CRIM-negative infantile Pompe disease: characterization of immune responses in patients treated with ERT monotherapy.
OBJECTIVE
Enzyme replacement therapy (ERT) with recombinant human acid α-glucosidase (rhGAA) prolongs survival in infantile Pompe disease (IPD). However, the majority of cross-reactive immunologic material (CRIM)-negative (CN) patients have immune responses with significant clinical decline despite continued ERT. We aimed to characterize immune responses in CN patients with IPD receiving ERT monotherapy.


METHODS
A chart review identified 20 CN patients with IPD treated with ERT monotherapy for ≥6 months. Patients were stratified by anti-rhGAA antibody titers: high sustained antibody titers (HSAT; ≥51,200) at least twice; low titers (LT; <6,400) throughout treatment; or sustained intermediate titers (SIT; 6,400-25,600).


RESULTS
Despite early initiation of treatment, the majority (85%) of CN patients developed significant antibody titers, most with HSAT associated with invasive ventilation and death. Nearly all patients with HSAT had at least one nonsense GAA mutation, whereas the LT group exclusively carried splice-site or frameshift mutations. Only one patient in the HSAT group is currently alive after successful immune modulation in the entrenched setting.


CONCLUSIONS
Immunological responses are a significant risk in CN IPD; thus induction of immune tolerance in the naive setting should strongly be considered. Further exploration of factors influencing immune responses is required, particularly with the advent of newborn screening for Pompe disease.
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Kathryn L
KL
Berrier
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Zoheb B
http://orcid.org/0000-0002-0447-2764
ZB
Kazi
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Sean N
SN
Prater
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Deeksha S
DS
Bali
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Jennifer
J
Goldstein
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Mihaela C
MC
Stefanescu
Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA.
Catherine W
http://orcid.org/0000-0003-4924-9010
CW
Rehder
Department of Human Genetics, Emory University, Atlanta, Georgia, USA.
Eleanor G
EG
Botha
Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia.
Carolyn
C
Ellaway
Western Sydney Genetics Program, Children's Hospital at Westmead, Sydney, Australia.
Kaustuv
K
Bhattacharya
Department of Pediatrics, Nutrition and Metabolic Diseases, The Children's Memorial Health Institute, Warsaw, Poland.
Anna
A
Tylki-Szymanska
Center for Pediatric and Adolescent Medicine, University Medical Center, Mainz, Germany.
Nesrin
N
Karabul
Amy S
AS
Rosenberg
Department of Pediatrics, Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, USA.
Priya S
PS
Kishnani
D003429:Cross Reactions / Q000276:immunology*; D056947:Enzyme Replacement Therapy / Q000009:adverse effects; D005260:Female; D006009:Glycogen Storage Disease Type II / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology* / Q000401:mortality; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007223:Infant; D007231:Infant, Newborn; D007518:Isoantibodies / Q000276:immunology*; D053208:Kaplan-Meier Estimate; D008297:Male; D009154:Mutation; D016896:Treatment Outcome; D000520:alpha-Glucosidases / Q000097:blood / Q000235:genetics / Q000627:therapeutic use*
D007074:Immunoglobulin G; D007518:Isoantibodies; D000520:alpha-Glucosidases