Progressive external ophthalmoplegias (PEO) characterized by accumulation of large-scale mitochondrial DNA (mtDNA) deletions are rare human diseases. We mapped a new locus for dominant PEO at 15q22-q26 in a Belgian pedigree and identified a heterozygous mutation (Y955C) in the polymerase motif B of the mtDNA polymerase gamma (POLG). We identified three additional POLG missense mutations compatible with recessive PEO In two nuclear families. POLG is the only DNA polymerase responsible for mtDNA replication.

Mutations in the catalytic subunit of the mitochondrial DNA polymerase gamma (POLG) have been found to be an important cause of neurological disease. Recently, we and collaborators reported a new neurodegenerative disorder with autosomal recessive ataxia in four patients homozygous for two amino acid changes in POLG: W748S in cis with E1143G. Here, we studied the frequency of this allele and found it to be among the most common genetic causes of inherited ataxia in Finland. We identified 27 patients with mitochondrial recessive ataxia syndrome (MIRAS) from 15 Finnish families, with a carrier frequency in the general population of 1 : 125. Since the mutation pair W748S+E1143G has also been described in European patients, we examined the haplotypes of 13 non-Finnish, European patients with the W748S mutation. Haplotype analysis revealed that all the chromosomes carrying these two changes, in patients from Finland, Norway, the United Kingdom, and Belgium, originate from a common ancient founder. In Finland and Norway, long, common, northern haplotypes, outside the core haplotype, could be identified. Despite having identical homozygous mutations, the Finnish patients with this adult- or juvenile-onset disease had surprisingly heterogeneous phenotypes, albeit with a characteristic set of features, including ataxia, peripheral neuropathy, dysarthria, mild cognitive impairment, involuntary movements, psychiatric symptoms, and epileptic seizures. The high carrier frequency in Finland, the high number of patients in Norway, and the ancient European founder chromosome indicate that this newly identified ataxia should be considered in the first-line differential diagnosis of progressive ataxia syndromes.

The clinical spectrum of recessive POLG mutations is expanded by sensory ataxic neuropathy, combined with variable features of involvement of CNS and other organs. Progressive external ophthalmoplegia, myopathy, ragged red fibers, and Southern blot abnormalities of muscle mitochondrial DNA also are not mandatory features associated with POLG mutations.

We observed a missense mutation in the peripheral myelin protein zero gene (MPZ, Thr124Met) in seven Charcot-Marie-Tooth (CMT) families and in two isolated CMT patients of Belgian ancestry. Allele-sharing analysis of markers flanking the MPZ gene indicated that all patients with the Thr124Met mutation have one common ancestor. The mutation is associated with a clinically distinct phenotype characterized by late onset, marked sensory abnormalities and, in some families, deafness and pupillary abnormalities. Nerve conduction velocities of the motor median nerve vary from <38 m/s to normal values in these patients. Clusters of remyelinating axons in a sural nerve biopsy demonstrate an axonal involvement, with axonal regeneration. Phenotype-genotype correlations in 30 patients with the Thr124Met MPZ mutation indicate that, based on nerve conduction velocity criteria, these patients are difficult to classify as CMT1 or CMT2. We therefore conclude that CMT patients with slightly reduced or nearly normal nerve conduction velocity should be screened for MPZ mutations, particularly when additional clinical features such as marked sensory disturbances, pupillary abnormalities or deafness are also present.

SummaryCharcot-Marie-Tooth disease (CMT) is the most common neuromuscular disorder. It represents a group of clinically and genetically heterogeneous inherited neuropathies. Here, we review the results of molecular genetic investigations and the clinical and neurophysiological features of the different CMT subtypes. The products of genes associated with CMT phenotypes are important for the neuronal structure maintenance, axonal transport, nerve signal transduction and functions related to the cellular integrity. Identifying the molecular basis of CMT and studying the relevant genes and their functions is important to understand the pathophysiological mechanisms of these neurodegenerative disorders, and the processes involved in the normal development and function of the peripheral nervous system. The results of molecular genetic investigations have impact on the appropriate diagnosis, genetic counselling and possible new therapeutic options for CMT patients.

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Generalized epilepsy with febrile seizures plus (GEFS+) is a clinically and genetically heterogeneous syndrome with childhood onset, characterized by febrile seizures (FS) and a variety of afebrile epileptic seizure types. The authors performed a mutational analysis of SCN1B on 74 unrelated probands with GEFS+, FS, or FS plus (FS+). In a family with FS+ and early-onset absence epilepsy, a mutation was identified that predicts a deletion of five amino acids in the extracellular immunoglobulin-like domain of SCN1B and potential loss of function. SCN1B mutations are associated with GEFS+ and may have a role in the elicitation of absence seizures.

Amyloidogenic processing of the amyloid precursor protein (APP) with deposition in brain of the 42 amino acid long amyloid beta-peptide (A beta(42)) is considered central to Alzheimer's disease (AD) pathology. However, it is generally believed that nonfibrillar pre-amyloid A beta(42) deposits have to mature in the presence of A beta(40) into fibrillar amyloid plaques to cause neurodegeneration. Here, we describe an aggressive form of AD caused by a novel missense mutation in APP (T714I) directly involving gamma-secretase cleavages of APP. The mutation had the most drastic effect on A beta(42)/A beta(40) ratio in vitro of approximately 11-fold, simultaneously increasing A beta(42) and decreasing A beta(40) secretion, as measured by matrix-assisted laser disorption ionization time-of-flight mass spectrometry. This coincided in brain with deposition of abundant and predominant nonfibrillar pre-amyloid plaques composed primarily of N-truncated A beta(42) in complete absence of A beta(40). These data indicate that N-truncated A beta(42) as diffuse nonfibrillar plaques has an essential but undermined role in AD pathology. Importantly, inhibiting secretion of full-length A beta(42 )by therapeutic targeting of APP processing should not result in secretion of an equally toxic N-truncated A beta(42).