Lysosomal Storage Disorders More Common Than Thought

Megan Brooks

December 02, 2011

December 2, 2011 — Lysosomal storage disorders such as Fabry's disease and Pompe's disease are much more common than previously thought, particularly atypical later-onset forms, a new study suggests.

A new nationwide study from Austria, using dried blood-spot specimens from newborns, shows a higher-than-expected frequency of mutations for lysosomal storage disorders, mostly those associated with late-onset phenotypes.

Lysosomal storage disorders "should not be underestimated," coauthor Berthold Streubel, MD, from the Department of Pathology at the Medical University of Vienna, Austria, told Medscape Medical News. "Late-onset cases may be an underestimated health problem," he added.

The study also demonstrates the feasibility of performing population-based neonatal screening, the researchers say. "Personally, I would be happy if we have a screening available to identify early-onset cases," Dr. Streubel commented. "The earlier we identify these patients the better."

The results were published online November 30 in The Lancet.

Difficult Questions

Michael Kruer, MD, associate scientist at Children's Health Research Center at Sanford Research and attending pediatric neurologist at Sanford Children's Hospital, Sioux Falls, South Dakota, said: "The difficulty arises in deciding when we should perform screening."

Dr. Kruer, who was not involved in the study, noted that "across medicine, early intervention has been accepted as the gold standard for treatment. Although conceptually this makes sense, it has often been accepted with little proof. Should we perform more/better longitudinal treatment follow-up studies in these disorders before embarking on screening programs? [It] is an open question," Dr. Kruer commented.

He also noted that for many lysosomal storage disorders, effective enzyme replacement therapies have been developed; however, enzyme replacement therapy comes at "an exorbitant cost, is not available for many lysosomal storage disorders, and does not penetrate the blood–brain barrier well enough to impact neurological symptoms."

Therefore, "a loaded question," Dr. Kruer told Medscape Medical News, is whether it's "worth performing screening for family planning purposes (ie, so that parents can avoid having 2 children affected by a devastating disease), even if effective treatment is unavailable."

"Unexpected' Results

Lead author Thomas P. Mechtler, MD, from the Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, and colleagues analyzed anonymous samples of dried blood spots from 34,736 predominantly white newborns that were collected consecutively from January 2010 to July 2010 as part of the national routine Austrian newborn screening program.

The researchers used electrospray ionization tandem mass spectrometry to analyze the samples for enzyme activity indicative of a lysosomal storage disorder (ie, activities of acid β-glucocerebrosidase, α-galactosidase, α-glucosidase, and acid sphingomyelinase) and performed genetic mutation analyses in samples with suspected enzyme deficiency.

All 34,736 samples were successfully analyzed; low enzyme activities were detected in 38 babies, and mutation analysis confirmed lysosomal storage disorders in 15 of the children. The overall incidence of lysosomal storage disorders was 1 per 2315 births, which is "higher than expected," Dr. Mechtler and colleagues note. Before this study, the combined incidence of lysosomal storage disorders had been estimated at 1 per 7700 births, they say.

The most frequent mutations were found for Fabry's disease (1/3859 births), followed by Pompe's disease (1/8684 births) and Gaucher's disease (1/17,368 births). The positive predictive values were in the range of 32% to 80%. This is similar to the positive predictive values of other metabolites analyzed in the neonatal screening panel for metabolic and endocrine disorders, the researchers point out.

It is noteworthy, they say, that mutational analysis detected predominantly missense mutations associated with a late-onset phenotype. The "high frequency of late-onset mutations makes lysosomal storage disorders a broad health problem beyond childhood," they write.

The "frequency, positive predictive value, and technical practicability make nationwide neonatal screening for lysosomal storage disorders technically feasible," Dr. Mechtler and colleagues conclude.

"Holy Grail" of Preventive Medicine

Dr. Kruer noted that the study relied on the interpretation of DNA mutations combined with enzyme analysis to arrive at a final consensus as to whether or not a child was affected. "This works well for well-characterized lysosomal storage disorders, but would likely prove problematic for others where DNA mutations have been incompletely catalogued," he said.

He also noted that genotype-phenotype analysis is "often challenging, and it is difficult to know where to draw the line in concluding that decreased enzyme activity is pathologic. Ongoing studies and expert consensus are probably going to be needed," Dr. Kruer said.

Summing up, Dr. Kruer said, "The promise of identifying patients before they are symptomatic from often-catastrophic diseases is one of the holy grails of preventative medicine and is becoming closer to reality with enzyme replacement therapy and other therapies under development. This study demonstrates that such presymptomatic screening and treatment is currently possible in select cases."

There is growing interest in screening for lysosomal storage disorders in the United States. Three states have passed legislation to include several lysosomal storage disorders in their neonatal screening programs in the near future, and Washington is doing a pilot study to detect Pompe's disease, Fabry's disease, and mucopolysaccharidosis type I. In Europe, the regional neonatal lysosomal storage disorders screening program in Florence, Italy, gets underway this year.

In a linked comment, Janice Fletcher, MD, from the University of Adelaide, Australia, and Bridget Wilcken, MD, from the University of Sydney, Australia, point out that opinions about which disorders should be included in screening "vary substantially," ranging from the conservative 5 disorders sanctioned in the United Kingdom to more than 50 recommended in the United States.

Dr. Fletcher and Dr. Wilcken say, "Although there are currently many uncertainties about neonatal screening for lysosomal storage disorders, as suggested by Mechtler and colleagues discussion needs to happen, because this is but one example of what is to come; therapeutic and technological possibilities inexorably advance, and the ability to make an early diagnosis by screening efficiently and cheaply will be relevant to many disorders in the foreseeable future."

The study was supported by the Austrian Ministry of Health, Family and Women. Dr. Mechtler and colleagues, Dr. Kruer, and Dr. Wilcken have disclosed no relevant financial relationships. Dr. Fletcher has received funding to attend lysosomal storage disease meetings sponsored by Genzyme, Shire, and Actelion and a gift from Actelion of miglustat for research studies, and has participated in advisory boards for Actelion and Protalix.

Lancet. Published online November 30, 2011. Abstract, Comment

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