An Asn > Lys substitution in saposin B involving a conserved amino acidic residue and leading to the loss of the single N-glycosylation site in a patient with metachromatic leukodystrophy and normal arylsulphatase A activity. (1/118)

Sphingolipid activator proteins are small glycoproteins required for the degradation of sphingolipids by specific lysosomal hydrolases. Four of them, called saposins, are encoded by the prosaposin gene, the product of which is proteolytically cleaved into the four mature saposin proteins (saposins A, B, C, D). One of these, saposin B, is necessary in the hydrolysis of sulphatide by arylsulphatase A where it presents the solubilised substrate to the enzyme. As an alternative to arylsulphatase A deficiency, deficiency of saposin B causes metachromatic leukodystrophy. We identified a previously undescribed mutation (N215K) in the prosaposin gene of a patient with metachromatic leukodystrophy but with normal arylsulphatase A activity and elevated sulphatide in urine. The mutation involves a highly conserved amino acidic residue and abolishes the only N-glycosylation site of saposin B.  (+info)

Arylsulfatase A pseudodeficiency in healthy Brazilian individuals. (2/118)

Molecular alterations associated with arylsulfatase A pseudodeficiency (ASA-PD) were characterized by PCR and restriction endonuclease analysis in a sample of healthy individuals from Brazil. ASA activity was also assayed in all subjects. Two individuals homozygous for the N350S and 1524+95A<--G mutations were detected, corresponding to a frequency of 1.17% (4 of 324 alleles). The individual frequency of the N350S mutation was 20.7% (71 of 342 alleles) and 7.9% (27 of 342 alleles) for the 1524+95A<--G mutation. The frequency of the ASA-PD allele in our population was estimated to be 7.9%. This is the first report of ASA-PD allele frequency in a South American population. In addition, the methods used are effective and suitable for application in countries with limited resources. All patients with low ASA activity should be screened for ASA-PD as part of the diagnostic protocol for metachromatic leukodystrophy.  (+info)

Spontaneous rupture of the diaphragm. (3/118)

A 2.5 year old girl with metachromatic leukodystrophy presented with acute respiratory distress and was initially wrongly diagnosed with pneumothorax. Barium meal showed bowel loops in the left hemithorax, which prompted surgical intervention; spontaneous rupture of the diaphragm was diagnosed at surgery.  (+info)

Retrovirally expressed human arylsulfatase A corrects the metabolic defect of arylsulfatase A-deficient mouse cells. (4/118)

A deficiency of arylsulfatase A (ASA) causes the lysosomal storage disease metachromatic leukodystrophy (MLD) which is characterized primarily by demyelination of the central nervous system. ASA-deficient mice develop a disease which resembles MLD in many respects and thus serve as an appropriate animal model for this disease. To establish gene therapy protocols for ASA-deficient mice, we constructed two retroviral vectors based on the murine stem cell virus. Both vectors harbor the human ASA cDNA controlled by the retroviral promoter/enhancer element, but differ by the presence or absence of a neomycin resistance gene driven by an internal promoter. A comparative analysis of the one- versus the two-gene vector and an amphotropic versus an ecotropic producer cell line revealed that the amphotropic producer cell line for the one-gene vector transfers ASA overexpression to the target cells most efficiently. The human ASA encoded by this vector is correctly expressed in heterologous mouse cells and corrects the metabolic defect of transduced ASA-deficient murine cells. The constructed one-gene vector might thus be a potentially useful tool for the development of a gene-based therapy for ASA-deficient mice. Gene Therapy (2000) 7, 805-812.  (+info)

Concepts of myelin and myelination in neuroradiology. (5/118)

Until the advent of MR imaging, knowledge of the structure of myelin and the process of myelination were of little importance to the neuroradiologist. Other than some mild changes in the attenuation of white matter, myelination resulted in no significant alterations of CT (1) or sonographic studies. MR studies, on the other hand, have been increasingly used for pediatric brain imaging. MR imaging's greater sensitivity to small changes in the water content of brain tissue, to changes in the binding of free water (revealed by magnetization transfer), and to the extent and anisotropy of water diffusion (revealed by diffusion imaging) has cast new light on this very complex and important molecule. Assessing myelination has become a key component of evaluating the child with delayed development. Moreover, better understanding of the nature of myelin and the effect of its different components on MR imaging parameters may help us to understand and diagnose inborn errors of metabolism better. In this review, I discuss what is known regarding the function and structure of CNS myelin and the effects of the various components of myelin on the signal imparted to the MR image. Summary Abnormalities of myelin can cause a wide variety of disorders of the nervous system. MR imaging is a powerful tool for the study of myelin and its disorders. However, only by understanding the physiologic properties and structure of myelin can we use MR imaging to its fullest capacity for studying patients with myelin disorders. In this review, I have discussed the structure of myelin as it relates to MR imaging of normal myelination and to neurologic disorders resulting from abnormalities of myelin. Thinking of myelin and its disorders in this manner will be critical to using MR imaging techniques optimally to diagnose and study these disorders further.  (+info)

Leucodystrophy and oculocutaneous albinism in a child with an 11q14 deletion. (6/118)

We report a patient with an undetermined leucodystrophy associated with type 1A oculocutaneous albinism (OCA). Type 1 OCA results from recessive mutations in the tyrosinase gene (TYR) located in 11q14.3. The patient was found by FISH to carry a deletion of at least the first exon of the TYR gene on one chromosome and a (TG) deletion at codon 244/245 on the second chromosome. The existence of the microdeletion suggested that a gene responsible for leucodystrophy was located in the vicinity of the TYR gene. A combination of a test of hemizygosity and contig mapping studies allowed us to map the gene within a 0.6 cM region flanked by microsatellite markers D11S1780 and D11S931.  (+info)

Above-normal urinary excretion of urinary ceramides in Farber's disease, and characterization of their components by high-performance liquid chromatography. (7/118)

We compared the sphingolipid content of urine from a patient with Farber's disease with that of control urine. The ceramides were measured by high-performance liquid chromatography. The patient's urine contained 1.2 mug of ceramides per milligram of creatinine, more than 200-fold the normal amount. The urinary ceramides were isolated by high-performance liquid chromatography for further identification. They contained mainly nonhydroxy fatty acids and only a small quantity of those with 2-hydroxy fatty acids. This contrasts with the previously described composition of the patient's renal and cerebellar tissue. The fatty acid and long-chain base compositions of the urinary ceramides containing nonhydroxy fatty acids were nearly identical to those of the patient's kidney.  (+info)

Childhood organic neurological disease presenting as psychiatric disorder. (8/118)

Over a period of one year 12 children with complaints which had been diagnosed as due to a psychiatric disorder presented to a paediatric neurological unit where neurological disease was diagnosed. The group was characterized by behavioural symptoms such as deteriorating school performance, visual loss, and postural disturbance, which are unusual in children attending child psychiatric departments. It is suggested that where there is diagnostic uncertainty the presence of these physical symptoms calls for periodic neurological reassessment, and attention is drawn to the rare but serious disorders which may thus be diagnosed. Making an organic diagnosis, however, should not preclude psychosocial management of emotional reactions in these families.  (+info)