[The long-term follow-up of enzyme replacement treatment in late onset Pompe disease]. / A késoi kezdetu Pompe-kórban szenvedok enzimpótló kezelésének hosszú távú követése.

Pompe disease (PD) is a rare lysosomal disease caused by the deficient activity of acid alpha-glucosidase (GAA) enzyme due to mutations in the GAA gene. The enzymatic deficiency leads to the accumulation of glycogen within the lysosomes. Clinically, the disease has been classically classified in infantile and childhood/adult forms. Presently cc. close to 600 mutations distributed throughout the whole gene have been reported. The c.-32-13T>G splice mutation that is very common in patients of Caucasian origin affected by the childhood/adult form of the disease, with an allelic frequency close to 70%. Enzyme replacement treatment (ERT) is available for the patients with Pompe disease (Myozyme). In this paper, we are presenting the long term follow up of 13 adult onset cases treated more than 5 years. The longest follow up was 15 years. To evaluate the treatment efficacy, the 6 minutes walking test (6MWT) and the respiratory functions were monitored annually. The analysis revealed that at the beginning of ERT for 3-4 years the 6MWT had been generally increasing, then it declined, and after 10 years it was lower in 77% of the cases than it had been at the start of the treatment. In 23% of the cases the 6MWT increased during the follow up time. Only one of the patients become wheelchair dependent during the follow-up period. The respiratory function showed similar results especially in supine position. A high degree of variability was observed among patients in their responses to the treatment, which only partially associated with the antibody titer against the therapeutic protein. The efficacy of the ERT was associated with the type of the disease causing mutation, the baseline status of the disease, the lifestyle and the diet of the patient. The long-term follow up of the patients with innovative orphan drugs is necessary to really understand the value of the treatment and the need of the patients.

Do Hungarian multiple sclerosis care units fulfil international criteria?

A PATIENTS: Because of the past 3 decades' extensive research, several disease modifying therapies became available, thus a paradigm change is multiple sclerosis care was necessary. In 2018 a therapeutic guideline was created recommending that treatment of persons with multiple sclerosis should take place in specified care units where the entire spectrum of disease modifying therapies is available, patient monitoring is ensured, and therapy side effects are detected and treated promptly. In 2019 multiple sclerosis care unit criteria were developed, emphasizing personnel and instrumental requirements to provide most professional care. However, no survey was conducted assessing the real-world adaptation of these criteria. OBJECTIVE: To assess whether Hungarian care units fulfil international criteria. METHODS: A self-report questionnaire was assembled based on international guidelines and sent to Hungarian care units focusing on 3 main aspects: personnel and instrumental background, disease-modifying therapy use, number of people living with multiple sclerosis receiving care in care units. Data on number of persons with multiple sclerosis were compared to Hungarian prevalence estimates. Descriptive statistics were used to analyse data. RESULTS: Out of 27 respondent care units, 3 fulfilled minimum requirements and 7 fulfilled minimum and recommended requirements. The least prevalent neighbouring specialties were spasticity and pain specialist, and neuro-ophthalmologist and oto-neurologist. Only 15 centres used all available disease modifying therapies. A total number of 7213 people with multiple sclerosis received care in 27 respondent centres. Compared to prevalence estimates, 2500 persons with multiple sclerosis did not receive multiple sclerosis specific care in Hungary. CONCLUSION: Less than half of Hungarian care units provided sufficient care for people living with multiple sclerosis. Care units employing fewer neighbouring specialties, might have difficulties diagnosing and providing appropriate care for persons with multiple sclerosis, especially for people with progressive disease course, contributing to the reported low number of persons living with multiple sclerosis.

Correlation of GAA Genotype and Acid-α-Glucosidase Enzyme Activity in Hungarian Patients with Pompe Disease.

Pompe disease is caused by the accumulation of glycogen in the lysosomes due to a deficiency of the lysosomal acid-α-glucosidase (GAA) enzyme. Depending on residual enzyme activity, the disease manifests two distinct phenotypes. In this study, we assess an enzymatic and genetic analysis of Hungarian patients with Pompe disease. Twenty-four patients diagnosed with Pompe disease were included. Enzyme activity of acid-α-glucosidase was measured by mass spectrometry. Sanger sequencing and an MLPA of the GAA gene were performed in all patients. Twenty (83.33%) patients were classified as having late-onset Pompe disease and four (16.66%) had infantile-onset Pompe disease. Fifteen different pathogenic GAA variants were detected. The most common finding was the c.-32-13 T > G splice site alteration. Comparing the α-glucosidase enzyme activity of homozygous cases to the compound heterozygous cases of the c.-32-13 T > G disease-causing variant, the mean GAA activity in homozygous cases was significantly higher. The lowest enzyme activity was found in cases where the c.-32-13 T > G variant was not present. The localization of the identified sequence variations in regions encoding the crucial protein domains of GAA correlates with severe effects on enzyme activity. A better understanding of the impact of pathogenic gene variations may help earlier initiation of enzyme replacement therapy (ERT) if subtle symptoms occur. Further information on the effect of GAA gene variation on the efficacy of treatment and the extent of immune response to ERT would be of importance for optimal disease management and designing effective treatment plans.

Severity of carotid atherosclerosis unrelated to Chlamydia pneumoniae infection in acute ischemic stroke patients: a clinicopathological study.

BACKGROUND: Both clinical and pathological alterations of the carotid arteries were correlated with Chlamydia pneumoniae infection in 67 acute ischemic stroke patients with severe neurological symptoms. METHODS: In the clinical study, intima-media thickness (IMT) of the common carotid arteries was determined in vivo by B-mode ultrasound measurement and C. pneumoniae-specific IgG and IgA responses were detected. In the pathological study, the absolute wall thickness of the common, internal and external carotid arteries was measured postmortem in specimens obtained at the autopsy of patients who died due to complications of acute stroke. In the atherosclerotic plaques of the autopsy specimens, C. pneumoniae genomic DNA was detected by polymerase chain reaction amplification. RESULTS: The Spearman's rho correlation coefficient of IMT with the average wall thickness of the common, internal and external carotid arteries was 0.51 (p = 0.002), 0.34 (p = 0.052) and 0.58 (p < 0.001), respectively. Anti-C. pneumoniae IgG and IgA antibodies were detected in 43 (73%) and 29 (49%) patients, but neither antibody marker correlated with IMT (median: 0.91 mm in IgG positives vs. 0.90 mm in IgG negatives, p = 0.86; 0.88 mm in IgA positives vs. 0.90 mm in IgA negatives, p = 0.53). The presence of C. pneumoniae DNA was detected in the carotid plaques of 21 (54%) of the 39 tested patients, independently of either IMT values or the average wall thickness of all carotid arteries. CONCLUSIONS: In acute ischemic stroke patients, C. pneumoniae infection was frequently detected in the arteriosclerotic plaques of the carotid arteries but it did not correlate with the severity of carotid arteriosclerosis.

Effects of vinpocetine on the redistribution of cerebral blood flow and glucose metabolism in chronic ischemic stroke patients: a PET study.

The pharmacological effects of the neuroprotective drug vinpocetine, administered intravenously in a 14-day long treatment regime, on the cerebral blood flow and cerebral glucose metabolism in chronic ischemic stroke patients (n=13) were studied with positron emission tomography in a double-blind design. The regional and global cerebral metabolic rates of glucose (CMRglc) and cerebral blood flow (CBF) as well as vital physiological parameters, clinical performance scales, and transcranial Doppler parameters were measured before and after the treatment period in patient groups treated with daily intravenous infusion with or without vinpocetine. While the global CMRglc values did not change markedly as a result of the infusion treatment with (n=6) or without (n=7) vinpocetine, the global CBF increased and regional CMRglc and CBF values showed marked changes in several brain structures in both cases, with more accentuated changes when the infusion contained vinpocetine. In the latter case the highest rCBF changes were observed in those structures in which the highest regional uptake of labelled vinpocetine was measured in other PET studies (thalamus and caudate nucleus: increases amounting to 36% and 37%, respectively). The findings indicate that a 2-week long intravenous vinpocetine treatment can contribute effectively to the redistribution of rCBF in chronic ischemic stroke patients. The effects are most pronounced in those brain regions with the highest uptake of the drug.

Positron emission tomography of striatal serotonin transporters in Parkinson disease.

BACKGROUND: Little is known about serotonin neurons in Parkinson disease (PD). OBJECTIVE: To study the serotonin system in PD with positron emission tomography, using the serotonin transporter radioligand [11C](+)McN5652. DESIGN AND PATIENTS: We measured the density of the serotonin transporter and the density of [11C]WIN35,428-labeled dopamine transporters in the striatum of 13 adults with PD and 13 age- and sex-matched controls. To assess the effects of possible differences in blood flow or brain atrophy, we also measured regional cerebral blood flow and the size of the regions of interest for the caudate nucleus and putamen. RESULTS: Patients with PD showed reductions in the specific distribution volumes of [11C](+)McN5652 in the caudate (P<.01) and putamen (P<.01), along with the expected reductions in striatal [11C]WIN35,428 binding (P<.01). There were no reductions in regional cerebral blood flow or the sizes of the regions of interest, mitigating against potential confounding effects of blood flow, brain atrophy, or partial volume effects. Reductions in serotonin transporter binding correlated with ratings of disease staging. CONCLUSIONS: These results suggest that the density of serotonin transporters, like that of dopamine transporters, is reduced in the striatum of patients with PD and that these changes are related to disease stage.

Correlations between the atherosclerotic changes of femoral, carotid and coronary arteries: a post mortem study.

OBJECTIVE: To compare the severity of atherosclerosis in the carotid, coronary and femoral arteries in autopsy findings of stroke patients. METHODS AND RESULTS: 40 patients (age: 75.2 (12.3) years, 21 men, 19 women) were investigated, who died of ischemic stroke. Carotid, femoral and coronary arteries were removed and cut into slices. Atherosclerotic changes were scored and compared. The severity of atherosclerotic changes of the common carotid artery did not correlate with any other arteries. Atherosclerotic parameters of the internal carotid artery correlated with those of the deep femoral and common femoral arteries (r=0.457-0.459; P=0.022-0.028 respectively). We found significant correlations between the deep femoral artery and left anterior descendent coronary arteries (r=0.513; P=0.012). External carotid artery correlated with both the left anterior descendent coronary and deep femoral arteries (r=0.458-0.473 and P=0.028-0.017 respectively). CONCLUSIONS: The severity of atherosclerosis in the external carotid arteries and/or the femoral arteries showed a stronger correlation with the atherosclerosis in the coronaries than that of the common carotid arteries.

Role of hyperlipidemia in atherosclerotic plaque formation in the internal carotid artery.

PURPOSE: The role of hyperlipidemia in atherosclerotic changes of the carotid artery is controversial. The aims of this retrospective study were to assess (1) the relationship between total serum cholesterol and triglyceride and the grade of internal carotid artery stenosis and (2) whether total serum cholesterol and triglyceride levels are independent risk factors for internal carotid artery atherosclerosis. METHODS: The files of 1,934 acute ischemic stroke patients were investigated retrospectively. The atherosclerotic involvement of the internal carotid artery was assessed via duplex sonography as percent of stenosis and was graded as follows: group 1, no plaque; group 2, <30% stenosis; group 3, 30-99% stenosis; and group 4, occlusion. RESULTS: The mean age of the patients was 66.9 +/- 12.8 years. Patients without any plaque had significantly lower cholesterol levels compared with those with any degree of internal carotid artery stenosis. Univariate analysis revealed that age (p < 0.001), sex (p < 0.001), hypertension (p < 0.05), cholesterol (p < 0.01), triglycerides(p < 0.05), and smoking (p < 0.001) were significant contributors to atherosclerosis. In the ordinal logistic regression model, age (p < 0.001), sex (p < 0.001), smoking(p < 0.001), and cholesterol (p < 0.05) remained independent predictors of internal carotid artery atherosclerosis. CONCLUSIONS: Total serum cholesterol level seems to be an independent risk factor of atherosclerosis in the carotid artery.

Use of positron emission tomography to study AT1 receptor regulation in vivo.

Increased sodium intake and enhanced sodium sensitivity are implicated in the pathogenesis of hypertension and in the control of a major regulator of BP, the type 1 angiotensin receptor (AT(1) receptor). An in vivo technique to study changes of renal AT(1) receptors by dietary sodium was developed that uses positron emission tomography (PET). PET revealed that renal cortical AT(1) receptor binding was increased in sodium-loaded compared with sodium-deprived dogs, which correlated with ex vivo estimations of AT(1) receptor numbers. Plasma renin activity, angiotensin II, and aldosterone were inversely related to changes in AT(1) receptor binding. These results demonstrate, for the first time in vivo, that the renal AT(1) receptor is inversely related to the activity of the renin angiotensin system, which may provide a compensatory mechanism to prevent inappropriate fluctuations in arterial BP. The ability to measure AT(1) receptor binding in vivo has potential significance for clinical studies of AT(1) receptors, because PET is a noninvasive imaging technique that is readily applicable in humans.