Mitochondrial DiseasesSFN_childrenNCT05645874
Reference Values of Intraepidermal Nerve Fiber Density in Children and Small Fiber Neuropathy in Neurodevelopmental Disorders
An observational study of Mitochondrial Diseases and Developmental Delay Disorder, run by Heinrich-Heine University, Duesseldorf at 1 site in Germany.
Trial summary
Background: Small-Fiber-Neuropathy describes the degeneration of mildly or unmyelinated nerve fibers and causes neuropathic pain and autonomic dysfunction. Gold standard for the diagnosis is a small skin punch biopsy from the lower leg and the histological quantification of the intraepidermal nerve fiber density… Read more about this study
- Who is it for?
- Any ageHealthy volunteers can take part
- Conditions the study is for
- Mitochondrial Diseases, Developmental Delay Disorder, Small Fiber Neuropathy
- What is being tested?
- Skin biopsy
- How many people
- 203 participants
- Where
- 1 siteGermany
- Study dates
- 1 Feb 2022to 31 Dec 2024
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- Healthy volunteers accepted
- Child, Adult, Older adult
Study population: 1. Control (no underlying neurological disorder) individuals 2. Neurodevelopmental disorder_Genetic cause known 3. Neurodevelopmental disorder_Acquired (cause known, for example perinatal asphyxia or intracranial bleeding) 4. Neurodevelopmental disorder_Cause unknown
Who may be able to join
- Elective surgical intervention from lower leg
- Interest to participate in the study, informed consent
- Unremarkable neurological development
- Neurodevelopmental problems (developmental delay, muscular hypotonia, seizures, ataxia,...) with age of onset before the age of 18 years
- Interest to participate in the study, informed consent
Who cannot join
- Clinical signs of polyneuropathy, autonomic dysfunction
- Skin inflammation, scar, skin disease, other known chronic diseases that can cause small fiber pathology
- Neurodevelopmental patients
- Known polyneuropathy
- Skin inflammation, scar, skin disease, other known chronic diseases that can cause small fiber pathology
Trial locations and contacts
1 site in 1 country.
Germany1 site
University Hospital Düsseldord, Department of General Pediatrics, Neonatology and Pediatric Cardiology
Düsseldorf, 40225
About this study
Official title: Reference Values of Intraepidermal Nerve Fiber Density in Children and Small Fiber Neuropathy in Children With Acquired and Genetic Neurodevelopmental Disorders - An Unrecognized Cause of Pain and Window Into Brain Pathology ? -
Background: Small-Fiber-Neuropathy describes the degeneration of mildly or unmyelinated nerve fibers and causes neuropathic pain and autonomic dysfunction. Gold standard for the diagnosis is a small skin punch biopsy from the lower leg and the histological quantification of the intraepidermal nerve fiber density (IENFD). In children, the normal IENFD has not been systematically assessed and normal reference values are needed. In Parkinson´s disease, the neurodegeneration also affects the peripheral nerves and SFN is present already in the early stages. Whether neurodevelopmental disorders (NDDs) in childhood are likewise associated with SFN is largely unknown. The IENFD is age-dependent and declines with age.
Aims: In this study, we are establishing the reference values for the physiological IENFD in children from 0-18 years. Moreover, we are investigating if children with NDDs have a reduced IENFD and if SFN is a clinically relevant cause of pain and autonomic dysfunction.
Read the detailed description
In the first part of the study, skin biopsies will be collected from the leg from children with a normal neurological development (healthy children) in the setting of elective orthopedic surgery (during general anesthesia; from surgical crop margins).
The IENFD is determined by staining and quantification of PGP9.5-positive intraepidermal nerve fibers on 40 µm thick skin sections.
The skin biopsies will be collected from the site of orthopedic surgical procedure. For example, if the child is undergoing corrective osteotomy of genu valgum, the skin biopsy is drawn from the most distal part of surgical incision sides (distal leg); if the child is undergoing orthopedic surgery in the context of epiphyseolysis capitis femoris, the skin biopsy is drawn from the thigh (proximal leg):
In adults, the IENFD is higher in specimens derived from the proximal leg than in skin from the distal leg. Because in small fiber neuropathy the small nerve fiber degeneration often starts distally, the recommended sampling site for the quantification of IENFD in adults is the distal leg. That is why the calculation of the 5th percentile as the cutoff for reduced IENFD in children will be based on skin biopsies collected from the distal leg.
Due to the limited number of surgeries on the distal leg and distal biopsies in certain age groups of healthy participants (e.g. 4-8), cases with skin biopsies taken from the proximal leg will also be included. The IENFD from cases drawn from the proximal leg and cases from the distal leg will be compared. The samples drawn from the distal or proximal leg will be labelled accordingly. If the IENFD is comparable between the distal and proximal cases, a pooled analysis including proximal and distal cases will be performed.
In the second part of the study, skin biopsies from the distal leg will be collected from children with neurodevelopmental disorders of acquired, genetic and initially unexplained etiology in the setting of local anesthesia, whenever possible during an elective intervention with sedation/general anesthesia. IENFD below the predicted age- and sex-specific 5th percentile will be classified "reduced", otherwise as "normal".
A literature review will be performed to identify those neurodevelopmental disorders that have been associated with peripheral neuropathy in the past.
In cases with a yet unexplained etiology of neurodevelopmental disorder (no perinatal asphyxia, postnatal asphyxia, no cardiopulmonary resuscitation, no extreme prematurity, no encephalitis others, no stroke, or cerebral tumor), genetic testing (exome or genome sequencing and microarray analysis) will be performed.
Clinical symptoms of SFN (distal sensory signs and autonomic dysfunction) In adults the diagnosis of SNF is also based on the presence of distal sensory signs. Therefore, all participants or their legal guardians will be requested to answer questionnaires [(SFN-symptom inventory questionnaire (SFN-SIQ) and the SFN-Screening list (SFNSL)] that specifically assess distal sensory and autonomic symptoms related to SFN.
Additional exploratory subgroup analysis 1): In adults the diagnosis of SNF is also based on abnormal thermal perception assessed by quantitative sensory testing (QST). In collaboration with the University Children´s Hospital of the Ruhr University Bochum, QST will be performed in those children that are old enough and who have the cognitive ability to undergo QST. Small nerve fiber function including thermal perception will be assessed.
Additional exploratory subgroup analysis 2): Small fiber neuropathy can be associated with large fiber neuropathy. Therefore, the proportion of abnormal findings of electrophysiological studies in medical record of children with a reduced versus normal IENFD will be assessed.
- Conditions
- Mitochondrial Diseases, Developmental Delay Disorder, Small Fiber Neuropathy, Cerebral Palsy
- Being tested
- Skin biopsy
- Medical subject headings
- Mitochondrial Diseases, Developmental Disabilities, Small Fiber Neuropathy, Cerebral Palsy
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Skin biopsyDiagnostic test
Control skin biopsies from children without a chronic underlying disease are drawn from surgical crop margins during elective orthopedic surgery of the lower leg (n<80). Skin punch biopsies from children with acquired (n<80) or genetic NDD (n<80) or unknown etiology (N<80) are drawn in the setting of elective interventions during sedation or after local anesthesia. IENFD is quantified by immunohistochemistry and compared between the control and NDD group.
| Study group | Role | What they receive |
|---|---|---|
| Control (no underlying neurological disorder) | Neurologically healthy individuals undergoing elective surgical intervention on the leg Receives: Diagnostic Test: Skin biopsy | |
| Neurodevelopmental disorder_Genetic cause known | Individuals with neurodevelopmental symptoms (developmental delay, muscular hypotonia, seizures, ataxia, etc) with age of onset before the age of 18 years. Genetic etiology, if a genetic diagnosis had been established before inclusion to the study Receives: Diagnostic Test: Skin biopsy | |
| Neurodevelopmental disorder_Acquird (cause known) | Individuals with neurodevelopmental symptoms (developmental delay, muscular hypotonia, seizures, ataxia, etc) with age of onset before the age of 18 years.
Acquired etiology, if a plausible cause of NDD was known (including but not limited to perinatal asphyxia, postnatal asphyxia or cardiopulmonary resuscitation, premature birth with periventricular leukomalacia, premature birth with severe intracranial bleeding, brain damage due to encephalitis, stroke, cerebral tumor; no red flags of genetic disease, such as syndromic features), Receives: Diagnostic Test: Skin biopsy | |
| Neurodevelopmental disorder_Unexplained etiology | Individuals with neurodevelopmental symptoms (developmental delay, muscular hypotonia, seizures, ataxia, etc) with age of onset before the age of 18 years.
Unexplained etiology, if there is no genetic diagnosis established so far and if there is no history of perinatal risk factors for brain injury or if there are other red flags for genetic cause (e.g., normal magnetic resonance findings or delayed myelination; findings suggestive of syndromic disease). Receives: Diagnostic Test: Skin biopsy |
What is being measured
The primary outcome is the main question the study is designed to answer.
Part 1 - Cutoff for reduced intraepidermal nerve fiber density (IENFD) in children
Age- and sex-specific 5th percentile of IENFD in the distal leg of neurologically healthy children aged 0-18 years (controls) as the cutoff for reduced IENFD.
Measured: 2 years
Part 2 - Proportion of children with reduced IENFD among children with neurodevelopmental disorders (NDDs).
Proportion of children with genetic, acquired NDDs or NDDs of initially unexplained etiology whose IENFD falls below the predicted, age- and sex-specific 5th percentile (cutoff) that was calculated in part 1.
Measured: 2 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Dec 2022
- Study start1 Feb 2022
- Primary completion31 Dec 2024
- Study completion31 Dec 2024
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Mitochondrial DiseasesStudies of the same condition, open and under way.
- More trials run by Heinrich-Heine University, DuesseldorfThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Enrolment
- 203 participants (actual)
Sponsor and investigators
- Lead sponsor
- Heinrich-Heine University, Duesseldorf
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Felix Distelmaier, Principal investigator, Department of General Pediatrics, Heinrich-Heine-University, Düsseldorf, Germany.
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05645874
- Sponsor's protocol ID
- SFN children
- Other IDs
- 2021-1556
- Acronym
- SFN_children
- Status last verified
- Mar 2025
- First submitted
- 30 Nov 2022
- Last updated
- 28 Nov 2025
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Yes: All IPD that underlie results in a publication
Publications
Lauria G, Bakkers M, Schmitz C, Lombardi R, Penza P, Devigili G, Smith AG, Hsieh ST, Mellgren SI, Umapathi T, Ziegler D, Faber CG, Merkies IS. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst. 2010 Sep;15(3):202-7. doi: 10.1111/j.1529-8027.2010.00271.x.
PubMed 21040142
Study at a glance
From the registry record, last updated by the sponsor on 28 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Reference Values of Intraepidermal Nerve Fiber Density in Children and Small Fiber Neuropathy in Children With Acquired and Genetic Neurodevelopmental Disorders - An Unrecognized Cause of Pain and Window Into Brain Pathology ? -
- ClinicalTrials.gov ID
- NCT05645874
- Acronym / sponsor ID
- SFN_children / SFN children
- Conditions
- Mitochondrial Diseases, Developmental Delay Disorder, Small Fiber Neuropathy, Cerebral Palsy
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 203 participants (actual)
- Lead sponsor
- Heinrich-Heine University, DuesseldorfUniversity, hospital or other
- Study start
- 1 Feb 2022 (actual)
- Primary completion
- 31 Dec 2024 (actual)
- Study completion
- 31 Dec 2024 (actual)
- First posted
- 12 Dec 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Background: Small-Fiber-Neuropathy describes the degeneration of mildly or unmyelinated nerve fibers and causes neuropathic pain and autonomic dysfunction. Gold standard for the diagnosis is a small skin punch biopsy from the lower leg and the histological quantification of the intraepidermal nerve fiber density (IENFD). In children, the normal IENFD has not been systematically assessed and normal reference values are needed. In Parkinson´s disease, the neurodegeneration also affects the peripheral nerves and SFN is present already in the early stages. Whether neurodevelopmental disorders (NDDs) in childhood are likewise associated with SFN is largely unknown. The IENFD is age-dependent and declines with age.
Aims: In this study, we are establishing the reference values for the physiological IENFD in children from 0-18 years. Moreover, we are investigating if children with NDDs have a reduced IENFD and if SFN is a clinically relevant cause of pain and autonomic dysfunction.
Detailed description
In the first part of the study, skin biopsies will be collected from the leg from children with a normal neurological development (healthy children) in the setting of elective orthopedic surgery (during general anesthesia; from surgical crop margins).
The IENFD is determined by staining and quantification of PGP9.5-positive intraepidermal nerve fibers on 40 µm thick skin sections.
The skin biopsies will be collected from the site of orthopedic surgical procedure. For example, if the child is undergoing corrective osteotomy of genu valgum, the skin biopsy is drawn from the most distal part of surgical incision sides (distal leg); if the child is undergoing orthopedic surgery in the context of epiphyseolysis capitis femoris, the skin biopsy is drawn from the thigh (proximal leg):
In adults, the IENFD is higher in specimens derived from the proximal leg than in skin from the distal leg. Because in small fiber neuropathy the small nerve fiber degeneration often starts distally, the recommended sampling site for the quantification of IENFD in adults is the distal leg. That is why the calculation of the 5th percentile as the cutoff for reduced IENFD in children will be based on skin biopsies collected from the distal leg.
Due to the limited number of surgeries on the distal leg and distal biopsies in certain age groups of healthy participants (e.g. 4-8), cases with skin biopsies taken from the proximal leg will also be included. The IENFD from cases drawn from the proximal leg and cases from the distal leg will be compared. The samples drawn from the distal or proximal leg will be labelled accordingly. If the IENFD is comparable between the distal and proximal cases, a pooled analysis including proximal and distal cases will be performed.
In the second part of the study, skin biopsies from the distal leg will be collected from children with neurodevelopmental disorders of acquired, genetic and initially unexplained etiology in the setting of local anesthesia, whenever possible during an elective intervention with sedation/general anesthesia. IENFD below the predicted age- and sex-specific 5th percentile will be classified "reduced", otherwise as "normal".
A literature review will be performed to identify those neurodevelopmental disorders that have been associated with peripheral neuropathy in the past.
In cases with a yet unexplained etiology of neurodevelopmental disorder (no perinatal asphyxia, postnatal asphyxia, no cardiopulmonary resuscitation, no extreme prematurity, no encephalitis others, no stroke, or cerebral tumor), genetic testing (exome or genome sequencing and microarray analysis) will be performed.
Clinical symptoms of SFN (distal sensory signs and autonomic dysfunction) In adults the diagnosis of SNF is also based on the presence of distal sensory signs. Therefore, all participants or their legal guardians will be requested to answer questionnaires [(SFN-symptom inventory questionnaire (SFN-SIQ) and the SFN-Screening list (SFNSL)] that specifically assess distal sensory and autonomic symptoms related to SFN.
Additional exploratory subgroup analysis 1): In adults the diagnosis of SNF is also based on abnormal thermal perception assessed by quantitative sensory testing (QST). In collaboration with the University Children´s Hospital of the Ruhr University Bochum, QST will be performed in those children that are old enough and who have the cognitive ability to undergo QST. Small nerve fiber function including thermal perception will be assessed.
Additional exploratory subgroup analysis 2): Small fiber neuropathy can be associated with large fiber neuropathy. Therefore, the proportion of abnormal findings of electrophysiological studies in medical record of children with a reduced versus normal IENFD will be assessed.
Study design
- Observational model
- Case-control
- Time perspective
- Cross-sectional
- Number of arms
- 4
| Arm | Type | Receives |
|---|---|---|
| Control (no underlying neurological disorder) | – | Diagnostic Test: Skin biopsyNeurologically healthy individuals undergoing elective surgical intervention on the leg |
| Neurodevelopmental disorder_Genetic cause known | – | Diagnostic Test: Skin biopsyIndividuals with neurodevelopmental symptoms (developmental delay, muscular hypotonia, seizures, ataxia, etc) with age of onset before the age of 18 years. Genetic etiology, if a genetic diagnosis had been established before inclusion to the study |
| Neurodevelopmental disorder_Acquird (cause known) | – | Diagnostic Test: Skin biopsyIndividuals with neurodevelopmental symptoms (developmental delay, muscular hypotonia, seizures, ataxia, etc) with age of onset before the age of 18 years. Acquired etiology, if a plausible cause of NDD was known (including but not limited to perinatal asphyxia, postnatal asphyxia or cardiopulmonary resuscitation, premature birth with periventricular leukomalacia, premature birth with severe intracranial bleeding, brain damage due to encephalitis, stroke, cerebral tumor; no red flags of genetic disease, such as syndromic features), |
| Neurodevelopmental disorder_Unexplained etiology | – | Diagnostic Test: Skin biopsyIndividuals with neurodevelopmental symptoms (developmental delay, muscular hypotonia, seizures, ataxia, etc) with age of onset before the age of 18 years. Unexplained etiology, if there is no genetic diagnosis established so far and if there is no history of perinatal risk factors for brain injury or if there are other red flags for genetic cause (e.g., normal magnetic resonance findings or delayed myelination; findings suggestive of syndromic disease). |
Who may qualify
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Child, Adult, Older adult
- Study population
- 1. Control (no underlying neurological disorder) individuals 2. Neurodevelopmental disorder_Genetic cause known 3. Neurodevelopmental disorder_Acquired (cause known, for example perinatal asphyxia or intracranial bleeding) 4. Neurodevelopmental disorder_Cause unknown
Key inclusion criteria (5 listed)
- Elective surgical intervention from lower leg
- Interest to participate in the study, informed consent
- Unremarkable neurological development
- Neurodevelopmental problems (developmental delay, muscular hypotonia, seizures, ataxia,...) with age of onset before the age of 18 years
- Interest to participate in the study, informed consent
Key exclusion criteria (5 listed)
- Clinical signs of polyneuropathy, autonomic dysfunction
- Skin inflammation, scar, skin disease, other known chronic diseases that can cause small fiber pathology
- Neurodevelopmental patients
- Known polyneuropathy
- Skin inflammation, scar, skin disease, other known chronic diseases that can cause small fiber pathology
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Skin biopsyControl skin biopsies from children without a chronic underlying disease are drawn from surgical crop margins during elective orthopedic surgery of the lower leg (n<80). Skin punch biopsies from children with acquired (n<80) or genetic NDD (n<80) or unknown etiology (N<80) are drawn in the setting of elective interventions during sedation or after local anesthesia. IENFD is quantified by immunohistochemistry and compared between the control and NDD group. | Diagnostic test | Control (no underlying neurological disorder), Neurodevelopmental disorder_Acquird (cause known), Neurodevelopmental disorder_Genetic cause known, Neurodevelopmental disorder_Unexplained etiology |
Primary outcome
Part 1 - Cutoff for reduced intraepidermal nerve fiber density (IENFD) in children
Time frame: 2 years
Age- and sex-specific 5th percentile of IENFD in the distal leg of neurologically healthy children aged 0-18 years (controls) as the cutoff for reduced IENFD.
Part 2 - Proportion of children with reduced IENFD among children with neurodevelopmental disorders (NDDs).
Time frame: 2 years
Proportion of children with genetic, acquired NDDs or NDDs of initially unexplained etiology whose IENFD falls below the predicted, age- and sex-specific 5th percentile (cutoff) that was calculated in part 1.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Nov 2025.
- Background: PubMed 21040142Lauria G, Bakkers M, Schmitz C, Lombardi R, Penza P, Devigili G, Smith AG, Hsieh ST, Mellgren SI, Umapathi T, Ziegler D, Faber CG, Merkies IS. Intraepidermal nerve fiber density at the distal leg: a worldwide normative reference study. J Peripher Nerv Syst. 2010 Sep;15(3):202-7. doi: 10.1111/j.1529-8027.2010.00271.x.
- Individual participant dataSharing planned: Yes. All IPD that underlie results in a publication
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Felix Distelmaier principal investigator
Department of General Pediatrics, Heinrich-Heine-University, Düsseldorf, Germany.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Mitochondrial Diseases and Developmental Delay Disorder, run by Heinrich-Heine University, Duesseldorf at 1 site in Germany.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 5 inclusion and 5 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Germany. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Part 1 - Cutoff for reduced intraepidermal nerve fiber density (IENFD) in children (time frame: 2 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT05645874, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Nov 2025.