👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

NCL7 is inherited in an autosomal recessive pattern and is caused by biallelic pathogenic variants in MFSD8.

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:35154277 SUPPORT Human Clinical

"Neuronal ceroid lipofuscinosis 7 (CLN7), one of the late infantile-onset NCLs, is an autosomal recessive disorder caused by mutations in the MFSD8 gene on chromosome 4q28."

This directly states autosomal recessive inheritance and MFSD8 causation for CLN7.

⚙

Pathophysiology

7

MFSD8 lysosomal membrane protein dysfunction

MFSD8 encodes a polytopic major facilitator superfamily protein that localizes mainly to lysosomes. Pathogenic MFSD8 variants impair the CLN7 lysosomal membrane protein and initiate the NCL7 disease process.

neuron link

MFSD8 link

lysosomal transport link ↕ DYSREGULATED

transmembrane transporter activity link ↕ DYSREGULATED

lysosomal membrane link

Downstream

Lysosomal autofluorescent storage material accumulation MFSD8 dysfunction is part of the NCL pathway that produces abnormal lysosomal storage material.

Impaired autophagy CLN7/MFSD8 loss-of-function model data link the upstream gene defect to autophagy failure.

Show evidence (2 references)

PMID:17564970 SUPPORT In Vitro

"Like the majority of the previously identified NCL proteins, MFSD8 localizes mainly to the lysosomal compartment."

Experimental localization data place MFSD8 in the lysosomal compartment, supporting a lysosomal membrane-protein mechanism.

PMID:35025759 SUPPORT Other

"Neuronal ceroid lipofuscinosis type 7 (CLN7) disease is a lysosomal storage disease caused by mutations in the facilitator superfamily domain containing 8 (MFSD8) gene, which encodes a membrane-bound lysosomal protein, MFSD8."

This statement directly links the human CLN7 disease to MFSD8 mutations and a membrane-bound lysosomal protein defect.

Lysosomal autofluorescent storage material accumulation

CLN7 belongs to the neuronal ceroid lipofuscinoses, which are defined by abnormal lysosomal accumulation of autofluorescent storage material. Reported MFSD8 cases show ultrastructural storage material in multiple patterns consistent with NCL.

neuron link

lysosomal transport link ↕ DYSREGULATED

Downstream

Progressive neurodegeneration Lysosomal storage pathology contributes to progressive neuronal dysfunction and loss.

Show evidence (2 references)

PMID:25270050 SUPPORT Human Clinical

"Neuronal ceroid lipofuscinosis (NCL) refers to a growing heterogeneous group of neurodegenerative disorders characterized by lysosomal accumulation of abnormal autofluorescent material."

This establishes abnormal lysosomal autofluorescent storage as the defining NCL pathology.

PMID:25270050 SUPPORT Human Clinical

"Ultrastructural studies of brain and rectal mucosa disclosed accumulation of storage material in various patterns including fingerprint, curvilinear, and granular osmiophilic deposits consistent with the diagnosis of NCL."

The MFSD8 family report documents NCL-type storage material in affected tissues.

Impaired autophagy

CLN7 loss-of-function model data show that autophagy failure is an early downstream cellular mechanism.

neuron link

autophagy link ↓ DECREASED

Downstream

Abnormal neuronal mitochondria accumulation Autophagy failure leads to accumulation of damaged neuronal mitochondria.

Show evidence (1 reference)

PMID:35087090 SUPPORT Model Organism

"failure in autophagy causes accumulation of structurally and bioenergetically impaired neuronal mitochondria."

CLN7 mouse model data support autophagy failure as a discrete pathogenic mechanism.

Abnormal neuronal mitochondria accumulation

Impaired autophagy causes structurally and bioenergetically abnormal neuronal mitochondria to accumulate in CLN7 model neurons.

neuron link

mitochondrion organization link ⚠ ABNORMAL

Downstream

Elevated mitochondrial reactive oxygen species Damaged neuronal mitochondria generate elevated mitochondrial reactive oxygen species.

Show evidence (1 reference)

PMID:35087090 SUPPORT Model Organism

"failure in autophagy causes accumulation of structurally and bioenergetically impaired neuronal mitochondria."

This directly supports abnormal mitochondrial accumulation downstream of autophagy failure.

Elevated mitochondrial reactive oxygen species

Accumulated abnormal mitochondria in CLN7 model neurons produce elevated mitochondrial reactive oxygen species signaling.

neuron link

reactive oxygen species metabolic process link ↑ INCREASED

Downstream

Aberrant PFKFB3 activation Elevated mitochondrial ROS drives PFKFB3 activation in CLN7 model neurons.

Show evidence (1 reference)

PMID:35087090 SUPPORT Model Organism

"In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis."

This identifies elevated mitochondrial ROS as a discrete intermediate between abnormal mitochondria and PFKFB3 activation.

Aberrant PFKFB3 activation

Mitochondrial ROS stabilizes and activates the glycolytic enzyme PFKFB3 in CLN7 model neurons, contributing to disease hallmarks.

neuron link

glycolytic process link ↑ INCREASED

6-phosphofructo-2-kinase activity link ↑ INCREASED

Downstream

Progressive neurodegeneration Aberrant neuronal PFKFB3 activation contributes to CLN7 pathogenesis and downstream neurodegeneration.

Show evidence (1 reference)

PMID:35087090 SUPPORT Model Organism

"Thus, aberrant upregulation of the glycolytic enzyme PFKFB3 in neurons may contribute to CLN7 pathogenesis"

This supports PFKFB3 activation as a downstream contributor to CLN7 pathogenesis in neurons.

Progressive neurodegeneration

NCL7 causes a progressive neurodegenerative phenotype that manifests as seizures, psychomotor deterioration, myoclonus, visual loss, cognitive decline, motor decline, and premature death.

neuron link

Downstream

Seizures Progressive neuronal dysfunction contributes to epileptic seizures.

Psychomotor deterioration Progressive neuronal disease produces loss of acquired motor and cognitive function.

Retinal degeneration and visual impairment NCL7 neurodegeneration includes progressive retinal disease and loss of vision.

Cognitive decline Progressive neurodegeneration causes cognitive decline in MFSD8-related disease.

Motor decline Progressive neurodegeneration causes motor decline in MFSD8-related disease.

Behavioral impairment Progressive neurodegeneration can include behavioral impairment.

Myoclonus Progressive neuronal dysfunction produces myoclonus in classic CLN7 disease.

Visual impairment Retinal and neuronal degeneration causes progressive visual impairment.

Show evidence (1 reference)

PMID:21990111 SUPPORT Human Clinical

"Clinical features include a variable age of onset, motor and mental decline, epilepsy, visual loss, and premature death."

This NCL mutation-spectrum review summarizes the core neurodegenerative clinical pattern that includes MFSD8/CLN7.

⬡

Pathograph

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

●

Phenotypes

8

Eye 1

Visual impairment Visual impairment (HP:0000505)

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:17564970 SUPPORT Human Clinical

"including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death."

The original MFSD8 paper lists loss of vision among the classic clinical manifestations.

Nervous System 5

Seizures Seizure (HP:0001250)

Show evidence (2 references)

PMID:17564970 SUPPORT Human Clinical

"including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death."

The original MFSD8 study lists epileptic seizures as part of the classic clinical presentation.

PMID:25270050 SUPPORT Human Clinical

"presented in early childhood with intractable seizures, severe cognitive and motor decline, behavioral impairment and progressive retinal degeneration."

This family study documents intractable seizures in MFSD8-related disease.

Psychomotor deterioration Developmental regression (HP:0002376)

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:17564970 SUPPORT Human Clinical

"including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death."

Psychomotor deterioration in childhood supports progressive developmental regression.

Cognitive decline Mental deterioration (HP:0001268)

Course: PROGRESSIVE

Show evidence (2 references)

PMID:25270050 SUPPORT Human Clinical

"presented in early childhood with intractable seizures, severe cognitive and motor decline, behavioral impairment and progressive retinal degeneration."

This directly describes severe cognitive decline in affected MFSD8 cases.

PMID:39555201 SUPPORT Human Clinical

"Two years later, she developed seizures and cognitive impairment, leading to a diagnosis of NCL7 resulting from a homozygote mutation in the MFSD8 gene."

This case report documents cognitive impairment emerging after visual presentation in MFSD8-related NCL7.

Behavioral impairment Atypical behavior (HP:0000708)

Show evidence (1 reference)

PMID:25270050 SUPPORT Human Clinical

"presented in early childhood with intractable seizures, severe cognitive and motor decline, behavioral impairment and progressive retinal degeneration."

This family study directly reports behavioral impairment in affected MFSD8-related vLINCL patients.

Myoclonus Myoclonus (HP:0001336)

Show evidence (1 reference)

PMID:17564970 SUPPORT Human Clinical

"including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death."

The MFSD8 locus paper explicitly includes myoclonus in the clinical presentation.

Other 2

Motor decline Functional motor deficit (HP:0004302)

Course: PROGRESSIVE

Show evidence (1 reference)

PMID:25270050 SUPPORT Human Clinical

"presented in early childhood with intractable seizures, severe cognitive and motor decline, behavioral impairment and progressive retinal degeneration."

The reported family had severe motor decline, supporting progressive motor deterioration as a clinical feature.

Retinal degeneration and visual impairment Retinal degeneration (HP:0000546)

Course: PROGRESSIVE

Show evidence (2 references)

PMID:25270050 SUPPORT Human Clinical

"presented in early childhood with intractable seizures, severe cognitive and motor decline, behavioral impairment and progressive retinal degeneration."

This directly documents progressive retinal degeneration in MFSD8-related disease.

PMID:39555201 SUPPORT Human Clinical

"She originally presented with visual failure, which rapidly progressed to near total bilateral blindness."

This case report shows visual failure as an early and rapidly progressive manifestation of NCL7.

🧬

Genetic Associations

1

MFSD8 (Causal biallelic pathogenic variants)

Show evidence (3 references)

PMID:17564970 SUPPORT Human Clinical

"We identified six different mutations in the MFSD8 gene (previously denoted "MGC33302"), which encodes a novel polytopic 518-amino acid membrane protein that belongs to the major facilitator superfamily of transporter proteins."

The original mapping study identifies MFSD8 mutations as the genetic cause of CLN7/variant late-infantile NCL.

PMID:19177532 SUPPORT Human Clinical

"We identified nine children harboring 11 different mutations in MFSD8/CLN7."

This patient cohort expands the MFSD8 mutation spectrum in variant-late-infantile NCL.

PMID:35154277 SUPPORT Human Clinical

"we report a 4-year-old boy with CLN7 harboring compound heterozygous mutations in the MFSD8 gene, including one novel two-nucleotide deletion c.136_137delAT (p. M46Vfs*22) and one whole gene deletion of MFSD8 confirmed by Sanger sequencing, genomic quantitative PCR and CNV-seq."

This case report shows that copy-number loss can contribute to biallelic MFSD8 disease, supporting deletion/duplication-aware genetic testing.

💊

Treatments

3

AAV9/MFSD8 gene therapy

Action: gene therapy MAXO:0001001

MFSD8 gene replacement is a preclinical disease-targeted strategy. AAV9/MFSD8 improved lysosomal function in patient fibroblasts and extended lifespan in Mfsd8-deficient mice, but the cited evidence remains preclinical.

Mechanism Target:

RESTORES MFSD8 lysosomal membrane protein dysfunction — Gene replacement aims to restore MFSD8 expression upstream of lysosomal dysfunction and storage pathology.

Show evidence (1 reference)

PMID:35025759 SUPPORT In Vitro

"an in vitro study demonstrated that AAV2/MFSD8 dose dependently rescued lysosomal function in fibroblasts from a CLN7 patient."

Patient-fibroblast rescue directly supports MFSD8 gene replacement as restoring lysosomal function in an MFSD8-deficient cellular system.

Show evidence (2 references)

PMID:35025759 PARTIAL In Vitro

"an in vitro study demonstrated that AAV2/MFSD8 dose dependently rescued lysosomal function in fibroblasts from a CLN7 patient."

Patient-fibroblast rescue supports the biological plausibility of MFSD8 gene replacement but is not clinical efficacy evidence.

PMID:35025759 PARTIAL Model Organism

"A high dose of AAV9/MFSD8 at P7-P10 resulted in widespread MFSD8 mRNA expression, tendency of amelioration of subunit c of mitochondrial ATP synthase accumulation and glial fibrillary acidic protein immunoreactivity, normalization of impaired behaviors, doubled median life span, and extended..."

Mouse efficacy data support AAV9/MFSD8 as a promising preclinical disease-targeted treatment, so support is partial for human treatment.

Milasen (patient-customized splice-modulating ASO)

Action: Pharmacotherapy NCIT:C15986

Agent: milasen

Milasen is an investigational n-of-1 splice-modulating antisense oligonucleotide developed for a single CLN7 patient whose MFSD8 intron 6 SVA retrotransposon insertion created a cryptic splice-acceptor site. It is designed to occlude that cryptic site and restore normal MFSD8 splicing. Milasen is customized to that patient's specific mutation and is not a generalizable CLN7 therapy; the evidence is a single expanded-access case.

Mechanism Target:

RESTORES MFSD8 lysosomal membrane protein dysfunction — Milasen targets the patient-specific i6.SA cryptic splice-acceptor site to correct MFSD8 missplicing and restore functional MFSD8 expression upstream of lysosomal storage pathology.

Show evidence (2 references)

PMID:31597037 SUPPORT In Vitro

"correct missplicing and restore MFSD8 expression in our patient, we designed antisense oligonucleotides to target the i6.SA cryptic splice-acceptor site and nearby splice enhancers"

The ASO was designed to occlude the cryptic splice-acceptor site and restore normal MFSD8 splicing, directly targeting MFSD8 dysfunction.

PMID:31597037 SUPPORT In Vitro

"All these phenotypes were alleviated by milasen administration, indicating that treatment could rescue not only splicing but also function."

In patient fibroblasts, milasen rescued lysosomal phenotypes, supporting restoration of MFSD8 function at the cellular level.

Show evidence (2 references)

PMID:31597037 PARTIAL Human Clinical

"We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient."

Establishes milasen as a splice-modulating ASO developed for this CLN7 patient; support is partial because the evidence is a single n-of-1 case.

PMID:31597037 PARTIAL Human Clinical

"There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting)."

The n-of-1 clinical course showed acceptable safety and objective seizure reduction; partial because a single uncontrolled case cannot establish efficacy.

PFKFB3 inhibitor AZ67

Action: Pharmacotherapy NCIT:C15986

Agent: AZ67

PFKFB3 inhibition is an experimental downstream strategy in CLN7 model systems. AZ67 rectified key disease hallmarks in Cln7 mouse brain and patient-derived cells, but the evidence is preclinical.

Mechanism Target:

INHIBITS Aberrant PFKFB3 activation — PFKFB3 inhibition targets the downstream glycolytic enzyme activation implicated in CLN7 pathogenesis.

Show evidence (2 references)

PMID:35087090 SUPPORT Model Organism

"Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks."

The mouse-brain component supports AZ67 as an in vivo PFKFB3-inhibitor intervention against CLN7 disease hallmarks.

PMID:35087090 SUPPORT In Vitro

"Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks."

The patient-derived-cell component supports AZ67 as an in vitro PFKFB3-inhibitor intervention against CLN7 disease hallmarks.

Show evidence (2 references)

PMID:35087090 PARTIAL Model Organism

"Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks."

The mouse-brain component of this preclinical result supports PFKFB3 inhibition as an experimental treatment strategy.

PMID:35087090 PARTIAL In Vitro

"Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks."

The patient-derived-cell component supports in vitro rescue, but not yet clinical efficacy.

🔬

Biochemical Markers

2

Mitochondrial reactive oxygen species (INCREASED)

Context: Elevated mitochondrial reactive oxygen species are a model-based cellular readout of the abnormal-mitochondria branch in CLN7 loss of function.

Pathograph Readouts

Readout Of Elevated mitochondrial reactive oxygen species Positive Monitoring

Increased mitochondrial ROS directly reports the ROS node downstream of impaired autophagy and abnormal mitochondria.

Show evidence (1 reference)

PMID:35087090 SUPPORT Model Organism

"In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis."

The mouse-model study directly identifies elevated mitochondrial ROS in CLN7 neurons.

Show evidence (1 reference)

PMID:35087090 SUPPORT Model Organism

"In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis."

This supports mitochondrial ROS as an increased model-system readout.

PFKFB3 activation (INCREASED)

Context: PFKFB3 protein stabilization and activation is a downstream model-system readout of mitochondrial ROS signaling and a pharmacodynamic target of AZ67.

Pathograph Readouts

Readout Of Aberrant PFKFB3 activation Positive Pharmacodynamic

Increased PFKFB3 reports activation of the glycolytic-enzyme node and can be used to read response to PFKFB3 inhibition in model systems.

Show evidence (1 reference)

PMID:35087090 SUPPORT Model Organism

"Mechanistically, mROS sustains a signaling cascade leading to protein stabilization of PFKFB3, normally unstable in healthy neurons."

This directly supports PFKFB3 stabilization as the readout of the PFKFB3 activation mechanism.

Show evidence (1 reference)

PMID:35087090 SUPPORT Model Organism

"Thus, aberrant upregulation of the glycolytic enzyme PFKFB3 in neurons may contribute to CLN7 pathogenesis"

This supports PFKFB3 upregulation as a model-system biomarker and pathogenic mechanism readout.

{ }

Source YAML

click to show

name: Neuronal Ceroid Lipofuscinosis 7
category: Mendelian
creation_date: '2026-05-06T11:55:32Z'
updated_date: '2026-05-20T22:18:05Z'
description: >
  Neuronal ceroid lipofuscinosis 7 is an autosomal recessive MFSD8-related
  neuronal ceroid lipofuscinosis. Classic disease usually presents in early
  childhood as a variant late-infantile NCL with epilepsy, psychomotor and
  motor deterioration, myoclonus, progressive visual loss from retinal
  degeneration, cognitive decline, lysosomal autofluorescent storage material,
  and premature death. MFSD8 encodes a lysosomal membrane protein; loss of
  CLN7/MFSD8 function disrupts lysosomal biology and is linked in model systems
  to impaired autophagy, damaged neuronal mitochondria, oxidative stress, and
  aberrant PFKFB3 activation.
disease_term:
  preferred_term: neuronal ceroid lipofuscinosis 7
  term:
    id: MONDO:0012588
    label: neuronal ceroid lipofuscinosis 7
synonyms:
- CLN7
- CLN7 disease
- neuronal ceroid lipofuscinosis type 7
- MFSD8 neuronal ceroid lipofuscinosis
- ceroid lipofuscinosis, neuronal, type 7
- variant late-infantile neuronal ceroid lipofuscinosis 7
parents:
- Neuronal Ceroid Lipofuscinosis
- Late Infantile Neuronal Ceroid Lipofuscinosis
- Lysosomal Storage Disease
- Neurodegenerative Disease
inheritance:
- name: Autosomal recessive inheritance
  description: >
    NCL7 is inherited in an autosomal recessive pattern and is caused by
    biallelic pathogenic variants in MFSD8.
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:35154277
    reference_title: "Case Report: Novel MFSD8 Variants in a Chinese Family With Neuronal Ceroid Lipofuscinoses 7."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuronal ceroid lipofuscinosis 7 (CLN7), one of the late infantile-onset NCLs, is an autosomal recessive disorder caused by mutations in the MFSD8 gene on chromosome 4q28."
    explanation: >
      This directly states autosomal recessive inheritance and MFSD8 causation
      for CLN7.
progression:
- phase: Classic variant late-infantile onset
  age_range: Early childhood
  notes: >
    Classic NCL7 overlaps clinically with variant late-infantile NCL, often
    beginning between ages two and seven years with seizures and progressive
    neurodevelopmental deterioration.
  evidence:
  - reference: PMID:17564970
    reference_title: "The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death."
    explanation: >
      The original MFSD8 locus paper describes the typical Turkish variant
      late-infantile NCL phenotype and onset window.
- phase: Severe progressive neurologic decline
  age_range: Childhood to adolescence
  notes: >
    Severe childhood-onset cases may progress to loss of independent function,
    advanced neurologic impairment, and premature death by adolescence or young
    adulthood.
  evidence:
  - reference: PMID:25270050
    reference_title: "Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disease course was severe; all patients were in a vegetative state by the second decade of life, and eventually die prematurely (except in one case)."
    explanation: >
      This family study documents severe progression and premature mortality in
      MFSD8-related vLINCL.
genetic:
- name: MFSD8
  association: Causal biallelic pathogenic variants
  presence: Positive
  gene_term:
    preferred_term: MFSD8
    term:
      id: hgnc:28486
      label: MFSD8
  notes: >
    Disease-causing MFSD8 variants include missense, nonsense, splice-site,
    frameshift, small-deletion, and whole-gene deletion alleles. Variant type
    does not fully explain clinical severity in reported cohorts.
  evidence:
  - reference: PMID:17564970
    reference_title: "The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified six different mutations in the MFSD8 gene (previously denoted \"MGC33302\"), which encodes a novel polytopic 518-amino acid membrane protein that belongs to the major facilitator superfamily of transporter proteins."
    explanation: >
      The original mapping study identifies MFSD8 mutations as the genetic
      cause of CLN7/variant late-infantile NCL.
  - reference: PMID:19177532
    reference_title: "Mutations in MFSD8/CLN7 are a frequent cause of variant-late infantile neuronal ceroid lipofuscinosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified nine children harboring 11 different mutations in MFSD8/CLN7."
    explanation: >
      This patient cohort expands the MFSD8 mutation spectrum in
      variant-late-infantile NCL.
  - reference: PMID:35154277
    reference_title: "Case Report: Novel MFSD8 Variants in a Chinese Family With Neuronal Ceroid Lipofuscinoses 7."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we report a 4-year-old boy with CLN7 harboring compound heterozygous mutations in the MFSD8 gene, including one novel two-nucleotide deletion c.136_137delAT (p. M46Vfs*22) and one whole gene deletion of MFSD8 confirmed by Sanger sequencing, genomic quantitative PCR and CNV-seq."
    explanation: >
      This case report shows that copy-number loss can contribute to biallelic
      MFSD8 disease, supporting deletion/duplication-aware genetic testing.
pathophysiology:
- name: MFSD8 lysosomal membrane protein dysfunction
  description: >
    MFSD8 encodes a polytopic major facilitator superfamily protein that
    localizes mainly to lysosomes. Pathogenic MFSD8 variants impair the CLN7
    lysosomal membrane protein and initiate the NCL7 disease process.
  genes:
  - preferred_term: MFSD8
    term:
      id: hgnc:28486
      label: MFSD8
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  molecular_functions:
  - preferred_term: transmembrane transporter activity
    modifier: DYSREGULATED
    term:
      id: GO:0022857
      label: transmembrane transporter activity
  biological_processes:
  - preferred_term: lysosomal transport
    modifier: DYSREGULATED
    term:
      id: GO:0007041
      label: lysosomal transport
  cellular_components:
  - preferred_term: lysosomal membrane
    term:
      id: GO:0005765
      label: lysosomal membrane
  evidence:
  - reference: PMID:17564970
    reference_title: "The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Like the majority of the previously identified NCL proteins, MFSD8 localizes mainly to the lysosomal compartment."
    explanation: >
      Experimental localization data place MFSD8 in the lysosomal compartment,
      supporting a lysosomal membrane-protein mechanism.
  - reference: PMID:35025759
    reference_title: "AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Neuronal ceroid lipofuscinosis type 7 (CLN7) disease is a lysosomal storage disease caused by mutations in the facilitator superfamily domain containing 8 (MFSD8) gene, which encodes a membrane-bound lysosomal protein, MFSD8."
    explanation: >
      This statement directly links the human CLN7 disease to MFSD8 mutations
      and a membrane-bound lysosomal protein defect.
  downstream:
  - target: Lysosomal autofluorescent storage material accumulation
    description: MFSD8 dysfunction is part of the NCL pathway that produces abnormal lysosomal storage material.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Impaired autophagy
    description: CLN7/MFSD8 loss-of-function model data link the upstream gene defect to autophagy failure.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Lysosomal autofluorescent storage material accumulation
  description: >
    CLN7 belongs to the neuronal ceroid lipofuscinoses, which are defined by
    abnormal lysosomal accumulation of autofluorescent storage material.
    Reported MFSD8 cases show ultrastructural storage material in multiple
    patterns consistent with NCL.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: lysosomal transport
    modifier: DYSREGULATED
    term:
      id: GO:0007041
      label: lysosomal transport
  evidence:
  - reference: PMID:25270050
    reference_title: "Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neuronal ceroid lipofuscinosis (NCL) refers to a growing heterogeneous group of neurodegenerative disorders characterized by lysosomal accumulation of abnormal autofluorescent material."
    explanation: >
      This establishes abnormal lysosomal autofluorescent storage as the
      defining NCL pathology.
  - reference: PMID:25270050
    reference_title: "Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ultrastructural studies of brain and rectal mucosa disclosed accumulation of storage material in various patterns including fingerprint, curvilinear, and granular osmiophilic deposits consistent with the diagnosis of NCL."
    explanation: >
      The MFSD8 family report documents NCL-type storage material in affected
      tissues.
  downstream:
  - target: Progressive neurodegeneration
    description: Lysosomal storage pathology contributes to progressive neuronal dysfunction and loss.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Impaired autophagy
  description: >
    CLN7 loss-of-function model data show that autophagy failure is an early
    downstream cellular mechanism.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: autophagy
    modifier: DECREASED
    term:
      id: GO:0006914
      label: autophagy
  evidence:
  - reference: PMID:35087090
    reference_title: "Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "failure in autophagy causes accumulation of structurally and bioenergetically impaired neuronal mitochondria."
    explanation: >
      CLN7 mouse model data support autophagy failure as a discrete pathogenic
      mechanism.
  downstream:
  - target: Abnormal neuronal mitochondria accumulation
    description: Autophagy failure leads to accumulation of damaged neuronal mitochondria.
    causal_link_type: DIRECT
- name: Abnormal neuronal mitochondria accumulation
  description: >
    Impaired autophagy causes structurally and bioenergetically abnormal
    neuronal mitochondria to accumulate in CLN7 model neurons.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: mitochondrion organization
    modifier: ABNORMAL
    term:
      id: GO:0007005
      label: mitochondrion organization
  evidence:
  - reference: PMID:35087090
    reference_title: "Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "failure in autophagy causes accumulation of structurally and bioenergetically impaired neuronal mitochondria."
    explanation: >
      This directly supports abnormal mitochondrial accumulation downstream of
      autophagy failure.
  downstream:
  - target: Elevated mitochondrial reactive oxygen species
    description: Damaged neuronal mitochondria generate elevated mitochondrial reactive oxygen species.
    causal_link_type: DIRECT
- name: Elevated mitochondrial reactive oxygen species
  description: >
    Accumulated abnormal mitochondria in CLN7 model neurons produce elevated
    mitochondrial reactive oxygen species signaling.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  biological_processes:
  - preferred_term: reactive oxygen species metabolic process
    modifier: INCREASED
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
  evidence:
  - reference: PMID:35087090
    reference_title: "Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis."
    explanation: >
      This identifies elevated mitochondrial ROS as a discrete intermediate
      between abnormal mitochondria and PFKFB3 activation.
  downstream:
  - target: Aberrant PFKFB3 activation
    description: Elevated mitochondrial ROS drives PFKFB3 activation in CLN7 model neurons.
    causal_link_type: DIRECT
- name: Aberrant PFKFB3 activation
  description: >
    Mitochondrial ROS stabilizes and activates the glycolytic enzyme PFKFB3 in
    CLN7 model neurons, contributing to disease hallmarks.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  molecular_functions:
  - preferred_term: 6-phosphofructo-2-kinase activity
    modifier: INCREASED
    term:
      id: GO:0003873
      label: 6-phosphofructo-2-kinase activity
  biological_processes:
  - preferred_term: glycolytic process
    modifier: INCREASED
    term:
      id: GO:0006096
      label: glycolytic process
  evidence:
  - reference: PMID:35087090
    reference_title: "Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Thus, aberrant upregulation of the glycolytic enzyme PFKFB3 in neurons may contribute to CLN7 pathogenesis"
    explanation: >
      This supports PFKFB3 activation as a downstream contributor to CLN7
      pathogenesis in neurons.
  downstream:
  - target: Progressive neurodegeneration
    description: Aberrant neuronal PFKFB3 activation contributes to CLN7 pathogenesis and downstream neurodegeneration.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
- name: Progressive neurodegeneration
  description: >
    NCL7 causes a progressive neurodegenerative phenotype that manifests as
    seizures, psychomotor deterioration, myoclonus, visual loss, cognitive
    decline, motor decline, and premature death.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  evidence:
  - reference: PMID:21990111
    reference_title: "Update of the mutation spectrum and clinical correlations of over 360 mutations in eight genes that underlie the neuronal ceroid lipofuscinoses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical features include a variable age of onset, motor and mental decline, epilepsy, visual loss, and premature death."
    explanation: >
      This NCL mutation-spectrum review summarizes the core neurodegenerative
      clinical pattern that includes MFSD8/CLN7.
  downstream:
  - target: Seizures
    description: Progressive neuronal dysfunction contributes to epileptic seizures.
    causal_link_type: DIRECT
  - target: Psychomotor deterioration
    description: Progressive neuronal disease produces loss of acquired motor and cognitive function.
    causal_link_type: DIRECT
  - target: Retinal degeneration and visual impairment
    description: NCL7 neurodegeneration includes progressive retinal disease and loss of vision.
    causal_link_type: DIRECT
  - target: Cognitive decline
    description: Progressive neurodegeneration causes cognitive decline in MFSD8-related disease.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25270050
      reference_title: "Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "presented in early childhood with intractable seizures, severe cognitive and motor decline, behavioral impairment and progressive retinal degeneration."
      explanation: >
        The family study directly links MFSD8-related disease to severe
        cognitive decline.
  - target: Motor decline
    description: Progressive neurodegeneration causes motor decline in MFSD8-related disease.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25270050
      reference_title: "Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "presented in early childhood with intractable seizures, severe cognitive and motor decline, behavioral impairment and progressive retinal degeneration."
      explanation: >
        The family study directly links MFSD8-related disease to severe motor
        decline.
  - target: Behavioral impairment
    description: Progressive neurodegeneration can include behavioral impairment.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25270050
      reference_title: "Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "presented in early childhood with intractable seizures, severe cognitive and motor decline, behavioral impairment and progressive retinal degeneration."
      explanation: >
        The family study directly reports behavioral impairment in the severe
        MFSD8-related phenotype.
  - target: Myoclonus
    description: Progressive neuronal dysfunction produces myoclonus in classic CLN7 disease.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17564970
      reference_title: "The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death."
      explanation: >
        The original MFSD8 locus paper includes myoclonus in the progressive
        CLN7 clinical presentation.
  - target: Visual impairment
    description: Retinal and neuronal degeneration causes progressive visual impairment.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:17564970
      reference_title: "The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death."
      explanation: >
        The original MFSD8 locus paper lists loss of vision as part of the
        classic CLN7 phenotype.
phenotypes:
- name: Seizures
  category: Neurologic
  description: >
    Epileptic seizures are a core manifestation of classic CLN7 disease and can
    be intractable in severe cases.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:17564970
    reference_title: "The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death."
    explanation: >
      The original MFSD8 study lists epileptic seizures as part of the classic
      clinical presentation.
  - reference: PMID:25270050
    reference_title: "Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented in early childhood with intractable seizures, severe cognitive and motor decline, behavioral impairment and progressive retinal degeneration."
    explanation: >
      This family study documents intractable seizures in MFSD8-related
      disease.
- name: Psychomotor deterioration
  category: Neurologic
  description: >
    Children with classic NCL7 lose motor and cognitive abilities during disease
    progression.
  phenotype_term:
    preferred_term: Psychomotor deterioration
    term:
      id: HP:0002376
      label: Developmental regression
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:17564970
    reference_title: "The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death."
    explanation: >
      Psychomotor deterioration in childhood supports progressive developmental
      regression.
- name: Cognitive decline
  category: Neurologic
  description: >
    Progressive cognitive decline is part of the severe neurologic
    deterioration in MFSD8-related disease.
  phenotype_term:
    preferred_term: Cognitive decline
    term:
      id: HP:0001268
      label: Mental deterioration
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:25270050
    reference_title: "Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented in early childhood with intractable seizures, severe cognitive and motor decline, behavioral impairment and progressive retinal degeneration."
    explanation: >
      This directly describes severe cognitive decline in affected MFSD8 cases.
  - reference: PMID:39555201
    reference_title: "Cone-Rod Dystrophy and Progressive Visual Loss as the First Manifestation of Neuronal Ceroid Lipofuscinosis Type 7: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Two years later, she developed seizures and cognitive impairment, leading to a diagnosis of NCL7 resulting from a homozygote mutation in the MFSD8 gene."
    explanation: >
      This case report documents cognitive impairment emerging after visual
      presentation in MFSD8-related NCL7.
- name: Motor decline
  category: Neurologic
  description: >
    Severe motor decline accompanies cognitive deterioration in classic
    MFSD8-related NCL7.
  phenotype_term:
    preferred_term: Motor decline
    term:
      id: HP:0004302
      label: Functional motor deficit
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:25270050
    reference_title: "Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented in early childhood with intractable seizures, severe cognitive and motor decline, behavioral impairment and progressive retinal degeneration."
    explanation: >
      The reported family had severe motor decline, supporting progressive
      motor deterioration as a clinical feature.
- name: Behavioral impairment
  category: Psychiatric
  description: >
    Behavioral impairment can accompany the progressive neurologic phenotype in
    severe childhood-onset MFSD8-related disease.
  phenotype_term:
    preferred_term: Behavioral impairment
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:25270050
    reference_title: "Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented in early childhood with intractable seizures, severe cognitive and motor decline, behavioral impairment and progressive retinal degeneration."
    explanation: >
      This family study directly reports behavioral impairment in affected
      MFSD8-related vLINCL patients.
- name: Myoclonus
  category: Neurologic
  description: >
    Myoclonus is included in the classic variant late-infantile NCL phenotype
    associated with CLN7/MFSD8.
  phenotype_term:
    preferred_term: Myoclonus
    term:
      id: HP:0001336
      label: Myoclonus
  evidence:
  - reference: PMID:17564970
    reference_title: "The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death."
    explanation: >
      The MFSD8 locus paper explicitly includes myoclonus in the clinical
      presentation.
- name: Retinal degeneration and visual impairment
  category: Ophthalmologic
  description: >
    Retinal degeneration causes progressive visual loss and can be the initial
    presentation before seizures and cognitive impairment.
  phenotype_term:
    preferred_term: Retinal degeneration
    term:
      id: HP:0000546
      label: Retinal degeneration
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:25270050
    reference_title: "Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presented in early childhood with intractable seizures, severe cognitive and motor decline, behavioral impairment and progressive retinal degeneration."
    explanation: >
      This directly documents progressive retinal degeneration in MFSD8-related
      disease.
  - reference: PMID:39555201
    reference_title: "Cone-Rod Dystrophy and Progressive Visual Loss as the First Manifestation of Neuronal Ceroid Lipofuscinosis Type 7: A Case Report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She originally presented with visual failure, which rapidly progressed to near total bilateral blindness."
    explanation: >
      This case report shows visual failure as an early and rapidly progressive
      manifestation of NCL7.
- name: Visual impairment
  category: Ophthalmologic
  description: >
    Progressive loss of vision is part of the classic CLN7 disease phenotype.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:17564970
    reference_title: "The novel neuronal ceroid lipofuscinosis gene MFSD8 encodes a putative lysosomal transporter."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "including age at onset from 2 to 7 years, epileptic seizures, psychomotor deterioration, myoclonus, loss of vision, and premature death."
    explanation: >
      The original MFSD8 paper lists loss of vision among the classic clinical
      manifestations.
biochemical:
- name: Mitochondrial reactive oxygen species
  biomarker_term:
    preferred_term: reactive oxygen species
    term:
      id: NCIT:C80367
      label: Reactive Oxygen Species
  presence: INCREASED
  context: >
    Elevated mitochondrial reactive oxygen species are a model-based cellular
    readout of the abnormal-mitochondria branch in CLN7 loss of function.
  readouts:
  - target: Elevated mitochondrial reactive oxygen species
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >
      Increased mitochondrial ROS directly reports the ROS node downstream of
      impaired autophagy and abnormal mitochondria.
    evidence:
    - reference: PMID:35087090
      reference_title: "Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis."
      explanation: >
        The mouse-model study directly identifies elevated mitochondrial ROS in
        CLN7 neurons.
  evidence:
  - reference: PMID:35087090
    reference_title: "Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In vivo genetic approach reveals elevated mitochondrial reactive oxygen species (mROS) in Cln7∆ex2 neurons that mediates glycolytic enzyme PFKFB3 activation and contributes to CLN7 pathogenesis."
    explanation: >
      This supports mitochondrial ROS as an increased model-system readout.
- name: PFKFB3 activation
  biomarker_term:
    preferred_term: 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3
    term:
      id: NCIT:C102810
      label: 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 3
  presence: INCREASED
  context: >
    PFKFB3 protein stabilization and activation is a downstream model-system
    readout of mitochondrial ROS signaling and a pharmacodynamic target of AZ67.
  readouts:
  - target: Aberrant PFKFB3 activation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: PHARMACODYNAMIC
    interpretation: >
      Increased PFKFB3 reports activation of the glycolytic-enzyme node and can
      be used to read response to PFKFB3 inhibition in model systems.
    evidence:
    - reference: PMID:35087090
      reference_title: "Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Mechanistically, mROS sustains a signaling cascade leading to protein stabilization of PFKFB3, normally unstable in healthy neurons."
      explanation: >
        This directly supports PFKFB3 stabilization as the readout of the
        PFKFB3 activation mechanism.
  evidence:
  - reference: PMID:35087090
    reference_title: "Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Thus, aberrant upregulation of the glycolytic enzyme PFKFB3 in neurons may contribute to CLN7 pathogenesis"
    explanation: >
      This supports PFKFB3 upregulation as a model-system biomarker and
      pathogenic mechanism readout.
diagnosis:
- name: Clinic-molecular diagnosis
  description: >
    Diagnosis should integrate the clinical NCL phenotype with molecular
    testing for MFSD8 sequence variants and deletion/duplication events; tissue
    ultrastructure can support NCL classification when available.
  evidence:
  - reference: PMID:25270050
    reference_title: "Clinico-pathological manifestations of variant late infantile neuronal ceroid lipofuscinosis (vLINCL) caused by a novel mutation in MFSD8 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This study underscores the importance of a combined clinic-molecular workup in NCLs and other neurodegenerative conditions."
    explanation: >
      This supports integrating clinical presentation with molecular analysis.
  - reference: PMID:35154277
    reference_title: "Case Report: Novel MFSD8 Variants in a Chinese Family With Neuronal Ceroid Lipofuscinoses 7."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This is one case report describing a whole gene deletion in a Chinese patient with CLN7, suggesting the diagnosis of CLN7 should be based on clinical suspicion and genetic testing."
    explanation: >
      This supports genetic testing and copy-number-aware evaluation in
      suspected CLN7.
treatments:
- name: AAV9/MFSD8 gene therapy
  description: >
    MFSD8 gene replacement is a preclinical disease-targeted strategy. AAV9/MFSD8
    improved lysosomal function in patient fibroblasts and extended lifespan in
    Mfsd8-deficient mice, but the cited evidence remains preclinical.
  treatment_term:
    preferred_term: gene therapy
    term:
      id: MAXO:0001001
      label: gene therapy
  target_mechanisms:
  - target: MFSD8 lysosomal membrane protein dysfunction
    treatment_effect: RESTORES
    description: >
      Gene replacement aims to restore MFSD8 expression upstream of lysosomal
      dysfunction and storage pathology.
    evidence:
    - reference: PMID:35025759
      reference_title: "AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "an in vitro study demonstrated that AAV2/MFSD8 dose dependently rescued lysosomal function in fibroblasts from a CLN7 patient."
      explanation: >
        Patient-fibroblast rescue directly supports MFSD8 gene replacement as
        restoring lysosomal function in an MFSD8-deficient cellular system.
  evidence:
  - reference: PMID:35025759
    reference_title: "AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "an in vitro study demonstrated that AAV2/MFSD8 dose dependently rescued lysosomal function in fibroblasts from a CLN7 patient."
    explanation: >
      Patient-fibroblast rescue supports the biological plausibility of MFSD8
      gene replacement but is not clinical efficacy evidence.
  - reference: PMID:35025759
    reference_title: "AAV9/MFSD8 gene therapy is effective in preclinical models of neuronal ceroid lipofuscinosis type 7 disease."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "A high dose of AAV9/MFSD8 at P7-P10 resulted in widespread MFSD8 mRNA expression, tendency of amelioration of subunit c of mitochondrial ATP synthase accumulation and glial fibrillary acidic protein immunoreactivity, normalization of impaired behaviors, doubled median life span, and extended normal body weight gain."
    explanation: >
      Mouse efficacy data support AAV9/MFSD8 as a promising preclinical
      disease-targeted treatment, so support is partial for human treatment.
- name: Milasen (patient-customized splice-modulating ASO)
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  aso_details:
    aso_mechanism: SPLICE_MODULATION_EXON_SKIPPING
    target_gene:
      preferred_term: MFSD8
      term:
        id: hgnc:28486
        label: MFSD8
    target_transcript: MFSD8 pre-mRNA (cryptic splice-acceptor from intron 6 SVA insertion)
    aso_chemistry: TWO_PRIME_O_METHOXYETHYL
    conjugation: UNCONJUGATED
  description: >
    Milasen is an investigational n-of-1 splice-modulating antisense
    oligonucleotide developed for a single CLN7 patient whose MFSD8 intron 6
    SVA retrotransposon insertion created a cryptic splice-acceptor site. It is
    designed to occlude that cryptic site and restore normal MFSD8 splicing.
    Milasen is customized to that patient's specific mutation and is not a
    generalizable CLN7 therapy; the evidence is a single expanded-access case.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: milasen
  target_mechanisms:
  - target: MFSD8 lysosomal membrane protein dysfunction
    treatment_effect: RESTORES
    description: >
      Milasen targets the patient-specific i6.SA cryptic splice-acceptor site to
      correct MFSD8 missplicing and restore functional MFSD8 expression upstream
      of lysosomal storage pathology.
    evidence:
    - reference: PMID:31597037
      reference_title: "Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "correct missplicing and restore MFSD8 expression in our patient, we designed antisense oligonucleotides to target the i6.SA cryptic splice-acceptor site and nearby splice enhancers"
      explanation: >
        The ASO was designed to occlude the cryptic splice-acceptor site and
        restore normal MFSD8 splicing, directly targeting MFSD8 dysfunction.
    - reference: PMID:31597037
      reference_title: "Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "All these phenotypes were alleviated by milasen administration, indicating that treatment could rescue not only splicing but also function."
      explanation: >
        In patient fibroblasts, milasen rescued lysosomal phenotypes, supporting
        restoration of MFSD8 function at the cellular level.
  evidence:
  - reference: PMID:31597037
    reference_title: "Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe how molecular diagnosis of a rare, fatal neurodegenerative condition led to the rational design, testing, and manufacture of milasen, a splice-modulating antisense oligonucleotide drug tailored to a particular patient."
    explanation: >
      Establishes milasen as a splice-modulating ASO developed for this CLN7
      patient; support is partial because the evidence is a single n-of-1 case.
  - reference: PMID:31597037
    reference_title: "Patient-Customized Oligonucleotide Therapy for a Rare Genetic Disease."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "There were no serious adverse events, and treatment was associated with objective reduction in seizures (determined by electroencephalography and parental reporting)."
    explanation: >
      The n-of-1 clinical course showed acceptable safety and objective seizure
      reduction; partial because a single uncontrolled case cannot establish
      efficacy.
- name: PFKFB3 inhibitor AZ67
  description: >
    PFKFB3 inhibition is an experimental downstream strategy in CLN7 model
    systems. AZ67 rectified key disease hallmarks in Cln7 mouse brain and
    patient-derived cells, but the evidence is preclinical.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: AZ67
  target_mechanisms:
  - target: Aberrant PFKFB3 activation
    treatment_effect: INHIBITS
    description: >
      PFKFB3 inhibition targets the downstream glycolytic enzyme activation
      implicated in CLN7 pathogenesis.
    evidence:
    - reference: PMID:35087090
      reference_title: "Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks."
      explanation: >
        The mouse-brain component supports AZ67 as an in vivo PFKFB3-inhibitor
        intervention against CLN7 disease hallmarks.
    - reference: PMID:35087090
      reference_title: "Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks."
      explanation: >
        The patient-derived-cell component supports AZ67 as an in vitro
        PFKFB3-inhibitor intervention against CLN7 disease hallmarks.
  evidence:
  - reference: PMID:35087090
    reference_title: "Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis."
    supports: PARTIAL
    evidence_source: MODEL_ORGANISM
    snippet: "Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks."
    explanation: >
      The mouse-brain component of this preclinical result supports PFKFB3
      inhibition as an experimental treatment strategy.
  - reference: PMID:35087090
    reference_title: "Aberrant upregulation of the glycolytic enzyme PFKFB3 in CLN7 neuronal ceroid lipofuscinosis."
    supports: PARTIAL
    evidence_source: IN_VITRO
    snippet: "Administration of the highly selective PFKFB3 inhibitor AZ67 in Cln7∆ex2 mouse brain in vivo and in CLN7 patients-derived cells rectifies key disease hallmarks."
    explanation: >
      The patient-derived-cell component supports in vitro rescue, but not yet
      clinical efficacy.
references:
- reference: PMID:20301601
  title: Neuronal Ceroid Lipofuscinoses Overview.
  tags:
  - GeneReviews

📚

References & Deep Research

References

1

PMID:20301601

Neuronal Ceroid Lipofuscinoses Overview.

No top-level findings curated for this source.

Deep Research

1

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Neuronal Ceroid Lipofuscinosis 7. Core disease mechanisms, molecular and c...

Asta Scientific Corpus Retrieval 20 citations 2026-05-06T10:31:29.623524

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Neuronal Ceroid Lipofuscinosis 7. Core disease mechanisms, molecular and c...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Recent insights into the networking of CLN genes and proteins in mammalian cells

Authors: R. Huber
Year: 2023
Venue: Journal of Neurochemistry
URL: https://www.semanticscholar.org/paper/cc429c474e95d5a631782adfbe20b36532519e9c
DOI: 10.1111/jnc.15822
PMID: 37022340
Citations: 13
Summary: A deeper understanding of the pathways and cellular processes impacted by mutations in CLN genes will not only strengthen the knowledge of the pathological mechanisms underlying the NCLs but may also provide new insight into related forms of neurodegeneration.
Evidence snippets:
Snippet 1 (score: 0.570) > Ceroid lipofuscinosis neuronal (CLN) genes encode 13 proteins that localize throughout the endomembrane system to regulate a variety of cellular processes. In humans, mutations in CLN genes cause a devastating form of neurodegeneration called neuronal ceroid lipofuscinosis (NCL), commonly known as Batten disease. Each CLN gene is associated with a specific subtype of the disease that differ from each other in severity and age of onset. The NCLs affect all ages and ethnicities worldwide but primarily affect children. The pathology underlying the NCLs is poorly understood, which has prevented the development of a cure or effective therapy for most subtypes of the disease. A growing body of literature supports the networking of CLN genes and proteins within cells, which aligns with the broadly similar cellular and clinical manifestations among the different subtypes of NCL. Here, all relevant literature is reviewed to provide a comprehensive overview of our current understanding of how CLN genes and proteins are networked in mammalian cells with an aim toward revealing new molecular targets for therapy development. Intriguingly, CLN gene and protein networking extends beyond the NCLs as recent work has linked several CLN genes and proteins to other forms of neurodegeneration such as Alzheimer's disease and Parkinson's disease. Thus, a deeper understanding of the pathways and cellular processes impacted by mutations in CLN genes will not only strengthen our knowledge of the pathological mechanisms underlying the NCLs but may also provide new insight into related forms of neurodegeneration.

[2] SEPN1-Related Myopathy: The Importance of Diagnosis and Challenges to Management of CMD in Resource Poor Settings

Authors: Siddhartha Gajam, Madhuri Maganthi, A. Mathew, S. Rath
Year: 2021
Venue: Annals of Indian Academy of Neurology
URL: https://www.semanticscholar.org/paper/902b89dd4f88b87201e0e41fd04a49521a6383ac
DOI: 10.4103/aian.AIAN_655_20
PMID: 35359550
PMCID: 8965955
Citations: 2
Summary: Current and emerging treatment strategies for neuronal ceroid lipofuscinoses are presented and the state of clinical and morphological features in human NCL is reviewed.
Evidence snippets:
Snippet 1 (score: 0.534) > Annals of Indian Academy of Neurology ¦ Volume 24 ¦ Issue 6 ¦ November-December 2021 955 1980;64:726‐32. 2. Ekazi J, Kominami E. Symposium: The neuronal ceroid‐ lipofuscinoses (NCL)—a group of lysosomal storage diseases come of age. The intracellular location and function of proteins of neuronal ceroid lipofuscinoses. Brain Pathol 2004;14:77‐85. 3. Goebel H, Wisniewski K. Symposium: The neuronal ceroid‐ lipofuscinoses (NCL)—a group of lysosomal storage diseases come of age. Current state of clinical and morphological features in human NCL. Brain Pathol 2004;14:61‐9. 4. Uvebrant P, Hagberg B. Neuronal ceroid lipofuscinoses in scandinavia. Epidemiology and clinical pictures. Neuropediatrics 1997;28:6‐8. 5. The International Batten Disease Consortium. Isolation of a novel gene underlying batten disease, CLN3. Cell 1995;82:949‐57. 6. Mink JW, Augustine EF, Adams HR, Marshall FJ, Kwon JM. Classification and natural history of the neuronal ceroid lipofuscinoses. J Child Neurol 2013;28:1101‐5. 7. Sinha S, Satishchandra P, Santosh V, Gayatri N, Shankar SK. Neuronal ceroid lipofuscinosis: A clinicopathological study. Seizure 2004;13:235‐40. 8. Mantel I, Brantley MA Jr, Bellmann C, Robson AG, Holder GE, Taylor A, et al. Juvenile neuronal ceroid lipofuscinosis (Batten disease) CLN3 mutation (Chrom 16p11.2) with different phenotypes in a sibling pair and low intensity in vivo autofluorescence. Klin Monbl Augenheilkd 2004;221:427‐30. 9. Kohlschütter A, Schulz A, Bartsch U, Storch S. Current and emerging treatment strategies for

[3] Neuronal Ceroid Lipofuscinoses: Connecting Calcium Signalling through Calmodulin

Authors: Sabateeshan Mathavarajah, D. O’Day, R. Huber
Year: 2018
Venue: Cells
URL: https://www.semanticscholar.org/paper/3d007c8ea7ed8f4da2c267fc85c5aa5f10a1c1d1
DOI: 10.3390/cells7110188
PMID: 30380624
PMCID: 6262527
Citations: 13
Summary: It is shown that 11 of the 13 NCL proteins contain putative CaM-binding domains (CaMBDs), which indicates that targeting CaM may be a valid therapeutic approach for treating the disease.
Evidence snippets:
Snippet 1 (score: 0.531) > The first clinical diagnosis of Batten disease was in 1903, and since then, great strides have been made in our understanding of the cellular and molecular mechanisms underlying this devastating neurological disorder [1].Batten disease, which is clinically known as neuronal ceroid lipofuscinosis (NCL), is a form of neurodegeneration that has a global distribution and affects people of all ages [2].Clinical manifestations of the disease include vision loss, seizures, progressive loss of motor function and cognitive ability, and a reduced lifespan [3].The only clinically-approved therapeutic for the NCLs is Brineura, which is an enzyme replacement therapy specific for only one subtype of the disease (i.e., CLN2 disease) [4].The absence of therapeutics stems from our poor understanding of NCL proteins and their primary functions.In total, 13 genetically distinct genes are linked to the disease (CLN1-8, CLN10-14) [2].These 13 genes encode enzymes (CLN1, CLN2, CLN5, CLN10, and CLN13), transmembrane proteins (CLN3, CLN7, and CLN12), membrane proteins that localize to the endoplasmic reticulum (CLN6 and CLN8), cytoplasmic proteins (CLN11 and CLN14), and a protein found on synaptic vesicles (CLN4) [2].Along with distinct localizations, the NCL proteins have been linked to fundamental cellular processes, including sphingolipid metabolism, protein degradation, and lysosomal pH homeostasis, among others [5][6][7][8][9][10].Since mutations in NCL proteins cause nearly identical clinical phenotypes, they are thought to participate in shared or convergent biological pathways [11].However, the common link between the proteins has yet to be revealed. > For clues to explain the molecular networking of NCL proteins, research groups have looked for reoccurring phenotypes in NCL patients [12].

[4] Induced Pluripotent Stem Cells Derived from a CLN5 Patient Manifest Phenotypic Characteristics of Neuronal Ceroid Lipofuscinoses

Authors: K. Uusi-Rauva, T. Blom, Carina von Schantz-Fant, Tomas Blom, A. Jalanko et al.
Year: 2017
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/be3792a8185e9d7a32a9b59780e8ec7c1f39220a
DOI: 10.3390/ijms18050955
PMID: 28468312
PMCID: 5454868
Citations: 33
Summary: Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive progressive encephalopathies caused by mutations in at least 14 different genes. Despite extensive studies performed in different NCL animal models, the molecular mechanisms underlying neurodegeneration in NCLs remain poorly understood. To model NCL in human cells, we generated induced pluripotent stem cells (iPSCs) by reprogramming skin fibroblasts from a patient with CLN5 (ceroid lipofuscinosis, neuronal, 5) disease, the late inf...
Evidence snippets:
Snippet 1 (score: 0.530) > Neuronal ceroid lipofuscinoses (NCLs) are autosomal recessive progressive encephalopathies caused by mutations in at least 14 different genes. Despite extensive studies performed in different NCL animal models, the molecular mechanisms underlying neurodegeneration in NCLs remain poorly understood. To model NCL in human cells, we generated induced pluripotent stem cells (iPSCs) by reprogramming skin fibroblasts from a patient with CLN5 (ceroid lipofuscinosis, neuronal, 5) disease, the late infantile variant form of NCL. These CLN5 patient-derived iPSCs (CLN5Y392X iPSCs) harbouring the most common CLN5 mutation, c.1175_1176delAT (p.Tyr392X), were further differentiated into neural lineage cells, the most affected cell type in NCLs. The CLN5Y392X iPSC-derived neural lineage cells showed accumulation of autofluorescent storage material and subunit C of the mitochondrial ATP synthase, both representing the hallmarks of many forms of NCLs, including CLN5 disease. In addition, we detected abnormalities in the intracellular organelles and aberrations in neuronal sphingolipid transportation, verifying the previous findings obtained from Cln5-deficient mouse macrophages. Therefore, patient-derived iPSCs provide a suitable model to study the mechanisms of NCL diseases.

[5] Current Insights in Elucidation of Possible Molecular Mechanisms of the Juvenile Form of Batten Disease

Authors: E. Shematorova, G. V. Shpakovski
Year: 2020
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/140bc3d40a51eb872ceb3c3d39dcc450eff8c479
DOI: 10.3390/ijms21218055
PMID: 33137890
PMCID: 7663513
Citations: 4
Summary: The main recorded to date changes in cell metabolism, to some extent contributing to the emergence and progression of JNCL disease, and human-specific molecular features of CLN3 gene expression are summarized and critically discussed with an emphasis on the possible molecular mechanisms of the malady appearance and progression.
Evidence snippets:
Snippet 1 (score: 0.530) > The neuronal ceroid lipofuscinoses (NCLs) collectively constitute one of the most common forms of inherited childhood-onset neurodegenerative disorders. They form a heterogeneous group of incurable lysosomal storage diseases that lead to blindness, motor deterioration, epilepsy, and dementia. Traditionally the NCL diseases were classified according to the age of disease onset (infantile, late-infantile, juvenile, and adult forms), with at least 13 different NCL varieties having been described at present. The current review focuses on classic juvenile NCL (JNCL) or the so-called Batten (Batten-Spielmeyer-Vogt; Spielmeyer-Sjogren) disease, which represents the most common and the most studied form of NCL, and is caused by mutations in the CLN3 gene located on human chromosome 16. Most JNCL patients carry the same 1.02-kb deletion in this gene, encoding an unusual transmembrane protein, CLN3, or battenin. Accordingly, the names CLN3-related neuronal ceroid lipofuscinosis or CLN3-disease sometimes have been used for this malady. Despite excessive in vitro and in vivo studies, the precise functions of the CLN3 protein and the JNCL disease mechanisms remain elusive and are the main subject of this review. Although the CLN3 gene is highly conserved in evolution of all mammalian species, detailed analysis of recent genomic and transcriptomic data indicates the presence of human-specific features of its expression, which are also under discussion. The main recorded to date changes in cell metabolism, to some extent contributing to the emergence and progression of JNCL disease, and human-specific molecular features of CLN3 gene expression are summarized and critically discussed with an emphasis on the possible molecular mechanisms of the malady appearance and progression.

[6] An altered transcriptome underlies cln5-deficiency phenotypes in Dictyostelium discoideum

Authors: William D. Kim, R. Huber
Year: 2022
Venue: Frontiers in Genetics
URL: https://www.semanticscholar.org/paper/efb8f8960b6eb7c4d516f1194de8dbffd5d61fb0
DOI: 10.3389/fgene.2022.1045738
PMID: 36437924
PMCID: 9686302
Citations: 2
Summary: The impact of cln5-deficiency on gene expression in D. discoideum is revealed, insight is provided on the genes and proteins that play a role in regulating ClN5-dependent processes, and light is shed on the molecular mechanisms underlying CLN5 disease.
Evidence snippets:
Snippet 1 (score: 0.526) > The neuronal ceroid lipofuscinoses (NCLs), also known as Batten disease, are a family of neurodegenerative diseases linked to mutations in 13 ceroid lipofuscinosis neuronal (CLN) genes (CLN1-8, CLN10-14) (Schulz et al., 2013;Mole and Cotman, 2015). Each of the 13 different subtypes of NCL are characterized by the lysosomal accumulation of autoflourescent lipid-protein aggregates called ceroid lipofuscin in neurons, as well as other cell types outside the central nervous system (Palmer et al., 1992;Mole and Cotman, 2015). The accumulation of ceroid lipofuscin has been associated with numerous clinical symptoms, including seizures, reduced motor, visual, and cognitive function, as well as a reduced lifespan (Schulz et al., 2013;Mole and Cotman, 2015). While most of the CLN genes have been studied, the precise cellular mechanisms impacted by CLN gene mutations remain elusive. > Mutations in CLN5 cause the CLN5 disease subtype of NCL (Schulz et a., 2013;Mole and Cotman, 2015). CLN5 is a soluble lysosomal and extracellular protein that is predicted to function as either a glycoside hydrolase or depalmitoylase (Isosomppi et al., 2002;Hughes et al., 2014;Jules et al., 2017;Huber and Mathavarajah, 2018a;Basak et al., 2021b;Luebben et al., 2022). CLN5 has been linked to several cellular processes including, but not limited to, endosomal sorting, biometal homeostasis, sphingolipid metabolism, and autophagy (El Haddad et al., 2012;Mamo et al., 2012;Grubman et al., 2014;Doccini et al., 2020;McLaren et al., 2021). However, like most CLN proteins, the association of CLN5 with a defined biological pathway is still under investigation.

[7] Editorial: Neuronal ceroid lipofuscinosis: A multidisciplinary update

Authors: Alessandro Simonati, R. E. Williams, Angela Schulz
Year: 2022
Venue: Frontiers in Neurology
URL: https://www.semanticscholar.org/paper/c6c2f43109e69130ad717ac0c0cac6dac945c199
DOI: 10.3389/fneur.2022.1083113
PMID: 36468054
PMCID: 9710275
Summary: a
Evidence snippets:
Snippet 1 (score: 0.520) > Eleven papers and fifty-one authors from seven countries have contributed to the Research Topic Neuronal Ceroid Lipofuscinosis: a Multidisciplinary Update. Both clinical and research issues have been addressed in this collection of articles. The first paper provides a broad introduction and subsequent articles cover epidemiology and genetics, diagnosis, natural history studies, treatment and ethical implications of novel therapies, cardiac involvement in the later stages of disease and the underlying pathological mechanisms. > The state-of-art in the field of childhood NCLs was described from a number of perspectives in the first review paper of the series (Simonati and Williams). Following a brief historical survey, a clinically-oriented approach was used to describe how the early symptoms and signs represent topographical signatures of the underlying brain dysfunction and may provide clues helping clinicians to reach a conclusive NCL diagnosis rapidly. The paper goes on to document advances in NCL research and the contributions of different experimental models to enhance knowledge of the pathogenic mechanisms underlying cellular pathology in this group of diseases. Lastly, translation of experimental data into novel therapeutic approaches and the importance of symptomatic treatments, which remain the main available therapeutic approaches, were outlined. > The world-wide distribution of NCL was emphasized by the retrospective epidemiological study from South America and the Caribbean region, in which CLN2, CLN6, and CLN3 disorders were identified as the most common NCL types in those regions (Guelbert et al.). The authors have stressed that synergy between health providers, parent support organizations and the pharmaceutical industry have accelerated the use of modern diagnostic procedures. > The significance of the advances in genetic studies in NCL was discussed in the review article by Gardner and Mole which focuses on the genetic basis of phenotypic heterogeneity (Gardner and Mole). Since the discovery of the first causative genes, more than 530 mutations have been identified across 13 NCL genes. Increasing numbers of variant disease phenotypes are being described. Identification of phenotypic heterogeneity combined with the genetic background of each patient is necessary in order to facilitate individually tailored precision medicine in order to modify disease progression in the approaching genomic medicine era.

[8] The converging roles of Batten disease proteins in neurodegeneration and cancer

Authors: S. Q. Yap, Sabateeshan Mathavarajah, R. Huber
Year: 2021
Venue: iScience
URL: https://www.semanticscholar.org/paper/d5a9630c4e492fd532c0ccc5c7543b976dd78e6a
DOI: 10.1016/j.isci.2021.102337
PMID: 33889828
PMCID: 8050770
Citations: 16
Influential citations: 1
Summary: It is proposed that further research on the relationship between cancer and the NCLs may help shed light on the roles of NCL genes in both diseases and possibly guide therapy development.
Evidence snippets:
Snippet 1 (score: 0.512) > patient-database). Each gene is associated with a different subtype of NCL (Mole and Cotman, 2015). A recent study showed that mutations in the TBCK (TBC1 domain-containing kinase) gene present characteristics and clinical pathology that resemble other NCL subtypes, and thus, may be classified as a new NCL subtype, CLN15 disease (Beck- Wo ¨dl et al., 2018). The NCL family of proteins comprises soluble lysosomal enzymes (CLN1/PPT1, palmitoyl protein thioesterase 1; CLN2/TPP1, tripeptidyl peptidase 1; CLN5, ceroid lipofuscinosis neuronal 5; CLN10/CTSD, cathepsin D; CLN13/CTSF, cathepsin F), lysosomal transmembrane proteins (CLN3, ceroid lipofuscinosis neuronal 3; CLN7/MFSD8, major facilitator superfamily domain-containing 8; CLN12/ATP13A2, ATPase 13A2), proteins associated with vesicular membranes (CLN4/DNAJC5, DnaJ heat shock protein family member C5; CLN14/KCTD7, potassium channel tetramerization domain-containing 7), membrane proteins that reside in the endoplasmic reticulum (ER) (CLN6, ceroid lipofuscinosis neuronal 6; CLN8, ceroid lipofuscinosis neuronal 8) and a secreted glycoprotein (CLN11/ PGRN, progranulin) (Ca ´rcel-Trullols et al., 2015). Despite the molecular genetic heterogeneity of these proteins, research in non-mammalian and mammalian models suggests that the NCL proteins may participate in shared or converging pathways (Huber, 2020;Persaud-Sawin et al., 2007). However, the precise functions of NCL proteins, their interactions with one another, and the underlying mechanisms that lead to NCL pathology are poorly understood, which has severely hindered therapy development.

[9] Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model

Authors: Keigo Takahashi, Elizabeth M. Eultgen, Sophie H. Wang, N. Rensing, H. Nelvagal et al.
Year: 2023
Venue: The Journal of Clinical Investigation
URL: https://www.semanticscholar.org/paper/d4b32684c244c570a7ff5c79b249440a291ee06b
DOI: 10.1172/JCI165908
PMID: 37104037
PMCID: 10266778
Citations: 14
Summary: Investigation of the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype, and highlights the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.
Evidence snippets:
Snippet 1 (score: 0.508) > Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal administration of adeno-associated virus serotype 9–mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the life span of Cln2R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.

[10] CLN8 Gene Compound Heterozygous Variants: A New Case and Protein Bioinformatics Analyses

Authors: R. Sharkia, Abdelnaser Zalan, Hazar Zahalka, Amit Kessel, Ayman Asaly et al.
Year: 2022
Venue: Genes
URL: https://www.semanticscholar.org/paper/10d2f0913f50a81aa537459dbb641e38b708009c
DOI: 10.3390/genes13081393
PMID: 36011304
PMCID: 9407845
Citations: 5
Summary: Two patients who presented with atypical phenotypic manifestation and protracted clinical course of CLN8 carrying a novel compound heterozygous variant at theCLN8 gene are described, which confirmed and expanded the effect of compoundheterozygous variants in CLn8 disease.
Evidence snippets:
Snippet 1 (score: 0.503) > Neuronal ceroid lipofuscinosis (NCL) refers to a group of rare disorders that affects human neurons which is one of the most common causes of progressive neurological deterioration in childhood. It involves the buildup of an abnormal material called lipofuscin in the brain. NCL is inherited from the parents by their progeny in an autosomal recessive manner. There are three main types of NCL namely, Adult (Kufs or Parry disease), Juvenile (Batten disease), and Late infantile (Jansky-Bielschowsky disease) [1]. The late infantile type is the most heterogeneous one, with several variants and four genes identified: CLN2, CLN5, CLN6, and CLN8 [2]. > The accumulation of autofluorescent lysosomal storage material in the central nervous system is a key pathological finding of NCL. Several possible candidate genes (13 genes) are involved in this process, namely, CLN1 to CLN8, and CLN10 to CLN14 [3]. To date, more than 430 pathogenic variants in the above 13 candidate genes have been reported in human NCLs, and most have been registered in the NCL Mutation Database [4][5][6]. As a collective group, NCL patients are typically defined by observation of cognitive and visual impairments, epileptic seizures, and deterioration of motor skills and balance issues [7]. Unfortunately, there is no cure for NCL disorders. Therapeutic approaches for the treatment of many NCLs include the administration of immunosuppressive agents to antagonize neuroinflammation associated with neurodegeneration, the use of various small molecules, stem cell therapy, and gene therapy [8]. > The CLN8 disease type is clinically recognized during childhood in which two main clinical phenotypes were described, namely "Northern Epilepsy" known as the Finnish type characterized by intractable epilepsy and cognitive regression at the ages 5-10 years [9]. The second phenotype was the late-infantile NCL characterized by earlier onset and more rapid progressive course with visual failure, ataxia, mental decline, and epilepsy [10,11].

[11] Benchmarking Nanopore Sequencing for CLN2 (TPP1) Mutation Detection: Integrating Rapid Genomics and Orthogonal Validation for Precision Diagnostics

Authors: Betül Teker, Gokce Akan, H. Kazan, Özge Özgen, S. Tatonyan et al.
Year: 2025
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/17ab4c1d747ef2acbf7649f4009dc7c8e878e55f
DOI: 10.3390/ijms26115037
PMID: 40507848
PMCID: 12155472
Summary: This study aimed to benchmark the performance of Oxford Nanopore long-read sequencing (ONT-LRS) for targeted TPP1 mutation detection in a Turkish CLN2 cohort and to assess its concordance with orthogonal validation methods, including Sanger sequencing and enzymatic activity assays.
Evidence snippets:
Snippet 1 (score: 0.494) > Neuronal ceroid lipofuscinosis type 2 (CLN2) disease (OMIM 204500), also known as Jansky-Bielschowsky, represents an exceptionally rare lysosomal storage disorder within the neuronal ceroid lipofuscinosis (NCL) family, collectively termed Batten disease. Previously known as late-infantile neuronal ceroid lipofuscinosis (LINCL), CLN2 disease is an early childhood onset disorder caused by autosomal recessive mutations in the TPP1 gene (GenBank accession no. NM_000391.3) localized on chromosome 11p15. These mutations result in deficient activity of the lysosomal exopeptidase tripeptidyl peptidase 1 (TPP1) (EC 3.4.14.9) [1]. Similar to other NCL disorders (CLN1-CLN14), CLN2 disease involves lysosomal dysfunction, which culminates in the accumulation of autofluorescent storage materials, subsequent neuronal loss, and neurodegeneration. However, the precise in vivo substrates and the complete pathologic mechanisms remain incompletely characterized [2]. > Pathogenic TPP1 gene variants, including splice site, missense, and nonsense mutations, as well as small deletions or insertions, primarily result in diminished or absent enzyme activity, impaired neuropeptide degradation, and the accumulation of subunit c of ATP synthase. This results in the lysosomal accumulation of ceroid lipofuscin, glial activation, and neuronal loss [3]. These mutations lead to reduced or absent TPP1 activity, resulting in lysosomal accumulation of ceroid lipofuscin, a hallmark of the CLN2 phenotype [4][5][6]. Ultrastructural analysis of lysosomal storage in CLN2 disease reveals a characteristic curvilinear profile [6,7]. Clinically, symptom onset correlates with peak TPP1 expression (ages 2-4) and includes new-onset seizures, ataxia, and a history of language delay [8].

[12] Recent Insight into the Genetic Basis, Clinical Features, and Diagnostic Methods for Neuronal Ceroid Lipofuscinosis

Authors: Konrad Kaminiów, S. Kozak, J. Paprocka
Year: 2022
Venue: International Journal of Molecular Sciences
URL: https://www.semanticscholar.org/paper/afdbc0b7fdf7649d5c1ae6309a182f7c4c222633
DOI: 10.3390/ijms23105729
PMID: 35628533
PMCID: 9145894
Citations: 31
Influential citations: 2
Summary: An overview of the current knowledge regarding the pathophysiology, genetics, and clinical manifestation of these conditions, as well as the approach to diagnosis is provided.
Evidence snippets:
Snippet 1 (score: 0.493) > The situation is different, for example, in infantile neuronal ceroid lipofuscinosis type 1 (CLN1), where seizure frequency tends to decrease in the later stages of the disease, or in patients with classic juvenile CLN3, where seizures are rare and only moderate severity occurs in the later stages of the disease [3,[141][142][143]. As the disease progresses, the benefits and harms of specific medications should be reconsidered, as these drugs, while tolerable and effective in the earlier stages of the disease, may prove ineffective after progression and cause only side effects [143]. > Typical neurological manifestations of NCL also include motor symptoms, such as ataxia, dysphagia, myoclonus, chorea, tremors, and dystonia [3]. These especially occur in the classic and late infantile phenotypes [3,13]. In addition, parkinsonism is also present, especially in juvenile CLN3 disease, and some stereotypic movements have also been described in various types of NCL with late infantile and juvenile onset [3,13]. Table 3 shows the clinical characteristics of the different subtypes of neuronal ceroid lipofuscinoses.

[13] Neuronal Ceroid Lipofuscinosis: The Multifaceted Approach to the Clinical Issues, an Overview

Authors: A. Simonati, Ruth E. Williams
Year: 2022
Venue: Frontiers in Neurology
URL: https://www.semanticscholar.org/paper/958b94cb5357170fef4d725e2b10655492abf845
DOI: 10.3389/fneur.2022.811686
PMID: 35359645
PMCID: 8961688
Citations: 61
Influential citations: 2
Summary: The main aim of this review is to summarize the current state-of-art in the field of childhood Neuronal Ceroid Lipofuscinosis, a group of rare neurodegenerative disorders, and describe the large variety of experimental models which have aided this research, as well as the most recent technological developments which have shed light on the main mechanisms involved in the cellular pathology.
Evidence snippets:
Snippet 1 (score: 0.493) > The main aim of this review is to summarize the current state-of-art in the field of childhood Neuronal Ceroid Lipofuscinosis (NCL), a group of rare neurodegenerative disorders. These are genetic diseases associated with the formation of toxic endo-lysosomal storage. Following a brief historical review of the evolution of NCL definition, a clinically-oriented approach is used describing how the early symptoms and signs affecting motor, visual, cognitive domains, and including seizures, may lead clinicians to a rapid molecular diagnosis, avoiding the long diagnostic odyssey commonly observed. We go on to focus on recent advances in NCL research and summarize contributions to knowledge of the pathogenic mechanisms underlying NCL. We describe the large variety of experimental models which have aided this research, as well as the most recent technological developments which have shed light on the main mechanisms involved in the cellular pathology, such as apoptosis and autophagy. The search for innovative therapies is described. Translation of experimental data into therapeutic approaches is being established for several of the NCLs, and one drug is now commercially available. Lastly, we show the importance of palliative care and symptomatic treatments which are still the main therapeutic interventions.

[14] Behavioural and Medical Differentials of Cognitive Decline and Dementia in Dogs and Cats

Authors: S. Denenberg, F. Liebel, J. Rose
Year: 2017
Venue: Canine and Feline Dementia
URL: https://www.semanticscholar.org/paper/c55376bb9d5213c0a38e6aa0bffd5f54e6bd5df6
DOI: 10.1007/978-3-319-53219-6_2
PMCID: 7121040
Citations: 9
Summary: Cognitive dysfunction syndrome (CDS) is a diagnosis of exclusion given that there is no specific diagnostic test or tool and that medical disorders can cause the same set of signs.
Evidence snippets:
Snippet 1 (score: 0.491) > Aetiopathogenesis Ceroid lipofuscinosis is a neurodegenerative disease characterised by the accumulation of autofluorescent lipopigments (ceroid-or lipofuscin-like lipopigments) in neurons and other cells within the body. While most affected dogs and cats will present with signs early in life (within the first 2 years), ceroid lipofuscinosis is one of the few storage diseases that can present in adulthood. This is particularly true in the Tibetan terrier and dachshund breeds who may develop obvious signs when 6 years or older and can survive past 10 years of age. The pathophysiology of the disease is yet to be elucidated as it is unclear whether the mechanism of injury is a direct consequence of the pigment accumulation in cells or if it involves an abnormal mitochondrial function. The advances of molecular genetics have permitted the identification of multiple gene defects causing enzymatic dysfunction, leading to ceroid lipofuscinosis in specific dog breeds.

[15] MRI findings of neuronal ceroid lipofuscinosis in a cat

Authors: Crystal White, J. Mortier, R. Verin, T. Maddox, R. Gonçalves et al.
Year: 2018
Venue: JFMS Open Reports
URL: https://www.semanticscholar.org/paper/0a2ded6cbd632857d491140a57f2773c3610b10b
DOI: 10.1177/2055116918757330
PMID: 29531776
PMCID: 5843104
Citations: 6
Influential citations: 1
Summary: MRI examination revealed generalised cerebral and cerebellar atrophy, diffuse T2-weighted hyperintensity of the white matter and meningeal thickening, the first report of the MRI findings of neuronal ceroid lipofuscinosis in a cat.
Evidence snippets:
Snippet 1 (score: 0.488) > Traditionally and still commonly encountered in the literature, nomenclature was based on the age of clinical presentation, for example infantile/juvenile/adult. The storage material, along with its ultrastructure, is variable for each neuronal ceroid lipofuscinosis type, and, although similar, the clinical course is slightly altered for each one. Molecular analysis has identified the genetic loci for the neuronal ceroid lipofuscinosis types in humans, with the exception of the CLN9 gene, which remains elusive. 23 The differences in the mutations account for the variable phenotypes between the types. 24 ][27][28] Sequencing of the exons of CLN1, CLN3, CLN5, CLN8 and CLN10 in a confirmed case of feline neuronal ceroid lipofuscinosis failed to identify the molecular cause in that patient. 4 The genes involved in the development of feline neuronal ceroid lipofuscinosis remain unidentified. > In humans and dogs, neuronal ceroid lipofuscinosis has been shown to be a recessively inherited disease with the progeny of two carrier parents having a one in four chance of developing the disease. 14 A second cat, from the same litter as the cat in this case, developed similar clinical signs 4 weeks after its littermate and was euthansed owing to severity of clinical signs. Histopathology and TEM confirmed neuronal ceroid lipofuscinosis in this second cat with central nervous system morphological changes similar to the cat described in this case. MRI was not performed in this second case, but pathological findings and the relationship between the two littermates reinforce the hypothesis of an inherited mutation in cats. 3

[16] S-Palmitoylation of Synaptic Proteins in Neuronal Plasticity in Normal and Pathological Brains

Authors: A. Buszka, Agata Pytyś, Domnic Colvin, J. Włodarczyk, T. Wójtowicz
Year: 2023
Venue: Cells
URL: https://www.semanticscholar.org/paper/e804de43357e439c5aa0f43b76899084f5414b6c
DOI: 10.3390/cells12030387
PMID: 36766729
PMCID: 9913408
Citations: 33
Influential citations: 1
Summary: Experimental work devoted to understanding the impact of protein palmitoylation on functional changes in the excitatory and inhibitory synapses associated with neuronal activity and neuronal plasticity are discussed.
Evidence snippets:
Snippet 1 (score: 0.487) > The neuronal ceroid lipofuscinoses (NCLs) (also known as Batten disease) are a class of inherited nervous system disorders associated with mutations in 13 genes (CLN1 to CLN14) that most often begin in childhood and interfere with a cell's ability to recycle a cellular residue called lipofuscin [231]. NCL-associated proteins are localized to lysosomes, endoplasmic reticulum, and other cellular locations; but CLN gene mutations lead primarily to dysfunction in lysosomes. One class of diseases called infantile neuronal ceroid lipofuscinosis (CLN1 disease) is caused by a mutation in CLN1, which encodes palmitoyl-protein thioesterase 1 (PPT1) [223] and may have several phenotypes and types of symptom progressions [232]. In the infantile form, difficulties in acquiring skills such as standing, walking, and talking occur between 6-12 months, and may progress with age into vision loss, seizures, psychomotor deterioration, and premature death [233]. > The molecular mechanism explaining how PPT1-deficiency may affect cell physiology was studied in various systems. In Drosophila, loss of PPT1 causes defects in endocytic trafficking [234] and exocytosis and endocytosis of synaptic vesicles [235]. In mice, PPT1 knockout resulted in reduced expression of presynaptic proteins (e.g., SNAP25), a smaller number of synaptic vesicles, and abnormal expression of NMDAR, contributing to excitotoxicity [223]. PPT1 deficiency caused persistent membrane anchorage of the palmitoylated SV proteins, which hindered the recycling of the vesicle components that normally fuse with the presynaptic plasma membrane during SV exocytosis both in postmortem brain tissues from patients and in brain tissues from PPT1 knockout mice [211]. Altogether, loss of PPT1 in infantile ceroid lipofuscinosis may result in degeneration of excitatory and inhibitory cells and impaired synaptic transmission [223,236].

[17] Revoking the Seize Order: Preventing Spontaneous Seizures With AAV in a CLN2 Mouse Model

Authors: Gordon F. Buchanan
Year: 2023
Venue: Epilepsy Currents
URL: https://www.semanticscholar.org/paper/385f73ebc8d00dc9e7c2f433dd8be7625868cc8f
DOI: 10.1177/15357597231200702
PMID: 38269343
PMCID: 10805085
Summary: Investigation of the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype, and highlights the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.
Evidence snippets:
Snippet 1 (score: 0.486) > Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2 R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. Further histological analysis revealed early localized microglial activation months before neuron loss started in the thalamocortical system and spinal cord, which was accompanied by astrogliosis. This pathology was more pronounced and occurred in the cortex before the thalamus or spinal cord and differed markedly from the staging seen in mouse models of other forms of neuronal ceroid lipofuscinosis. Neonatal administration of adeno-associated virus serotype 9-mediated gene therapy ameliorated the seizure and gait phenotypes and prolonged the life span of Cln2 R207X mice, attenuating most pathological changes. Our findings highlight the importance of clinically relevant outcome measures for judging preclinical efficacy of therapeutic interventions for CLN2 disease.

[18] Brain gene expression profiles of Cln1 and Cln5 deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases

Authors: Carina von Schantz, J. Saharinen, O. Kopra, J. Cooper, M. Gentile et al.
Year: 2008
Venue: BMC Genomics
URL: https://www.semanticscholar.org/paper/1c92c71a25fbe16f17a3f791fa960e5d711aa90d
DOI: 10.1186/1471-2164-9-146
PMID: 18371231
PMCID: 2323392
Citations: 59
Summary: BackgroundThe neuronal ceroid lipofuscinoses (NCL) are a group of children's inherited neurodegenerative disorders, characterized by blindness, early dementia and pronounced cortical atrophy. The similar pathological and clinical profiles of the different forms of NCL suggest that common disease mechanisms may be involved. To explore the NCL-associated disease pathology and molecular pathways, we have previously produced targeted knock-out mice for Cln1 and Cln5. Both mouse-models replicate t...
Evidence snippets:
Snippet 1 (score: 0.486) > BackgroundThe neuronal ceroid lipofuscinoses (NCL) are a group of children's inherited neurodegenerative disorders, characterized by blindness, early dementia and pronounced cortical atrophy. The similar pathological and clinical profiles of the different forms of NCL suggest that common disease mechanisms may be involved. To explore the NCL-associated disease pathology and molecular pathways, we have previously produced targeted knock-out mice for Cln1 and Cln5. Both mouse-models replicate the NCL phenotype and neuropathology; the Cln1-/- model presents with early onset, severe neurodegenerative disease, whereas the Cln5-/- model produces a milder disease with a later onset.ResultsHere we have performed quantitative gene expression profiling of the cortex from 1 and 4 month old Cln1-/- and Cln5-/- mice. Combined microarray datasets from both mouse models exposed a common affected pathway: genes regulating neuronal growth cone stabilization display similar aberrations in both models. We analyzed locus specific gene expression and showed regional clustering of Cln1 and three major genes of this pathway, further supporting a close functional relationship between the corresponding gene products; adenylate cyclase-associated protein 1 (Cap1), protein tyrosine phosphatase receptor type F (Ptprf) and protein tyrosine phosphatase 4a2 (Ptp4a2). The evidence from the gene expression data, indicating changes in the growth cone assembly, was substantiated by the immunofluorescence staining patterns of Cln1-/- and Cln5-/- cortical neurons. These primary neurons displayed abnormalities in cytoskeleton-associated proteins actin and β-tubulin as well as abnormal intracellular distribution of growth cone associated proteins GAP-43, synapsin and Rab3.ConclusionOur data provide the first evidence for a common molecular pathogenesis behind neuronal degeneration in INCL and vLINCL. Since CLN1 and CLN5 code for proteins with distinct functional roles these data may have implications for other forms of NCLs as well.

[19] Distinct Early Molecular Responses to Mutations Causing vLINCL and JNCL Presage ATP Synthase Subunit C Accumulation in Cerebellar Cells

Authors: Yi Cao, J. Staropoli, Sunita Biswas, J. Espinola, M. MacDonald et al.
Year: 2011
Venue: PLoS ONE
URL: https://www.semanticscholar.org/paper/7d10d5c633d3cad6487630260b0648abf3a05166
DOI: 10.1371/journal.pone.0017118
PMID: 21359198
PMCID: 3040763
Citations: 66
Influential citations: 3
Summary: The hypothesis that CLN6 and CLN3 mutations trigger distinct processes that converge on a shared pathway, which is responsible for proper subunit c protein turnover and neuronal cell survival, is supported.
Evidence snippets:
Snippet 1 (score: 0.479) > Variant late-infantile neuronal ceroid lipofuscinosis (vLINCL), caused by CLN6 mutation, and juvenile neuronal ceroid lipofuscinosis (JNCL), caused by CLN3 mutation, share clinical and pathological features, including lysosomal accumulation of mitochondrial ATP synthase subunit c, but the unrelated CLN6 and CLN3 genes may initiate disease via similar or distinct cellular processes. To gain insight into the NCL pathways, we established murine wild-type and CbCln6 nclf/nclf cerebellar cells and compared them to wild-type and CbCln3 Δex7/8/Δex7/8 cerebellar cells. CbCln6 nclf/nclf cells and CbCln3 Δex7/8/Δex7/8 cells both displayed abnormally elongated mitochondria and reduced cellular ATP levels and, as cells aged to confluence, exhibited accumulation of subunit c protein in Lamp 1-positive organelles. However, at sub-confluence, endoplasmic reticulum PDI immunostain was decreased only in CbCln6 nclf/nclf cells, while fluid-phase endocytosis and LysoTracker® labeled vesicles were decreased in both CbCln6 nclf/nclf and CbCln3 Δex7/8/Δex7/8 cells, though only the latter cells exhibited abnormal vesicle subcellular distribution. Furthermore, unbiased gene expression analyses revealed only partial overlap in the cerebellar cell genes and pathways that were altered by the Cln3 Δex7/8 and Cln6 nclf mutations. Thus, these data support the hypothesis that CLN6 and CLN3 mutations trigger distinct processes that converge on a shared pathway, which is responsible for proper subunit c protein turnover and neuronal cell survival.

[20] Epilepsy in neurodegenerative diseases.

Authors: S. Neri, G. Mastroianni, E. Gardella, U. Aguglia, G. Rubboli
Year: 2022
Venue: Epileptic disorders : international epilepsy journal with videotape
URL: https://www.semanticscholar.org/paper/3a35529b660901b3c98f454b81976b96a350406c
DOI: 10.1684/epd.2021.1406
PMID: 35596580
Citations: 57
Influential citations: 1
Summary: An updated overview of the clinical features, pathophysiological mechanisms and diagnostic and treatment approaches of epilepsy in the most common neurodegenerative disorders (such as Alzheimer disease and other types of dementia, Parkinson disease, Down syndrome, prion diseases, and progressive myoclonus epilepsies) is provided to provide a tool that can help epileptologists and neurologists in the diagnosis and management of this increasingly reported comorbidity.
Evidence snippets:
Snippet 1 (score: 0.473) > Neuronal ceroid lipofuscinosis (NCL), also known as Batten disease, comprises a group of neurodegenerative lysosomal storage disorders resulting in excessive accumulation of lipopigments [96]. NCLs are characterized by progressive decline of cognitive and motor functions, retinopathy with evolution to blindness, varying degrees of brain atrophy, and myoclonic epilepsy [95]. There are 14 forms of neuronal ceroid lipofuscinosis, classified according to age of symptom onset (varying from infancy and childhood to adulthood) and causative gene mutation [96]. ASMs commonly used are lamotrigine and valproic acid. Topiramate and levetiracetam can be also effective while carbamazepine, phenytoin and gabapentin may worsen myoclonic seizures [95]. Infantile NCL is a severe disease of infancy, which presents with seizures, developmental arrest and regression, and visual loss. The main gene involved in this form is CLN1, which encodes a lysosomal palmitoyl protein thioesterase. More severe than CLN1 is CLN10, which is a congenital fatal condition characterized by encephalopathy with respiratory insufficiency and status epilepticus. CLN10 encodes the lysosomal protease, cathepsin D [96]. Late-infantile NCL presents with onset in early childhood and is caused by pathogenic variants of the CLN2 gene. This disorder is characterized at the onset by a very severe myoclonic epilepsy, followed during the course of the disease, by cognitive and motor decline, and later by visual loss. CLN2 encodes a lysosomal tripeptidyl peptidase. Other NCLs such as CLN5, CLN6, CLN7, CLN8, and CLN14 mimic, to various extents, the clinical phenotype of the classic CLN2. Mild CLN6 mutations are another cause of adolescence or adult-onset PME [96]. CLN6 encodes an endoplasmic reticulum protein of unclear function.

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Relevant Papers

[1] Recent insights into the networking of CLN genes and proteins in mammalian cells

[2] SEPN1-Related Myopathy: The Importance of Diagnosis and Challenges to Management of CMD in Resource Poor Settings

[3] Neuronal Ceroid Lipofuscinoses: Connecting Calcium Signalling through Calmodulin

[4] Induced Pluripotent Stem Cells Derived from a CLN5 Patient Manifest Phenotypic Characteristics of Neuronal Ceroid Lipofuscinoses

[5] Current Insights in Elucidation of Possible Molecular Mechanisms of the Juvenile Form of Batten Disease

[6] An altered transcriptome underlies cln5-deficiency phenotypes in Dictyostelium discoideum

[7] Editorial: Neuronal ceroid lipofuscinosis: A multidisciplinary update

[8] The converging roles of Batten disease proteins in neurodegeneration and cancer

[9] Gene therapy ameliorates spontaneous seizures associated with cortical neuron loss in a Cln2R207X mouse model

[10] CLN8 Gene Compound Heterozygous Variants: A New Case and Protein Bioinformatics Analyses

[11] Benchmarking Nanopore Sequencing for CLN2 (TPP1) Mutation Detection: Integrating Rapid Genomics and Orthogonal Validation for Precision Diagnostics

[12] Recent Insight into the Genetic Basis, Clinical Features, and Diagnostic Methods for Neuronal Ceroid Lipofuscinosis

[13] Neuronal Ceroid Lipofuscinosis: The Multifaceted Approach to the Clinical Issues, an Overview

[14] Behavioural and Medical Differentials of Cognitive Decline and Dementia in Dogs and Cats

[15] MRI findings of neuronal ceroid lipofuscinosis in a cat

[16] S-Palmitoylation of Synaptic Proteins in Neuronal Plasticity in Normal and Pathological Brains

[17] Revoking the Seize Order: Preventing Spontaneous Seizures With AAV in a CLN2 Mouse Model

[18] Brain gene expression profiles of Cln1 and Cln5 deficient mice unravels common molecular pathways underlying neuronal degeneration in NCL diseases

[19] Distinct Early Molecular Responses to Mutations Causing vLINCL and JNCL Presage ATP Synthase Subunit C Accumulation in Cerebellar Cells

[20] Epilepsy in neurodegenerative diseases.

Notes