Pediatric Neurotransmitter Deficiency Disorders

Pediatric Neurotransmitter Deficiency Disorders

What are Pediatric Neurotransmitter Deficiency Disorders (PNDs)?

The term “neurotransmitter disorders” constitutes a broad and increasingly complex spectrum of neurologic conditions associated with defects in the production, transport, release and reuptake of a variety of chemical compounds involved in the ability of nerve cells in the brain and spinal cord to communicate with each other (see Figure 1). The purpose of this section is to provide an overview of such disorders, with an emphasis on disorders associated with a dopamine or serotonin deficiency state.

 

OverviewSymptomsDiagnosisManagement & TreatmentStudies & Research

OculogyricScreening for this group of disorders occurs mostly by recognition of key neurologic symptoms (reviewed under symptoms), at the discretion of the examining neurologist, rather than a standardized diagnostic evaluation. Symptoms such as a dystonic gait disorder, childhood-onset parkinsonism or involuntary eye movements have a much higher likelihood of an associated dopamine deficiency state, and patients with classic symptoms therefore have a greater likelihood of receiving accurate diagnosis and treatment.

However, the wide spectrum of symptoms associated with dopamine deficiency states and overlap with other disorders with shared features can make accurate diagnosis of these disorders challenging. The routine availability of more sophisticated diagnostic tools including cerebrospinal fluid (CSF) neurotransmitter metabolite studies, CSF and urine biopterin studies, neuroimaging studies (MRI or more specific scans, such as PET), phenylalanine loading studies, enzyme assays in blood cells or skin fibroblasts and molecular studies have greatly increased our ability to accurately diagnose and treat patients in a timely fashion.

For ease of classification, these disorders can be divided into four groups:

Uliano Convergence

Neurologic Symptoms Associated with PNDs Symptoms
Are symptoms which can occur alone or as part of a constellation of features associated with a dopamine deficiency state, include the following:

  • Unilateral or asymmetric limb dystonia (twisted postures of extremities)
  • Postural tremor
  • Progressive dystonic gait disorder
  • Diurnal variation of signs or symptoms: Worse in the afternoon or evening, improved after sleep
  • Increased lower extremity tone (muscle tightness)
  • Torticollis (head tilted or turned to one side)
  • Involuntary tongue thrusting, particularly when associated with abnormal eye movements
  • Involuntary eye movements or frank oculogyric crises
  • Ptosis (droopy or tired looking eyes), blepharospasm (eye squinting)
  • Autonomic symptoms including hypothermia (inability to maintain body temperature), gastrointestinal dysmotility (reflux, constipation, poor tolerance for feeds), hypoglycemia (low blood sugar), diaphoresis (sweating)
  • Juvenile-onset parkinsonism syndrome (usually characterized by tremor, rigidity, slow or overall reduction in movement)
  • Infantile hypotonia (floppy baby) or dystonia with encephalopathy (dull affect, apparent cognitive impairments), hypokinesia (reduced movement) and involuntary eye movements
  • Infantile parkinsonism with bradykinesia (slowed responses), rigidity, tremor

View the Gait Dystonia video

DIAGNOSIS

PNDs With Normal Phenylalanine Levels

  • Segawa’s Syndrome
  • Tyrosine Hydrosxlase Deficiency (TH)
  • Dopa-decarboxylase Deficiency (AADC)
  • Sepiapterin Reductase Deficiency (SPR)
  • Rare Specific Disorders

PNDs With Elevated Phenylalanine Levels

  • 6-pyruvoyltetrahydropterin Synthase Deficiency (6-PTS/PTPS)
  • Dihydropteridine Reductase Deficiency (DHPR)
  • Guanosine Triphosphate Cyclohydrolase Deficiency (GTP)
  • Role of BH4 in the Central Nervous System (CNS)

Treatment Of Motor Manifestations In Patients With Dopa-Responsive Dystonia

Levodopa (L-dopa). Primary manifestations in patients with autosomal dominant and recessive forms of dopa-responsive dystonia are predominantly motor; these symptoms are most effectively treated with levodopa. Optimal dosing requirements may vary with age, physical activity and growth. L-dopa must be used in conjunction with an inhibitor of AADC activity, such as carbidopa, in order to allow the precursor to effectively cross the blood-brain barrier, where it can be converted to dopamine in neuronal cells.

In more severely affected individuals who have L-dopa dose-related dyskinesia, other therapies may help augment the L-dopa therapy, thus reducing the sometimes significant peak and trough fluctuations in motor function associated with the short half life of L-dopa. Slow release formulations are available for adults but not children.

Because patients with neurotransmitter deficiency disorders may have been deficient for prolonged periods before treatment, they can be extremely sensitive to initiation of neurotransmitter precursors. Patients with TH deficiency seem particularly susceptible in this regard. Starting with extremely conservative dosages, increasing the dosage slowly over weeks or months and ensuring that peripheral aromatic L-amino acid decarboxylase is fully blocked by providing ample carbidopa can make the transition to treatment much easier. The rate or degree to which children respond depends on a variety of factors including age of diagnosis, specific disorder and mutation, presence or absence of elevated  phenylalanine levels and presence or absence of central BH4 deficiency. In general, optimism regarding improvement is warranted.

Institution of neurotransmitter precursor treatment may lead to new problems, such as intermittent dyskinesia related to a peak dose effect, changes in appetite, gastroesophageal reflux, diarrhea or constipation. These problems, greatest in the first few weeks of treatment, tend to improve with time. With regard to replacement of L-dopa, use of a slow release form of the medication may theoretically be ideal. However, such formulations are not dosed for use in children, but for use in adults with Parkinson’s disease. In addition, dividing standard dosage forms marketed for adults make adequate dosing in infants and young children a significant challenge. Thus, ideal dosage forms may need to be formulated in compounded preparations, rather than via commercially marketed dosage preparations. Support for parents and children during this often difficult period of transition from initiation of treatment to adjustment of medications is critical, because these patients will likely require neurotransmitter precursor replacement throughout their lifetimes.

Other: The monoamine oxidase B (MAO-B) inhibitor selegeline slows the catabolism of dopamine and significantly augments the effectiveness of levodopa/carbidopa therapy in some individuals. Anticholinergic agents, such as trihexyphenidyl and amantidine, have also proved modestly helpful in augmenting motor benefit of levodopa/carbidopa and in smoothing out motor fluctuations.

See also special treatment considerations in AADC deficiency

Pediatric Motor Disorders Database

In order to improve our understand on the various motor disorders, the Pediatric Motor Disorders Research Program has established a database for Pediatric Neurotransmitter Deficiency Disorders (PNDs) patients associated with dopamine deficiency.

For information about participation in the database, please contact one of our clinical study coordinators at (801) 585-9717.