Patients and methods

PATIENT 1

Clinical findings for this patient have been previously reported.7 He presented at the age of 40 with cardiac arrhythmia and raised muscle creatine kinase concentrations. There were 3% of acanthocytes in blood smears and the McLeod phenotype was diagnosed because of characteristic weak reactions in the Kell blood group system. A deletion of about 50 000 bp in the region of the McLeod gene was detected. Abnormal movements of his arms and legs were first noted at the age of 51. They seemed unmotivated, occurred abruptly, and were described by the patient as “semivoluntary”. The choreic movements progressed dramatically until the age of 60. Proximal arm and leg movements were unsuppressable. An irregular resting tremor of the right arm, tic-like contractions of the left angle of the mouth, and grunting vocalisations appeared. Neuropsychological investigation showed distinct deficits in performance IQ, verbal long term memory, encoding and recognition, information processing, attention, resistance to cognitive interference, and planning. Cranial CT disclosed a reduced size of the caudate nucleus with increase of bicaudate diameter and bicaudate index. On MRI the globus pallidus showed bilateral signal inhomogeneity in T2 weighted images whereas the putamen, substantia nigra, and red nucleus appeared normal. IBZM SPECT disclosed diffuse reduction of dopamine D2 binding sites in the region of the caudate nucleus and putamen bilaterally. Positron emission tomography imaging was performed at the age of 57.

PATIENT 2

This 27 year old administration clerk presented with slight generalised weakness, pronounced in the lower limbs. On clinical examination areflexia and mild calf hypertrophy were found. No other abnormalities were present; in particular, there were no signs of a movement disorder until the age of 30. Electromyography and neurography disclosed mild sensorimotor axonal neuropathy. Blood smears contained 5% acanthocytes and immunohaematological analysis showed the McLeod phenotype with low antigens of the Kell system. Genetic analysis disclosed a point mutation of 2 bp of Xk resulting in a stop codon and premature termination of protein synthesis. Clinical higher function testing and the results of a psychometric examination using an identical protocol as in patient 1 were normal. There was no abnormality on MRI, in particular no basal ganglia pathology. Density of dopamine D2 receptors in the striatum was normal according to IBZM SPECT.

CONTROL GROUP

The control group comprised one woman and six men aged between 16 and 31 years (mean 27 years). Control subjects showed no psychiatric or neurological abnormalities.

POSITRON EMISSION TOMOGRAPHY

Forty five minutes after intravenous injection of 180–250 MBq 2-[¹⁸F]-2-deoxy-D-glucose (FDG) 20 minute emission scans were acquired from each patient's brain using an ECAT EXACT 47 (921) PET scanner (CTI/Siemens). Transaxial images were reconstructed by filtered back projection using a Hanning filter with cut off 1.0 of the Nyquist frequency. Calculated attenuation correction was applied. Volumes of interest (VOIs) were placed in both cortical and subcortical structures. This was done by automatic coregistration of individual data to fit the stereotactic space of the computerised PET brain atlas from the Computerised Brain Atlas (CBA) software package.12 This performs inelastic intersubject registration by adapting parameters for position, size, and shape. After fitting individual data to the defined atlas space, FDG uptake was normalised to the subject's average brain uptake in the 15% of voxels with the highest uptake. The mean value of these voxels was set to 100. A total number of 49 structures were analysed with corresponding VOIs predefined in the atlas for right and left brain hemispheres. Maximum FDG uptake of each structure was measured in all subjects (“hottest voxel analysis”). Average maximum uptake of each structure was calculated for the control group. The standardised deviate or Z value was computed for each structure—that is, the difference between maximum uptake in each patient and average maximum uptake in the control group in units of the SD in the control group. Z Values equal to or greater than 2.5 was considered to be significantly abnormal.

Results

A consistent pattern of reduced FDG uptake for both patients was only detected in the striatum (table 1). In patient 1, FDG uptake in the striatum was reduced on both sides (figure). This was most pronounced in the caudate, particularly on the left, and it was also significant in the putamen. Patient 2 also showed reduced bilateral FDG uptake in the caudate (fig 1). The corresponding Z values missed the threshold of Z=2.5 for statistical significance, but nevertheless indicated a tendency. In the putamen no significant abnormal reduction of FDG uptake was found on either side.

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Figure 1

FDG-PET images of patient 1, patient 2, and a control subject. These transaxial sections at the level of the striatum lie in parallel with the horizontal plane that is defined by the AC-PC line connecting the anterior and posterior commissure. Marked reduction of glucose uptake occurs in the caudate of both patients, with accentuation in patient 1 (arrows).

In both patients there was a reduction of FDG uptake in the occipital lobe, but not a significant abnormality. In both patients uptake in frontal, thalamic, and cerebellar regions was not different from respective control values.

Discussion

Choreic movement disorders associated with acanthocytosis, grouped under the umbrella term “choreoacanthocytosis”, comprise heterogenous conditions. Neuroimaging findings in choreoacanthocytosis mostly describe slight generalised cortical and pronounced caudate atrophy on CT or MRI in patients with clinically manifest choreic movements.11 13 14 Functional imaging may show reduced striatal glucose utilisation in FDG PET,15-17 frontal hypoperfusion in 99mTc-HMPAO SPECT18 and C¹⁵O₂ PET,19 decreased fluorodopa uptake in the posterior putamen, and a decline of dopamine D2 receptor density in caudate and putamen measured by raclopride PET.19 There are few reports of neuroimaging findings in proved McLeod syndrome in the literature5 11 other than our own patients, describing also mild generalised cortical and caudate atrophy in CT or MRI in symptomatic patients. Given the primary haematological interest in McLeod syndrome, few patients have yet been documented with sufficient neurological detail. Neurological abnormalities, in particular chorea, usually seem to occur later in the course of the disease.2 5 10 11 The median age at presentation of chorea in all reported cases was 47 years (age range 27 to 57).

Preclinical evaluation of cerebral involvement in McLeod syndrome has only been performed in our patient 2 so far. FDG-PET showed a tendency to bilateral caudate hypometabolism whereas metabolism of the putamen, striatal D2 receptors, and gross brain morphology was not affected when he was investigated at the age of 28. In the absence of a plasma input function for compartment model analysis a widely used semiquantitative evaluation of PET data was applied. The PET images were normalised to the subject's brain uptake in the 15% voxels with the highest uptake. This normalisation generally implies that voxels with the highest FDG uptake are not affected by the disease of the patient. According to our findings this assumption is not fulfilled completely: The putamen and caudate belong to the 15% brain voxels with highest uptake. However, as the total volume of putamen and caudate (about 30 ml) is only about 20% of the normalisation volume, the effect of a reduced FDG uptake in these structures on the normalisation might be neglected.

Caudate atrophy in CT or signal abnormalities in T2 weighted MRI as demonstrated in patient 1 and reduced striatal FDG tracer uptake in PET are also features of Huntington's disease. Reduced striatal FDG uptake in the asymptomatic patient 2 may indicate that disturbance of glucose metabolism in the striatum also precedes clinical symptoms in McLeod choreoacanthocytosis as it is known from patients at risk for Huntington's disease. Neuropsychological investigation of patient 1 disclosed marked deficits related to frontal lobe function as described in other forms of choreoacanthocytosis.18 20 By contrast with findings in Huntington's disease17 21 22 frontal lobe glucose metabolism, however, was normal in both patients. We cannot give a conclusive interpretation of the occipital reduction of FDG uptake prominent on the left side which just misses statistical significance. It will be necessary to examine more patients to confirm this finding.

Degeneration of striatal neurons in McLeod syndrome may be related to glutamate toxicity, as Kx, the malfunctioning or absent membrane protein, resembles Na⁺ dependent glutamate transporters.3 The much needed understanding of the mechanisms involved in basal ganglia degeneration and the resulting chorea will profit from functional characterisation of Kx, which has, up to now, only been studied in red blood cells. Given the similarities of Huntington's disease and McLeod choreoacanthocytosis at the clinical and neuropathological level, it could be argued that there are parallels in the final pathophysiological pathway.