Mother, 34 years of age and G2P1, delivered a term male, 3489 g, following an uncomplicated pregnancy
and labour. Apgar scores were 4, 9, and 10. Over the first 2 days the baby had difficulty breast
feeding and showed some inspiratory stridor. Investigations revealed a minor degree of laryngomalacia.
He was discharged at 10 days of age but readmitted 3 days later because of increasing feeding
difficulties and episodes of tachycardia and worsened stridor.
Readmission chest radiographs showed mild cardiomegaly, ECG demonstrated diffuse ST-T segment changes,
and echocardiogram revealed left ventricular and asymmetric septal hypertrophy, mild anterior systolic
mitral valve motion, but no outflow tract obstruction. Lactate concentrations were elevated (serum 15.5
mmol/L, CSF 3.2 mmol/L). At this time, the clinical differential diagnosis included infantile
presentation of familial hypertrophic cardiomyopathy and metabolic cardiomyopathy such as
mitochondriopathy or storage disorder. The combination of hypertrophic cardiomyopathy with lactic
acidosis favored mitochondrial cardiomyopathy. Numerous biochemical and genetic investigations were
Quadriceps muscle biopsy was performed 7 days after admission. This suggested myopathy but no
specific diagnosis. Histochemical staining was positive for NADH, SDH, cytochrome c oxidase, and focal lipid. Ultrastructural examination showed mitochondria with
mildly irregular size and shape but normal cristae and no inclusions, normal myofibers, and no storage
The baby deteriorated over the next several days, requiring intubation and assisted ventilation.
Attempts to wean were unsuccessful. Seizures occurred. The baby's prognosis was deemed very poor and
after consultation, parents requested withdrawal of respiratory support. The baby died shortly after. A
"metabolic autopsy" was performed. The submitted slide is a transverse section from the mid
interventricular septum of the heart.
Case 2 - Figure 1 - Electron micrograph of quadriceps muscle biopsy showing essentially unremarkable somewhat elongated mitochondria with normal cristae and matrix (original magnification x 25,000).
Case 2 - Figure 2 - Autopsy myocardium demonstrating the "hallmark" features of mitochondriopathy - fusiform swelling, perinuclear clearing, and perinuclear granules (Masson trichrome, x 200).
Case 2 - Figure 3 - Electron micrograph from autopsy myocardium (12 hours postmortem) showing proliferation of variable size and irregular shape mitochondria, dispersing contractile elements (original magnification x 5400).
Case 2 - Figure 4 - More marked cardiac myocyte mitochondrial pleomorphism and size variation, and abnormal tubular cristae shown in higher power electron micrograph (original magification x 11,750).
Samples of skeletal muscle and liver were obtained 80 minutes after death. The autopsy was completed
12 hours after death. Growth parameters were at the tenth percentile. There were no dysmorphic
features. The heart was enlarged, 42.5 g (23 +/- 7 g), with prominent left ventricular and septal
hypertrophy (free wall LV 1.1 cm, expected 0.6 +/- 0.2 cm). No endocardial fibroelastosis or structural
malformation was present. A small left periventricular cyst was found in the brain, which was slightly
small but otherwise grossly normal. Other organs were unremarkable.
Heart microscopy revealed hypertrophic and diffusely mildly swollen cardiac myocytes. Many had mild
perinuclear cytoplasmic clearing or granularity. Myofiber "disarray," defined by arcuate and branching
hypertrophied myocytes, occupied less than 5% of the surface area of the transverse section of
interventricular septum. Myocarditis, myocardial necrosis, interstitial fibrosis, and endocardial
fibroelastosis were absent. The liver had mild micro- and macrovesicular steatosis. The brain showed
diffusely distributed hypertrophic astrocytes and cysts in the centrum semiovale, consistent with
Histochemical staining of myocardium sampled 12 hours after death showed diffuse positive staining for
succinic dehydrogenase but essentially no staining for cytochrome c oxidase.
Autolysis partially obscured the ultrastructure of a 12 hour post mortem myocardial specimen. However,
the myocardium demonstrated increased numbers, size variability, and pleomorphism of mitochondria. There
were no mitochondrial matrix inclusions, but cristae generally were tubular.
Extensive biochemical and molecular genetic testing was performed on tissues obtained from the
autopsy. Mitochondrial electron transport chain complex analyses confirmed decrease of cytochrome c oxidase activity in the myocardium and in skeletal muscle, but activity in
cultured fibroblasts was normal. No mutation of mitochondrial DNA was found in skin fibroblasts.
Molecular studies performed by Dr. DiMauro's laboratory in New York revealed a mutation in SCO2, a
nuclear gene involved with assembly of cytochrome c oxidase.1
Final Diagnosis - Lethal Neonatal Mitochondrial
Cardiomyopathy (complex IV defect due to SCO2 deficiency)
This case provides an instructive example of the multidisciplinary investigations required for the
diagnosis of a rare group of diseases, lethal neonatal mitochondrial
cardiomyopathy.. Although there are clinical and morphologic diagnostic hallmarks, mitochondrial
heteroplasmy and heterogenous genetics often confound investigations. The pathologist, usually presented
with only a clinical suspicion for the condition, becomes central to the successful resolution of the
case: morphologic findings direct the biochemical and molecular genetic investigations.
Infantile Lethal Mitochondrial Cardiomyopathy: BCCH cases
lactic acidosis, cardiomegaly
failure to thrive, lactic acidosis, cardiomegaly
lactic acidosis, cardiomegaly
failure to thrive, lactic acidosis, cardiomegaly, nystagmus
failure to thrive, lactic acidosis, cardiomegaly
failure to thrive, lactic acidosis, cardiomegaly
Clinical suspicion for neonatal mitochondrial cardiomyopathy arises with presentation of failure to
thrive, lactic acidosis, and cardiomegaly.2, 3 However, these are not specific signs and definitive
diagnosis requires additional often highly specialized investigations.
The morphologic hallmarks are also not specific, but include gross, microscopic, and ultrastructural
Hypertrophic Cardiomyopathy in Infants
- infantile presentation of genetic hypertrophic cardiomyopathy
- Pompe disease
- LAMP deficiency
- glycogen storage disease III
- Hurler disease
- MPS VII
- carnitine deficiency
- mitochondrial cardiomyopathy
- infant of a diabetic mother
- ACTH administration
- dexamethasone administration
Most often neonatal/infantile mitochondrial cardiomyopathy presents with hypertrophic morphology.4
This may be associated with endocardial fibroelastosis and asymmetric septal hypertrophy. In childhood,
mitochondriopathy rarely manifests as dilated cardiomyopathy. The differential diagnosis for infantile
hypertrophic cardiomyopathy is long and encompasses genetic, metabolic, and transient environmental
etiologies. Biventricular concentric hypertrophy with pale tan myocardium points to the possibility of
mitochondrial cardiomyopathy, but this also occurs with storage disorders.
The microscopic hallmark of mitochondrial cardiomyopathy is the swollen and "cleared" cardiac myocyte.
Affected myocytes have fusiform enlargement around the perinuclear region with either cytoplasmic
clearing or replacement of cross striations by fine granules. The granules represent marked
proliferation of mitochondria. At one extreme, the changes are pronounced and diffuse. However, due to
mitochondrial heteroplasmy and variability of expression, the changes may be more subtle and focal.
Swollen and "cleared" cardiac myocytes occur with other conditions, such as glycogen storage disease or
vacuolar degeneration due to hypoxic cell injury. Fetal or premature neonatal myocardium normally
appears vacuolated due to abundant glycogen reserves and the relative paucity of sarcomeres and other
Histochemical staining of fresh frozen myocardium for oxidative phosphorylation complex function may
be invaluable in directing additional studies. Our practice is to screen using NADH reductase (for
complex I), succinic dehydrogenase (complex II), and cytochrome c oxidase
(complex IV). This screening does not encompass complex III, except as part of a multiple OXPHOS complex
disorder. Normal histochemical staining does not exclude a primary mitochondriopathy. As well,
cytochrome c oxidase deficiency develops secondary to chronic disease and
aging.6 In mitochondrial cardiomyopathies, succinic dehydrogenase often shows diffuse strong
positivity, indicating compensatory proliferation of mitochondria. Histochemical staining degrades with
lengthened post mortem interval, but we have seen satisfactory staining up to 24 hours after death.
Often lipid accumulates in mitochondrial cardiomyopathy, and oil-red-O staining is a good adjunct.
Ultrastructural Findings in Mitochondrial Cardiomyopathy (BCCH Experience)
- pronounced mitochondrial hyperplasia displaces or replaces contractile elements
- marked variation in mitochondrial size; giant forms
- variable pleomorphism
- cristae may be tubular rather than lamellar
- peri- or intramitochondrial lipid droplets common
Ultrastructurally, mitochondriopathy has been defined as excessive and/or abnormally structured
mitochondria.7 This definition is unsatisfactory because mitochondrial morphologic abnormalities
commonly occur secondarily in a wide variety of conditions and, conversely, patients with molecular
genetically defined mitochondriopathies may have normal appearing mitochondria.8 However, like with
hypertrophic gross morphology and swollen and "cleared" cardiac myocytes, certain ultrastructural
findings suggest primary mitochondrial cardiomyopathy. Arbustini et al studied endomyocardial biopsies
from adults with dilated cardiomyopathy looking to correlate mitochondrial ultrastructural abnormalities
with mitochondrial DNA mutations.9 Increased number, giant mitochondria, abnormal inclusions and
circular, concentric or, whorled cristae were found in 85 of 601 patients. Of these "positive" cases, 19
had mitochondrial DNA mutations. None of the 516 "negative" cases had mutations.
Ultrastructural assessment requires consideration for autolysis, especially important with autopsy
tissue. We try to obtain autopsy tissues destined for electron microscopy within an hour of death.
However, ultrastructural features suggesting mitochondrial cardiomyopathy may survive even 24 hours of
autolysis. In addition to autolysis, other ultrastructural caveats requiring consideration are
nonspecific mitochondrial proliferation occurring with hypertrophy from any cause and finding occasional
abnormal forms of mitochondria (i.e., "cup" mitochondria, "chondriospheres") in normal or damaged tissues.10, 11
The challenge presented by infantile mitochondrial cardiomyopathy results from the rarity of the
condition and the variations of clinical course, genetic expression, and tissue or organ involvement. To
meet this challenge, the pathologist requires a clinically primed suspicion for the diagnosis, knowledge
of the appropriate disposition and study for the autopsy or biopsy-derived tissue specimens, willingness
to obtain the specimens expeditiously, and close collaboration with biochemical and molecular genetic
peers. As this case showed, morphology can point the direction towards a specific molecular genetic
diagnosis and subsequent optimal management of the affected family.
- Papdopoulou LC, Sue CM, Davidson MM, Tanji K, Nishino I, Sadlock JE, et al. Fatal infantile
cardioencephalomyopathy with COX deficiency and mutations in SCO2, a COX assembly gene. Nature Genetics
- Hart Z, Chang C-H. A newborn infant with respiratory distress and persistent stridulous breathing.
J Pediatr 1988;113:150-5.
- Zeviani M, Van Dyke DH, Servidei S, Bauserman SC, Bonilla E, Beaumont ET, et al. Myopathy and fatal
cardiopathy due to cytochrome c oxidase deficiency. Arch Neurol 1986;43:1198-202.
- Guenthard J, Wyler F, Fowler B, Baumgartner R. Cardiomyopathy in respiratory chain disorders. Arch
Dis Child 1995;72:223-6.
- Anderson PAW. Immature myocardium. In: Moller JH, Neal WA, editors. Fetal, Neonatal, and Infant
Cardiac Disease. Norwalk, Connecticut: Appleton & Lange; 1990. p. 35-71.
- Muller-Hocker J. Cytochrome-c-oxidase deficient cardiomyocytes in the human heart - an age-related
phenomenon. A histochemical and ultracytochemical study. Am J Pathol 1989;134:1167-73.
- Sengers RCA, Stadhouders AM, Trijbels JMF. Mitochondrial myopathies: clinical, morphological and
biochemical aspects. Eur J Pediatr 1984;141:192-207.
- DiMauro S, Bonilla E, Zeviani M, Nakagawa M, DeVivo DC. Mitochondrial myopathies. Ann Neurol
- Arbustini E, Diegoli M, Fasani R, Grasso M, Morbini P, Banchieri N, et al. Mitochondrial DNA
mutations and mitochondrial abnormalities in dilated cardiomyopathy. Am J Pathol 1998;153:1501-10.
- Pelosi G, Agliati G. The heart muscle in functional overload and hypoxia. A biochemical and
ultrastructural study. Lab Invest 1968;18:86-93.
- Brega A, Narula J, Arbustini E. Functional, structural, and genetic mitochondrial abnormalities in
myocardial diseases. Journal of Nuclear Cardiology. 2001;8(1):89-97.