A Woman with Type 1 Diabetes Mellitus and Obtundation

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What are some of the causes of a low serum ceruloplasmin level?

Low signal intensity on T2-weighted magnetic resonance imaging can be caused by gadolinium-based contrast material, hemoglobin-breakdown products, melanin, mucus- or protein-containing lesions, highly cellular lesions, turbulent and rapid blood and CSF flow, air, and excessive mineralization, which most commonly involves calcium, copper, manganese, or iron. Read the NEJM Case Records of the Massachusetts General Hospital here.

Clinical Pearls

Q: What are some of the causes of a low serum ceruloplasmin level?

A: Because serum ceruloplasmin is produced and secreted in the liver, a common cause of low ceruloplasmin levels is liver disease. Low ceruloplasmin levels can also result from nutritional deficiencies such as copper deficiency. Low serum ceruloplasmin and copper levels are also seen in rare genetic diseases, including diseases of copper metabolism such as Wilson’s disease or Menkes disease, as well as in primary hereditary aceruloplasminemia.

Q: Copper deposition typically occurs in what regions of the brain in patients with Wilson’s disease?

A: Wilson’s disease, caused by excess copper, can result in lesions with hyperintensity, hypointensity, or mixed intensity in the putamen, globus pallidus, caudate nucleus, and thalamus. In addition, scattered abnormal signals have been observed in the cerebral cortex, temporal lobe (in 3.3% of cases), parietal lobe (3.3%), and frontal lobe (3.2%) but not in the occipital lobe.


Morning Report Questions

Q: What is the most common manifestation of symptomatic central nervous system (CNS) disease in patients with chronic lymphocytic leukemia?

A: Chronic lymphocytic leukemia spreads to the brain and meninges fairly frequently; however, CNS involvement is rarely symptomatic. A recent review showed that 0.4% of patients with chronic lymphocytic leukemia had CNS symptoms that were attributable to spread of the disease. Most patients with symptomatic CNS disease have cranial-nerve palsies; 15% have an altered mental state, and 12% have cognitive decline. Progressive multifocal leukoencephalopathy has been reported in patients with chronic lymphocytic leukemia, especially those who have been treated with rituximab.

Q: What is aceruloplasminemia?

A: Aceruloplasminemia is an autosomal recessive disease that is caused by a mutation in the gene that encodes ceruloplasmin. The classic clinical triad of aceruloplasminemia includes neurologic dysfunction, retinal degeneration, and diabetes mellitus due to iron deposition in the brain, retina, and pancreas. The first sign of disease is often diabetes mellitus, followed by microcytic anemia with a low iron level and an elevated ferritin level in serum. Neurologic symptoms include dementia, other neuropsychiatric symptoms, and motor symptoms. Among people who are homozygous for this mutation (85%), the first neurologic symptom is often cognitive impairment (in 42%). Widespread cortical iron deposition sets aceruloplasminemia apart from the other forms of neurodegeneration with brain iron accumulation. Serum levels of iron and total iron-binding capacity are low and the ferritin level is very high. Treatment is challenging, given the rarity of aceruloplasminemia and the dearth of information on how to effectively treat patients who have it.

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