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Translational studies in Zellweger spectrum disorders
Berendse, K.
Publication date
2016
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Final published version
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Citation for published version (APA):
Berendse, K. (2016). Translational studies in Zellweger spectrum disorders.
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Chapter 7
High prevalence of primary adrenal insufficiency in
Zellweger spectrum disorders
Kevin Berendse 1,2, Marc Engelen 1, Gabor E. Linthorst 3, A.S. Paul van
Trotsenburg 4, Bwee Tien Poll–The 1
1 Department of Paediatric Neurology, Emma Children’s Hospital / Academic Medical
Centre, The Netherlands
2 Laboratory for Genetic Metabolic Diseases, Emma Children’s Hospital / Academic Medical
Centre, Amsterdam, The Netherlands
3 Department of Endocrinology and Metabolism, Academic Medical Centre, Amsterdam,
The Netherlands
4 Department of Paediatric Endocrinology, Emma Children’s Hospital / Academic Medical
Centre, Amsterdam, The Netherlands
Orphanet Journal of Rare Diseases (2014) 9:133 (published in abbreviated form)
7
158 159
Chapter 7 Primary adrenal insufficiency
Abstract
Introduction: Zellweger spectrum disorders (ZSDs) are a group of autosomal recessive disorders characterized by impaired peroxisome functions due to mutations in
PEX genes. The clinical spectrum is broad, ranging from the classical Zellweger
syndrome with death in early infancy to patients with a relatively mild phenotype reaching adulthood. Treatment options are currently limited to symptomatic and supportive therapy. It is important to detect impaired adrenal function because it has treatment implications. This study aims to determine the prevalence of adrenocortical dysfunction in a cohort of ZSD patients.
Methods: Thirty-six patients with a ZSD were identified in the Academic Medical Centre in Amsterdam. Adrenal function was tested in 24 patients using an adrenocorticotrophic hormone (ACTH) stimulation test, while 12 patients had to be excluded. Primary adrenal insufficiency was diagnosed when the maximal plasma cortisol concentration was lower than 550 nmol/l after injection of synthetic ACTH.
Results: Primary adrenal insufficiency was found in 7/24 patients examined, with 4 patients (57%) being asymptomatic.
Conclusion: A high prevalence (29%) of unrecognized adrenocortical dysfunction was observed in ZSD patients. Primary adrenal insufficiency might be overlooked because of the other severe symptoms these patients exhibit. Systematic evaluation of adrenal function should be included in the clinical management of patients with a ZSD. Treatment is available and may have an important impact on quality of life.
Introduction
Peroxisomal disorders are a group of genetic disorders with impairment in one or more peroxisomal functions 1.The peroxisomal disorders are divided into two
major categories: (1) the peroxisome biogenesis disorders with multiple metabolic abnormalities, and (2) the disorders with a deficiency of a single peroxisomal enzyme or transporter. The most common peroxisome biogenesis disorders are the Zellweger spectrum disorders (ZSDs, OMIM #601539) and the most frequent single peroxisomal enzyme disorder is X-linked adrenoleukodystrophy (X-ALD, OMIM #300100). X-ALD is characterized by accumulation of very long-chain fatty acids (VLCFA, ≥C22:0) primarily in the adrenal cortex, central nervous system, testes and plasma. X-ALD results from mutations in the ABCD1 gene, which encodes
a peroxisomal membrane transport protein 2. X-ALD patients have an impaired
peroxisomal beta-oxidation of VLCFA. It is clinically classified into a wide range of phenotypes that are determined by the age of onset, the organs involved and the rate of progression of neurological symptoms. Adrenal insufficiency, either subclinical or overt as well as the late onset form, is found in the majority of these patients, and frequently precede the neurological symptoms giving rise to the “Addison-only” phenotype 3.
Addison crises as a manifestation of adrenal insufficiency may also occur in patients with a ZSD. The ZSDs are autosomal recessive disorders with an estimated prevalence of 1:50.000 and are characterized by impairment of multiple peroxisomal functions due to mutations in 13 different PEX genes 1. Clinically, the ZSDs
constitute a spectrum of disease severity, ranging from severe (Zellweger syndrome (ZS), OMIM #214100) to attenuated phenotypes, like infantile Refsum disease (IRD, OMIM # 266510). ZS is an early lethal multisystem disease distinguished by congenital developmental abnormalities 4. However, most ZSD patients have
disorders in the milder end of the spectrum (i.e. IRD) and should be follow-up for symptomatic and supportive therapy. IRD patients can reach adolescence or even adulthood 5. These patients typically come to attention because of developmental
delays, sensorineural hearing loss and/or visual impairment. The clinical course is variable, while the condition is often slowly progressive worsening with age. Due to peroxisomal dysfunctions, patients accumulate VLCFA, bile acid intermediates, branched-chain fatty acids and pipecolic acid in plasma. In erythrocytes, a decrease in plasmalogen levels can be found.
During routine follow-up we discovered impaired adrenocortical function in some of our ZSD patients. Because most of the patients have severe neurological symptoms,
7
primary adrenal insufficiency might be easily overlooked. To determine whether or not routine testing in these patients is useful, an estimation of the prevalence of adrenal insufficiency is necessary. Untreated adrenocortical dysfunction may have serious consequences, while treatment is available 6.
The aim of this study was to assess the prevalence of primary adrenal insufficiency in patients with a ZSD. In addition, we evaluated whether potential predictors for primary adrenal insufficiency (e.g. sex, PEX mutation or VLCFA concentration) could
be detected.
Material and methods
All patients were followed in the outpatient clinic of the Academical Medical Centre (AMC), The Netherlands. Admission required biochemical and genetic proof of a ZSD. Having noticed several cases with adrenal dysfunction we included a total of thirty-six ZSD patients with no history of adrenal dysfunction at regular follow-up visits to guarantee complete medical care. Twelve patients had to be excluded because the test could not be performed (e.g. due to their severe cognitive impairment). Adrenocortical function was investigated by means of a “classical” ACTH stimulation (Synacthen) test 7, conducted according to the standard AMC
protocol. During the ACTH stimulation test 250 µg Cosyntropin (1-24 ACTH) was injected intravenously and plasma cortisol concentrations were measured before, 30 and 60 minutes after injection (all blood samples were drawn between 9.00 AM and 2.30 PM). ACTH concentration was measured before injection. Primary adrenal insufficiency was considered to be present when the maximum cortisol concentration was lower than 550 nmol/l in the presence of a raised ACTH level. Cortisol and ACTH concentrations were determined in heparin and EDTA plasma, respectively, in the laboratory for endocrinology of the AMC. Cortisol (basal reference interval: 100-650 nmol/l) and ACTH (reference interval: 1-55 ng/l) concentrations were measured by in-house immunoassay methods.
VLCFA concentrations in plasma were determined as previously described by Dacremont et al 8. The average C26:0 concentration in plasma was calculated using
a total of 1 to 43 (median 12) biochemical analyses per patient. Complementation analysis followed by Sanger sequencing was done for each patient on genomic DNA and the mutation was confirmed in parents/family in 20/24 patients. Reference sequence of PEX1, PEX10 and PEX26 are respectively NM_000466.2, NM_002617.3 and NM_017929.4. Nucleotide numbering starting at the first adenine of the translation initiation codon ATG. For statistical analysis, Mann-Whitney U tests were performed using the IBM Statistical package for the Social Sciences (SPSS) software version 20 (IBM, U.S.A.).
Results
The characteristics of the patients are presented in table 1. Twenty-four patients with a ZSD, age ranging from 2.8-34.6 years (median 15.4 years) underwent a Synacthen test. An inadequate increase in plasma cortisol concentrations was found in 7/24 (29%) patients and an adequate response in cortisol (>550 nmol/l) was seen in the others. Four of the 7 patients (57%) diagnosed with primary adrenal insufficiency, were asymptomatic. The 3 patients with clinical manifestations of adrenal insufficiency presented with muscle and/or joint pain, vomiting or hyperpigmentation. We found one patient (number 4) with additional adrenocortical dysfunction (i.e. hyperkalemia) as a sign of hypoaldosteronism 9. Plasma renin
was normal in 6/7 patients. Oral hydrocortisone (and fludrocortisone in patient 4) treatment was started in all diagnosed patients.
The phenotypic severity of the ZSDs ranged from individuals with severe intellectual impairment being completely dependent on parents or caregivers, to patients presenting with only minor facial dysmorphism (i.e. attached earlobes and epicanthal folds), minor motor dysfunction and a relatively mild intellectual disability. All patients had a hearing and visual impairment. Few patients had clinical signs of liver dysfunction (patient 11, 15, 16) and/or presented with renal pelvic stones (patient 11, 20). Patient 11 died at the age of 18 years of liver failure. To obtain a framework for comparing severity of the clinical phenotype and adrenal insufficiency we delineated three categories on the basis of the degree of communication and motor function (table 1).
Elevated plasma VLCFA (C26:0) concentrations were present in 22/24, with an abnormal C26:0/C22:0 ratio in 24/24. Baseline plasma cortisol concentrations ranged from 85-902 nmol/l (median 272 nmol/l) and baseline plasma ACTH concentrations from 9-390 ng/l (median 33 ng/l), with one patient having 5140 ng/l.
We found a correlation between the average concentrations of C26:0 and C26:0 levels around the time of the ACTH test in plasma and the occurrence of an adrenal insufficiency (figure 1). There was no correlation between age, sex, PEX mutation or
7
162 163
Chapter 7 Primary adrenal insufficiency
Case Pr esent age, y Age at test, y
C26:0 in plasma around time of Synacthen (0.45-1.32)
A
verage C26:0 in plasma*
(0.45-1.32)
; STD
Basal ACTH (1-55) Basal cortisol /30’/60’ after injection
(>550) Clinical symptoms Plasma r enin levels (0-7.5) Phenotype PEX mutation 1 Comm unication Motor function 1 6.6 5.9 10.28 7.75 ; 1.57 100 203 / 275 / 290 asymp 5.5 ++ ++ PEX1 c.2528G>A 2 4.4 2.8 7 6.28 ; 1.13 180 201 / 254 / 260 asymp 5.5 ─ ─ PEX1 c.2528G>A 3 20.4 18.5 4.63 5.45 ; 2.47 # 112 / 273 / 306 asymp 5.1 ─ ─ PEX1 c.2528G>Ac.2097insT 4 8.4 3.0 4.43 4.93 ; 0.99 # 200 / 260 / 190 v >576 ─ + PEX1 c.2528G>A 5 14.5 12.2 3.38 3.87 ; 1.37 5140 185 / 203 / 167 hp 4.9 ─ ++ PEX1 c.2528G>A 6 24.7 22.9 2.73 2.90 ; 0.78 66 156 / 203 / 202 hp, mp 2.7 ++ ─ PEX26 c.292C>T 7 11.8 10.1 2.28 2.40 ; 0.34 390 535 / 477 / 524 asym 6.3 + ++ PEX1 c.2528G>A 8 24.3 24.2 2.44 4.91 ; 3.98 53 428 / 734 / 781 + ─ PEX1 c.2528G>A 9 24.2 23.8 2.79 4.13 ; 1.10 44 441 / 624 / 624 + ─ PEX1 c.2528G>A/unknown 10 6.8 5.8 3.38 3.94 ; 1.06 nd 370 / nd / 990 ─ ─ PEX1 c.2528G>A 11 10.3 9.1 3.78 3.94 ; 1.15 17 125 / 458 / 607 ─ ─ PEX1 c.2528G>A/c.2097insT 12 8.7 8.2 3.21 3.77 ; 0.69 35 85 / 425 / 557 ++ ++ PEX1 c.2528G>A 13 29.8 29.4 3.7 3.71 ; 0.78 27 902 / 1079 / 1090 ++ + PEX1 c.2528G>A/ unknown 14 22.8 22.2 3.51 2.69 ; 1.28 26 306 / 629 / 701 ++ ++ PEX1 c.2528G>A 15 17.3 16.9 2.35 2.45 ; 0.46 20 270 / 601 / 698 ++ ++ PEX1 c.2528G>A 16 35.0 34.6 3.31 2.17 ; 0.67 9 342 / 624 / 648 ++ ++ PEX1 c.2528G>A 17 19.0 18.6 1.63 1.82 ; 0.46 25 430 / 668 / 778 ++ ++ PEX1 c.2528G>A 18 8.1 7.5 1.24 1.78 ; 0.18 44 571 / 726 / 690 ++ ++ PEX1 c.2528G>A 19 11.8 11.2 1.2 1.53 ; 0.35 33 189 / 601 / 687 ++ ++ PEX1 c.2528G>A 20 8.3 7.6 0.81 1.50 ; 0.74 34 588 / 910 / 993 ++ ++ PEX10 c. 1A>G/c.199C>T 21 29.7 29.3 1.38 1.38 ; ** nd 215 / 620 / 705 ++ ++ PEX11 β c.64C>T 22 15.4 14.6 1.8 1.38 ; 0.27 18 227 / 519 / 618 ++ ++ PEX26 c.292C>T 23 30.3 29.9 1.98 1.35 ; 0.39 19 274 / 579 / 709 ++ ++ PEX1 c.2528G>A 24 16.7 16.1 1.2 8 1.34 ; 0.34 17 356 / 593 / 665 ++ ++ PEX1 c.2528G>A Table 1
Clinical, laboratory and genetic findings in 24 patients with a mild ZSD
*= average concentration of C26:0 in plasma during life, ranging fr
om 1 analysis to 43 (median 12) analyses per patient, **= only one C26:0 measur
ement, # = unr
eliable measur
ement,
i.e. loss of ACTH immunor
eactivity caused by hemolysis. Phenotype:
─
=
no communication or wheelchair bound,
+
= non-verbal communication or walk with support,
++
= verbal
communication or independent walking.
1 =
PEX
mutations ar
e homozygous if one sequence is given.
Abbr eviations : Asym = asymptomatic; hp = hyper pigmentation; mp = muscle pain; nd = not determined; STD = standar d deviation, v
= vomiting. ACTH in ng/l, cortisol in nmol/l, C26:0 in
µmol/l, r
enin in ugA1/L/U. The r
efer
ence intervals ar
e indicated between brackets and all r
esults outside the intervals ar
e depicted in
bold.
Adrenal insuf.
Figure 1 Boxplots showing median, range and interquartile range of the VLCFA
concentrations in plasma of the patients with or without a primary adrenal insufficiency. (A) Mean of all VLCFA concentrations in time per patient (B) VLCFA concentrations around time of ACTH stimulation test. Statistical analyses were performed with a Mann-Whitney U test
(A)
7
Discussion
In 1984, Govaerts et al revealed the occurrence of primary adrenal insufficiency in a small series of severe ZS patients 10. The prevalence in ZSD patients with an
attenuated phenotype has not yet been investigated. In this study we found a high prevalence (29%) of primary adrenal insufficiency in a cohort of ZSD patients. This is much higher than the prevalence in the normal population, which is approximately 93–144 per million in western-Europe 6 and demonstrates that adrenocortical
dysfunction is a frequent and relevant problem among ZSD patients. The prevalence of primary adrenal insufficiency in X-ALD ranges from 80% in the most severe childhood cerebral ALD to 50% in the milder adrenomyeloneuropathy 11.
The pathophysiological mechanism underlying the primary (usually only glucocorticoid) adrenocortical dysfunction in ZSDs and X-ALD is unknown. Govaerts et al hypothesised that a lack of responsiveness to ACTH is secondary to an abnormality of the ACTH receptor in the adrenocortical cells 12. In 1980, Powers
et al. studied thirty adrenal glands from patients with X-ALD and hypothesized that VLCFA are responsible for the adrenocortical cell dysfunction due to their cytotoxicity
13. Further studies showed that the VLCFA accumulation in X-ALD patients increased
the micro viscosity of erythrocytes. It is possible that the accumulation of VLCFA in the adrenal glands also results in increased micro viscosity of these cells and subsequently to alterations in ACTH sensitivity, leading to adrenal insufficiency 14. In
addition, Whitcomb et al. demonstrated that cultured adrenocortical cells, incubated with hexacosanoic acid (C26:0), showed decreased cortisol response compared to controls, when stimulated with ACTH 15. They further revealed significantly lower
basal cortisol concentrations and increased micro viscosity in these cells. Rats, with experimentally elevated concentrations of VLCFA (C26:0), showed a decreased corticosterone response after ACTH administration 16. Microscopy studies in post
mortem material from ZS and X-ALD patients showed striated adrenocortical cells, caused by the accumulation of lamellar-lipid profiles which represent bilayers or bimolecular leaflets of VLCFA-cholesterol esters, probably causing the cellular damage 1718.
Because both ZSD and X-ALD patients are affected by primary (usually only glucocorticoid) adrenocortical dysfunction 3, and the only common biomarker is the
elevated concentration of VLCFA, we postulate that these VLCFAs must play a role in the pathogenesis. However, a correlation between the concentrations of VLCFAs in plasma and the prevalence of adrenal insufficiency in X-ALD patients was not found 19. We found a correlation between the occurrence of an adrenal insufficiency
and the concentration of C26:0 in plasma. Because plasma C26:0 concentrations can fluctuate over time due to for instance diet, we used the average of all C26:0 values over time for each patient (figure 1). We observed no adrenal insufficiency
when the average concentration of C26:0 in plasma was below 2.40 µmol/l, while all patients with an average C26:0 >4.91 µmol/l had adrenocortical dysfunction (table 1, n=4). Because of the cross-sectional design we cannot precisely determine the age of onset in our patients or correlate the age of onset to VLCFA concentrations. Due to the single time point data, small size of our cohort and large variation in age, the importance of the correlation between VLCFA concentrations in plasma and adrenal insufficiency should not be overrated and needs confirmation in future studies. C26:0 concentrations or clinical parameters are not yet usable to predict onset of adrenal insufficiency and to determine which patients are at risk. However, it is possible that concentrations of VLCFA (C26:0) early in life are predictive for adrenal insufficiency. Further follow-up is necessary to determine the exact role of the VLCFA in the pathogenesis and onset of the dysfunction in both X-ALD and ZSDs. Probably, there are other (not yet discovered) biomarkers that play an important role in the pathogenesis and in addition there could be specific genetic confounders that play an important role in this process. C26:0 lysophosphatidylcholine, used for X-ALD new-born screening 20, may be a good candidate.
In this study we found a high prevalence (29%) of primary adrenal dysfunction in ZSD patients, with some being asymptomatic at the time of ACTH test. We therefore recommend that all ZSD patients should be screened for adrenal insufficiency during routine follow-up, in order to initiate appropriate therapy (additional file 1).
Acknowledgments
The authors thank the patients and their families for their cooperation and the referring physicians, especially Prof. B.H.R. Wolffenbuttel (University Medical Centre Groningen, The Netherlands); Dr. M.E.J. Wegdam-den Boer (Medical Spectrum Enschede, The Netherlands); Drs. A.B.C. Roeleveld-Versteegh (Catharina Hospital Eindhoven, The Netherlands) and Drs. I. N. Snoeck-Streef (Haga Hospital The Hague, The Netherlands) for providing data of their patients. We thank Dr. F. Vaz and Dr. H.R. Waterham (Academic Medical Centre, The Netherlands) for providing biochemical and genetic data. This work is supported financially by the Foundations “Stichting Steun Emma” and “Metakids”, Amsterdam, The Netherlands.
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Chapter 7 Primary adrenal insufficiency
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Additional file 1: Recommendations on the management of primary adrenal
insufficiency
The treatment of adrenal insufficiency in the Academic Medical Centre, at the department of Paediatric Endocrinology, consists of oral administration of the glucocorticoid hydrocortisone (cortisol) in a dose of approximately 10 mg per m2 per day, and (often) the mineralocorticoid fludrocortisone (50 to 200 microgram
per day in one or two doses). Fifty percent of the total daily hydrocortisone dose should be administered in the morning, 25 percent between noon and 2:00 PM, and 25 percent between 4:00 to 8:00 PM. Extra doses should be given under time of physical stress, including infection, trauma or anesthesia. Threefold the doses when stress is moderate, fivefold when severe (e.g. high fever). Furthermore, the total daily dose should then be equally divided in four six-hourly administrations. In case of an adrenal crisis, i.e. severe signs and symptoms of cortisol deficiency like, persistent vomiting, breathing fast, hypotension and even loss of consciousness, hydrocortisone should be administered parenterally (intramuscular or intravenous) without delay. In infants the first dose should be 25 mg, between the ages of 1 and 6 years 50 mg, and thereafter 100 mg. Because of its life threatening character, adrenal insufficiency is an indication for wearing a Medical Alert bracelet at all times that indicates that he/she has an adrenal insufficiency. To exclude mineralocorticoid deficiency, plasma aldosterone and renin should be measured and monitored.
