Survey of health status and complications among propionic acidemia patients

1. Survey of health status and complications among propionic acidemia patients registered with the Propionic Acidemia Foundation Loren D. Peña, MD, PhD#±* and Barbara Burton, MD# #Children’s Memorial Medical Center, Northwestern University Feinberg School of Medicine and ±The University of Chicago, Chicago, Illinois Objective Results Discussion To determine the health and developmental complications among propionic acidemia patients registered with the Propionic Acidemia Foundation (PAF). Propionic acidemia presents early in life and can be fatal even when treated promptly. Advances in medical and dietary treatment have allowed for improved outcomes and survival among affected individuals. Our understanding of the range and frequency of complications and outcomes, however, remains limited. We have partnered with the PAF to distribute a detailed questionnaire that would allow us to extend our understanding of the outcomes for patients as well as the frequency of self-reported complications. We have received 24 completed questionnaires to date corresponding to 23 living and 1 deceased individual. The age range of affected individuals in this sample is 14 months to 33 years (average 9.8 years), the age at diagnosis ranges from in utero to 4 years, with the majority of patients receiving a diagnosis in the first two weeks of life. The most commonly reported medical complications are seizures and leukopenia (38% and 33%, respectively). Almost 1/3 of the individuals in the sample (29%) reported arrhythmias, most commonly long QT syndrome, and 21% reported having cardiomyopathy in the mild to moderate range. Three patients reported having symptoms of pancreatitis, with one having had two episodes to date, and an additional patient reported having chronic elevations of lipase without physical symptoms of pancreatitis. We also observed that 60% of patients in our sample had more than 10 hospitalizations in their lifetime (range 2-150), which provides evidence of the severity of the disorder. A significant portion of our sample of affected individuals also reported developmental and cognitive complications related to PA. Most commonly reported were cognitive impairment in the moderate to severe range and a requirement of special education (42% and 54%, respectively). Impairment of fine motor skills was also reported more frequently than language or gross motor skills. Approximately 21% were reported to have signs and symptoms of Attention Deficit/Hyperactivity Disorder (ADD/ADHD). Although the number of participants to date is limited, we have been able to obtain frequency data on some of the more common complications. In particular, we note that although five patients with pancreatitis have been reported in the medical literature, 3/24 in our sample have reported this complication. It will be important to continue enrollment in our study, as a larger patient sample would improve our frequency estimates of various complications. This knowledge would be beneficial to PA patients and their families and to the physicians who provide their care. Introduction Medical complications reported among 24 patients with propionic acidemia Propionic acidemia (PA) is a disorder of amino and fatty acid metabolism that usually presents early in life with symptoms of lethargy, poor feeding, vomiting, and metabolic acidosis, hypoglycemia, and hyperammonemia related to inhibition of the urea cycle. PA is a rare inborn error of metabolism, with incidence estimated to range from 1 in 165,000 in Italy (Dionisi-Vici et al. 2002) to 1 in 277,000 in Germany (Klose et al. 2002). Although the initial description of the disorder occurred nearly five decades ago, our knowledge of the health status, developmental outcome, and complications related to PA is limited in part by the rarity of the disease. The three series reporting a variety of complications in the literature include 49 European patients (Sass et al. 2004), 30 European patients (Lehnert et al. 1994) and 65 patients with PA in the USA and Canada (Wolf et al. 1981). Other case series and reports focus on specific complications associated with PA, such as cardiomyopathy, arrhythmias, pancreatitis, visual disturbances, and skin rashes. For example, Massoud and Leonard (1993) comment on the clinical, electrographic, and radiographic findings for 6 patients with PA and cardiomyopathy. Baumgartner et al. (2007) report an incidence of electrocardiographic abnormalities in 70% of the PA patients that participated in the study and evidence of cardiac dysfunction in 40% of the patients studied. Pancreatitis has been reported in the literature in five patients with PA, some of which had multiple recurrences of pancreatitis (Gilmore et al. 2008, Bultron et al. 2008, Burlina et al. 1995, and Marsden et al. 1994). Ianchulev et al. report abnormalities in the optic nerve of 3 of 6 PA patients examined in their study (2003). Finally, two case reports have described particular skin rashes observed in two patients with PA, which were attributed to protein deficiency (Lane et al. 2007, De Raeve et al. 1994). Other reported complications in PA include decreased bone density, bone fractures, strokes, damage to particular structures of the brain, and movement disorders (Deodato et al. 2006). Data regarding the incidence of these complications is sparse, as the observations are published as case reports or case series based on a small number of patients. There is also very limited information on the health status of older children and adults with PA. Percentage of patients Figure 1. Percentage of most commonly reported medical complications among 24 patients with PA. Developmental and cognitive complications reported among 24 patients with propionic acidemia References Baumgartner D, Scholl-Bürgi S, Sass JO, Sperl W, Schweigmann U, Stein J-I, Karall D. Prolonged QTc intervals and decreased left ventricular contractility in patients with propionic acidemia. The Journal of Pediatrics (2007) 150: 192-197.  Bultron G, Seashore MR, Pashankar DS, Husain SZ. Recurrent acute pancreatitis associated with propionic acidemia. Journal of Pediatric Gastroenterology and Nutrition (2008) 47: 370-371.  Burlina AB, Dionisi-Vici C, Piovan S, Saponara I, Bartuli A, Sabetta G, Zacchello F. Acute pancreatitis in propionic acidaemia. Journal of Inherited Metabolic Diseases (1995) 18: 169-172.  Deodato F, Boenzi S, Santorelli FM, Dionisi-Vici C. Methylmalonic and propionic aciduria. Americal Journal of Medical Genetics Part C (Seminars in Medical Genetics) (2006) 142C: 104-112.  DeRaeve L, DeMeirleir L, Ramet J, Vandenplas Y, Gerlo E. Acrodermatitis enteropathica-like cutaneous lesions in organic aciduria. The Journal of Pediatrics (1994) 124: 416- 420. Dionisi-Vici C, Rizzo C, Burlina AB, Caruso U, Sabetta G, Uziel G, Abeni D. Inborn errors of metabolism in the Italian pediatric population: A national retrospective survey. The Journal of Pediatrics (2002) 140: 321-327.  Gilmore A, Bock H-G, Nowicki M. Hyperamylasemia/hyperlipasemia in a child with propionic acidemia. American Journal of Medical Genetics Part A (2008) 146A: 3090- 3091.  Ianchulev T, Kolin T, Moseley K, Sadun A. Optic nerve atrophy in propionic acidemia. Ophthalmology (2003) 110: 1850-1854.  Klose DA, Kolker S, Heinrich B, prietsch V, Mayatepek E, von Kris R, Hoffmann GF. Incidence and short-term outcomes of children with symptomatic presentation of organic acid and fatty acid oxidation disorders in Germany. Pediatrics (2002) 110: 1204-1211.  Lane Tn, Spraker MK, Parker SS. Propionic acidemia manifesting with low isoleucine generalized exfoliative dermatosis. Pediatric Dermatology (2007) 24: 508-510.  Lehnert W, Sperl W, Suormala T, Baumgartner ER. Propionic acidaemia: Clinical, biochemical and therapeutic aspects. Experience in 30 patients. European Journal of Pediatrics (1994) 153 (Supplement 1): S68-S80.  Marsden D, Barshop BA, Capistrano-Estrada S, Rice M, Prodanos C, Sartoris D, Wolff J, Jones KL, Spector S, Nyhan WL. Anabolic effect of human growth hormone: Management of inherited disorders of catabolic pathways. Biochemical Medicine and Metabolic Biology (1994) 52: 145-154. Massoud AF, Leonard JV. Cardiomyopathy in propionic acidaemia. European Journal of Pediatrics (1993) 152: 441-445. Sass JO, Hofmann M, Skladal D, Mayatepek E, Schwahn B, Sperl W. Propionic acidemia revisited: A workshop report. Clinical Pediatrics (2004) 43: 837-843. Wolf B, Hsia YE, Sweetman L, Gravel R, Harris DJ, Nyhan WL. Propionic acidemia: A clinical update. The Journal of Pediatrics (1981) 99: 835-846. Methods To determine the range and frequency of complications related to PA, we secured the support of the PAF, a non-profit organization with over 200 members that is dedicated to the education and support of individuals with PA, their families, and health professionals. We hypothesize that the range and frequency of PA-related complications can be better understood with a larger patient sample. Anyone with a diagnosis of PA, living or deceased, is eligible to participate. We have distributed the questionnaire to approximately 80 members of the PAF through an email distribution list maintained by the PAF and online on the PAF website at www.pafoundation.com. Affected individuals (if cognitively intact) or their guardians are able to report data related to their diagnosis, current treatment, developmental and functional status, and complications on the questionnaire. We have received approximately 24 responses to date. The completed surveys were tabulated to yield frequency estimates of each complication among those who have elected to participate. Acknowledgements Percentage of patients Figure 2. Frequency at which each skill/attribute was reported or rated to be moderately or severely impaired. The authors would like to thank the PAF Board of Directors and membership for their continued support and enthusiasm for participating in this study. * Current affiliation: University of Illinois at Chicago, Chicago, Illinois