Neuroradiologic Phenotyping of Galactosemia: From the Neonatal Form to the Chronic Stage.

Galactosemia is a rare genetic condition caused by mutation of enzymes involved in galactose and glucose metabolism. The varying clinical spectrum reflects the genetic complexity of this entity manifesting as acute neonatal toxicity syndrome, requiring prompt diagnosis and treatment, to more insidious clinical scenarios as observed in the subacute and chronic presentations. The current literature predominantly focuses on the long-standing sequelae of this disease. The purpose of this multicenter clinical report comprising 17 patients with galactosemia is to highlight the MR imaging patterns encompassing the whole spectrum of galactosemia, emphasizing the 3 main clinical subtypes: 1) acute neonatal presentation, with predominant white matter edema; 2) subacute clinical onset with a new finding called the "double cap sign"; and 3) a chronic phase of the disease with heterogeneous imaging findings. The knowledge of these different patterns together with MR spectroscopy and the clinical presentation may help in prioritizing galactosemia over other neonatal metabolic diseases and prevent possible complications.

Gray and white matter are both affected in classical galactosemia: An explorative study on the association between neuroimaging and clinical outcome.

BACKGROUND: Classical Galactosemia (CG) is an inherited disorder of galactose metabolism caused by a deficiency of the galactose-1-phosphate uridylyltransferase (GALT) enzyme resulting in neurocognitive complications. As in many Inborn Errors of Metabolism, the metabolic pathway of CG is well-defined, but the pathophysiology and high variability in clinical outcome are poorly understood. The aim of this study was to investigate structural changes of the brain of CG patients on MRI and their association with clinical outcome. METHODS: In this prospective cohort study an MRI protocol was developed to evaluate gray matter (GM) and white matter (WM) volume of the cerebrum and cerebellum, WM hyperintensity volume, WM microstructure and myelin content with the use of conventional MRI techniques, diffusion tensor imaging (DTI) and quantitative T1 mapping. The association between several neuroimaging parameters and both neurological and intellectual outcome was investigated. RESULTS: Twenty-one patients with CG (median age 22 years, range 8-47) and 24 controls (median age 30, range 16-52) were included. Compared to controls, the WM of CG patients was lower in volume and the microstructure of WM was impaired both in the whole brain and corticospinal tract (CST) and the lower R1 values of WM, GM and the CST were indicative of less myelin. The volume of WM lesions were comparable between patients and controls. The 9/16 patients with a poor neurological outcome (defined as the presence of a tremor and/or dystonia), demonstrated a lower WM volume, an impaired WM microstructure and lower R1 values of the WM indicative of less myelin content compared to 7/16 patients without movement disorders. In 15/21 patients with a poor intellectual outcome (defined as an IQ < 85) both GM and WM were affected with a lower cerebral and cerebellar WM and GM volume compared to 6/21 patients with an IQ ≥ 85. Both the severity of the tremor (as indicated by the Tremor Rating Scale) and IQ (as continuous measure) were associated with several neuroimaging parameters such as GM volume, WM volume, CSF volume, WM microstructure parameters and R1 values of GM and WM. CONCLUSION: In this explorative study performed in patients with Classical Galactosemia, not only WM but also GM pathology was found, with more severe brain abnormalities on MRI in patients with a poor neurological and intellectual outcome. The finding that structural changes of the brain were associated with the severity of long-term complications indicates that quantitative MRI techniques could be of use to explain neurological and cognitive dysfunction as part of the disease spectrum. Based on the clinical outcome of patients, the absence of widespread WM lesions and the finding that both GM and WM are affected, CG could be primarily a GM disease with secondary damage to the WM as a result of neuronal degeneration. To investigate this further the course of GM and WM should be evaluated in longitudinal research, which could also clarify if CG is a neurodegenerative disease.

Early neurological complications in children with classical galactosemia and p.gln188arg mutation.

BACKGROUND: Despite implementation of a controlled diet, children with classical galactosemia (CG) may develop a variety of developmental and cognitive problems. In this study, we examined the early developmental status of, as well as the neurological and neuroradiological findings for, children with CG. METHODS: We retrospectively evaluated 46 galactosemia patients who were followed between 2003 and 2017. We included those who exhibited CG and p.gln188arg homozygous mutation without concomitant disease and who had undergone detailed neurological examination, brain magnetic resonance imaging (MRI), and Denver II developmental testing. RESULTS: The mean ages at the time of the most recent neurological examination and Denver II testing were 48.5 ±â€¯28.5 months and 34.4 ±â€¯18.2 months, respectively. Developmental delay was defined as developmental age ≥ 20% lower than chronological age. The results were normal in 25 patients and delayed ≥ 20% in least in one domain, primarily in language development, in 21 patients. Brain MRI was abnormal in 22 patients. CONCLUSIONS: This analysis of the youngest children with the same genetic mutation reported thus far showed that, despite treatment, developmental delays and abnormalities on brain MRI may begin at an early age.

Exploration of the Brain in Rest: Resting-State Functional MRI Abnormalities in Patients with Classic Galactosemia.

Patients with classic galactosemia, a genetic metabolic disorder, encounter cognitive impairments, including motor (speech), language, and memory deficits. We used functional magnetic resonance imaging to evaluate spontaneous functional connectivity during rest to investigate potential abnormalities in neural networks. We characterized networks using seed-based correlation analysis in 13 adolescent patients and 13 matched controls. Results point towards alterations in several networks, including well-known resting-state networks (e.g. default mode, salience, visual network). Particularly, patients showed alterations in networks encompassing medial prefrontal cortex, parietal lobule and (pre)cuneus, involved in spatial orientation and attention. Furthermore, altered connectivity of networks including the insula and superior frontal gyrus -important for sensory-motor integration and motor (speech) planning- was demonstrated. Lastly, abnormalities were found in networks involving occipital regions, linked to visuospatial capacities and working memory. Importantly, across several seeds, altered functional connectivity to the superior frontal cortex, anterior insula, parietal lobule and the (pre)cuneus was observed in patients, suggesting special importance of these brain regions. Moreover, these alterations correlated with neurocognitive test results, supporting a relation with the clinical phenotype. Our findings contribute to improved characterization of brain impairments in classic galactosemia and provide directions for further investigations.

Grey matter density decreases as well as increases in patients with classic galactosemia: A voxel-based morphometry study.

Brain impairments have been observed in patients with classic galactosemia, an inherited metabolic disorder resulting in a particular neuro-cognitive profile. Neuroimaging studies showed abnormalities such as diffuse white mater (WM) abnormalities and grey matter (GM) atrophy. Our current study analysed grey matter density using voxel-based morphometry (VBM) and compared the brains of eight adolescent patients with classic galactosemia with eight healthy gender- and aged-matched controls. GM density differences were found in several regions. Decreased GM density was found in the patients in the bilateral putamen and bilateral occipital cortex. Increased GM density in the patients, on the other hand, was found in the bilateral inferior frontal and medial prefrontal cortex. The anatomical profile of the abnormalities is in line with the neuro-cognitive profile of patients with classic galactosemia, including motor dysfunction, speech and language difficulties and higher order cognitive problems. Less favourable GM densities in patients (either increased or decreased compared to controls) correlated with younger age, a worse visual working memory performance, and an older age at initiation of the galactose-restricted diet. To conclude, this explorative study is the first to analyse the GM using VBM in this population, and demonstrates a mixed profile of both increased and decreased GM density in these patients.

FDG-PET findings in patients with galactosaemia.

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 eight similarly aged controls received brain [(18)F]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.

Usefulness of per-rectal portal scintigraphy with Tc-99m pertechnetate for galactosemia in infants.

Galactosemia discovered by newborn screening is rarely caused by enzyme deficiency. It has recently been reported that among patients without enzyme deficiency portosystemic shunting may be a cause of galactosemia in some patients. We did per-rectal portal scintigraphy in patients with such galactosemia detected during screening of newborns to examine the usefulness of this method for the diagnosis of portosystemic shunts via the inferior mesenteric vein. The subjects were eight neonates with galactosemia without enzyme deficiency detected during screening. A solution containing technetium-99m pertechnetate was instilled into the rectum, and serial scintigrams were taken while radioactivity curves for the liver and heart were recorded sequentially. The per-rectal portal shunt index was determined by calculating the ratio for counts of the liver to counts for the heart integrated for 24 seconds immediately after the appearance of the liver time-activity curve. A portosystemic shunt was detected in both of the patients with a shunt index of 30% or more, but not in the six patients with a shunt index less than 30%. The blood galactose levels of these six patients later entered the reference range. This method is noninvasive and there is little exposure to the radionuclide. It seemed to be useful for the diagnosis of portosystemic shunt in newborns with galactosemia without enzyme deficiency.

Effect of hypogonadism and deficient calcium intake on bone density in patients with galactosemia.

Forty children and adults with classic galactosemia had vertebral bone density determined by standard quantitative computed tomography at 3.4 to 44.2 years of age. Compared with age- and sex-matched control subjects, patients with galactosemia had diminished bone density (p = < 0.001). Prepubertal patients of both sexes had bone density determinations below those of the control group (p = 0.008); similar findings were seen in postpubertal patients as well (women, p = 0.001; men, p = 0.008). Women receiving replacement estrogen-progestin therapy for premature ovarian failure had abnormal bone density (136.3 +/- 17.3 mg/cm3 vs 166.0 +/- 17.5 mg/cm3 for control subjects; p = 0.002); patients with evidence of ovarian insufficiency not receiving replacement sex steroids had even lower bone density (92.4 +/- 14.3 mg/cm3 vs 160.2 +/- 20.2 mg/cm3 for control subjects; p < 0.001). Calcium intake for the entire galactosemia group was 540 +/- 344 mg/day. Calcium intake correlated positively with bone density in women given exogenous estrogen (r = 0.87; p = 0.002) and in men (r = 0.74; p = 0.009). Thus the diminished mineralization of bones appears to be another abnormality associated with galactosemia. The results of our study suggest that this is likely secondary to abnormal levels of sex steroids in female patients, low calcium intake, and perhaps an intrinsic defect in the normal galactosylation of the collagen matrix of bone caused by the enzyme defect. Strategies to improve bone formation should be considered to diminish morbidity in patients with this inborn error of metabolism.