White matter abnormalities in patients with treated hyperphenylalaninaemia: Magnetic resonance relaxometry and proton spectroscopy findings

In order to further clarify the pathogenesis and clinical significance of MRI white matter abnormalities in treated hyperphenylalaninaemia (HPA), ten patients (seven type I HPA, two type II and one type III) underwent T₂ relaxometry (n=8) and/or¹H spectroscopy (n=7) in addition to conventional MR spin-echo imaging at 1.5 T. Two patients with severe MRI abnormalities had repeat examinations during and after a 6-to 8-month period of strict diet control. The clinical evaluation included a detailed neurological examination. In nine out of ten patients visual evoked potentials (VEP) were obtained parallel to the MR examination. MR imaging demonstrated typical symmetrical areas of prolonged T₂ relaxation time predominantly in the posterior periventricular white matter in all but one of type I and II patients. There was no consistent relationship between MRI findings and time of diagnosis/initiation of therapy, IQ or visual evoked potential changes. MRI abnormalities tended to be more severe in patients with poor dietary control and high current plasma phenylalanine levels, whereas a normal MRI was found only in patients with plasma phenylalanine levels continuously below 0.36 mmol/l. There was marked regression of MRI abnormalities already after 3 months of strict diet control. T₂ relaxometry showed a bi-exponential behaviour of T₂ in the affected white matter, with a slow component of about 200–450 ms, indicating an increase in free (extracellular) water.¹H spectroscopy revealed no signs of severe neuronal damage. We conclude, that the observed white matter changes in treated HPA probably represent reversible structural myelin changes rather than permanent demyelination.     

In vivo proton magnetic resonance spectroscopy in phenylketonuria

In vivo nuclear magnetic resonance spectroscopy permits the non-invasive examination of metabolic characteristics of the human brain in a clinical environment. Methods to detect elevated phenylalanine (Phe) in patients with phenylketonuria (PKU) using difference spectroscopy and to estimate absolute brain Phe concentrations, [Phe]_brain, have been developed. In patients with classical PKU, [Phe]_brain typically varied between 0.14 and 0.78 mmol/l depending upon actual blood Phe concentrations, [Phe]_blood, between 0.47 and 2.30 mmol/l. Dynamic investigations can be used to extract information about Phe transport at the human blood-brain barrier, which may be described by a symmetric Michaelis-Menten model. Carrier saturation and competitive inhibition of the influx of other large neutral amino acids can be expected at blood levels usually found in PKU patients. In single cases of untreated, normal intelligent patients, abnormally low [Phe]_brain h 0.15 mmol/l were observed despite high stationary Phe levels ([Phe]_blood=1.15 - 0.10 mmol/l). Conclusion Significant variations in phenylalanine transport parameters in untreated, normal intelligent patients indicated that blood-brain barrier transport or intracerebral phenylalanine consumption are causative factors for the individual vulnerability to phenylketonuria.     

Early detection of abnormalities in partial epilepsy using magnetic resonance

The incidence of brain abnormalities determined by magnetic resonance in 30 consecutive children presenting with intractable complex partial seizures is reported. Images were optimised to visualise the hippocampus and cortical grey matter. Abnormalities of the hippocampus or temporal lobe were seen in all 19 children with clinical features of temporal lobe epilepsy and in six of the seven children with clinically unlocalised epilepsy. By contrast, in the four children with a clinical diagnosis of extratemporal epilepsy, no temporal or hippocampal abnormalities were seen. Generalised cortical abnormalities of uncertain significance were found in a total of 14 children from all groups. The identification of focal brain abnormalities using optimised magnetic resonance imaging enables early non-invasive assessment of children with intractable seizure disorders and the identification of patients for whom epilepsy surgery may be appropriate. It may also lead to a better understanding of the structural basis of intractable epilepsy, and thereby contribute to early treatment decisions.     

Biochemical control,genetic analysis and magnetic resonance imaging in patients with phenylketonuria

Thirteen patients with phenylketonuria, detected by neonatal screening and started on diet within 16 days of age, were investigated between 10 and 18 years of age by magnetic resonance imaging (MRI) of the brain. Biochemical control was assessed from: (1) the life time blood phenylalanine (Phe) control (as determined from (a) the mean yearly exposure to Phe; (b) the accumulated time for each patient that Phe was <120 mol/l; (c)>400 mol/l; (d)>800 mol/l; and (e)>1200 mol/l); and (2) the blood Phe control over the 5 years prior to imaging (assessed for each patient by the mean yearly Phe exposure over that period). In all patients the phenylalanine hydroxylase gene locus was studied using restriction fragment length polymorphism haplotypes and mutant genes were screened for a variety of specific mutations which have been reported in other European populations or in populations of north European descent. Two patients had significant abnormalities of cerebral white matter. Although both showed poor biochemical control this did not reach statistical significance when compared to those with normal imaging. DNA haplotype patterns could be assigned to 11 patients and mutant genes were identified in 12. One patient with abnormal imaging and 4 patients without abnormalities had mutations on both chromosomes identified. In these 5 patients there was significant correlation between their genotype and biochemical control. Mutations resulting in residual in vitro enzyme activity were associated with normal imaging.     

Early detection of abnormalities in partial epilepsy using magnetic resonance.

The incidence of brain abnormalities determined by magnetic resonance in 30 consecutive children presenting with intractable complex partial seizures is reported. Images were optimised to visualise the hippocampus and cortical grey matter. Abnormalities of the hippocampus or temporal lobe were seen in all 19 children with clinical features of temporal lobe epilepsy and in six of the seven children with clinically unlocalised epilepsy. By contrast, in the four children with a clinical diagnosis of extratemporal epilepsy, no temporal or hippocampal abnormalities were seen. Generalised cortical abnormalities of uncertain significance were found in a total of 14 children from all groups. The identification of focal brain abnormalities using optimised magnetic resonance imaging enables early non-invasive assessment of children with intractable seizure disorders and the identification of patients for whom epilepsy surgery may be appropriate. It may also lead to a better understanding of the structural basis of intractable epilepsy, and thereby contribute to early treatment decisions.     

Brain magnetic resonance imaging abnormalities in merosin-positive congenital muscular dystrophy.

We report the brain magnetic resonance imaging (MRI) findings in 23 patients with merosin-positive congenital muscular dystrophy (CMD). Twelve patients had normal scans. Eight other children had essentially normal scans but showed mild non-specific periventricular white matter changes. Three children had structural abnormalities on imaging. The first patient, a 15-month-old boy with hypotonia, muscle weakness and global development delay, had moderate cerebellar atrophy and mild dilatation of the lateral ventricles. The second child, a 3-year-old ambulant girl with subtle learning problems, had mild cerebellar hypoplasia and a large subarachnoid space when scanned at 16 months. The third patient, a 15-year-old ambulant male with normal intelligence and complex partial seizures, had polymicrogyria of both temporoparietal lobes on brain MRI. The clinical features and motor ability of children with merosin-positive CMD are variable, although usually milder than merosin-deficient CMD. Our findings confirm that central nervous system involvement can occur in some merosin-positive cases. We suggest performing brain MRI in children with merosin-positive CMD, as this may help in our understanding of this very heterogeneous disease.     

Adult care in phenylketonuria and hyperphenylalaninaemia: the relevance of neurological abnormalities

Neurological abnormalities in phenylketonuria were described before dietary treatment became possible. These included tremor, clumsiness, epilepsy, spastic paraparesis and occasionally extrapyramidal features. Neurological deterioration after childhood was recognised. Patients with neurological deterioration described recently have been late diagnosed or intellectually impaired or both. No early diagnosed patient who was well treated and of good intellectual outcome has yet shown neurological deterioration after stopping diet but it may happen. Conclusion The fascinating links between pathology, magnetic resonance imaging appearances, magnetic resonance spectroscopy results and clinical features are not yet clearly understood. Patients must understand the possible risks of stopping diet and make their choice. All patients need help, support and follow-up regardless of the choices they make over continuing diet.     

Brain abnormalities in Williams syndrome: A review of structural and functional magnetic resonance imaging findings

Williams syndrome (WS) is rare genetic form of mental retardation caused by a microdeletion on chromosome 7q11.23 that causes cognitive impairment and a variety of physical abnormalities. MRI studies of WS have demonstrated a series of brain abnormalities, including decreased brain size, with a relatively greater decrease in the volume of the cerebral white matter volume as compared to the cerebral gray matter. Moreover there is evidence that the posterior cerebrum is more affected in that persons with WS have a greater ratio of frontal to posterior regional volume. These findings are further supported by automated analyses that have shown reduced gray matter density in the superior parietal lobe areas. Functional MRI studies have demonstrated hypofunction immediately adjacent to, and anterior to, the intraparietal sulcus, a region in which structural brain differences had been identified. These anatomical and functional differences are consistent with the neuropsychological profile of WS – in particular, with evidence of dorsal stream visual processing deficits. To date, however, studies have always been performed in comparison to intellectually average controls. It is not clear, therefore, if findings are specific to the WS population or whether they represent a morphological disturbance characteristic of mental retardation, irrespective of genetic etiology. In this article, we reviewed recent advances underlying the structural and functional neural substrate of WS in Medical Literature Analysis and Retrieval System Online (MEDLINE; 1997–2007).     

White matter abnormalities in Leber's hereditary optic neuropathy due to the 3460 mitochondrial DNA mutation.

Leber's hereditary optic neuropathy is a maternally inherited disorder characterized by acute or subacute loss of central vision leading to severe optic atrophy. It is caused by mutations in the mitochondrial genome. Primary mutations are located at nucleotide positions 3460, 11778 and 14484 in genes encoding subunits of complex I of the respiratory chain. The occurrence of a demyelinating disease such as multiple sclerosis has been reported mainly in females with the 11778 mutation. We report a patient with Leber's hereditary optic neuropathy, kyphosis and white matter lesions in association with the 3460 mtDNA mutation. It is suggested that multiple sclerosis-like illness and deformities of the vertebral column may be associated pathogenically with Leber's hereditary optic neuropathy.     

Psychopathology of patients treated early for phenylketonuria: results of the German collaborative study of phenylketonuria

At the age of 13 years, 60 adolescents, suffering from phenylalaninemia due to hydroxylase deficiency, and their mothers were simultaneously investigated with standardized psychiatric interview in order to determine the adolescents' psychiatric status. Forty symptoms related to emotional disorders, antisocial and conduct disorders, hyperkinetic syndromes, and specific symptoms like psychophysiological pains, enuresis, encopresis, tics, stereotypies, and eating disorders were examined. Severity level was rated as undisturbed, mild, moderate, and severe disturbance. Comparison with representative sample of 191 age mates revealed a double rate of moderate disturbances for the PKU sample. There was no association between severity level and sex as well as mean phenylalanine level during the first 13 years of the patients' lives. No PKU specific diagnosis could be determined. WISC-R-IQ below 90 was associated with threefold risk of more severe disturbance and patients with more than three adverse familial circumstances had a 50% chance of getting a psychiatric diagnosis. It is concluded that the observed disturbances result from stress associated more with the chronic condition than with the increased phenylalanine level.     

Localized proton magnetic resonance spectroscopy of cerebral abnormalities in children with carbohydrate-deficient glycoprotein syndrome

Morphologic and metabolic abnormalities in six children aged 2-9 years with carbohydrate-deficient glycoprotein (CDG) syndrome were assessed by magnetic resonance imaging (MRI) and localized proton magnetic resonance spectroscopy (MRS). In all patients, MRI revealed pronounced cerebellar atrophy. Follow-up examinations in two patients suggested early onset and rapid progression in the first years of life. Further pathologies comprised Dandy-Walker malformation, atrophy of the pons, brain stem and olives, supratentorial frontotemporal cortical atrophy, slightly dilated ventricles and a small corpus callosum. Two patients presented with small cysts in the white matter. The prominent metabolic abnormality detected by proton MRS in five patients was a reduction in N-acetylaspartate in white matter by more than 20%, indicating loss of vital neuroaxonal tissue. Further findings in white matter were glutamine and 7-aminobutyrate increases by a factor of 2. One patient with type III CDG syndrome showed the most severe alterations of metabolite concentrations. CDG syndrome, cerebellar atrophy, magnetic resonance imaging, proton magnetic resonance spectroscopy     

Cerebral magnetic resonance imaging in the neonatal period. Initial results

The place of neonatal cerebral MRI and its specific contribution compared with conventional imaging techniques were evaluated in 36 patients. The difficulties specific to the patient population studied met during this preliminary period are described, with their local solutions. A preliminary evaluation of the diagnostic and prognostic value of MRI according to the disease state and gestational age is presented. The specific contribution of MRI compared with transfontanellar ultrasonography and CT scan is discussed.     

Phase-contrast magnetic resonance angiography measurements of global cerebral blood flow in the neonate

Cerebral blood flow (CBF) alterations are important in pathogenesis of neonatal ischemic/hemorrhagic brain damage. In clinical practice, estimation of neonatal CBF is mostly based on Doppler-measured blood flow velocities in major intracranial arteries. Using phase-contrast magnetic resonance angiography (PC-MRA), global CBF can be estimated, but there is limited neonatal experience. The objective of this study was to gain experience with PC-MRA for the determination of global CBF in neonates. In infants eligible for MRI, PC-MRA global CBF was determined by measuring volume blood flow in both internal carotid arteries (ICAs) and basilar artery (BA). Thirty newborns (GA, 25.7-42.1 wk; weight, 1050-5858 g; postconceptional age, 225-369 d) were investigated. Total PC-MRA CBF ranged from 27 to 186 mL/min. Significant correlations between PC-MRA CBF and postconceptional age and weight were detected. When calculating PC-MRA measured CBF per kilogram body weight, brain perfusion was about stable over the range of postconceptional ages and ranged between 11 and 48 mL/min/kg (median, 25 mL/min/kg). In conclusion, neonatal PC-MRA CBF seems to be a useful technique to estimate noninvasive CBF.     

Defining the nature of the cerebral abnormalities in the premature infant: a qualitative magnetic resonance imaging study

OBJECTIVES: The aim of this study was to define qualitatively the nature and extent of white and gray matter abnormalities in a longitudinal population-based study of infants with very low birth weight. Perinatal factors were then related to the presence and severity of magnetic resonance imaging (MRI) abnormalities. METHODS: From November 1998 to December 2000, 100 consecutive premature infants admitted to the neonatal intensive care unit at Christchurch Women's Hospital were recruited (98% eligible) after informed parental consent to undergo an MRI scan at term equivalent. The scans were analyzed by a single neuroradiologist experienced in pediatric MRI, with a second independent scoring of the MRI using a combination of criteria for white matter (cysts, signal abnormality, loss of volume, ventriculomegaly, corpus callosal thinning, myelination) and gray matter (gray matter signal abnormality, gyration, subarachnoid space). Results were analyzed against individual item scores as well as the presence of moderate-severe white matter score, total gray matter score, and total brain score. RESULTS: The mean gestational age was 27.9+/-2.4 weeks (range, 23-32 weeks), and mean birth weight was 1063+/-292 g. The greatest univariate predictors for moderate-severe white matter abnormality were lower gestational age (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.1-1.7; P<.01), maternal fever (OR, 2.2; 95% CI, 1.1-4.6; P<.04), proven sepsis in the infant at delivery (OR, 1.8; 95% CI, 1.1-3.6; P=0.03), inotropic support (OR, 2.7; 95% CI, 1.5-4.5; P<.001), patent ductus arteriosus (OR, 2.2; 95% CI, 1.2-3.8; P=.01), grade III/IV intraventricular hemorrhage (P=.015), and the occurrence of a pneumothorax (P=.05). There was a significant protective effect of intrauterine growth restriction (OR, 0.51; 95% CI, 0.23-0.99; P=.04). Gray matter abnormality was highly related to the presence and severity of white matter abnormality. A unique pattern of cerebral abnormality consisting of significant diffuse white matter atrophy, ventriculomegaly, immature gyral development, and enlarged subarachnoid space was found in 10 of 11 infants with birth gestation <26 weeks. Given the later outcome of these infants, this pattern may have very high risk for later global neurodevelopmental disability. CONCLUSIONS: This MRI study confirms a high incidence of cerebral white matter abnormality at term in an unselected population of premature infants, which is predominantly a result of noncystic injury in the extremely immature infant. We confirm that the major perinatal risk factors for white matter abnormality are related to perinatal infection, particularly maternal fever and infant sepsis, and hypotension with inotrope use. We have defined a distinct pattern of diffuse white and gray matter abnormality in the extremely immature infant.     

Postmortem magnetic resonance imaging as an adjunct to perinatal autopsy for renal-tract abnormalities

The aim of this study was to compare postmortem magnetic resonance imaging (MRI) of the renal system with autopsy in perinatal and fetal deaths. 37 deaths were studied and renal abnormalities were found in five of these cases. Postmortem MRI provided information of diagnostic utility comparable to that obtained by autopsy.