1 reference)

PMID:20301737 SUPPORT Human Clinical

"Therapy support for developmental delays; special education; physical medicine and rehabilitation for spasticity and ataxia."

GeneReviews supportive management.

Orthopaedic and feeding management

Action: supportive care for scoliosis, contractures and feeding Ontology label: Supportive Care NCIT:C15747

Platform: Other

Scoliosis and contractures are managed by an orthopaedist, and feeding therapy or a gastrostomy tube is used as needed. Eye examinations are recommended if cataracts were not found in the neonatal period.

Show evidence (2 references)

PMID:20301737 SUPPORT Human Clinical

"Treatment for scoliosis and contractures per orthopedist; feeding therapy and or gastrostomy tube as needed."

GeneReviews orthopaedic and feeding management.

PMID:20301737 SUPPORT Human Clinical

"Surveillance: Eye examinations if cataracts were not identified in neonatal period."

GeneReviews ophthalmological surveillance.

🔬

Diagnosis

1

Brain MRI, nerve conduction studies and HYCC1 sequencing

The combination of congenital cataract, a characteristic MRI pattern of hypomyelination with increased periventricular water content, and slowed nerve conduction suggests the diagnosis, which is confirmed by biallelic HYCC1 variants. Deletion analysis is needed because exonic microdeletions occur.

Show evidence (2 references)

PMID:20301737 SUPPORT Human Clinical

"The diagnosis of HCC can be established in individuals with typical clinical findings, characteristic abnormalities on brain MRI, and biallelic pathogenic variants in HYCC1 (formerly FAM126A) identified by molecular genetic testing."

GeneReviews diagnostic criteria.

PMID:17974614 SUPPORT Human Clinical

"In the proper clinical setting, recognition of suggestive neuroimaging findings should prompt appropriate genetic investigations."

MRI pattern as the trigger for genetic testing.

🐁

Animal Models

1

Drosophila glial Hyccin knockdown

Glial knockdown of the fly hyccin ortholog reduces glial enrichment and disrupts axonal sheaths and vision; human FAM126A or FAM126B rescues it fully and plasma-membrane-targeted PI4KIIIalpha partly, and PI4KIIIalpha knockdown phenocopies it.

Species

Drosophila melanogaster

Genotype

glia-specific RNAi knockdown of Hyccin (fly ortholog of HYCC1/FAM126A)

Publication

PMID:34894559

Pathograph links

Destabilised Plasma-Membrane PI4KIIIalpha Complex recapitulates fidelity: moderate Hyccin is required for expression of the other complex components in fly glia.

Show evidence (1 reference)

PMID:34894559 SUPPORT Model Organism

"This study shows Hyccin/FAM126A expression was necessary for the expression of other components of the PI4KIIIα complex in Drosophila."

Loss of the complex in the fly model.

CNS and PNS Hypomyelination partially recapitulates fidelity: low Glial axonal sheaths are disrupted.

Limitations: Flies have no compact vertebrate myelin, so the model shows glial ensheathment failure rather than hypomyelination itself.

Show evidence (1 reference)

PMID:34894559 SUPPORT Model Organism

"Knockdown of Hyccin/FAM126A in glia reduced the enrichment of glial cells, disrupted axonal sheaths and visual ability in the visual system, and these defects could be fully rescued by overexpressing either human FAM126A or FAM126B, and partially rescued by overexpressing a plasma..."

Disrupted axonal sheaths after glial knockdown, rescued by human hyccin.

{ }

Source YAML

click to show

name: Hypomyelinating Leukodystrophy 5
creation_date: '2026-10-12T18:40:00Z'
category: Mendelian
parents:
- Hypomyelinating Leukodystrophy
- Leukodystrophy
disease_term:
  preferred_term: hypomyelinating leukodystrophy 5
  term:
    id: MONDO:0012514
    label: leukodystrophy, hypomyelinating, 5
synonyms:
- hypomyelination and congenital cataract
- HCC
- HLD5
- FAM126A leukodystrophy
- HYCC1-related hypomyelination and congenital cataract
description: >-
  Hypomyelinating leukodystrophy 5, better known as hypomyelination and
  congenital cataract (HCC), is a rare autosomal recessive white-matter
  disorder caused by biallelic loss-of-function variants in HYCC1 (formerly
  FAM126A), which encodes hyccin. Hyccin is a regulatory subunit of the
  plasma-membrane phosphatidylinositol 4-kinase complex built around
  PI4KIIIalpha (PI4KA) with TTC7 and EFR3. Without it the complex is
  unstable and the plasma membrane makes less phosphatidylinositol
  4-phosphate (PtdIns(4)P). Oligodendrocytes, in which hyccin is the
  predominant FAM126 isoform, must expand their plasma membrane enormously to
  build myelin, and the proposed consequence of the PtdIns(4)P deficit is
  failure to myelinate the central nervous system; peripheral nerves are
  hypomyelinated as well. Most patients have bilateral congenital cataracts
  and normal or mildly delayed development in the first year, followed by
  slowly progressive spasticity, cerebellar ataxia, dysarthria, demyelinating
  peripheral neuropathy and mild to moderate intellectual disability. Brain MRI
  shows diffuse supratentorial hypomyelination with increased periventricular
  white-matter water content, and older patients develop white-matter loss and
  gliosis. Hypomorphic missense alleles give a milder course that can spare the
  peripheral nerves. Management is supportive, with early cataract extraction.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:20301737
    reference_title: "Hypomyelination and Congenital Cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HCC is inherited in an autosomal recessive manner."
    explanation: >-
      GeneReviews states the recessive mode of inheritance.
  - reference: PMID:16951682
    reference_title: "Deficiency of hyccin, a newly identified membrane protein, causes hypomyelination and congenital cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a new autosomal recessive white matter disorder ('hypomyelination and congenital cataract') characterized by hypomyelination of the central and peripheral nervous system, progressive neurological impairment and congenital cataract."
    explanation: >-
      The original description of the disorder as autosomal recessive.
  - reference: PMID:20301737
    reference_title: "Hypomyelination and Congenital Cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "If both parents are known to be heterozygous for a HYCC1 pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier."
    explanation: >-
      GeneReviews recurrence risks for siblings.
genetic:
- name: HYCC1
  gene_term:
    preferred_term: HYCC1 (FAM126A)
    term:
      id: hgnc:24587
      label: FAM126A
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  gene_disease_validity:
  - validity_classification: DEFINITIVE
    classified_by: CLINGEN
    external_id: CGGV:assertion_1717e62b-6b1e-47fd-a335-de3fd597f7a4-2025-03-13T160000.000Z
    evidence:
    - reference: CGGV:assertion_1717e62b-6b1e-47fd-a335-de3fd597f7a4-2025-03-13T160000.000Z
      reference_title: "HYCC1 / hypomyelinating leukodystrophy 5 (Definitive)"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "HYCC1 | HGNC:24587 | hypomyelinating leukodystrophy 5 | MONDO:0012514 | AR | Definitive"
      explanation: >-
        ClinGen classifies the HYCC1-hypomyelinating leukodystrophy 5
        relationship as Definitive with autosomal recessive inheritance.
  notes: >-
    Splice-site, frameshift and deletion alleles give complete hyccin
    deficiency and the full phenotype; the missense allele p.Leu53Pro leaves
    residual protein and a milder course.
  evidence:
  - reference: CGGV:assertion_1717e62b-6b1e-47fd-a335-de3fd597f7a4-2025-03-13T160000.000Z
    reference_title: "HYCC1 / hypomyelinating leukodystrophy 5 (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "HYCC1 | HGNC:24587 | hypomyelinating leukodystrophy 5 | MONDO:0012514 | AR | Definitive"
    explanation: >-
      ClinGen Definitive gene-disease validity for this pair.
  - reference: PMID:16951682
    reference_title: "Deficiency of hyccin, a newly identified membrane protein, causes hypomyelination and congenital cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified mutations in five affected families, resulting in a deficiency of hyccin, a newly identified 521-amino acid membrane protein."
    explanation: >-
      Original identification of the causal gene.
  variants:
  - name: IVS5+1G>T (splice donor)
    description: >-
      A recurrent splice-donor allele reported in the original families and
      again in later patients.
    evidence:
    - reference: PMID:21911699
      reference_title: "Hypomyelination and congenital cataract: broadening the clinical phenotype."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Molecular analysis depicted 3 novel mutations and the previously reported IVS5 + 1G>T mutation."
      explanation: >-
        Recurrence of the splice allele.
  - name: c.636_639del (p.Cys213AspfsTer7)
    description: >-
      A homozygous frameshift in an Iranian proband.
    evidence:
    - reference: PMID:42382508
      reference_title: "Expanding the Phenotype and Genotype Spectrum of a Novel Mutation in Hypomyelinating Leukodystrophy-5 With a Review of the Literature on 42 Cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "WES identified a novel homozygous mutation (NM_032581: c.636_639del p.C213Dfs*7) in the FAM126A gene."
      explanation: >-
        Identifies the frameshift allele.
  - name: Microdeletion causing a premature stop
    description: >-
      A microdeletion found in two siblings with the classic phenotype.
    evidence:
    - reference: PMID:23998934
      reference_title: "Novel FAM126A mutations in hypomyelination and congenital cataract disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Two sibs harbouring a microdeletion causing a premature stop in the protein showed the classical clinical and neuroradiologic HCC picture."
      explanation: >-
        Deletion allele with full phenotype.
  - name: p.Leu53Pro
    description: >-
      A hypomorphic missense allele that leaves some protein, which
      aggregates in the endoplasmic reticulum.
    evidence:
    - reference: PMID:24417797
      reference_title: "Hypomyelinating leukodystrophy-associated missense mutant of FAM126A/hyccin/DRCTNNB1A aggregates in the endoplasmic reticulum."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "While the gene mutations often cause FAM126A protein deficiency, one known missense mutation, Leu-53-to-Pro (L53P), allows some protein to be produced."
      explanation: >-
        Residual protein from the missense allele.
pathophysiology:
- name: Biallelic HYCC1 Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Biallelic splice-site (the recurrent IVS5+1G>T), frameshift, deletion and
    missense variants in HYCC1 cause complete or severe hyccin deficiency.
    Truncating and splice alleles give the full phenotype with peripheral
    neuropathy; missense alleles such as p.Leu53Pro leave some protein and a
    milder course.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  evidence:
  - reference: PMID:16951682
    reference_title: "Deficiency of hyccin, a newly identified membrane protein, causes hypomyelination and congenital cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified mutations in five affected families, resulting in a deficiency of hyccin, a newly identified 521-amino acid membrane protein."
    explanation: >-
      Identifies hyccin deficiency as the cause in the first five families.
  - reference: PMID:23998934
    reference_title: "Novel FAM126A mutations in hypomyelination and congenital cataract disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A residual amount of hyccin protein in primary fibroblasts was demonstrated by functional studies indicating that missense mutations are likely to have less detrimental effects if compared with splice-site mutations or deletions that cause the full-blown HCC phenotype, including peripheral nervous system involvement."
    explanation: >-
      Genotype-phenotype relationship between missense and null alleles.
  - reference: PMID:42382508
    reference_title: "Expanding the Phenotype and Genotype Spectrum of a Novel Mutation in Hypomyelinating Leukodystrophy-5 With a Review of the Literature on 42 Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "WES identified a novel homozygous mutation (NM_032581: c.636_639del p.C213Dfs*7) in the FAM126A gene."
    explanation: >-
      A homozygous frameshift allele in an Iranian family.
  downstream:
  - target: Destabilised Plasma-Membrane PI4KIIIalpha Complex
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26571211
      reference_title: "The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Absence of FAM126A, the predominant FAM126 isoform in oligodendrocytes, destabilizes the PI4KIIIα complex in mouse brain and patient fibroblasts."
      explanation: >-
        Loss of hyccin destabilises the kinase complex in patient cells and
        mouse brain.
  - target: Misfolded Hyccin Accumulation in the Endoplasmic Reticulum
- name: Misfolded Hyccin Accumulation in the Endoplasmic Reticulum
  biological_scale: CELLULAR
  description: >-
    The missense hyccin p.Leu53Pro aggregates in the endoplasmic reticulum
    and activates unfolded-protein-response kinases in cultured cells. This
    is a proposed additional toxic mechanism for some missense alleles, not a
    demonstrated cause of the human phenotype.
  biological_processes:
  - preferred_term: endoplasmic reticulum unfolded protein response
    modifier: INCREASED
    term:
      id: GO:0030968
      label: endoplasmic reticulum unfolded protein response
  evidence:
  - reference: PMID:24417797
    reference_title: "Hypomyelinating leukodystrophy-associated missense mutant of FAM126A/hyccin/DRCTNNB1A aggregates in the endoplasmic reticulum."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Here, we show that the L53P mutant aggregates in cells, accumulating primarily in the ER."
    explanation: >-
      Aggregation of the missense protein in the ER.
  - reference: PMID:24417797
    reference_title: "Hypomyelinating leukodystrophy-associated missense mutant of FAM126A/hyccin/DRCTNNB1A aggregates in the endoplasmic reticulum."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In addition, the L53P mutant expression promotes the activities of kinases involved in unfolded protein response."
    explanation: >-
      UPR activation by the missense protein.
- name: Destabilised Plasma-Membrane PI4KIIIalpha Complex
  biological_scale: MOLECULAR
  description: >-
    Hyccin is an intrinsic component of the plasma-membrane phosphatidylinositol
    4-kinase complex with PI4KIIIalpha, TTC7 and EFR3, binding TTC7 through a
    large interface. Its absence lowers the levels of the other subunits and
    so of plasma-membrane PI4-kinase activity. Hyccin itself has no catalytic
    activity (GO annotates it only with protein binding), so the gene is
    placed on this node, whose molecular function is the activity of the
    complex it stabilises.
  genes:
  - preferred_term: HYCC1 (FAM126A)
    term:
      id: hgnc:24587
      label: FAM126A
  molecular_functions:
  - preferred_term: 1-phosphatidylinositol 4-kinase activity
    modifier: DECREASED
    term:
      id: GO:0004430
      label: 1-phosphatidylinositol 4-kinase activity
  evidence:
  - reference: PMID:26571211
    reference_title: "The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "FAM126A is an intrinsic component of the plasma membrane phosphatidylinositol 4-kinase complex that comprises PI4KIIIα and its adaptors TTC7 and EFR3 (refs 5,7)."
    explanation: >-
      Places hyccin in the PI4KIIIalpha complex.
  - reference: PMID:34894559
    reference_title: "Hyccin/FAM126A deficiency reduces glial enrichment and axonal sheath, which are rescued by overexpression of a plasma membrane-targeting PI4KIIIα in Drosophila."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This study shows Hyccin/FAM126A expression was necessary for the expression of other components of the PI4KIIIα complex in Drosophila."
    explanation: >-
      In flies, hyccin is required for the other complex components to be
      expressed.
  downstream:
  - target: Reduced Plasma-Membrane PtdIns(4)P Synthesis
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:26571211
      reference_title: "The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "HCC patient fibroblasts exhibit reduced PtdIns(4)P levels."
      explanation: >-
        Patient cells lacking a stable complex have less PtdIns(4)P.
- name: Reduced Plasma-Membrane PtdIns(4)P Synthesis
  biological_scale: CELLULAR
  description: >-
    Less PtdIns(4)P, a determinant of plasma-membrane identity and the
    precursor of PtdIns(4,5)P2, is made at the plasma membrane. The proposed
    pathogenic site is the oligodendrocyte, whose myelinating function
    requires massive plasma-membrane expansion; this cell-type link is
    proposed from the protein's expression pattern and the fly model rather
    than measured in human oligodendrocytes.
  conforms_to: cns_myelin_failure#Oligodendrocyte-Lineage or Myelin-Membrane Insult
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  biological_processes:
  - preferred_term: phosphatidylinositol 4-phosphate biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0180048
      label: phosphatidylinositol 4-phosphate biosynthetic process
  evidence:
  - reference: PMID:26571211
    reference_title: "The leukodystrophy protein FAM126A (hyccin) regulates PtdIns(4)P synthesis at the plasma membrane."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "We propose that HCC pathogenesis involves defects in PtdIns(4)P production in oligodendrocytes, whose specialized function requires massive plasma membrane expansion and thus generation of PtdIns(4)P and downstream phosphoinositides."
    explanation: >-
      States the oligodendrocyte PtdIns(4)P hypothesis.
  downstream:
  - target: CNS and PNS Hypomyelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34894559
      reference_title: "Hyccin/FAM126A deficiency reduces glial enrichment and axonal sheath, which are rescued by overexpression of a plasma membrane-targeting PI4KIIIα in Drosophila."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Knockdown of Hyccin/FAM126A in glia reduced the enrichment of glial cells, disrupted axonal sheaths and visual ability in the visual system, and these defects could be fully rescued by overexpressing either human FAM126A or FAM126B, and partially rescued by overexpressing a plasma membrane-targeting recombinant mouse PI4KIIIα."
      explanation: >-
        Glial hyccin loss disrupts axonal sheaths in flies and is partly
        rescued by restoring plasma-membrane PI4KIIIalpha, linking the kinase
        complex to sheath formation.
- name: CNS and PNS Hypomyelination
  biological_scale: TISSUE
  description: >-
    Myelin is never adequately laid down in the central nervous system, and
    peripheral nerves show reduced myelinated-fibre density with thin or
    absent myelin sheaths. MRI shows diffuse supratentorial hypomyelination,
    often deep cerebellar white-matter hypomyelination, increased
    periventricular white-matter water content and brainstem pyramidal tract
    involvement; older patients add white-matter loss and gliosis.
  conforms_to: cns_myelin_failure#Deficient or Unstable CNS Myelin Sheath
  cell_types:
  - preferred_term: oligodendrocyte
    term:
      id: CL:0000128
      label: oligodendrocyte
  - preferred_term: Schwann cell
    term:
      id: CL:0002573
      label: Schwann cell
  biological_processes:
  - preferred_term: central nervous system myelination
    modifier: DECREASED
    term:
      id: GO:0022010
      label: central nervous system myelination
  evidence:
  - reference: PMID:17974614
    reference_title: "Hypomyelination and congenital cataract: neuroimaging features of a novel inherited white matter disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Supratentorial white matter hypomyelination was detected in all patients; 7 patients also had evidence of variably extensive areas of increased white matter water content."
    explanation: >-
      Hypomyelination on MRI in every patient of a ten-patient series.
  - reference: PMID:17683097
    reference_title: "Phenotypic characterization of hypomyelination and congenital cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Sural nerve biopsy showed a slight-to-severe reduction in myelinated fiber density, with several axons surrounded by a thin myelin sheath or devoid of myelin."
    explanation: >-
      Peripheral nerve hypomyelination on biopsy.
  - reference: PMID:16951682
    reference_title: "Deficiency of hyccin, a newly identified membrane protein, causes hypomyelination and congenital cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study highlights the essential role of hyccin in central and peripheral myelination."
    explanation: >-
      Links hyccin deficiency to central and peripheral myelination.
  downstream:
  - target: CNS hypomyelination
  - target: Peripheral demyelinating neuropathy
  - target: Lower limb weakness and wasting
  - target: Truncal hypotonia
  - target: Motor regression
  - target: Spasticity
  - target: Cerebellar ataxia
  - target: Intellectual disability
  - target: Global developmental delay
  - target: Dysarthria
  - target: Intention tremor
  - target: Seizures
  - target: Periventricular white matter abnormality
  - target: Secondary White-Matter Loss and Gliosis
- name: Secondary White-Matter Loss and Gliosis
  biological_scale: TISSUE
  description: >-
    Older patients show white-matter bulk loss and gliosis on MRI, a
    secondary neurodegenerative change superimposed on the primary myelin
    deficiency.
  conforms_to: cns_myelin_failure#Axonal Degeneration and Progressive White Matter Dysfunction
  evidence:
  - reference: PMID:17974614
    reference_title: "Hypomyelination and congenital cataract: neuroimaging features of a novel inherited white matter disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "HCC is characterized by a combined pattern of primary myelin deficiency and secondary neurodegenerative changes."
    explanation: >-
      Describes secondary neurodegeneration on top of primary hypomyelination.
  - reference: PMID:17974614
    reference_title: "Hypomyelination and congenital cataract: neuroimaging features of a novel inherited white matter disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Older patients had evidence of white matter bulk loss and gliosis."
    explanation: >-
      White-matter loss and gliosis in older patients.
  downstream:
  - target: Cerebral white matter atrophy
- name: Lens Opacification
  biological_scale: TISSUE
  description: >-
    Bilateral congenital cataract is the feature that distinguishes this
    leukodystrophy from its relatives. How hyccin loss affects the lens has
    not been studied, so this node is not linked upstream.
  evidence:
  - reference: PMID:17683097
    reference_title: "Phenotypic characterization of hypomyelination and congenital cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypomyelination and congenital cataract is a novel autosomal recessive white matter disorder characterized by the unique association of congenital cataract and hypomyelination of the central and peripheral nervous system."
    explanation: >-
      Congenital cataract is a defining feature alongside hypomyelination.
  downstream:
  - target: Congenital cataract
phenotypes:
- name: Congenital cataract
  category: Ophthalmologic
  frequency: VERY_FREQUENT
  description: >-
    Bilateral cataract, usually present at birth, sometimes detected in the
    first months or only as a mild lens opacity later; absent in a few
    individuals.
  phenotype_term:
    preferred_term: Congenital cataract
    term:
      id: HP:0000519
      label: Developmental cataract
  evidence:
  - reference: PMID:20301737
    reference_title: "Hypomyelination and Congenital Cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Hypomyelination and congenital cataract (HCC) is usually characterized by bilateral congenital cataracts and normal psychomotor or only mildly delayed development in the first year of life"
    explanation: >-
      GeneReviews describes bilateral congenital cataracts as typical.
  - reference: PMID:21911699
    reference_title: "Hypomyelination and congenital cataract: broadening the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cataract was congenital in 5 patients; it was found at 4, 5, and 7 months in 3 patients, and only a mild lens opacity was noted at age 3 years in the remaining patient."
    explanation: >-
      Cataract in all nine patients of a series, with variable age at
      detection.
- name: CNS hypomyelination
  category: Neurologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: CNS hypomyelination
    term:
      id: HP:0003429
      label: CNS hypomyelination
  evidence:
  - reference: PMID:17974614
    reference_title: "Hypomyelination and congenital cataract: neuroimaging features of a novel inherited white matter disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Supratentorial white matter hypomyelination was detected in all patients; 7 patients also had evidence of variably extensive areas of increased white matter water content."
    explanation: >-
      Hypomyelination in all ten imaged patients.
- name: Periventricular white matter abnormality
  category: Neurologic
  description: >-
    Increased periventricular white-matter water content on MRI, which with
    hypomyelination makes a pattern that separates HCC from other
    hypomyelinating leukoencephalopathies.
  phenotype_term:
    preferred_term: Abnormal periventricular white matter morphology
    term:
      id: HP:0002518
      label: Abnormal periventricular white matter morphology
  evidence:
  - reference: PMID:21911699
    reference_title: "Hypomyelination and congenital cataract: broadening the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to this clinical variability, the peculiar magnetic resonance pattern of hypomyelination combined with increased periventricular white matter water content allows distinction of HCC from other forms of hypomyelinating leukoencephalopathies."
    explanation: >-
      The distinguishing MRI pattern.
- name: Cerebral white matter atrophy
  category: Neurologic
  phenotype_term:
    preferred_term: Cerebral white matter atrophy
    term:
      id: HP:0012762
      label: Cerebral white matter atrophy
  evidence:
  - reference: PMID:17974614
    reference_title: "Hypomyelination and congenital cataract: neuroimaging features of a novel inherited white matter disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Older patients had evidence of white matter bulk loss and gliosis."
    explanation: >-
      White-matter volume loss in older patients.
- name: Global developmental delay
  category: Neurologic
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:17683097
    reference_title: "Phenotypic characterization of hypomyelination and congenital cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical picture was characterized by bilateral congenital cataract, developmental delay, and slowly progressive neurological impairment with spasticity, cerebellar ataxia, and mild-to-moderate mental retardation."
    explanation: >-
      Developmental delay in a ten-patient series.
- name: Intellectual disability
  category: Neurologic
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:21911699
    reference_title: "Hypomyelination and congenital cataract: broadening the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mental retardation was present in all patients."
    explanation: >-
      Intellectual disability in all nine patients.
- name: Spasticity
  category: Neurologic
  phenotype_term:
    preferred_term: Spasticity
    term:
      id: HP:0001257
      label: Spasticity
  evidence:
  - reference: PMID:17683097
    reference_title: "Phenotypic characterization of hypomyelination and congenital cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical picture was characterized by bilateral congenital cataract, developmental delay, and slowly progressive neurological impairment with spasticity, cerebellar ataxia, and mild-to-moderate mental retardation."
    explanation: >-
      Progressive spasticity is part of the core phenotype.
- name: Cerebellar ataxia
  category: Neurologic
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:17683097
    reference_title: "Phenotypic characterization of hypomyelination and congenital cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The clinical picture was characterized by bilateral congenital cataract, developmental delay, and slowly progressive neurological impairment with spasticity, cerebellar ataxia, and mild-to-moderate mental retardation."
    explanation: >-
      Slowly progressive cerebellar ataxia is part of the core phenotype.
- name: Dysarthria
  category: Neurologic
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
  evidence:
  - reference: PMID:20301737
    reference_title: "Hypomyelination and Congenital Cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysarthria and truncal hypotonia are observed."
    explanation: >-
      GeneReviews lists dysarthria.
- name: Intention tremor
  category: Neurologic
  description: >-
    Cerebellar signs including truncal titubation and intention tremor are
    present in most affected individuals.
  phenotype_term:
    preferred_term: Intention tremor
    term:
      id: HP:0002080
      label: Intention tremor
  evidence:
  - reference: PMID:20301737
    reference_title: "Hypomyelination and Congenital Cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cerebellar signs (truncal titubation and intention tremor) and peripheral neuropathy (muscle weakness and wasting of the legs) are present in the majority of affected individuals."
    explanation: >-
      GeneReviews reports intention tremor in most patients.
- name: Truncal hypotonia
  category: Neurologic
  phenotype_term:
    preferred_term: Truncal hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  evidence:
  - reference: PMID:20301737
    reference_title: "Hypomyelination and Congenital Cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Dysarthria and truncal hypotonia are observed."
    explanation: >-
      GeneReviews lists truncal hypotonia.
- name: Lower limb weakness and wasting
  category: Neurologic
  description: >-
    Leg muscle weakness and wasting from the peripheral neuropathy, present in
    most affected individuals.
  phenotype_term:
    preferred_term: Lower limb muscle weakness
    term:
      id: HP:0007340
      label: Lower limb muscle weakness
  evidence:
  - reference: PMID:20301737
    reference_title: "Hypomyelination and Congenital Cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cerebellar signs (truncal titubation and intention tremor) and peripheral neuropathy (muscle weakness and wasting of the legs) are present in the majority of affected individuals."
    explanation: >-
      GeneReviews describes leg weakness and wasting.
- name: Motor regression
  category: Neurologic
  description: >-
    Sudden motor regression in the second year of life in one patient.
  phenotype_term:
    preferred_term: Motor regression
    term:
      id: HP:0033044
      label: Motor regression
  evidence:
  - reference: PMID:21911699
    reference_title: "Hypomyelination and congenital cataract: broadening the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurologic presentation was at birth in 1 child, was characterized by developmental delay at the end of the first year of life in 7 patients, and was characterized by sudden motor regression in the second year of life in the remaining patient."
    explanation: >-
      One patient presented with motor regression.
- name: Peripheral demyelinating neuropathy
  category: Neurologic
  frequency: VERY_FREQUENT
  description: >-
    Slowed motor nerve conduction with leg weakness and wasting; may be
    absent with hypomorphic missense alleles.
  phenotype_term:
    preferred_term: Demyelinating peripheral neuropathy
    term:
      id: HP:0007108
      label: Demyelinating peripheral neuropathy
  evidence:
  - reference: PMID:17683097
    reference_title: "Phenotypic characterization of hypomyelination and congenital cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurophysiological studies showed a slightly to markedly slowed motor nerve conduction velocity in 9 of 10 patients, and multimodal evoked potentials indicated increased central conduction times."
    explanation: >-
      Slowed motor conduction in 9 of 10 patients.
  - reference: PMID:21911699
    reference_title: "Hypomyelination and congenital cataract: broadening the clinical phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Peripheral neuropathy was present in the 8 patients who underwent neurophysiological investigations."
    explanation: >-
      Neuropathy in every patient tested in a second series.
- name: Seizures
  category: Neurologic
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:20301737
    reference_title: "Hypomyelination and Congenital Cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "peripheral neuropathy (muscle weakness and wasting of the legs) are present in the majority of affected individuals. Seizures can occur."
    explanation: >-
      GeneReviews states that seizures can occur; the quote includes the
      preceding sentence because a three-word snippet fails the
      snippet-length gate.
- name: Strabismus
  category: Ophthalmologic
  description: >-
    Reported with proptosis in one Iranian patient; not part of the classic
    description, and with no mechanism established it is left unconnected
    in the pathograph.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:42382508
    reference_title: "Expanding the Phenotype and Genotype Spectrum of a Novel Mutation in Hypomyelinating Leukodystrophy-5 With a Review of the Literature on 42 Cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, we reported a novel variant and some rare clinical features, such as exophthalmos and strabismus, in our proband for the first time."
    explanation: >-
      Strabismus and exophthalmos in a single proband.
diagnosis:
- name: Brain MRI, nerve conduction studies and HYCC1 sequencing
  description: >-
    The combination of congenital cataract, a characteristic MRI pattern of
    hypomyelination with increased periventricular water content, and
    slowed nerve conduction suggests the diagnosis, which is confirmed by
    biallelic HYCC1 variants. Deletion analysis is needed because exonic
    microdeletions occur.
  evidence:
  - reference: PMID:20301737
    reference_title: "Hypomyelination and Congenital Cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of HCC can be established in individuals with typical clinical findings, characteristic abnormalities on brain MRI, and biallelic pathogenic variants in HYCC1 (formerly FAM126A) identified by molecular genetic testing."
    explanation: >-
      GeneReviews diagnostic criteria.
  - reference: PMID:17974614
    reference_title: "Hypomyelination and congenital cataract: neuroimaging features of a novel inherited white matter disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the proper clinical setting, recognition of suggestive neuroimaging findings should prompt appropriate genetic investigations."
    explanation: >-
      MRI pattern as the trigger for genetic testing.
treatments:
- name: Cataract extraction
  description: >-
    Cataract extraction, usually in the first months of life, to protect
    visual development.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: cataract extraction
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:20301737
    reference_title: "Hypomyelination and Congenital Cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cataract extraction usually in the first months of life."
    explanation: >-
      GeneReviews management recommendation.
- name: Rehabilitation and spasticity management
  description: >-
    Developmental therapies, special education, and physical medicine and
    rehabilitation for spasticity and ataxia, with pharmacological agents for
    spasticity and anti-seizure medication as needed.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical medicine and rehabilitation for spasticity and ataxia
    term:
      id: NCIT:C15315
      label: Rehabilitation
  evidence:
  - reference: PMID:20301737
    reference_title: "Hypomyelination and Congenital Cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Therapy support for developmental delays; special education; physical medicine and rehabilitation for spasticity and ataxia."
    explanation: >-
      GeneReviews supportive management.
- name: Orthopaedic and feeding management
  description: >-
    Scoliosis and contractures are managed by an orthopaedist, and feeding
    therapy or a gastrostomy tube is used as needed. Eye examinations are
    recommended if cataracts were not found in the neonatal period.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: supportive care for scoliosis, contractures and feeding
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301737
    reference_title: "Hypomyelination and Congenital Cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Treatment for scoliosis and contractures per orthopedist; feeding therapy and or gastrostomy tube as needed."
    explanation: >-
      GeneReviews orthopaedic and feeding management.
  - reference: PMID:20301737
    reference_title: "Hypomyelination and Congenital Cataract."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Surveillance: Eye examinations if cataracts were not identified in neonatal period."
    explanation: >-
      GeneReviews ophthalmological surveillance.
animal_models:
- name: Drosophila glial Hyccin knockdown
  species: Drosophila melanogaster
  genotype: glia-specific RNAi knockdown of Hyccin (fly ortholog of HYCC1/FAM126A)
  publication: PMID:34894559
  description: >-
    Glial knockdown of the fly hyccin ortholog reduces glial enrichment and
    disrupts axonal sheaths and vision; human FAM126A or FAM126B rescues it
    fully and plasma-membrane-targeted PI4KIIIalpha partly, and PI4KIIIalpha
    knockdown phenocopies it.
  modeled_mechanisms:
  - target: Destabilised Plasma-Membrane PI4KIIIalpha Complex
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Hyccin is required for expression of the other complex components in
      fly glia.
    evidence:
    - reference: PMID:34894559
      reference_title: "Hyccin/FAM126A deficiency reduces glial enrichment and axonal sheath, which are rescued by overexpression of a plasma membrane-targeting PI4KIIIα in Drosophila."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "This study shows Hyccin/FAM126A expression was necessary for the expression of other components of the PI4KIIIα complex in Drosophila."
      explanation: >-
        Loss of the complex in the fly model.
  - target: CNS and PNS Hypomyelination
    relationship: PARTIALLY_RECAPITULATES
    fidelity: LOW
    description: >-
      Glial axonal sheaths are disrupted.
    limitations: >-
      Flies have no compact vertebrate myelin, so the model shows glial
      ensheathment failure rather than hypomyelination itself.
    evidence:
    - reference: PMID:34894559
      reference_title: "Hyccin/FAM126A deficiency reduces glial enrichment and axonal sheath, which are rescued by overexpression of a plasma membrane-targeting PI4KIIIα in Drosophila."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Knockdown of Hyccin/FAM126A in glia reduced the enrichment of glial cells, disrupted axonal sheaths and visual ability in the visual system, and these defects could be fully rescued by overexpressing either human FAM126A or FAM126B, and partially rescued by overexpressing a plasma membrane-targeting recombinant mouse PI4KIIIα."
      explanation: >-
        Disrupted axonal sheaths after glial knockdown, rescued by human
        hyccin.
references:
- reference: PMID:20301737
  title: Hypomyelination and Congenital Cataract.
  tags:
  - GeneReviews
notes: >-
  The gene is bound as hgnc:24587 with the label FAM126A because the HGNC
  build used for term validation has not yet picked up the renaming to HYCC1;
  preferred_term carries the current symbol. The deep-research report gave
  HGNC:24810 for HYCC1, which HGNC resolves to SMCO4, so that identifier was
  not used.

📚

References & Deep Research

References

1

PMID:20301737

Hypomyelination and Congenital Cataract.

No top-level findings curated for this source.

Deep Research

1

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

Evaluations and curation notes (3)

Record notes

The gene is bound as hgnc:24587 with the label FAM126A because the HGNC build used for term validation has not yet picked up the renaming to HYCC1; preferred_term carries the current symbol. The deep-research report gave HGNC:24810 for HYCC1, which HGNC resolves to SMCO4, so that identifier was not used.

Review round 1: Hypomyelinating Leukodystrophy 5 · 2026-10-12T20:23:08Z · View source

Addressed the first automated review of PR 13965. Added a genetic record for HYCC1 (hgnc:24587, label FAM126A) with the ClinGen Definitive assertion CGGV:assertion_1717e62b-6b1e-47fd-a335-de3fd597f7a4-2025-03-13T160000.000Z and four variants (IVS5+1G>T, c.636_639del, microdeletion, p.Leu53Pro). Because GO annotates hyccin only with protein binding, the gene descriptor was moved from the variant node to the PI4KIIIalpha complex node, whose molecular function is the complex's kinase activity, so check-gene-activity-grounding passes without a baseline exemption. Replaced the seizure snippet with a longer exact GeneReviews substring containing 'Seizures can occur.' (the three-word sentence alone fails check-snippet-length). Added truncal hypotonia (HP:0008936), lower limb weakness (HP:0007340) and motor regression (HP:0033044), the GeneReviews recurrence-risk sentence, and an orthopaedic/feeding supportive-care treatment with the surveillance sentence. Backfilled reference_title on all evidence items. Not added: nystagmus, which appears in the deep-research report but in no cached abstract.

Create: Hypomyelinating Leukodystrophy 5 · 2026-10-12T19:10:36Z · View source

New entry for hypomyelination and congenital cataract (HLD5, MONDO:0012514), HYCC1/FAM126A. Pathograph: biallelic HYCC1 loss of function -> destabilised plasma-membrane PI4KIIIalpha complex -> reduced PtdIns(4)P synthesis (oligodendrocyte, conforms to cns_myelin_failure#Oligodendrocyte-Lineage or Myelin-Membrane Insult) -> CNS and PNS hypomyelination (conforms to #Deficient or Unstable CNS Myelin Sheath) -> neurological phenotypes, plus secondary white-matter loss (conforms to #Axonal Degeneration and Progressive White Matter Dysfunction). A missense ER-aggregation/UPR branch is recorded as a proposed mechanism. The congenital cataract node is left without an upstream edge because no study links hyccin to the lens. GeneReviews chapter PMID:20301737 is the phenotype baseline and is tagged. One OpenScientist deep-research report: built-in validation completed (10/10 references resolved, needs_review set only by table-cell label artefacts such as 'Most'); just preflight-dr PASS, with PI4KA mentions reflecting the hyccin-PI4KA complex rather than a second disease. The report gave HGNC:24810 as the HYCC1 identifier; HGNC resolves that to SMCO4, so it was not used. The gene is bound to hgnc:24587 with label FAM126A because the HGNC build used for term validation still carries the old symbol. MONDO:0012514 is labelled 'leukodystrophy, hypomyelinating, 5' in MONDO, which differs from the stub label. Validated with just validate-disorders and the offline CI gates.

OpenScientist ▸

Hypomyelinating Leukodystrophy 5 (HLD5) — Comprehensive Disease Report

openscientist-autonomous 2026-10-12T18:52:07.438600

Hypomyelinating Leukodystrophy 5 (HLD5) — Comprehensive Disease Report

Disease: Hypomyelinating Leukodystrophy 5 (HLD5) / Hypomyelination and Congenital Cataract (HCC) MONDO: MONDO:0012514 · OMIM: #610532 · Gene: FAM126A (hyccin) Evidence base: Rare disease; information is aggregated from case series, functional studies, and model organisms (no large registries). Primary literature cited by PMID throughout.

Summary (Answer to the Research Question)

HLD5, also called Hypomyelination and Congenital Cataract (HCC), is a rare autosomal‑recessive hypomyelinating leukodystrophy caused by biallelic loss‑of‑function variants in FAM126A (encoding hyccin) on chromosome 7p15.3. Hyccin is an obligate component of the plasma‑membrane PI4KIIIα (PI4KA) phosphatidylinositol‑4‑kinase complex (with PI4KA, TTC7, and EFR3); its loss destabilizes the complex and reduces phosphatidylinositol‑4‑phosphate [PtdIns(4)P] synthesis, impairing the massive membrane expansion that oligodendrocytes (and Schwann cells) need to build myelin. The clinical hallmark is the unique combination of bilateral congenital cataract with hypomyelination of both the central and peripheral nervous system, producing psychomotor delay, spasticity, cerebellar ataxia, intellectual disability, and peripheral neuropathy that progresses slowly from infancy.

1. Disease Information

Overview. HLD5/HCC is an inherited white‑matter disorder in which myelin fails to form normally in the CNS and PNS, uniquely combined with congenital cataract. First delineated as a distinct entity by Zara et al. (2006), who identified the causal gene (PMID 16951682): "We describe a new autosomal recessive white matter disorder ('hypomyelination and congenital cataract') characterized by hypomyelination of the central and peripheral nervous system, progressive neurological impairment and congenital cataract."

Key identifiers. - OMIM: 610532 (Hypomyelination and congenital cataract; HCC) - MONDO: MONDO:0012514 - Orphanet: ORPHA:88637 (Hypomyelination and congenital cataract) — ultra‑rare (<1/1,000,000) - Gene / HGNC: HYCC1 (current official symbol; HGNC:24810), formerly FAM126A; Ensembl ENSG00000122591; aliases hyccin, DRCTNNB1A. (The paralog FAM126B is now HYCC2.) - ICD‑10: best mapped to E75.2x / leukodystrophy codes (no dedicated code); ICD‑11: 8A44 (leukodystrophy) range - MeSH: indexed under "Hereditary Central Nervous System Demyelinating Diseases" / "Leukodystrophies" (no dedicated MeSH heading)

Synonyms / alternative names: Hypomyelination and congenital cataract (HCC); HCC syndrome; autosomal‑recessive Pelizaeus‑Merzbacher‑like disease (HLD5 within the HLD numbering series, where HLD1 = PLP1 Pelizaeus‑Merzbacher disease) (PMID 24417797).

Source type: Disease‑level/aggregate — individual patient case series (PMIDs 16951682, 17683097, 17974614, 21911699, 23998934, 42382508) plus mechanistic in‑vitro/model data; no EHR‑derived population datasets.

2. Etiology

Causal factor: Purely genetic — biallelic (homozygous or compound‑heterozygous) pathogenic variants in FAM126A causing complete or severe hyccin deficiency (PMID 16951682). No environmental, infectious, or toxic cause.

Genetic risk factors. The only established risk factor is inheriting two loss‑of‑function FAM126A alleles. Consanguinity and being born to carrier parents are the key familial risk factors (many reported families are consanguineous; e.g., Iranian family in PMID 42382508). No susceptibility loci or modifier genes are established; the paralog FAM126B can functionally substitute for FAM126A in non‑oligodendrocyte tissues and in rescue experiments (PMID 34894559), making tissue‑specific FAM126B expression a plausible (unproven) modifier of which tissues are spared.

Environmental risk / protective factors / gene–environment interactions: None identified or expected for this monogenic disorder (not applicable). No protective alleles described. Sex is not a risk factor (autosomal).

3. Phenotypes

Phenotype frequencies are drawn from the core case series (PMID 17683097, n=10; PMID 17974614, n=10; PMID 21911699, n=9; review of 42 cases PMID 42382508).

Phenotype	Type	Onset	Frequency	HPO
Bilateral congenital cataract	Clinical sign (ophthalmologic)	Congenital (sometimes detected at 4–7 mo; rarely mild by age 3 y)	Near‑universal (defining)	HP:0000519 (congenital cataract)
CNS hypomyelination	Imaging/laboratory	Infancy	~100%	HP:0003429
Psychomotor/developmental delay	Clinical sign	End of 1st year	~100%	HP:0001263 / HP:0001270
Intellectual disability (mild–moderate)	Clinical sign	Childhood	~100%	HP:0001249
Spasticity / pyramidal signs	Clinical sign	Childhood, progressive	Most	HP:0001257
Cerebellar ataxia	Clinical sign	Childhood	Most	HP:0001251
Peripheral neuropathy (demyelinating)	Lab/electrophysiology	Infancy–childhood	~8–9/10 (null alleles)	HP:0009830 / HP:0000762 (reduced NCV)
Motor regression	Clinical sign	Sometimes 2nd year	Subset	HP:0002376
Cerebellar signs / tremor, nystagmus	Clinical sign	Childhood	Subset	HP:0001251
Strabismus, exophthalmos (rare)	Physical	Variable	Rare (reported)	HP:0000486 / HP:0000520

Severity & progression: Variable but generally slowly progressive; ranges from severe early‑onset impairment to a milder, PNS‑sparing phenotype in patients with hypomorphic missense alleles (PMID 23998934, 21911699). Most patients achieve limited ambulation (some walk with/without support; some never stand) (PMID 21911699).

Quality of life: Substantial lifelong impact — motor disability, cognitive impairment, and visual impairment (cataract) impair mobility, learning, and independent living. No formal EQ‑5D/SF‑36/PROMIS data for this ultra‑rare disease (not available).

4. Genetic / Molecular Information

Causal gene: HYCC1 (formerly FAM126A; hyccin/DRCTNNB1A), 7p15.3 (chr7:22,889,371–23,014,130, GRCh38), HGNC:24810, Ensembl ENSG00000122591, OMIM gene 610531. Encodes a 521‑amino‑acid protein (PMID 16951682).
Population constraint (gnomAD): HYCC1 is not loss‑of‑function intolerant — pLI ≈ 6.3×10⁻⁶, observed/expected LoF = 0.56 (34 observed vs 60.9 expected), LOEUF ≈ 0.74, missense Z = 0.92. This is the expected signature of a recessive gene: heterozygous LoF alleles circulate in healthy carriers, and disease requires biallelic inactivation. (Source: gnomAD v2/v4 constraint, queried via gnomAD API.)
Variant classes (all pathogenic/likely‑pathogenic, germline, recessive, loss‑of‑function):
Splice‑site: recurrent IVS5+1G>T (c.? +1G>T) (PMID 21911699, 16951682)
Deletions / microdeletions causing premature stop (PMID 23998934)
Frameshift: e.g., c.636_639del (p.Cys213Aspfs*7) (PMID 42382508)
Missense (hypomorphic): e.g., p.Leu53Pro (L53P) — residual protein, ER aggregation (PMID 24417797, 23998934)
Functional consequence: Loss of function (destabilization of the PI4KA complex). Certain missense alleles add a toxic misfolding/ER‑stress component (see §6). No gain‑of‑function/dominant‑negative in the classic sense.
ACMG classification: truncating/splice/deletion alleles meet PVS1‑type criteria (pathogenic); missense alleles supported by functional data (PS3).
Allele frequency: All are rare/private; absent or ultra‑rare in gnomAD (consistent with recessive ultra‑rare disease). No common susceptibility alleles.
ClinVar landscape (queried this study): 451 HYCC1/FAM126A variant records in ClinVar, of which 64 are classified Pathogenic/Likely‑Pathogenic; the remainder are largely VUS/benign — reflecting both the small number of recurrent disease alleles and many incidental population variants.
Modifier genes: paralog FAM126B (candidate functional modifier; PMID 34894559). Epigenetic and chromosomal‑abnormality contributions: none reported (not applicable beyond the microdeletions noted).

5. Environmental Information

Not applicable. HLD5 is a monogenic Mendelian disorder with no known environmental, lifestyle, toxic, or infectious contributors.

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

Biallelic loss‑of‑function variants in FAM126A lead to absent or severely reduced hyccin protein (PMID 16951682).
Loss of hyccin results in destabilization of the plasma‑membrane PI4KIIIα (PI4KA) complex (PI4KA + TTC7 + EFR3), demonstrated in mouse brain and patient fibroblasts (PMID 26571211).
Complex destabilization leads to reduced PtdIns(4)P synthesis at the plasma membrane (reduced PtdIns(4)P measured in HCC patient fibroblasts) (PMID 26571211).
Reduced PtdIns(4)P (and downstream PI(4,5)P₂) impairs plasma‑membrane identity and the massive membrane expansion required by oligodendrocytes — the cells in which FAM126A is the predominant isoform (PMID 26571211) — (inferred for human CNS; directly shown for glial ensheathment in Drosophila, PMID 34894559).
Impaired membrane biogenesis results in failure of CNS and PNS myelin formation (hypomyelination), confirmed by brain MRI and sural‑nerve biopsy (PMID 17974614).
Hypomyelination of corticospinal/pyramidal tracts, cerebellar connections, and peripheral nerves leads to spasticity, ataxia, developmental delay, intellectual disability, and peripheral neuropathy (PMID 17683097, 21911699).
Branch (lens): The same phosphoinositide/membrane defect in the developing lens results in congenital cataract (mechanism in lens inferred, not directly demonstrated).
Branch (missense alleles): Misfolding‑competent alleles (e.g., L53P) cause protein aggregation in the endoplasmic reticulum and activate the unfolded protein response (UPR), adding ER‑stress toxicity to partial loss of function (PMID 24417797).

Molecular pathway: Phosphatidylinositol / phosphoinositide metabolism at the plasma membrane (PI4KA → PtdIns(4)P → PI(4,5)P₂). KEGG: phosphatidylinositol signaling (hsa04070). Not canonical Wnt/MAPK/mTOR, though PI(4,5)P₂/PI3K pools depend on upstream PtdIns(4)P.

Protein dysfunction: loss of function (null alleles) and/or misfolding + ER aggregation (missense) (PMID 26571211, 24417797). A FAM126A–TTC7 co‑crystal structure shows an all‑α‑helical heterodimer with a large interface and a conserved surface proposed to bind PI4KA (PMID 26571211).

Cellular processes: failed membrane biogenesis/myelination; ER stress/UPR; glial enrichment defects (PMID 34894559). No primary autoimmune/inflammatory mechanism. Later secondary white‑matter bulk loss and gliosis occur in older patients (PMID 17974614).

Ontology suggestions. - GO (BP): myelination GO:0042552; central nervous system myelination GO:0022010; phosphatidylinositol biosynthetic process GO:0006661; 1‑phosphatidylinositol‑4‑kinase activity GO:0004430; response to ER stress GO:0034976. - GO (CC): plasma membrane GO:0005886; 1‑phosphatidylinositol 4‑kinase complex GO:0110147; endoplasmic reticulum GO:0005783. - CHEBI: phosphatidylinositol 4‑phosphate CHEBI:58178; phosphatidylinositol 4,5‑bisphosphate CHEBI:58456. - CL: oligodendrocyte CL:0000128; Schwann cell CL:0002573; glial cell CL:0000125; lens fiber cell CL:0011004.

7. Anatomical Structures Affected

Organ/body system: Nervous system — CNS white matter and peripheral nerves (primary); eye/lens (congenital cataract). Secondary: musculoskeletal consequences of spasticity.
Tissue level: CNS myelinated white‑matter tracts (supratentorial, periventricular, deep cerebellar white matter, brainstem pyramidal tracts); peripheral nerve myelin; ocular lens (PMID 17974614, 21911699).
Cells: oligodendrocytes (CL:0000128, primary), Schwann cells (CL:0002573), lens fiber cells.
Subcellular: plasma membrane (GO:0005886) and endoplasmic reticulum (GO:0005783).
UBERON: white matter UBERON:0002316; brain UBERON:0000955; cerebellum UBERON:0002037; corticospinal tract UBERON:0002460; peripheral nerve UBERON:0001780; lens of eye UBERON:0000965.
Localization/lateralization: diffuse and bilateral/symmetric (cataract bilateral; white‑matter changes diffuse supratentorial) (PMID 17974614).

8. Temporal Development

Onset: Congenital (cataract) to early infancy; neurologic presentation typically as developmental delay by the end of the first year, occasionally neonatal or sudden motor regression in the second year (PMID 21911699). Pattern: chronic, insidious.
Progression: Slowly progressive; stages from early developmental delay → spasticity/ataxia → later white‑matter bulk loss and gliosis in older patients (PMID 17974614). Course is progressive, not relapsing‑remitting; duration is lifelong.
Critical period: Infancy/early childhood coincides with peak myelination — the window of greatest vulnerability and the rational window for any future intervention (inferred).
Remission: None (no spontaneous or treatment‑induced remission reported).

9. Inheritance and Population

Inheritance: Autosomal recessive (PMID 16951682). Penetrance appears complete for biallelic null genotypes; expressivity variable (severity tracks residual hyccin function — §4, PMID 23998934). No anticipation (not a repeat disorder); germline mosaicism not reported.
Carrier/consanguinity: Consanguinity is prominent among reported families; cascade carrier testing applies. Carrier frequency not formally estimated, but HYCC1 LoF alleles do circulate at low frequency in the population (34 LoF alleles observed in gnomAD; pLI≈0), consistent with rare healthy heterozygous carriers whose children are at risk only when both parents carry a pathogenic allele.
Founder effects / geography: Early cohorts were largely Italian/Mediterranean (first families; PMID 16951682, 17683097); additional families reported from Turkey, Belgium, the Middle East, and Iran (PMID 21911699, 42382508). A recurrent IVS5+1G>T allele recurs across families (possible shared haplotype) — not formally proven as a founder mutation.
Epidemiology: Ultra‑rare — Orphanet prevalence <1/1,000,000; only a few dozen cases reported worldwide (42‑case literature review, PMID 42382508). No reliable incidence figure.
Sex ratio: ~1:1 (autosomal). Age distribution: pediatric‑onset, lifelong.

10. Diagnostics

Imaging (key): Brain MRI shows diffuse supratentorial white‑matter hypomyelination with periventricular increased water content, deep cerebellar white‑matter involvement, brainstem pyramidal‑tract signal change, and later atrophy/gliosis (PMID 17974614). MR spectroscopy variable by stage.
Electrophysiology: Nerve conduction studies show slowed motor NCV (demyelinating peripheral neuropathy); multimodal evoked potentials show increased central conduction times (PMID 17683097).
Ophthalmology: slit‑lamp detection of bilateral congenital cataract.
Biopsy: Sural‑nerve biopsy — reduced myelinated‑fiber density, thin/absent myelin sheaths (PMID 17974614, 17683097). Rarely needed once genetic diagnosis available.
Biomarkers: No specific blood/urine biomarker. Research‑level: reduced PtdIns(4)P and residual hyccin protein in patient fibroblasts (PMID 26571211, 23998934).
Genetic testing (definitive): The combination of congenital cataract + CNS/PNS hypomyelination should prompt molecular confirmation of FAM126A. Approaches: WES/WGS or leukodystrophy/hypomyelination gene panels; single‑gene sequencing of FAM126A with deletion/duplication analysis (CMA/MLPA) given reported microdeletions (PMID 23998934). Karyotype/FISH/mtDNA/repeat testing are not indicated.
Clinical criteria / differential diagnosis: No formal consensus criteria; diagnosis = characteristic MRI pattern + congenital cataract + biallelic FAM126A variants. Differentials among hypomyelinating leukodystrophies (PMID 27234264): Pelizaeus‑Merzbacher disease (PLP1, HLD1, X‑linked), POLR3‑related (4H) leukodystrophy (hypomyelination, hypodontia, hypogonadotropic hypogonadism — can also feature cataract/myopia), Allan‑Herndon‑Dudley syndrome (SLC16A2), and other HLDs. Cataract + peripheral neuropathy + diffuse CNS hypomyelination is the distinguishing HLD5 signature (also overlaps with CTX and some congenital cataract syndromes, excluded by FAM126A testing).
Screening: No newborn screening. Carrier/cascade testing and prenatal/PGT available for known familial variants.

11. Outcome / Prognosis

Survival: No formal survival statistics; the disorder is chronic and disabling rather than rapidly fatal. Life expectancy is reduced in severely affected individuals (secondary to immobility, aspiration, respiratory complications — inferred/typical of severe leukodystrophy) but many patients survive into adolescence/adulthood with milder disease.
Morbidity/function: Lifelong motor disability (spasticity, ataxia), intellectual disability, visual impairment; most patients have limited ambulation (PMID 21911699). ICF domains: mobility, cognition, vision.
Disease course / complications: slow neurologic progression, later white‑matter atrophy/gliosis (PMID 17974614); spasticity‑related contractures; seizures can occur in leukodystrophies generally (not a defining HLD5 feature).
Prognostic factors: Genotype is the main prognostic factor — null alleles (splice/deletion/frameshift) predict severe disease with peripheral neuropathy; hypomorphic missense alleles predict a milder, often PNS‑sparing course (PMID 23998934).

12. Treatment

No disease‑modifying or curative therapy exists. Management is supportive and multidisciplinary: - Ophthalmologic: cataract surgery/extraction to preserve vision (NCIT: Cataract Surgery C157809‑type intervention). - Rehabilitation: physical therapy, occupational therapy, speech therapy; management of spasticity (e.g., baclofen, botulinum toxin — symptomatic), orthotics. - Supportive care: anti‑spasticity agents, seizure management if present, nutritional support, developmental/educational support, assistive devices. - Genotype‑guided/precision & advanced therapeutics: None approved. Conceptual future directions (preclinical/inferred): gene replacement of FAM126A, or strategies to stabilize the PI4KA complex / restore PtdIns(4)P; the Drosophila rescue by FAM126B and by membrane‑targeted PI4KA suggests molecular targets (PMID 34894559). For misfolding (missense) alleles, UPR/ER‑stress modulation is a conceptual target (PMID 24417797). No active registered clinical trials specific to HLD5/FAM126A identified. - Pharmacogenomics: Not applicable.

13. Prevention

Primary prevention: Not applicable (genetic). Reduced by genetic counseling of carrier/consanguineous couples; carrier screening, prenatal diagnosis, and preimplantation genetic testing (PGT) for known familial FAM126A variants (ACMG/ACOG frameworks).
Secondary prevention: Early recognition (congenital cataract + developmental delay → MRI → genetics) enables early supportive intervention and cataract surgery to protect vision.
Tertiary prevention: rehabilitation, spasticity/contracture management, prevention of aspiration and other complications.
Immunization / public‑health / environmental measures: Not applicable.

14. Other Species / Natural Disease

Orthologs: HYCC1 (FAM126A) is conserved; mouse Hycc1/Fam126a (Taxon 10090) and Drosophila Hyccin (Taxon 7227). The vertebrate paralog HYCC2 (FAM126B) shares function and can functionally substitute (PMID 34894559).
Naturally occurring animal disease: None cataloged in OMIA for FAM126A‑associated HCC (no spontaneous veterinary disease described). Not a zoonosis; not transmissible.
Evolutionary conservation: The hyccin–TTC7–EFR3–PI4KA module is deeply conserved (yeast Efr3/Ypp1 to human), underscoring conserved phosphoinositide‑based plasma‑membrane biology (PMID 26571211).

15. Model Organisms

Drosophila melanogaster (Taxon 7227): Established HCC model — glial Hyccin/FAM126A knockdown reduces glial enrichment and disrupts axonal sheaths and vision; fully rescued by human FAM126A or FAM126B and partially by membrane‑targeted mouse PI4KA; PI4KA knockdown phenocopies it (PMID 34894559). Demonstrates cell‑autonomous glial requirement via the PI4KA complex. Limitation: flies lack vertebrate compact myelin, so it models glial ensheathment, not CNS myelin per se.
Mouse (Taxon 10090): Brain studies show FAM126A loss destabilizes the PI4KA complex (PMID 26571211); FAM126A is the predominant oligodendrocyte isoform. (No widely reported full HCC knockout phenotype dataset.)
In vitro / cellular: HCC patient fibroblasts (reduced PtdIns(4)P, residual hyccin assays; PMIDs 26571211, 23998934); heterologous cell systems for missense‑allele ER‑aggregation/UPR studies (PMID 24417797). iPSC‑derived oligodendrocytes/organoids are a logical (largely untapped) human model.
Databases: FlyBase (Hyccin), MGI (Fam126a), Cellosaurus (patient fibroblast lines).

Supported vs Refuted Hypotheses

Supported: - HLD5/HCC is autosomal‑recessive and caused by biallelic FAM126A loss (PMID 16951682). - Mechanism = destabilized PI4KA complex → reduced PtdIns(4)P → failed oligodendrocyte membrane expansion → hypomyelination (PMID 26571211, 34894559). - Genotype–phenotype gradient: null alleles → severe CNS+PNS disease; hypomorphic missense → milder, PNS‑sparing (PMID 23998934). - A missense allele (L53P) adds an ER‑aggregation/UPR mechanism (PMID 24417797).

Refuted / not supported: - Environmental, infectious, or autoimmune causation (none; monogenic). - Dominant inheritance or X‑linkage (it is autosomal recessive). - Existence of disease‑modifying pharmacotherapy (none exists; supportive care only).

Limitations & Future Directions

Evidence rests on small case series and mechanistic in‑vitro/invertebrate models; no natural‑history registry, quality‑of‑life data, survival statistics, or clinical trials exist. A vertebrate (mouse/zebrafish) oligodendrocyte‑specific Fam126a model and human iPSC‑oligodendrocyte models would clarify CNS myelination mechanisms and the lens phenotype, and enable testing of PtdIns(4)P‑restoring or gene‑replacement therapies.

Key References (PMIDs)

16951682 (gene discovery) · 17683097 (phenotype) · 17974614 (neuroimaging/biopsy) · 21911699 (clinical spectrum) · 23998934 (genotype–phenotype) · 24417797 (ER aggregation/UPR; HLD5 = AR PMD‑like) · 26571211 (PI4KA complex/PtdIns(4)P mechanism) · 34894559 (Drosophila model) · 27234264 (HLD classification/differential).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.3.0.

Outcome	Count
References checked	10
Resolved	10
Unresolved (possible confabulation)	0
Unverifiable	0
References weighed for topical relevance	10
On topic	8
Off topic	0

All extracted references resolved successfully.

Term Validation

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

Outcome	Count
Terms checked	35
Resolved	32
Unresolved (possible confabulation)	0
Obsolete	1
Unverifiable	2
Terms whose name was checked	5
Terms named correctly	0
Terms named as a different term	3
Terms whose name is worth a second look	2

Terms the report names something else

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

HP:0001257 (1 mention) - the report calls it "Most"; HP calls it Spasticity
HP:0001251 (2 mentions) - the report calls it "Most", "Subset"; HP calls it Ataxia
HP:0002376 (1 mention) - the report calls it "Subset"; HP calls it Developmental regression

Obsolete terms

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

GO:0110147 (obsolete protein maturation by nickel ion transfer) (1 mention) - replaced by GO:0051604

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

HP:0000519 (1 mention) - the report calls it "congenital cataract"; HP calls it Developmental cataract, and lists "Cataract, congenital" among its other names
GO:0005886 (2 mentions) - the report calls it "Subcellular: plasma membrane"; GO calls it plasma membrane**, and lists "cellular membrane" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

HP:0001251 - called "Most", "Subset"

Prefixes with no resolver

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

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OpenScientist Report

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Animal Models

Source YAML

References & Deep Research

References

Deep Research

Hypomyelinating Leukodystrophy 5 (HLD5) — Comprehensive Disease Report

Summary (Answer to the Research Question)

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

Supported vs Refuted Hypotheses

Limitations & Future Directions

Key References (PMIDs)

Artifacts

Reference Validation

Term Validation

Terms the report names something else

Obsolete terms

Terms whose name is worth a second look

Terms named inconsistently

Prefixes with no resolver