A novel TYMP mutation in a French Canadian patient with mitochondrial neurogastrointestinal encephalomyopathy.

Mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) is a rare autosomal recessive disorder characterized by gastrointestinal, extraocular muscle, peripheral nerve, and cerebral white matter involvement. Mutations in the nuclear gene TYMP encoding for thymidine phosphorylase (TP) cause loss of TP activity, systemic accumulation of its substrates in plasma and tissues, as well as alterations in mitochondrial DNA including deletions, depletion, and somatic point mutations. To date, more than 30 mutations have been reported in diverse ethnic populations.

Synthesis, short-range structure, and electrochemical properties of new phases in the Li-Mn-N-O system.

A crystal-chemical exploration of part of the Li-Mn-N-O system was carried out. Several samples were synthesized using Li(3)N, Mn(x)N and Li(2)O and characterized with chemical analysis, XRD, XAS, and NMR. An increase in the starting proportion of Li(2)O increases the amounts of lithium and oxygen in the compounds, but, according to the XANES Mn K-edge spectra, all the oxynitrides still contain Mn(5+) ions preferentially coordinated by N(3-), forming [MnN(4)] tetrahedra.

A novel duplication confirms the involvement of 5q23.2 in autosomal dominant leukodystrophy.

Objective: To identify the underlying locus and disease-causing mutation for adult-onset autosomal dominant leukodystrophy (ADLD).

Design: Previously, an adult-onset ADLD locus on chromosome 5q23 was mapped between markers D5S1495 and CTT/CCT15. This region contains 13 known and putative candidate genes.

Contribution of TARDBP mutations to sporadic amyotrophic lateral sclerosis.

Aims And Background: Mutations in the TARDBP gene, which encodes the TAR DNA binding protein (TDP-43), have been described in individuals with familial and sporadic amyotrophic lateral sclerosis (ALS). We screened the TARDBP gene in 285 French sporadic ALS patients to assess the frequency of TARDBP mutations in ALS.

Results: Six individuals had potentially deleterious mutations of which three were novel including a Y374X truncating mutation and P363A and A382P missense mutations.

A novel mutation in a large French-Canadian family with LGMD1B.

Background: Limb girdle muscular dystrophy type 1B is an autosomal dominant disease characterized by late onset proximal muscle involvement associated with cardiac complications such as atrioventricular conduction blocks, dilated cardiomyopathy, and sudden death.

Objective: Define the full phenotypic spectrum of a new mutation in the LMNA gene causing limb girdle muscular dystrophy type 1B.

Methods: We identified a large French Canadian family with the LGMD 1B phenotype and a cardiac conduction disease phenotype that carried a new mutation in the LMNA gene and sought to define its full phenotypic spectrum by performing complete neurological and cardiac evaluations, muscle biopsy, RNA and DNA studies.

Association of paraoxonase gene cluster polymorphisms with ALS in France, Quebec, and Sweden.

Background: The paraoxonase gene cluster on chromosome 7 comprising the PON1-3 genes is an attractive candidate for association in amyotrophic lateral sclerosis (ALS) given the role of paraoxonase genes during the response to oxidative stress and their contribution to the enzymatic break down of nerve toxins. Oxidative stress is considered one of the mechanisms involved in ALS pathogenesis. Evidence for this includes the fact that mutations of SOD1, which normally reduce the production of toxic superoxide anion, account for 12% to 23% of familial cases in ALS.

Intra-arterial milrinone for reversible cerebral vasoconstriction syndrome.

Reversible cerebral vasoconstriction syndrome (RCVS) usually presents with recurrent thunderclap headaches and is characterized by multifocal and reversible vasoconstriction of cerebral arteries that can sometimes evolve to severe cerebral ischemia and stroke. We describe the case of a patient who presented with a clinically typical RCVS and developed focal neurological symptoms and signs despite oral treatment with calcium channel blockers. Within hours of neurological deterioration, she was treated with intra-arterial milrinone, a phosphodiesterase inhibitor, which resulted in a rapid and sustained neurological improvement.

50bp deletion in the promoter for superoxide dismutase 1 (SOD1) reduces SOD1 expression in vitro and may correlate with increased age of onset of sporadic amyotrophic lateral sclerosis.

The objective was to test the hypothesis that a described association between homozygosity for a 50bp deletion in the SOD1 promoter 1684bp upstream of the SOD1 ATG and an increased age of onset in SALS can be replicated in additional SALS and control sample sets from other populations. Our second objective was to examine whether this deletion attenuates expression of the SOD1 gene. Genomic DNA from more than 1200 SALS cases from Ireland, Scotland, Quebec and the USA was genotyped for the 50bp SOD1 promoter deletion.

Founder SH3TC2 mutations are responsible for a CMT4C French-Canadians cluster.

Charcot-Marie-Tooth polyneuropathies (CMT) are clinically and genetically heterogeneous. We describe a French-Canadian cluster of 17 recessive CMT cases belonging to 10 families with variable early-onset CMT and scoliosis. The patients demonstrate great intra- and inter-familial variability.

TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis.

Recently, TDP-43 was identified as a key component of ubiquitinated aggregates in amyotrophic lateral sclerosis (ALS), an adult-onset neurological disorder that leads to the degeneration of motor neurons. Here we report eight missense mutations in nine individuals--six from individuals with sporadic ALS (SALS) and three from those with familial ALS (FALS)--and a concurring increase of a smaller TDP-43 product. These findings further corroborate that TDP-43 is involved in ALS pathogenesis.

Autosomal dominant sensory ataxia: a neuroaxonal dystrophy.

Autosomal dominant sensory ataxia (ADSA), a rare hereditary ataxia, is characterized by progressive dysfunction of central sensory pathways. Its pathological features have not been previously documented. We report a case of a 61-year-old man with ADSA who died of congestive heart failure.

[Hereditary ataxias, spastic parapareses and neuropathies in Eastern Canada].

It has been demonstrated, for many inherited diseases, that historical events have shaped the various regional gene pools of Eastern Canada. In so doing, it has given rise to the increased prevalence of some rare diseases due, to founder effects. The following neurogenetic disorders were first identified in patients from Eastern Canada: AOA-2, Arsacs, HSN-2, Arca-1, HMSN/ACC and Arsal.

Clinical, electrophysiologic, and genetic study of non-dystrophic myotonia in French-Canadians.

Thirty-three French-Canadian families with non-dystrophic myotonia were identified. Fifty subjects were recruited and submitted to a complete clinical, electrophysiologic and genetic evaluation. Thirteen mutations were identified in CLCN1 and five mutations were identified in SCN4A.

A locus for primary lateral sclerosis on chromosome 4ptel-4p16.1.

Background: Primary lateral sclerosis (PLS) is an adult-onset upper motor neuron disease resulting in spinal and bulbar spasticity. A family with 8 individuals diagnosed with PLS was previously reported.

Objective: To identify a locus for a large family with PLS.

Using in vitro transcription to construct scaffolds for one-dimensional arrays of mercuric ions.

In vitro transcription by T7 RNA polymerase can be used to construct scaffolds for the one-dimensional arrangement of mercury(II) ions. In these constructs, the metal ions are located inside of RNA double helices. By replacing the amide protons of two oppositely located uracil residues of complementary strands, mercury(II) becomes coordinated in a linear fashion to form metal-ion mediated base pairs, analogous to the well-known thymine-Hg-thymine base pair in DNA.

A novel founder SCN4A mutation causes painful cold-induced myotonia in French-Canadians.

Background: Myotonia is observed in classic congenital myotonia caused by CLCN1 mutations and in sodium-channel myotonia (SCM) due to SCN4A mutations.

Methods: We assessed 66 electrically proven cases of myotonia belonging to 17 French-Canadian families living in the Saguenay Lac St-Jean area of Quebec, a region well known for its genetic founder effects. The CLCN1 gene was sequenced in one affected member of each family.

Conformational change induced by metal-ion-binding to DNA containing the artificial 1,2,4-triazole nucleoside.

A conformational switch can be induced upon the addition of transition-metal ions to oligonucleotides that contain a row of successive artificial nucleobases flanked by complementary sequences of natural nucleobases, provided that the artificial bases cannot undergo self-pairing via hydrogen bonding but only via the formation of metal-ion-mediated base pairs. Such oligonucleotides adopt a hairpin structure in the absence of transition-metal ions, yet they show a preference for the formation of a regular double helix if the appropriate metal ions are present. We report here our experimental data on the structure of the oligonucleotide d(A7X3T7) (A=adenine, T=thymine, X=1,2,4-triazole) in the absence and presence of silver(I).

Distal truncation of KCC3 in non-French Canadian HMSN/ACC families.

Background: Hereditary motor and sensory neuropathy with agenesis of the corpus callosum (HMSN/ACC) is a severe and progressive autosomal recessive polyneuropathy. Mutations in the potassium-chloride cotransporter 3 gene (KCC3) were identified as responsible for HMSN/ACC in the French Canadian (FC) population. In the present study, the authors were interested in finding new mutations in non-FC populations, assessing the activity of mutant proteins and refining genotype-phenotype correlations.

LRRK2 is not a significant cause of Parkinson's disease in French-Canadians.

Background: An old founder mutation (G2019S) was found with high frequency in the North African Arabs (30%) and Ashkenazi Jews (18% ).

Objective: Demonstrate if mutations in the LRRK2 gene are a significant cause of Parkinson's disease (PD) in the French-Canadian founder population.

Methods: Cases were recruited through a designated movement disorder clinic in Quebec City.

SPG4 founder effect in French Canadians with hereditary spastic paraplegia.

Background: The most common cause of autosomal dominant Hereditary Spastic Paraplegia (HSP) is mutations in the SPG4 gene. We have previously identified novel SPG4 mutations in a collection of North American families including the c.G1801A mutation present in two families from Quebec.

Clinical and genetic study of autosomal recessive cerebellar ataxia type 1.

Objective: Define the phenotype and genotype of a cluster of families with a relatively pure cerebellar ataxia referred to as autosomal recessive cerebellar ataxia type 1 (ARCA-1).

Methods: We ascertained 64 probands and affected members of 30 French-Canadian families all showing similar clinical features and originating from the same region of Quebec. After informed consent, we performed detailed clinical history, neurological examination, brain imaging, nerve conduction studies, and SYNE1 mutation detection of all available subjects.