[Globoid cell leukodystrophy of adult. A first case in Poland]. / Leukodystrofia globoidalna doroslych. Pierwszy przypadek w Polsce.

Krabbe disease (globoid cell leukodystrophy) is a progressive, autosomal recessive disorder affecting peripheral and central nervous system. This disease is associated with mutation in GALC gene and its locus has been mapped to chromosome 14q31. GALC gene codes lysosomal hydrolytic enzyme: galactocerebroside ß-galactosidase (galactosylceramidase) which is crucial for degradation of galactolipids, mostly galactosylceramide and galactosylsphingosine (psychosine). The disease may be subdivided into four types: infantile form with onset within the first six months, child form presenting between 6 months and 3 years, juvenile form presenting between 3 and 10 years and the rarest adult form with onset after 10 years. The diagnosis of Krabbe disease is based on clinical findings and confirmed with galactocerebroside ß-galactosidase deficiency. We have found family with adult-onset disease. To our knowledge, this is the first observation of patient with adult form of Krabbe disease in Poland.

Enzyme replacement therapy for mucopolysaccharidosis II from 3 months of age: a 3-year follow-up.

AIM: We present a 3-year follow-up of a boy with mucopolysaccharidosis type II (MPS II) who had idursulfase therapy initiated at the age of 3 months and compare his clinical course to his healthy twin brother. METHODS: Detailed anthropometric features, ultrasound studies of liver and spleen volumes, echocardiography and audiological examinations, psychological tests, joint range of motion (ROM) and skeletal radiographs were monitored. RESULTS: After 3 years of treatment, the patient has not developed any clinical manifestations of MPS II. He did not develop coarse facial features, joint disease, or organomegaly, and his cardiac function remained normal. There were no pronounced signs of dysostosis multiplex on radiographs. The only difference when compared with his healthy twin brother was lower IQ (Termann-Merrill 98 vs. 118) and mild deformity of one vertebrae. CONCLUSION: Our study suggests that early initiation of enzyme replacement therapy may significantly slow or prevent the development of irreversible disease manifestations and therefore modify the natural history of MPS II.

Female Hunter syndrome caused by a single mutation and familial XCI skewing: implications for other X-linked disorders.

Familial X-chromosome inactivation (XCI) skewing was investigated in a family in which a female mucopolysaccharidosis type II (MPS II) (Hunter syndrome, an X-linked genetic disease) occurred. Among eight related females aged under 60 years from three generations who were tested, four revealed a non-random pattern of XCI. Detailed genetic analysis failed to find mutations in genes that were previously reported as important for the XCI process. Haplotype analysis excluded linkage of non-random XCI with genes localized on the X-chromosome. We propose that analysis of the XCI pattern should be taken into consideration when assessing risk factors for X-linked recessive genetic disorders.

Non-neuronopathic Gaucher disease due to saposin C deficiency.

Gaucher disease is generally caused by a deficiency of the lysosomal enzyme glucocerebrosidase. The degradation of glycosphingolipids requires also the participation of sphingolipid activator proteins. The prosaposin PSAP gene codes for a single protein which undergoes post-translational cleavage to yield four proteins named saposins A, B, C and D. Saposin (SAP-) C is required for glucosylceramide degradation, and its deficiency results in a variant form of Gaucher disease. In this report, we present clinical, biochemical, and molecular findings in a 36-year-old man and his 30-year-old sister with non-neuronopathic Gaucher disease due to SAP-C deficiency. Very high levels of chitotriosidase activity, chemokine CCL18, and increased concentration of glucosylceramide in plasma and normal beta-glucosidase activity in skin fibroblasts were observed in the patients. A molecular genetics study of the PSAP gene enabled the identification of one missense mutation, p.L349P, located in the SAP-C domain and another mutation, p.M1L, located in the initiation codon of the prosaposin precursor protein. The presented findings describe the first cases where the non-neuronopathic Gaucher disease has been definitely demonstrated to be a consequence of SAP-C deficiency. Three previously described cases in the literature displayed a Gaucher type 3 phenotype.

Molecular and phenotypic characteristics of metachromatic leukodystrophy patients from Poland.

The occurrence and genotype-phenotype correlations of the eight most common mutations in the arylsulfatase A (ARSA) gene were studied in 43 unrelated Polish patients suffering from different types of metachromatic leukodystrophy (MLD). Screening for mutations p.R84Q, p.S96F, c.459+1G>A, p.I179S, p.A212V, c.1204+1G>A, p.P426L, and c.1401-1411del allowed the identification of 53.5% of the mutant alleles. In the whole investigated group of patients, mutations c.459+1G>A and p.P426L were the most frequent, 19 and 17%, respectively. The prevalence of the third most frequent mutation, i.e. p.I179S (13%), seems to be higher than that in other populations. The incidence of c.1204+1G>A was 5%, which is higher than reported earlier (2%). It seems that p.I179S and c.1204+1G>A are more prevalent in MLD patients from Poland than from other countries. In the group examined by us, mutations p.R84Q, p.S96F, p.A212V, and c.1401-1411del were not detected; thus, 46.5% of MLD alleles remained unidentified. This indicates that other, novel or already described, but rare, mutations exist in Polish population. In late infantile homozygotes for c.459+1G>A and one homozygote for c.1204+1G>A, first clinical symptom was motor deterioration. In adult homozygotes for p.P426L, the disease onset manifested as gait disturbances, followed by choreoathetotic movements, difficulties in swallowing, dysarthria, tremor, and nystagmus. In the carriers of the p.I179S mutation, the hallmark of the clinical picture was psychotic disturbances.

Assessment of relations between clinical outcome of ischemic stroke and activity of inflammatory processes in the acute phase based on examination of selected parameters.

BACKGROUND AND PURPOSES: Inflammatory factors play an important role in the pathogenesis of ischemic stroke. They may influence circulation during the acute phase of stroke and enhance the ischemic region. MATERIALS AND METHODS: We examined 51 patients--36 patients in the early stage of stroke, i.e. the first 24 h after onset. Of these, 15 patients had infection and 21 had no infection during the week preceding stroke. There were 15 patients with noninflammatory diseases in the control group. We analyzed parameters of inflammation such as: activity of serum chitotriosidase by fluorimetric assay, C-reactive proteins (CRP), number of white body cells (WBCs), IgG and fibrinogen. We also assessed the neurological stage according to the Scandinavian Stroke Scale (SSS). RESULTS: In our study, we observed a statistically significant difference (p < 0.05) in the activity of most parameters of inflammation. This difference could be seen in the levels of CRP, number of WBCs and the activity of chitotriosidase, apart from IgG and fibrinogen, between the control group and groups with versus without infection. A significantly increased level of CRP (p < 0.0005) and fibrinogen (p > 0.01) was found on the first day in the stroke group as compared to the control group. The neurological stage on day 4 after stroke, assessed according to the SSS, was significantly worse in the group of patients with infection before stroke than in stroke patients without infection (p < 0.008). CONCLUSION: These results suggest the importance of active inflammatory processes in the pathogenesis of stroke. We observed increased activity of chitotioridase, a parameter of the inflammatory process, in stroke. This study is one more proof that inflammatory processes caused by infection may influence the occurrence of stroke and worsen its outcome. It could be another step towards understanding immunological processes during the acute phase of stroke. The study may also help establish new diagnostic and therapeutic strategies and could be a useful tool for prophylaxis.

Prevalence of arylsulfatase A pseudodeficiency allele in metachromatic leukodystrophy patients from Poland.

Arylsulfatase A (ASA) pseudodeficiency (PD) allele was searched for in 22 patients originating from Poland and suffering from different types of metachromatic leukodystrophy (MLD). Four of them carried the PD allele in a heterozygous state. The prevalence of the PD allele among investigated MLD patients was revealed to be 9%, while the frequency of the PD allele in healthy controls was estimated at 6-7%. One of the examined MLD patients was additionally a carrier of an isolated mutation leading to the loss of the N-glycosylation site. The question arises whether and how MLD mutations create a convenient milieu for PD mutations to occur (or inversely).

Characterization of the sialidase molecular defects in sialidosis patients suggests the structural organization of the lysosomal multienzyme complex.

Sialidosis is an autosomal recessive disease caused by the genetic deficiency of lysosomal sialidase, which catalyzes the hydrolysis of sialoglycoconjugates. The disease is associated with progressive impaired vision, macular cherry-red spots and myoclonus (sialidosis type I) or with skeletal dysplasia, Hurler-like phenotype, dysostosis multiplex, mental retardation and hepatosplenomegaly (sialidosis type II). We have analyzed the genomic DNA from nine sialidosis patients of multiple ethnic origin in order to find mutations responsible for the enzyme deficiency. The activity of the identified variants was studied by transgenic expression. One patient had a frameshift mutation (G623delG deletion), which introduced a stop codon, truncating 113 amino acids. All others had missense mutations: G679G-->A (Gly227Arg), C893C-->T (Ala298Val), G203G-->T (Gly68Val), A544A-->G (Ser182Gly) C808C-->T (Leu270Phe) and G982G-->A (Gly328Ser). We have modeled the three-dimensional structure of sialidase based on the atomic coordinates of the homologous bacterial sialidases, located the positions of mutations and estimated their potential effect. This analysis showed that five mutations are clustered in one region on the surface of the sialidase molecule. These mutations dramatically reduce the enzyme activity and cause a rapid intralysosomal degradation of the expressed protein. We hypothesize that this region may be involved in the interface of sialidase binding with lysosomal cathepsin A and/or beta-galactosidase in their high-molecular-weight complex required for the expression of sialidase activity in the lysosome.

[Hyperactivity and behavioral disorders in Sanfilippo A (mucopolysaccharidosis type IIIA)--case report and review of the literature]. / Nadpobudliwosc psychoruchowa i zaburzenia behawioralne w przebiegu choroby Sanfilippo A (mukopolisacharydozy typu IIIA)--opis przypadku i przeglad pismiennictwa.

Sanfilippo syndrome is one of mucopolysaccharidoses. The main symptom of this syndrome is regression of psychomotor development and neurological signs which occur between 2 and 6 years old. Unlike other mucopolysaccharidoses body dysmorfic features are relatively rare. Course of disease is progressive, most of the patients die before 20. The diagnosis is often difficult. In our opinion in each case presenting psychomotor regression of unknown origin metabolic disease should be excluded (e.g. urine analysis for mucopolysaccharides should be indicated). A 6 year old boy has been under psychiatric and psychological control since he was 3 due to psychomotor retardation, hyperactivity, autistic features, and behavioural disorder. In paediatric examination thickened facial features, coarse hair, knock-knees, short neck were noted. Genetic consultation set up the diagnosis of mucopolysaccharidosis type IIIA (Sanfilippo A disease).

Type III D mucopolysaccharidosis (Sanfilippo D): clinical course and symptoms.

A case of a rare form of Sanfilippo disease, mucopolysaccharidosis type III D is presented. The cause of the disease is a deficit of N-acetylglycosamine-6-sulfate sulfatase. Differences in clinical course and symptoms with type A and B Sanfilippo disease are shown (later presentation of symptoms, milder course, lack of distinct psychomotor regression and differences in characteristic phenotypic traits, such as facial features, joint contracture, tall height). It is suggested that type III D mucopolysaccharidosis be taken into account in the differentiation of mental retardation syndromes with hyperactivity.

Serum chitotriosidase activity in Gaucher patients on enzyme replacement therapy (ERT).

OBJECTIVE: Changes of serum chitotriosidase activity during Ceredase treatment of Gaucher patients. DESIGN AND METHODS: Ten Gaucher patients were treated with Ceredase for up to 30 months. Serum or plasma chitotriosidase activity was measured using 4-methylumbelliferyl-beta-D-N,N',N"triacetyl-chitotrioside. RESULTS: In untreated patients, serum chitotriosidase activity did not depend on the patient's age and was not a measure of clinical status, type or progress of the disease. Chitotriosidase activity declined during treatment with Ceredase, but still remained high. The largest decline in enzyme activity was observed in patients with type III of the disease who had intact spleens; splenectomized type III patients, and type I patients reacted more slowly. CONCLUSIONS: Serum chitotriosidase activity may indicate that a patient has reacted to treatment, however, it can not be considered a direct marker of treatment effectiveness.

Practical suggestions in diagnosing metachromatic leukodystrophy in probands and in testing family members.

Metachromatic leukodystrophy (MLD) is one of the most severe genetically determined demyelination diseases. It is caused by a deficit in the activity of sulfatide sulfatase. The diagnosis is made by demonstrating a deficiency of arylsulfatase A (ASA) activity in leukocytes or cultured skin fibroblasts. Diagnosis based only on the activity of ASA is complicated by the fact that there exists a condition of ASA pseudodeficiency (Pd). Due to the relatively high risk of the MLD/Pd and MLDPd/Pd genotypes among families of patients, it is possible to make an erroneous diagnosis on the basis of only ASA activity. Nonetheless, it seems necessary to develop a reliable and simple diagnostic procedure so as to enable diagnosis and genetic counseling for carriers. We present two diagnostic flow charts entailing determination of ASA activity, identification of the pseudodeficit mutation and detection of sulfatides in a 24-hour urine collection.

Clinical, biochemical and molecular findings in a two-generation Morquio A family.

Mucopolysaccharidosis type IVA (Morquio A) is caused by a deficiency of N-acetylgalactosamine-6-sulfatase (GALNS), an enzyme capable of cleaving the sulfate group from both N-acetylgalactosamine-6-sulfate and galactose-6-sulfate. We describe here a two-generation Morquio A family with two distinct clinical phenotypes. The two probands from the second generation showed intermediate signs of the disease whereas their affected mother, aunt and two uncles had only very mild symptoms. Galactose-6-sulfatase (GALS) activity in leukocytes and fibroblasts of the affected family members was clearly deficient. Molecular genetic analysis of the GALNS gene revealed that two different point mutations segregate in the family, which correlated well with the clinical phenotype. The probands with intermediate symptoms were compound heterozygotes for the mutations R259Q and R94G, the latter one being inherited from the unaffected father. The mother and her affected siblings with the unusually mild phenotype were proven to be homozygous for the novel missense point mutation R259Q.

[Familial metachromatic leukodystrophy as a cause of psychotic manifestations in young adults]. / Rodzinna leukodystrofia metachromatyczna jako przyczyna zaburzen psychicznych u mlodych osób doroslych.

Cases of metachromatic leucodystrophy in brother and sister are presented. The clinical pattern in the female was characterised by the progressing dementia, whereas in the male the first symptom was the manic syndrome. The neurological status was normal. The cases were diagnosed by the demyelination visible in MRI pattern and in the decreased activity of arylsulphatase A in blood leukocytes.

Two distinct deletions in the IDS gene and the gene W: a novel type of mutation associated with the Hunter syndrome.

A novel mutation has been identified in a patient with the Hunter syndrome (mucopolysaccharidosis type II), in whom the disorder is associated with two distinct deletions separated by 30 kb. The deletions were characterized by Southern blot and PCR analyses, and the nucleotide sequences at both junctions were determined. The first deletion, corresponding to a loss of 3152 bp of DNA, included exons 5 and 6 of the iduronate-2-sulfatase (IDS) gene. The second deletion was 3603 bp long and included exons 3 and 4 of gene W, which is located in the DXS466 locus telomeric of the IDS gene. Both deletions are the result of nonhomologous (illegitimate) recombination events between short direct repeats at the deletion breakpoints. An interesting finding was the presence of the heptamer sequence 5'-TACTCTA-3' present at both deletion junctions, suggesting that this motif might be a hot spot for recombination. We propose that the double deletion is the result of homology-associated nonhomologous recombinations caused by the presence of large duplicated regions in Xq27.3-q28.

Identification of 31 novel mutations in the N-acetylgalactosamine-6-sulfatase gene reveals excessive allelic heterogeneity among patients with Morquio A syndrome.

Mutation analysis of the N-acetylgalactosamine-6-sulfate sulfatase gene was performed in a group of 35 patients with mucopolysaccharidosis type IVA from 33 families, mainly of European origin. By nonradioactive SSCP screening, 35 different gene mutations were identified, 31 of them novel. Together they account for 88.6% of the disease alleles of the patients investigated. The vast majority of the gene alterations proved to be point mutations, 23 missense, 2 nonsense, and 3 affecting splicing. Six small deletions (1-27 bp) and one insertion were also characterized. In a Polish family, two mildly affected siblings were compound heterozygotes for R94G and R259Q. Their mother was homozygous for the latter point mutation, leading to enzyme deficiency and a borderline disease phenotype.