Christine Verellen

A conserved sorting-associated protein is mutant in chorea-acanthocytosis.

Chorea-acanthocytosis (CHAC, MIM 200150) is an autosomal recessive neurodegenerative disorder characterized by the gradual onset of hyperkinetic movements and abnormal erythrocyte morphology (acanthocytosis). Neurological findings closely resemble those observed in Huntington disease. We identified a gene in the CHAC critical region and found 16 different mutations in individuals with chorea-acanthocytosis. CHAC encodes an evolutionarily conserved protein that is probably involved in protein sorting.

Temperature-sensitive mutations in the III–IV cytoplasmic loop region of the skeletal muscle sodium channel gene in paramyotonia congenita

Paramyotonia congenita (PMC), a dominant disorder featuring cold-induced myotonia (muscle stiffness), has recently been genetically linked to a candidate gene, the skeletal muscle sodium channel gene SCN4A. We have now established that SCN4A is the disease gene in PMC by identifying two different single-base coding sequence alterations in PMC families. Both mutations affect highly conserved residues in the III-IV cytoplasmic loop, a portion of the sodium channel thought to pivot in response to membrane depolarization, thereby blocking and inactivating the channel. Abnormal function of this cytoplasmic loop therefore appears to produce the Na+ current abnormality and the unique temperature-sensitive clinical phenotype in this disorder.

Mutations in GDAP1 - Autosomal recessive CMT with demyelination and axonopathy

Background: Mutations in the ganglioside-induced differentiation-associated protein 1 gene (GDAP1) were recently shown to be responsible for autosomal recessive (AR) demyelinating Charcot–Marie–Tooth disease (CMT) type 4A (CMT4A) as well as AR axonal CMT with vocal cord paralysis. Methods: The coding region of GDAP1 was screened for the presence of mutations in seven families with AR CMT in which the patients were homozygous for markers of the CMT4A locus at chromosome 8q21.1. Results: A nonsense mutation was detected in exon 5 (c.581C>G, S194X), a 1-bp deletion in exon 6 (c.786delG, G262fsX284), and a missense mutation in exon 6 (c.844C>T, R282C). Conclusions: Mutations in GDAP1 are a frequent cause of AR CMT. They result in an early-onset, severe clinical phenotype. The range of nerve conduction velocities (NCV) is variable. Some patients have normal or near normal NCV, suggesting an axonal neuropathy, whereas others have severely slowed NCV compatible with demyelination. The peripheral nerve biopsy findings are equally variable and show features of demyelination and axonal degeneration.

Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors in parathyroids, enteropancreatic endocrine tissues, anterior pituitary, and other tissues. The gene for MEN1 has recently been cloned and shown to code for a 610‐amino acid protein of enigmatic function which probably acts as a tumor suppressor. Several mutations causing the MEN1 phenotype have been recently identified. In order to determine the spectrum of MEN1 gene mutations in a sample of 25 Belgian patients, we have systematically screened the 10 exons and adjacent sequences of the MEN1 gene by means of an automatic sequencing protocol. Twelve different mutations were identified including nonsense, frameshift, splicing, and missense mutations. Two of these mutations (D172Y and 357del4) occurred more than once. A missense mutation was also found in a kindred with familial hyperparathyroidism. We observed no significant correlation between the nature or position of mutation and the clinical status. We have also detected 6 intragenic polymorphisms and DNA sequence variants and have analyzed their frequencies in our population. Hum Mutat 13:54–60, 1999.

Chorea-acanthocytosis: Genetic linkage to chromosome 9q21

Chorea-acanthocytosis (CHAC) is a rare autosomal recessive disorder characterized by progressive neurodegeneration and unusual red-cell morphology (acanthocytosis), with onset in the third to fifth decade of life. Neurological impairment with acanthocytosis (neuroacanthocytosis) also is seen in abetalipoproteinemia and X-linked McLeod syndrome. Whereas the molecular etiology of McLeod syndrome has been defined (Ho et al. 1994), that of CHAC is still unknown. In the absence of cytogenetic rearrangements, we initiated a genomewide scan for linkage in 11 families, segregating for CHAC, who are of diverse geographical origin. We report here that the disease is linked, in all families, to a 6-cM region of chromosome 9q21 that is flanked by the recombinant markers GATA89a11 and D9S1843. A maximum two-point LOD score of 7.1 (theta = .00) for D9S1867 was achieved, and the linked region has been confirmed by homozygosity-by-descent, in offspring from inbred families. These findings provide strong evidence for the involvement of a single locus for CHAC and are the first step in positional cloning of the disease gene.

Tibial muscular dystrophy in a Belgian family

We report a Belgian family with autosomal dominant, late‐onset, distal myopathy with selective foot extensor muscle involvement of the lower legs. Linkage to the tibial muscular dystrophy (TMD) locus 2q31 was not evident at first because of incomplete disease penetrance in a 50‐year‐old asymptomatic family member. An abnormal tibialis anterior muscle biopsy established her subclinical status and linkage of the family to the TMD locus. Mutation analysis showed a disease‐specific, heterozygous point mutation in the last exon, Mex6, of the titin gene. This is the third mutation found in TMD and the second European family with TMD outside the Finnish population, suggesting that titinopathies may occur in various populations. Ann Neurol 2003

Preterm premature rupture of membranes in a patient with the hypermobility type of the Ehlers-Danlos syndrome : A case report

Objectives: This report wants to focus on the risk of severe prematurity in patients with the hypermobility type of the Ehlers-Danlos syndrome (EDS), a heritable disorder of connective tissue. Although various obstetrical complications have been reported in patients with EDS, most reports specifically comment on the severe complications in patients with the vascular type of EDS, including uterine and arterial rupture. Pregnancy outcome in patients presenting the hypermobility type of EDS is poorly documented. Case: A 33-year-old nullipara was referred for preconceptual genetic counseling with a history of easy bruising, generalized joint hypermobility and chronic arthralgia and myalgia. The diagnosis of the hypermobility type of EDS was confirmed on clinical examination. During her first pregnancy, she underwent a prophylactic McDonald cerclage at 14 weeks’ gestation. Premature rupture of membranes occurred at 23 weeks’ gestation. A female infant was delivered at 26 weeks and died 3 h after birth. Electron-microscopic examination showed collagen fibre abnormalities in the fetus’ skin, which were compatible with the diagnosis of EDS. Conclusions: Patients with the hypermobility type of EDS can have an increased risk for pregnancy complications, including prematurity due to cervical incompetence and to premature rupture of membranes. We therefore demand the clinician’s alertness for possible signs of this underdiagnosed type of EDS and recommend the collaboration between the obstetrician and the medical geneticist in the obstetrical management of these patients.