Charcot-Marie-Tooth disease (CMT) with autosomal recessive (AR) inheritance is a heterogeneous group of inherited motor and sensory neuropathies. In some families from Japan and Brazil, a demyelinating CMT, mainly characterized by the presence of myelin outfoldings on nerve biopsies, cosegregated as an autosomal recessive trait with early-onset glaucoma. We identified two such large consanguineous families from Tunisia and Morocco with ages at onset ranging from 2 to 15 years. We mapped this syndrome to chromosome 11p15, in a 4.6-cM region overlapping the locus for an isolated demyelinating ARCMT (CMT4B2). In these two families, we identified two different nonsense mutations in the myotubularin-related 13 gene, MTMR13. The MTMR protein family includes proteins with a phosphoinositide phosphatase activity, as well as proteins in which key catalytic residues are missing and that are thus called "pseudophosphatases." MTM1, the first identified member of this family, and MTMR2 are responsible for X-linked myotubular myopathy and Charcot-Marie-Tooth disease type 4B1, an isolated peripheral neuropathy with myelin outfoldings, respectively. Both encode active phosphatases. It is striking to note that mutations in MTMR13 also cause peripheral neuropathy with myelin outfoldings, although it belongs to a pseudophosphatase subgroup, since its closest homologue is MTMR5/Sbf1. This is the first human disease caused by mutation in a pseudophosphatase, emphasizing the important function of these putatively inactive enzymes. MTMR13 may be important for the development of both the peripheral nerves and the trabeculum meshwork, which permits the outflow of the aqueous humor. Both of these tissues have the same embryonic origin.

Summary:Purpose: The goal of the study was to assess the health-related quality of life (HRQOL) of persons with epilepsy (PWE) by using the short form survey 36 , to compare it with that of a control group and to detect factors influencing it.Methods: We collected clinical and demographic data and information on health status by using the Arabic translation of the SF-36 questionnaire from two groups: (a) 120 PWE consulting our outpatient clinic during a period of 4 months, and (b) 110 Tunisian citizens, representative of the Tunisian general population, as a control group.Results: The mean age of PWE group was 32.74 years, and 45.5% were men. Idiopathic generalized epilepsies were observed in 44.5% of cases, and symptomatic partial epilepsies, in 30%. The most commonly prescribed drug was sodium valproate (VPA). For the SF-36, PWE had lower scores than the control group for only three subscales: general health perception, mental health, and social functioning. Seizure frequency, time since last seizure, and the antiepileptic drug (AED) side effects were the most important variables influencing the HRQOL among PWE. Seizure-free adults have HRQOL levels comparable to those of the control group. Sociodemographic variables had no influence on the SF-36 subscales.Conclusions: HRQOL is impaired in Tunisian PWE. The influencing factors identified in this study differ from the previously published data. Several possible reasons such as family support and cultural and religious beliefs are proposed to explain these cross-cultural differences. A larger study should be conducted to verify such findings.

Progressive myoclonus epilepsy of the Unverricht-Lundborg type (EPM1) is a rare, autosomal recessive disorder characterized by onset at age 6-16 years, generalized seizures, incapacitating myoclonus, and variable progression to cerebellar ataxia. The gene that causes EPM1, cystatin B, encodes a cysteine proteinase inhibitor. Only a minority of EPM1 patients carry a point mutation within the transcription unit. The majority of EPM1 alleles contain large expansions of a dodecamer repeat, CCC CGC CCC GCG, located upstream of the 5' transcription start site of the cystatin B gene; normal alleles contain two or three copies of this repeat. All EPM1 alleles with an expansion were resistant to standard PCR amplification. To precisely determine the size of the repeat in affected individuals, we developed a detection protocol involving PCR amplification and subsequent hybridization with an oligonucleotide containing the repeat. The largest detected expansion was approximately 75 copies; the smallest was approximately 30 copies. We identified affected siblings with repeat expansions, of different sizes, on the same haplotype, which confirms the repeat's instability during transmissions. Expansions were observed directly; contractions were deduced by comparison of allele sizes within a family. In a sample of 28 patients, we found no correlation between age at onset of EPM1 and the size of the expanded dodecamer. This suggests that once the dodecamer repeat expands beyond a critical threshold, cystatin B expression is reduced in certain cells, with pathological consequences.

A door-to-door survey was made in Kelibia, Tunisia to determine the prevalence of major neurologic disorders, including epilepsy. The survey was made according to a World Health Organization (WHO) protocol (1981). All individuals responding positively to the screening tool were examined by a neurologic team using well-defined diagnostic criteria. One hundred forty-one individuals, alive on prevalence day (July 1, 1985), were identified as having active epilepsy, giving a crude prevalence ratio of 4.04 per 1,000 and an age-adjusted (on WHO population) prevalence ratio of 3.64 per 1,000. Prevalence ratios increase with age (in children and young adults with the highest prevalence ratio at approximately 20 years) and decrease after 40 years. The most frequently identified type was generalized convulsive seizures (93%). The most frequently associated conditions were cerebral palsy and mental retardation.

Unverricht-Lundborg disease (ULD) is a progressive myoclonus epilepsy common in Finland and North Africa, and less common in Western Europe. ULD is mostly caused by expansion of a dodecamer repeat in the cystatin B gene ( CSTB) promoter. We performed a haplotype study of ULD chromosomes (ULDc) with the repeat expansion. We included 48 West European Caucasian (WEC) and 47 North African (NA) ULDc. We analysed eight markers flanking CSTB(GT10-D21S1890-D21S1885-D21S2040-D21S1259- CSTB-D21S1912-PFKL-D21S171) and one intragenic variant in the CSTB 3' UTR (A2575G). We observed a founder effect in most of the NA ULD patients, as 61.7% of the NA ULDc (29/47) shared the same haplotype, A1 (1-1-A-1-6-7), for markers D21S1885-D21S2040-A2575G-D21S1259-D21S1912-PFKL. Moreover, if we considered only the markers D21S1885, D21S2040, A2575G and D21S1259, 43 of the 47 NA ULDc shared the same alleles 1-1-A-1, haplotype A. As previously shown, the WEC ULDc were heterogeneous. However, the Baltic haplotype, A3 (5-1-1-A-1-1), was observed in ten WEC ULDc (20.8%) and the CSTB 3'UTR variant, which we called the Alps variant, was observed in 17 ULDc (35.4%). Finally, as almost all NA patients, like Scandinavian patients, were of the haplotype A, we assumed that there was an ancient common founder effect in NA and Baltic ULD patients. We estimated that the putative most recent common ancestral ULD carrier with this haplotype A must have existed about 2,500 years ago (100-150 generations). Finally, this work provides evidence for the existence of only a small number of founder mutations in ULD.