-
[show abstract]
[hide abstract]
ABSTRACT: Metabolic myopathies include a broad group of diseases involving inherited enzyme defects in the various metabolic pathways and skeletal musculature. They show an extensive phenotypic variability of symptoms and different ages of manifestation. Symptoms often included intolerance to duress or permanent paresis. Some forms of metabolic myopathy, in particular mitochondriopathy, are associated with multsystemic organ participation. The diagnostics must be adjusted to individual cases and carried out in stages. Primary investigations should include blood parameters (e.g. creatine kinase measurement, muscle load tests and determination of the acylcarnitine spectrum) and a second step includes muscle biopsy for histological and enzyme investigations and special molecular genetic tests although the causative enzyme defect cannot be clarified in every case. On the other hand by means of a thorough investigation it is particularly important in patients with load intolerance to differentiate between other causes, in particular psychosomatic diseases. If this is not done there is a danger of classifying the symptoms of a metabolic myopathy as a somatoform disorder. Therapy is mostly symptom-oriented as Pompe disease is the only one which can be treated with enzyme replacement therapy.
Zeitschrift für Rheumatologie 04/2013; 72(3):242-54. · 0.46 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: This article describes two patients with late onset myofibrillary myopathy due the ZASP mutation Ala147Thr. The Z-band alternatively spliced PDZ motif containing protein (ZASP) is a sarcomeric protein and interacts with α-actinin at the Z-disk. So far, myopathy due the ZASP mutation Ala147Thr was usually associated with distal and proximal involvement. The two patients with the ZASP mutation Ala147Thr described here showed only distal involvement of the legs without proximal weakness and involvement of the upper limb 6 and 19 years after onset of muscle weakness, respectively.
Der Nervenarzt 12/2012; · 0.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mutations in C19orf12 have been recently identified as the molecular genetic cause of a subtype of neurodegeneration with brain iron accumulation (NBIA). Given the mitochondrial localization of the gene product the new NBIA subtype was designated mitochondrial membrane protein-associated neurodegeneration. Frequent features in the patients described so far included extrapyramidal signs and pyramidal tract involvement. Here, we report three C19orf12-mutant patients from two families presenting with predominant upper and lower motor neuron dysfunction mimicking amyotrophic lateral sclerosis with juvenile onset. While extrapyramidal signs were absent, all patients showed neuropsychological abnormalities with disinhibited or impulsive behavior. Optic atrophy was present in the simplex case. T2-weighted cranial MRI showed hypointensities suggestive of iron accumulation in the globi pallidi and the midbrain in all patients. Sequence analysis of C19orf12 revealed a novel mutation, p.Gly66del, compound heterozygous with known mutations in all patients. These patients highlight that C19orf12 defects should be considered as a differential diagnosis in patients with juvenile onset motor neuron diseases. Patients have to be examined carefully for neuropsychological abnormalities, optic neuropathy, and signs of brain iron accumulation in MRI.
Journal of Neurology 05/2012; · 3.47 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Background
McArdle disease, a common metabolic myopathy with autosomal recessive inheritance, is caused by a frequent R50X mutation and
many rare mutations in the myophosphorylase gene.
Objectives
To identify spectrum and frequencies of myophosphorylase gene mutations in a large cohort of patients with McArdle disease,
to discuss diagnostic implications, and to analyse genotype–phenotype relationship.
Methods
Molecular genetic analysis of 56 index patients with muscle biopsy-proven myophosphorylase deficiency from Germany (n = 35),
UK (n = 13), and several other countries (n = 8) was performed using direct sequencing.
Results
Allele frequency of the R50X mutation was 58%, and 71% of the patients carried this mutation at least on one allele. We detected
26 other less common mutations, 13 of which are novel: G157V, R161C, Q337R, E384K, S450L, G486D, R570W, K575E, IVS6-2A>T,
IVS10+1G>A, R650X, c.1354insC, c.1155_1156delGG. There was no genotype-phenotype correlation with respect to age of onset
and severity. R270X was the most frequent mutation among the less common mutations reaching an allele frequency of 5% followed
by R94W and G686R representing a frequency of 4% each.
Conclusions
The study further extends the genetic heterogeneity of myophosphorylase gene mutations showing no mutational hotspot and no
genotype–phenotype correlation. Most novel missense mutations were located in secondary structures or active sites of the
enzyme. Some of the less common mutations are recurrent with different frequencies within Europe. Ethnic origin and frequency
of less common mutations must be considered to establish efficient strategies in molecular genetic testing. Performing molecular
testing can avoid muscle biopsy.
Key words
genetic testing-McArdle disease-mutations-myophosphorylase deficiency
Journal of Neurology 04/2012; 254(6):797-802. · 3.47 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Recessive mutations in the anoctamin 5 (ANO5) gene have been recently identified in families with limb girdle muscular dystrophy (LGMD2L) and distal non-dysferlin Miyoshi myopathy. Anoctamin 5 is supposed to be a putative calcium-activated chloride channel. We report five German patients (four index patients) with muscle dystrophy due to mutations in the ANO5 gene. Sequencing of the ANO5 exons 5, 13 and 20 was performed to screen for a common c.191dupA mutation and two other reported mutations (c.1295C>G and p.R758C). The whole coding region of the ANO5 gene was sequenced to identify new mutations. Phenotypically, three patients showed LGMD and one patient Miyoshi type distal myopathy. One sibling had asymptomatic hyperCKemia. The age at onset was 64, 38 and 40 years in patients with LGMD and 23 years in the patient with distal myopathy. The four symptomatic patients showed remarkable asymmetric muscle involvement. There was marked CK elevation (11 to 30 times). Electron microscopy showed multifocal gaps in the sarcolemmal membrane. All patients harboured the common c.191dupA mutation in at least one allele. Two patients with LGMD were homozygous and the third patient and his asymptomatic sister were compound heterozygous for the c.191dupA mutation and a novel p.T548I mutation. The patient with distal myopathy harboured the p.R758C mutation in the second allele. Mutations in the ANO5 gene seem to be a relatively common cause of muscular dystrophy in Germany. Cases with late onset or asymptomatic hyperCKemia can occur. Clinically, asymmetric manifestation is typical.
Der Nervenarzt 07/2011; 82(12):1596-603. · 0.68 Impact Factor
-
Clinical biochemistry 05/2011; 44(7):476. · 2.02 Impact Factor
-
Neuromuscul Disord. 10/2010;
-
A D Funke,
M Esser,
A Krüttgen,
J Weis,
M Mitne-Neto,
M Lazar,
A L Nishimura,
A D Sperfeld,
P Trillenberg,
J Senderek,
M Krasnianski,
M Zatz,
S Zierz, M Deschauer
Clinical Genetics 03/2010; 77(3):302-3. · 3.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The term chronic progressive external ophthalmoplegia (CPEO) is not only a symptom but is also used as a syndrome within the group of mitochondrial diseases. However, the symptom CPEO might also occur in other well defined mitochondrial syndromes such as MELAS, MNGIE, SANDO. The molecular bases of the syndrome CPEO are mostly single or multiple deletions of the mtDNA, less frequently point mutations. Multiple deletions are caused by defects of nuclear encoded proteins. In this case, the mode of inheritance might be autosomal dominant or recessive. However, all these types of mtDNA mutations are not only associated with the symptom or syndrome of CPEO but might also cause other well defined mitochondrial syndromes. Thus, the diagnosis of CPEO either as a symptom or as a syndrome requires the subtle characterisation of the complete clinical phenotype as well as the precise genotype. Only on this basis a valid prognosis and information about the mode of inheritance are possible.
Klinische Monatsblätter für Augenheilkunde 10/2009; 226(10):822-8. · 0.51 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In congenital myasthenic syndrome with DOK7 mutations ephedrine was reported to be beneficial in single patients. We carried out a small, open and prospective cohort study in eight European patients manifesting from birth to 12 years. Five patients showed limb-girdle and facial weakness, three a floppy infant syndrome with bulbar symptoms and/or respiratory distress. Ephedrine was started with 25 mg/day and slowly increased to 75-100 mg/day. Within weeks after starting therapy an improvement was observed in all patients and clinical follow-up disclosed positive effects more pronounced on proximal muscle weakness and strength using MRC scale. Effects on facial weakness were less pronounced. Vital capacity measurements and repetitive stimulation tests did not improve in the same way as clinical symptoms did. These investigations are appropriate to confirm the diagnosis in case of pathological results, but they might not be appropriate means to monitor patients under ephedrine therapy.
Neuromuscular Disorders 10/2009; 19(12):828-32. · 2.80 Impact Factor
-
Neuromuscul Disord. 09/2009;
-
S Strothotte,
N Strigl-Pill,
B Grunert,
C Kornblum,
K Eger,
C Wessig, M Deschauer,
F Breunig,
F X Glocker,
S Vielhaber,
A Brejova,
M Hilz,
K Reiners,
W Müller-Felber,
E Mengel,
M Spranger,
Benedikt Schoser
[show abstract]
[hide abstract]
ABSTRACT: Late-onset glycogen storage disease type 2 (GSD2)/Pompe disease is a progressive multi-system disease evoked by a deficiency of lysosomal acid alpha-glucosidase (GAA) activity. GSD2 is characterized by respiratory and skeletal muscle weakness and atrophy, resulting in functional disability and reduced life span. Since 2006 alglucosidase alfa has been licensed as a treatment in all types of GSD2/Pompe disease. We here present an open-label, investigator-initiated observational study of alglucosidase alfa enzyme replacement therapy (ERT) in 44 late-onset GSD2 patients with various stages of disease severity. Alglucosidase alfa was given i.v. at the standard dose of 20 mg/kg every other week. Assessments included serial arm function tests (AFT), Walton Gardner Medwin scale (WGMS), timed 10-m walk tests, four-stair climb tests, modified Gowers' maneuvers, 6-min walk tests, MRC sum score, forced vital capacities (FVC), creatine kinase (CK) levels and SF-36 self-reporting questionnaires. All tests were performed at baseline and every 3 months for 12 months of ERT. We found significant changes from baseline in the modified Gowers' test, the CK levels and the 6-min walk test (341 +/- 149.49 m, median 342.25 m at baseline; 393 +/- 156.98 m; median 411.50 m at endpoint; p = 0.026), while all other tests were unchanged. ERT over 12 months revealed minor allergic reactions in 10% of the patients. No serious adverse events occurred. None of the patients died or required de novo ventilation. Our clinical outcome data imply stabilization of neuromuscular deficits over 1 year with mild functional improvement.
Journal of Neurology 09/2009; 257(1):91-7. · 3.47 Impact Factor
-
Neurology 02/2009; 72(1):96-7. · 8.31 Impact Factor
-
Neuromuscul Disord. 10/2008;
-
[show abstract]
[hide abstract]
ABSTRACT: In patients with late-onset glycogen storage disease type II, one mutation, c.-32-13T>G, in the α-glucosidase (GAA) gene is identified frequently in European populations from different regions along with many rarer mutations. We have performed molecular genetic investigations in 18 German index patients with late-onset disease. The c.-32-13T>G, c.525delT (p.Glu176fsX45), and c.2481+102_2646+31del mutations were detected by PCR/restriction enzyme digest. Other mutations were detected by sequencing. All patients were compound heterozygous and 17 patients harboured the c.-32-13T>G mutation. Seven other previously described mutations (including the c.-32-13T>G) were identified, of which the p.C103G (c.307T>G) and the c.2481+102_2646+31del mutations were present each in three unrelated patients. Sequencing revealed five novel mutations. CONCLUSIONS: Genetic testing was able to identify the genetic defects in all patients and screening of the c.-32-13T>G mutation identified 94% of the cases. This is important for quick and reliable diagnosis, especially in view of enzyme replacement. Among the rarer mutations, c.2481+102_2646+31del and p.C103G are rather frequent in Germany.
Journal of Inherited Metabolic Disease 08/2008; 31 Suppl 2:S261-5. · 3.58 Impact Factor
-
Journal of Neurology 05/2008; 255(4):609-11. · 3.47 Impact Factor
-
B Winchester,
D Bali,
O A Bodamer,
C Caillaud,
E Christensen,
A Cooper,
E Cupler, M Deschauer,
K Fumić,
M Jackson, [......],
M Piraud,
A Reuser,
T Rupar,
I Sinigerska,
M Szlago,
F Verheijen,
O P van Diggelen,
B Wuyts,
E Zakharova,
J Keutzer
[show abstract]
[hide abstract]
ABSTRACT: Pompe disease is an autosomal recessive disorder of glycogen metabolism caused by a deficiency of the lysosomal enzyme acid alpha-glucosidase (GAA). It presents at any age, with variable rates of progression ranging from a rapidly progressive course, often fatal by one-year of age, to a more slowly, but nevertheless relentlessly progressive course, resulting in significant morbidity and premature mortality. In infants, early initiation of enzyme replacement therapy is needed to gain the maximum therapeutic benefit, underscoring the need for early diagnosis. Several new methods for measuring GAA activity have been developed. The Pompe Disease Diagnostic Working Group met to review data generated using the new methods, and to establish a consensus regarding the application of the methods for the laboratory diagnosis of Pompe disease. Skin fibroblasts and muscle biopsy have traditionally been the samples of choice for measuring GAA activity. However, new methods using blood samples are rapidly becoming adopted because of their speed and convenience. Measuring GAA activity in blood samples should be performed under acidic conditions (pH 3.8-4.0), using up to 2 mM of the synthetic substrate 4-methylumbelliferyl-alpha-D-glucoside or glycogen (50 mg/mL), in the presence of acarbose (3-9 microM) to inhibit the isoenzyme maltase-glucoamylase. The activity of a reference enzyme should also be measured to confirm the quality of the sample. A second test should be done to support the diagnosis of Pompe disease until a program for external quality assurance and proficiency testing of the enzymatic diagnosis in blood is established.
Molecular Genetics and Metabolism 04/2008; 93(3):275-81. · 3.19 Impact Factor
-
Journal of Neurology 08/2007; · 3.47 Impact Factor
-
Neurology 06/2007; 68(20):1741-2. · 8.31 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: McArdle disease, a common metabolic myopathy with autosomal recessive inheritance, is caused by a frequent R50X mutation and many rare mutations in the myophosphorylase gene.
To identify spectrum and frequencies of myophosphorylase gene mutations in a large cohort of patients with McArdle disease, to discuss diagnostic implications, and to analyse genotype-phenotype relationship.
Molecular genetic analysis of 56 index patients with muscle biopsy-proven myophosphorylase deficiency from Germany (n = 35), UK (n = 13), and several other countries (n = 8) was performed using direct sequencing.
Allele frequency of the R50X mutation was 58%, and 71% of the patients carried this mutation at least on one allele. We detected 26 other less common mutations, 13 of which are novel: G157V, R161C, Q337R, E384K, S450L, G486D, R570W, K575E, IVS6-2A>T, IVS10+1G>A, R650X, c.1354insC, c.1155_1156delGG. There was no genotype-phenotype correlation with respect to age of onset and severity. R270X was the most frequent mutation among the less common mutations reaching an allele frequency of 5% followed by R94W and G686R representing a frequency of 4% each.
The study further extends the genetic heterogeneity of myophosphorylase gene mutations showing no mutational hotspot and no genotype-phenotype correlation. Most novel missense mutations were located in secondary structures or active sites of the enzyme. Some of the less common mutations are recurrent with different frequencies within Europe. Ethnic origin and frequency of less common mutations must be considered to establish efficient strategies in molecular genetic testing. Performing molecular testing can avoid muscle biopsy.
Journal of Neurology 06/2007; 254(6):797-802. · 3.47 Impact Factor
