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Meeting Addresses Pediatric Neurotransmitter Disease and Autism Commonalities

September 08, 2008

Medical Management of Pediatric Neurotransmitter Disease:
A Multidisciplinary Approach

Herndon, VA
Friday, July 18 - Saturday, July 19, 2008

As the diagnosis of autism is based only on observable symptoms, researchers increasingly recognize that the underlying biological causes for its presentation are likely to be multiple and varied. Co-occurring conditions and symptoms sometimes provide clues to biological influences or related disorders and can give us insight into the development of autism — even if only in a rare number of cases. For years autism research has employed the perspective that better understanding of overlapping and related conditions, such as the genetic disorders Fragile X or Tuberous Sclerosis, might provide insights that would be beneficial to understanding the pathways and biochemical alterations that could result in idiopathic autism as well.

In recent years, as awareness of Pediatric Neurotransmitter Diseases has increased, so has the recognition of rare overlaps with autism in certain individuals. Because of these overlaps, Autism Speaks sent representatives to the Pediatric Neurotransmitter Disease (PND) Association meeting in Washington D.C. in July, joining with clinicians, basic scientists and families affected by PNDs to learn more about these rare disorders. It is known that some children with PNDs have symptoms of autism (some families report autism as their child's initial diagnosis), and clinicians at the meeting reported that autism appears to be relatively more common in families with PNDs, either in the affected children or their siblings. Like autism, early recognition and treatment has a significant benefit to long-term prognosis. In addition, it is suspected that these disorders are under-diagnosed due to limited recognition and the special diagnostic procedures and analyses required for their detection. As more investigation is being done into the metabolic aspects of autism, some clinicians and scientists are considering the possibility of children with autism who also have an underlying PND.

What is a PND?

Currently, PND represents a collection of rare diseases in children related to abnormalities in the synthesis and breakdown of the neurotransmitters dopamine, serotonin and GABA. Neurotransmitters are chemicals that communicate information between cells in the nervous system. They can be excitatory, inhibitory or modulatory. All movement and thought, as well as homeostatic regulation in the body, is controlled by a delicate neurotransmitter balance. Any disruption of this balance, especially in a developing brain, can result in a collection of motor, cognitive and regulatory disturbances that can be difficult to match with a specific diagnosis. Most of the currently recognized PNDs are diagnosed in children with considerable early motor, mobility and feeding challenges, often those who might first have a diagnosis of cerebral palsy.

Dopamine and Serotonin-related diseases

Patients with errors in dopamine and serotonin metabolism can develop motor disorders, dysregulation of the autonomic nervous system (which controls things like blood pressure, temperature and sweating) and cognitive impairments. Symptoms can range from mild to severe; mild symptoms often present as clumsiness, postural oddities, and attention disturbances, and severe cases present with physical disability as early as infancy. Diagnosis of these rare disorders requires measurement of neurotransmitter metabolites from the spinal fluid that bathes the central nervous system, and samples of this fluid are acquired via lumbar puncture (spinal tap). Treatments are available and variously successful depending on the type and the severity of the disorder.

Dopamine is manufactured in cells by a series of enzymatic actions. Tyrosine hydroxylase is known as the rate-limiting enzyme in this cascade, and a deficiency in this enzyme (TH deficiency) causes a debilitating disease that results in a deficiency of not only dopamine, but also several other related neurotransmitters, due to their common pathways of synthesis. Current treatments involve increasing dopamine levels in the brain, and treatment therefore includes the classes of drugs used to treat Parkinson's Disease, which is also due to loss of dopamine (however, by different means and usually occurs later in life). Guanosine Triphosphate Cyclohydrolase I Deficiency (GTPCH) and Sepiapterin Reductase Deficiency (SR) are both rare disorders of neurotransmitter synthesis that involve a cofactor, tetrahydrobiopterin (BH4), that is required to prepare the pathways for enzymes to create dopamine and serotonin. Some forms of GTPCH Deficiency present as Segawa's disease and are rather treatable, while others are not. Many cases of SR Deficiency appear to respond to L-Dopa treatments. The final rare metabolic disorder in this group is called Aromatic L-Amino Acid Decarboxylase Deficiency (AADC). AADC Deficiency results from the lack of an enzyme that modifies other dopamine and serotonin precursors. In both cases, the appropriate neurotransmitter levels are altered and the delicate signaling pathways in the brain are thrown off balance. Patients with AADC commonly have "attacks" or "spells" of increased irritability, motor abnormalities (including eye movements), postural oddities and rattled breathing.

GABA-related disease

Common manifestations of the recognized GABA-related PND include delayed motor and cognitive development, delayed speech and low muscle tone. Some children may be diagnosed with autism, seizures or affective or sleep disorders. Succinic Semialdehyde Dehydrogenase Deficiency (SSADH) produces a build-up of a GABA break-down product (gammahydroxybutyric acid, or GHB) as a result of a deficiency of an enzyme in the pathway that breaks down GABA. GHB itself has neurotransmitter-like qualities and can disrupt processing in neural circuits throughout the brain. Diagnosis of SSADH deficiency is made through urinary analysis of organic acid or blood amino acid profiles. Treatments are not readily available or effective, but there are pharmacological agents that limit the availability of GABA in the brain and research into more effective treatments is under way.

Since it is a relatively recently established set of syndromes, the Pediatric Neurotransmitter Diseases are not well recognized in the clinical community and they appear to be rare, though true prevalence is unknown. In the infrequent cases where individuals with autism also exhibit recognized symptoms of PNDs, evaluation of these disorders and possible targeted interventions may be warranted. In addition, it is anticipated that the scientific community can benefit from further understanding of the biochemistry and pathways that might result in overlapping symptoms, and Autism Speaks intends to continue to collaborate and benefit from the improved perspectives that come from exploring common ground with associated fields of research and treatment.

More information on the PNDs can be found at the PND Association's website at