Top

Published in:

Open Access 01-12-2024 | Gene Therapy in Oncology | Position statement

A position statement on the post gene-therapy rehabilitation of aromatic I-amino acid decarboxylase deficiency patients

Authors: Hui-Min Lee, Saadet Mercimek-Andrews, Gabriella Horvath, Diana Marchese, Richard E. Poulin III, Alexis Krolick, Kati-Lyn Tierney, Jasmine Turna, Judy Wei, Wuh-Liang Hwu

Published in: Orphanet Journal of Rare Diseases | Issue 1/2024

Abstract

Aromatic l-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder of monoamine neurotransmitter synthesis that presents with a range of symptoms, including motor dysfunction and limited attainment of developmental motor milestones. The approval of eladocagene exuparvovec, a gene therapy for AADC deficiency with demonstrated efficacy for motor improvements, now expands the range of motor outcomes possible for patients with this disorder. However, recommendations and guidelines for therapy following treatment with gene therapy are lacking. To ensure patients can reach their full potential following treatment with gene therapy, it is essential they receive rehabilitation therapies designed specifically with their impairments and goals in mind. Therefore, we highlight specific rehabilitative needs of patients following gene therapy and propose a set of recommendations for the post-treatment period based on collective experiences of therapists, physicians, and caregivers treating and caring for patients with AADC deficiency who have been treated with gene therapy. These recommendations include a focus on periods of intensive therapy, facilitating active movements, training for functional abilities, cognitive and communication training, parent/caregiver empowerment, collaboration between therapists and caregivers to develop in-home programs, and the incorporation of supplemental forms of therapy that patients and their families may find more enjoyable and engaging. Many of these rehabilitative strategies may be employed prior to gene therapy. However, these recommendations will be valuable for therapists, caregivers, and wider treatment teams as they prepare for the post-treatment journey with these patients. Furthermore, the considerations and recommendations presented here may prove beneficial outside the AADC deficiency community as gene therapies and other treatments are developed and approved for other rare diseases.

OMIM. Aromatic L-amino acid decarboxylase deficiency; AADCD. Accessed 4 Nov 2022. https://www.omim.org/entry/608643

BRENDA. Information on EC 4.1.1.28 -aromatic-L-amino-acid decarboxylase. Accessed 4 Nov 2022. https://www.brenda-enzymes.org/enzyme.php?ecno=4.1.1.28

Himmelreich N, Montioli R, Bertoldi M, et al. Aromatic amino acid decarboxylase deficiency: molecular and metabolic basis and therapeutic outlook. Mol Genet Metab. 2019;127(1):12–22. https://doi.org/10.1016/j.ymgme.2019.03.009.CrossRefPubMed

Wassenberg T, Molero-Luis M, Jeltsch K, et al. Consensus guideline for the diagnosis and treatment of aromatic l-amino acid decarboxylase (AADC) deficiency. Orphanet J Rare Dis. 2017;12(1):12. https://doi.org/10.1186/s13023-016-0522-z.CrossRefPubMedPubMedCentral

Brun L, Ngu LH, Keng WT, et al. Clinical and biochemical features of aromatic L-amino acid decarboxylase deficiency. Neurology. 2010;75(1):64–71. https://doi.org/10.1212/WNL.0b013e3181e620ae.CrossRefPubMed

Swoboda KJ, Saul JP, McKenna CE, Speller NB, Hyland K. Aromatic L-amino acid decarboxylase deficiency: overview of clinical features and outcomes. Ann Neurol. 2003;54(Suppl 6):S49-55. https://doi.org/10.1002/ana.10631.CrossRefPubMed

Pearson TS, Gilbert L, Opladen T, et al. AADC deficiency from infancy to adulthood: symptoms and developmental outcome in an international cohort of 63 patients. J Inherit Metab Dis. 2020;43(5):1121–30. https://doi.org/10.1002/jimd.12247.CrossRefPubMedPubMedCentral

Williams K, Skrobanski H, Werner C, O’Neill S, Buesch K, Acaster S. Symptoms and impact of aromatic l-amino acid decarboxylase (AADC) deficiency: a qualitative study and the development of a patient-centred conceptual model. Curr Med Res Opin. 2021;37(8):1353–61. https://doi.org/10.1080/03007995.2021.1932449.CrossRefPubMed

Wang H, Li J, Zhou J, et al. Oculogyric crisis mimicked epilepsy in a Chinese aromatic L-amino acid decarboxylase-deficiency patient: A case report. Front Neurol. 2022;13: 919583. https://doi.org/10.3389/fneur.2022.919583.CrossRefPubMedPubMedCentral

10.

PTC Therapeutics. Upstaza™ granted marketing authorization by European Commission as first disease-modifying treatment for AADC deficiency. July 20, 2022. Accessed 4 Nov 2022. https://www.prnewswire.com/news-releases/upstaza-granted-marketing-authorization-by-european-commission-as-first-disease-modifying-treatment-for-aadc-deficiency-301589884.html#:~:text=Upstaza%20is%20the%20first%20approved,patients%2018%20months%20and%20older. 2022.

11.

PTC Therapeutics I. Upstaza™ gene therapy granted marketing authorization for AADC deficiency by UK's MHRA. November 17, 2022. Accessed 5 Dec 2022. https://www.prnewswire.com/news-releases/upstaza-gene-therapy-granted-marketing-authorization-for-aadc-deficiency-by-uks-mhra-301681531.html. 2022.

12.

Upstaza. Summary of product characteristics. PTC Therapeutics, Inc. 2022.

13.

Tai CH, Lee NC, Chien YH, et al. Long-term efficacy and safety of eladocagene exuparvovec in patients with AADC deficiency. Mol Ther. 2022;30(2):509–18. https://doi.org/10.1016/j.ymthe.2021.11.005.CrossRefPubMed

14.

Sanger WG, Dave B, Stuberg W. Overview of genetics and role of the pediatric physical therapist in the diagnostic process. Pediatr Phys Ther. 2001;13(4):164–8.CrossRefPubMed

15.

Shurtleff TL, Engsberg JR. Changes in trunk and head stability in children with cerebral palsy after hippotherapy: a pilot study. Phys Occup Ther Pediatr. 2010;30(2):150–63. https://doi.org/10.3109/01942630903517223.CrossRefPubMed

16.

Santonja-Medina CS, Marrades-Caballero E, Santonja-Medina F, Sanz-Mengibar JM. Neurologic music therapy improves participation in children with severe cerebral palsy. Front Neurol. 2022;13:795533. https://doi.org/10.3389/fneur.2022.795533.CrossRefPubMedPubMedCentral

17.

Romero-Ayuso D, Ruiz-Salcedo M, Barrios-Fernández S, et al. Play in children with neurodevelopmental disorders: psychometric properties of a parent report measure “My Child’s Play.” Children (Basel). 2021. https://doi.org/10.3390/children8010025.CrossRefPubMedPubMedCentral

18.

Nijhof SL, Vinkers CH, van Geelen SM, et al. Healthy play, better coping: the importance of play for the development of children in health and disease. Neurosci Biobehav Rev. 2018;95:421–9. https://doi.org/10.1016/j.neubiorev.2018.09.024.CrossRefPubMed

19.

Lotan M, Elefant C. Rett syndrome: dual intervention - music and physical therapy. Nord J Music Ther. 2004;13:172–82. https://doi.org/10.1080/08098130409478114.CrossRef

20.

Escobar Torres L, Sanders ME, Belenguer Benitez C, Melendez OA. Efficacy of an aquatic exercise program for 3 cases of Rett syndrome. Pediatr Phys Ther. 2019;31(4):E6-e13. https://doi.org/10.1097/pep.0000000000000655.CrossRefPubMed

21.

Onuki Y, Ono S, Nakajima T, et al. Dopaminergic restoration of prefrontal cortico-putaminal network in gene therapy for aromatic l-amino acid decarboxylase deficiency. Brain Commun. 2021;3(3):fcab078. https://doi.org/10.1093/braincomms/fcab078.CrossRefPubMedPubMedCentral

22.

Christy JB, Saleem N, Turner PH, Wilson J. Parent and therapist perceptions of an intense model of physical therapy. Pediatr Phys Ther. 2010;22(2):207–13. https://doi.org/10.1097/PEP.0b013e3181db8151.CrossRefPubMed

23.

Arpino C, Vescio MF, De Luca A, Curatolo P. Efficacy of intensive versus nonintensive physiotherapy in children with cerebral palsy: a meta-analysis. Int J Rehabil Res. 2010;33(2):165–71. https://doi.org/10.1097/MRR.0b013e328332f617.CrossRefPubMed

24.

Shamir M, Dickstein R, Tirosh E. Intensive intermittent physical therapy in infants with cerebral palsy: a randomized controlled pilot study. Isr Med Assoc J. 2012;14(12):737–41.PubMed

25.

Trahan J, Malouin F. Intermittent intensive physiotherapy in children with cerebral palsy: a pilot study. Dev Med Child Neurol. 2002;44(4):233–9. https://doi.org/10.1017/s0012162201002006.CrossRefPubMed

26.

Alternating Hemiplegia of Childhood Foundation. Intensive model of therapy (IMOT). Accessed 4 Nov 2022. http://ahckids.org/resources/intensive-model-of-therapy-imot/

27.

Hwu P, Wang A, Russell A, Turna J, Tai C. Early clinical improvements following treatment with eladocagene exuparvovec in patients with aromatic L amino acid decarboxylase deficiency. Poster presented at: International Symposium on Paediatric Movement Disorders; February 9–11, 2022.

28.

Sakzewski L, Ziviani J, Boyd RN. Efficacy of upper limb therapies for unilateral cerebral palsy: a meta-analysis. Pediatrics. 2014;133(1):e175-204. https://doi.org/10.1542/peds.2013-0675.CrossRefPubMed

29.

Myrhaug H, Østensjø S, Larun L, Odgaard-Jensen J, Jahnsen R. Intensive training of motor function and functional skills among young children with cerebral palsy: a systematic review and meta-analysis. BMC Pediatr. 2014;14:292. https://doi.org/10.1186/s12887-014-0292-5.CrossRef

30.

Lillo-Navarro C, Medina-Mirapeix F, Escolar-Reina P, Montilla-Herrador J, Gomez-Arnaldos F, Oliveira-Sousa SL. Parents of children with physical disabilities perceive that characteristics of home exercise programs and physiotherapists’ teaching styles influence adherence: a qualitative study. J Physiother. 2015;61(2):81–6. https://doi.org/10.1016/j.jphys.2015.02.014.CrossRefPubMed

31.

Novak I. Parent experience of implementing effective home programs. Phys Occup Ther Pediatr. 2011;31(2):198–213. https://doi.org/10.3109/01942638.2010.533746.CrossRefPubMed

32.

McCoy SW, Palisano R, Avery L, et al. Physical, occupational, and speech therapy for children with cerebral palsy. Dev Med Child Neurol. 2020;62(1):140–6. https://doi.org/10.1111/dmcn.14325.CrossRefPubMed

33.

Hall JB, Woods ML, Luechtefeld JT. Pediatric physical therapy telehealth and COVID-19: factors, facilitators, and barriers influencing effectiveness-a survey study. Pediatr Phys Ther. 2021;33(3):112–8. https://doi.org/10.1097/pep.0000000000000800.CrossRefPubMed

34.

Cottrell MA, Galea OA, O’Leary SP, Hill AJ, Russell TG. Real-time telerehabilitation for the treatment of musculoskeletal conditions is effective and comparable to standard practice: a systematic review and meta-analysis. Clin Rehabil. 2017;31(5):625–38. https://doi.org/10.1177/0269215516645148.CrossRefPubMed

35.

Piek JP. The contribution of spontaneous movements in the acquisition of motor coordination in infants. In: Glencross DJ, Piek JP, editors. Advances in psychology. North-Holland; 1995. p. 199–230.

36.

WHO Motor Development Study. windows of achievement for six gross motor development milestones. Acta Paediatr Suppl. 2006;450:86–95. https://doi.org/10.1111/j.1651-2227.2006.tb02379.x.CrossRef

37.

Abdel-Rahman SA, Elsaied S, Elshamy M, Mohamed S, El-Dien N. Effectiveness of play therapy on gross manual dexterity in children with hemiparetic cerebral palsy. IJRAMR. 2022;6(2):4637–41.

38.

Pitroda N, Sethi J. The effect of play therapy over conventional therapy in improving the hand function of spastic diplegic cerebral palsy children. Indian J Physiother Occup Ther. 2008;2:8–15.

39.

Kratz SV. Sensory integration intervention: historical concepts, treatment strategies and clinical experiences in three patients with succinic semialdehyde dehydrogenase (SSADH) deficiency. J Inherit Metab Dis. 2009;32(3):353–60. https://doi.org/10.1007/s10545-009-1149-1.CrossRefPubMed

40.

Kantor J, Hlaváčková L, Du J, et al. The effects of Ayres sensory integration and related sensory based interventions in children with cerebral palsy: a scoping review. Children. 2022. https://doi.org/10.3390/children9040483.CrossRefPubMedPubMedCentral

41.

Paleg GS, Smith BA, Glickman LB. Systematic review and evidence-based clinical recommendations for dosing of pediatric supported standing programs. Pediatr Phys Ther. 2013;25(3):232–47. https://doi.org/10.1097/PEP.0b013e318299d5e7.CrossRefPubMed

42.

Bunge LR, Davidson AJ, Helmore BR, et al. Effectiveness of powered exoskeleton use on gait in individuals with cerebral palsy: a systematic review. PLoS ONE. 2021;16(5): e0252193. https://doi.org/10.1371/journal.pone.0252193.CrossRefPubMedPubMedCentral

43.

Marrades-Caballero E, Santonja-Medina CS, Sanz-Mengibar JM, Santonja-Medina F. Neurologic music therapy in upper-limb rehabilitation in children with severe bilateral cerebral palsy: a randomized controlled trial. Eur J Phys Rehabil Med. 2018;54(6):866–72. https://doi.org/10.23736/s1973-9087.18.04996-1.CrossRefPubMed

44.

Champagne D, Dugas C. Improving gross motor function and postural control with hippotherapy in children with Down syndrome: case reports. Physiother Theory Pract. 2010;26(8):564–71. https://doi.org/10.3109/09593981003623659.CrossRefPubMed

45.

Huguet-Rodríguez M, Arias-Buría JL, Huguet-Rodríguez B, Blanco-Barrero R, Braña-Sirgo D, Güeita-Rodríguez J. Impact of aquatic exercise on respiratory outcomes and functional activities in children with neuromuscular disorders: findings from an open-label and prospective preliminary pilot study. Brain Sci. 2020. https://doi.org/10.3390/brainsci10070458.CrossRefPubMedPubMedCentral

46.

Crocker LD, Heller W, Warren SL, O’Hare AJ, Infantolino ZP, Miller GA. Relationships among cognition, emotion, and motivation: implications for intervention and neuroplasticity in psychopathology. Front Hum Neurosci. 2013;7:261. https://doi.org/10.3389/fnhum.2013.00261.CrossRefPubMedPubMedCentral

47.

Braver TS, Krug MK, Chiew KS, et al. Mechanisms of motivation-cognition interaction: challenges and opportunities. Cogn Affect Behav Neurosci. 2014;14(2):443–72. https://doi.org/10.3758/s13415-014-0300-0.CrossRefPubMedPubMedCentral

48.

Beukelman DR, Light JC. Augmentative and alternative communication processes for children and adults with complex communication needs. Augmentative & Alternative Communication. Paul Brookes; 2020. p. 3–15.

49.

TalkTools. What is OPT? Accessed 4 Nov 2022. https://talktools.com/pages/what-is-opt#:~:text=Oral%20Placement%20Therapy%20is%20a,with%20placement%20and%20movement%20deficits

50.

Gosa MM, Dodrill P, Lefton-Greif MA, Silverman A. A multidisciplinary approach to pediatric feeding disorders: roles of the speech-language pathologist and behavioral psychologist. Am J Speech Lang Pathol. 2020;29(2s):956–66. https://doi.org/10.1044/2020_ajslp-19-00069.CrossRefPubMed

51.

Skrobanski H, Williams K, Werner C, O’Neill S, Buesch K, Acaster S. The impact of caring for an individual with aromatic l-amino acid decarboxylase (AADC) deficiency: a qualitative study and the development of a conceptual model. Curr Med Res Opin. 2021;37(10):1821–8. https://doi.org/10.1080/03007995.2021.1955668.CrossRefPubMed

52.

Centers for Disease Control and Prevention. Concerned about your childs development? Accessed 4 Nov 2022. https://www.cdc.gov/ncbddd/actearly/concerned.html

53.

Ontario. Infant child development program. Accessed 4 Nov 2022. https://www.ontario.ca/page/infant-child-development-program

54.

Ontario. Children with special needs. Accessed 4 Nov 2022. https://www.ontario.ca/page/children-special-needs

55.

British Columbia. Early childhood intervention programs. Accessed 4 Nov 2022. https://www2.gov.bc.ca/gov/content/health/managing-your-health/child-behaviour-development/assessing-child-development-38610

56.

Kuo HT, Muo CH, Chang YT, Lin CK. Change in prevalence status for children with developmental delay in Taiwan: a nationwide population-based retrospective study. Neuropsychiatr Dis Treat. 2015;11:1541–7. https://doi.org/10.2147/ndt.S84088.CrossRefPubMedPubMedCentral

57.

Adolph KE, Franchak JM. The development of motor behavior. Wiley Interdiscip Rev Cogn Sci. 2017. https://doi.org/10.1002/wcs.1430.CrossRefPubMed

58.

O'Donnell M. HIP surveillance: bottom line ‘evidence-informed’ recommendations for the HIP surveillance in individuals with cerebral palsy. 2017. Accessed 4 Nov 2022. https://www.aacpdm.org/UserFiles/file/hip-surveillance-care-pathway.pdf. 2017; p. 1–3.

59.

Findley PA. Social work practice in the chronic care model: chronic illness and disability care. J Soc Work. 2014;14(1):83–95. https://doi.org/10.1177/1468017313475381.CrossRef

60.

Bergman AS, Lewiston NJ, West AM. Social work practice and chronic pediatric illness. Soc Work Health Care. 1979;4(3):265–74. https://doi.org/10.1300/J010v04n03_02.CrossRef

61.

Jones K, Hawke F, Newman J, et al. Interventions for promoting physical activity in people with neuromuscular disease. Cochrane Database Syst Rev. 2021;5(5):Cd013544. https://doi.org/10.1002/14651858.CD013544.pub2.CrossRefPubMed

62.

Leuzzi V, Mastrangelo M, Polizzi A, et al. Report of two never treated adult sisters with aromatic L-amino acid decarboxylase deficiency: a portrait of the natural history of the disease or an expanding phenotype? JIMD Rep. 2015;15:39–45. https://doi.org/10.1007/8904_2014_295.CrossRefPubMed

63.

Bailes AF, Reder R, Burch C. Development of guidelines for determining frequency of therapy services in a pediatric medical setting. Pediatr Phys Ther. 2008;20(2):194–8. https://doi.org/10.1097/PEP.0b013e3181728a7b.CrossRefPubMed

64.

Academy of Pediatric Physical Therapy. Intensity of service in an outpatient setting for children with chronic conditions: fact sheet. American Physical Therapy Association. 2012.

65.

American Physical Therapy Association. Standards of practice for physical therapy: fact sheet. 2020. American Physical Therapy Association.

66.

Folio MR, Fewell RR. Peabody developmental motor scales: Examiner's Guide. 2nd ed. Pro-Ed; 2000.

67.

Provost B, Heimerl S, McClain C, Kim NH, Lopez BR, Kodituwakku P. Concurrent validity of the Bayley Scales of Infant Development II Motor Scale and the Peabody Developmental Motor Scales-2 in children with developmental delays. Pediatr Phys Ther. 2004;16(3):149–56. https://doi.org/10.1097/01.Pep.0000136005.41585.Fe.CrossRefPubMed

68.

Piper M, Darrah J, eds. Alberta Infant Motor Scale: construction of a motor assessment tool for the developing infant. In: Motor assessment of the developing infant. Saunders; 1994, p. 25–35

Title: A position statement on the post gene-therapy rehabilitation of aromatic I-amino acid decarboxylase deficiency patients
Authors: Hui-Min Lee
Saadet Mercimek-Andrews
Gabriella Horvath
Diana Marchese
Richard E. Poulin III
Alexis Krolick
Kati-Lyn Tierney
Jasmine Turna
Judy Wei
Wuh-Liang Hwu
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Gene Therapy in Oncology
Physical Therapy
Published in: Orphanet Journal of Rare Diseases / Issue 1/2024
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-024-03019-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

A position statement on the post gene-therapy rehabilitation of aromatic I-amino acid decarboxylase deficiency patients

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2024

Embracing the unknown: investigating medical communication around uncertainty and the implications on patient and family well-being

The Prader-Willi syndrome Profile: validation of a new measure of behavioral and emotional problems in Prader-Willi syndrome

Long-term outcome and fertility results of intraplacental choriocarcinoma: a retrospective study of 14 patients and literature review

Patient experiences of interprofessional collaboration and intersectoral communication in rare disease healthcare in Germany – a mixed-methods study

Patients’ and physicians’ awareness of clinical symptoms and disease severity in tuberous sclerosis complex

Sleep disturbance in Angelman syndrome patients