Hereditary elevation of angiotensin converting enzyme suggesting neurosarcoidosis

Linnebank, Michael; Kesper, K.; Jeub, Monika; Urbach, Haley M; Wüllner, U.; Klockgether, Thomas; Schmidt, Susanne Eva Maria

doi:10.1212/01.wnl.0000098990.12845.da

Cited by 16 publications

(17 citation statements)

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“…A genetically predisposed condition of selective involvement of the nervous system can also be suggested by the evidence of a significant and specific elevation of some biomarkers in neurosarcoidosis in comparison to controls, revealing that neurosarcoidosis could be sustained partly by specific genetic profiles as found for sarcoidosis in general (29)(30)(31).…”

Section: Etiology Of Sarcoidosis and Selective Involvement Of The Nermentioning

confidence: 95%

Challenges in the diagnosis and treatment of neurosarcoidosis

et al. 2015

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The diagnosis and treatment of neurosarcoidosis can be very challenging for several reasons. It affects clinically 5%-10% of sarcoidosis patients, but can be found in up to 25% of autopsies. These data reveal that a high percentage of asymptomatic or misdiagnosed cases can be missed at an initial diagnostic approach. Clinical and imaging findings are often non-specific since they can be found in a large number of neurological disorders. Histopathology can also be confounding if not performed by an expert pathologist and not placed in an appropriate clinical context. In this review, we discuss clinical features, laboratory findings, imaging, and histology of neurosarcoidosis, and we report current evidence regarding drug therapy. We conclude that a correct diagnostic approach should include a multidisciplinary evaluation involving clinicians, radiologists, and pathologists and that future studies should evaluate the genetic signature of neurosarcoidosis as they could be helpful in the assessment of this uncommon disease. With head-to-head comparisons of medical treatment for neurosarcoidosis still lacking due to the rarity of the disease and an increasing number of immunomodulating therapies at hand, novel therapeutic approaches are to be expected within the next few years. Key messages Neurosarcoidosis is a rare disorder that affects clinically 5%-10% of sarcoidosis patients, but can be found in up to 25% of autopsies, revealing that a high percentage of asymptomatic or misdiagnosed cases can be missed at an initial diagnostic approach. A multidisciplinary evaluation is useful to achieve a correct diagnosis because clinical and imaging findings are often non-specific. Corticosteroids are the first-line treatment for neurosarcoidosis, followed by steroid-sparing immune-modulating agents if prednisone therapy is insufficient. Dear Author, Please check these proofs carefully. It is the responsibility of the corresponding author to check against the original manuscript and approve or amend these proofs. A second proof is not normally provided. Informa Healthcare cannot be held responsible for uncorrected errors, even if introduced during the composition process. The journal reserves the right to charge for excessive author alterations, or for changes requested after the proofing stage has concluded.The following queries have arisen during the editing of your manuscript and are marked in the margins of the proofs. Unless advised otherwise, submit all corrections using the CATS online correction form. Once you have added all your corrections, please ensure you press the ''Submit All Corrections'' button.Please review the table of contributors below and confirm that the first and last names are structured correctly and that the authors are listed in the correct order of contribution. The diagnosis and treatment of neurosarcoidosis can be very challenging for several reasons. It affects clinically 5%-10% of sarcoidosis patients, but can be found in up to 25% of autopsies. These data reveal that a high percenta...

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Section: Etiology Of Sarcoidosis and Selective Involvement Of The Nermentioning

confidence: 95%

Challenges in the diagnosis and treatment of neurosarcoidosis

et al. 2015

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“…Recently, a mutation in the stalk region of ACE – Pro1199Leu [28]–[29] – explained a dramatic (5-fold) increase in ACE activity in the blood of affected individuals from Holland [28], Germany [30], and USA [31]. Despite the fact that people with this mutation exhibit no clinical abnormalities [28], testing for this mutation is of considerable clinical importance.…”

Section: Introductionmentioning

confidence: 99%

“…Despite the fact that people with this mutation exhibit no clinical abnormalities [28], testing for this mutation is of considerable clinical importance. For example, failure to appreciate that elevation of ACE level is genetically determined in an affected individual may lead to false diagnosis of neurosarcoidosis and consequently to unnecessary long-term immunosuppressive treatment [30] or diagnostic procedures [32].…”

Section: Introductionmentioning

confidence: 99%

Angiotensin I-Converting Enzyme Mutation (Trp1197Stop) Causes a Dramatic Increase in Blood ACE

et al. 2009

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BackgroundAngiotensin-converting enzyme (ACE) metabolizes many peptides and plays a key role in blood pressure regulation and vascular remodeling. Elevated ACE levels may be associated with an increased risk for different cardiovascular or respiratory diseases, including asthma. Previously, a molecular mechanism underlying a 5-fold familial increase of blood ACE was discovered: Pro1199Leu substitution enhanced the cleavage-secretion process. Carriers of this mutation were Caucasians from Europe (mostly Dutch) or had European roots.Methodology/Principal FindingsWe have found a family of African-American descent whose affected members' blood ACE level was increased 13-fold over normal. In affected family members, codon TGG coding for Trp1197 was substituted in one allele by TGA (stop codon). As a result, half of ACE expressed in these individuals had a length of 1196 amino acids and lacked a transmembrane anchor. This ACE mutant is not trafficked to the cell membrane and is directly secreted out of cells; this mechanism apparently accounts for the high serum ACE level seen in affected individuals. A haplotype of the mutant ACE allele was determined based on 12 polymorphisms, which may help to identify other carriers of this mutation. Some but not all carriers of this mutation demonstrated airflow obstruction, and some but not all have hypertension.Conclusions/SignificanceWe have identified a novel Trp1197Stop mutation that results in dramatic elevation of serum ACE. Since blood ACE elevation is often taken as a marker of disease activity (sarcoidosis and Gaucher diseases), it is important for clinicians and medical scientists to be aware of alternative genetic causes of elevated blood ACE that are not apparently linked to disease.

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“…Often these patients had undergone extensive diagnostic evaluation (23 ). The genetically determined increase in blood ACE may lead to incorrect diagnosis of (neuro)sarcoidosis and unwarranted treatment with immunosuppressants (24 ). With the assays we propose here, it is possible that, in the case of increased ACE activity, hyperACE can be diagnosed straightforwardly, without need for further evaluation.…”

mentioning

confidence: 99%

“…The same phenotype and autosomal-dominant inheritance pattern have been described in Japan (21 ) and Italy (22 ). Despite the fact that patients with this mutation at first scrutiny do not have clinical abnormalities (19 ), the finding of increased ACE has led to confusion for treating physicians (23,24 ).…”

mentioning

confidence: 99%