Atypical immunologic response in a patient with CRIM-negative Pompe disease.
ABSTRACT We report the clinical course of a patient with severe infantile onset Pompe disease [cross-reactive immunologic material (CRIM) negative, R854X/R854X] who was diagnosed prenatally and received standard dosing of alglucosidase alfa (Myozyme®) enzyme replacement therapy (ERT) from day 10 of life until she passed away at the age of 3 years 9 months. In the immediate neonatal period there was cardiomegaly on chest X-ray, cardiac hypertrophy by echocardiogram, and development of a wide complex tachycardia. CRIM negative (CN) status was suspected based on her family history, and the available data at the time indicated that CN patients had limited survival even with ERT. However, given the opportunity for very early treatment, the treating provider and family elected to initiate treatment with ERT, without immune modulation. By 9 months of age echocardiogram was normal. Early motor development was within normal limits but by 2 years of age her developmental progress had slowed. She seroconverted by the 4th month of ERT, and anti-rhGAA antibody titers peaked at 25,600 in the 27th month. Immunomodulatory therapy was considered but declined by family. She acquired Influenza A at 2 years 6 months, which led to a prolonged hospitalization with invasive respiratory support, and placement of tracheostomy and gastrostomy tube. Her developmental progress ceased, and she died suddenly at home from a presumed cardiac event at age 3 years 9 months. The poor outcomes observed in CN patients have been attributed to the development of high sustained antibody titers. Although this CN patient's anti-rhGAA response was elevated and sustained, it is unlike any of the 3 patterns that have been previously described: high titer CN, high titer CRIM positive (HTCP), and low titer CP (LTCP) patients. This patient's clinical course, with achievement of 24 months of motor gains, 30 months of ventilator-free survival and 45 month survival, is like that of only a fraction of ERT treated CN patients, yet it is identical to other reported CN patients in its relentless progression and early fatality. The immunologic response (moderate sustained antibody titers) described here has not been previously reported and may have played a role in the overall pattern of developmental decline. In light of proposed universal newborn screening for Pompe disease, there is an urgent need for improved understanding of the interplay between immunologic responses to the only available treatment, ERT, and the relentless nature of this disease in CN patients.
- Journal of Inherited Metabolic Disease 07/2013; · 4.07 Impact Factor
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ABSTRACT: Enzyme-replacement therapy (ERT) in Pompe disease-an inherited metabolic disorder caused by acid α-glucosidase deficiency and characterized in infants by generalized muscle weakness and cardiomyopathy-can be complicated by immune responses. Infants that do not produce any endogenous acid α-glucosidase, so-called CRIM-negative patients, reportedly develop a strong response. We report the clinical outcome of our Dutch infants in relation to their CRIM status and immune response. Eleven patients were genotyped and their CRIM status was determined. Antibody formation and clinical outcome were assessed for a minimum of 4 years. ERT was commenced between 0.1 and 8.3 months of age, and patients were treated from 0.3 to 13.7 years. All patients developed antibodies. Those with a high antibody titer (above 1:31,250) had a poor response. The antibody titers varied substantially between patients and did not strictly correlate with the patients' CRIM status. Patients who started ERT beyond 2 months of age tended to develop higher titers than those who started earlier. All three CRIM-negative patients in our study succumbed by the age of 4 years seemingly unrelated to the height of their antibody titer. Antibody formation is a common response to ERT in classic infantile Pompe disease and counteracts the effect of treatment. The counteracting effect seems determined by the antibody:enzyme molecular stoichiometry. The immune response may be minimized by early start of ERT and by immune modulation, as proposed by colleagues. The CRIM-negative status itself seems associated with poor outcome.Journal of Inherited Metabolic Disease 04/2014; · 4.07 Impact Factor
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ABSTRACT: Since the discovery of the lysosome in 1955, advances have been made in understanding the key roles and functions of this organelle. The concept of lysosomal storage diseases (LSDs)-disorders characterized by aberrant, excessive storage of cellular material in lysosomes-developed following the discovery of α-glucosidase deficiency as the cause of Pompe disease in 1963. Great strides have since been made in understanding the pathobiology of LSDs and the neuronal ceroid lipofuscinoses (NCLs). The NCLs are neurodegenerative disorders that display symptoms of cognitive and motor decline, seizures, blindness, early death, and accumulation of lipofuscin in various cell types, and also show some similarities to 'classic' LSDs. Defective lysosomal storage can occur in many cell types, but the CNS and PNS are particularly vulnerable to LSDs and NCLs, being affected in two-thirds of these disorders. Most LSDs are inherited in an autosomal recessive manner, with the exception of X-linked Hunter disease, Fabry disease and Danon disease, and a variant type of adult NCL (Kuf disease). This Review provides a summary of known LSDs, and the pathways affected in these disorders. Existing therapies and barriers to development of novel and improved treatments for LSDs and NCLs are also discussed.Nature Reviews Neurology 08/2013; · 15.52 Impact Factor