Case 435 -- A 10 month-old girl with hypotonia

Contributed by Craig Horbinski, MD, PhD, Charleen T. Chu, MD, PhD, David Finegold, MD, and Mohamed A. Virji, MD, PhD
Published on line in August 2005


The patient is a 10 month-old girl who was born after a full term pregnancy via cesarean section secondary to failure to progress. The pregnancy was notable for polyhydramnios, well-controlled gestational diabetes, and decreased fetal movements late in the third trimester. At birth the baby was found to have a cardiac murmur and was mildly hypotonic, with difficulty feeding. An echocardiogram at 3 months showed mild asymmetric septal hypertrophy with possible biventricular hypertrophy, which at the time was attributed to gestational diabetes. Laboratory tests at 6 months showed elevated liver enzymes. The patient's development over time was notable for delayed achievements of new motor milestones, as well as the loss of achieved milestones.

Over the next few months a variety of diseases were ruled out, including spinal muscular atrophy, Angelman syndrome, congenital myotonic dystrophy, HIV, and viral hepatitis. The karyotype was normal (46, XX), as were screenings for urine organic acids and serum amino acids.

At 10 months the patient was brought to her primary care physician for increased difficulty breathing. After examination the PCP sent the child to Children's Hospital ER. Vitals were blood pressure 102/60 mm Hg, temperature 37.3C, pulse 124/minute, respirations 32/minute, and O2 saturation 94% on room air. Physical examination revealed macrocephaly with frontal bossing, marked breathing retractions, and global hypotonia. Arterial blood gases were pH 7.4, pCO2 48 mm Hg, pO2 56 mm Hg, and HCO3 30 mEq/L. Creatine phosphokinase was 558 IU/L (normal 0-200), alanine aminotransferase (ALT) 201 IU/L (normal <40), and aspartate aminotransferase (AST) 395 IU/L (normal <40). A chest X-ray [image 1] showed mild cardiomegaly and right upper lobe infiltrates; a barium swallow supported the suspicion of aspiration pneumonia. An electrocardiogram and echocardiogram showed right ventricular hypertrophy and severe concentric LVH.

The patient was admitted and put on ampicillin with sulbactam (for pneumonia) and propranolol (for persistent hypertrophic cardiomyopathy). The patient improved briefly, but soon regressed and developed pulmonary edema, which was treated with furosemide. A metabolic disorder was suspected, prompting a skin biopsy/fibroblast culture for an alpha-glucosidase activity assay. In the context of a presumptive diagnosis (to be revealed later), the patient's prognosis was considered poor, so the parents elected comfort measures only. The following day, she died in her mother's arms.

A postmortem exam was significant for cardiomegaly (weight 82 grams, expected 37 grams) with numerous cardiomyocyte vacuoles containing PAS-positive, diastase-sensitive material [images 2, 3 and 4], hepatomegaly (weight 391 grams, expected 254 grams) with diffuse hepatocyte vacuolation similar to that in the heart [images 5, 6 and 7], increased brain weight (weight 883 grams, expected 714) with neuronal vacuolation, especially in the anterior horn cells and brainstem motor nuclei [image 8], and macroglossia. Transmission electron microscopy of several tissues, including the vacuolated neurons, demonstrated distended membrane-bound vacuoles containing glycogen particles [images 9 & 10].

Several weeks later, the alpha-glucosidase activity of the patient's cultured fibroblasts was found to be 1.00 nM per mg protein per hour (normal 16-32), which provided confirmation of the presumptive diagnosis.


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