RESUMEN
Sialic acid storage diseases (SASD, MIM 269920) are autosomal recessive neurodegenerative disorders that may present as a severe infantile form (ISSD) or a slowly progressive adult form, which is prevalent in Finland (Salla disease). The main symptoms are hypotonia, cerebellar ataxia and mental retardation; visceromegaly and coarse features are also present in infantile cases. Progressive cerebellar atrophy and dysmyelination have been documented by magnetic resonance imaging (ref. 4). Enlarged lysosomes are seen on electron microscopic studies and patients excrete large amounts of free sialic acid in urine. A H+/anionic sugar symporter mechanism for sialic acid and glucuronic acid is impaired in lysosomal membranes from Salla and ISSD patients. The locus for Salla disease was assigned to a region of approximately 200 kb on chromosome 6q14-q15 in a linkage study using Finnish families. Salla disease and ISSD were further shown to be allelic disorders. A physical map with P1 and PAC clones was constructed to cover the 200-kb area flanked by the loci D6S280 and D6S1622, providing the basis for precise physical positioning of the gene. Here we describe a new gene, SLC17A5 (also known as AST), encoding a protein (sialin) with a predicted transport function that belongs to a family of anion/cation symporters (ACS). We found a homozygous SLC17A5 mutation (R39C) in five Finnish patients with Salla disease and six different SLC17A5 mutations in six ISSD patients of different ethnic origins. Our observations suggest that mutations in SLC17A5 are the primary cause of lysosomal sialic acid storage diseases.
Asunto(s)
Proteínas Portadoras/genética , Transporte Iónico/genética , Mutación , Enfermedades Neurodegenerativas/genética , Enfermedades Neurodegenerativas/metabolismo , Ácidos Siálicos/metabolismo , Adulto , Secuencia de Aminoácidos , Proteínas de Transporte de Anión , Secuencia de Bases , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Cartilla de ADN/genética , Femenino , Expresión Génica , Genes Recesivos , Humanos , Lactante , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Linaje , ARN Mensajero/genética , ARN Mensajero/metabolismo , Homología de Secuencia de Aminoácido , Distribución TisularRESUMEN
Lysinuric protein intolerance (LPI; OMIM 222700) is a rare, recessive disorder with a worldwide distribution, but with a high prevalence in the Finnish population; symptoms include failure to thrive, growth retardation, muscle hypotonia and hepatosplenomegaly. A defect in the plasma membrane transport of dibasic amino acids has been demonstrated at the baso-lateral membrane of epithelial cells in small intestine and in renal tubules and in plasma membrane of cultured skin fibroblasts from LPI patients. The gene causing LPI has been assigned by linkage analysis to 14q11-13. Here we report mutations in SLC7A7 cDNA (encoding y+L amino acid transporter-1, y+LAT-1), which expresses dibasic amino-acid transport activity and is located in the LPI region, in 31 Finnish LPI patients and 1 Spanish patient. The Finnish patients are homozygous for a founder missense mutation leading to a premature stop codon. The Spanish patient is a compound heterozygote with a missense mutation in one allele and a frameshift mutation in the other. The frameshift mutation generates a premature stop codon, eliminating the last one-third of the protein. The missense mutation abolishes y+LAT-1 amino-acid transport activity when co-expressed with the heavy chain of the cell-surface antigen 4F2 (4F2hc, also known as CD98) in Xenopus laevis oocytes. Our data establish that mutations in SLC7A7 cause LPI.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Proteínas Portadoras/genética , Proteínas de la Membrana/genética , Eliminación de Secuencia , Adolescente , Secuencia de Aminoácidos , Sistemas de Transporte de Aminoácidos Básicos , Animales , Arginina/metabolismo , Transporte Biológico , Proteínas Portadoras/metabolismo , Desoxirribonucleasas de Localización Especificada Tipo II/genética , Femenino , Finlandia , Heterocigoto , Humanos , Intrones , Leucina/metabolismo , Lisina/orina , Masculino , Proteínas de la Membrana/metabolismo , Datos de Secuencia Molecular , Mutación , Oocitos/fisiología , XenopusRESUMEN
A defective efflux of free sialic acid from the lysosomal compartment has been found in the clinically heterogeneous group of sialic acid storage disorders. Using radiolabeled sialic acid (NeuAc) as a substrate, we have recently detected and characterized a proton-driven carrier for sialic acid in the lysosomal membrane from rat liver. This carrier also recognizes and transports other acidic monosaccharides, among which are uronic acids. If no alternative routes of glucuronic acid transport exist, the disposal of uronic acids can be affected in the sialic acid storage disorders. In this study we excluded the existence of more than one acidic monosaccharide carrier by measuring uptake kinetics of labeled glucuronic acid [( 3H]GlcAc) in rat lysosomal membrane vesicles. [3H]GlcAc uptake was carrier-mediated with an affinity constant of transport (Kt) of 0.3 mM and the transport could be cis-inhibited or trans-stimulated to the same extent by sialic acid or glucuronic acid. Human lysosomal membrane vesicles isolated from cultured fibroblasts showed the existence of a similar proton-driven transporter with the same properties as the rat liver system (Kt of [3H]GlcAc uptake 0.28 mM). Uptake studies with [3H]NeuAc and [3H]GlcAc in resealed lysosome membrane vesicles from cultured fibroblasts of patients with different clinical presentation of sialic acid storage showed defective carrier-mediated transport for both sugars. Further evidence that the defective transport of acidic sugars represents the primary genetic defect in sialic acid storage diseases was provided by the observation of reduced, half-normal transport rates in lymphoblast-derived lysosomal membrane vesicles from five unrelated obligate heterozygotes. This study reports the first observation of a human lysosomal transport defect for multiple physiological compounds.
Asunto(s)
Errores Innatos del Metabolismo de los Carbohidratos/metabolismo , Lisosomas/metabolismo , Ácidos Siálicos/metabolismo , Animales , Transporte Biológico , Células Cultivadas , Glucuronatos/metabolismo , Ácido Glucurónico , Heterocigoto , Humanos , Concentración de Iones de Hidrógeno , Técnicas In Vitro , Membranas Intracelulares/metabolismo , Cinética , Hígado/metabolismo , RatasRESUMEN
Cells cultured from second trimester human amniotic fluid were characterized in indirect immunofluorescence (IIF) microscopy using specific antibodies against the subunit proteins of different types of cytoskeletal intermediate filaments. Most of the amniotic fluid cell cultures contained only epithelial cells as indicated by the positive keratin-fluorescence in IIF. Five distinct types of keratin-positive cells could be characterized. A dominating cell type (E-1) in most cultures were rapidly proliferating epithelial cells, previously called amniotic fluid cells (AF-cells). These cells showed a fibrillar cytoplasmic fluorescence both with keratin antibodies and with antibodies against vimentin, the fibroblast type of intermediate filament protein. E-1 cells did not show the typical cell-to-cell arrangement of keratin fibrils between the adjacent cells, a characteristic previously found in most cultured epithelial cells. Most of the cultures also contained large epitheloid cells (E-2), showing a fine fibrillar cytoplasmic organization of both keratin- and vimentin filaments, clearly different from that seen in E-1 cells. Several cultures contained two additional epithelial cells both showing the typical cell-to-cell arrangement of keratin fibrils (E-3 and E-4). These two cell types could be distinguished because of their distinct difference in size. E-4 cells typically grew as small cell islands among other epitheloid cells. Amniotic fluid cell cultures occasionally contained also large multinucleated cells (E-5), which appeared to contain large amount of fibrillar keratin. Fibroblastic cells, identified by their decoration only with antibodies against vimentin, were rarely found in amniotic fluid cell cultures. Interestingly, in such cultures some cells with a fibroblastoid appearance were identified as epithelial cells on the basis of the positive keratin-fluorescence. The results show the suitability of IIF with cytoskeletal antibodies in characterization of heterogenous cell populations and indicate that normal amniotic fluid cell cultures mostly contain epithelial cells.
Asunto(s)
Líquido Amniótico/citología , Gránulos Citoplasmáticos/ultraestructura , Anticuerpos , Células Cultivadas , Epitelio/análisis , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Queratinas/análisis , Embarazo , Proteínas/análisisRESUMEN
Salla disease is a lysosomal storage disorder characterized by mental retardation and disturbed sialic acid metabolism. To study endogenous synthesis and breakdown of sialic acid, fibroblasts were incubated for 5 d in the presence and then in the absence of N-[3H]acetylmannosamine. Labeling of free sialic acid was 5-10 times higher in mutant than in normal cells. Radioactivity decreased in 4 d by 75% in normal but only by 30% in mutant fibroblasts. The labeling pattern was not normalized upon coculture of mutant and normal cells. To study the metabolism of extracellular sialic acid, low-density lipoprotein (LDL) was labeled in the sialic acid moiety (periodate-NaB3H4) or in the protein moiety (125I). Binding, internalization, lysosomal degradation, and exit of products of protein catabolism were similar in normal and mutant fibroblasts. Upon incubation with LDL labeled in the sialic acid moiety, mutant cells accumulated 2-3 times more free sialic acid radioactivity than normal fibroblasts, mostly in the lysosomal fraction. After a 24-h chase incubation, radioactivity in free sialic acid decreased by 70-80% in normal but only by 10-30% in mutant cells. In mutant fibroblasts, 40% of the radioactivity remained in lysosomes, whereas no labeled free sialic acid was detected in lysosomes from normal fibroblasts. We conclude that in Salla disease, fibroblast endogenous synthesis of sialic acid and lysosomal cleavage of exogenous glycoconjugates is normal, but free sialic acid cannot leave the lysosome. These findings suggest that the basic defect in Salla disease is deficient transport of free sialic acid through the lysosomal membrane.
Asunto(s)
Fibroblastos/metabolismo , Lisosomas/metabolismo , Errores Innatos del Metabolismo/metabolismo , Ácidos Siálicos/metabolismo , Células Cultivadas , Hexosaminas/metabolismo , Humanos , Lipoproteínas LDL/metabolismo , Ácido N-Acetilneuramínico , TritioRESUMEN
The synthesis of pregnancy-specific beta-1-glycoprotein (SP1) was studied in amniotic fluid cell cultures using RIA, immunoperoxidase, and immunofluorescence techniques. SP1 was found by RIA in all 11 sonicates and in 21 of 26 culture media. The SP1-immunoreactive material was immunologically similar to maternal serum SP1. Immunoperoxidase and indirect immunofluorescence staining were positive in large cells identified as epithelial amniotic cells by labeling with antikeratin antibodies. Fibroblast-like cells were occasionally found in cultures, but they did not contain demonstrable amounts of SP1. The physiological significance of the findings presented remains unclear.
Asunto(s)
Líquido Amniótico/metabolismo , Proteínas Gestacionales/biosíntesis , Glicoproteínas beta 1 Específicas del Embarazo/biosíntesis , Células Cultivadas , Femenino , Técnica del Anticuerpo Fluorescente , Histocitoquímica , Humanos , Técnicas para Inmunoenzimas , Embarazo , RadioinmunoensayoRESUMEN
The frequency of carriers of the AGUFin mutation, the predominant mutation causing aspartylglucosaminuria in Finland, was determined in a population sample comprising 553 newborns from a delivery hospital in southern Finland, and 607 from a hospital in northern Finland. The AGUFin point mutation was identified from cord blood samples using the PCR-based, solid-phase minisequencing method. Nineteen carriers of the AGUFin mutation were detected, 8 (1:69) in the sample from the southern and 11 (1:55) from the northern population, respectively. The solid-phase minisequencing method proved to be rapid and convenient for the detection of the AGUFin mutation, and can readily be applied in large-scale carrier screening at the population level.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Aspartilglucosilaminasa/genética , Tamización de Portadores Genéticos , Pruebas Genéticas , Finlandia , Humanos , Recién Nacido , Mutación Puntual , Reacción en Cadena de la PolimerasaRESUMEN
Y chromosomal polymorphisms were studied in 502 males from 16 Eurasian ethnic groups including the Finns, Saami (Inari Lake area and Skolt Saami), Karelians, Mari, Mokshas, Erzas, Hungarians (Budapest area and Csángós), Khanty, Mansi, Yakuts, Koryaks, Nivkhs, Mongolians, and Latvians. The samples were analysed for polymorphisms in the Y chromosome specific Alu insertion (YAP) and six microsatellites (DYS19, DYS389-I and II, DYS390, DYS392, DYS393). The populations were also screened for the recently described Tat polymorphism. The incidence of YAP+ type was highest in the Csángós and in other Hungarians (37.5% and 17.5%, respectively). In the Karelians and the Latvians it was present at approximately the same level as commonly found in other European populations, whilst absent in our further samples of Eurasian populations, including the Finns and the Saami. Aside from the Hungarians, the C allele of the Tat polymorphism was common in all the Finno-Ugric speaking populations (from 8.2% to 63.2%), with highest incidence in the Ob-Ugrian Khanty. The C allele was also found in the Latvians (29.4%). The haplotypes found associated with the Tat C allele showed consistently lower density than those associated with the T allele, indicating that the T allele is the original form. The computation of the age of the Tat C suggested that the mutation might be a relatively recent event giving a maximum likelihood estimate of 4440 years (95% confidence interval about 3140-6200 years). The distribution patterns of the 222 haplotypes found varied considerably among the populations. In the Finns a majority of the haplotypes could be assigned to two distinct groups, one of which harboured the C allele of the Tat polymorphism, indicating dichotomous primary source of genetic variation among Finnish males. The presence of a bottleneck or founding effect in the male lineages of some of the populations, namely in the Finns and the Saami, would appear to be one likely interpretation for these findings.
Asunto(s)
Etnicidad/genética , Efecto Fundador , Genética de Población , Polimorfismo Genético , Cromosoma Y/genética , Elementos Alu/genética , ADN/genética , Europa Oriental , Asia Oriental , Finlandia , Genes tat/genética , Haplotipos , Humanos , Masculino , Repeticiones de Microsatélite/genéticaRESUMEN
The mitochondrial DNA (mtDNA) sequence variation of 24 Finnish Leber hereditary optic neuroretinopathy (LHON) probands was characterized by sequencing and restriction endonuclease analyses. All LHON-associated substitutions and Caucasoid haplogroup-specific mutations were screened in the families. Analysis of the mtDNAs revealed that the Finnish LHON families have two unique features: an absence of the ND6/14484 mutation and a high number of families (10/24) without the primary mutations ND1/3460 and ND4/11778. Furthermore, the LHON families showed considerable mtDNA heterogeneity: among 24 families 22 haplotypes were detected. Overall, the haplogrouping of LHON families was similar to other European populations. However, the frequency of ND4/11778-positive families in haplogroup J was high, which may indicate that background mutations in this haplogroup together with the ND4/11778 primary mutation promote the penetrance of LHON.
Asunto(s)
ADN Mitocondrial/genética , Haplotipos , Atrofias Ópticas Hereditarias/genética , Filogenia , Adolescente , Adulto , Niño , Femenino , Finlandia , Heterogeneidad Genética , Variación Genética/genética , Humanos , Masculino , Persona de Mediana Edad , Atrofias Ópticas Hereditarias/fisiopatología , Linaje , Polimorfismo de Longitud del Fragmento de Restricción , Población Blanca/genéticaRESUMEN
Lysinuric protein intolerance (LPI) is an autosomal recessive disorder in which transport of the cationic amino acids lysine, arginine and ornithine is defective at the basolateral membrane of the epithelial cells in the intestine and renal tubules. LPI is unusually common in Finland, but patients have been described on all continents. Linkage analysis in Finnish LPI families recently assigned the LPI gene locus to a 10 cM interval between markers D14S72 and MYH7 on the long arm of chromosome 14. In the present study linkage analysis of LPI families from six different non-Finnish populations strongly suggests genetic homogeneity in LPI. Peak lod scores were obtained at the chromosomal area between D14S72 and MYH7 with the same markers as in the Finnish families. The non-Finnish families showed no linkage disequilibrium except in an Italian family cluster, whereas strong allelic association in the Finnish families implies that LPI in Finland is caused by a founder mutation.
Asunto(s)
Errores Innatos del Metabolismo de los Aminoácidos/genética , Lisina/orina , Mapeo Cromosómico , Cromosomas Humanos Par 14 , Ligamiento Genético , Haplotipos , Humanos , Recombinación GenéticaRESUMEN
A lowered efficiency of oxidative phosphorylation was recently found in a Leber hereditary optic neuropathy (LHON) proband carrying a mutation in the mtDNA gene for subunit 6 of the membrane-bound F0 segment of the F1F0-ATP synthase [9]. This phenotype was transferred to cytoplasmic hybrid cells together with the mutation, proving its functional significance. Increasing the respiratory rate in the mitochondria from this mutant raised the ATP/2e- ratio back to normal values. A different mutation in the same mtDNA gene has been found in patients with the NARP syndrome [10]. Although the ATP/2e- ratio is also decreased in this mutant, in this case an increase in the respiratory rate could not compensate for it. Whilst both mutations affect subunit 6 of the proton-translocating F0 segment, the LHON mutation induces a proton leak whereas the NARP mutation blocks proton translocation. Hence, the latter will have much more destructive metabolic consequences in agreement with the large clinical differences between the two diseases.
Asunto(s)
Mutación , Atrofias Ópticas Hereditarias/genética , ATPasas de Translocación de Protón/genética , Adenosina Trifosfato/biosíntesis , ADN Mitocondrial , Humanos , Cinética , Fosforilación Oxidativa , ATPasas de Translocación de Protón/metabolismo , SíndromeRESUMEN
Severe mental retardation, coarse facial features, clumsiness, and speech failure were common findings in three brothers and one female third-cousin of a family from northern Finland. All the patients had vacuolated lymphocytes in peripheral blood smears, and electron microscopy of fresh skin biopsy specimens showed abundant cytoplasmic inclusions in various types of cells of the skin. Eight lysosomal hydrolases were assayed in peripheral blood lymphocytes and cultured skin fibroblasts, but no enzyme deficiency was detected. Urinary excretion of mucopolysaccharides, amino acids, glycoasparagines, and oligosaccharides was normal. Clinical findings, course of the disease, and the presence of cytoplasmic inclusions, indicating lysosomal storage phenomenon, suggest that the patients suffer from a genetic lysosomal storage disorder not described earlier. The eponym "Salla disease" was introduced, referring to the geographically restricted area where the family resides.
Asunto(s)
Discapacidad Intelectual/enzimología , Lisosomas/enzimología , Adulto , Células Cultivadas , Fibroblastos/enzimología , Fibroblastos/ultraestructura , Finlandia , Humanos , Hidrolasas/metabolismo , Discapacidad Intelectual/genética , Discapacidad Intelectual/patología , Linfocitos/enzimología , Linfocitos/ultraestructura , Lisosomas/ultraestructura , Masculino , Neuronas/ultraestructura , Trastornos Psicomotores/enzimología , Trastornos Psicomotores/genética , Trastornos Psicomotores/patología , Piel/ultraestructura , Vacuolas/ultraestructuraRESUMEN
OBJECTIVE: To evaluate the degree of possible peripheral nervous system (PNS) involvement in addition to CNS manifestations in Salla disease, a free sialic acid storage disorder leading to severe mental retardation with a wide clinical variation. BACKGROUND: Salla disease is a lysosomal storage disorder that affects the white matter of the CNS. MRI findings and recent 1H MRS study results provide evidence for delayed central myelination, but there is no previous evidence for PNS involvement in this disease. The gene coding for a presumptive sialic acid transport protein has recently been identified, and the first disease-causing mutations have been characterized. METHODS: Nerve conduction studies; evoked potentials to visual (VEP), brainstem auditory (BAEP), and somatosensory stimuli (SEP); and EEG were carried out on 22 patients (age range 2 months to 57 years) with biochemically and genetically confirmed Salla disease. Brain MRI were available on 14 patients. RESULTS: Nerve conduction studies revealed abnormalities in nearly half of the patients (10/21). The four severely disabled patients and the oldest patient had greatly reduced nerve conduction velocities and prolonged distal latencies compatible with demyelinating polyneuropathy. In addition, SEP was abnormal in the majority of the patients, but VEP and BAEP in only a few cases. PNS involvement was clearly associated with both the phenotypic severity and MRI findings. CONCLUSIONS: The results indicate that dysmyelination in Salla disease occurs not only in the CNS but also in the peripheral nervous system, contributing to the phenotypic variation, which can now be correlated with the molecular basis of the disease.
Asunto(s)
Sistema Nervioso Central/patología , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/patología , Mucolipidosis/patología , Sistema Nervioso Periférico/patología , Adolescente , Adulto , Sistema Nervioso Central/fisiopatología , Niño , Preescolar , Electroencefalografía , Potenciales Evocados/fisiología , Femenino , Genotipo , Humanos , Lactante , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/genética , Enfermedades por Almacenamiento Lisosomal del Sistema Nervioso/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Mucolipidosis/genética , Mucolipidosis/fisiopatología , Conducción Nerviosa/fisiología , Sistema Nervioso Periférico/fisiopatología , FenotipoRESUMEN
Salla disease is a lysosomal storage disorder associated with increased urinary excretion of free sialic acid. The main clinical features in 34 patients were severe psychomotor retardation of early onset, ataxia, athetosis, rigidity, spasticity, and impaired speech. Growth retardation, thick calvarium, and exotropia were present in about half the patients. The amplitude of EEG decreased progressively with increasing age. Life span appears to be normal; the age range of the patients was 3 to 63 years. Genealogic studies suggest an autosomal mode of inheritance. A thin-layer method is described for the detection of increased urinary free sialic acid excretion. The basic defect is so far unknown.
Asunto(s)
Errores Innatos del Metabolismo/fisiopatología , Ácidos Siálicos/metabolismo , Adolescente , Adulto , Ataxia/genética , Ataxia/fisiopatología , Niño , Preescolar , Femenino , Humanos , Lisosomas/ultraestructura , Masculino , Errores Innatos del Metabolismo/genética , Errores Innatos del Metabolismo/patología , Persona de Mediana Edad , Trastornos Psicomotores/genética , Trastornos Psicomotores/fisiopatología , Ácidos Siálicos/orinaRESUMEN
OBJECTIVE: To determine whether N-acetylaspartate (NAA) is reduced in patients with Salla disease, a neurodegenerative disorder. BACKGROUND: 1H MRS allows the brain metabolism to be studied noninvasively in vivo. N-acetyl (NA) is composed primarily of NAA, which is regarded as a neuronal marker. The NA signal in 1H MRS is reduced in several neurodegenerative disorders. Increased NA signal has thus far only been found in Canavan's disease as a result of NAA accumulation in the brain tissue. In Salla disease, an autosomal recessive free sialic acid storage disorder, N-acetylneuraminic acid (NANA), accumulates in lysosomes of brain tissue. METHODS: The authors studied eight patients with Salla disease (age range, 6 to 44 years) and eight age-matched healthy volunteers using quantitative 1H MRS. The spectra were obtained from two selected 8-cm3 volumes of interest localized in the basal ganglia and in the parietal white matter using conventional 1.5-T MRI equipment. The spectral resonance lines of NA groups, creatine and phosphocreatine (Cr), and choline-containing compounds (Cho) were analyzed quantitatively. All MR images were evaluated to verify the state of myelination. RESULTS: 1H MRS from parietal white matter revealed 34% higher NA and 47% higher Cr concentrations, and a 35% lower Cho concentration in the patients with Salla disease compared with the age-matched control subjects. The patients had a 22% higher water content in their parietal white matter, whereas in the basal ganglia the water concentrations did not differ significantly. In the patients' basal ganglia the Cr concentration was 53% higher. CONCLUSIONS: NAA is considered to be a neuronal marker that, except for Canavan's disease, has been found or assumed to be either stable or reduced. However, in Salla disease the high NA signal may have a contribution from accumulated lysosomal NANA, which offsets the possible loss of NAA. The high Cr is in line with the increased glucose uptake found in our earlier 2-fluoro-2-deoxy-D-glucose-PET study, reflecting increased energy demand. It is worth noting that in a conventional 1H MRS ratio-based analysis these underlying abnormalities would have remained undetected. Our study thus emphasizes the importance of a quantitative assessment of metabolite concentrations in 1H MRS for detecting altered brain metabolism.
Asunto(s)
Encéfalo/metabolismo , Enfermedades por Almacenamiento Lisosomal/metabolismo , Espectroscopía de Resonancia Magnética/métodos , Adolescente , Adulto , Encéfalo/patología , Niño , Humanos , Enfermedades por Almacenamiento Lisosomal/patología , Imagen por Resonancia Magnética , ProtonesRESUMEN
An epidemiological study of hereditary neuropathy with liability to pressure palsies (HNPP) was carried out in south western Finland, with a population of 435,000. The diagnosis was established in 69 patients from 23 unrelated families through family and medical history, clinical neurological and neurophysiological examinations and with documentation of the deletion at gene locus 17p11.2 in at least one member of each family. This gave a prevalence of at least 16/100,000, which is remarkably high. However, due to the insidious nature of HNPP, most probably it is still an underestimation. This is the first population-based prevalence figure reported for HNPP. The prevalence is somewhat lower than that obtained for CMT in the same population, which agrees with the proposal that HNPP and CMT 1A are reciprocal products of the same unequal crossing-over. The clinical pictures of our patients were, in general, similar to those previously described in HNPP.
Asunto(s)
Eliminación de Gen , Neuropatía Hereditaria Motora y Sensorial/epidemiología , Adolescente , Adulto , Edad de Inicio , Anciano , Niño , Preescolar , Femenino , Finlandia/epidemiología , Neuropatía Hereditaria Motora y Sensorial/genética , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Longitud del Fragmento de Restricción , PrevalenciaRESUMEN
UNLABELLED: Salla disease is an autosomal recessive lysosomal free sialic acid storage disorder characterized by psychomotor retardation and ataxia. MRI studies have revealed evidence of dysmyelination, but the biological mechanism of the brain dysfunction is unknown. METHODS: Nine patients with Salla disease (age 2.5 mo-42 y) presenting the disease in varying degrees of severity were studied by PET using 2-fluoro-2-deoxy-D-glucose (FDG) as a tracer. Local cerebral metabolic rates for glucose (LCMRGlc) in individual brain regions were compared with controls. RESULTS: The FDG PET results showed significantly increased LCMRGlc values in the frontal and sensorimotor cortex and especially in the basal ganglia of the patients. Cerebellar hypometabolism was present in all seven patients with marked ataxia, whereas the less severely affected patients without obvious ataxia had normal or even high glucose uptake in the cerebellum. CONCLUSION: The increased cerebral glucose utilization is a constant finding in Salla disease and may reflect the basic defect of the sialic acid metabolism in this disorder. The FDG PET findings in the cerebellum suggest a correlation between glucose uptake and the severity of the clinical symptoms.
Asunto(s)
Encéfalo/metabolismo , Glucosa/metabolismo , Enfermedades por Almacenamiento Lisosomal/metabolismo , Ácidos Siálicos/metabolismo , Adolescente , Adulto , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Niño , Preescolar , Fluorodesoxiglucosa F18 , Humanos , Lactante , Enfermedades por Almacenamiento Lisosomal/patología , Imagen por Resonancia Magnética , Radiofármacos , Tomografía Computarizada de EmisiónRESUMEN
Salla disease is an autosomal recessive lysosomal storage disease relatively common in the Finnish population. The main manifestations of more than 70 patients detected to date are severe psychomotor retardation and ataxia of early onset. Intracellular free N-acetylneuraminic acid (sialic acid) is increased 10-20-fold and localized in the lysosomes. Four pregnancies at risk were monitored by quantitation of free and total sialic acid in amniocytes and supernatant amniotic fluid by high-performance liquid chromatography. In 3 children results were normal. Free sialic acid content of the amniocytes from one affected child was 2.6 nmol/mg protein, which was approximately 5 times higher than that of the 3 unaffected children (0.3 to 0.8) and 14 control samples (0.3 to 0.9). The ratio of free/total sialic acid of the amniocytes also clearly distinguished the affected pregnancy (13.8%) from the unaffected (2.3-4.8%) and control individuals (1.8-5.3%). This represents the first successful prenatal identification of a patient with Salla disease and indicates that both free sialic acid and free/total sialic acid ratio should be monitored in pregnancies at risk for the disease.
Asunto(s)
Amniocentesis , Líquido Amniótico/citología , Ataxia/genética , Errores Innatos del Metabolismo/complicaciones , Trastornos Psicomotores/genética , Ácidos Siálicos/metabolismo , Ataxia/etiología , Células Cultivadas , Niño , Preescolar , Cromatografía Líquida de Alta Presión , Femenino , Genes Recesivos , Humanos , Masculino , Trastornos Psicomotores/etiologíaRESUMEN
The prenatal diagnosis of aspartylglucosaminuria (AGU), a lysosomal storage disorder of glycoprotein degradation, was made by demonstrating the deficiency of N-aspartylglucosaminidase on cultured cells from a midterm amniotic fluid sample. Four other amniotic fluid studies from at-risk pregnancies gave a normal or a heterozygote level of enzyme activity. These pregnancies have gone to term and the delivery of healthy babies. The pregnancy with the affected fetus was terminated and the prenatal diagnosis was verified by enzyme assays on cord blood lymphocytes, cultured cells from skin biopsy, and from placental villi. Electron microscopic evidence of lysosomal storage was seen in several organs of the fetus with the notable exception of the central nervous system. The undifferentiated mesenchymal fibroblasts particularly were heavily loaded with cytoplasmic inclusions in skin, liver, kidney, and placenta.
Asunto(s)
Acetilglucosamina/análogos & derivados , Amidohidrolasas/deficiencia , Líquido Amniótico/enzimología , Aspartilglucosaminuria , Glucosamina/análogos & derivados , Diagnóstico Prenatal , Acetilglucosamina/orina , Aspartilglucosilaminasa/análisis , Células Cultivadas , Vellosidades Coriónicas/enzimología , Femenino , Feto/patología , Heterocigoto , Humanos , Lisosomas/enzimología , Masculino , EmbarazoRESUMEN
We report on a 10-year-old Caucasian male with a prematurely aged appearance, delayed bone maturation and dental development, pronounced acro-osteolysis with brachydactyly, and distinctive cutaneous findings including hard, confluent skin lesions with some clinical and histologic resemblance to those of juvenile hyaline fibromatosis (JHF). He also had hyperopia, sensorineural hearing loss, and elevated TSH. Linear growth and intellectual functions were normal. We believe that this patient represents a new progeroid disorder.