Xavier has his first ever plane flight, he's so excited that he only sleeps for half an hour during the flight from Brussels to Chicago. Finally he falls asleep during the afternoon whilst we are waiting to catch the flight to Durham but the wait is much longer than expected due to bad weather (we have to wait for them to de-ice the plane).   One of Duke Hospitals courtesy cars comes to collect us at Durham airport to take us to the Millenium hotel, Xavier is still sleeping and won't wake up until the following morning.   Don Harden, the coordinator at Duke, is able to get a special rate for us at the Millenium. The staff at the Millenium also allow us free access to the internet as well as free shuttle passes for the duration of the stay. The kindness and discretion of the staff touches us to the quick.   Xavier doesn't understand the real reason that he's there, for him it's just new horizons to discover. Besides this, without crying but quite worried, Xavier has his first real experiences in water and as soon as he discovers the jacuzzi, he loses all interest in the swimming pool, brrr.... It's too cold! He plays by running up and down the corridors, uses the bagage trolley as his own personal train, plays hide and seek under the stairs, finds great amusement in the lift buttons and even manages to set off the alarm which makes us all the more vigilant.   Even when we get to Duke for his examinations, he is very happy at having the car ride, Xavier is on Holiday... At the Mall he has no intention what so ever of getting off of the merry-go-round, insisting on changing horses every time (his mum puts up with this 12 times!) and at the supermarket, to the horror of his father, he does his shopping whilst eating a banana.   Whether at Duke, in Dr Kurtzberg's service or at Chapel Hill in Dr Escolar's, we have been very impressed with their knowledge of the illness, their openness, their availabilty and their concern in keeping us informed. Every examination has been explained to us in detail, at no moment were we excluded from the proceedings and a copy or the results as well as a note of explication was always provided.   Understanding our search for information and vis-a-vis our doubts :   - Dr. Kurtzberg had prepared for us a case study including a film of the progression, before and after transplant, of two patients suffering, like Xavier, from late onset infantile Krabbe's Disease: The first with a better MRI and displaying no problems, the second with a poorer MRI and displaying a few symptoms. After the transplant: The least affected of the two children had only small stability problems which were easily remedied by orthopedic shoes, whereas the second child is in a wheel chair and does not have full use of his hands. Regardless of this, both are still alive and very happy to be.   - Dr. Escolar explained to us what would be waiting for Xavier if we did nothing : severe hypotonia of the torso, rigidity in the face as well as the hands and feet, ending in a vegetative state and finaly death before his fourth birthday.   At the end of our stay we had the answers we had be looking for and we had no doubts left about which decision to take, this trip, although very expensive was really worth it: you can read below extracts from the evaluation done by Dr. Kurtzberg and Dr. Escolar.    We know now that we will need to regularily revist Chapel Hill for Xavier's continuing evaluations, because we will proceed with the transplant of stem cells despite the risks this entails.   Xavier's Mum and Grandma.

	DEPARTMENT OF PEDIATRICS PEDIATRIC STEM CELL TRANSPLANT PROGRAM PEDIATRIC STEM CELL LABORATORY CAROUNAS CORD BLOOD BANK Joanne Kurtzberg, MD Telephone (919) 668-1119 Laboratory (919) 668-1177 FAX (919) 668-1183 www.cancer.duke.edu/pbmt   January 3,2005   Re: Xavier Kent DOB: 9/24/2002 Duke History #: ••••••   To Whom It May Concem:   " I am writing to summarize the evaluation of Xavier Kent, a 27 month old Caucasian boy who was recently diagnosed with late onset, infantile Krabbe Disease. Xavier was evaluated at Duke University Medical Center by the Pediatric Blood and Marrow Transplant Program from 12/27- 1/7/2005 to determine the status of his Krabbe Disease and his candidacy for transplantation therapy.   Xavier underwent multiple studies at Duke. He was admitted to the hospital on 12/27/2004 for sedation for an MRI with tensor weighted diffusion imaging and a lumbar puncture under sedation. He was slow to wake up from sedation and required hydration and observation overnight. He stabilized approximately 26 hours after the procedure and was discharged. Initial blood work was also performed during the admission. Subsequently, Xavier underwent further testing in the outpatient setting. These tests included an EEG, BAER, VEP, Nerve conduction studies and a neurocognitive evaluation by Dr. Maria Escolar and her team at the Center for Child Development and Learning at the University of North Carolina at Chapel Hill.   ••• Briefly, MRI demonstrated involvement of the periventricular regions, cerebral peduncles, but sparing of the brainstem at this time. CSF protein was normal. EEG showed slowing consistent with encephalopathy but no epileptiform waves or seizures. BAER, VEP and Nerve Conduction studies were normal. Neurocognitive testing revealed that at a chronological age of 27 months, Xavier is functioning at a developmental age between 9-21 months with most serious deficits in language and fine motor skills (full report attached). In summary, Xavier has the late infantile form of Krabbe Disease currently with CNS involvement but without a significant amount of peripheral nerve disease. He is an excellent candidate for transplantation therapy. If this therapy is performed in the next 1-2 months, he should stabilize with preserved neurologic function and the potential for continued cognitive and motor development over time.   Krabbe is a rare, inherited genetic disease, which causes a deficiency of an enzyme called galactocerebrosidase (GALC). This enzyme is necessary for early brain development and myelination of the brain. Without this enzyme, children cannot undergo normal neurological development. There are three forms of the disease each with different ages of onset and severity, early infantile, late infantile and juvenile. Babies with the early infantile form of the disease usually appear normal at birth, but develop early symptoms between 3-6 months of age. Without treatment, death occurs between 1-2 years of age. Children with the late infantile form of the disease develop symptoms between 1-2 years of age and experience slower progression of disease. Without transplantation therapy, these children die within 2-4 years of diagnosis. The same is true of the juvenile form of the disease, except that symptoms appear when children are 3-16 years of age.   Transplantation with unrelated umbilical cord blood stem cells can arrest the progression of all forms of Krabbe Disease. The efficancy of the procedure is greatest when transplantation therapy is performed early in the course of the disease. Children eligible for the procedure undergo a 2-3 week outpatient evaluation to determine candidacy for the procedure. During the workup, an unrelated umbilical cord blood donor is identified and tested. Eligible patients undergo placement of a double centrallines by a Pediatric Surgeon under general anesthesia and are subsequently admitted to the hospital and treated with 9 days of high dose chemotherapy with busulfan, cyclophosphamide and ATG. The transplant is given intravenously on the 10th day.   Over the subsequent month, the child experiences serious and potentially life threatening side effects secondary to the chemotherapy including but not limited to very low blood counts, infections, mucositis leading to problems with eating, vomiting and diarrhea, kidney, lung, and heart problems, high blood pressure, seizures and muscle weakness. During this phase of treatment, children are hospitalized in an inpatient, intensive care, isolation unit with 2:1 nursing, protective airflow HEPA filtration and positive pressure) and special diets. They need extensive supportive care with intravenous antibiotics, irradiated leukocyte depleted packed red blood cell and platelet transfusions, antifungal and antiviral medications, total parenteral nutrition, parenteral analgesia, NIG, G-CSF, low dose heparin, anti-GvHD medications, antiemetics, antihypertensives and other medications as needed.   After approximately one month, donor cells begin to repopulate the blood. At this point in time, children may experience a complication called graft-versus host disease. If this occurs, hospitalization may be prolonged for several more weeks. If not, children generally can be discharged to the outpatient setting with 1-2 months from transplant, At that point, children still receive IV medications in the outpatient and day hospital setting on a daily basis for another 2-3 months. They continue to have a significant risk for developing a serious or life-threatening infection for up to one year post transplant. Our day hospital is open 7 days per week, 12 hours per day and staffed by Pediatric Transplant Nurse Practitioners and Attending Physicians trained to deliver care to post transplant patients. In addition, if a child is sick at night, they are seen in a treatment room on the Pediatric Bone Marrow Transplant Unit to avoid exposure to patients with contagious infectious diseases in the Emergency Room. During this time period, children cannot be in public places of any kind. Most children must take medications for up to one year post transplant.   In general, after the first 100 days post transplant, children require visits to the clinic 1-2 times per week. IV infusions are required every 1-4 weeks in the clinic. Medications must be monitored on a weekly basis. We require that international patients remain in the U.S. in Durham, North Carolina to receive care at our center through the first 4 months post transplant. After that time, if there is a transplant physician in their country of origin willing and able to provide their care, we transition them back home. They generally continue to require weekly clinic visits and labs, monthly IVIG and PCP prophylaxis until a full year post transplant. After the one year post transplant evaluation, preferably performed at our center, clinic visits for follow-up are required on a quarterly basis and can be arranged with a hematologist/oncologist, neurologist and pediatrician in Belgium. After two years post transplant, children are followed on a yearly basis to screen for late effects including but not limited to heart, lung, liver or kidney dysfunction, growth disturbances, problems with vision or hearing, seizures, development delay and motor dysfunction.   Over the past 10 years, approximately 4000 patients have been treated with unrelated umbilical cord blood transplantation worldwide. Duke has performed >600 of these transplants including >38 transplants in babies and children with Krabbe Disease and >90 transplants in babies with other lysosomal storage diseases. Cord blood, in contrast to bone marrow, appears to confer better correction of disease in both the central and peripheral nervous systems.   Cord blood transplantation is a highly complicated process. Outcomes after transplantation therapy are vastly superior in an experienced center. In patients with Krabbe Disease, the timing of the transplant is also critical. Delays of a few months could mean the difference between a child who walks or is wheelchair bound. ln extreme cases, it could even mean the difference between life and death.   We have transplanted 33 babies and children (•••) with Krabbe Disease at Duke. The first transplant was perfonned in 1995. Currently we treat 7 -14 patients with Krabbe Disease per year . Over 70% of the children have survived the treatment and are living 1-9 years later. Their disease has been arrested. Children transplanted in the first month of life or before the onset of clinical symptoms have the best outcomes with prevention of neurologic damage. Older children stabilize their disease, have normal IQs, can communicate well and can enjoy their families with varying degrees of motor disabilities.   •••   While Xavier's family is finalizing their plans for his treatment, he and bis younger brother should not receive any live immunizations.   •••   Sincerely,   Joanne Kurtzberg, MD Professor of Pediatrics Director, Pediatric Stem Cell Transplantation Program"

	THE UNIVERSITY  of NORTH CAROLINA at CHAPEL HILL CLINICAL CENTER FOR THE STUDY OF DEVELOPMENT AND LEARNING   THE EXCHANGE AT MEADOWMONT 1450 RALEIGH ROAD, SUITE 100 CHAPEL HILL, NC 27517-8833   T 919.966.5171 F 919.966.2230   www.cdl.unc.edu   Mailing Address CAMPUS BOX 7255 CHAPEL HILL, NC 27599-725         PROGRAM FOR NEURODEVELOPMENTAL FUNCTION IN RARE DISORDERS   KENT, XAVIER UNCH#: 158-26-04-3 DOB : 9/24/02 AGE: 2 years 3 months DOE: 1-4-05 EC: Reinhartsen   EVALUATION PARTICIPANTS   Maria Luisa Escolar, M.D. (Developmental-Behavioral Pediatrician) Rebecca Edmondson Pretzel, Ph.D. (Licensed Psychologist, #1968) Meredith A. Holcomb, BA (Audiology Trainee)   Holly Martin, M.D., (Clinical Fellow, Developmental-Behavioral Pediatrics) Debra B. Reinhartsen, Ph.D., CCC-SLP (Speech-Language Pathologist) Angela Rosenberg, Dr. P.H., PT (PhysicaITherapist)   Jackson Roush, Ph.D. (Audiologist)   Bobbie A. Vereen, PT (Physical Therapy Fellow)   REFERRAL CONCERNS AND BACKGROUND INFORMATION   " Xavier is a 27 month-old boy with late infantile Krabbe Disease. He was referred by Duke University Medical Center (DUMC) to Dr. Maria L. Escolar for baseline evaluation of neurodevelopmental function before considering treatment with unrelated umbilical cord transplant. Xavier was accompanied by his parents.   •••   FAMILY AND ENVIRONMENT   There is no family history of significant learning difficulties nor genetic or neurological problems. His father works in computer publishing and his mother is on maternity leave from her work as an accountant. The family lives in Belgium.   BEHAVIORAL OBSERVATIONS   Xavier was quite energetic and enjoyed exploring the variety of items in the room. He was receptive to abjects being given to him and would sit briefly and attempt most things. Although his attention span was limited, he often returned to abjects (tasks) after a break. Xavier put many things in his mouth and was observed to shake, poke and take things out and put them back in containers. Xavier often brought things to his parents for them to open for him but did nat appear to show joint attention with these objects. Xavier responded much better to directions given with accompanying gestures rather than verbalizations alone. Although some fleeting eye contact was made, he primarily focused his eye gaze on objects rather than people. He smiled and laughed with physical activities and enjoyed climbing up and down stairs. He vocalized several times during the assessment and was overheard to make several vowel and consonant sounds, with occasional two-syllable vocalizations. He showed increased interest in computers.   HEARING   Acoustic Immittance Measures Tympanometry revealed bilateral Type B tympanogram with large equivalent volume, consistent with patent (open) PE tubes.   Visual Reinforcement Audiometry (VRA) Responses were observed at 20-25 dB HL for the frequencies of 500-6000 Hz in the sound field. Visual reinforcement audiometry is consistent with normal hearing sensitivity in the better ear. However it is likely that both ears have similar hearing sensitivity.   Today's testing revealed patent (open) PE tubes bilaterally and normal hearing sensitivity bilaterally.   PHYSICAL EXAM   Xavier's weight was 11.7 kg (1Oth-25th%ile), his height was 89 cm (25th-50th%ile), and his head circumference was 47 cm (5th%ile). Xavier has left side plagiocephaly, microcephaly and thin hair. His pupils were equal and reacted normally with a full range of eye movements, normal alignment. His ears, nose, and throat were normal. Xavier's respiratory, cardiovascular, and abdominal exams were normal. Expiratory wheezing was heard occasionally and increased upper respiratory secretions. He was drooling frequently and opened his mouth intermittently. Genitalia were normal and appropriately developed. There was full range of motion of the extremities. His spine was straight. Xavier's cranial nerves were intact. He has overall hypotonia, with absent deep tendon reflexes in lower extremities and +1 in upper extremities. He has tendency to pronate his arms and occasional involuntary thumb clasp. He has internal pronation and internal rotation of both feet and walks with a wide base of support and his arms elevated. He has poor head control. Bilateral postural responses are brisk but frontal are delayed.   NEURODEVELOPMENTAL FUNCTION   Visual Processing. Xavier demonstrated an early understanding of cause and effect, activating several push-button toys in the room. He also showed basic object permanence as he was able to find a toy hidden under a cloth. He made early object associations, putting a spoon in his mouth and trying to drink from a cup. Xavier was able to put two shapes (circle, square) into a formboard and matched objects. On this subtest of the Mullen, he achieved an age equivalence of 17 months.   COMMUNICATION   Speech. Language. Functional Communication. Xavier's speech and language skills were assessed through observation, parent report, and standardized testing. Mr. and Mrs. Kent reported that Xavier does not "really talk." He will make isolated sounds and will produce two words consistently, "encore for more" and "elo" for "hello." During the assessment, Xavier produced the phonemes, Id, y, I, o, al and speech sounds "e" as in "bet" and "u" as in "cup." He combined several sounds into various word shapes such as vowel-consonant-vowel, consonant- vowel, and vowel-consonants. He was not observed to produce the word, "encore," however, did say, "alo" when handed his father's cell phone.   Receptively, Xavier played appropriately with the blocks and spoon, used more than one object in play, understood the words, "clap" and "socks," and responded to a firm "no" when spoken by his father. Xavier also will respond to his name when called by his father and looked for the source of sound when out of his direct line of vision.   Expressively, Xavier protests by shaking his head, "no" and pushing things away, vocalizes different consonant and vowels sounds, seeks attention from his parents by taking toys to them, and communicates nonverbally by taking his parents by the hand and directing them to something he wants, using a variety of facial expressions, reaching for things he wants, and by sharing something interesting with them like a new toy. Xavier has a vocabulary of at least 2 words.   ADAPTIVE AND SELF-HELP   Based on information provided by Xavier's parents, the Early Development Form of the SIB-R was completed. Xavier's adaptive behaviors are at an approximate age equivalence of 17 months and are considered limited to age appropriate. He is feeding himself using a spoon and drinking from a cup, although is still slightly messy with both. He attempts to go up and down stairs alternating feet and Gan open a door on his own. He Gurrently shakes his head 'no' but not for 'yes'.   Feeding / Swallowing. Xavier will eat most any type of food, but cannot eat chunks of food mixed in with a liquid or sauce of any type. This type of food evokes a gag, which ultimately results in vomiting. Mrs. Kent reported that Xavier eats beef, green beans, mashed potatoes, etc., however, she blends all of them together in a "smooth" mixture. She has tried blending each one individually, but Xavier will choose his favorite flavor and not eat the rest. This is of concern to her and her husband. On occasion, Xavier will eat solid foods such as biscuits or grapes. He prefers to have frequent snacks.   NEUROMOTOR   Oral Motor   Xavier was not stimulatable for oral motor movements due to his diminished attention to tasks, however, he was noted to round his lips to blow bubbles, open and close his mouth in play, protrude his tongue in effort to catch a bubble and maintain a closed mouth posture at rest.   Fine Motor   Xavier achieved an approximate age equivalence of 14 months. He is not demonstrating a refined pincer grasp that hindered his ability to put coins in a slotted bank although he tried repeatedly to do so. Xavier took blocks out of a container and put them back in. He put one block on top of another but did not continue this effort. He frequently picked up books and was able to turn pages several at a time. Xavier imitated making marks on a paper but did not attempt directional strokes in imitation.   Gross Motor   Xavier was very mobile during the locomotion subtest. He was independent and moved effortlessly through ali transfers: supine to sit, sit to stand, prone to side-Iying/supine, kneeling to stand and/or sit. He ambulated greater than 25 feet independently, with arms abducted, flexed and stabilized against his trunk. Both lower extremities were internally rotated (Ieft greater than right) with noticeable over pronation of the feet.   Xavier was able to squat and pick up a small toy without losing his balance. He climbed on/off of small chairs and sat without assistance or difficulty. Xavier demonstrated a quick walk when attempting to run. He scored at the 15-month age equivalent for this section.   Stationary balance measured Xavier's ability to maintain upright balance with a decreased base of support such as with single leg stance. Xavier was able to sit unsupported in a child's chair without arms for greater than 3 minutes. Without hesitation or losing his balance, he leaned forward and laterally to reach for "Smacks" cereal. Xavier was able to kneel greater than 5 seconds and reach for his mother without difficulty. He did not demonstrate standing on one foot or standing on his tiptoes. However, Mr Kent reported that Xavier could easily stand on his tiptoes when reaching for objects overhead. Xavier scored at the 21-month age equivalent in this section.   In the last skill domain of object manipulation or bail skills, Xavier scored at the 12-month age equivalent. He was not interested in playing with a small bail and did not attempt to catch, throw or kick it. From parent report, Xavier was able to catch a small ball. Xavier was observed flinging his small cereal bowl. He flung it without extending the arm at the elbow.   SUMMARY   Xavier is a 27 month-old boy with late infantile Krabbe Disease. Unlike most patients with Krabbe Disease, his area of relative strength is gross motor function. He displayed strengths in the locomotion subtests while his weaknesses were in object manipulation and stationary. He demonstrates mild neurologic abnormalities that are not affecting acquisition of motor skills but movement quality. On the other hand his expressive language is an area of weakness. It is possible that Xavier was going to have speech difficulties that are unrelated to his diagnosis but that could be exacerbated by his disease. Therefore his prognosis for motor development (the area most affected by the disease process) is excellent if treated within the next 4 weeks with unrelated cord blood transplantation since other areas of development are typically less affected by the disease. Xavier's later onset and minimal involvement of neurodevelopmental function warrants immediate treatment.   RECOMMENDATIONS   1. Xavier should begin receiving intense speech and language intervention as soon as possible. He is motivated to communicate and the communicative intent is present. He just needs a means by which to communicate. This could be through the use of sign language or through the use of alternative communication such as voice output devices. He should have an augmentative and alternative communication evaluation as quickly as possible. If there are questions about this type of intervention, please feel free send e-mail to: Debbie.Reinhartsen@cdl.unc.edu.   2. Each time Xavier makes a sound, imitate it back to him. Even though he might not imitate initially, keep trying! Xavier is doing some nice gestural imitation, so the vocal imitation should come. Whenever he makes a sound that is similar to a real word, interpret it as that word and pair it with whatever he said. If he says it enough times and each time you pair it with the object, Xavier will eventually learn that the object has that name.   3. In every situation possible, label the people, objects, and events that are occurring around Xavier so that he learns that each person, object, or event has a word associated with it. You can never label too often!   4. It is recommended that Xavier continue to receive physical therapy services 3 times per week to address gross motor developmental delay, strength and balance.   5. Xavier would benefit from participation in gross motor activities, such as swimming, to support development of overall fitness and muscle strength. In addition, activities such as therapeutic horseback riding would assist in advancing coordination, balance, and trunk stabilization .   6. Xavier should continue to receive audiologic follow-up in conjunction with NFRD developmental assessments.   7. We would like to follow up with Xavier when he returns for his next comprehensive evaluation at Duke University Medical Center.   Maria Luisa Escolar, M.D. Developmental-Behavioral Pediatrician Director, Program for the Study of Neurodevelopmental Function in Rare Disorders "