Case 1

submitted by:
Hannes Vogel
Stanford University Medical Center
Stanford, California

Clinical Summary:

This male patient was a former 6lb 12oz product of a full term pregnancy. He had been previously diagnosed at 2-3 months of age with hypertrophic cardiomyopathy, hypotonia, lactic acidosis and poor control of oral feeds. He had gastroesophageal reflux and subsequently required nasogastric tube feeds. A gastrostomy button and fundoplication were performed as well as a left thigh muscle biopsy. The biopsy showed features "suggestive of" a mitochondrial myopathy and subsequent mitochondrial enzyme analyses revealed reduced activities in complexes I, II-III, and IV which approached statistical significance but were not quite at 2 standard deviations below the normal reference mean. Ophthalmologic exam was normal and head MRI was normal except for extra axial fluid collections.

He was unable to sit alone and was not crawling. He spoke a few intelligible words. He had global hypotonia with absent deep tendon reflexes. Chest x-ray demonstrated marked cardiomegaly with normal pulmonary vascular markings. From the time of initial echocardiogram, cardiac ejection fraction had declined from 67% to 39%.

At 15 months of age he developed acute severe respiratory distress and despite maximal efforts he experienced irreversible cardiopulmonary arrest.

A full autopsy was performed. The brain weighed 785.7 grams. The gyral pattern was well developed. The cerebellum and brain stem were normal. There was a slight discoloration of the white matter of the temporal lobes; no lesions were seen in the basal ganglia or thalami. Serial sections of the brain stem perpendicular to its long axis show a slightly dilated aqueduct and no grossly identifiable lesion or discoloration in the midbrain, pons, or medulla.

Histologic section from the pons is submitted.

Case 1 - Figure 1 - Ventral pons focus showing demyelination and gliosis with preservation of neurons.

Case 1 - Figure 2 - Oncocytic change involving choroid plexus.

Case 2

submitted by:
Glenn Taylor
Children's and Women's Health Center
Vancouver, British Columbia

Clinical Summary:

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 instituted.

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 product accumulation.

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).

Case 3

submitted by:
Jim Dimmick
University of British Columbia
Vancouver, British Columbia

Clinical Summary:

A male infant was born at term gestation following a normal pregnancy and was normal in early infancy. The mother in a previous marriage had one normal child, a girl, now 6 years old and healthy. The baby under discussion is the second born with her current spouse; the first born, a male, developed progressively worsening liver failure and died at 9 months - an etiologic diagnosis was not established. This the second male baby presented at 3 months with poor feeding, irritability, lethargy and jaundice. The infant had hepatomegaly of 4 cm. Investigations demonstrated hypoglycemia, conjugated hyperbilirubinemia, elevated alkaline phosphatase 574 ( normal 110-320 units), AST 190 ( normal 20-60 units), ALT 144 ( 6-50 units ), GGT 624, amino acid analysis, abnormal but not specific and in keeping with liver disease, organic acid analysis normal, alpha feto protein elevated ( 300,000 units), very long chain fatty acids, normal, lactate elevated , 7.6 units, no ketosis, ammonia elevated, 40 units, prolonged PT, total carnitine normal, free carnitine markedly reduced , 0.8 ( normal 30.3 - 40.5 ) acyl carnitine profile normal, 93.1. All studies for an infectious etiology were negative. Muscle and liver biopsies were done; the muscle biopsy by H and E, histochemistry and electron microscopy was normal. Mitochondrial DNA depletion was documented in liver, but not in fibroblasts. A mutation in the deoxyguanosine kinase ( dGK ) gene was excluded.

Case 3 - Figure 1 - The light microscopic slides of liver show steatosis cholestasis and minimal portal mononuclear inflammation. The electron microscopic photograph demonstrates hepatic mitochondrial pleomorphism.

Case 3 - Figure 2 - The light microscopic slides of liver show steatosis cholestasis and minimal portal mononuclear inflammation. The electron microscopic photograph demonstrates hepatic mitochondrial pleomorphism.

Case 3 - Figure 3 - The light microscopic slides of liver show steatosis cholestasis and minimal portal mononuclear inflammation. The electron microscopic photograph demonstrates hepatic mitochondrial pleomorphism.

Case 3 - Figure 4 - The light microscopic slides of liver show steatosis cholestasis and minimal portal mononuclear inflammation. The electron microscopic photograph demonstrates hepatic mitochondrial pleomorphism.

Case 4

submitted by:
Kathleen Patterson
Children's Hospital and Regional Medical Center
and University of Washington
Seattle, Washington

Clinical Summary:

16 year male with ptosis first noted in school photographs 5 years earlier. He was an otherwise healthy young man with a history of learning difficulties requiring special education. The ptosis persisted despite attempted surgical repair X 2. Ophthalmologic examination uncovered concomitant ophthalmoplegia and retinal pigment changes. Mitochondrial DNA studies on his blood were normal. The ophthalmologist then referred him to a geneticist who suggested a muscle biopsy to further evaluate his neuromuscular status.

Case 4 - Figure 1 - Trichrome stain; NADH.

Case 4 - Figure 2 - SDH; COX.

Case 4 - Figure 3 - Transmission electron microscopy (low and high magnification).