ABSTRACT
The authors report the long-term course of two siblings with L-dopa responsive dystonia (DRD) associated with a compound heterozygous mutation in the tyrosine hydroxylase (TH) gene. Both siblings manifested with lower-limb onset generalized DRD and had a sustained response to low-dose L-dopa therapy for over 35 years. Although the l-dopa therapy was delayed up to 20 years after disease onset, there were no cognitive or neurologic sequelae of the long-term catecholamine deficit.
Subject(s)
Brain Chemistry/genetics , Catecholamines/deficiency , Dystonia/enzymology , Levodopa/therapeutic use , Point Mutation/genetics , Tyrosine 3-Monooxygenase/deficiency , Adult , Age of Onset , Brain/enzymology , Brain/pathology , Brain/physiopathology , Catecholamines/biosynthesis , DNA Mutational Analysis , Disease Progression , Dopamine Agents/adverse effects , Dopamine Agents/therapeutic use , Dystonia/drug therapy , Dystonia/genetics , Heterozygote , Humans , Levodopa/adverse effects , Longitudinal Studies , Magnetic Resonance Imaging , Male , Middle Aged , Panic Disorder/chemically induced , Siblings , Time , Tyrosine 3-Monooxygenase/geneticsABSTRACT
We report on 8 Dutch patients with McArdle's disease from 6 unrelated families. Molecular analysis revealed the presence of four previously described mutations: the common R49X mutation, the IVS14+1G>A mutation and the recently reported R269X and Y84X nonsense mutations; and two new molecular defects: a missense mutation R138W in the homozygous state in two siblings, and a frameshift mutation c.1797delT. This first genetic study of patients from The Netherlands with McArdle's disease confirms that the R49X mutation is also the most common in Dutch patients, and that there is genetic heterogeneity within this population. Moreover, our data support the hypothesis that the Y84X mutation is a relatively frequent mutation in McArdle's patients with a Central European background, and expand the already crowded map of mutations within the PYGM gene responsible for McArdle's disease.
Subject(s)
Glycogen Phosphorylase, Muscle Form/genetics , Glycogen Storage Disease Type V/genetics , Base Sequence , DNA Primers , Female , Genetic Heterogeneity , Glycogen Storage Disease Type V/enzymology , Humans , Male , Mutation , NetherlandsABSTRACT
Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease caused by a deficiency of the mitochondrial enzyme 27-sterol hydroxylase (CYP 27), due to mutations in its gene. In this study we report on mutations in 58 patients with CTX out of 32 unrelated families. Eight of these were novel mutations, two of which were found together with two already known pathogenic mutations. Twelve mutations found in this patient group have been described in the literature. In the patients from 31 families, mutations were found in both alleles. In the literature, 28 mutations in 67 patients with CTX out of 44 families have been described. Pooling our patient group and the patients from the literature together, 37 different mutations in 125 patients out of 74 families were obtained. Identical mutations have been found in families from different ethnic backgrounds. In 41% of all the patients, CYP 27 gene mutations are found in the region of exons 6-8. This region encodes for adrenodoxin and haem binding sites of the protein. Of these 125 patients, a genotype-phenotype analysis was done for 79 homozygous patients harbouring 23 different mutations, out of 45 families. The patients with compound heterozygous mutations were left out of the genotype-phenotype analysis. The genotype-phenotype analysis did not reveal any correlation.
Subject(s)
Cytochrome P-450 Enzyme System/genetics , Mutation , Steroid Hydroxylases/genetics , Xanthomatosis, Cerebrotendinous/genetics , Xanthomatosis, Cerebrotendinous/pathology , Adolescent , Adult , Age of Onset , Amino Acid Substitution , Brain/pathology , Child , China , Cholestanetriol 26-Monooxygenase , Ethnicity/genetics , Europe , Exons , Female , Humans , Magnetic Resonance Imaging , Male , Netherlands , Point Mutation , Sequence Deletion , Tunisia , Xanthomatosis, Cerebrotendinous/physiopathologyABSTRACT
Two types of myoadenylate deaminase (MAD) deficiency have been described, primary or inherited, and secondary or acquired MAD deficiency. In this study, we investigated whether secondary MAD deficiency is indeed acquired or merely coincidental. We demonstrated the same underlying molecular defect, a C34T transition, in both types of deficiency. Furthermore, the same frequency of the mutant MAD allele was found in the general population as in patients with neuromuscular complaints. We therefore conclude that in the Dutch population, secondary MAD deficiency is merely a "coincidental" finding, and that MAD deficiency is a harmless genetic variant.