Stage II: Summary Report Secondary Findings in Adults Non-diagnostic, excludes newborn screening & prenatal testing/screening Stage I Survey Update History Stage 2 Status (Adult):Incomplete (WARNING: Incomplete Stage 2 curation.)

GENE/GENE PANEL: ACADVL
Condition: Very Long Chain Actyl-CoA Dehydrogenase Deficiency (ACADVLD)
GENEDISEASE PAIRS: ACADVL201475
Topic
Narrative Description of Evidence
Ref
1. What is the nature of the threat to health for an individual carrying a deleterious allele?
Prevalence of the Genetic Disorder
Based on newborn screening data, the incidence of the deficiency of very long-chain acyl-coA dehydrogenase (ACADVLD) has been estimated from 1/30,000 to 1/95,000. Prevalence estimates range from 1/100,000 to 9/100,000.
1 2 3 4
Clinical Features
(Signs / symptoms)
ACADVLD is an inborn error of mitochondrial long-chain fatty acid (LCFA) oxidation, which results in impaired energy production from exogenous and endogenous fatty acids. ACADVLD is associated with three phenotypes. The severe, early-onset form has high mortality and typically presents in the first months of life with cardiomyopathy, pericardial effusion, and arrhythmias, as well as hypotonia, hepatomegaly, and intermittent hypoglycemia. The intermediate form typically presents in infancy or early childhood with hypoketotic hypoglycemia and hepatomegaly, but without cardiomyopathy, and is associated with a lower mortality than the severe form. The later-onset form, probably the most common phenotype, presents with intermittent rhabdomyolysis, muscle cramps and/or pain, and/or exercise intolerance. Hypoglycemia typically is not present at the time of symptoms, though some patients may have a previous history of hypoglycemia.
5 1 2 4 6
Natural History
(Important subgroups & survival / recovery)
While ACADVLD can be detected through newborn screening, there is a paucity of data regarding which individuals are at risk for neonatal or childhood symptoms. The later-onset myopathic form typically presents in later childhood or adulthood. Episodes are usually triggered by exercise, fasting, cold/heat and/or stress but viral infection can also precipitate/exacerbate this presentation. In rare cases it can lead to renal failure and can be fatal.
1 4
2. How effective are interventions for preventing harm?
Information on the effectiveness of the recommendations below was not provided unless otherwise stated.
Patient Management
To establish the extent of disease and needs in an individual diagnosed with ACADVLD, the following evaluations are recommended:
 
• Measurement of baseline plasma (serum) creatine kinase (CK) concentration
 
• Measurement of baseline liver transaminases
 
• Cardiac echocardiography
 
• Electrocardiogram
 
• Clinical genetics consultation. (Tier 4)
4
Emergency treatment aims to prevent mobilization of fat by providing ample glucose, enterally or intravenously. In adult patients, early signs of metabolic decompensation are predominated by muscle symptoms. Hypoglycemia only occurs at a relatively late stage. The aim of emergency treatment should always be to intervene while blood glucose is normal. It is advised that individuals undertake a regimen of high glucose drinks at the first sign of feeling unwell or have loss of appetite. (Tier 2)
7 8
Most dietary recommendations are focused on infants and children and are based on case reports and expert opinion due to lack of evidence-based protocols. Individuals with late-onset ACADVLD older than 12 months are recommended to have some sort of dietary modification. Specifically, an age-appropriate ‘‘heart-healthy” diet supplemented with medium chain triglycerides (MCT) has been recommended. For those patients who have symptomatic myopathy, a diet with more stringent LCFA restriction may be considered. However, for asymptomatic patients, the role of LCFA consumption in the development of later-onset myopathy is not known and there is some concern that a highly restricted or less palatable diet could contribute to catabolism or essential fatty acid deficiency. (Tier 2)
2 9
Administration of MCT prior to exercise has demonstrated benefit in older individuals with LCFA defects who have exercise intolerance. However, one report of 2 adult men with ACADVLD deficiency with exercise intolerance did not respond to intravenous glucose or MCT. (Tier 3)
5 4
Severe exercise (e.g., military training) has unmasked symptoms in previously asymptomatic adults, emphasizing that exercise should be guided by the individual’s tolerance level. (Tier 3)
4
Surgical procedures in patients with metabolic disorders require specific perioperative and anesthetic measures based on the nature of the disorder. During surgery, prolonged fasting, perioperative stress, and certain anesthetics can lead to metabolic derangements. Using two children, symptomatic and diagnosed during infancy with ACADVLD, as an illustration of the unpredictability of perioperative response, where one patient deteriorated with perioperative precautions and one patient did well without any precautions, some specific perioperative precautions have been advised:
 
1. Undergo age and weight appropriate glucose infusion perioperatively
 
2. Undergo pre- (during) and postoperative monitoring of glucose and CK
 
3. Prevent perioperative stress by providing adequate premedication
 
4. Avoid volatile anesthetics
 
5. Avoid anesthetics containing high dose of long chain fatty acids like propofol and etomidate. (Tier 2)
6
ACADVLD is a therapeutic challenge during pregnancy given the risk of metabolic decompensation during catabolic states, such as labor and early postpartum period. One case report indicated that placental and fetal LCFA oxidation may temporize or even improve maternal LCFA oxidation during pregnancy. The multidisciplinary care plan implemented for this patient (vaginal delivery, spontaneous birth, avoidance of inhaled anesthetics, availability of high-carbohydrate liquids throughout labor and postpartum period, and monitoring of renal function) resulted in an uncomplicated delivery and postpartum course with return of symptoms around 8 weeks postpartum. It was recommended that cesarean delivery in ACADVLD should be reserved for obstetrical indications or clear maternal or fetal benefit. (Tier 3)
4
Surveillance
No surveillance recommendations have been provided.
 
Family Management
It is appropriate to evaluate the older and younger sibs of a proband with ACADVLD in order to identify as early as possible those who would benefit from institution of treatment and preventive measures. If the pathogenic variants in the family are known, molecular genetic testing can be used to clarify the genetic status of at-risk sibs. (Tier 4)
4
Circumstances to Avoid
Individuals with ACADVLD should avoid fasting (Tier 4)
4
Patients should avoid myocardial irritation (e.g., cardiac catheterization). (Tier 4)
4
Patients should avoid dehydration due to risk for acute tubular necrosis (Tier 4)
4
Patients should avoid a high-fat diet, including ketogenic or carbohydrate-restricted diets, for the purpose of weight loss. Careful weight reduction without side effects has been shown in 2 patients with adult-onset LCFA defects (1 with ACADVLD and 1 with carnitine palmitoyl-CoA transferase 2) by restricting LCFAs and calories, supplementing with calories provided through MCT, and limiting overnight catabolism with uncooked cornstarch. Any weight loss should be performed under the guidance of a metabolic dietician. (Tier 3)
4
Patients should limit exercise and cold/heat exposure. (Tier 4)
1
3. What is the chance that this threat will materialize?
Mode of Inheritance
Autosomal Recessive
 
Prevalence of Genetic Mutations
Information on the prevalence of genetic variants associated with ACADVLD was not available.
 
However, the prevalence of homozygotes should be similar to the prevalence of ACADVLD detected during newborn screening, which can identify asymptomatic individuals. Based on newborn screening data, the incidence of ACADVLD has been estimated from 1/95,000 to 1/30,000. (Tier 3)
3 4
Using the ACADVLD prevalence estimate of 1/31,000 based on newborn screening data, the carrier frequency has been estimated as 1/90. (Tier 5)
10
Penetrance
OR
Relative Risk
(Include any high risk racial or ethnic subgroups)
No information on penetrance of signs and symptoms in adults identified based on genetic status was identified.
 
Severe forms are suspected to be fully penetrant. However, since the later-onset forms may have vague or intermittent symptoms, it is possible that some individuals will have no symptoms during their lifetime. (Tier 4)
4
A retrospective analysis of outcomes of 52 individuals diagnosed with ACADVLD by newborn screening in the US aged 1-18 years found that most individuals remained asymptomatic during the observed periods. Of the 52 individuals, cardiomyopathy was diagnosed in 2 (4%), 14 (27%) had elevated serum kinase (usually diagnosed between ages 1-3), and 11 (21%) developed rhabdomyolysis. A report of 22 patients identified by newborn screening in Australia followed for a median of 104 months on a low fat diet found no episodes of encephalopathy or hypoglycemia, but 3 (14%) cases had muscle pain with or without rhabdomyolysis. (Tier 3)
5
Among 13 clinically diagnosed patients (age of onset: birth to 13 years; median age at examination: 30.5 years) all patients were found to have exercise intolerance and recurrent rhabdomyolysis episodes generally triggered by strenuous exercise, fasting, cold, or fever (median age at onset: 10 years). (Tier 3)
4
Information on relative risk was not available.
 
 
Expressivity
There is a strong genotype-phenotype correlation in ACADVLD, with severe disease associated with no residual enzyme activity (often resulting from null variants) and milder childhood and adult forms are often associated with residual enzyme activity (often resulting from pathogenic missense variants). (Tier 3)
2 4
4. What is the Nature of the Intervention?
Nature of Intervention
Interventions identified in this report include dietary modifications, MCT supplementation (typically taken as a liquid), adjustment to exercise regimens, and extra precautions during surgical procedures.
 
5. Would the underlying risk or condition escape detection prior to harm in the settting of recommended care?
Chance to Escape Clinical Detection
Patients with ACADVLD were traditionally diagnosed after developing symptoms of the disorder. However, expanded newborn screening now provides pre-symptomatic diagnosis in infants, typically through elevation of C14:1 acylcarnitine and other acylcarnitines. (Tier 3)
2 9
However, complete ascertainment by newborn screening is not assured. Newborn screening data have affirmed that acylcarnitine analysis during periods of physiologic wellness often fails to identify affected individuals who have the milder phenotypes. In addition, many children ascertained by newborn screening are asymptomatic, suggesting that these individuals may have gone undiagnosed prior to population-based screening. (Tier 4)
4
Two individuals, both previously asymptomatic, were diagnosed following episodes during military training which required airlift rescue. (Tier 3)
4

 
Final Consensus Scores
Outcome / Intervention Pair
Severity
Likelihood
Effectiveness
Nature of the
Intervention
Total
Score
Rhabdomyolysis, muscle cramps, and exercise intolerance / Multidisciplinary care
2
2D
2D
3
9DD
Perinatal or delivery complications / High risk pregnancy management
2
0D
2D
3
7DD
Surgical complications / High risk surgical and anesthesia management
2
0D
2D
3
7DD
To see the scoring key, please go to: https://clinicalgenome.org/working-groups/actionability/projects-initiatives/actionability-evidence-based-summaries/
Description of sources of evidence:
Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review.
Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review.
Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited.
Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources.
Tier 5: Evidence from a non-systematically identified source.
Reference List
1. Very long chain acyl-CoA dehydrogenase deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=26793
2. Arnold GL, Van Hove J, Freedenberg D, Strauss A, Longo N, Burton B, Garganta C, Ficicioglu C, Cederbaum S, Harding C, Boles RG, Matern D, Chakraborty P, Feigenbaum A. A delphi clinical practice protocol for the management of very long chain acyl-coa dehydrogenase deficiency. Mol Genet Metab. (2009) 96(3):85-90.
3. Lindner M, Hoffmann GF, Matern D. Newborn screening for disorders of fatty-acid oxidation: experience and recommendations from an expert meeting. J Inherit Metab Dis. (2010) 33(5):521-6.
4. ND Leslie, CA Valencia, AW Strauss, JA Connor, K Zhang. Very long-chain acyl-coenzyme a dehydrogenase deficiency. 2009 May 28 [Updated 2014 Sep 11]. In: RA Pagon, MP Adam, HH Ardinger, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018. Available from: http://www.ncbi.nlm.nih.gov/books/NBK6816
5. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. Acyl-coa dehydrogenase, very long-chain, deficiency of; acadvld. MIM: 201475: 2016 Dec 08. World Wide Web URL: http://omim.org.
6. Vellekoop P, Diekman EF, van Tuijl I, de Vries MM, van Hasselt PM, Visser G. Perioperative measures in very long chain acyl-coa dehydrogenase deficiency. Mol Genet Metab. (2011) 103(1):96-7.
7. British Inherited Metabolic Disease Group (BIMDG). Adult emergency management oral emergency regiment (er). (2012) Accessed: 2017-03-08. Website: http://www.bimdg.org.uk/store/guidelines/BIMDG_ADULT-OralERGeneral_2012R-183465-01-01-2013.pdf
8. British Inherited Metabolic Disease Group (BIMDG). Adult emergency management of long chain fatty acid oxidation defects. (2007) Accessed: 2017-03-08. Website: http://www.bimdg.org.uk/store/guidelines/ADULT_FAOD-rev_2015_428281_09012016.pdf
9. Spiekerkoetter U, Lindner M, Santer R, Grotzke M, Baumgartner MR, Boehles H, Das A, Haase C, Hennermann JB, Karall D, de Klerk H, Knerr I, Koch HG, Plecko B, Roschinger W, Schwab KO, Scheible D, Wijburg FA, Zschocke J, Mayatepek E, Wendel U. Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop. J Inherit Metab Dis. (2009) 32(4):498-505.
10. Mendez-Figueroa H, Shchelochkov OA, Shaibani A, Aagaard-Tillery K, Shinawi MS. Clinical and biochemical improvement of very long-chain acyl-coa dehydrogenase deficiency in pregnancy. J Perinatol. (2010) 30(8):558-62.
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