Lil’ Brave One (Hrabriša)

Cycle 3

Web:

https://www.hrabrisa.rs/en

Contact:

Pediatric Neurotransmitter Disease is an umbrella term for genetic disorders that affect the synthesis, metabolism and catabolism of neurotransmitters in children. Inborn neurotransmitters related diseases belong to the rare metabolic, potentially treatable, genetic disorders, with clinical manifestation during childhood. The clinical phenotype is not characteristic but can mimic other neurological disorders.

Last updated 04/30/2026

Clinical

Disease Class

Epilepsy and seizure disorders

Genetic diseases

Inherited metabolic disorder

Intellectual disability and developmental syndromes

Neurological diseases

Body Systems

Digestive

Endocrine

Metabolic

Muscular / Skeletal

Nervous / Sensory

Respiratory

Organs

Bones

Brain

Connective tissue / joints

Eyes

Heart

Intestines

Liver

Muscles

Nerves

Nose

Pituitary glands

Thyroid

Known Genetic Link

Yes, one or more genes directly cause the condition

Causative Genes

ABAT

ALDH5A1

AMT

DBH

DDC

DHFR

DHPR

DNAJC12

FOLR1

GCH1

GCSH

GLDC

MAOA

PHGDH

PSAT1

PSPH

PTS

QDPR

SLC6A3

SLC6A9

SPR

Contributory Genes

None specified / unknown

Type of Inheritance

Autosomal dominant

Autosomal recessive

De novo

X-linked dominant

Newborn Screening

Yes, for some genes

Yes, in some states

Disease Mechanism(s)

Amino acid metabolism defect

Cofactor/vitamin deficiency or defect

Enzyme deficiency

Myelination defect

Neurotransmitter synthesis/metabolism defect

Protein misfolding

Receptor defect

Transport defect

Age of Onset

Adolescence (12-17)

Adulthood (age 18-64)

Early childhood (age 1+-5)

Infancy (age 0-1)

Middle childhood (6-11)

Prebirth

Average Age at Diagnosis

Adolescence (12-17)

Adulthood (age 18-64)

Early childhood (age 1+-5)

Infancy (age 0-1)

Middle childhood (6-11)

Pre-Birth

Life Expectancy

Adolescence (12-17)

Adulthood (age 18-64)

Early childhood (age 1+-5)

Elderly (age 65+)

Infancy (age 0-1)

Middle childhood (6-11)

Affected Sex(es)

Female

Intersex

Male

National Prevalence

11-50

Global Prevalence

101-1000

National Incidence

Less than 10

Global Incidence

11-50

Populations and/or ancestry with higher prevalence

Only for one subgroup of RNDs (AADC deficiency), there is a so-called founder mutation known in Taiwanese of Chinese origin, resulting in higher prevalence and incidence.

Symptoms / Phenotypes

abnormal eye morphology

abnormality of limbs

autistic behavior

behavioral changes

breathing difficulties

cardiac abnormalities

constipation

developmental delay

diarrhea

dysarthria

enlarged liver / hepatomegaly

exaggerated startle response

excessive salivation

failure to thrive

fatigue

feeding difficulties

gastroesophageal reflux

gastrointestinal disorders

hyperhidrosis

hypoglycemia

hypogonadism

hypotension

hypotonia

inappropriate crying

increased circulating prolactin concentration

microcephaly

movement disorders / ataxia / tremor

muscle weakness

nasal congestion

poor head control

seizures / epilepsy

sleep disorders

temperature instability

vision problems

Biomarkers

Diagnostic

· CSF biomarkers - 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), 3-methoxy-4-hydroxyphenylglycol (MHPG), (2) pterins including neopterin and biopterin, 3-O-methyldopa (3-OMD), L-Dopa and 5-OH tryptophan (5-HTP), 5-methyltetrahydrofolate (5-MTHF); GABA, GBF, primapterin, serine, glycine, beta- alanine. 3OMD dry blood spot biomarker. GHB, phenylalanine. Serum glycemia, ammoniemia.

Monitoring

· HVA homovanillic acid, 5HIAA, glycine, serine, Phe, tyrosine

Prognostic

· HVA homovanillic acid

Therapeutic

· HVA, 5HIAA, glycine, serine, Phe, tyrosine, 3OMD

Existing Therapies

Off-Label Drug Use

Regulatory Agency-Approved for Symptom Relief

· methylphenidate, thioridazine, risperidone or fluoxetine Baclofen, inhibitors MAO, psychiatric drugs

Regulatory Agency-Approved to Cure or Modify the Disease

· Kuvan (Sapropterin Dihydrochloride), Kebilidi (eladocagene exuparvovec-tneq, FDA approval), Upstaza (Eladocagene exuparvovec, EMA approval), L-dopa/decarboxylase inhibitor; sodium benzoate, folinic acid, pramipexole;

Therapies in Development

Dietary & metabolic therapies (medical food, dietary restriction, supplements, etc.)

Gene therapy

· 1. AADC Upstaza EMA approval, AADC Kebilidi FDA approval. 2. SSADH gene therapy in research phase (name can not be included. Confidential)

Other (please specify)

· Sephience Sepiapterin EMA approved for HPA and PKU

Repurposed drug

· 1. Sepiapterin for TH deficiency, research phase (not approved). 2. SSADH repurposing

Therapeutic Development Stages

Approved/Available

In research/exploratory phase

Therapeutic Development Role

Access to registry or natural history study

Other

· Engagement in multi-stakeholder meetings (patients, researchers, clinicians), without direct involvement in the approval process.

Results dissemination (including publications)

Organizational & Research

Cell Lines

iPSCs

Cell Lines, Institution

Universitätsklinikum Heidelberg

Cell Lines, Involvement

Consulted

Cell Lines, share

Unsure

Disease Model

None

Disease Model, share

N/A

Organizational Challenges

From a patient perspective, we do not identify any new specific challenges at this stage, beyond the ongoing and well-known ones; such as limited resources and the inherent challenges of rare diseases, ranging from infrastructure gaps to cost–benefit considerations for very small patient populations.

Clinical Trial Role

Data analysis

Data sharing

Funding

Other

Outcome measures, development

Recruitment and outreach, patients

Results dissemination, publication

Study material design, review (not protocol)

Clinical Trial Types

Observational

Biobank, Institution

None

Center of Excellence, Institution

Universitätsklinikum Heidelberg

Center of Excellence, Involvement

Consulted

Funded

Registry

Yes, we have collaborated on a registry

Data Collected, Registry

Clinical data

Genetic data

Imaging data

Longitudinal natural history data

Medication usage

Other

Patient-reported data

Data Entered by, Registry

Clinicians

Platform, Registry

REDCap

Natural History Study

Yes, we have collaborated on a natural history study

Data Collected, Natural History Study

Clinical endpoints (outcomes)

Genetic data

Imaging data

Medication usage

Patient-reported outcomes

Retrospective data

Platform, Natural History Study

REDCap

FDA Patient Listening Session

FDA Patient-Focused Drug Development (PFDD) Program

ICD Codes

We use an ICD-10 code capturing the family of diseases to which our disease belongs

Diagnostic Guidelines

Yes, we have published formal guidelines in a peer-reviewed journal

Science Advisory Board Policies

Yes, willing to share SAB policies

Research Network Policies

Has CRN but no policies

Patient Priority Survey

Yes

Patient Priority Survey, share

Yes, will share

Research Roadmap

We don't have a Research Roadmap

None

Europe

North America

Europe