Alessandro P. Burlina

Diagnosis and management of glutaric aciduria type I - revised recommendations

Glutaric aciduria type I (synonym, glutaric acidemia type I) is a rare organic aciduria. Untreated patients characteristically develop dystonia during infancy resulting in a high morbidity and mortality. The neuropathological correlate is striatal injury which results from encephalopathic crises precipitated by infectious diseases, immunizations and surgery during a finite period of brain development, or develops insidiously without clinically apparent crises. Glutaric aciduria type I is caused by inherited deficiency of glutaryl-CoA dehydrogenase which is involved in the catabolic pathways of L-lysine, L-hydroxylysine and L-tryptophan. This defect gives rise to elevated glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine which can be detected by gas chromatography/mass spectrometry (organic acids) or tandem mass spectrometry (acylcarnitines). Glutaric aciduria type I is included in the panel of diseases that are identified by expanded newborn screening in some countries. It has been shown that in the majority of neonatally diagnosed patients striatal injury can be prevented by combined metabolic treatment. Metabolic treatment that includes a low lysine diet, carnitine supplementation and intensified emergency treatment during acute episodes of intercurrent illness should be introduced and monitored by an experienced interdisciplinary team. However, initiation of treatment after the onset of symptoms is generally not effective in preventing permanent damage. Secondary dystonia is often difficult to treat, and the efficacy of available drugs cannot be predicted precisely in individual patients. The major aim of this revision is to re-evaluate the previous diagnostic and therapeutic recommendations for patients with this disease and incorporate new research findings into the guideline.

Guideline for the diagnosis and management of glutaryl-CoA dehydrogenase deficiency (glutaric aciduria type I).

SummaryGlutaryl-CoA dehydrogenase (GCDH) deficiency is an autosomal recessive disease with an estimated overall prevalence of 1 in 100 000 newborns. Biochemically, the disease is characterized by accumulation of glutaric acid, 3-hydroxyglutaric acid, glutaconic acid, and glutarylcarnitine, which can be detected by gas chromatography–mass spectrometry of organic acids or tandem mass spectrometry of acylcarnitines. Clinically, the disease course is usually determined by acute encephalopathic crises precipitated by infectious diseases, immunizations, and surgery during infancy or childhood. The characteristic neurological sequel is acute striatal injury and, subsequently, dystonia. During the last three decades attempts have been made to establish and optimize therapy for GCDH deficiency. Maintenance treatment consisting of a diet combined with oral supplementation of L-carnitine, and an intensified emergency treatment during acute episodes of intercurrent illness have been applied to the majority of patients. This treatment strategy has significantly reduced the frequency of acute encephalopathic crises in early-diagnosed patients. Therefore, GCDH deficiency is now considered to be a treatable condition. However, significant differences exist in the diagnostic procedure and management of affected patients so that there is a wide variation of the outcome, in particular of pre-symptomatically diagnosed patients. At this time of rapid expansion of neonatal screening for GCDH deficiency, the major aim of this guideline is to re-assess the common practice and to formulate recommendations for diagnosis and management of GCDH deficiency based on the best available evidence.

The pulvinar sign: frequency and clinical correlations in Fabry disease

Fabry disease is an X-linked lysosomal deficiency of α-galactosidase A that results in cellular accumulation of galactoconjugates, mainly globotriaosylceramide, particularly in blood vessels. Neuroradiological findings include ischemic stroke, white matter lesions, vascular abnormalities (vertebrobasilar dolichoectasia and vessel tortuosity), and posterior thalamus involvement (the so called pulvinar sign). The purpose of our study was to investigate the presence of the increased pulvinar signal intensity on T1-weighted imaging – pulvinar sign and its relationship with other clinical findings, in a non-selected cohort of Fabry patients.MethodsWe performed a prospective analysis of two populations of patients (36 subjects) with Fabry disease. Patients were followed-up at the Department of Internal Medicine of the Bichat Hospital in Paris (France) and at the Neurological Clinic of the University Hospital of Padova (Italy). Brain MR studies of each patient included T1- and T2- weighted images, FLAIR sequences, and in some cases diffusion weighted images.ResultsA total of 36 patients (16 males, 20 females) were investigated in 14 families. The pulvinar sign was found in 5 male patients, but not in female patients. Seven patients had had at least one stroke (territorial or lacunar). There was no correlation between stroke and the pulvinar sign. All patients with the pulvinar sign had hypertrophic cardiomyopathy. Four patients out of five with the pulvinar sign were on dialysis or had a kidney transplantation.ConclusionsOur findings suggest that the pulvinar sign is a highly specific sign of Fabry disease, found in male patients with cardiac signs and severe kidney involvement.

Measurement of neurotransmitter metabolites in the cerebrospinal fluid of phenylketonuric patients under dietary treatment

Recently many studies have focused on long-term follow-up of phenylketonuria (PKU McKusick 261600) patients, especially regarding discontinuation of diet in adulthood and subsequent possible neurological involvement. Neurological symptoms have been observed in some patients after discontinuation of diet, with improvements after reintroduction of a phenylalanine-restricted diet (Pietz et al 1998). Brain magnetic resonance imaging (MRI) revealed white-matter abnormalities in patients with neurological impairment but also in many patients without neurological symptoms (Burgard et al 1999). Myelin changes observed by brain MRI are similar in early-treated, late-treated and untreated patients, differing only in extension. Neurological investigations of treated adult PKU patients revealed minor neurological signs (tremor, brisk deep tendon reflexes, clumsy motor coordination) indicating the possibility of a specific neurological syndrome in adult PKU patients off diet. Even early-treated phenylketonuric patients show subtle symptoms of CNS damage, in addition to neuropsychological, neurophysiological and brain imaging abnormalities (Pietz et al 1998). Therefore, further investigations are necessary to evaluate the presence of biochemical changes, even in early-treated patients, that could be implicated in the neurological alterations. The aim of our study was to investigate dopamine and serotonin metabolism (homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), respectively) in early-treated PKU patients with white-matter abnormalities on magnetic resonance imaging.

Uptake of acetyl-L-carnitine in the brain.

Analysis in mouse brain slices of the uptake of acetyl-l-[N-methyl-14C]carnitine with time showed it to be concentrative, and kinetic analysis gave aKm of 1.92 mM and aVmax of 1.96 μmol/min per ml, indicating the presence of a low-affinity carrier system. The uptake was energy-requiring and sodium-dependent, being inhibited in the presence of nitrogen (absence of O2), sodium cyanide, low temperature (4°C), and ouabain, and in the absence of Na+. The uptake of acetyl-l-carnitine was not strictly substrate-specific; γ-butyrobetaine,l-carnitine,l-DABA, and GABA were potent inhibitors, hypotaurine andl-glutamate were moderate inhibitors, and glycine and β-alanine were only weakly inhibitory. In vivo, acetyl-l-carnitine transport across the blood-brain barrier had a brain uptake index of 2.4±0.2, which was similar to that of GABA. These results indicate an affinity of acetyl-l-carnitine to the GABA transport system.

Agalsidase beta treatment is associated with improved quality of life in patients with Fabry disease: Findings from the Fabry Registry

Disclosure: The Fabry Registry is sponsored by Genzyme Corporation. U.F.-R., K.S., R.J.H., M.B., A.M., and A.P.B. serve on the Genzyme-sponsored Fabry Registry Boards of Advisors. D.B.-J. and F.O.B. are full-time employees of Genzyme Corporation. T.W. has received unrestricted grants from Genzyme for other research projects.Purpose: To evaluate the effect of agalsidase beta on longitudinal health-related quality of life in patients with Fabry disease.Methods: The SF-36® Health Survey was used to measure health-related quality of life in Fabry Registry patients. Seventy-one men and 59 women who were treated with agalsidase beta (median dose: 1.0 mg/kg/2 weeks) and who had baseline and at least 2 yearly posttreatment health-related quality of life measurements were included in these analyses. A repeated measures model was used to analyze change in score from baseline.Results: Men improved in the physical component summary and in all eight scales of the SF-36 after 1 and 2 years and in the mental component summary after 1 year of agalsidase beta treatment (P < 0.05). Women improved in the mental component summary and in six of the eight scales after 1 and/or 2 years of treatment. Patients whose baseline SF-36 scores were below the median showed the greatest improvements. These responses were comparable with or greater than the published effects of various treatments for multiple sclerosis, rheumatoid arthritis, central neuropathic pain, and Gaucher disease.Conclusion: Long-term treatment with agalsidase beta resulted in substantial improvements in health-related quality of life in both men and women; the effect was more pronounced in men.

Cerebrovascular Involvement in Fabry Disease: Current Status of Knowledge

Fabry disease (FD) is a rare and highly debilitating lysosomal storage disorder that results from a total lack of, or deficiency in, the enzyme α-galactosidase A (α-Gal A) because of mutations in the GLA gene.1 FD is inherited as an X-linked trait; many of the male patients develop a classic severe phenotype with early onset of symptoms, whereas heterozygous females exhibit phenotypes ranging from asymptomatic to major involvement of vital organs.2 Most families inherit private mutations; to date, >600 mutations have been identified and are listed in the online FD database (Fabry-database.org).3 The deficiency in α-Gal A causes the accumulation of globotriaosylceramide (GL-3; also abbreviated Gb3) in various cellular compartments, particularly lysosomes, causing structural damage and cellular dysfunction, as well as triggering secondary, tissue-level responses, such as inflammation, ischemia, hypertrophy, and the development of fibrosis resulting in progressive organ dysfunction.4 Deacylated globotriaosylceramide (lyso- globotriaosylceramide [lyso-GL-3]) has also been shown to be present in increased concentrations in the plasma of patients with FD. It has been suggested that lyso-GL-3 promotes GL-3 accumulation, induces proliferation of smooth muscle cells in vitro, and may have deleterious effects on the intima and media of small arterioles.5 Many cell types are involved in FD pathology, including vascular cells (endothelial and smooth muscle cells), cardiac cells (cardiomyocytes and valvular cells), a variety of renal cells (tubular and glomerular cells, and podocytes), and nerve cells.2 The underlying pathophysiological mechanisms of FD are complex and incompletely understood.6 Early pathophysiological changes are thought to predominantly involve the microvasculature.7 As age increases, arterial remodeling and intima-media thickening in medium-to-large caliber vessels occur.2 The first clinical symptoms of FD occur in childhood (eg, neuropathic pain, hypohidrosis, and gastrointestinal problems)8 and are primarily because of autonomic neuropathy.9 As the disease …

Magnetic resonance imaging changes in Fabry disease

UNLABELLED Recognized magnetic resonance imaging (MRI) abnormalities in the brains of patients with Fabry disease include the consequences of infarction and haemorrhage, non-specific white and grey matter lesions, vascular anomalies, in particular dolicho-ectasia, and a characteristic appearance of the posterior thalamus. A preliminary analysis of MRI findings in patients registered in FOS, the Fabry Outcome Survey, indicates that most patients had abnormal scans (25/47). The commonest abnormality, in males and females, was the presence of cerebral white matter lesions, the number of which increased with patient age. CONCLUSION MRI is a valuable resource for assessing the CNS complications of Fabry disease, and their response to time and treatment.

Mast Cells Contain Large Quantities of Secretagogue‐Sensitive N‐Acetylaspartate

Abstract: Mast cells play a central role in both immediate allergic reactions and inflammation. A functional nerve‐mast cell interaction has been proposed, given the morphological association between mast cells and neuropeptide‐containing peripheral nerves. We now show that purified rat peritoneal mast cells contain large quantities of N‐acetylaspartate (NAA; 747.50 nmol/mg of protein). Mast cell levels of NAA were rapidly reduced, by 64.0 and 86.4%, following treatment with compound 48/80 and mastoparan, respectively. These secretagogues strongly decreased mast cell histamine content over the same time period, suggesting also that NAA is stored in secretory granules. The data are the first to show that NAA is present in an immune effector cell type. Because NAA may be involved in myelin synthesis and glutamyl peptide metabolism, NAA released from mast cells following nervous or other stimuli could participate in neuroimmune interactions. Mast cells in multiple sclerosis plaques may contribute to the reported elevations in brain NAA in this disease.

MR spectroscopy: a powerful tool for investigating brain function and neurological diseases.

Magnetic resonance spectroscopy (MRS) has attracted much attention in recent years and has become an important tool to study in vivo particular biochemical aspects of brain disorders. Since the proton is the most sensitive stable nucleus for MRS, and since almost all metabolites contain hydrogen atoms, investigation by in vivo 1H MRS provides chemical information on tissue metabolites, thus enabling a non-invasive assessment of changes in brain metabolism underlying several brain diseases. In this review a brief description of the basic principles of MRS is given. Moreover, we provide some explanations on the techniques and technical problems related to the use of 1H MRS in vivo including water suppression, localization, editing, quantitation and interpretation of 1H spectra. Finally, we discuss the more recent advancement in three major areas of neurological diseases: brain tumors, multiple sclerosis, and inborn errors of metabolism.