J. H. Walter

Inborn metabolic diseases

Inborn metabolic diseases , Inborn metabolic diseases , کتابخانه دیجیتالی دانشگاه علوم پزشکی و خدمات درمانی شهید بهشتی

Natural history, outcome, and treatment efficacy in children and adults with glutaryl-CoA dehydrogenase deficiency.

Glutaryl-CoA dehydrogenase (GCDH) deficiency is a rare inborn disorder of l-lysine, l-hydroxylysine, and l-tryptophan metabolism complicated by striatal damage during acute encephalopathic crises. Three decades after its description, the natural history and how to treat this disorder are still incompletely understood. To study which variables influenced the outcome, we conducted an international cross-sectional study in 35 metabolic centers. Our main outcome measures were onset and neurologic sequelae of acute encephalopathic crises. A total of 279 patients (160 male, 119 female) were included who were diagnosed clinically after clinical presentation (n = 218) or presymptomatically by neonatal screening (n = 23), high-risk screening (n = 24), or macrocephaly (n = 14). Most symptomatic patients (n = 185) had encephalopathic crises, characteristically resulting in bilateral striatal damage and dystonia, secondary complications, and reduced life expectancy. First crises usually occurred during infancy (95% by age 2 y); the oldest age at which a repeat crisis was reported was 70 mo. In a few patients, neurologic disease developed without a reported crisis. Differences in the diagnostic criteria and therapeutic protocols for patients with GCDH deficiency resulted in a huge variability in the outcome worldwide. Recursive partitioning demonstrated that timely diagnosis in neurologically asymptomatic patients followed by treatment with l-carnitine and a lysine-restricted diet was the best predictor of good outcome, whereas treatment efficacy was low in patients diagnosed after the onset of neurologic disease. Notably, the biochemical phenotype did not predict the clinical phenotype. Our study proves GCDH deficiency to be a treatable disorder and a good candidate for neonatal screening.

Magnetic resonance imaging of the brain in phenylketonuria.

Abnormalities of magnetic resonance imaging (MRI) of the brain occur in some patients with phenylketonuria but the clinical importance of this finding is not clear. In order to determine the frequency and functional significance of changes on MRI we investigated 77 adolescent and adult patients with phenylketonuria. Patients aged 14-49 years and taking a restricted diet of 1 g/kg protein underwent clinical examination, IQ testing, neurophysiological investigation, and MRI of the brain. Patients aged between 10-14 years taking a low phenylalanine diet with amino acid supplements had MRI of the brain only. Biochemical control was assessed from: the lifetime blood phenylalanine determined from the mean blood concentration throughout life; the accumulated time for each patient that phenylalanine was < 120 mumol/L; the accumulated time for each patient that phenylalanine was > 1200 mumol/L); mean blood concentration in the first 4 years of life; and the mean blood phe concentration in the 5 years prior to imaging. MRI changes, compatible with a disturbance in the water content of white matter, were present in all but 1 patient. The severity of abnormality was most strongly associated with the blood phenylalanine concentration at the time of imaging. Clinical and neurophysiological abnormalities were less common and usually mild. 3 patients had prolonged central motor conduction time, 7 had prolonged visual evoked potentials, and 5 had impaired peripheral sensory nerve conduction. There was no significant association between the extent of MRI abnormalities and IQ, and the presence of neurophysiological, or clinical abnormalities. An abnormal brain scan in PKU may reflect present biochemical control rather than indicate significant neurological damage. As yet there is little evidence that in most patients with PKU these MRI changes are of clinical importance.

Magnetic resonance imaging in phenylketonuria: Reversal of cerebral white matter change

OBJECTIVES To investigate the extent to which the abnormalities in cerebral white matter in adolescents and adults with phenylketonuria (PKU) are reversible. METHOD Magnetic resonance imaging (MRI) of the brain was repeated in 41 patients with PKU (age range, 14 to 49 years) after an interval (median, 9 months; range, 3 to 12 months) of dietary intervention. Scans were scored according to the extent of the white matter involvement. After an initial MRI, five patients returned to a strict low-phenylalanine diet with amino acid supplement; 21 patients started a low-protein diet (1 gm/kg) with amino acids supplement; and 15 patients made no dietary alteration. RESULTS Scans improved in all five patients who returned to a strict low-phenylalanine diet, in 5 of the 21 patients on the low-protein diet plus amino acid supplement, and in 4 of the 15 patients who made no dietary change. There was a significant association between change in the MRI findings and in the blood phenylalanine concentration (Pearson correlation: r = 0.55; p < 0.0002) and between change in the MRI and in the phenylalanine level at the time of the second scan (r = 0.58; p < 0.0001). Improvement was seen primarily in those in whom phenylalanine levels were reduced to less than 900 mumol/L. There was no obvious change in MRI score after 3 weeks of strict phenylalanine restriction for the two adults who underwent serial scanning. CONCLUSION The MRI changes in PKU are at least partially reversible by lowering the blood phenylalanine concentration.

Clinical approach to treatable inborn metabolic diseases: An introduction

SummaryIn view of the major improvements in treatment, it has become increasingly important that in order for first-line physicians not to miss a treatable disorder they should be able initiate a simple method of clinical screening, particularly in the emergency room. We present a simplified classification of treatable inborn errors of metabolism in three groups. Group 1 includes inborn errors of intermediary metabolism that give rise to an acute or chronic intoxication. It encompasses aminoacidopathies, organic acidurias, urea cycle disorders, sugar intolerances, metal disorders and porphyrias. Clinical expression can be acute or systemic or can involve a specific organ, and can strike in the neonatal period or later and intermittently from infancy to late adulthood. Most of these disorders are treatable and require the emergency removal of the toxin by special diets, extracorporeal procedures, cleansing drugs or vitamins. Group 2 includes inborn errors of intermediary metabolism that affect the cytoplasmic and mitochondrial energetic processes. Cytoplasmic defects encompass those affecting glycolysis, glycogenosis, gluconeogenesis, hyperinsulinisms, and creatine and pentose phosphate pathways; the latter are untreatable. Mitochondrial defects include respiratory chain disorders, and Krebs cycle and pyruvate oxidation defects, mostly untreatable, and disorders of fatty acid oxidation and ketone bodies that are treatable. Group 3 involves cellular organelles and includes lysosomal, peroxisomal, glycosylation, and cholesterol synthesis defects. Among these, some lysosomal disorders can be efficiently treated by enzyme replacement or substrate reduction therapies. Physicians can be faced with the possibility of a treatable inborn error in an emergency, either in the neonatal period or late in infancy to adulthood, or as chronic and progressive symptoms – general (failure to thrive), neurological, or specific for various organs or systems. These symptoms are summarized in four tables. In addition, an extensive list of medications used in the treatment of inborn errors is presented.

Strategies for the treatment of cystathionine β-synthase deficiency: the experience of the Willink Biochemical Genetics Unit over the past 30 years

Abstract Strategies for the treatment of cystathionine β-synthase (CBS) deficiency include (1) increasing residual enzyme activity by giving pyridoxine in those patients with vitamin responsive variants, (2) reducing the load on the affected pathway with a low methionine diet and supplementing the diet with cysteine; and (3) giving betaine in order to utilise alternative pathways to remove homocyst(e)ine. In our experience of over 30 years in the diagnosis and management of patients with CBS deficiency, a normal outcome can only be achieved in patients diagnosed and treated from infancy. Pyridoxine combined with folic acid prevents further deterioration in pyridoxine responsive patients. Dietary treatment of patients with non-pyridoxine reponsive CBS deficiency becomes more difficult outside childhood but since late complications are not uncommon must be continued for life. Betaine can be effective in this group but compliance is often poor.

An overview of L‐2‐hydroxyglutarate dehydrogenase gene (L2HGDH) variants: a genotype–phenotype study

L‐2‐Hydroxyglutaric aciduria (L2HGA) is a rare, neurometabolic disorder with an autosomal recessive mode of inheritance. Affected individuals only have neurological manifestations, including psychomotor retardation, cerebellar ataxia, and more variably macrocephaly, or epilepsy. The diagnosis of L2HGA can be made based on magnetic resonance imaging (MRI), biochemical analysis, and mutational analysis of L2HGDH. About 200 patients with elevated concentrations of 2‐hydroxyglutarate (2HG) in the urine were referred for chiral determination of 2HG and L2HGDH mutational analysis. All patients with increased L2HG (n=106; 83 families) were included. Clinical information on 61 patients was obtained via questionnaires. In 82 families the mutations were detected by direct sequence analysis and/or multiplex ligation dependent probe amplification (MLPA), including one case where MLPA was essential to detect the second allele. In another case RT‐PCR followed by deep intronic sequencing was needed to detect the mutation. Thirty‐five novel mutations as well as 35 reported mutations and 14 nondisease‐related variants are reviewed and included in a novel Leiden Open source Variation Database (LOVD) for L2HGDH variants (http://www.LOVD.nl/L2HGDH). Every user can access the database and submit variants/patients. Furthermore, we report on the phenotype, including neurological manifestations and urinary levels of L2HG, and we evaluate the phenotype–genotype relationship. Hum Mutat 30:1–11, 2010.

Increased risk of vitamin B12 deficiency in patients with phenylketonuria on an unrestricted or relaxed diet.

OBJECTIVE To investigate whether dietary relaxation or cessation in patients with phenylketonuria (PKU) predisposes to vitamin B12 deficiency. STUDY DESIGN Patients with PKU aged 11 to 38 years underwent a neurologic examination and dietetic assessment and were divided according to their diet into 1 of 3 groups: Strict - those on a strict low phenylalanine (phe) diet with amino acid, mineral, and vitamin supplements; Relaxed - those on a total protein intake of approximately 1 g/kg/d with 50% of this from natural protein and 50% from amino acid, mineral, and vitamin supplements; Unrestricted - those on no formal protein restriction and not taking amino acid supplements. Assays of blood samples were taken for vitamin B12 and folate levels by standard assays. Results were analyzed with Student t test. RESULTS Vitamin B12 levels were significantly lower in the PKU groups on relaxed or unrestricted diets compared with the normal population (P <.0001 [unrestricted] and.0034 [relaxed]). Folate levels were significantly elevated in all PKU groups (<.0001). CONCLUSION Patients with PKU who are no longer under strict dietary control may be at risk from vitamin B12 deficiency. We recommend that all patients should remain under medical and dietetic supervision and in particular have their vitamin B12 status monitored.

l-2-Hydroxyglutaric Aciduria: Pattern of MR Imaging Abnormalities in 56 Patients

PURPOSE To describe the pattern of magnetic resonance (MR) imaging abnormalities in l-2-hydroxyglutaric aciduria (L2HGA) and to evaluate the correlation between imaging abnormalities and disease duration. MATERIALS AND METHODS MR images in 56 patients (30 male, 26 female; mean age +/- standard deviation, 11.9 years +/- 8.5) with genetically confirmed L2HGA were retrospectively reviewed, with institutional review board approval and waiver of informed consent. At least one complete series of transverse T2-weighted images was available for all patients. The images were evaluated by using a previously established scoring list. The correlation between MR imaging abnormalities and disease duration was assessed (Mann-Whitney or Kruskal-Wallis test). RESULTS The cerebral white matter (WM) abnormalities preferentially affected the frontal and subcortical regions. The abnormal subcortical WM often had a mildly swollen appearance (37 patients). Initially, the WM abnormalities were at least partially multifocal (32 patients). In patients with longer disease duration, the WM abnormalities became more confluent and spread centripetally, but the periventricular rim remained relatively spared (41 patients). The mean disease duration in patients with WM atrophy (14.8 years) was significantly longer (P = .001) than that in patients without atrophy (6.7 years). Bilateral involvement of the globus pallidus (55 patients), caudate nucleus (56 patients), and putamen (56 patients) was seen at all stages. The cerebellar WM was never affected. The dentate nucleus was involved bilaterally in 55 of 56 patients. CONCLUSION L2HGA has a distinct highly characteristic pattern of MR imaging abnormalities: a combination of predominantly subcortical cerebral WM abnormalities and abnormalities of the dentate nucleus, globus pallidus, putamen, and caudate nucleus. With increasing disease duration, WM abnormalities and basal ganglia signal intensity abnormalities become more diffuse and cerebral WM atrophy ensues.

Carnitine transporter defect: Diagnosis in asymptomatic adult women following analysis of acylcarnitines in their newborn infants

SummaryCarnitine transporter defect (CTD) is an autosomal recessive disorder characterized by episodes of non-ketotic hypoglycaemia, hyperammonaemia and liver disease, or by the development of cardiomyopathy, both of which occur in infancy and childhood. Blood carnitine concentrations are extremely low. The diagnosis can be confirmed by finding abnormal fat oxidation and carnitine uptake in skin fibroblasts. The condition has not previously been thought to present later in life or to be benign. We report the identification of four women discovered to have CTD as a consequence of finding low carnitine concentrations in the cord blood or newborn samples from their infants. All four mothers had been asymptomatic and none had a cardiomyopathy.