Frequently Asked Questions

The following questions were obtained from a poll of PND Families and were asked at the First PND Medical Symposiums session on "Everything you ever wanted to ask about PND's". Some additional questions and answers have been added since that time.  If you have a general question pertaining to PND's that you would like to ask please forward it to the PND Association at [email protected]  and we will try to provide an answer.  Thank you to the PND Medical & Scientific Advisory Board for their continuous support and for providing such important information to our families and children.

I. Succinic Semialdehyde Dehydrogenase Deficiency

Q.  Do we know how many people have SSADH? Are there any children or adults functioning independently or "near normal" with treatment? Have any of them deteriorated over time? 

A.  Approximately 400 persons in the world have been identified as having SSADH deficiency.  Some children in the preschool and elementary school years appear to be progressing fairly well, particularly in socialization, although we are not aware of an adult who could function independently. Verbal expression appears to be the predominant deficit leading to the extent of the disability.  About 10% of patients have deteriorated over time, with respect to worsening seizures or movement disorders.
Phillip L. Pearl MD

Q.  My son has SSADH and has very low muscle tone. He also has hyperlaxity of his ligaments - is this common in SSADH? Has anyone looked at muscle biopsies in these children and if so what are the results?

A.  These are typical findings in SSADH deficiency.  The hypotonia, as well as "ataxia" or gait in-coordination, actually seem to improve over time.  There have been some muscle biopsies without specific abnormalities.  One report disclosed ragged red fibers, which indicates mitochondrial dysfunction.  The SSADH enzyme is located in the mitochondria, although SSADH deficiency is not a classic mitochondrial disorder.
Phillip L. Pearl MD

Q.  My son is tactilely defensive and seems to need deep pressure to activate his muscles, is this normal in SSADH, and if so why?

A.  This is very common in SSADH, as well as many neurodevelopmental disorders where there is decreased muscle tone and developmental delay.  This represents some degree of sensorimotor integration difficulty, and occupational and physical therapy may be helpful to augment fine motor and gross motor skill development.
Phillip L. Pearl MD

Q.  My son seldom vocalises - why do children with SSADH have speech problems?

A.  This is a cardinal feature in SSADH although we do not have a good explanation.  One theory is that the excessive GABA. Levels interfere with nerve signalling in the language related processing areas of the cerebral cortex.  Trials are in planning (in both the mouse model and humans) to address this theory.
Phillip L. Pearl MD

Q.  Some children with SSADH have seizures - can they start at any time or is there a "typical" time when they start?

A.  The seizures can start in infancy, childhood, adolescence, or even early adulthood.  They are usually of the absence (petit mal) and generalized tonic-clonic (grand mal) type.  EEGs may show bursts of activity such as spike discharges that are known as epileptiform activity.
Phillip L. Pearl MD


II. Tyrosine Hydroxylase Deficiency

Q.  How is TH different from GTP-1?

A.  Tyrosine Hydroxylase (TH) deficiency is a specific enzyme deficiency that results in decreased production of the neurotransmitter, dopamine.  GTP Cyclohydrolase deficiency leads to a decrease in the production of a chemical known as tetrahydrobiopterin (BH4).  This BH4 is required to be present before a range of enzymes can fully work.  These enzymes include not only tyrosine hydroxylase but also tryptophan hydroxylase.  These enzymes are needed to be fully active in order to produce dopamine and serotonin. So, for TH only tyrosine hydroxylase is not functioning.  For GTP-1, BH4 is missing and this result in the slowing down of a range of enzymes.
Simon Heales BSC PhD FRCPath

II. Autosomal Dominant GTP Cyclohydrolase I (AD GCH I) Deficiency (also known as Segawa Disease)   
                                                     
Q.  Which is the most commonly used term to describe GTP Cyclohydrolase I Deficiency and do they all refer to the exact same disease? AD GCH-I Deficiency/Segawa Disease/GTP- I Cycloydrolase Deficiency/Dopa-Responsive Dystonia (DRD)

A.  The term commonly used may be Segawa Disease. However the most proper nomenclature is autosomal dominant GTP cyclohydrolase I (AD GCH I) deficiency. GTP cyclohydrolase I (GCH I) deficiency is not proper because there is recessive GCH I deficiency which show severe central nervous system disturbance due to marked decrease of the serotonergic activity. Dopa-responsive dystonia (DRD) at first is proposed as a diagnostic term for AD GCH I deficiency. However, as there are other DRD than AD GCH I deficiency, this term is better used for a comprehensive nomenclature representing all dystonia's which respond to l-dopa. More research and data collection is needed on the recessive form of GCH I.
Masaya Segawa MD

Q.  Do we know how many people have Dominant GTP Cyclohydrolase I Deficiency ? Are there any children or adults functioning independently or "near normal" with treatment? Have any of them deteriorated over time?
 
A.  There is no exact data about the number of patients with autosomal dominant GCH-I (AD GCH-I) deficiency. However, before discovery of the gene there was a report of Dr. Nygaard suggested the incidence of DRD as 1 in 2,000,000 in England and Japan. In 1993, when Nomura collected the published reports of the world the total number of hereditary progressive dystonia with marked diurnal fluctuation were 65 in Japan, 55 in North America and 66 in Europe. All patients with AD GCH-I deficiency having been treated with L-Dopa are completely independent without any symptoms. In our experience nine patients are under L-Dopa more than 35 years the current age ranges from 38 to 85 years. No one has deteriorated.
Masaya Segawa MD

Q.  We heard there was research in Europe to replace GTP-1 enzyme itself instead of using Sinemet. Is there any truth to this?

A.  We have not known any information about it. Levodopa or Sinemet shows complete and life long effects, though they have to take it life long.
Masaya Segawa MD

Q.  Are there any documented cases of effective long-term treatment for AD GCH I or does Sinemet lose its effectiveness over time, like in Parkinson's?

A.  Yes, there are. As mentioned in the answer to the first questions Sinemet has not lost in its effectiveness with long-term administration. In fact we can decrease the doses after the ages of 40's or so.
Masaya Segawa MD

Q.  If a person has AD GCHI, are they more prone to developing other disease like Parkinson's?

A.  No. They do not develop Parkinson's disease. In fact AD GCH-I deficiency or Segawa disease is a functional disorder and does not deteriorate. However, theoretically, it has deficiency of the serotonergic neurons and may develop migraine or depression though they are very mild.
Masaya Segawa MD

Q.  Are there any known cases of AD GCH I patients who are also parents? Are their children affected in some way?

A.  Yes, there are. Among over 46 patients 7 patients have married after the diagnosis are made. Of them, five have children and one of them has same disease, that is AD GCH-I deficiency. Before the discovery of this disease there are affected parents or grand parents, 2 and one respectively. In one family, the father developed the symptoms in 58 years, more than 20 years after the diagnosis of his daughter.
Masaya Segawa MD

Q.  Since there are range perimeters for normal neurotransmitters I was wondering if there is anyone  who has been charting where  children's LP levels are in comparison to how they are responding to the medications. Different dosages vx. diff. weights etc. Also  Where do the a-atypical GTPCH def. (autosomal recessive)  children's neurotransmitters fall in comparison to the typical GTPCH def. children (autosomal dominant)  who  respond well to treatment?

A.  Answering specific medical questions in the field of neurotransmitter disorders is almost impossible as results of lumbar punctures were not systematically validated. Especially the children with dominant GTPCH deficiency do almost never receive lumbar punctures. Most do not even have a lumbar puncture before the diagnosis is made and the treatment initiated. In that sense I am sure that there are no data comparing -atypical GTPCH deficiency (recessive) children to atypical GTPCH deficiency (dominant)  children. Logically it would be wise to check the neurotransmitters under treatment. It will however only be one point within the diagnostic and therapeutic decisions.
Univ.-Prof. Dr. med., Prof. h.c. (RCH) Georg F. Hoffmann

A. If the GTPCH deficiency of a child appearing in this question is autosomal dominant GTPCH deficiency, the optional doses of l-Dopa is 4 to 5mg/kg/day with carbidopa, that is, menesit or 20mg/kg/day with plain l-Dopa, that is, without carbidopa. With these doses the effects sustain more than 20-to 30 years and in some after 30 years of age, the dosis can be reduced slightly. However, at the first step of l-Dopa treatment, there are patients whose response to l-Dopa is not marked or who show aggravation of symptoms, particularly active backward extension of the neck (action retrocollis) or upward derivation of the eye balls (oculogyric crisis) or show involuntary movements such as choreic movements. For the former patients l-Dopa should be started with small dosis and finally rather higher dosis are necessary. In some administration of tetrahydrobiopterin in
addition to l-Dopa is effective. For the latter patients, it is necessary to reduce the dosis of l-Dopa and to start the treatment with smaller dosis and to increase to the optional dosis shown above slowly. In patients with oculogyric crisis combination treatment of l-Dopa with anticholinergics (only in initial stage) may make the response smooth. Anyhow in patients with dominant GTPCH deficiency all patients can attain almost normal life, though they have to take l-Dopa regularly.
However for more precise comments, I like to know more details on clinical symptoms of your child.
Masaya Segawa, MD