Genomic screening of Fabry disease in young stroke patients: the Taiwan experience and a review of the literature.

BACKGROUND AND PURPOSE: Fabry disease is an X-linked disease, and enzyme-based screening methods are not suitable for female patients. METHODS: In total, 1000 young stroke patients (18-55 years, 661 with ischaemic stroke and 339 with hypertensive intracerebral hemorrhage) were recruited. The Sequenom iPLEX assay was used to detect 26 Fabry related mutation genes. The frequency of Fabry disease in young stroke was reviewed and compared between Asian and non-Asian countries. RESULTS: Two male patients with ischaemic stroke were found to have a genetic mutation of IVS4+919G>A. There was no α-galactosidase A (GLA) gene mutation in female patients. The frequency in Asian stroke patients was 0.62% (male vs. female 0.63% vs. 0.58%) with 0.72% for ischaemic stroke and none for hemorrhagic stroke, compared to 0.88% (0.77% vs. 1.08%) with 0.83% for ischaemic stroke and 1.40% for hemorrhagic stroke reported in western countries. CONCLUSION: IVS4+919G>A is the GLA mutation in Taiwanese young ischaemic stroke patients. Fabry disease is more frequent among non-Asian patients compared to Asian patients.

Malignant brain tumors in patients with glutaric aciduria type I.

Three young patients with glutaric aciduria type I (age 6-23 years) of different ethnic origins, treated for their metabolic disease since early childhood, presented with malignant central nervous system tumors. We recommend continuing clinical follow-up, including monitoring of neurological manifestations and neuroradiological findings, in all patients with glutaric aciduria type I beyond early childhood, especially if adherence to diet is poor or the treatment was not started neonatally.

The Utility of CSF for the Diagnosis of Primary and Secondary Monoamine Neurotransmitter Deficiencies.

Biogenic amine defects constitute a complex and expanding group of neurotransmitter disorders affecting cognitive, motor and autonomic system development, mostly in the pediatric age. In recent years different enzymatic defects have been identified impairing the tetrahydrobiopterin cofactor pathway and/or biogenic amine synthesis, catabolism and transport, with subsequent new disease entities described. The lumbar puncture, with subsequent withdrawal of cerebrospinal fluid (CSF), remains a key step in the diagnostic procedure. Due to the specific nature of CSF, timing of analysis, sample collection and storage, technical issues of the analytic process are still crucial for the diagnosis and follow-up of patients. A progressive approach to the diagnosis of biogenic amine defects is presented, pointing out criticalities and difficulties concerning sample collection and results interpretation, especially due to the increasing reports of secondary neurotransmitter alterations that, at present, constitute a challenge.

Niemann-Pick Type C-2 Disease: Identification by Analysis of Plasma Cholestane-3ß,5α,6ß-Triol and Further Insight into the Clinical Phenotype.

INTRODUCTION: Niemann-Pick type C disease is a rare disorder caused by impaired intracellular lipid transport due to mutations in either the NPC1 or the NPC2 gene. Ninety-five % of NPC patients show mutations in the NPC1 gene. A much smaller number of patients suffer from NPC2 disease and present respiratory failure as one of the most frequent symptoms. Several plasma oxysterols are highly elevated in NPC1 and can be used as a biomarker in the diagnosis of NPC1. METHODS: Plasma cholestane-3ß,5α,6ß-triol was evaluated as biomarker for NPC2 by GC/MS and LC-MS/MS analysis. The diagnosis was confirmed by Sanger sequencing and filipin staining. RESULTS: We report three NPC2 patients with typical respiratory problems and a detailed description of the nature of the lung disease in one of them. All patients had elevated levels of plasma cholestane-3ß,5α,6ß-triol. In two of these patients, the positive oxysterol result led to a rapid diagnosis of NPC2 by genetic analysis. The phenotype of the third patient has been described previously. In this patient a cholestane-3ß,5α,6ß-triol concentration markedly above the reference range was found. CONCLUSIONS: Measurement of plasma cholestane-3ß,5α,6ß-triol enables to discriminate between controls and NPC1 and NPC2 patients, making it a valuable biomarker for the rapid diagnosis not only for NPC1 but also for NPC2 disease.The measurement of oxysterols should be well kept in mind in the differential diagnosis of lysosomal diseases, as the elevation of oxysterols in plasma may speed up the diagnosis of NPC1 and NPC2.

Clinical and molecular spectra in galactosemic patients from neonatal screening in northeastern Italy: structural and functional characterization of new variations in the galactose-1-phosphate uridyltransferase (GALT) gene.

Classical galactosemia is an autosomal recessive inborn error of metabolism due to mutations of the GALT gene leading to toxic accumulation of galactose and derived metabolites. With the benefit of early diagnosis by neonatal screening and early therapy, the acute presentation of classical galactosemia can be prevented. However, despite early diagnosis and treatment, the long term outcome for these patients is still unpredictable because they may go on to develop cognitive disability, speech problems, neurological and/or movement disorders and, in females, ovarian dysfunction. The objectives of the current study were to report our experience with a group of galactosemic patients identified through the neonatal screening programs in northeastern Italy during the last 30years. No neonatal deaths due to galactosemia complications occurred after the introduction of the neonatal screening program. However, despite the early diagnosis and dietary treatment, the patients with classical galactosemia showed one or more long-term complications. A total of 18 different variations in the GALT gene were found in the patient cohort: 12 missense, 2 frameshift, 1 nonsense, 1 deletion, 1 silent variation, and 1 intronic. Six (p.R33P, p.G83V, p.P244S, p.L267R, p.L267V, p.E271D) were new variations. The most common variation was p.Q188R (12 alleles, 31.5%), followed by p.K285N (6 alleles, 15.7%) and p.N314D (6 alleles, 15.7%). The other variations comprised 1 or 2 alleles. In the patients carrying a new mutation, the biochemical analysis of GALT activity in erythrocytes showed an activity of <1%. In silico analysis (SIFT, PolyPhen-2 and the computational analysis on the static protein structure) showed potentially damaging effects of the six new variations on the GALT protein, thus expanding the genetic spectrum of GALT variations in Italy. The study emphasizes the difficulty in establishing a genotype-phenotype correlation in classical galactosemia and underlines the importance of molecular diagnostic testing prior to making any treatment.

Wernicke-like encephalopathy during classic maple syrup urine disease decompensation.

We describe a new neuroradiologic picture observed during metabolic decompensation in two maple syrup urine disease (MSUD) patients that resembles Wernicke encephalopathy (WE). Clinical observations and the review of the literature regarding WE and MSUD pathophysiology prompted us to hypothesize a pathogenic link between these two disorders. Based on these findings, clinicians and neuroradiologists should be aware of MSUD as a possible predisposing factor of WE in children.

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy and right-to-left shunt: lack of evidence for an association in a prevalence study.

BACKGROUND/AIMS: Up to more than 50% of cryptogenetic stroke patients and patients with migraine with aura (MA) are found to have a right-to-left shunt (RLS), which is usually due to a patent foramen ovale. Moreover, both MA and stroke are cardinal features of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Notch3 mutations have been suggested to induce an abnormally high incidence of atrial septal defects in a family harbouring an Arg141Cys pathogenetic mutation. We sought to determine the prevalence of RLS in CADASIL patients with different Notch3 mutations, both with and without migraine as a clinical feature. METHODS: Subjects with a molecular diagnosis of CADASIL were tested for the presence of an RLS by means of contrast-enhanced transcranial Doppler (TCD). The diagnosis of migraine was made according to the 2004 International Headache Classification. RESULTS: Sixteen CADASIL patients were tested; 6 had MA. Four patients displayed an RLS on contrast-enhanced TCD examination. Three of these patients had MA. Both patients with Arg141Cys displayed a large RLS. CONCLUSION: We conclude that RLS is not necessarily linked to CADASIL as a comorbidity factor. Nevertheless, there could be a relation between RLS and specific Notch3 mutations, such as Arg141Cys.

Central nervous system involvement in Anderson-Fabry disease: a clinical and MRI retrospective study.

BACKGROUND: Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by deficiency of alpha-galactosidase A. Central nervous system (CNS) manifestations consist mainly of cerebrovascular events. Brain MRI results are often abnormal. PURPOSE: The aim of the study was to describe CNS involvement in a group of Italian patients with AFD. METHODS: Clinical and brain MRI data of 43 patients with AFD (25 men, 41.94+/-10.83 years old and 18 women, 52.48+/-17.50 years old) were analysed retrospectively. 17 male patients and 7 female patients were under treatment with enzyme replacement therapy (ERT). RESULTS: All 43 patients had signs or symptoms of AFD. 16 men (64%) and 13 women (72%) demonstrated CNS involvement, although with varying severity. Overall, 6 men and 5 women had suffered from cerebrovascular accidents with an age at onset of 33.64+/-13.65 years and 53.68+/-11.71 years, respectively. Brain MR images were abnormal in 16/25 men and in 13/16 women. During CNS monitoring, some patients receiving ERT (5/17 men and 2/6 women) demonstrated neurological deterioration, especially those who had presented with cerebrovascular disease already before starting ERT. CONCLUSIONS: The study demonstrated a high frequency of CNS involvement in homozygous and heterozygous AFD patients, often characterised by early age at onset and abnormal brain MRIs. At present, ERT is widely used; however, potential beneficent effects may be disguised by the progression of irreversible pathology in short-term follow-up. Therefore, primary and secondary prophylaxes of cerebrovascular disease are extremely important.

GJA12 mutations are a rare cause of Pelizaeus-Merzbacher-like disease.

BACKGROUND: Pelizaeus-Merzbacher-like disease (PMLD) is a genetically heterogeneous disorder within the group of hypomyelinating leukoencephalopathies. Mutations of the gap junction protein alpha 12 (GJA12) gene are known to cause one autosomal recessive PMLD form. Few patients with GJA12 mutated PMLD have been reported, and to date, the frequency as well as the genotypic and phenotypic spectrum of GJA12 related PMLD is unclear. METHODS: We report mutation analysis of the GJA12 gene in a clinical and radiologic well-characterized multiethnic cohort of 193 patients with PMLD from 182 families. RESULTS AND CONCLUSIONS: Only 16 patients (8.3%) from 14 families (7.7%) carry GJA12 mutations including five families where we detected only one mutated allele. Among those, we identified 11 novel alterations. Thus, GJA12 mutations are a rather rare cause for Pelizaeus-Merzbacher-like disease. The clinical phenotype of patients with a GJA12 mutation was evaluated and is overall comparable to the clinical features seen in mild forms of proteolipid protein 1 (PLP1) related disorder but with better cognition and earlier signs of axonal degeneration.

Double blind placebo control trial of large neutral amino acids in treatment of PKU: effect on blood phenylalanine.

Large neutral amino acids (LNAA) have been used on a limited number of patients with phenylketonuria (PKU) with the purpose of decreasing the influx of phenylalanine (Phe) to the brain. In an open-label study using LNAA, a surprising decline of blood Phe concentration was found in patients with PKU in metabolic treatment centres in Russia, the Ukraine, and the United States. To validate the data obtained from this trial, a short-term double-blind placebo control study was done using LNAA in patients with PKU, with the participation of three additional metabolic centres--Milan, Padua and Rio de Janeiro. The results of the short trial showed significant lowering of blood Phe concentration by an average of 39% from baseline. The data from the double-blind placebo control are encouraging, establishing proof of principle of the role of orally administered LNAA in lowering blood Phe concentrations in patients with PKU. Long-term studies will be needed to validate the acceptability, efficacy and safety of such treatment.

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

Glutaryl-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.

An unusual clinical and biochemical presentation of ornithine transcarbamylase deficiency in a male patient.

We report a male patient with a history of recurrent idiopathic vomiting, normal plasma ammonia and glutamine concentrations in acute phase, who died at 3 years of age. Ornithine transcarbamylase deficiency was diagnosed after detecting elevated urinary orotate concentrations in a sample collected just before death, and the diagnosis was confirmed by DNA analysis.

Management of movement disorders in glutaryl-CoA dehydrogenase deficiency: anticholinergic drugs and botulinum toxin as additional therapeutic options.

Glutaric aciduria type I is an inborn error of metabolism due to the deficiency of glutaryl-CoA dehydrogenase, an enzyme responsible for the catabolism of lysine, hydroxylysine and tryptophan. The most important neurological symptoms include dyskinesia and dystonia, which can be focal, segmental or generalized. Treatment of the extrapyramidal syndrome is often unsatisfactory. We report our experience in the treatment of generalized and focal dystonia with anticholinergic drugs and botulinum toxin type A, respectively. Both therapies proved beneficial.

Follow-up of a child with hypoacetylaspartia.

We provide a 5-year follow-up of a patient previously reported to have no NAA signal on neurospectroscopy. At 8 years this boy was found to have profound neurological dysfunction: he had truncal ataxia, no expressive speech, behaviour abnormalities, secondary microcephaly and cognitive achievements corresponding to less than 12 months of age. He started to have generalized seizures at 5 years 9 months. Although not directly proven we assume an inborn error of NAA metabolism, possibly a defect of the anabolic enzyme L-aspartate N-acetyltransferase (EC 2.3.1.17).

Diffusion-weighted imaging in the assessment of neurological damage in patients with methylmalonic aciduria.

Diffusion-weighted magnetic resonance imaging (DW-MRI) of the brain was performed in two patients with methylmalonic aciduria who presented signs and symptoms of neurological involvement without metabolic decompensation. Patient 1 presented acute metabolic stroke and patient 2 presented subacute encephalopathy. Brain DW-MRI confirmed very recent damage in patient 1, while the absence of brain lesions on brain DW-MRI indicates the development of more chronic damage in patient 2. Brain DW-MRI represents an additional and complementary tool in the assessment of brain damage in methylmalonic aciduria patients who develop neurological syndrome.

Treatable neurotransmitter deficiency in mild phenylketonuria.

The authors describe a case of neurologic involvement in mild hyperphenylalaninemia (HPA), not due to tetrahydrobiopterin (BH(4)) deficiency, with low levels of monoamine neurotransmitter metabolites in CSF. The combined BH(4)-Phe loading test suggested a BH(4) response, confirmed by clinical improvement after BH(4) therapy. Molecular study revealed a compound heterozygosity of the phenylalanine hydroxylase alleles: a mild HPA-associated mutation (T380M) and the new mutation D151E. This case demonstrates that even mild HPA, generally considered a benign disorder, may present neurologic impairment.

Propionic acidaemia with basal ganglia stroke: treatment of acute extrapyramidal symptoms with L-DOPA.

A 15-year-old male with propionic acidaemia developed neurological complications secondary to basal ganglia involvement. Treatment with L-DOPA had a positive effect on his extrapyramidal syndrome.

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.