MSUD Newsletter

NATIONAL CONFERENCE IN OHIO

Overview of Conference
Kay Larsen

Dublin, Ohio was the site of the National Coalition for PKU and Allied Disorders Metabolic Conference on the weekend of May 3, 4, and 5. Attendees gathered at the beautiful Embassy Suite Hotel for a jam-packed conference, starting with reception on Thursday evening, and finishing off with a question and answer session with a professional panel on Saturday afternoon.

Friday morning and afternoon were devoted to breakout sessions for the following diseases: phenylketonuria (PKU), MSUD, organic acidemias (OAs), fatty oxidation disorders FODs, homocystinuria (HCU), and tyrosinemia (TYR). On Friday evening from 7 p.m. until 10:30 p.m., there were talks on different aspects of newborn screening with a question and answer time at the conclusion. On Saturday, the entire group came together in the large ballroom for back to back lectures on the following topics:

• Self Esteem Issues of A Child with an Inborn Error of Metabolism
• The Prevalence of ADHD in Metabolic Disorders
• Federal Legislation for Metabolic Formulas
• Universal Newborn Screening, It's Time Has Arrived!
• Obtaining Metabolic Formula Reimbursement
• Gene Therapy Update

There was a great deal of sharing and interacting among the families. For many of the families it was their first opportunity to attend a conference like this. There were approximately 320 people (families and professionals) present from thirty-one states and seven foreign countries. Twenty-one metabolic disorders were represented. Eight MSUD families attended.

Description & Treatment of Maple Syrup Urine Disease

1. Branched-chain amino acids (BCAA): leucine, isoleucine & valine.
2. Keto acid (2-Oxoacid) derivatives: a-ketoisocaproate (KIC), a-ketomethylvalerate (KMV) a-ketoisovalerate (KIV).
3. Alloisoleucine—diagnostic compound from isoleucine metabolites.

Branched-chain amino acids (BCAA)

1. Essential amino acids—building blocks for the body.
2. Used to make:
1. Body tissue (especially skeletal muscle 35%).
2. Glucose (gluconeogenic).
3. Ketone bodies (ketogenic).
   1. Fatty acids and cholesterol (needed to make hormones).
   2. Energy.

MSUD results from

1. Decreased activity of the enzyme Branched-Chain a-Keto acid Dehydrogenase (BCKD).
2. BCKD—large complex molecule with 6 components, coded for by 6 different genes.
   1. Carboxylase (thiamine co-factor).
   1. Subunit a ( E1a), 22 mutations.
      1. Classic: Mennonites & others in U.S.
   2. Intermediate: Hispanic.
   2. Subunit b (E1b), 7 mutations.
   1. Intermediate & Intermittent.
   2. French Canadian, Afro-American & Whites.
   2. Transacylase (E2), 28 mutations: Japanese.
   3. Dehydrogenase (E3), 5 mutations.
   1. Japanese (Ashkenazi).
   2. Eastern European Jews.
   4. Kinase (activator).
   5. Phosphorylase (inactivator).
   
   
   

History

1.    1954 Beginning of amino acid analysis.
2.    1954 Menkes, Hurst, Craig: first to describe MSUD; identified urine odor.
3.    1960 Dancis: demonstrated deficiency in decarboxylation of BCAA.
4.    1964 Snyderman: developed diet restricting BCAA; determined amount of BCAAs needed by the body.
5.    1971 Scriver: described a thiamine-responsive form of MSUD.
6.    1976 Means of identifying organic acids became available.
7.    1978 Reed: purification of the BCKD.
8.   1980s Beginning of molecular genetics and the identification of the subunits of the enzyme, BCKD.
9.    1990s Morton: improved treatment.

Types of MSUD

1. Classic —less than 2% of normal activity of BCKD.
1. Most severe, most common.
2. Leucine more elevated than other BCAAs.
3. Symptoms—usually begin appearing at 4-7 days of age.
1. Lethargy.
2. Poor suck.
3. Decreased intake.
4. Weight loss.
5. Neurologic signs.
1. Alternating increased & decreased motor tone.
2. Abnormal movements (dystonia).
6. Ketosis—positive DNPH (dinitrophenylhydrazine).
7. Abnormal maple syrup odor (recognizable in ear wax before urine).
8. Seizures, coma, cerebral edema, death.
4. Even with newborn screening, some infants will be symptomatic before or at the time the testing results are known.
5. Various degrees of disabilities in many depending on when treatment was stared and how well controlled.



2. Intermediate—3-30% of normal activity of BCKD.
1. Less severe than classic; less common.
2. Symptoms appear later; may not be diagnosed until 5 months to 7 years of age when evaluated for delayed development.
3. All BCAAs elevated, leucine less high than in classics.
4. Catastrophic brain symptoms (encephalopathy) usually not present during newborn period.
5. Delayed development, maple syrup odor, seizures.



3. Intermittent—5-20% of normal activity of BCKD.
1. Less severe than classic; less common.
2. Usually no symptoms during newborn period.
3. Episodes of acute loss of metabolic control usually begin between 5 months and 2 years.
1. Present with ketosis & hypoglycemia.
2. During episodes:
1. Difficulty walking and keeping balance.
2. Lethargy.
3. Behavior/personality changes.
4. Maple syrup odor in urine.
3. Abnormal BCAAs only present with episodes.
4. Growth and development usually normal.



4. Thiamine-responsive—30-40% of normal activity of BCKD.
1. Similar to intermediate/intermittent although less common.
2. Usually no symptoms during newborn period.
3. Episodes of acute loss of metabolic control may begin in infancy or early childhood.
4. Abnormal BCAAs only present with episodes.
5. Delayed development possible.
6. Responsive to thiamine in daily doses of 100-150 mg.
5. E3-combined dehydrogenase deficiencies (BCKD, pyruvate, 2-oxoglutarate).
1. Similar to intermediate form; very rare (4 or 5 reported cases).
2. Symptoms may appear during the newborn period, but more often, later.
3. Symptoms include a severe lactic acidosis.
4. Elevated lactic acid and 2-oxoglutarate.

Treatment (Classic type)

1. Acute newborn crisis or acute metabolic crisis:
1. Goal: to achieve control of leucine levels by providing enough calories and special medical food to stop catabolism (breaking down of own body stores).
2. Hyper-caloric approach: is preferred treatment used today—superior to dialysis used in the past.
3. Monitor BCAA levels every 12 hours to guide therapy.
4. Stop all sources of protein including those from formulas and breast milk.
5. Start special medical food (devoid of BCAAs). Give by nasogastric tube (NG) if cannot be taken by mouth due to poor suck.
6. Add leucine to diet in the form of regular formula or table foods only when leucine levels are normalized.
7. If special medical food cannot be tolerated, use special IV hyperalimentation [TPN] (complete feeding) low in the BCAAs.
8. Supplement with other amino acids.
   1. Isoleucine and valine. (Inversely related to the leucine levels; can protect the brain from high leucine levels— important to keep these levels from becoming deficient.)
   2. Tyrosine (also decreases leucine brain levels.)
   3. Glutamine and alanine (Brain levels of these neurotransmitters are low if leucine is high.)
9. May need:
   1. IV intralipids 20% to increase calories.
   2. IV Insulin (promotes glucose intake in cells).
   3. IV Propanolol (catecholamine antagonist).
10. Cerebral edema (brain swelling) must be prevented—the usual cause of death.
    1. Behavior changes are an important predictor.
    2. Use hypertonic saline solutions (high normal sodium, diuretics, Mannitol).
       
       
2. Treatment of asymptomatic MSUD newborns [diagnosed before clinical symptoms appear]:

1. Start special medical food to prevent catabolism.
2. Initial leucine intake: zero.
3. Add glutamine, alanine, and salt.
4. Add isoleucine and valine in approximately two days.
5. Give thiamine, 10mg/Kg daily on a trial basis, if not Mennonite classic.
6. Monitor blood levels at least daily.
7. Add leucine when leucine levels normalize.

4. Long Term Treatment
   1. Requires the use of special medical food to provide protein intake of 2-2.5 gm/kg daily.
   2. Diet low in leucine—only amount needed for growth.
      1. Varies with age—most needed per kg of weight during newborn period.
      2. By age 2-3 years, 300-600 mg and maintained daily for rest of life.
      3. Select and use one food list consistently.
         1. Leucine values vary from list to list
         2. Leucine can be figured in milligrams or exchanges.
   3. Supply isoleucine and valine.
      1. To meet growth needs and avoid deficiencies.
      2. To protect against high leucine levels.
   4. Add glutamine and alanine to prevent low levels of these two amino acids.
   5. Add table salt (sodium chloride) to offset high salt loss through kidneys, especially when leucine is high.
   6. Avoid prolonged low levels of the BCAA—leads to poor growth, decreased appetite, rashes and skin infections.
      
      

4. Provide adequate caloric intake—the mainstay in the treatment of MSUD
1. To promote growth and avoid catabolism.
2. Initially supplied by formula, later from table foods.
3. Based on age and activity.



5. Thiamine
1. Give approximately 10 mg/Kg daily (50-300 mg per day) for at least 3 weeks as a trial.
2. Mennonite classic is not a thiamine-responsive type.



6. Blood monitoring
   1. Quantitative measurement of BCAAs using blood or blood filter paper card.
   2. Quick turn-around time very important.
   3. Done weekly until age 6-12 months; thereafter depending on leucine tolerance.
   4. When ill or suspect elevated levels.
   5. After changing diet.
      
      
7. DNPH (2,4 dinitrophenylhydrazine) monitoring
   1. Usually positive with leucine level over 450 mmol/l (6 mg/dl).
   2. Best done on morning urine specimen.
   3. Daily when starting initial treatment.
   4. When ill or suspect elevated levels.
   5. After changing diet.


8. Traveling
   1. Plan daily intake ahead of time.
   2. Take enough supplies, including for illness.
   3. Check itinerary for available resources along the route— children's hospitals, medical centers, etc.?
   4. Contact and alert the specialist in your travel area.
   5. Carry a "Help Letter" from your doctor—include enough information to prompt the local ER physician into action.

 

9. "Sick Day" management
   1. Have a "sick day" diet plan. (Update every time recommended intake changes.)
   2. Usual plan: give special medical food—no regular formula—and extra isoleucine and valine. (Give extra formula, not extra clear fluids.)
   3. Leucine intake from table food is minimal/zero.
   4. Give extra calories! calories! calories!
   5. Routine treatment for other medical illnesses (i.e., antibiotics for ear infection, etc.).
   6. Zofran may help for nausea and vomiting (not a sedative but stops vomiting at the brain stem).
   7. Monitor BCAAs levels as often as daily.
   8. If no improvement within 12 hours, or symptoms are worse, seek professional help.

Outcome

1. Best outcomes occur in siblings of older affected children (diagnosed at birth) and in those on diet by 10 days of age.
2. Those diagnosed and treated later than 14 days of age rarely have a normal outcome.
3. Approximately 1/3 have IQs over 90 (normal); 1/3 have IQs between 70 and 90 (borderline); and 1/3 have IQs less than 70 (handicapped).
4. May have problems with attention span and learning disabilities.
5. May have problems with motor control (some severe, similar to what is seen with cerebral palsy).
6. Special education and rehabilitation services may be needed.
7. Strict dietary control is needed for life.
   

1. Genetic counseling: The family has a 1 in 4 (25%) chance of having another affected baby with each subsequent pregnancy.
   1. Prenatal diagnosis is available.
   2. Early detection and treatment during the newborn period improves the outcome.
2. Carrier testing can be done by means of the newer molecular genetic tests that are available.
   1. If the gene mutations are known in the family.
   2. If the family is of Mennonite [Swiss/German] background.

    

The chart illustrates the rapid rate of growth in the first year of life, especially during the first 6 to 8 months. This is why the protein per kilogram of weight is much greater in infancy than at any other time in life. At some time between 8 and 12 months, the growth significantly slows and blood monitoring and diet adjustments are critical to prevent loss of control. An increase in the rate of growth occurs during teen years, but it does not compare with the early growth rate.

MSUD in Saudi Arabia
Report by Kay Larsen

From the presentation given at the National Coalition for PKU and Allied Disorders Metabolic Conference in Ohio in May 2001.

During the breakout session on Friday, the MSUD families heard Dr. Pinar Ozand of Saudi Arabia. A graduate of Ankara University School of Medicine, Ankara, Turkey, Dr. Ozand has studied and worked extensively in the United States. Since 1985, when he was recruited by the Saudi government, he has operated a very sophisticated clinical center for the diagnosis and treatment of inborn errors of metabolism at King Faisal Specialist Hospital in Riyadh. He gave us a new perspective on the care of these difficult metabolic diseases, especially MSUD, in a culture so different from our own.

One of the difficult problems in places such as Saudi Arabia, and other middle eastern countries, is that families tend to "hide" those suffering from diseases such as this. If parents do bring a child to be treated, they may not tell the rest of the family. It makes it very difficult to test other family members to see if they are carriers, and it can make it harder to nsure good follow-up care.

Dr. Ozand told us of his many early "bitter" failures in his attempts to treat MSUD. He sees three distinct time periods in his nearly 17-year-long career treating metabolic diseases: a period in which all his patients died; a period where he had limited success in treating the diseases; and a third period up to the present where he has been very successful in keeping the patients alive and has secured good outcomes.

Currently, Dr. Ozand has over 2,500 patients with over 140 different metabolic disorders under current follow-up in his own clinic. Metabolic cases are referred to him from all over the Arabian Peninsula.

An enthusiastic proponent of Tandem Mass Spectrometry, he opened the first mass scale application of it in Saudi Arabia in 1991. The clinic receives 400 to 500 new patients with inborn errors of metabolism each year; and thousands of blood samples are received each year for tandem MS and urine testing.

Dr. Ozand told us there are more MSUD in Saudi Arabia than PKU. He averages one new MSUD patient per month. He is a very busy doctor in a very needy area.

This is part of the MSUD Parent Group at the National Coalition Conference

Gene Therapy
Reported by Kay Larsen

From the presentation given at the National Coalition for PKU and Allied Disorders Metabolic Conference in Ohio in May 2001.

• What is the reason for hope in gene therapy?
• Why is it so popular with inborn errors of metabolism?
• What are the problems?
• Where are we now in reaching the goal of gene therapy?

Currently, the hope of gene therapy involves a threefold approach:

• Add a good gene and allow the body to make the necessary product—one not being made by the mutant gene [such as is the case with MSUD].
• Add a gene to stimulate the immune system.
• Add a gene to kill cancer cells.

The ultimate goal is to eventually replace a bad gene or to repair it completely.

The fact that inborn errors of metabolism involve only single gene defects means that replacement would offer a permanent cure and NO MORE DIET! Correction has been demonstrated in cultured cells for many single gene traits. There has been some success in rodents and some recent positive results in experiments with lower primates. But that is a long way from making it work in humans.

Certainly, it would be a mistake to minimize the problems that we face in making gene therapy feasible for humans. The problems include the health of the recipient and the questions of timing (i.e. do you treat in utero, in the new-born period, or later?). Each period for treatment presents its own set of problems. Only somatic (mostly non-dividing) cells can be treated, not embryonic stem cells. Can specific tissues be targeted? MSUD genes are expressed throughout the body; how can expression be regulated? How do we insure that the gene, once introduced, will continue to work; and what is the immune response of the body going to be to a new protein introduced into it? The mutant gene will still be present—how will that affect the functioning of the new gene? What will be the method of delivering the new gene into the system? The ever present bottom line is, of course, who is going to pay for the research needed and for the implementation of treatment when, and if, it becomes feasible?

The ideal vector for gene delivery into the body:

• Should be easy to produce.
• Should produce no immune response in the patient.
• Should ensure that the product is continually produced after delivery.
• Must ensure that it is expressed in the desired tissue (meaning you only want it to work where you want it to work).
• Cannot restrict the size of the delivered gene.
• Must be able to enter dividing and non-dividing cells.
• Must be controlled expression of the gene.

How do you go about putting genes into cells? So far, researchers have used physical means such as electroporation, microinjection and liposomes to introduce the gene. They are now experimenting with viruses.

The non-viral system for gene therapy, naked DNA and liposomes, has the advantage of being inexpensive (relative to other systems), easy to produce, not toxic or immunogenic (having the ability to stimulate the formation of antibodies). However, on the downside, this system is inefficient because the effects don't last, and the procedure has to be repeated again and again.

Using viruses as a delivery system has the advantage of being easy to deliver into the cells and can produce the gene in many cells. Again, the flip side: gene size is limited; some viruses will only infect dividing cells; sometimes hard to produce in large amounts; and they do produce, to varying degrees, an immune system response in the patient.

Several different viruses are being studied for possible use in this way—including the virus which causes the common cold. Each virus has advantages and disadvantages which must be overcome. Some only work on non-dividing cells, some are highly toxic, some have a very short life. The ones that seem to have the greatest advantages, also seem to have the most disadvantages. For instance, the Herpes Simplex virus works in dividing or non-dividing cells and neurons, but is highly toxic. The cold virus also works on dividing and non-dividing cells but has a very short life and is antigenic (capable of causing the production of an antibody).

The history of gene therapy (from 1980 to 2000) is one of limited successes and spectacular failures. Currently, there are more than 400 approved clinical trials ongoing worldwide. However, less than 15% of these are for single gene traits, the majority being in the area of cancer treatment and cardiovascular disease.

The Prevalence of ADHD in Metabolic Disorders
Reported by Kay Larsen

From the presentation given at the National Coalition for PKU and Allied Disorders Metabolic Conference in Ohio in May 2001.

The terminology of the disorder has changed over the years. In the late forties, it was known as Strauss Syndrome, later Minimal Brain Damage, and still later, Hyperkinesis. By the eighties, it had become Attention Deficit Disorder with or without hyperactivity and residual type. In 1987, it was shortened to Attention Deficit Hyperactivity Disorder (ADHD). By 1994, three subtypes of the disorder were recognized—ADHD-Hyperactivity/ impulsive type (ADHD-H), ADHD-Inattentive type (ADHD-I) and ADHD-Combine type (ADHD-C).

There are certain criteria for a diagnosis of ADHD:

1. There must be a persistent pattern of inattention and/or hyperactivity.
2. The symptoms must be present before the age of 7 and have lasted at least six months.
3. The symptoms must have been observed in at least two settings, such as home and school.
4. The symptoms must be severe enough to clearly interfere with developmentally appropriate functioning.
5. The disturbance does not occur exclusively during the course of:
1. Developmental disorders (such as mental retardation).
2. Schizophrenia or other psychotic disorders.
3. It cannot be better accounted for by another psychological disorder such as mood or anxiety disorders.

The symptoms that differentiate the subtypes are:

1. Hyperactivity/impulsivity produces a peculiar behavior pattern where the child
1. Fidgets and squirms in his/her seat, or just leaves his/her seat in the classroom.
2. Runs about or climbs excessively in situations where inappropriate.
3. Cannot play quietly, is always "on the go," or acts as if being driven by something.
4. Talks excessively and blurts out answers.
5. Has trouble waiting his turn, interrupts, intrudes on others.



2. Symptoms of inattention displayed by the child:
1. Seems to make careless mistakes, or doesn't seem to pay attention to details.
2. Has trouble sustaining attention, and does not seem to listen when spoken to directly.
3. Fails to finish tasks, and has trouble organizing tasks and activities.
4. Avoids tasks requiring sustained mental effort, and often loses things necessary for a task or activity (never remembers to bring a pencil to class or leaves his homework at school every day).
5. Easily distracted by extraneous stimuli, and forgetful in daily activities.

To be diagnosed as ADHD-H, the child must display six or more symptoms of hyperactivity/impulsivity but less than six symptoms of inattention. Again, these must be observed in at least two settings and have lasted for more than six months. More males than females are diagnosed with this condition.

To be diagnosed with ADHD-I, there must be evidence of six or more symptoms of inattention, but less than six symptoms of hyperactivity/impulsivity that have been clearly observed in the two settings and have been present for six months or more. More females than males are diagnosed with this subtype. This diagnosis can be more easily missed because the child usually doesn't cause trouble for anyone (except, perhaps, the mother, who wonders why on earth the child can't remember to put her socks on in the morning). ADHD-I is more likely to be overlooked or diagnosed much later than the other types.

In the combined subtype, ADHD-C, there must be six or more symptoms of inattention and six or more symptoms of hyperactivity/impulsivity present with the symptoms observed in at least two settings and having the requisite duration of six months or more. This is the most common subtype, and the behavior of the child is more likely to cause peer rejection. It is the most common and most frustrating form, because it is the most resistant to treatment. Most children with ADHD-C engage in acts that are considered socially objectionable. Their excesses in behavior result from a combination of high social interest, explosive temperaments, and an impulsive style. They are often out of sync with the events around them.

ADHD can be inherited and the chances range from 25 to 31% if one parent has ADHD. The chances increase if both parents are affected. Even if a parent has never been diagnosed with ADHD, the child has a greater chance of having the disorder if an aunt or uncle have ADHD.

About 3 to 5% of school-age children in this country have been diagnosed with ADHD, and there are no striking cultural or ethnic differences. It is usually first diagnosed in the elementary school years and is difficult, if not impossible, to diagnose in children under 4 or 5. In fact, Dr. Antshel stated his belief that to diagnose a child any earlier would be very wrong. Almost any two year old, for instance, has behaviors that would be consistent with ADHD. These behaviors are normal for that age, and the child will outgrow them in the normal course of events.

There are certain disorders that are associated with ADHD. These include learning disabilities, Oppositional-Defiant Disorder, and mood and anxiety disorders.

Currently there are only two metabolic disorders considered to be definitely associated with ADHD—PKU and the Urea Cycle Disorders. In PKU there is an area of the brain called the hypodopaminergic prefrontal cortex that appears to be compromised. There is also delayed myelination and structural brain damage caused by high blood Phe levels early in life and a "toxic" effect caused by concurrent Phe levels. Myelin is a fat-like substance, the principal component of a sheath that surrounds the nerve fibers in the brain and spinal cord. It protects the nerve fibers and allows for the conduction of nerve impulses. In the Urea Cycle Disorders, the high ammonia levels can give a presentation of ADHD particularly in the partial defects.

MSUD and Homocystinuria are two metabolic orders that are presently considered likely to be associated with ADHD. In MSUD there is also the phenomenon of delayed myelination, and there appears to be nerve cell loss in an area of the brain called the substantia nigra. Homocystinuria presents with decreased myelination, and isolated cell death occurs in a part of the brain called the globus pallidus. Other metabolic disorders are not, at this time, recognized as being associated with ADHD.

If you suspect that your child has ADHD, check with the school and arrange to have a multi-disciplinary evaluation. Treatment may involve therapy (behavioral and/or family), making academic modifications, medication and continued monitoring.

The bottom line is that some metabolic disorders are associated with an increased risk for ADHD and research is ongoing to determine whether there may be more. ADHD is treatable and treatment should be multifaceted. Research continues in new pharmacological and ecological treatments.

Resources are available for understanding and dealing with ADHD. Children and Adults with Attention-deficit/Hyperactivity Disorder (CHADD) is an organization devoted to informing people about the disorder. It can be accessed by mail at 8181 Professional Place, Suite 201, Landover, MD 20785 or on the web at www.chadd.org. An ADHD Consensus Statement is accessible at http://odp.od.nih. gov/consensus/cons/10/110_statement.htm, and The ADHD Report is available from Guilford Publications on their web site: www.guilford.com or call 800-365-7006 or 212-431-9800.

There is a heart-warming story regarding the desire of one family to attend the National Coalition Conference, and the wonderful way the funds were provided. It all began in Florida earlier this year. Lou Ann Justus works for the Scholastic Book Fairs. Twice a year the employees have a book and gift fair. The proceeds from the "extravaganza" are donated to a worthy charity. Lou Ann submitted a proposal asking that the funds from the current fair be given to MSUD. Following is the letter Lou Ann wrote to the employees where she works explaining her family's involvement with MSUD.

Lou Ann's Letter

A cure—how wonderful that would be—is probably a pretty lofty hope at this time. In our day-to-day life we hope to make sound decisions regarding the feeding and care of our daughter. We hope that we will recognize signs of distress. We hope that we can continue to learn more to help us as she grows. We cannot lose sight of the sobering reality that without proper education and excellent management our daughter Katie could lose her battle to maple syrup urine disease at any time . . . with very little notice.

Many of you know Katie, as you have been very supportive in her first two years. She is just one of this small group of spercial children afflicted with this disease. Most stories of the first months of these children's lives are very much like Katie's. They were born perfectly healthy babies and went home with very happy parents. Within a few days, they stopped eating, became lethargic, and in most cases began to have extreme difficulty breathing. Their brain is affected and progressively attacks each of their functions. Most are in intensive care within the first week, dependent on machines to help them stay alive. The long term effects in each case vary dependening on the number of days required for diagnosis. If the children were treated immediately, they would begin to recover and thrive on their own within a short period of time. If diagnosis took longer they would continually worsen as each of their bodily functions were attacked. Extreme brain swelling would usually result in permanent brain damage. Most times if diagnosis took longer than 12 to 15 days, the babies would die.

We were one of the fortunate families. A miracle occurred. It is possible that Katie has a variant form of this disease.

Although Katie was finally diagnosed at 28 days, was completely dependent on machines to keep her alive, and suffered extreme brain swelling, she appears to have suffered no permanent damage. We are also extremely fortunate because most of the children afflicted with classic MSUD are regularly hospitalized for episodes where their diet (protein levels) are out of control. Every normal childhood illness (even a cold) can throw the protein levels into a potentially deadly fluctuation. With each episode, there is an extreme risk of additional brain damage. Again, we have been blessed; Katie has not been in the hospital since she was released at 2¸ months old.

Maintenance is not easy. Continual education is vital. When Katie was diagnosed, we were devastated to hear that there were no adults with this disease. That evening we learned through the MSUD Family Support Group on the Internet that, YES indeed, there were in fact adults with this disease. A 22 year old was recently married and just announced that she was pregnant. We began to have hope. We are continually in touch with the Support Group as they provide a variety of helpful resources, family stories, helpful diets and tested ways to help children like Katie as they move through each developmental stage. The MSUD Support Group is a nonprofit organization serving many families like ours throughout the world.

Many of the families find difficulty contacting qualified labs and physicians to help in the care of these children. The Clinic for Special Children has been a great source for many families around the world. The Clinic is dedicated to the care of children afflicted with metabolic disorders and serves as a state of the art research facility in finding a cure for these children.

Please help us support these two organizations, so that they can continue to help families like ours around the world.

Thank you from Katie's family,
Lou Ann and Rick Justus,
Christopher and Michael

We applaud the efforts of one of our "family" members, Lou Ann Justus, and the generosity of the employees in the corporate office of Scholastic Book Fairs who raised $5,415 and divided the proceeds between the Clinic for Special Children and the MSUD Family Support Group. We thank you on behalf of all the families in our Support Group.

When Lou Ann called about the donation to our organization, she asked if there was anything in particular it would be used for. Yes; the Ali Akhlaghi family wanted to attend the National Coalition for PKU and Allied Disorders Conference in Ohio. They had asked if the MSUD Family Support Group would have some funds to help them pay travel and conference costs. The Support Group had no funds designated to help families attend this conference as it does for our MSUD Symposiums. The Lord was answering prayers to somehow provide the means for this family to attend possibly the only informative conference they would have the opportunity to attend while in the States.

Lou Ann thought that using some of the money for this purpose would be fine. Ali was notified. What a blessing that money was to one family and the remainder will help others.

The Family From Iran

Let me tell you a little about this interesting family from Iran. Mohammad Ali Aklaghi (a computer programer) and his wife Dr. Simin Nejabati (an anesthesiologist) were living quite comfortably in Iran. Their son, Ashkan was born on July 20, 2000 and soon became very sick. On Sept. 1, I received a fax from them asking about the Total Parenteral Nutrition IV solution which Ali read about on our web site. He also contacted Dr. Holmes Morton at the same time. Ashkan had been diagnosed at about 4 weeks of age. He had been hospitalized for 14 days and repeatedly dialyzed. They knew their child was being mismanaged as he was not improving and had severe diarrhea. Since MSUD is not well known in Iran, all the children who do survive are severely damaged.

Ali and Simin were desperate to get good care for their son. So desperate in fact, when their doctor would not follow Dr. Morton's instructions, they sold their possessions and left their careers in Iran to come to the U.S. with their son. They persevered through a great deal of legal
technicalities to get visas. In the meantime, Dr. Morton was able to get amino acids to them via individuals willing to help. They made their own formula for Ashkan and followed instructions from Dr. Morton via fax and e-mail. In November 2000, they arrived in Maryland and soon moved to Lancaster, Pennsylvania to be near Dr. Morton's Clinic.

According to Dr. Morton, Ashkan has done remarkably well. He expects Ashkan will meet the normal milestones in development and his speech and intellectual function will be good. Ali and
Simin are eager to meet other families and to learn all they can about MSUD. Following is the thank you note Ali wrote to Lou Ann.

Dear Lou Ann Justus:

I would like to express my deep appreciation for the donation you and the employees made to MSUD Family Support Group. Your donation made it possible for me and my family along with our only son with MSUD, to attend the Metabolic Conference held in Dublin, Ohio May 4-5, 2001.

We learned a lot about MSUD and met families with the same concern. I would particularly mention a lady with classic MSUD who had gone through pregnancy and has a perfectly healthy baby girl. I was impressed and encouraged as well to see how well these patients can do provided the disease can be well controlled and managed.

We gained knowledge of (1) MSUD: the disease, its management, relevant current studies (2) the diet including the available products (3) prevalence of ADHD in metabolic disorders (4) federal legislation for metabolic formulas and (5) the Scott C. Foster Metabolic Research Fund.

We came from Iran on Dec. 10, 2000 to save our 9-month-old son with MSUD. With the great help of Dr. Morton from the Clinic for Special Children and the MSUD Support Family Group, we have our son in normal condition and development. Otherwise he would have become profoundly mentally retarded and physically disabled.

If the donations were not made, organizations such as the MSUD Family Support Group and the Clinic for Special Children could not exist. I would like to thank you again and wish you and your families the best. I would also like to thank the MSUD Family Support Group for the help and support they have provided for us. And special thanks to Dr. Morton for his great help since we left Iran, without which Ashkan would certainly not have survived. May the grace of God be with you all.

Sincerely yours,
Ali Akhlaghi

Section 1 / Section 2