Trial document





This trial has been registered retrospectively.
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  DRKS00010150

Trial Description

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Title

Investigation of the underlying pathomechanisms found in defects of the neurotransmitter, Pterine -, phenyl alanine, and 5-Methyltetrahydrofolate metabolism in induced pluripotent stem cells (iPSC) and derivatives

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Trial Acronym

PaNeM

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URL of the Trial

[---]*

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Brief Summary in Lay Language

Disorders of the neurotransmitter metabolism and deficiencies in folic acid metabolism, phenylalanine and Pterine metabolism cause severe neurological disorders shortly after the birth. The description of the clinical (and biochemical) phenotype of these neurometabolic diseases is based on small usually pediatric patient groups or even on single patients. The long term outcome of the most neurometabolic diseases remains uncertain. The occurrence of rare disease manifestations or variant severity grades is insufficiently investigated yet. Diagnostic and therapeutic strategies are mostly based on the experience of single centers or single experts. Specially for AADC deficiency the therapeutic options available and the response to treatment are very limited. In particular, the underlying molecular Pathomechanisms are still widely unknown.

The for the disease cause of the disease responsible pathological mutations lead to changes in the amino acid sequence of the affected enzyme, causing incorrect folding of the protein or changes at the Active Center, which can dramatically reduce the catalytic activity of the enzyme or induce even the proteasomalen removal.
Also for some other enzymes of the neurotransmitter metabolism similar structure function correlations are described. However, it is often unclear whether and how incorrect folding of enzymes cause an aggregation and/or the degradation of proteins. Also there are so far no studies about how the different enzyme deficiencies, that are mentioned above, manifest in the different tissues on molecular level. The main manifestation is neurological, never the less long term studies, that can detect possible defects/ problems in further organ systems systematically as well as molecular analysis are not available.
Until today, a genotype-phenotype correlation at the molecular level could not be made due to the small patient number for each of the deficiencies in the neurotransmitter, Pterine - or folic acid metabolism.

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Brief Summary in Scientific Language

Neurometabolic diseases represent a group of rare metabolic diseases, whose unifying characteristics are an inborn error of metabolism of the brain and the manifestation of a neurological clinical picture (including global or circumscribed developmental disorder, muscular hypo - or hypertension, movement disorders, epilepsy, behavioral problems). According to the Orphanet (www.orpha.net), currently 130 congenital syndromic and non-syndromic disease patterns are among the neuro-metabolic diseases. The congenital disorders of the metabolism of biogenic amines, Pterine, amino acids and folate are an important sub group. They cause a lack of both neurotransmitters dopamine and serotonin or the necessary for their education due tetrahydrobiopterin (BH4).

Disorders of the neurotransmitter metabolism and deficiencies in folic acid metabolism, phenylalanine and Pterine metabolism cause severe neurological disorders ("infantile Parkinsonism") shortly after the birth. The description of the clinical (and biochemical) phenotype of these neurometabolic diseases is based on small usually pediatric patient groups or even on single patients. The long term outcome of the most neurometabolic diseases remains uncertain. The occurrence of rare disease manifestations or variant severity grades is insufficiently investigated yet. Diagnostic and therapeutic strategies are mostly based on the experience of single centers or single experts. Specially for AADC deficiency the therapeutic options available and the response to treatment are very limited (Opladen et al, 2014). In particular, the underlying molecular Pathomechanisms are still widely unknown.

The for the disease cause of the disease responsible pathological mutations lead to changes in the amino acid sequence of the affected enzyme, causing incorrect folding of the protein or changes at the Active Center, which can dramatically reduce the catalytic activity of the enzyme or induce even the proteasomalen removal (Montioli et al, 2014;) Daniele et al, 2008; Fossbakk et al, 2014). The first comprehensive functional study of the impact of specific mutations on the enzyme activity was published recently by Montioli et al (2014) for AADC deficiency and was able to show that all tested the AADC gene mutations lead to a decreased value of kcat and often affect the tertiary structure. This leads to a defective Apo to holo conversion of the enzyme, which leads to reduction in activity or even to a complete loss of activity.

Also for some other enzymes of the neurotransmitter metabolism similar structure function correlations are described (Montioli et al, 2014). However, it is often unclear whether and how incorrect folding of enzymes cause an aggregation and/or the degradation of proteins. Also there are so far no studies about how the different enzyme deficiencies, that are mentioned above, manifest in the different tissues on molecular level. The main manifestation is neurological, never the less long term studies, that can detect possible defects/ problems in further organ systems systematically as well as molecular analysis are not available.
Until today, a genotype-phenotype correlation at the molecular level could not be made due to the small patient number for each of the deficiencies in the neurotransmitter, Pterine - or folic acid metabolism.

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Organizational Data

  •   DRKS00010150
  •   2016/03/10
  •   [---]*
  •   yes
  •   Approved
  •   S-523/2015, Ethik-Kommission I der Medizinischen Fakultät Heidelberg
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Secondary IDs

  • [---]*
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Health Condition or Problem studied

  •   G24.8 -  Other dystonia
  •   G90.8 -  Other disorders of autonomic nervous system
  •   G31.8 -  Other specified degenerative diseases of nervous system
  •   E70.8 -  Other disorders of aromatic amino-acid metabolism
  •   E70.1 -  Other hyperphenylalaninaemias
  •   D52.8 -  Other folate deficiency anaemias
  •   Aromatic amino acid decarboxylase (AADC) deficiency
  •   Tyrosine hydroxylase (TH) deficiency
  •   Dopamine beta-hydroxylase (DßH) deficiency
  •   Monoamine oxidase A (MAOA) deficiency
  •   Dopamine transporter (DAT) deficiency
  •   Vesicular monoamine transporter 2 (VMAT) deficiency
  •   Autosomal recessive GTP cyclohydrolase deficiency
  •   Autosomal dominant GTP cyclohydrolase deficiency (Segawa disease)
  •   6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency
  •   Dihydropteridine reductase (DHPR) deficiency
  •   Sepiapterin reductase (SR) deficiency
  •   Folate receptor alpha (FOLR1) deficiency
  •   Dihydrofolate reductase (DHFR) deficiency
  •   E70.1 -  Other hyperphenylalaninaemias
  •   Further monogenetic diseases
  •   Congenital hepatopathias caused by mutations in NBAS, SCYL1, IARS and LARS
  •   Congenital disorders of glycosylation: PMM2-CDG (CDG-Ia), MPI-CDG (CDG-Ib), PGM1-CDG
  •   Further monogenetic disorders
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Interventions/Observational Groups

  •   Arm 1: Single drawl of maximum 10 ml of blood or skin biopsy. No follow-up required
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Characteristics

  •   Interventional
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  •   Single arm study
  •   Open (masking not used)
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  •   Uncontrolled/Single arm
  •   Other
  •   Single (group)
  •   N/A
  •   N/A
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Primary Outcome

Identification of molecular pathomechanism by using patient-specific inducible pluripotent stem cells and of differentiated cell types (neurons, hepatocytes

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Secondary Outcome

Development of novel therapies after the identification of new therapeutic target structures in the cell.

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Countries of Recruitment

  •   Germany
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Locations of Recruitment

  • University Medical Center 
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Recruitment

  •   Actual
  •   2016/02/10
  •   50
  •   Monocenter trial
  •   National
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Inclusion Criteria

  •   Both, male and female
  •   no minimum age
  •   no maximum age
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Additional Inclusion Criteria

• Children and adults with confirmed diagnosis of Neurotransmitter disorders
o Aromatic amino acid decarboxylase (AADC) deficiency
o Tyrosine hydroxylase (TH) deficiency
o Dopamine beta-hydroxylase (DßH) deficiency
o Monoamine oxidase A (MAOA) deficiency
o Dopamine transporter (DAT) deficiency
o Vesicular monoamine transporter 2 (VMAT) deficiency
• Children and adults with confirmed diagnosis of BH4 Deficiencies
o Autosomal rezessive GTP cyclohydrolase deficiency
o Autosomal dominant GTP cyclohydrolase deficiency (Segawa disease)
o 6-Pyruvoyl-tetrahydropterin synthase (PTPS) deficiency
o Dihydropteridine reductase (DHPR) deficiency
o Sepiapterin reductase (SR) deficiency
• Children and adults with confirmed diagnosis of cerebral folate deficiencies:
o Folate receptor alpha (FOLR1) deficiency
o Dihydrofolate reductase (DHFR) deficiency
• Children and adults with further monogenetic diseases
• Written informed consent given by the patient, the parents or the legal representatives

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Exclusion Criteria

None

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Addresses

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    • Universitätsklinikum Heidelberg
    • Im Neuenheimer Feld 672
    • 69120  Heidelberg
    • Germany
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    • Zentrum für Kinder-und Jugendmedizin HeidelbergSektion für Neuropädiatrie und Stoffwechselmedizin
    • Mr.  PD Dr.  Thomas  Opladen 
    • Im Neuenheimer Feld 669
    • 69120  Heidelberg
    • Germany
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    • Zentrum für Kinder-und Jugendmedizin HeidelbergSektion für Neuropädiatrie und Stoffwechselmedizin
    • Mr.  PD Dr.  Thomas  Opladen 
    • Im Neuenheimer Feld 669
    • 69120  Heidelberg
    • Germany
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Sources of Monetary or Material Support

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Status

  •   Recruiting ongoing
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Trial Publications, Results and other Documents

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* This entry means the parameter is not applicable or has not been set.