Case 1: Barth syndrome
A male who presented with heart gallop within hours of birth was found to have lactic acidosis and severe left ventricular (LV) dysfunction characterized by severe dilated cardiomyopathy and an ejection fraction (EF) of approximately 20%. The cardiomyopathy was unresponsive to medical management. Exome sequencing identified a pathogenic variant in Tafazzin (TAZ), consistent with a diagnosis of Barth syndrome (diagnoses based on entry in a previous study at 3 weeks of age that included rapid genome sequencing) and related cardiomyopathy. It was decided to initiate elamipretide at 3 weeks of age as his EF had not significantly improved on maximal medical therapy that included milrinone, sacubitril/valsartan, and carvedilol. The initial dose of elamipretide was 0.25 mg/kg administered intravenously with weight-based upward titration to 0.5 mg/kg beginning at 1 week. Each dose was administered over 2 hours. At 4 weeks, the patient was switched to subcutaneous (SQ) dosing at 0.5 mg/kg/day (10 mg/mL formulation of elamipretide) and discharged from the hospital on that dose. Additional medications since discharge included filgrastim, arginine, sacubitril/valsartan, carvedilol, and spironolactone. This dosing schema resulted in a gradual improvement of the EF to between 45% and 55% although dyskinesia of the LV remained (Table 1). Neutropenia was improved on filgrastim, with normal absolute neutrophil counts ranging from 1020 to 1200/mm3 after therapy was started. The hepatic enzymes AST, ALT, and CK were normal after 1 month of age, although there was a mild persistent lactic acidosis ranging from 2.0 to 4.4 mmol/L. At 4 months of age, the patient was meeting all developmental milestones. There were no adverse events related to elamipretide, regardless of the route of administration (IV or SC). Unfortunately, the patient died at 5.5 months of age as a result of his underlying disease, with a normal appearing heart on autopsy. The total time on treatment with elamipretide for this patient was 150 days.
Table 1. Barth Syndrome patient (Patient Case 1) imaging data
Date
|
Modality
|
SF%
|
EF%
|
LVEDDmm (Z)
|
LV Hypertrophy
|
LV Function
|
RV Function
|
11/12/20
|
TTE
|
13
|
26-39
|
19 (–0.1)
|
|
Mod-severe
|
Normal
|
11/13/20
|
TTE
|
21
|
44-48
|
19 (0)
|
|
Mild, dyskinetic
|
Low normal to mild dysfxn
|
11/14/20
|
TTE
|
26
|
|
|
Severe
|
Mild, dyskinetic
|
Mild
|
11/15/20
|
TTE
|
19
|
45
|
20 (+0.8)
|
|
Mild, dyskinetic
|
Mild
|
11/19/20
|
TTE
|
10
|
40-50
|
21 (+1.1)
|
|
Moderate, dyskinetic
|
Mild
|
11/24/20
|
TTE
|
17
|
25-28
|
23 (+2.6)
|
Moderate
|
Severe, dyskinetic
|
Normal
|
11/25/20
|
TTE
|
11
|
35
|
21 (+1.2)
|
Moderate
|
Severe, dyskinetic
|
Normal
|
11/30/20
|
TTE
|
13
|
26-32
|
22 (+1.8)
|
Moderate
|
Severe, dyskinetic
|
Normal
|
12/02/20 Initiation of sacubitril-valsartan
12/4/20
|
TTE
|
18
|
37-38
|
20 (+0.7)
|
Moderate
|
Moderate, dyskinetic
|
Low normal
|
12/05/20 Initiation of elamipretide at 0.25mg/kg
12/7/20
|
TTE
|
15
|
39-66
|
20 (–0.3)
|
Mild
|
Low normal (to my eyes mild-mod)
|
Normal
|
12/10/20 Off milrinone last
12/12/20 Elamipretide to 0.5 mg/kg
12/12/20
|
TTE
|
22
|
41-53
|
18 (–1.0)
|
Mild
|
Mild-mod, dyskinetic
|
Normal
|
12/16/20
|
TTE
|
|
41-54
|
20 (+0.2)
|
Mild
|
Mild, dyskinetic
|
Normal
|
12/22/20
|
TTE
|
29
|
48
|
21 (+0.3)
|
Mild
|
Mild, dyskinetic
|
Normal
|
12/30/20
|
TTE
|
23
|
51-54
|
20 (–0.3)
|
Mild, LVNC
|
Mild, dyskinetic
|
Normal
|
1/15/21
|
TTE
|
21
|
44-46
|
22 (–0.1)
|
Mild, LVNC
|
Mild, dyskinetic
|
Normal
|
2/19/21
|
TTE
|
22
|
58
|
19 (–2.4)
|
Mild, LVN
|
Mild, dyskinetic
|
Normal
|
4/15/2021
|
TTE
|
30
|
50-57
|
23 (–0.8)
|
Mild, LVN
|
Low-normal, dyskinesia
|
Normal
|
Case 2: MEGDEL syndrome
A male patient presented to the clinic with MEGDEL syndrome. The patient had experienced significant developmental delays in early motor development (ie, not sitting alone until 14 months or crawling until 20 months and ambulating with a walker at 3 years). Dysarthria resulted in impediments to communication that caused him to be difficult to be understood. At his best, he spoke in 4-to-5-word sentences, and his speech was approximately 50% understandable to a stranger. Although he experienced sporadic brief regressions with illness, he mostly gained skills until the age of 5 years when he began to display regression. After this age, he began to lose the ability to use his walker and by age 6 could no longer stand. Language also became progressively more dysarthric. An echocardiogram and renal evaluations at age 4 revealed no abnormalities. At 3 years of age the patient experienced an acute episode in which he was found unresponsive and had a lactic acid level of 7.9 mmol/L. He received IV fluids, and symptoms resolved after an overnight hospitalization. The symptoms have not recurred. At 6 years and 7 months of age, elamipretide was initiated at a subcutaneous dose of 10 mg/day (0.58 mg/kg/day) with a predetermined plan to increase the dose to 20 mg/day when he reached a weight of 20 kg. Since this weight has not been attained, the patient remains on 10 mg SQ daily at 7 years and 10 months. There have been no adverse reactions to the elamipretide, and after 1 year and 3 months of therapy at this dose, the patient has demonstrated not only a lack of continued regression but developmental progress. The patient’s parents have noted improved stamina and strength. He is again speaking in 3-to-4-word sentences, and speech is more understandable. He is able to sit alone, stand with support, and is using his gait trainer.
Case 3: Sengers syndrome
This male patient presented at 3 weeks of age with severe hypertrophic cardiomyopathy, bilateral cataracts, and significant hypotonia. Whole genome analysis revealed he was homozygous for an Icelandic founder mutation (p.Ile348AsnfsTer39) in the acylglycerol kinase (AGK) gene, and a diagnosis of Sengers syndrome was made based on symptoms and genotype. Genetic analysis also revealed that he was a carrier of two variants in the GPT2 gene, one from his mother [c.247C>T p(Arg92*)] and the other from his father [c.371G>C p(Ser124ThrI)], the latter being a variant of uncertain significance; however, his phenotype was not consistent with GPT2-deficiency, so this diagnosis was disregarded. However, it is worth noting that his presentation was unusually aggressive compared to other Icelandic patients carrying these particular founder variants, so it is not impossible that the other variants affected the phenotype in some way. The boy was initiated on beta blocker therapy which was gradually titrated up (including during the trial with elamipretide) and, beginning at age 3 months, he received elamipretide (0.25mg/kg IV infused over 2 hours [per protocol], every 24 hours) and at 4 months of age, it was increased to 0.50mg/kg IV infused over 2 hours every 24 hours. This dose was then increased per weight but not otherwise modified. Therapy with elamipretide continued for approximately 6 months. The Child was also treated with Carnitine and Q10 supplements by neurologist. The total time on treatment with elamipretide for this patient was 187 days.
Pharmacokinetic (PK) analysis showed that elamipretide exposure was similar to that observed in other elamipretide trials. Following the initiation of therapy, the patient experienced subjective improvements from the prior week’s evaluation in 13 of 21 visits using a clinical global impression scale with the global score improving from “markedly ill” to “borderline ill” during treatment (Figure 1). Cardiac improvements included an increase in the LV end-diastolic internal dimension (Z-score from −2.7 to +0.7), a decrease ventricular septal thickness (Z-score from 4.7 to 3.5), and a decrease in LV posterior wall thickness (Z-score from 5.8 to 4.7). There were no side effects that were attributable to elamipretide. The patient experienced intermittent lactic acidosis and neutropenia that were considered secondary to his condition. After 6 months of treatment, the patient underwent an elective PEG placement after which he experienced cardiac decompensation, followed by multi-organ failure and death.
Case 4: ACAD9 Deficiency
A 29-year-old female with a history of chronic hypertrophic cardiomyopathy and lactic acidosis, identified at approximately 12 years of age (gene panel negative at that time), presented in acute cardiogenic shock from a referring hospital to the Cardiology Intensive Care Unit (ICU) with an Impella 2.5 device in place via the right axillary artery. Cardiogenic shock was triggered by lying supine in a cardiac magnetic resonance imaging machine due to worsening dyspnea on exertion (DOE) for a septal ablation procedure. The last available lab values, obtained at age 18, were: normal CK of 33, lactate of 5.9, pyruvate of 0.22 with L:P ratio of 27, and normal acylcarnitine profile.
On hospital day 2, the patient went to the operating room for Impella removal and consideration for extracorporeal membrane oxygenation (ECMO) because of the large amount of hemolysis from the Impella. Patient was in shock on arrival to the operating room with a pH of 6.9 and relatively high inotropic and pressor requirements. The Impella device was removed following correction of metabolic derangements, and the patient went to the cardiothoracic surgical ICU on reasonable doses of inotropic and pressor support. Over the next several hours, the patient hemodynamically declined and was cannulated for ECMO support. The patient had persistent lactic acidosis (12 mM), renal failure, and hepatic failure from shock. Initial cardiac dysfunction was severely depressed with an estimated EF of 15–20%. Other metabolic laboratory values included highly elevated creatine kinase, elevated lactate to pyruvate ratio, elevated alanine, and organic acids in the urine.
She was started on supportive therapy for this condition, including N-acetylcysteine, l-carnitine, and dextrose. Three days after ECMO cannulation, the patient was started on elamipretide in consideration of the severity of illness and the success of this medication in similar patient presentations. The patient was initiated on elamipretide 0.5 mL SC daily (40-mg equivalent dose) and maintained on that dose for 90 days as an inpatient. Her estimated EF continued to improve to 25% 4 days after ECMO cannulation. The patient continued to hemodynamically improve and was decannulated from ECMO 5 days after initial cannulation. Heart function continued to improve, and the patient was noted to have an EF of 44% 6 days after ECMO cannulation. Although the hospital course was complicated by ventilator-dependent respiratory failure, renal failure, and ventilator-associated pneumonia, which led to a prolonged stay, the patient was eventually discharged to inpatient rehab on hospital day 102.
Additional diagnostic testing completed during her admission included a muscle biopsy and whole exome sequencing. Muscle biopsy was sent for mitochondrial DNA sequencing and deletions, which did not show a mitochondrial DNA pathogenic variant, but did show multiple low-level deletions of unknown significance. Mitochondrial DNA copy number in muscle was normal at 93% (no depletion). Electron transport chain analysis unexpectedly showed a normal complex I activity of 128%, with complex II at 530% (perhaps due to overcompensation). Complex III and IV were normal, as was citrate synthase. Whole exome sequencing revealed compound heterozygous variants in ACAD9 [c.1594 C>T (p.R532W) (pathogenic) and c.1646 G>A (p.R549Q) (likely pathogenic)], consistent with a diagnosis of ACAD9-related disease. This entity, in its later onset form, explains very well her clinical presentation, including her lactic acidosis, cardiomyopathy, and skeletal muscle weakness. She was then started on riboflavin supplementation and continued a mitochondrial cocktail with N-acetylcysteine, levocarnitine, and thiamine. ACAD9 is typically associated with complex I deficiency; thus, it is unclear why her activity would have been normalized, although there are reports of individuals with later-onset disease related to ACAD9 with normal complex I activity.6
Elamipretide was discontinued after having been administered for 65 days, with no intent to restart due to the patient’s wish to discontinue, and follow-up continued with the genetics/metabolism group at the Hospital of the University of Pennsylvania.