Carlos Cervera

Molecular heterogeneity of myophosphorylase deficiency (McArdle's disease): a genotype-phenotype correlation study.

We report on 54 Spanish patients with McArdles disease from 40 unrelated families. Molecular analysis revealed that the most common R49X mutation was present in 70% of patients and 55% of alleles. The G204S mutation was less frequent and found in 14.8% of patients and 9% of mutant alleles. The W797R mutation was observed in 16.5% of patients, accounting for 13.7% of mutant alleles. Moreover, 78% of mutant alleles among Spanish patients can be identified by using polymerase chain reaction‐restriction fragment length polymorphism analysis for the R49X, G204S, and W797R mutations, which makes noninvasive diagnosis possible through molecular genetic analysis of blood DNA. Six novel mutations were found. Three were missense mutations, E348K, R601W, and A703V; two nonsense mutations, E124X and Q754X; and one single base pair deletion, 533 delA. No clear genotype‐phenotype correlation emerges from our study. Most of the mutations of uncharged and solvent inaccessible residues and the truncations must disrupt the basic structure of the protein. The mutations of charged residues would be expected to interfere with internal hydrogen bonding networks, introducing severe incompatible partnering that is caused by poor packing or electrostatic repulsions.

Flail arm syndrome of Vulpian-Bernhart's form of amyotrophic lateral sclerosis.

We read with interest the article by Hu et al 1 concerning flail arm syndrome, a distinctive variant of amyotrophic lateral sclerosis. The authors presented a subgroup of patients affected by amyotrophic lateral sclerosis that predominantly showed signs of lower motor neuron disease in the upper limbs without significant functional involvement of other regions upon clinical presentation. This subgroup of patients is clinically characterised by the display of progressive atrophy and weakness in the arms with little effect on the bulbar muscles or legs. Atrophy and loss of strength affect the upper limb muscles in a more or less symmetric manner, prevalent in the proximal muscles. The comparative study with …

A novel thymidine phosphorylase mutation in a Spanish MNGIE patient.

A 29-year-old Spanish man presented with chronic intestinal pseudo-obstruction, progressive external ophthalmoplegia, peripheral neuropathy, and diffuse leukoencephalopathy. This combination of clinical features is characteristic of mitochondrial neurogastrointestinal encephalomyopathy (MNGIE). Genetic analysis revealed a novel 18-base pair (bp) duplication (5044-5061 dup) in exon 8 of the thymidine phosphorylase (TP) gene. The mutation is predicted to produce a 6 amino acid insertion in the alpha-beta-domain of the protein. This 18-bp insertion in the thymidine phosphorylase gene is the first duplication mutation identified in MNGIE.

A novel exon 5 mutation (N139H) in the SOD1 gene in a Spanish family associated with incomplete penetrance

BACKGROUNDnAllelic heterogeneity and phenotype variability-especially in age at onset, penetrance and progression-are reported in ALS1 families. For this reason, SOD1 gene mutation data in ALS1 patients are currently being gathered to better understand the genotype-phenotype relationship in this disorder. Here, we report the clinical and molecular characteristics of a Spanish ALS1 family with incomplete penetrance.nnnPATIENTS AND METHODSnClinical data including age at onset, initial topography, progression and survival were available in three affected members. Erythrocyte SOD1 activity was measured in four individuals. Analysis of the SOD1 gene was performed by PCR and direct sequencing.nnnRESULTSnA novel missense mutation in the exon 5 of the SOD1 gene, an A-to-C transversion at nucleotide position 1485 leading to N139H residue change, was identified in three family members. The phenotype was similar in all cases, with initial symptoms in the distal limb muscles and a mean survival time of around 4 years. Incomplete penetrance was observed in our family, as two obligate carriers did not develop any symptoms of amyotrophic lateral sclerosis (ALS).nnnCONCLUSIONSnN139H is the fifth SOD1 gene mutation reported in Spain, and the first one presenting with incomplete penetrance. Genetic counseling for at-risk relatives in these low-penetrance families could be difficult as some individuals harbouring the mutation remain asymptomatic throughout their lives. Further genetic characterisation of ALS1 families should provide information regarding the distribution of SOD1 mutants in different ethnic groups.

A novel exon 3 mutation (D76V) in the SOD1 gene associated with slowly progressive ALS

INTRODUCTION: Details of the mutations in the Cu/Zn superoxide dismutase (SOD1) gene in patients with the familial form of amyotrophic lateral sclerosis are currently being gathered in order better to understand the genotype-phenotype relationship in this disorder. We report on a large family with 15 affected individuals spanning five generations. RESULTS: A novel mutation in the exon 3 of the SOD1 gene, an A-to-T transversion at nucleotide position 696 in the heterozygous state leading to a D76V amino acid change, was identified in four family members. Affected individuals showed a homogeneous phenotype, characterized by initial symptoms in the lower limbs, clinical onset in the fifth decade of life, long survival and high penetrance. DISCUSSION: Our results are discussed in relation to the previously reported exon 3 SOD1 mutations, paying particular attention to the phenotypic characteristics of ALS-SOD1 patients.

A new mutation in the myophosphorylase gene (Asn684Tyr) in a Spanish patient with McArdle's disease

We have identified a novel missense mutation, an A-T transition at codon 684 in exon 17, changing an encoded asparagine to a tyrosine (Asn684Tyr) in a Spanish patient with typical McArdles disease. The patient was a compound heterozygote, with a previously-described mutation (Gly204Ser) on the other allele. This report expands the molecular genetic heterogeneity in McArdles disease, emphasizes the presence of private mutations in specific ethnic groups, and indicates that geographic origin must be considered before undertaking DNA analysis for diagnosis.

Adult glycogenosis II with paracrystalline mitochondrial inclusions and Hirano bodies in skeletal muscle

Hirano bodies constitute eosinophilic intracytoplasmic inclusions, typically seen in the central nervous system, where they are related to senility and certain dementias such as Alzheimers disease or the Parkinson-dementia complex. They have been found in different tissues of experimental animals and, on rare occasions, in extraocular muscles of elderly individuals. However, to our knowledge they have not been described in skeletal muscle in locations other than extraocular muscles or associated with muscle pathology. Glycogenosis II or Pompes disease, is a metabolic disorder caused by acid maltase deficiency and is characterized by glycogen accumulation in lysosomes in various tissues, including skeletal muscle. There are three clinical forms depending on age at onset, the most frequent being the childhood form. We present the histopathological and ultrastructural findings of a muscle biopsy performed in a case of the adult form of glycogenosis II which showed, in addition to characteristic lysosomal glycogen storage, paracrystalline mitochondrial inclusions and, as an exceptional finding, intracytoplasmic Hirano bodies in some muscle fibres.

A new mutation in the regulatory domain of the myophosphorylase gene affecting protein dimer contact.

We have identified a novel missense mutation in the myophosphorylase gene in a Spanish patient with McArdles disease. The patient was homozygous for a T‐to‐C transition at codon 115 (L115P) in exon 3, which changed an encoded leucine (CUG) to a proline (CCG). This is the first mutation to be described in exon 3 and in a protein domain related to dimer contact. These data further emphasize the importance of private mutations in McArdles disease, some of which are associated with specific ethnic groups.

A new mtDNA mutation in the tRNALeu(UUR) gene associated with ocular myopathy

We studied a patient with ptosis, ophthalmoparesis, and exercise intolerance who showed in her muscle biopsy ragged-red fibers and combined defects of the complexes I and IV of the mitochondrial respiratory chain. Molecular analysis revealed a T3273C transition in the mitochondrial DNA tRNA(Leu(UUR)) gene. The mutation was heteroplasmic and very abundant in muscle from the proposita, less abundant in her other tissues studied, and still less abundant in blood from her maternal relatives. Single muscle fiber analysis showed significantly higher levels of mutant genomes in ragged-red fibers than in normal fibers. The T3273C mutation affects a strictly conserved base pair in the anticodon stem and was not found in controls, thus satisfying the accepted criteria for pathogenicity.

Atypical form of amyotrophic lateral sclerosis: a new term to define a previously well known form of ALS

We read with interest the article by Sasaki et al 1 concerning the atypical form of amyotrophic lateral sclerosis (ALS). The pattern of muscular atrophy in these patients differed from that of typical ALS in that severe muscle involvement was confined to the upper limbs, predominantly the proximal portion and shoulder girdle, sparing the face and the legs until late in the diseases course or until the terminal stage.nnOver the past few years, we have noticed a growing interest in the renaming of this clinical form of ALS, which has its origins and predomination in the proximal muscles and upper limbs and little or no effect of either a bulbar nature or in the lower limbs.nnThus Hu et al 2 coined the term flail arm syndrome, to describe a subgroup of patients affected by ALS that predominantly showed signs of lower motor neuron disease in the upper limbs, without significant functional involvement of other regions on clinical presentation. This subgroup of patients was clinically characterised by the display of progressive atrophy and weakness affecting the proximal muscles in the upper limb muscles in a more or less symmetric manner.nnRecently, along these lines, Katz et al 3 described a series of patients affected by an adult onset motor neuron disorder restricted to the upper limbs, with severe proximal and varying degrees …