Transcript Slide 1

Survey of health status and complications among propionic acidemia patients
registered with the Propionic Acidemia Foundation
Loren D. Peña, MD,
#Children’s
#±*
PhD
and Barbara Burton,
#
MD
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).
Introduction
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.
Medical complications reported among 24 patients with propionic acidemia
Mvmt d/o-b.g. damage
Stroke
Osteopenia
Thrombocytopenia
Pancreatitis
Cardiomyopathy
Immunedeficiency
Anemia
Arrhythmia
Leukopenia
Seizures
0%
5%
10%
15%
20%
25%
30%
35%
40%
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
Autism
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: 416420.
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: 30903091.
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.
ADD/ADHD
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.
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 selfreported 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.
Language skills
Gross motor skills
Fine motor skills
Cognitive impairment
Special education
0%
10%
20%
30%
Percentage of patients
40%
50%
Figure 2. Frequency at which each skill/attribute was reported or rated to be moderately or severely
impaired.
60%
Acknowledgements
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