Carnitine palmitoyltransferase II deficiency

Actionability Pediatric Summary Report

Secondary Findings in Pediatric Subjects. Non-diagnostic, excludes newborn screening & prenatal testing/screening.

• Gene: CPT2 (HGNC:2330)
• Mode(s) of Inheritance: Autosomal Recessive
• Literature Search: 12/26/2020
• Curation Status: Released (1.0.2)

Assertions and Scores

Actionability Assertions

Gene	Condition (MONDO ID)	OMIM ID	Final Assertion
CPT2	carnitine palmitoyltransferase II deficiency (0015515)	255110	Moderate Actionability
CPT2	carnitine palmitoyltransferase II deficiency (0015515)	600649	Assertion Pending
CPT2	carnitine palmitoyltransferase II deficiency (0015515)	608836	Assertion Pending

Actionability Assertion Rationale

• Evidence base for the myopathic form remains immature, based on evidence from other FAO disorders it seems reasonable to assert moderate actionability, but more evidence is needed. Information about the interventions for the lethal neonatal form and the infantile form is lacking.

Actionability Scores

Outcome / Intervention Pair	Severity	Likelihood	Effectiveness	Nature of Intervention	Total Score
Morbidity and mortality associated with metabolic decompensation / Metabolic management (dietary management and illness protocols)	2	2C	2C	2	8CC
Morbidity and mortality associated with metabolic decompensation / Triheptanoin treatment	2	2C	2N	2	8CN

Severity of Outcome

Prevalence of the Genetic Condition

The prevalence of carnitine palmitoyltransferase II (CPT II) deficiency is estimated to be 1-9/100,000. The lethal neonatal form of CPT II deficiency has been described about twenty families. Approximately 28 families with the severe infantile hepatocardiomuscular form have been described. More than 300 cases of the myopathic form of CPT II deficiency have been published. The myopathic form of CPT II deficiency is the most common disorder of lipid metabolism affecting skeletal muscle and the most frequent cause of hereditary myoglobinuria.

Clinical Features (Signs / symptoms)

CPT II deficiency is a long-chain fatty-acid oxidation (FAO) disorder and is associated with three clinical presentations, the lethal neonatal form, the severe infantile hepatocardiomuscular form, and the myopathic form. The lethal neonatal form and severe infantile hepatocardiomuscular form are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, cardiac arrhythmias, and seizures. Individuals with the lethal neonatal form can also have respiratory distress, facial abnormalities, or structural malformations such as cystic renal dysplasia, neuronal migration defects or brain dysgenesis. Individuals with the severe infantile form may also develop peripheral myopathy and have attacks of abdominal pain and headaches. The myopathic form of CPT II deficiency is characterized by attacks of rhabdomyolysis, muscle pain and weakness that are most commonly triggered by exercise, infections, fasting, cold exposure, stress, and other conditions that are normally associated with an increased dependency on muscle lipid metabolism. There are usually no signs of myopathy between attacks. End-stage renal disease caused by interstitial nephritis with acute tubular necrosis requiring dialysis occasionally occurs in the myopathic form of CPT II deficiency.

Natural History (Important subgroups & survival / recovery)

The lethal neonatal form of CPT II deficiency presents within days of birth. Death occurs within days to months. The severe infantile hepatocardiomuscular form of CPT II deficiency presents in the first year of life. Sudden death can result from cardiac arrhythmias in infancy. The myopathic form of CPT II deficiency is usually mild and can manifest from infancy to adulthood. Males are more likely to be affected than females. Heterozygotes are usually asymptomatic; however, manifesting carriers have been reported.

Likelihood of Outcome

Mode of Inheritance

Autosomal Recessive

Prevalence of Genetic Variants

Unknown

The population prevalence of CPT2 pathogenic variants was not available. More than 95% of cases of CPT II deficiency have a pathogenic variant in the CPT2 gene.

Tier 3

Unknown

The variant p.Ser113Leu accounts for 56-60% of pathogenic alleles in the myopathic form of CPTII deficiency. In a series of 32 affected individuals, 31 were determined to carry this common pathogenic variant (14 were homozygous and 17 were compound heterozygous).

Tier 3

Penetrance (Includes any high-risk racial or ethnic subgroups)

Unknown

All penetrance data below is related to the myopathic form of CPT II deficiency.

Tier Not provided

Unknown

Age at onset and age at diagnosis vary widely. Clinical data obtained from 23 of 32 individuals revealed age of onset ranging from one to 61 years; age at diagnosis ranged from seven to 62 years. In 70%, the disease started in childhood (age 0-12 years); in 26%, the first attacks occurred in adolescence (age 13-22 years); and in one individual, symptoms began in late adulthood (age 61 years).

Tier 3

>= 40 %

Episodes of rhabdomyolysis may be associated with extreme elevation of serum creatine phosphokinase (CPK) and myoglobinuria (75% of cases) and can lead to renal failure (in 8-25% of cases, but rarely requires dialysis).

Tier 4

>= 40 %

Almost all individuals with the myopathic form experience myalgia. Approximately 60% have muscle weakness during the attacks.

Tier 4

>= 40 %

Exercise-induced myalgia was reported as the most common symptom in a series of 28 patients, observed in 96% of patients.

Tier 3

Expressivity

The severity of exercise that triggers symptoms in the myopathic form of CPT II deficiency is highly variable. In some individuals, only long-term exercise induces symptoms, and in others, only mild exercise is necessary. Some individuals have only a few severe attacks and are asymptomatic most of their lives, whereas others have frequent myalgia, even after moderate exercise, such that daily activities are impaired, and disease may worsen.

Tier 4

Pathogenic null variants in CPT2 are typically associated with the lethal neonatal form of CPT II deficiency. Missense pathogenic variants in CPT2 are commonly associated with the myopathic form of CPT II deficiency. However, several pathogenic variants in CPT2 are associated with both the mild and severe forms of CPT II deficiency.

Tier 3

The ratio of males to females has been reported to be between 2 to 1 and 7.3 to 1. The reason for the preponderance of males is unknown; hormonal factors may play a role.

Tier 3

Heterozygotes have a biochemically intermediate phenotype (with markedly reduced enzyme activity) but generally do not display symptoms. However, a few symptomatic heterozygotes have been reported.

Tier 3

Intervention Effectiveness

Patient Management

The American College of Medical Genetics and Genomics (ACMG) has developed an ACT sheet to help clinical decision-making following newborn screening: https://www.acmg.net/PDFLibrary/Carnitine-Palmitoyltransferase-2-Deficiency-ACT-Sheet.pdf

To establish the extent of disease and needs in an individual diagnosed with CPT II deficiency, the following are recommended:

- Neurologic examination

- Strength testing

- Review of dietary association of symptoms

- Consultation with a clinical geneticist and/or genetic counselor.

Tier 4

The recommendation for treatment of CPT II deficiency is to follow current treatment for long-chain FAO disorders:

- Reduce the amount of long-chain dietary fat (<20%) while covering the need for essential fatty acids

- Provide carnitine to convert potentially toxic long-chain acyl-CoAs to acylcarnitines

- Provide a large fraction of calories as carbohydrates (70%) to reduce body fat utilization and prevent hypoglycemia

- Provide approximately one third of calories as even-chain medium chain triglycerides (MCT)

Tier 4

Evidence-based studies on management of long-chain fatty acid oxidation (FAO) disorders are lacking. A retrospective analysis of 75 patients with long-chain FAO disorders evaluated dietary treatment and disease outcome. Five patients had CPT II deficiency, however, due to the small number of cases and their heterogeneous presentation, disease management in CPT II deficiency was not evaluated. In the cohort, 25/27 of patients with enzymatically and/or molecularly confirmed VLCADD were on a long-chain triglyceride-restricted diet and most (21/27) received supplementation with MCT. In 9/22 patients with VLCADD, additional carbohydrates were supplemented, resulting in a hypercaloric diet. Optimal adherence to treatment was reported in 20/27 (74%) of patients with VLCADD. Despite high compliance, 38% of patients with VLCADD had intermittent muscle weakness and pain despite adhering to therapy. Five of the 13 patients with VLCADD and myopathy had symptoms during intercurrent illnesses and following exercise.

Tier 5

We did not identify a recommendation for triheptanoin treatment in CPTII deficiency. However, in June 2020, the FDA approved DOJOLVI (triheptanoin) for the treatment of pediatric and adult patients with molecularly confirmed long-chain FAO disorders. A double-blind randomized controlled trial of 32 patients (age range 7-64 years) with long-chain FAO disorders (11 patients with CPTII deficiency) were assigned a diet containing 20% of their total daily energy from either C7 (triheptanoin) or C8 (trioctanoin) for four months. Patients in the C7 group increased left ventricular (LV) ejection fraction by 7.4% (p=0.046) while experiencing a 20% (p.0.041) decrease in LV wall mass on resting echocardiogram. They also required a lower heart rate for the same amount of work during a moderate-intensity exercise stress test, when compared to patients taking C8. There was no significant difference between treatment groups in musculoskeletal symptoms (e.g., intermittent muscle pain, acute rhabdomyolysis) or any other secondary outcome measures over the 4‐month treatment period. Another study reported the safety and efficacy of 78 weeks of triheptanoin treatment versus a retrospective 78-week period (when patients were optimally managed under published dietary guidelines) in 29 patients (mean age 12.06 years, range 0.87-58.78 years) with symptomatic long chain FAO disorders (4 patients with CPTII deficiency). Following treatment, mean annualized major clinical event (MCE) rate decreased by 48.1% (p = 0.021) and mean annualized MCE event-day rate decreased by 50.3% (p = 0.028) independently from other dietary changes.

Tier 5

Emergency treatment aims to prevent mobilization of fat by providing ample glucose. In children and adults, early signs of decompensation may be subtle. 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. Early intervention is important and may prevent complications. It is advised that individuals undertake a regimen of high glucose drinks at the first sign of feeling unwell or have loss of appetite, if tolerated. A patient’s clinical status and previous decompensation history may warrant intravenous treatment. Some patients may be given carnitine orally.

Tier 2

There is a risk of metabolic decompensation during surgery, particularly if catabolism is precipitated by fasting and surgery. It is important to minimize catabolism by providing adequate amounts of carbohydrate prior to and during surgery. Operations should be postponed, if possible, in children who are unwell.

Tier 2

Surveillance

Annual or more frequent monitoring to regulate medication and diet is indicated.

Tier 4

Circumstances to Avoid

The role of carnitine in both the standard and emergency treatment of FAOs is controversial and should be avoided, especially intravenous carnitine, which may be arrhythmogenic.

Tier 2

Fasting should be avoided, even overnight fasting. There are suggested maximum fasting periods for patient during stable metabolic condition.

Tier 2

Prolonged exercise is to be avoided.

Tier 4

Reports of medication-induced side effects are rare. Relying mostly on case reports, the following agents should be avoided: Valproic acid and diazepam in high doses. General anesthesia should be avoided, as renal post-anesthetic failure in individuals with CPT II deficiency has been observed.

Tier 3

Nature of Intervention

Nature of Intervention

Interventions identified for CPT II deficiency include dietary modifications, avoidance of fasting, extra precautions before and during surgical procedures, and regular monitoring. These interventions may be burdensome, particularly in pediatric patients.

Context: Adult Pediatric

Treatment with triheptanoin appears to be well tolerated; minor adverse effects reported primarily consisted of gastrointestinal upset such as diarrhea (55%) and vomiting (48%).

Context: Adult Pediatric

Chance to Escape Clinical Detection

Symptoms of the myopathic form of CPT II deficiency can be mild and physical impairment may not occur. Females may be less likely to develop myoglobinuria and therefore remain undetected.

Context: Adult Pediatric

Tier 4

Gene Condition Association

Gene			Condition Associations
			OMIM Identifier	Primary MONDO Identifier	Additional MONDO Identifiers
			CPT2			255110	0015515	0009704
CPT2			600649	0015515	0010914
CPT2			608836	0015515	0012136

References List

Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Mirzaa G, Amemiya A. (1993) Carnitine Palmitoyltransferase II Deficiency. GeneReviews^®.

British Inherited Metabolic Diseases Group. Adult emergency management; Long chain fatty acid oxidation defects. (2018) Accessed: 2020-12-26. URL: https://bimdg.org.uk/store/guidelines/ADULT_FAOD-rev_2015_428281_09012016.pdf

British Inherited Metabolic Diseases Group. General Dietary Information for Emergency Regimens. (2016) Accessed: 2020-12-26. URL: https://bimdg.org.uk/store/guidelines/ER-LCFAO-v5_700028_05042017.pdf

British Inherited Metabolic Diseases Group. Long chain fat oxidation disorders - acute decompensation. (2017) Accessed: 2020-12-26. URL: https://bimdg.org.uk/store/guidelines/ER-LCFAO-v5_700028_05042017.pdf

British Inherited Metabolic Diseases Group. Management of surgery in children with disorders of fatty acid oxidation. (2017) Accessed: 2020-12-26. URL: https://bimdg.org.uk/store/guidelines/Management_of_surgery_in_children_with_fat_oxidation_disorde_846764_09092016.pdf

Carnitine palmitoyl transferase II deficiency, myopathic form. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=228302

Carnitine palmitoyl transferase II deficiency, neonatal form. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=228308

Carnitine palmitoyl transferase II deficiency, severe infantile form. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=228305

CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, INFANTILE. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 600649, (2016) World Wide Web URL: http://omim.org/

CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, LETHAL NEONATAL. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 608836, (2016) World Wide Web URL: http://omim.org/

CARNITINE PALMITOYLTRANSFERASE II DEFICIENCY, MYOPATHIC, STRESS-INDUCED. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 255110, (2017) World Wide Web URL: http://omim.org/

Carnitine palmitoyltransferase II deficiency. Orphanet encyclopedia, http://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=en&Expert=157

CARNITINE PALMITOYLTRANSFERASE II; CPT2. Online Medelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM: 600650, (2018) World Wide Web URL: http://omim.org/

DOJOLVI (triheptanoin) [label]. Publisher: Ultragenyx Pharmaceutical Inc. (2020) Accessed: 2021-04-08. URL: https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213687s000lbl.pdf

Gillingham MB, Heitner SB, Martin J, Rose S, Goldstein A, El-Gharbawy AH, Deward S, Lasarev MR, Pollaro J, DeLany JP, Burchill LJ, Goodpaster B, Shoemaker J, Matern D, Harding CO, Vockley J. (2017) Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders: a double blinded, randomized controlled trial. Journal of inherited metabolic disease. 40(1573-2665):831-843.

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. (2009) Treatment recommendations in long-chain fatty acid oxidation defects: consensus from a workshop. Journal of inherited metabolic disease. 32(4):498-505.

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, Röschinger W, Schwab KO, Scheible D, Wijburg FA, Zschocke J, Mayatepek E, Wendel U. (2009) Management and outcome in 75 individuals with long-chain fatty acid oxidation defects: results from a workshop. Journal of inherited metabolic disease. 32(1573-2665):488-97.

Vockley J, Longo N, Madden M, Dwyer L, Mu Y, Chen CY, Cataldo J. (2021) Dietary management and major clinical events in patients with long-chain fatty acid oxidation disorders enrolled in a phase 2 triheptanoin study. Clinical nutrition ESPEN. 41(2405-4577):293-298.