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

Study Overview
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Brief Summary
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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 SNF is a clinically relevant cause of pain and autonomic dysfunction.

Official Title
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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 ? -

Conditions
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Mitochondrial Diseases, Developmental Delay Disorder, Small Fiber Neuropathy, Cerebral Palsy

Intervention / Treatment
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* Diagnostic Test: Skin biopsy


Participation Criteria
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Eligibility Criteria
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control patients Inclusion Criteria: Elective surgical intervention from lower leg Interest to participate in the study, informed consent Unremarkable neurological development Exclusion Criteria: Clinical signs of polyneuropathy, autonomic dysfunction Skin inflammation, scar, skin disease, other known chronic diseases that can cause small fiber pathology Neurodevelopmental patients Inclusion Criteria: 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 Exclusion Criteria: Known polyneuropathy Skin inflammation, scar, skin disease, other known chronic diseases that can cause small fiber pathology

Ages Eligible for Study
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Minimum Age: 0 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Control (no underlying neurological disorder)<br> | Diagnostic Test: Skin biopsy<br>* 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.<br>|
| Neurodevelopmental disorder_Genetic cause known<br> | Diagnostic Test: Skin biopsy<br>* 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.<br>|
| Neurodevelopmental disorder_Acquird (cause known)<br> | Diagnostic Test: Skin biopsy<br>* 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.<br>|
| Neurodevelopmental disorder_Cause unknown<br> | Diagnostic Test: Skin biopsy<br>* 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intraepidermal nerve fiber density |  | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pathological protein deposits, morphological alterations of cell organells |  | 2 years |