J Inherit Metab Dis (2008) 31:533–539 DOI 10.1007/s10545-008-0806-0
ORIGINAL ARTICLE
FDG-PET findings in patients with galactosaemia J. G. Dubroff & C. Ficicioglu & S. Segal & N. A. Wintering & A. Alavi & A. B. Newberg
Received: 7 November 2007 / Submitted in revised form: 12 February 2008 / Accepted: 14 February 2008 / Published online: 20 May 2008 # SSIEM and Springer 2008
Summary Despite treatment with a galactose-restricted diet, many galactosaemia patients develop lifelong cognitive impairment, speech abnormalities and a gamut of neurological problems including cognitive impairment and tremors. No study has explored changes in cerebral glucose metabolism in patients with galactosaemia. Five patients with galactosaemia had ages ranging from 20 to 40 years (mean age 28 years) and
S. Segal deceased. Communicating editor: Michael Gibson Competing interests: None declared J. G. Dubroff : N. A. Wintering : A. Alavi : A. B. Newberg Division of Nuclear Medicine, Department of Radiology, The University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, USA C. Ficicioglu Section of Metabolism, The Children_s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA S. Segal Metabolic Research Laboratory, The Children_s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, USA A. B. Newberg (*) Department of Radiology, Nuclear Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Room 110 Donner Building, Philadelphia, PA 19104, USA e-mail:
[email protected]
eight similarly aged controls received brain [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET) scans. PET scans were analysed using a previously validated template methodology of regions of interest (ROIs). Count ratios for each anatomical ROI were compared between the galactosaemic patients and the healthy controls. Statistical parametric mapping (SPM) software was also used to further analyse the data. ROI analysis showed that galactosaemic patients had significant bilateral decreases in cerebral glucose metabolism in the superior temporal gyrus, medial occipital lobe, parietal lobe, cerebellum, calcarine cortex, superior frontal cortex, and superior parietal cortex when compared with controls. Significant increases were seen in the cingulate gyrus and temporal poles, bilaterally. SPM analysis revealed foci of decreased glucose metabolism in the caudate, cerebellum, precentral gyrus and cerebellar tonsils of galactosaemic patients. SPM also showed increased glucose metabolism in the subcallosal gyrus and claustrum. The results show significant abnormalities in cerebral function in patients with galactosaemia, particularly with widespread decreases in cortical metabolism. These abnormalities appear to be in brain regions that may be associated with the neuropsychological deficits in these patients. PET brain scans may be of value in galactosaemia patients to evaluate for dysfunction. Abbreviations FDG [18F]fluorodeoxyglucose ROI regions of interest SPM statistical parametric mapping PET positron emission tomography gal-1-P galactose 1-phosphate
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J Inherit Metab Dis (2008) 31:533–539
Introduction Galactosaemia is an inborn error of metabolism due to an inability to dispose of galactose in milk (Ridel et al 2005; Segal 1998). Galactosaemic patients lack nearly all expression of galactose-1-phosphate uridyltransferase which, in turn, causes an intracellular accumulation of galactose 1-phosphate (Ridel et al 2005; Wang et al 2001). This enzymatic deficiency is known to have an autosomal recessive pattern of inheritance (Ridel et al 2005; Segal 1998; Waggoner et al 1990). If not identified and treated as asymptomatic neonates, galactosaemic patients can develop vomiting, diarrhoea, cataracts, hepatomegaly and E. coli sepsis (Fridovich-Keil 2006). Even if those patients are treated with a galactoserestricted diet, many develop lifelong cognitive impairment, speech abnormalities and a gamut of neurological problems (Kaufman et al 1995b; Nelson et al 1991; Ridel et al 2005; Webb et al 2003). A single study was reported in the literature using structural MRI in 67 transferase-deficient galactosaemic patients (Nelson et al 1992). The findings from this study revealed that approximately one-third of the patients had mild cerebral atrophy, eight had cerebellar atrophy, and 11 had multiple small hyperintense lesions in the cerebral white matter on T2-weighted
images. The authors postulated that the abnormal signal intensity was due to altered myelin formation secondary to the inability to make sufficient and/or normal galactocerebroside. However, there have been no functional brain imaging studies of patients with galactosaemia. The potential role of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) in the evaluation of galactosaemia has not previously been reported. FDG-PET is generally capable of obtaining high-resolution functional maps of cerebral glucose metabolism with a test–retest variability less than approximately 8%. The purpose of this study was to determine whether there are alterations in cerebral glucose metabolism in patients with galactosaemia, especially those with neurological symptoms.
Subjects and methods Subjects Five patients with galactosaemia and 8 controls received brain FDG-PET . The patients had ages ranging from 20 to 40 years (mean age 28 years) and the controls had ages ranging from 22 to 52 years (mean
Table 1 Clinical findings for patients diagnosed with galactosaemia GALTa
RBC Gal-1-Pb (mg/dl) at the time of study
Liver function
Cataracts
IQVerbal / Performance / Average
Neurological findings
Q188R/ K258N
0.41
3.43
Normal
None
58 / 57 / 53
2 weeks
Q188R/ Q188R
0
3.13
Normal
None
61 / 55 / 54
F
2 weeks
Q188R/ Q188R
0
1.64
Normal
None
46 / 64 / 63
32
F
10 days
0
3.45
Normal
None
X / X / 84
40
M
3 weeks
Q188R/ Q188R Q188R/ Q188R
Fine tremors, cerebellar ataxia, speech defects Fine tremors, tremulous writing, gait, dystonic speech, decreased right arm swing Tremors, high-pitched dystonic speech, dystonic posturing, dysmetric finger-to-nose test Fine tremors
0
2.95
Normal
None
93 / 78 / 86
Subject
Age (y)
Sex
Age at diagnosis
Genotype
1
20
M
2 week
2
21
M
3
27
4 5
Fine tremors, dystonic movements by history
Characteristics of the five galactosaemia patients imaged in this study are shown. An FX_ represents data not available. GALT enzyme activity in mmol UDP-galactose per hour per gram of haemoglobin. The normal range is 15.9–26.4. b Normal value
