Polyarteritis nodosa gene discovery raises new possibilities for field



Autosomal recessive mutations in the gene CECR1 cause an inflammatory vasculopathy with a highly varied clinical presentation that often meets the criteria for polyarteritis nodosa and can occur with early-onset strokes, according to findings from two separate reports on families with several affected members as well as unrelated affected persons.

All but 2 of the combined total of 33 patients in both studies were younger than 18 years at the onset of disease, including 13 with a history of lacunar strokes and 12 who met criteria for polyarteritis nodosa (PAN) from the Paediatric Rheumatology European Society and the European League Against Rheumatism for those with an onset before 18 years of age or from the American College of Rheumatology at an onset of 18 years of age or older.

The studies identified 12 CECR1 (cat eye syndrome chromosome region, candidate 1) variants that encoded dysfunctional adenosine deaminase 2 (ADA2) proteins. In one report, Israeli and German researchers described individuals who presented primarily with features of polyarteritis nodosa. They identified mutations in 16 patients from five families of Georgian Jewish ancestry and four siblings from one family of German ancestry, as well as single cases in three unrelated patients of Georgian Jewish ancestry and 1 Turkish patient who had been referred to them (N. Engl. J. Med. 2014;370:921-31).

Maggie Bartlett, NHGRI

Dr. Dan Kastner

In the other report, researchers from the National Institutes of Health studied nine patients with pediatric onset of disease, including five patients from the United States, one from the United Kingdom, and three from Turkey, including one pair of siblings. Eight of the patients presented with a history of lacunar strokes (N. Engl. J. Med. 2014;370:911-20).

Both reports used whole-exome sequencing in most cases and candidate-gene sequencing in others to detect autosomally recessive mutations in CECR1 (cat’s eye syndrome chromosome region, candidate 1) that cause a deficiency in adenosine deaminase 2 (ADA2), including cases with heterozygous compound mutations. Cell culture experiments indicated that ADA2 is a growth factor for endothelial and leukocyte development and differentiation, and modeling of the mutations’ effects in zebrafish resulted in intracranial hemorrhages.

One of the main differences between the two studies was in the differing presentation of patients, with mainly strokes in the NIH study but more PAN-like disease and peripheral nervous system involvement in the Israeli and German study.

All of the patients in the Israeli and German study had highly variable disease severity, even within families. Of the 19 Georgian Jewish patients, 18 had cutaneous manifestation of the disease, mainly livedo reticularis, although some had ischemia and necrosis of the fingers and toes. Fever was present in 11, and myalgia and/or arthralgia occurred in 12. Ten had visceral features, six of which were gastrointestinal, and eight had neurologic disease, most of which occurred peripherally. Among the four German siblings, all had peripheral neuropathy, three had symptomatic or subclinical brain infarctions, three had cutaneous manifestations, and three had myalgia and/or arthralgia, but none had visceral involvement. The single Turkish patient had most of these clinical manifestations except for peripheral or central nervous system involvement. Not all of the 24 patients in the Israeli and German study were fully evaluated for PAN, but nearly all were suspected of having the disease.

The NIH team compiled cases that were most striking for the history of early-onset ischemic lacunar stroke in eight of the nine patients, including five from the United States who had strokes before the age of 5 years but showed no signs of cerebral vasculitis on MR angiography. Three patients also had hemorrhagic stroke or hemorrhagic transformation. All patients had recurrent fever, eight had livedo racemosa, and five had ophthalmologic involvement. Only the two Turkish siblings had a diagnosis of PAN.

The spectrum of disease observed in the studies could be related to what CECR1 mutation is present, with 12 overall reported in the two studies, according to one of the NIH study investigators, Dr. Daniel L. Kastner, a rheumatologist and scientific director of the National Human Genome Research Institute. He also is head of the inflammatory diseases section in the medical genetics branch of the Institute.

"It wouldn’t be surprising to me if certain mutations are associated with certain clinical presentations," he said in an interview.

The most common mutation reported among the Georgian Jewish patients – all of whom were diagnosed with PAN – was also found in the NIH study’s three Turkish patients, two of whom had a PAN diagnosis. This variant had a carrier frequency of about 10% in a control group of 246 unrelated Georgian Jewish controls, which would predict based on Mendelian genetic principles that 1 in 400 individuals in the Georgian Jewish population in Israel would carry two copies of the variant. The individuals who were homozygous for that variant in the Israeli and German study showed variability in phenotype, ranging from a diagnosis of diagnosed PAN to milder disease not meeting the full criteria for PAN. Given the relative commonality of the variant, ADA2-associated disease in Georgian Jewish people and other populations is likely underdiagnosed or being misdiagnosed for other conditions because of the clinical variability, Dr. Kastner said.

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