Reference Values of Intraepidermal Nerve Fiber Density in Children and Small Fiber Neuropathy in Neurodevelopmental Disorders

NCT05645874 | Completed

• 2 other identifiers: SFN children2021-1556
• Study Type: observational
• Target: 203
• Locations: 1 country
• Sites: 1

Brief 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 (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.

Conditions

Mitochondrial Diseases; Developmental Delay Disorder; Small Fiber Neuropathy; Cerebral Palsy

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  2 years

Study Arms (4)

Control (no underlying neurological disorder)

Neurologically healthy individuals undergoing elective surgical intervention on the leg

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

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),

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).

Diagnostic Test: Skin biopsy

Interventions

Skin biopsy DIAGNOSTIC_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.

Control (no underlying neurological disorder); Neurodevelopmental disorder_Acquird (cause known); Neurodevelopmental disorder_Genetic cause known; Neurodevelopmental disorder_Unexplained etiology

Eligibility Criteria

• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

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

You may qualify if:

• Elective surgical intervention from lower leg
• Interest to participate in the study, informed consent
• Unremarkable neurological development

You may not qualify if:

• Clinical signs of polyneuropathy, autonomic dysfunction
• Skin inflammation, scar, skin disease, other known chronic diseases that can cause small fiber pathology
• Neurodevelopmental patients
• 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
• Known polyneuropathy
• Skin inflammation, scar, skin disease, other known chronic diseases that can cause small fiber pathology

Sponsors & Collaborators

• Heinrich-Heine University, Duesseldorf: lead

Study Sites (1)

University Hospital Düsseldord, Department of General Pediatrics, Neonatology and Pediatric Cardiology

Düsseldorf, 40225, Germany

Location

Related Publications (1)

• 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.

  PMID: 21040142 BACKGROUND

Biospecimen

Retention: SAMPLES WITHOUT DNA

Skin biopsies

MeSH Terms

Conditions

Mitochondrial Diseases; Developmental Disabilities; Small Fiber Neuropathy; Cerebral Palsy

Condition Hierarchy (Ancestors)

Metabolic Diseases; Nutritional and Metabolic Diseases; Neurodevelopmental Disorders; Mental Disorders; Peripheral Nervous System Diseases; Neuromuscular Diseases; Nervous System Diseases; Brain Damage, Chronic; Brain Diseases; Central Nervous System Diseases

Study Officials

• Felix Distelmaier

  Department of General Pediatrics, Heinrich-Heine-University, Düsseldorf, Germany.

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: observational
• Observational Model: CASE CONTROL
• Time Perspective: CROSS SECTIONAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 30, 2022
• First Posted: December 12, 2022
• Study Start: February 1, 2022
• Primary Completion: December 31, 2024
• Study Completion: December 31, 2024
• Last Updated: November 28, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, ICF, CSR
• Time Frame: After publication
• Access Criteria: Email to principal investigators explaining why it might be helpful to share the data.

Locations

DE (1)