Not walking or communicating—is all well?

Abstract

In October, 2007, a 24-year-old woman was seen in our internal-medicine clinic. She had Rett’s syndrome, an X-linked neurodevelopmental disorder, and was brought up by a professional carer. Once she became ineligible for paediatric community care, she had no longer received regular specialist review. She was brought to us because she was no longer walking, having learnt to do so at 10 years of age; having been aware of other people, and able to signal basic needs, she was communicating only by brief eye contact with her carer. Initially, her deterioration (which had lasted several months) had been thought to refl ect the natural history of Rett’s syndrome. The patient also had longstanding gastrointestinal refl ux, which had been severe enough to stop her eating. Fundoplication, and a percutaneous feeding gastrotomy, had little eff ect, so she was fed by percutaneous jejeunostomy, with a preparation designed as a complete diet. Her body-mass index remained around 16 kg/m2. On examination, the patient was pale, with no observable subcutaneous fat. Blood tests revealed macrocytic anaemia (haemoglobin concentration 77 g/L; mean cell volume 131 fL), and neutropenia (0·1×109 cells per L); the platelet count was normal, as were results of other blood tests, including tests of kidney, liver, and thyroid function, and concentrations of iron, vitamin B12, and folate. A bone marrow aspirate from the posterior iliac crest contained few haemo poietic precursors. Histo pathological analysis showed replacement of haemo poietic and fat cells with amorphous material (fi gure). We concluded that haemopoietic tissue had undergone gelatinous trans formation to ground substance. This change is seen in protein-calorie malnutrition; how ever, the cytopenias were uncharacteristically severe for this diagnosis. At our laboratory, we routinely measure con cen trations of selected proteins: the caerulo plasmin concen tration was only 0·03 g/L (normal range 0·15–0·6 g/L). We wondered whether our patient’s neuro developmental delay might be caused by Wilson’s disease, especially since, unlike 70% of people with Rett’s syndrome, she seemed to have no mutation of the MECP2 gene. Her serum copper concentration was 1·9 μmol/L (normal range 11–26 μmol/L). A random urine sample contained no detectable copper; calculated free copper was 0·05 μmol/L (>4 μmol/L in active Wilson’s disease). A Google search, with the terms “anemia”, “neutropenia”, and “copper”, yielded reports that copper defi ciency causes neutropenia and (usually macrocytic) anaemia, without aff ecting platelet numbers. A sternal bone-marrow aspirate showed normal numbers of cells; however, many erythroid and myeloid progenitors contained vacuoles, and we saw many sideroblasts. All these changes were characteristic of copper defi ciency. We gave the patient a blood transfusion, and zinc-free copper chloride (PharmaLab, Lane Cove, Australia), 2 mg daily, for 5 days. Before the copper chloride became available, we administered granulocyte colony-stimulating factor (300 μg daily, for 5 days). On discharge, 16 days after admission, the patient’s neutrophil count had increased to 6·7×109 cells per L; she was communicating as she had before her deterioration, and could walk a few steps independently. Later, we briefl y repositioned the feeding tube in the duodenum, but recurrence of gastrooesophageal refl ux required us to return it to the jejunum. Our patient needs intra venous copper every 6 weeks to prevent cytopenias, and still has a mild macrocytosis. However, when last seen by us, in October, 2008, she had returned to sheltered employment, and was able to sit on a horse unaided. Causes of copper defi ciency include severe weight loss, gastric surgery, malnutrition, and zinc poisoning. Copper defi ciency causes myeloneuropathy, and can mimic subacute combined degeneration. Less commonly, it causes anaemia and neutropenia, sometimes mis diagnosed as myelodysplastic syndrome. Our patient’s haematological abnormalities were more severe than previously described, presumably due to gelatinous degeneration of bone marrow. Copper is absorbed primarily in the duodenum, where it competes with zinc—but our patient’s nutrition, although containing adequate copper, was delivered to the jejeunum. Unlike most patients with copper-defi ciency myeloneuropathy, our patient regained lost function: we speculate that some of her decline was caused by anaemia.