Explore the vast range of titles available.

Salla disease, a free sialic acid storage disorder, is one of the 36 currently known disorders in Finland that form the Finnish disease heritage. Salla disease leads to learning disability* with a wide clinical variation. Two main categories of the disease have been classified: a conventional subtype and a severe subtype with more severe defects. We present detailed neurocognitive profiles of 41 Finnish patients with Salla disease (19 females, 22 males; age range 11mo to 63y, median 19y). The neurocognitive development of patients with Salla disease was assessed by psychological and neuropsychological testing. All patients were also examined by a paediatric neurologist and a speech therapist. The characteristic cognitive profile consisted of a lower non‐verbal performance (mean developmental age 13mo) compared with linguistic skills (mean developmental age 17mo). In particular, spatial and visual‐constructive impairments were typical of these patients. Tactile and visual discrimination of forms was poor. Tasks demanding hand–eye coordination, maintenance of visual attention, and those requiring short‐term visual memory and executive skills were performed better. Receptive language skills were notably better compared with expressive speech. The patients’interactive and non‐verbal communication skills were quite strong. Another typical pattern with Salla disease was severe motor disability. After the second decade of life, the decline in these skills was more pronounced than patients’cognitive deterioration. Our results indicate that even though there is a considerable variation in the clinical findings of patients with Salla disease, the characteristic neurocognitive profile of the disease can be outlined.

The Finnish disease heritage refers to a group of monogenic diseases that are enriched in the Finnish population due to founder effect and genetic isolation. The molecular genetics of these diseases has recently been intensely studied, and several founder and private mutations have been identified. The purpose of the present study was to create a database of the presently known mutations of the Finnish disease heritage. Hum Mutat 19:16–22, 2002. © 2001 Wiley‐Liss, Inc.

Salla disease, a free sialic acid storage disorder, is one of the 36 currently known disorders in Finland that form the Finnish disease heritage. Salla disease leads to learning disability with a wide clinical variation. Two main categories of the disease have been classified: a conventional subtype and a severe subtype with more severe defects. We present detailed neurocognitive profiles of 41 Finnish patients with Salla disease (19 females, 22 males; age range 11mo to 63y, median 19y). The neurocognitive development of patients with Salla disease was assessed by psychological and neuropsychological testing. All patients were also examined by a paediatric neurologist and a speech therapist. The characteristic cognitive profile consisted of a lower non-verbal performance (mean developmental age 13mo) compared with linguistic skills (mean developmental age 17mo). In particular, spatial and visual-constructive impairments were typical of these patients. Tactile and visual discrimination of forms was poor. Tasks demanding hand–eye coordination, maintenance of visual attention, and those requiring short-term visual memory and executive skills were performed better. Receptive language skills were notably better compared with expressive speech. The patients' interactive and non-verbal communication skills were quite strong. Another typical pattern with Salla disease was severe motor disability. After the second decade of life, the decline in these skills was more pronounced than patients' cognitive deterioration. Our results indicate that even though there is a considerable variation in the clinical findings of patients with Salla disease, the characteristic neurocognitive profile of the disease can be outlined.

Our patient material included families and sporadic patients of Finnish origin with the diagnosis of Charcot‐Marie‐Tooth (CMT) disease types 1 and 2, Déjérine‐Sottas syndrome (DSS), and hereditary neuropathy with liability to pressure palsies (HNPP). We screened for mutations in the peripheral myelin protein genes connexin 32 (Cx32), myelin protein zero (P0) and peripheral myelin protein 22 (PMP22) by direct sequencing. All patients chosen for mutation screening were negative for the 1.5 Mb duplication/deletion at 17p11.2‐p12. Eleven Cx32 mutations were found in 12 families, six with a CMT2 diagnosis, three with a CMT1 diagnosis and three with unclassified CMT. The total number of patients in these 12 CMTX families was 61, giving a minimum prevalence of 1.2/100,000 for CMTX in Finland. Four of the mutations, Pro58Arg, Pro172Leu, Asn175Asp and Leu204Phe, have not been previously reported. One male patient with an early onset CMT had a double Cx32 mutation, Arg22Gln and Val63Ile. The double de novo mutation was found to be of maternal grandpaternal origin. In the P0 gene a Ser78Leu mutation was found in one family with severe CMT1 and a de novo Tyr82Cys mutation was found in one DSS patient. Both mutations have been previously reported in other CMT1 families. A novel PMP22 mutation, deletion of Phe84, was found in one sporadic DSS patient. Our mutation screening results show the necessity of molecular diagnosis, in addition to clinical and electrophysiological evaluation, for proper subtyping of the disease and for accurate genetic counseling. Hum Mutat 12:59–68, 1998. © 1998 Wiley‐Liss, Inc.

Salla disease (SD) is an autosomal recessive disorder in which free sialic acid (N-acetyl neuraminic acid) accumulates in lysosomes. A specific transport mechanism for acidic monosaccharides on the lysosomal membrane has recently been described, but the molecular deficiency causing SD is still unknown. We have previously mapped the SD gene to 6q14-q15 by means of genetic linkage analysis and restricted the positive chromosomal area to less than 100 kb with linkage disequilibrium mapping. The two best allelic association markers have now retrospectively been used in five prenatal analyses originally studied with sialic acid assays in chorionic villus specimens. In four cases an unaffected fetus was predicted with a probability level of more than 94%, which was in concordance with the biochemical data. One fetus was predicted to be affected with over 96% probability, as was shown by free sialic acid assays in a CVS sample and in fetal tissues after termination of the pregnancy. Risk calculations incorporating disequilibrium were also used to predict the carrier status in members of six families with previous SD cases, and also in a few cases with no known family history of SD. DNA marker based analysis thus provides a reliable method for risk estimations in prenatal cases and for carrier identification of SD.

Leber hereditary optic neuropathy (LHON) is a maternally inherited eye disease most commonly caused by mitochondrial DNA (mtDNA) point mutation at position 11778, 3460, or 14484. Approximately 14% of families show heteroplasmy for the pathogenic mutations but little is known about the mutational burden in different tissues of these heteroplasmic individuals. Consequently, estimating the risks of visual loss is difficult. This study presents quantitative mutation analyses of tissues representing all embryonal layers in two families heteroplasmic for the 11778 mutation. These analyses show that a high amount of mutated mtDNA in leukocytes is correlated with a high proportion of mutated mtDNA in other tissues. Hum Mutat 9:412–417, 1997. © 1997 Wiley‐Liss, Inc.

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. 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. 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. 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.

The structural gene encoding human α -L-iduronidase has been assigned to chromosome 22 by using immunologic, electrophoretic, and somatic cell hybridization techniques. Polyclonal rabbit antibodies raised against purified human low-uptake α -L-iduronidase were used to discriminate the human and murine isozymes by a sensitive immunoprecipitation assay. The human chromosome constitution of each clone was determined by cytogenetic and enzyme marker electrophoretic techniques. In 65 human (fibroblast)--mouse (RAG) somatic cell hybrids (from four independent fusions), the expression of human α -L-iduronidase was 100% concordant with the presence of human chromosome 22; the assignment was confirmed by the demonstration of the human enzyme in tertiary somatic cell hybrids containing only chromosome 22. Further verification of the gene assignment was made by detection of the human enzyme in tertiary chromosome 22 positive hybrids by Ouchterlony immunodiffusion and rocket immunoelectrophoretic experiments with polyclonal anti-human α -L-iduronidase antibodies that were monospecific for the human enzyme. Expression of human enzymatic activity in chromosome 22 positive hybrid lines was markedly reduced; for example, a tertiary hybrid (R-G21-J-15), which contained an average of 1.7 chromosome 22s per cell, only had about 15% of the activity detected in normal diploid fibroblasts. Immunologic studies suggested that the reduced expression was due to abnormal post-translation processing or aggregation (or both) of the human and murine isozymes in these hybrids. Regional assignment of the human structural gene to 22pter → q11 was accomplished by gene dosage studies using diploid human fibroblast lines that were partially monosomic or trisomic for chromosome 22.

A study was carried out in which activity of gamma-glutamyl transpeptidase was measured in 259 samples of amniotic fluid obtained at various weeks of pregnancy. Two hundred and twenty-eight of the babies subsequently delivered had no chromosome abnormality and served as controls, while in 31 various chromosome abnormalities were detected. Mean activity of gamma-glutamyl transpeptidase in the control samples at 15 weeks was 602 U/1. Activity in the samples obtained in cases of fetal chromosome abnormality was generally below this: it was below the 10th percentile in 74% of the samples and below the 2.5th percentile in 52% of the cases. It is concluded that assay of gamma-glutamyl transpeptidase activity is a rapid preliminary test for prenatal diagnosis of chromosomal abnormalities.