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F Piccolo

Publications and source records attributed to F Piccolo.

17 recordsLinked to original sources
PubMed1997

A biochemical, genetic, and clinical survey of autosomal recessive limb girdle muscular dystrophies in Turkey.

Autosomal recessive limb girdle muscular dystrophy (LGMD2) is a clinically and genetically heterogenous group of diseases involving at least six different loci. Five genes have already been identified: calpain-3 at LGMD2A (15q15), and four members of the sarcoglycan (SG) complex, alpha-SG at LGMD2D (17q21), beta-SG at LGMD2E (4q12), gamma-SG at LGMD2C (13q12), and delta-SG at LGMD2F (5q33-q34). The gene product at LGMD2B (2p13-p16) is still unknown and at least one other gene is still unmapped. We investigated 20 Turkish families (18 consanguineous) diagnosed as having LGMD2. Most of our patients had onset of symptoms before age 10. The phenotypes varied from severe to benign. We analyzed the SG complex by immunofluorescence and/or western blot. Genotyping was performed using markers defining the six known loci and the suspected genes were screened for mutations. Six of 17 index cases showed deficiency of the SG complex, by immunofluorescence and/or western blot. Seven cases involved one of the known genes of the SG complex (alpha, 2; beta, 1; and gamma, 4 cases), and five mutations were documented in the alpha- and gamma-SG genes. After linkage analysis, 10 families were characterized as having LGMD2A (calpain-3 deficiency), and all mutations were eventually identified. One family was classified as having LGMD2B and 1 family that has normal SGs was linked to the chromosome 5q33-q34 locus (LGMD2F). In 1 family there was no linkage to any of the known LGMD2 loci. It appears that in Turkey, there is a broad spectrum of genes and defects involved in LGMD2. It may be possible to correlate genotype to phenotype in LGMD2. All severe cases belonged to the gamma-SG-deficiency group. Nine calpain-3-deficient cases had intermediate and 1 had moderate clinical courses. The LGMD2B patient had a moderate clinical expression, whereas the LGMD2F case was truly benign.

Adolescent↗
PubMed1997

Absence of alpha-sarcoglycan and novel missense mutations in the alpha-sarcoglycan gene in a young British girl with muscular dystrophy.

An 11-year-old white female presented with progressive proximal muscle weakness and marked calf hypertrophy. Muscle biopsy showed severe dystrophy with normal expression of dystrophin. There was complete absence of the 50kDa dystrophin-associated glycoprotein (alpha-sarcoglycan). DNA analysis showed novel point mutations (one missense and one splicing) in the alpha-sarcoglycan gene at chromosomal location 17q21, confirming the diagnosis of limb-girdle muscular dystrophy type 2D (LGMD-2D). We believe this is one of the first confirmed white cases of primary alpha-sarcoglycanopathy identified in the UK. This case supports the assumption of a wide geographic prevalence of severe childhood onset autosomal recessive muscular dystrophy and genetic heterogeneity. In the future, with improved diagnostic accuracy it is likely that more cases demonstrating primary or secondary deficiency of alpha-sarcoglycan will be identified. We would recommend staining for dystrophin-associated glycoproteins (sarcoglycans) in all new cases of muscular dystrophy with normal dystrophin, and confirmation with DNA analysis where possible.

Biopsy↗
PubMed1997

Mutational diversity and hot spots in the alpha-sarcoglycan gene in autosomal recessive muscular dystrophy (LGMD2D).

Sarcoglycanopathies are a genetically heterogeneous group of autosomal recessive muscular dystrophies in which the primary defect may reside in any of the genes coding for the different partners of the sarcolemmal sarcoglycan (SG) complex: the alpha-SG (LGMD2D at 17q21.2), the beta-SG (LGMD2E at 4q12), the gamma-SG (LGMD2C at 13q12), and the delta-SG (LGMD2F at 5q33). We report a series of 20 new unrelated families with 14 different mutations in the alpha-SG gene. Along with the mutations that we previously reported this brings our cohort of patients with alpha-sarcoglycanopathy to a total of 31 unrelated patients, carrying 25 different mutations. The missense mutations reside in the extracellular domain of the protein. Five of 15 missense mutations, carried by unrelated subjects on different haplotype backgrounds and of widespread geographical origins, account for 58% of the mutated chromosomes, with a striking prevalence of the R77C substitution (32%). The severity of the disease varies strikingly and correlates at least in part with the amount of residual protein and the type of mutation. The recurrent R284C substitution is associated with a benign disease course.

Base Sequence↗
PubMed1997

Primary adhalinopathy (alpha-sarcoglycanopathy): clinical, pathologic, and genetic correlation in 20 patients with autosomal recessive muscular dystrophy.

Primary adhalin (or alpha-sarcoglycan) deficiency due to a defect of the adhalin gene localized on chromosome 17q21 causes an autosomal recessive myopathy. We evaluated 20 patients from 15 families (12 from Europe and three from North Africa) with a primary adhalin deficiency with two objectives: characterization of the clinical phenotype and analysis of the correlation with the level of adhalin expression and the type of gene mutation. Age at onset and severity of the myopathy were heterogeneous: six patients were wheel-chair bound before 15 years of age, whereas five other patients had mild disease with preserved ambulation in adulthood. The clinical pattern was similar in all the patients with symmetric characteristic involvement of trunk and limb muscles, calf hypertrophy, and absence of cardiac dysfunction. Immunofluorescence and immunoblot studies of muscle biopsy specimens showed a large variation in the expression of adhalin. The degree of adhalin deficiency was fairly correlated with the clinical severity. There were 15 different mutations (10 missense, five null). Double null mutations (three patients) were associated with severe myopathy, but in the other cases (null/missense and double missense) there was a large variation in the severity of the disease.

Adolescent↗
PubMed1996

Abnormalities in alpha-, beta- and gamma-sarcoglycan in patients with limb-girdle muscular dystrophy.

We have identified 12 cases from a group of 45 patients with early onset limb-girdle muscular dystrophy (LGMD), who have a deficiency of the 50 kDa dystrophin-associated glycoprotein, alpha-sarcoglycan. An additional male sibling of one case was also studied clinically. All 12 patients showed a concomitant, but variable, deficiency of alpha-, beta- and gamma-sarcoglycan. None of our patients had a defect in only one component of the sarcoglycan complex. Molecular analysis confirmed that a total absence of one sarcoglycan, associated with reduced expression of the other two, indicates a primary defect. Immunocytochemistry is thus useful for directing molecular studies. Morphological features not usually observed in Xp21 dystrophies were peripheral accumulations of mitochondria, discrete core-like areas, and nemaline rods in one case. Clinical severity and progression was variable between and within families but early loss of ambulation, at or before the age of 12 years, was associated with a total absence of gamma-sarcoglycan. Common clinical features were calf hypertrophy, contractures of the tendo achilles, lumbar lordosis, winging of the scapulae, weak hamstrings and weak neck muscles. All cases had grossly elevated serum creatine kinase. In contrast to patients with Duchenne muscular dystrophy (DMD), our patients with sarcoglycan deficiencies had normal early motor milestones, normal intellect, and good respiratory and cardiac function. Our data confirm that the sarcoglycan complex acts as a unit and that morphological and clinical features can distinguish patients with defects in the sarcoglycans from those with Xp21 dystrophy. In our group of patients prognosis is better than in DMD, but clinical variability makes this difficult to predict in isolated cases.

Age of Onset↗
PubMed1996

A founder mutation in the gamma-sarcoglycan gene of gypsies possibly predating their migration out of India.

We investigated the molecular basis of a severe form of early onset autosomal recessive muscular dystrophy with sarcoglycan (SG) deficiency in seven large Gypsy families living in different parts of Western Europe and apparently not closely related. They were linked to the LGMD2C locus (13q12) suggesting a primary defect in the gamma-SG gene coding for the 35 kDa dystrophin-associated glycoprotein. All of the 18 investigated patients were homozygous for the same G-->A transition in codon 283 producing the replacement of a conserved cysteine of the extra-cellular domain of the protein by a tyrosine. All affected chromosomes in homozygous and heterozygous relatives carried the same allele 5 of the intragenic marker D13S232. Flanking markers were studied to delineate a common ancestral haplotype, the size of which was used to compute the date of the founding mutation. We found evidence that the mutation occurred between 60 and 200 generations ago, therefore possibly predating the commonly accepted date of migration of the Gypsy ancestors out of India.

Biomarkers↗
PubMed1995

Primary adhalinopathy: a common cause of autosomal recessive muscular dystrophy of variable severity.

Marked deficiency of muscle adhalin, a 50 kDa sarcolemmal dystrophin-associated glycoprotein, has been reported in severe childhood autosomal recessive muscular dystrophy (SCARMD). This is a Duchenne-like disease affecting both males and females first described in Tunisian families. Adhalin deficiency has been found in SCARMD patients from North Africa Europe, Brazil, Japan and North America (SLR & KPC, unpublished data). The disease was initially linked to an unidentified gene on chromosome 13 in families from North Africa, and to the adhalin gene itself on chromosome 17q in one French family in which missense mutations were identified. Thus there are two kinds of myopathies with adhalin deficiency: one with a primary defect of adhalin (primary adhalinopathies), and one in which absence of adhalin is secondary to a separate gene defect on chromosome 13. We have examined the importance of primary adhalinopathies among myopathies with adhalin deficiency, and describe several additional mutations (null and missense) in the adhalin gene in 10 new families from Europe and North Africa. Disease severity varies in age of onset and rate of progression, and patients with null mutations are the most severely affected.

Adolescent↗
PubMed1995

Frequency of duplication at 17p11.2 in families of northeast Italy with Charcot-Marie-Tooth disease type 1.

Charcot-Marie-Tooth disease type 1 (CMT 1) is the most common form of the hereditary motor sensory neuropathies (HMSN) with a prevalence in the Italian population of 9.4/100,000 inhabitants. CMT 1 is a genetically heterogeneous disorder. Forty CMT 1 families (35 with recurrence of cases and 5 sporadic cases) living in northeastern Italy were analyzed with the probe pVAW409R3 to reveal the presence of 17p11.2 duplication. The duplication frequency that resulted was about 82% and not significantly different in familial and in sporadic cases (p = 0.801). This kind of molecular analysis can be very useful for the differential diagnosis of CMT 1 and for the early diagnosis in the absence of a clear clinical manifestation.

Alleles↗
PubMed1994

Missense mutations in the adhalin gene linked to autosomal recessive muscular dystrophy.

Adhalin, the 50 kDa dystrophin-associated glycoprotein, is deficient in skeletal muscle of patients having severe childhood autosomal recessive muscular dystrophy (SCARMD). In several North African families, SCARMD has been linked to chromosome 13q, but SCARMD has been excluded from linkage to this locus in other families. We have now cloned human adhalin cDNA and mapped the adhalin gene to chromosome 17q12-q21.33, excluding it from involvement in 13q-linked SCARMD. However, one allelic variant of a polymorphic microsatellite located within intron 6 of the adhalin gene cosegregated perfectly with the disease phenotype in a large family. Furthermore, missense mutations were identified within the adhalin gene that might cause SCARMD in this family. Thus, the adhalin gene is involved in at least one form of autosomal recessive muscular dystrophy.

Amino Acid Sequence↗
PubMed1990

Inflammation and cartilage metabolism in rheumatoid arthritis. Studies of the blood markers hyaluronic acid, orosomucoid, and keratan sulfate.

Single analyses of peripheral blood of rheumatoid arthritis (RA) patients showed a significant reduction in the mean value for keratan sulfate (KS) compared with that in control subjects, but the mean value for orosomucoid (OM) was elevated compared with that in control subjects. Some RA patients displayed highly elevated levels of hyaluronic acid (HA), while others exhibited normal levels. There was a significant inverse correlation between OM and KS content in RA patients, as well as a direct correlation between HA and OM. In longitudinal studies of RA patients, parallel changes in OM and HA and inverse changes between KS and OM or HA were commonly observed. Clinical analyses revealed that there was an inverse correlation between KS and morning stiffness, and direct correlations between the number of tender joints and HA, and between HA or the erythrocyte sedimentation rate and the number of joints with effusions. The reason(s) for the inverse correlation between KS and OM as an index of systemic inflammation remains to be established. Circulating HA represents an index of joint inflammation, for which a marker has not been previously available.

Adult↗
PubMed1980

Albright's hereditary osteodystrophy.

The authors observed different clinical forms of Albright's hereditary osteodystrophy in 4 members of a family (two sisters, their mother and the maternal grandfather). The sisters were affected by pseudohypoparathyroidism type I, the older manifested the hypocalcemic variety, the younger the normocalcemic variety; the mother and the grandfather presented only with short stature and subcutaneous calcifications. The variety of clinical and biochemical alterations observed in these 3 generations supports evidence that Albright's hereditary osteodystrophy has a broad spectrum and that distinctions between the various forms of pseudohypoparathyroidsim should not be rigidly considered.

Adult↗
PubMed1980

Hypothalamic-pituitary-gonadotropic function in girls with premature thelarche.

Hypothalamic-pituitary-gonadotropic activity was investigated in 9 girls with premature thelarche, and compared with that in 9 healthy girls and 6 girls with true precocious puberty. The gonadotropin stimulation test with luteinising hormone-releasing hormone was used. Girls with premature thelarche showed luteinising hormone response resembling that of normal girls, and follicle-stimulating hormone (FSH) response quite similar to that of girls with precocious puberty. This suggests that in premature thelarche there is a partial activation of the diencephalic-hypophyseal-gonadal axis, which affects FSH only. Premature thelarche therefore, should be considered as one of the disorders due to altered sensitivity of the hypothalamic receptors which regulate sex maturation.

Breast↗