Overview:Tyrosine hydroxylase (TH) deficiency is a rare metabolic disorder characterized by lack of the enzyme involved in converting the amino acid tyrosine to L-dopa. L-dopa is an important chemical in producing dopamine in the brain. Dopamine is the major neurotransmitter which facilitates motor control and movement. A neurotransmitter is an important chemical messenger that helps nerve cells to communicate properly to each other. TH is a critical enzyme in normal dopamine production, and when it is not working properly to produce enough dopamine, major neurologic abnormalities can occur. In addition, dopamine is also important in making two other important neurotransmitters in the brain and body, norepinephrine (noradrenaline) and epinephrine (adrenaline). When dopamine is critically low, these neurotransmitters may be low too. They play important roles in the brain in regulating attention, and they help to maintain normal blood pressure, body temperature and blood sugar .
Symptoms:
Mild: In the mildest cases, walking or running may be clumsy but little else may be noticed, at least initially. These symptoms may progress slowly as the child gets older, and may not initially be apparent. Sometimes, one side of the body may seem weaker, or the child may begin to walk up on their tiptoes due to some tightness of the leg muscles. Sometimes these children are diagnosed with cerebral palsy; other times they are simply considered clumsy or uncoordinated. Sometimes these children demonstrate some attentional difficulties in school. Essentially all children with mild symptoms are readily treated with medication.
Moderate: In moderately affected cases, the child may not be able to walk at all, or walking may be extremely difficult. Many children demonstrate unusual arm posturing or positions of their arms with attempts to walk or walk on their toes. Speech delay may be present. Many of these children are diagnosed with cerebral palsy of unknown cause. Some of these children may have involuntary eye movements problems. The majority of these children have an excellent response to treatment, but full benefit may take many months.
Severe: In the most severe cases, children are disabled and affected from early infancy. This is sometimes known as the infantile Parkinson’s disease variant. infants may demonstrate muscle tightness and rigidity, arching, tremor and poor muscle control, abnormal eye movements which may include involuntary eye deviation upward, downward or towards the nose. They may be diagnosed with intermittent strabismus (cross-eyed). They may have ptosis, or droopiness of the eyelids. Severe gastro problems at birth. delay, or difficulties feeding, chewing or swallowing. Constipation is common. While most children tend toward increased muscle tone (in the legs especially), there are children who have generalized low muscle tone, with poor head control and inability to sit unsupported. They may have torticollis, or involuntary deviation of the head and neck. They may have difficulty directing their hands to a toy, generating a flinging hand motion. Occasional children have been found to suffer from intermittent color changes, unexplained low body temperature or fevers, low blood sugar, and difficulty regulating blood pressure. These symptoms are more likely to occur during another illness the child may be experiencing. Children in the more severely affected group of patients are more difficult to treat, and several medications may be needed to treat symptoms. They are unusually vulnerable to side effects of the medications, which can result in excessive movement and irritability. Response may be slow, with some continued benefit over months to years, but may not result in the complete resolution of all symptoms.
Who gets TH deficiency?It is unclear at present whether males or females are affected any differently. Only a few dozen cases have been identified to date worldwide as of 2008.
Testing/Diagnosis:
How is TH deficiency diagnosed?At present, the only reliable and readily available way to diagnose TH deficiency is by analyzing the cerebrospinal fluid for neurotransmitter metabolites. This means your doctor will need to perform a spinal tap to obtain this fluid for analysis. It has to be carefully handled and placed on ice immediately or the results will not be valid. Therefore, it is important to find a doctor who is comfortable in performing this procedure. Once the diagnosis is suspected on the basis of cerebrospinal fluid studies, the diagnosis should be confirmed by analysis of the TH gene itself. This is because the study of the spinal fluid may lead one to strongly suspect the diagnosis, but there are other reasons why the spinal fluid dopamine metabolite levels could be low, including neurodegenerative disorders which lead to a loss of the cells in the brain that produce dopamine. Therefore, if your children has atypical clinical symptoms including seizures, oror fails to respond as expected to treatment, other disorders need to be considered. Your doctor will work with you in helping to sort out these issues.
How is TH deficiency treated?The most well-established treatment for TH deficiency is to provide L-dopa to help restore normal dopamine levels. Dopamine itself cannot cross the blood-brain barrier directly, and so it is necessary to treat with a compound called L-dopa. L-dopa must be combined with another medication, carbidopa, in order for it to get into the brain properly. There is a commercially available medication called Sinemet which contains both carbidopa and L-dopa together in a single tablet. However, this preparation was designed to treat adults with Parkinson’s disease, and the dosage is much too high for many infants and young children with TH deficiency. Therefore, we often ask a pharmacist to order and compound special doses of L-dopa and carbidopa for our patients with this disorder. In general, it is advisable to start with no more than 5 to 10 mg Ldopa, combined with at least 15 to 25 mg carbidopa per dose depending on the size, age and severity of symptoms in the affected child. For some reason, the recessive form of dopa-responsive dystonia is very different from the dominantly inherited form in that children are much more likely to get excessive movement or irritability from low doses of L-dopa. Excessive starting doses of L-dopa can result in extreme irritability, sleeplessness or excessive sleepiness, vomiting or sudden intermittent or sustained jerking and twitching movements which can persist for several hours following a single dose. In children who are severely affected, less than one year of age, or prove intolerant of low dose L-dopa therapy, we typically recommend initial use of an anticholinergic agent such as trihexyphenidyl (Artane) to help reduce excessive muscle spasticity or rigidity. Anticholinergic agents can work in conjunction with dopaminergic agents to smooth out movements and reduce tremor. Adjunctive agents also include selegeline (Eldepryl), which is a monoamine oxidase Binhibitor which helps slow down the breakdown of dopamine in the body. Selegeline can greatly extend the timespan associated with L-dopa treatment, but can result in excessive movements; nausea, vomiting or reflux, or sleep disorder. It should generally be used only early in the day. There are other agents that your doctor may consider with similar mechanisms of action, and may be appropriate in the treatment of your particular child. It is important to remember that these agents all work together, and the presence of side effects doesn’t necessarily indicate that a particular medication is bad, just that it or others need to be adjusted appropriately for your child’s needs. Physical and occupational therapy can be very helpful, particularly during the period of institution of medication to help your child adjust to the medications. Speech therapy is also indicated in some children.
References/Resources:Althini S, Bengtsson H, Usoskin D, Soderstrom S, Kylberg A, Lindqvist
E, Chuva de
Sousa Lopes S, Olson L, Lindeberg J, Ebendal T. Normal nigrostriatal
innervation but
dopamine dysfunction in mice carrying hypomorphic tyrosine hydroxylase alleles.
Neurosci Res 2003 May 15;72(4):444-53.
www.pndassoc.org
Kathryn J. Swoboda, M.D. is a neurologist and geneticist working
closely with the PND association to establish a clinical database of
patients and families with TH deficiency to help us better understand
this disorder. Please contact Dr. Swoboda, Dr. Reyna or any of our
clinical coordinator associates if you, your patient or a family
member are interested in participating in the TH database and related
studies. Telephone: 801-585-9717, email swoboda@genetics.utah.edu
Olivia's Story
I had some complications through pregnancy starting around 34 weeks with non movement. We went through the normal procedures of stress test and the doctors agreed that I had passed all of them and sent me home. At 39 weeks I was induced and Olivia was born on August 4th 2010 @ 2:16 PM She was 7lbs 5oz and appeared to be healthy. The first couple of days was testing for me I knew that it was not ...normal that a child was throwing up as much as she was. The doctors said it was nothing to worry about that she just had extra fluid on her stomach making her sick. A week passed and I noticed that Olivia was sleeping 21 hours a day and still not keeping food down. She was looking skinny and pale. I made appointment with the peditrcian where he informed me that he was concerned about Olivias stomach and that she needed to go for a ultrasound. At our surprise Olivia's US came back normal. After finding nothing they scheduled her for a video swallowing study once again everything appeared normal. We were stumped and sent home. The months following would prove I wasnt worrying for nothing. Olivia went to high calorie formula and she was eating a half a ounce every half hour I couldnt even set her up or throw up would hit the wall. Frustrating YES! Around six months Despite the throwing up I started working with olivia in some of her motor skills. I notced her fist stayed clinched and that her legs were tight and in a frog leg position and I couldnt striaghten them. People started noticing that she was a little behind. We bruished it off as tummy problems but I was actually in denile.
At her nine month check up the doctor examined her and asked me normal questions is she sitting? no. Is she Rolling? No. and obviously not crawling. He stepped back and scratched his head and gave me a referal to First Steps Intervention. He didnt really give me an explanation why she would be delayed in all motor skills. During my consulatation with the PT she agreed with me that Olivia needed to see a Ortho and a Neurologist. We made an appointment with a Ortho where again he said everything is fine with her bones but she needs to see a Neurologist. That was the 2nd time that I had heard a Neurologist. To think that my daughter may have something wrong her brain saddened me deeply.
In august 2011 we made an appointment with Cincinnati Childrens. It was a Saturday Clinic. We were there four hours where he gave her an extensive exam. When he was done I can remember asking "Could this just be a delay, and she will catch up?" He said unfourtnanly I do not think so . I think one of three things is happening with Olivia. One she could have CP, two it could Muscular Dystrophy, or three a mitchondrial disease. I clinched my teeth and lips tightly. He said Lets go ahead and scheduled a MRI and Bloodwork up. When he left the room to get the paperwork I threw my head in my hands and cried deeply. I can remember Roger wrapping his arm around me and saying "We will make it through this" I started blaming myself. Did I do something wrong during pregnancy? The end of August after celebrating her first birthday Olivias MRI was done. When Childrens gave me the results they simply said your daughter seemed to have a stroke and has CP. They told me hey its not progressive so she will only get better. OF course I cried. She was in PT OT and DI. They fitted her for AFOS in October where her ankles seemed to stablelize some. I was happy. Late October we Had went for Pizza and as we were leaving the Pizza place Olivia was screaming in a Unfamiler scream! All the way home she did this. When I got in the house I noticed Olivias leg was locked at the knee and I couldnt straighten it out It was extreamly scary. I called the PT she said don't worry its just a spasm from the AFOS lots of heat should take care of it. I called the doctor and he said he was concerned to video tape it. I did and emailed it to him. I received a phone call as soon as he seen the video and said get her in here. She is having Dystonia.
After extensive research on his part he came up with a few answers. It is rare for a child her age to have dystonia epsiodes like her. He decided to start her on a trial of sinamet (parkinsons meds) to see if she responded within days. I seen a new Olivia and no dystonia it was if she had been healed. Her anxiety and sensory issues seemed to be less. After three weeks of improvment Olivia was taken off Sinamet to prepare for a spinal tap to check the Levels of Dopamine in her CSF. The week off the medicine was miserble she went right back to dystonia and it came mostly in the evening. She was in pain. The doctor moved her Spinal up a week. He said if we waited she would be in the hospital. The spinal results are back. Normal dopamine in a child her age are 120-160 Olivias was 22. Wow! How wonder she cant move. They knew then that Olivia had been Misdiagnosed with CP.
We now know Olivia suffers from a rare neurotransmitter disease that effects the production of dopamine in her brain. Tyrosine Hydroxylase Def . It mimics CP. When they body doesnt convert certain enzymes to dopamean the body starts to go haywire. Your brain stops commnicating to your muscles. Your muscle become stiff causing painful episodes of dystonia. Olivia continues medication ( sinamet) same medication as parkinson paitients that help control symptoms she takes four times daily. She is in Pt, OT, and DI weekly and is getting ready to see a special dystonia therapist at Childrens hopsital. She is 18 months and has not taken any independent steps but has a walker and does crawl. She is a very determined baby. We have good and Bad Days. Although the medication controls symptoms it is far from a cure. Olivia's Symptoms are only reversed around 60% we believe they may increase to around 75% with therapy. Olivias nuerotransmitter disease is expected to progress through the 2nd decade of life making mobilty a challenge everyday. Usually the onset of symptoms appear between age 6 and 9. Olivia has the rare form of infancy onset effecting less than 50 people worldwide. It effects movement, mood, anxiety, and sensory. Little is known about Tyrosine Hydroxylase Def DRD but it is being researched daily, and its my goal to spread awareness. I didn't choose this road but I know God has it laid out perfectly for Olivia and our family.
Contributed by MOM Melissa Phelps
Overview: Reflex Anoxic Seizures (RAS) is the term used for a particular fit which is neither epileptic nor due to cyanotic breath-holding, but which rather results from a brief stoppage of the heart through excessive activity of the vagus nerve. 
