SUPPLEMENTARY DATA
High incidence and variable clinical outcome of hypertrophic cardiomyopathy due to ACAD9
mutations in childhood
Marie Collet1, Zahra Assouline1, Damien Bonnet1, Marlène Rio1, Franck Iserin1, Daniel Sidi1, Alice
Goldenberg2, Caroline Lardennois2, Metodi Dimitrov Metodiev1, Birgit Haberberger3, Tobias Haack3,
Arnold Munnich1, Holger Prokisch3 and Agnès Rötig1
1
Departments of Pediatric, Cardiology and Genetics and INSERM U1163, Université Paris Descartes-
Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants-Malades, 149 Rue de Sèvres, 75015
Paris, France
2
Unité de Génétique Clinique, Department of Neonatal Medicine – Neuropediatrics and Functional
Education, CHU de Rouen, Hôpital Charles Nicolle, 1 Rue de Germont, 76031 Rouen, France
3 Institute
of Human Genetics, Helmholtz Zentrum, Ingolstaedter Landstr. 1, Munchen, Germany
Corresponding author: Agnès RÖTIG (agnes.rotig@inserm.fr)
Key words: mitochondria, ACAD9, cardiomyopathy
The clinical history of the 8 patients found to carry homozygote/compound heterozygote ACAD9
mutations is described here.
Patient 1, a boy, was the second child of healthy unrelated French parents (BW= 2000 g, OFC= 32
cm). His elder brother died at 6 hours of life. Patient 1 required resuscitation for respiratory distress, he
rapidly recovered but his condition worsened at two hours of life. Echocardiography revealed severe
HCM with bradycardia and large QRS complexes. He required intubation and was transferred in an
intensive care unit. He had collapse at seven hours and died at eleven hours of life.
Patient 2, a girl, was the first daughter of healthy, unrelated West African parents. She was born at 35
weeks of pregnancy by urgent cesarean section for cardiac arrhythmia (BW: 1495 g H: 31 cm, OFC:
30.5 cm). Chest X-rays detected major cardiomegaly ascribed to HCM (plasma lactate= 11 mmol/L,
pH= 7.10). Her condition transiently improved then worsened again at twenty days, with collapse,
bradycardia, desaturation requiring tracheal intubation and resuscitation. She had major hypertonia
and pyramidal syndrome. Brain MRI revealed periventricular leukodystrophia and she died at ten
weeks of life.
Patient 3, a girl, was the third child of healthy unrelated Portuguese parents. The first pregnancy
terminated with the delivery of a dead child. The second child, a boy, died at 6 days of life with
unexplained cardiomyopathy. She was born after a 36 weeks pregnancy and normal delivery (birth
weight: 3050 g). At 4-8 months, recurrent bronchitis, stridor, tachycardia (180/min), hypotonia and
psychomotor delay prompted to carry out echocardiography that revealed non obstructive HCM.
Cerebral CT revealed hyper intensity of basal ganglia (caudate and lenticular) with hypo intensity of
the white matter and dentate nuclei. She underwent a heart transplantation but died shortly thereafter.
Patient 4, a boy, was the second child of healthy French unrelated parents. His elder sister died at 16
hours with severe hypotonia of unknown origin. He was born after a term pregnancy (weight: 2990 g;
height 48 cm). He first came to medical attention aged 18 months for polypnea, muscle weakness and
fatigue ascribed to HCM. Retrospectively, the mother mentioned early polypnea and feeding
difficulties. At 18 months, he reportedly presented absence-seizures and was given sodium valproate.
HCM, muscle weakness, and exercise intolerance rapidly worsened and he underwent cardiac
transplantation at 9 years of age. His heart transplantation was successful but he slowly developed
mild proximal tubulopathy, and cerebellar ataxia with dysmetry, tremor and muscle weakness. He is
now a 15 years old boy with normal fundus, no pyramidal syndrome, neuropathic features or cranial
nerve involvement (weight: 31.5 kg, height: 138 cm, OFC: 53 cm). His 6 min walk-test is reduced to 96
meters. Skeletal muscle biopsy at 5 years revealed lipids droplets and ragged red fibers in 60% of
muscle cells.
Patient 5, a girl, was the second daughter of non-related French parents. Her elder sister had
moderate neonatal respiratory distress and difficulties to adapt to the extra uterine life but suddenly
died at 5 months of unexplained collapses. She presented with dyspnea and anorexia at 9 years of
age. Echocardiography showed HCM. Her condition worsened and she needed a cardiac
transplantation at 18 years of age. She is now a 35 years old woman, and she has developed
secondary infertility and severe kidney failure with unremarkable kidney morphological anomalies.
Skeletal muscle biopsy performed when she was 18 yrs old showed ragged red fibers.
Patient 6, a boy, was the second child of healthy, unrelated Caribbean parents. He was born after a
normal pregnancy (birth weight: 3500 g). He first came to medical attention aged 4 months for
dyspnea, liver enlargement and elevated blood pressure. Echocardiography showed concentric HCM.
Yet, his condition was relatively well tolerated and he did well during the next following years. At 6
years, his clinical condition was considered excellent. He had no liver, kidney or fundus involvement.
Yet, he had mildly elevated plasma and CSF lactate, and ERG alteration. Echocardiography showed a
33% left ventricular shortening fraction with mild hypertrophy (septum 1 cm, left ventricle posterior wall
thickness: 13 mm). He is now a 22 years old young man (weight: +0.5 SD, height: +2 DS) with mild
muscle weakness and dyspnea, but no other organ involvement or medication to date.
Patient 7, a girl, was the second child of healthy unrelated parents. She was born after a term
pregnancy obtained by in vitro fertilization. She could walk unaided aged 15 months, but she gradually
failed to thrive. She developed weakness, fatigue, severe anorexia and dyspnea, ascribed to HCM and
hyperlactatemia at 18 months of life (plasma lactate: 8 mmol/L. Her brain MRI and skeletal muscle
morphology were unremarkable and no other organ involvement was noted. Her condition rapidly
worsened, with collapse, bradycardia and desaturation, requiring tracheal intubation and resuscitation.
She died at 21 months of age.
Patient 8, a girl, was the unique child of healthy parents (BW: 3200g, H: 48cm, OFC: 33). Unexplained
feeding difficulties and failure to thrive were noted in the first year of life. She could sit unaided aged
12 months but her psychomotor development was reportedly normal. Systematic examination
detected HCM and elevated plasma lactate (5,5-14 mmol/L). Two sudden episodes of bradycardia and
collapse required resuscitation and she died at 18 months.