A preliminary report of the collaborative study of maternal phenylketonuria in the United States and Canada

Summary The Maternal Phenylketonuria Collaborative Study (MPKUCS), encompassing all the United States and provinces of Canada, is a prospective, longitudinal investigation designed to ascertain the efficacy of phenylalanine-restricted therapy in protecting the fetus from high maternal phenylalanine concentrations in women with hyperphenylalaninaemia.Preliminary findings are reported for 147 pregnancies for whom the recommended therapeutic range of blood phenylalanine was 120–360 µmol/L. Sixty-three pregnancies had complete data for analysis. Dietary control was attempted prior to conception in 10 out of 63 women. Significant negative correlations were noted in length, weight and head circumference and blood phenylalanine concentrations during pregnancy. Average reported phenylalanine levels by trimester for 63 hyperphenylalaninaemic pregnancies resulting in live births revealed that no group requiring treatment achieved levels below 360 µmol/L until the third trimester. Median birth measurement percentiles revealed that all groups studied generally had smaller head size compared with birth length and weight. Those started on diet after the first trimester achieved a head circumference below the 10th percentile.The implication of small head circumference for subsequent intellectual development is unclear at this time. Furthermore, the study must evaluate more offspring of women having optimal preconception and pregnancy restriction of phenylalanine.     

Neuropsychological outcome of experimental manipulation of phenylalanine intake in treated phenylketonuria

Blood phenylalanine concentrations were experimentally increased for 3 months by means of a phenylalanine-complemented amino acid supplement in a group of 16 children aged 10-16 years with classical phenylketonuria who had been treated early and who had remained on the restricted diet. Average concentrations achieved during challenge were between 1000 and 1300 µmol/L. Psychological outcome was measured by a neuropsychological battery consisting of tests of verbal and spatial memory, attention and fine motor coordination. A triple-blind, repeated measures, randomized, crossover design was adopted to control for practice and expectancy effects. Subjects were assessed at baseline and at the end of the first and second phenylalanine manipulation periods. Significant interactions (ANOVA) emerged as predicted for phenylalanine concentrations, but similar crossover effects were not found for any of the neuropsychological tests. The results suggested that medium-term hyperphenylalaninaemia in treated PKU is not harmful to psychological functioning in older children and adolescents who have been continuously treated up to and beyond age 10 years, though the susceptibility of executive functions needs to be further researched. The findings add some weight to the idea that by late childhood the vulnerability of the nervous system to the neurotoxic influence of phenylalanine may be much reduced.     

Brain magnetic resonance imaging in children with optimally controlled hyperphenylalaninaemia

Summary This study was undertaken to investigate whether the white-matter changes on MRI and the EEG abnormalities detectable in treated adolescents and adults with hyperphenylalaninaemia (HPA) can be detected in younger children on an optimally controlled diet. The study included 17 children, 7–12 years of age, with HPA. The MRI of five healthy children were included in the blind evaluation of the MR images. According to mutation genotype and dietary tolerance of phenylalanine, 9 patients have severe HPA and 8 have moderate HPA, all requiring dietary treatment. Mild white-matter hyperintensity was detected in 1 of the 5 healthy children and in 10 of 17 patients. EEG was abnormal in 2 patients. This group of children was compared with a previously reported group of adolescents with HPA who had been treated according to the same dietary regimen. MRI changes and EEG abnormalities were significantly less frequent in the group of children than in the group of adolescents. It is suggested that the more frequent MRI changes and EEG abnormalities seen in adolescents are related to the fact that a relaxation of the dietary treatment after the age of 8 years is often accepted.     

Silent cerebral white matter lesions and cognitive function in middle-aged essential hypertensive patients

BACKGROUND: An association between midlife blood pressure levels and late-life cognitive impairment has been reported. Hypertension is one of the most important factors related to the presence of cerebral white matter lesions, which is a prognostic factor for the development of cognitive impairment. Studies have shown a relationship between white matter lesions and cognitive decline in elderly hypertensive patients. The aim of the present study was to evaluate cognitive function in asymptomatic middle-aged hypertensive patients according to the presence or absence of white matter lesions. METHODS: Sixty never-treated essential hypertensive patients (38 men, 22 women), aged 50 to 60 years (mean age, 54.4 +/- 3.8 years), without clinical evidence of target organ damage, were studied. All patients underwent brain magnetic resonance imaging to establish the presence or absence of white matter lesions, using the Rotterdam criteria. Cognitive function was evaluated by a neuropsychologic test battery measuring attention, memory, intelligence, anxiety, and depression. RESULTS: Twenty-three hypertensive patients (38%) were found to have white matter lesions on brain resonance. These patients exhibited a significantly worse performance on digit span forward, a standardized measure of attention than hypertensives without white matter lesions (4.86 +/- 1.14 v 5.51 +/- 0.97; P =.027). Hypertensive patients with white matter lesions showed no differences on both visual and logical memory tests when compared with patients without lesions. CONCLUSIONS: We conclude that the presence of silent cerebral white matter lesions in middle-aged hypertensive patients is associated with a mild decline in basic attention.     

Mirtazapine in progressive multifocal leukoencephalopathy associated with polycythemia vera

Progressive multifocal leukoencephalopathy (PML) is a usually fatal cerebral white matter disease found in patients with human immunodeficiency virus infection and other immunocompromised states. We present the case of a 63-year-old woman with polycythemia vera who developed a progressive focal neurological deficit with white matter abnormalities on magnetic resonance images of the brain that was proved on biopsy to be PML. She was treated with the serotonin reuptake inhibitor mirtazapine and remains neurologically stable, with resolution of cerebral lesions, >2 years after diagnosis. We propose that mirtazapine should be investigated further for use in PML.     

Abstract and poster presentations

Summary Approximately 2% of newborns with hyperphenylalaninaemia are deficient in tetrahydrobiopterin. Selective screening must be performed in all instances where hyperphenylalaninaemia is detected by neonatal screening. In the last 20 years, 308 patients with tetrahydrobiopterin deficiencies have been recognized as a result of screening carried out, worldwide, in Departments of Paediatrics. Of these 308 patients, 181 suffered from 6-pyruvoyltetrahydropterin synthase deficiency, 92 from dihydropteridine reductase deficiency, 13 from pterin-4a-carbinolamine dehydratase deficiency, 12 from GTP cyclohydrolase I deficiency, and 10 are still unclassified. In the BIODEF database we have tabulated the most common clinical and laboratory data related to hyperphenylalaninaemia and tetrahydrobiopterin deficiencies. Additionally, there are data regarding treatment, outcome, and DNA analysis. Preliminary evaluation reveals that the degree of hyperphenylalaninaemia can vary from normal to 2500 µmol/L. Analyses of pterins in urine and measurement of dihydropteridine reductase activity from Guthrie cards are absolutely essential tests for accurate diagnosis. There is a regional (demographic) variation in the frequency of tetrahydrobiopterin deficiencies indicating the highest incidence in Saudi Arabia, probably a consequence of the high consanguinity rate.     

Brain MRI screening showing evidences of early central nervous system involvement in patients with systemic sclerosis

Systemic sclerosis is a multisystem autoimmune collagen disease where structural and functional abnormalities of small blood vessels prevail. Transient ischemic attacks, ischemic stroke, and hemorrhage have been reported as primary consequence of vascular central nervous system affection in systemic sclerosis. Magnetic resonance imaging is considered to be the most sensitive diagnostic technique for detecting symptomatic and asymptomatic lesions in the brain in cases of multifocal diseases. The objective of this study is to detect subclinical as well as clinically manifest cerebral vasculopathy in patients with systemic sclerosis using magnetic resonance imaging. As much as 30 female patients with systemic sclerosis aged 27–61 years old, with disease duration of 1–9 years and with no history of other systemic disease or cerebrovascular accidents, were enrolled. Age-matched female control group of 30 clinically normal subjects, underwent brain magnetic resonance examination. Central nervous system (CNS) involvement in the form of white matter hyperintense foci of variable sizes were found in significantly abundant forms in systemic sclerosis patients on magnetic resonance evaluation than in age-related control group, signifying a form of CNS vasculopathy. Such foci showed significant correlation to clinical features of organic CNS lesion including headaches, fainting attacks and organic depression as well as to the severity of peripheral vascular disease with insignificant correlation with disease duration. In conclusion, subclinical as well as clinically manifest CNS ischemic vasculopathy is not uncommon in systemic sclerosis patients and magnetic resonance imaging is considered a sensitive noninvasive screening tool for early detection of CNS involvement in patients with systemic sclerosis.     

Magnetic resonance imaging in systemic lupus erythematosus patients without a history of neuropsychiatric lupus erythematosus

Objective. To determine the prevalence of magnetic resonance imaging (MRI) lesions in systemic lupus erythematosus (SLE) patients without a history of neuropsychiatric symptoms and to correlate any MRI abnormalities with the patient's other disease manifestations or treatment. Methods. Prospective study of 32 consecutive patients with SLE without a history of neuropsychiatric symptoms, from inpatient and outpatient rheumatology services, who underwent MRI scan during a 3-year period. Results. Five patients had MRI abnormalities consisting of white matter lesions or periventricular hyperintensities; this is similar to the prevalence of these abnormalities in the general population. Conclusion. The prevalence of silent brain MRI abnormalities is not increased in SLE patients who do not have a history of neuropsychiatric manifestations.     

Comparative column chromatographic estimations of phenylalanine in plasma,whole blood,native and paper-dried capillary blood of healthy children and adults,and patients with hyperphenylalaninaemia

The concentration of phenylalanine in plasma, whole venous and capillary blood, and paper-dried blood of 75 probands (25 healthy adults, 27 healthy children, and 23 patients with hyperphenylalaninaemia) were measured by use of a sensitive short column chromatography method. The comparison of the values in each group of probands by several statistic methods showed an excellent correlation of the phenylalanine concentration in paper-dried whole blood to those measured in venous plasma. Evaluation of the analytical method revealed a high sensitivity and accuracy by use of a sample volume of 50 µl. We would therefore suggest that the estimation of phenylalanine for the diagnosis and therapy control in hyperphenylalanine is as accurate in paper-dried blood as in venous plasma and would simplify sampling for the patients as well as enhance the diagnosis and therapy control in hyperphenylalaninaemia.This paper is part of the inaugural dissertation of Johanna Harenz (University of Mainz, 1982).     

Cerebral white matter lesions in primary Sj?gren's syndrome: a controlled study.

OBJECTIVE: To determine the prevalence of neurological and magnetic resonance imaging (MRI) abnormalities in a well defined population of unselected patients with primary Sj?gren's syndrome (SS) and age and sex matched healthy patients. METHODS: Thirty patients with SS and 29 age and sex matched controls were examined by a neurologist and subsequently underwent MRI scanning with a 1.0 Tesla Siemens Impact MR scanner. Scans were graded by a neuroradiologist blinded to the clinical status of each subject. The number and location of white matter lesions > 3 mm in long axis (to exclude non-specific perivascular changes) were recorded for each subject. RESULTS: There was a significant increase in lesions detected by MRI in SS patients versus controls (p = 0.02) including deep white matter lesions (p = 0.03) and subcortical white matter lesions (p = 0.02). The presence of white matter lesions did not correlate with serum IgG or rheumatoid factor levels, or with presence of anticardiolipin antibodies. No subjects had symptoms or signs of serious neurological disease including multiple sclerosis, and corpus callosal lesions commonly seen in multiple sclerosis were notably absent in this study. CONCLUSION: Cerebral white matter lesions detected by MRI are more frequent in patients with primary SS than control subjects, yet do not appear to be associated with significant clinical manifestations. Although the pathological nature of these lesions is yet to be defined, their presence should not be over-interpreted.     

Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency in Dutch neonates

Four neonates with a positive phenylalanine screening test (Phe concentrations between 258 and 1250 mol/L) were investigated further to differentiate between phenylalanine hydroxylase (PAH) deficiency and variant hyperphenylalaninaemia (HPA) forms. In patients 1 and 2 a tetrahydrobiopterin (BH₄) load caused a significant decrease of the plasma Phe levels. A combined phenylalanine/BH₄ loading test was performed in patients 2, 3 and 4. In the latter two patients, plasma Phe concentrations completely normalized within 8 h after the BH₄ load (20 mg/kg). Basal urinary pterins were normal in all four patients. The activity of dihydropteridine reductase (DHPR) was normal in patients 1, 2 and 3 and 50% of control values in patient 4 (not in the range of DHPR-deficient patients). In patient 3 a subsequent phenylalanine loading test with concomitant analysis of plasma biopterins revealed a normal increase of biopterin, excluding a BH₄ biosynthesis defect. Pterins and neurotransmitter metabolites in CSF of patients 1, 3 and 4 were normal. DNA mutations detected in the PAH gene of patients 1–4 were A313T, and L367fsinsC; V190A and R243X; A300S and A403V; R241C and A403V. The results are suggestive for mutant PAH enzymes with decreased affinity for the cofactor BH₄.     

Central nervous system disease in primary Sjogrens syndrome: the role of magnetic resonance imaging

OBJECTIVES: To examine the frequency of central nervous system (CNS) disease in primary Sjogrens syndrome (pSS) and indicate ways in which cerebral magnetic resonance imaging (MRI) may help determine the significance of CNS involvement. METHODS: The current review was based on a Medline (Pubmed) literature search through May 2003, focused on Sjogrens syndrome, other vasculitides, multiple sclerosis (MS), specific MRI techniques, and MRI findings with regard to the above-mentioned diseases. Additional literature was identified in the reference sections of articles listed in Medline. RESULTS: Severe CNS manifestations reminiscent of MS have been described in pSS patients. Moreover, the prevalence of nonfocal neuropsychological abnormalities has been found to be elevated in some pSS patient populations. MRI studies suggest discrete cerebral tissue damage even in neurologically asymptomatic patients. However, small white matter lesions are nonspecific and may be related to age or cerebrovascular risk factors such as hypertension. A large controlled study, complementing established T2-weighted MRI with fluid-attenuated inversion recovery (FLAIR) to achieve high sensitivity in lesion detection, could indicate the disease specificity of white matter lesions in pSS. Newer MR techniques, such as spectroscopy and magnetization transfer imaging, applied, for example, in MS and systemic lupus erythematosus (SLE) to evaluate CNS tissue injury, could help determine the extent and mechanisms of macroscopic and microscopic CNS lesions in pSS. CONCLUSIONS: Future controlled studies will be necessary to more precisely estimate the prevalence of CNS lesions in pSS, specifically of discrete white matter abnormalities. Newer MRI techniques have the potential to provide information on the severity and pathophysiological mechanisms of CNS tissue damage.     

Intracranial findings in progressive facial hemiatrophy.

There have been infrequent reports of cerebral lesions associated with progressive facial hemiatrophy. Six children with progressive facial hemiatrophy were evaluated. Four were referred for evaluation of neurological deficits: 2 with seizures, one with left hemiparesis and one with learning problems. The remaining 2 patients had only facial hemiatrophy. Cranial computed tomography (CT) in 5 patients revealed the bony and soft tissue defects, but cerebral calcifications were seen in only 3 patients. Cranial magnetic resonance imaging (MRI) demonstrated areas of increased signal in the ipsilateral white matter on T2 weighted images in all 5 patients with upper facial atrophy. Ipsilateral cerebral lesions with progressive facial hemiatrophy may be more common than once believed. MRI sometimes reveals abnormalities of the white matter even in patients without neurologic symptoms, and may be more sensitive than CT in the diagnostic evaluation of patients with progressive facial hemiatrophy.     

The association between blood pressure, hypertension, and cerebral white matter lesions: cardiovascular determinants of dementia study

Cerebral white matter lesions are frequently observed on magnetic resonance imaging (MRI) scans in elderly people and are associated with stroke and dementia. Elevated blood pressure is presumed one of the main risk factors, although data are almost exclusively derived from cross-sectional studies. We assessed in 10 European cohorts the relation between concurrently and previously measured blood pressure levels, hypertension, its treatment, and severe cerebral white matter lesions. In total, 1805 nondemented subjects aged 65 to 75 years were sampled from ongoing community-based studies that were initiated 5 to 20 years before the MRI. White matter lesions in the periventricular and subcortical region were rated separately using semiquantitative measures. We performed logistic regression analyses adjusted for potential confounders in 1625 people with complete data. Concurrently and formerly assessed diastolic and systolic blood pressure levels were positively associated with severe white matter lesions. Both increases and decreases in diastolic blood pressure were associated with more severe periventricular white matter lesions. Increase in systolic blood pressure levels was associated with more severe periventricular and subcortical white matter lesions. People with poorly controlled hypertension had a higher risk of severe white matter lesions than those without hypertension, or those with controlled or untreated hypertension. Higher blood pressure was associated with an increased risk of severe white matter lesions. Successful treatment of hypertension may reduce this risk; however, a potential negative effect of decreasing diastolic blood pressure level on the occurrence of severe periventricular white matter lesions should be taken into account.     

Parkinsonism in patients with subcortical arteriosclerotic encephalopathy: A magnetic resonance imaging study

Background: The aim of the present paper was to determine anatomical brain damage causing parkinsonism in patients with subcortical arteriosclerotic encephalopathy.

Methods:

Methods: Using magnetic resonance imaging, the findings in 16 subcortical arterio-sclerotic encephalopathy patients with parkinsonism were compared with those of 16 subcortical arteriosclerotic encephalopathy patients without parkinsonism. In addition to conventional magnetic resonance imaging, the magnetization transfer technique was also employed, and the magnetization transfer ratios of white matter hyperintensity lesions in the frontal lobe were measured to detect structural changes.

Results:

Results: The extent of infarcted lesions in the lentiform nucleus of patients with parkinsonism was significantly greater than in patients without parkinsonism. Although white matter hyperintensity areas did not differ significantly between the two patient groups, magnetization transfer ratios in the white matter hyperintensity lesions of patients with parkinsonism were significantly lower than those of patients without parkinsonism. The lower magnetization transfer ratios suggest that tissue damage of white matter lesions in patients with parkinsonism is more severe than in patients without it.

Conclusion:

Conclusion: Both severe tissue damage in the frontal white matter and extensive infarcted lesions in the lentiform nucleus might be responsible for the development of parkinsonism in patients with subcortical arteriosclerotic encephalopathy.     

The pathogenesis of the white matter abnormalities in phenylketonuria. A multimodal 3.0 tesla MRI and magnetic resonance spectroscopy (1H MRS) study

Objective: To gain insights into the nature and pathogenesis of white matter (WM) abnormalities in PKU. Methods: Thirty-two patients with phenylalanine hydroxylase deficiency (21 with early and 11 with late diagnosis and treatment) and 30 healthy controls underwent an integrated clinical, neuroimaging (3.0 T MRI, diffusion-weighted imaging (DWI), diffusion tensor imaging (DTI)) and neurochemical (¹H MRS) investigation. Results: All patients had white matter abnormalities on T2-weighted (T2W) and fluid-attenuated inversion recovery (FLAIR) scans; parietal white was consistently affected, followed by occipital, frontal and temporal white matter. T1-weighted hypointense alterations were also found in 8 of 32 patients. DWI hyperintense areas overlapped with those detected on T2W/FLAIR. The apparent diffusion coefficient (ADC) was reduced and correlated inversely with severity of white matter involvement. Fractional anisotropy index, eigenvalues λ_min, λ_middle, λ_max obtained from DTI data, and the principal brain metabolites assessed by ¹H MRS (except brain phenylalanine (Phe)) were normal. Brain Phe peak was detected in all but two subjects. Brain and blood Phe were strictly associated. Blood Phe at the diagnosis, patient’s age, and concurrent brain Phe independently influence white matter alteration (as expressed by conventional MRI or ADC values). Conclusions: (a) MRI abnormalities in phenylketonuria are the result of a distinctive alteration of white matter suggesting the intracellular accumulation of a hydrophilic metabolite, which leaves unaffected white matter architecture and structure. (b) White matter abnormalities do not seem to reflect the mechanisms involved in the derangement of mental development in PKU. (c) Our data do not support the usefulness of conventional brain MRI examination in the clinical monitoring of phenylketonuria patients. Communicating editor: Georg Hoffmann Competing interests: None declared     

Biochemical,clinical and neuroradiological (MRI) correlations in late-detected PKU patients

Summary Brain magnetic resonance imaging (MRI) was performed in 17 late-detected PKU patients (aged 2.8–25 years). Twelve subjects had been treated late (0.7–4.5 years), and 5 not at all. Four were still on diet when the study was performed. Mental development was normal in 4 subjects, mildly retarded in 6, and moderately or severely retarded in 7. None had exhibited mental or neurological deterioration. On MRI examination a symmetrical increase of T2-weighted signal in the periventricular white matter was found in all patients, although to different degrees. Concomitant signal decrease on the T1-weighted sequences was detected in 9 patients. Ten subjects showed focal white-matter abnormalities. A variable degree of cortical and subcortical atrophy was found in 12 subjects, and asymmetry of lateral ventricles in 4. White-matter involvement correlated with phenylalanine concentrations during the year preceding (r _s=0.5706;p<0.02) and at the time of (r _s=0.6182,p<0.01) the investigation. Cortical and subcortical atrophy correlated with the patient's age (r _s=0.5889,p<0.02, andr _s=0.5929p<0.02, respectively). We conclude that late-detected PKU patients showed the same MRI abnormalities reported in early-treated subjects and in subjects who underwent neurological deterioration; white-matter abnormalities possibly result from the recent exposure to high phenylalanine concentrations; in late-detected PKU subjects cerebral atrophy could be the late result of chronic exposure to high phenylalanine concentrations.     

Commentary: What degree of hyperphenylalaninaemia requires treatment?

Despite some 50 years’ experience in the treatment of phenylketonuria and numerous scientific publications on the subject there is no clear consensus as to what degree of hyperphenylalaninaemia will result in intellectual impairment. Studies of three main types, on untreated cases of moderate hyperphenylalaninaemia, on treated cases of phenylketonuria, and on the effects of current blood phenylalanine concentration on executive function, have lead to different conclusions. Overall, there appears to be a fairly strong case for limiting dietary treatment to individuals whose blood phenylalanine levels would otherwise exceed 600 μmol/L. This is now policy in some European countries but a formal large-scale study of long-term outcomes to validate the approach is urgently required.     

Maternal phenylketonuria pregnancy outcome: a preliminary report of facial dysmorphology and major malformations

Conclusion It is clear from the preliminary data that major malformations, i.e. intrauterine growth retardation, microcephaly and cardiac defects, tend to decrease in frequency as the blood phenylalanine level drops, but not enough to suggest that phenylalanine levels of 600µmol/L are safe levels. The facial dysmorphic features may be used as a sensitive indicator that blood phenylalanine levels should be below 360µmol/L. It is hoped that at the end of the collaborative study more data will be available to suggest blood phenylalanine levels which will prevent the deleterious effects of maternal PKU syndrome.     

Cochlear implantation in children with white matter lesions: Prediction of hearing outcomes by multiple regression analysis

Brain magnetic resonance imaging (MRI) white matter lesions have been reported in some preoperative cochlear implant children. However, the role of white matter lesions in predicting the hearing outcome is yet unclear. The present study investigated the outcomes of cochlear implantation (CI) in 40 children with white matter lesions.The data from children with white matter lesions were reviewed in this retrospective study. Based on brain MRI, the patients were divided into 3 groups: mild, moderate, and severe. The children were treated with unilateral CI and monitored for a follow-up period of at least 3 years. The main outcome measures were category of auditory performance (CAP) and speech intelligibility rating (SIR). MRI white matter lesions, age at implant, gender, physical impairment, and cognitive impairment were obtained from a research database to assess the correlation with long-term CAP and SIR outcome by multiple regression analysis.The data of children with white matter lesions were reviewed (18 females and 23 males). The mean age at implantation was 31.6 months. Strikingly, all children obtained better CAP and SIR scores. The age at implantation, brain white matters lesions on MRI, and cognitive and physical disabilities were associated with CAP and SIR scores. Multiple regression established a weak correlation between the degree of white matter lesions on brain MRI and long-term CAP and SIR, while cognitive impairment strongly accounted for long-term CAP and SIR outcome.The majority of the children with brain white matter lesions obtained a satisfactory postoperative effect. The cognitive impairment before CI is a major factor, and such factor should be considered.