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H B Ginjaar,
A J van der Kooi,
H Ceelie,
A L Kneppers,
M van Meegen,
P G Barth,
H F Busch,
J H Wokke,
L V Anderson,
C G Bönnemann,
M Jeanpierre, P A Bolhuis,
A F Moorman,
M de Visser,
E Bakker,
G J Ommen
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ABSTRACT: Within a group of 76 sporadic/autosomal recessive limb girdle muscular dystrophy (LGMD) patients we tried to identify those with LGMD type 2C-E. Muscle biopsy specimens of 40 index patients, who had 22 affected sibs, were analyzed immuno-histochemically for the presence of three subunits: alpha-, beta-, and gamma-sarcoglycans. Abnormal sarcoglycan expression was established in eight patients, with six affected sibs. In one patient gamma-sarcoglycan was absent, and both alpha- and beta-sarcoglycans were reduced. In the remaining seven patients gamma-sarcoglycan was (slightly) reduced, and alpha- and beta-sarcoglycans were absent or reduced. By DNA sequencing mutations were detected in one of the three sarcoglycan genes in all eight cases. Three patients had mutations in the alpha-, three in the beta-, and two in the gamma-sarcoglycan gene. The patients with sarcoglycanopathy comprised the more severely affected cases (P=0.04). In conclusion, sarcoglycanopathy was identified in 23 % (14/62) of the autosomal recessive LGMD patients.
Journal of Neurology 08/2000; 247(7):524-9. · 3.47 Impact Factor
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ABSTRACT: LGMD1B is an autosomal dominantly inherited, slowly progressive limb girdle muscular dystrophy, with age-related atrioventricular cardiac conduction disturbances and the absence of early contractures. The disease has been linked to chromosome 1q11-q21. Within this locus another muscular dystrophy, the autosomal dominant form of Emery-Dreifuss muscular dystrophy (AD-EDMD) has recently been mapped and the corresponding gene identified. AD-ADMD is characterized by early contractures of elbows and Achilles tendons and a humero-peroneal distribution of weakness combined with a cardiomyopathy with conduction defects. The disease gene of AD-EDMD is LMNA which encodes lamins A/C, two proteins of the nuclear envelope. In order to identify whether or not LGMD1B and AD-EDMD are allelic disorders, we carried out a search for mutations in the LMNA gene in patients with LGMD1B. For this, PCR/SSCP/sequencing screening was carried out for the 12 exons of LMNA on DNA samples of individuals from three LGMD1B families that were linked to chromo-some 1q11-q21. Mutations were identified in all three LGMD1B families: a missense mutation, a deletion of a codon and a splice donor site mutation, respectively. The three mutations were identified in all affected members of the corresponding families and were absent in 100 unrelated control subjects. The present identification of mutations in the LMNA gene in LGMD1B demonstrates that LGMD1B and AD-EDMD are allelic disorders. Further analysis of phenotype-genotype relationship will help to clarify the variability of the phenotype observed in these two muscular dystrophies.
Human Molecular Genetics 06/2000; 9(9):1453-9. · 7.64 Impact Factor
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ABSTRACT: Barth syndrome (BTHS) is a rare X-linked recessive disorder characterized by cardiac and skeletal myopathy, neutropenia, and short stature. A gene for BTHS, G4.5, was recently cloned and encodes several novel proteins, named "tafazzins." Unique mutations have been found. No correlation between the location or type of mutation and the phenotype of BTHS has been found. Female carriers of BTHS seem to be healthy. This could be due to a selection against cells that have the mutant allele on the active X chromosome. We therefore analyzed X chromosome inactivation in 16 obligate carriers of BTHS, from six families, using PCR in the androgen-receptor locus. An extremely skewed X-inactivation pattern (>=95:5), not found in 148 female controls, was found in six carriers. The skewed pattern in two carriers from one family was confirmed in DNA from cultured fibroblasts. Five carriers from two families had a skewed pattern (80:20-<95:5), a pattern that was found in only 11 of 148 female controls. Of the 11 carriers with a skewed pattern, the parental origin of the inactive X chromosome was maternal in all seven cases for which this could be determined. In two families, carriers with an extremely skewed pattern and carriers with a random pattern were found. The skewed X inactivation in 11 of 16 carriers is probably the result of a selection against cells with the mutated gene on the active X chromosome. Since BTHS also shows great clinical variation within families, additional factors are likely to influence the expression of the phenotype. Such factors may also influence the selection mechanism in carriers.
The American Journal of Human Genetics 12/1998; 63(5):1457-63. · 10.60 Impact Factor
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ABSTRACT: In six families with hereditary neuropathy with liability to pressure palsies (HNPP) the 17p11.2 deletion was absent, but single strand conformation-analysis and subsequent sequencing demonstrated a heterozygous G-insertion in a stretch of six Gs at nt 276281 of the PMP22 gene, resulting in a frame shift after Gly94. Haplotype comparison of the six families revealed common ancestry. We compared the phenotype of 23 patients from these six families with the phenotype of 63 patients of 17 families with the common deletion. The patients with the G-insertion showed the clinical, electrophysiological and morphological characteristics of common HNPP, but in addition they had significantly more neuropathic features, mimicking hereditary motor and sensory neuropathy type I (HMSN I) or Charcot-Marie-Tooth disease type 1 (CMT1). To explain this distinct phenotype we suggest that, by translation of the mutated gene, a markedly changed polypeptide is formed without the normal cytoplasmic C-terminal of the native protein, resulting in a loss of function similar to that with the common deletion, but exerting an extra disturbance of Schwann cell functions, probably by hampering normal myelin formation or maintenance.
Brain 09/1998; 121 ( Pt 8):1451-8. · 9.46 Impact Factor
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ABSTRACT: Miyoshi-type distal muscular dystrophy (MMD) is an autosomal recessively inherited progressive disorder. The putative locus of MMD is linked to the limb-girdle muscular dystrophy 2B locus on chromosome 2p12-14. In this study three of four MMD pedigrees show non-linkage to the region spanned by D2S134-D2S358-D2S145 on chromosome 2p, indicating genetic heterogeneity. A genome wide screen was performed to identify loci linked to MMD. In two non-chromosome 2-linked families, a 23 cM region on chromosome 10 segregated with MMD.
Neuromuscular Disorders 07/1998; 8(5):317-20. · 2.80 Impact Factor
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ABSTRACT: Limb girdle muscular dystrophy is a heterogeneous group of disorders. One autosomal recessive subtype, LGMD2C, has been linked to chromosome 13, and is caused by gamma-sarcoglycan deficiency in muscle. This report describes a novel missense mutation identified in a large consanguineous Dutch family with LGMD. This mutation leads to reduction of gamma-sarcoglycan, and gives rise to a childhood-onset, slowly-progressive dystrophy.
Neuromuscular Disorders 07/1998; 8(5):305-8. · 2.80 Impact Factor
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P D'Adamo,
L Fassone,
A Gedeon,
E A Janssen,
S Bione, P A Bolhuis,
P G Barth,
M Wilson,
E Haan,
K H Orstavik,
M A Patton,
A J Green,
E Zammarchi,
M A Donati,
D Toniolo
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ABSTRACT: Barth syndrome (BTHS) is an X-linked disorder characterized clinically by the associated features of cardiac and skeletal myopathy, short stature, and neutropenia. The clinical manifestations of the disease are, in general, quite variable, but cardiac failure as a consequence of cardiac dilatation and hypertrophy is a constant finding and is the most common cause of death in the first months of life. X-linked cardiomyopathies with clinical manifestations similar to BTHS have been reported, and it has been proposed that they may be allelic. We have recently identified the gene responsible for BTHS, in one of the Xq28 genes, G4.5. In this paper we report the sequence analysis of 11 additional familial cases: 8 were diagnosed as possibly affected with BTHS, and 3 were affected with X-linked dilated cardiomyopathies. Mutations in the G4.5 gene were found in nine of the patients analyzed. The molecular studies have linked together what were formerly considered different conditions and have shown that the G4.5 gene is responsible for BTHS (OMIM 302060), X-linked endocardial fibroelastosis (OMIM 305300), and severe X-linked cardiomyopathy (OMIM 300069). Our results also suggest that very severe phenotypes may be associated with null mutations in the gene, whereas mutations in alternative portions or missense mutations may give a "less severe" phenotype.
The American Journal of Human Genetics 11/1997; 61(4):862-7. · 10.60 Impact Factor
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ABSTRACT: Despite much effort, a 74 year old man with progressive proximal weakness and sensory disturbances due to axonal neuropathy remained a diagnostic problem. Investigation of his family disclosed an additional patient with a cerebellar syndrome and a family member with mainly pyramidal features. Analysis of DNA showed a CAG repeat expansion in the Machado-Joseph disease gene in all three patients. Although not conclusively proved, we think that the neuropathy of the index case is linked to the CAG repeat expansion. Machado-Joseph disease should be considered in progressive axonal neuropathy.
Journal of Neurology Neurosurgery & Psychiatry 11/1997; 63(4):534-6. · 4.76 Impact Factor
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ABSTRACT: Leber hereditary optic neuropathy (LHON) is a maternally inherited disorder, associated with mutations in the mitochondrial DNA, which is notorious for its aspecific presentations. Two pedigrees are described with cases that are atypical for LHON with respect to sex, age of onset, interval between the eyes becoming affected, course of the disease, concomitant disorders, additional test results, final visual acuity, and/or results of mtDNA analysis. Moreover, the pedigrees themselves did not suggest maternal inheritance. We analysed the diagnostic and clinical genetic difficulties related to the atypical aspects of these pedigrees. We conclude that mtDNA analysis is justified in every case of optic nerve atrophy with no clear cause. Identification of one of the three LHON specifically associated mtDNA mutations is essential to confirm the diagnosis.
Clinical Genetics 07/1997; 51(6):388-93. · 3.13 Impact Factor
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ABSTRACT: Limb-girdle muscular dystrophy (LGMD) constitutes a clinically and genetically heterogeneous group of myogenic disorders with a limb-girdle distribution of weakness. One autosomal dominant family, LGMD1A, has been linked to chromosome 5q, whereas in other autosomal dominant families linkage to this chromosome has been excluded. We studied 58 members of three families with a newly recognized autosomal dominantly inherited LGMD with cardiac involvement. A search with highly polymorphic microsatellite markers was carried out. The gene for this newly recognized dominant form of LGMD was located on chromosome 1q11-21, with a combined maximum two-point LOD score >12 at theta = 0.
The American Journal of Human Genetics 05/1997; 60(4):891-5. · 10.60 Impact Factor
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ABSTRACT: Single-strand conformational polymorphisms (SSCP) of the connexin32 gene were analyzed in 121 patients possibly affected by Charcot-Marie-Tooth (CMT) disease. The 121 patients were selected from 443 possible CMT/HNPP (hereditary neuropathy with liability to pressure palsies) patients based on genetic linkage to Xq13.1, absence of the 17p12 duplication and deletion, and absence of point mutations in PMP22 and P0. We found five new mutations at nucleotides 105 (C-T), 316 (C-G), 321 (C-T), 328 (T-C), and 657 (G-C), and three mutations at nucleotide 126 (C-T), 249 (G-A), and 477 (G-A) previously described in other unrelated families. The nucleotide changes resulted in seven amino-acid substitutions and one premature stop codon.
Human Genetics 05/1997; 99(4):501-5. · 5.07 Impact Factor
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ABSTRACT: To investigate relations between clinical and neuropathological features and age of onset, presence of anticipation, and genetic linkage in autosomal dominant cerebellar ataxia type II (ADCA II).
The natural history of ADCA II was studied on the basis of clinical and neuropathological findings in two pedigrees and genetic linkage studies were carried out with polymorphic DNA markers in the largest, four generation, pedigree.
Ataxia was constant in all age groups. Retinal degeneration with early extinction of the electroretinogram constituted an important component in juvenile and early adult (< 25 years) onset but was variable in late adult presentation. Neuromuscular involvement due to spinal anterior horn disease was an important contributing factor to illness in juvenile cases. Postmortem findings in four patients confirm the general neurodegenerative nature of the disease, which includes prominent spinal anterior horn involvement and widespread involvement of grey and white matter. Genetic linkage was found with markers to chromosome 3p12-p21.1 (maximum pairwise lod score 4.42 at D3S1285).
The sequence of clinical involvement seems related to age at onset. Retinal degeneration is variable in late onset patients and neuromuscular features are important in patients with early onset. Strong anticipation was found in subsequent generations. Linkage of ADCA II to chromosome 3p12-p21.1 is confirmed.
Journal of Neurology Neurosurgery & Psychiatry 04/1997; 62(4):367-71. · 4.76 Impact Factor
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ABSTRACT: P0-glycoprotein, the major integral membrane protein of peripheral nerve myelin, is thought to mediate myelination and membrane interactions via its extracellular domain (P0-ED). Molecular modeling of P0-ED has suggested which of its amino acid side-chains may be involved in heterophilic and homophilic adhesions. We previously showed that some of these amino acids are the same ones that are substituted or deleted due to mutations in the human gene for P0 (MPZ), which correlate with certain cases of demyelinating motor and sensory peripheral neuropathies. In the current study, high magnification electron microscopy was used to examine the myelin membrane packing in sural nerve biopsies from patients with MPZ mutations. We found that there were distinguishable ultrastructural phenotypes that could be explained by the alterations in P0-ED. These phenotypes, which were not observed in a control nerve, included widening or irregularity of the extracellular apposition alone (delta Ser34; Arg69Cys), widening at both the extracellular and cytoplasmic appositions (Arg69His), the presence of focal bridges in the widened extracellular space (Arg69His), and a diminished (Arg69Cys) or absence (Arg69His) of staining of the double intraperiod line. Our study, which suggests that the altered P0 is incorporated into the myelin sheath, provides a unique basis for further molecular/ultrastructural correlations between P0-ED structure and myelination irregularities.
Journal of Neuroscience Research 12/1996; 46(4):502-8. · 2.74 Impact Factor
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ABSTRACT: Mutations in the major peripheral myelin protein zero (P0) gene on chromosome 1q21-q23 have been found with the hereditary demyelinating polyneuropathy Charcot-Marie-Tooth type 1B. Here, we describe 2 patients with distinct neurological characteristics, carrying different substitutions at the same codon--Arg69His and Arg69Cys. The patients were heterozygous for the mutation, which in both appeared to be de novo. Histological examination of sural nerve biopsy specimens revealed defective myelin as well as marked differences, confirming the importance of P0 in the compaction of myelin.
Annals of Neurology 11/1996; 40(4):672-5. · 11.09 Impact Factor
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A J van der Kooi,
P G Barth,
H F Busch,
R de Haan,
H B Ginjaar,
A J van Essen,
L J van Hooff,
C J Höweler,
F G Jennekens,
P Jongen,
H J Oosterhuis,
G W Padberg,
F Spaans,
A R Wintzen,
J H Wokke,
E Bakker,
G J van Ommen, P A Bolhuis,
M de Visser
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ABSTRACT: A cross-sectional study was performed in the Netherlands to define the clinical characteristics of the various subtypes within the broad and heterogeneous entity of limb girdle muscular dystrophy (LGMD). An attempt was made to include all known cases of LGMD in the Netherlands. Out of the reported 200 patients, 105 who fulfilled strictly defined criteria were included. Forty-nine patients, mostly suffering from dystrophinopathies and facioscapulohumeral muscular dystrophy, appeared to be misdiagnosed. Thirty-four cases were sporadic, 42 patients came from autosomal recessive and 29 from autosomal dominant families. The estimated prevalence of LGMD in the Netherlands was at least 8.1 x 10(-6). The clinical features of the autosomal recessive and sporadic cases were indistinguishable from those of the autosomal dominant patients, although calf hypertrophy was seen more frequently, and the course of the disease was more severe in autosomal recessive and sporadic cases. The pectoralis, iliopsoas and gluteal muscles, hip adductors and hamstrings were the most affected muscles. Distal muscle involvement occurred late in the course of the disease. Facial weakness was a rare phenomenon. The severity of the clinical picture was correlated with a deteriorating lung function. All autosomal dominantly inherited cases showed a mild course, although in two families life-expectancy was reduced because of concomitant cardiac involvement.
Brain 11/1996; 119 ( Pt 5):1471-80. · 9.46 Impact Factor
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A A Gabreëls-Festen,
J E Hoogendijk,
P H Meijerink,
F J Gabreëls, P A Bolhuis,
S van Beersum,
T Kulkens,
E Nelis,
F G Jennekens,
M de Visser,
B G van Engelen,
C Van Broeckhoven,
E C Mariman
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ABSTRACT: In seven unrelated patients with a demyelinating motor and sensory neuropathy, we found mutations in exons 2 and 3 of the P0 gene. Morphologic examination of sural nerve biopsy specimens showed a demyelinating process with onion bulb formation in all cases. In four patients, ultrastructural examination demonstrated uncompacted myelin in 23 to 68% of the myelinated fibers, which is in agreement with the widely accepted function of P0 as a homophilic adhesion molecule. Three patients showed normal compact myelin, but morphology was dominated by the abundant occurrence of focally folded myelin. The two divergent pathologic phenotypes exemplify that some mutations act differently on P0 protein formation or function than others, which is probably determined by site and nature of the mutation in the P0 gene.
Neurology 10/1996; 47(3):761-5. · 8.31 Impact Factor
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ABSTRACT: Among the diverse family of collagens, the widely expressed microfibrillar type VI collagen is believed to play a role in bridging cells with the extracellular matrix. Several observations imply substrate properties for cell attachment as well as association with major collagen fibers. Previously, we have established genetic linkage between the genes encoding the three constituent alpha-chains of type VI collagen and Bethlem myopathy. A distinctive feature of this autosomal dominant disorder consists of contractures of multiple joints in addition to generalized muscular weakness and wasting. Nine kindreds show genetic linkage to the COL6A1-COL6A2 cluster on chromosome 21q22.3 (refs 3,4; manuscript submitted) whereas one family shows linkage to markers on chromosome 2q37 close to COL6A3 (ref. 5). Sequence analysis in four families reveals a mutation in COL6A1 in one and a COL6A2 mutation in two other kindreds. Both mutations disrupt the Gly-X-Y motif of the triple helical domain by substitution of Gly for either Val or Ser. Analogous to the putative perturbation of the anchoring function of the dystrophin-associated complex in congenital muscular dystrophy with mutations in the alpha 2-subunit of laminin, our observations suggest a similar mechanism in Bethlem myopathy.
Nature Genetics 10/1996; 14(1):113-5. · 35.53 Impact Factor
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ABSTRACT: Fibroblasts were cultured from 5 unrelated familial amyotrophic lateral sclerosis (FALS) patients and from healthy control subjects. In parallel, fibroblasts were examined for signs of abnormal oxidative stress by study of reactive oxygen species metabolism and, concurrently, leukocyte DNA from the same patients was examined for superoxide dismutase 1 (SOD1) mutations. The endogenous production of reactive oxygen species was assessed by following the menadione-induced reduction of oxidized cytochrome o, added to the medium. FALS and control fibroblasts exhibited the same rate of metabolism. Also levels of thiobarbturic-acid-reactive species (TBARS), a marker of lipid peroxidation, were similar in fibroblasts from either group. The search for SOD1 mutations by linkage study and cycle sequencing proved negative. We did not find evidence for SOD1 mutations by either method of study. Our results provide no evidence for increased oxidative stress in fibroblasts from non-SOD1 mutant FALS.
Journal of the Neurological Sciences 09/1996; 139 Suppl:91-4. · 2.35 Impact Factor
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The American Journal of Human Genetics 09/1996; 59(2):481-5. · 10.60 Impact Factor
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M C Speer,
R Tandan,
P N Rao,
T Fries,
J M Stajich, P A Bolhuis,
G J Jöbsis,
J M Vance,
K D Viles,
K Sheffield,
C James,
S G Kahler,
M Pettenati,
J R Gilbert,
P H Denton,
L H Yamaoka,
M A Pericak-Vance
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ABSTRACT: The Bethlem myopathy, a childhood onset autosomal dominant myopathy with joint contractures, has recently been localized to 21q in a series of Dutch families and the alpha 1 and alpha 2 subunits of type VI collagen (COL6A1 and COL6A2) have been postulated as candidate genes. We investigate a large family of French Canadian descent (family 1489) in which the Bethlem myopathy is segregating. Family 1489 is unlinked to the region of interest on 21q, thus demonstrating locus heterogeneity within the Bethlem myopathy classification. In view of the localization of the genes coding the alpha 1 and alpha 2 subunits of type VI collagen on chromosome 21q, we carried out linkage analysis on chromosome 2q where the alpha 3 subunit of type VI collagen has been localized. We demonstrate linkage to markers in this region, define the region of disease gene localization, and confirm by FISH analysis that COL6A3 is located within the interval of interest making COL6A3 a feasible candidate gene for the Bethlem myopathy.
Human Molecular Genetics 08/1996; 5(7):1043-6. · 7.64 Impact Factor
