Advocacy for Epilepsy Surgery in Africa: Moroccan Experience of 132 Cases.

BACKGROUND: In Africa, epilepsy is a real burden. Temporal lobe epilepsy is the most common drug-resistant focal epilepsy disorder, and temporal lobectomy is the most common effective treatment for patients with drug-resistant epilepsy. OBJECTIVE: We aim to highlight the Moroccan experience in epilepsy surgery and to ascertain its long-term outcome. Through the results of surgical treatment in our series, we hope to raise awareness of the need for epilepsy surgery in Africa and contribute to its development. METHODS: We present a retrospective study of 132 patients who underwent surgery for epilepsy from January 2005 to December 2021 at our institution. The presurgical evaluation was based on clinical screening, interictal electroencephalography, video-electroencephalography, neuropsychological tests, magnetic resonance imaging, and positron emission tomography in some cases. Data are presented as the median and ranges. For all analyses, P values <0.05 were considered statistically significant. RESULTS: Our series includes 132 patients (69 males; 52.27%); the median age at surgery was 24 years (range, 1-64). One hundred and fifteen patients (87%) were operated on for temporal lobe epilepsy, of whom 98 (85%) had anterior temporal lobectomy and 17 (15%) had lesionectomy. Seventeen patients (13%) were operated on for extratemporal epilepsy, of whom 4 had lesionectomy, 7 functional hemispherotomy, and 5 Gamma Knife stereotactic radiosurgery. Our postoperative outcomes 3 months after surgery found 113 patients (85.6%) seizure-free (Engel class I), 16 with Engel class II (12.1%), and 3 with Engel class III (2.3%) in temporal lobe epilepsy. In extratemporal lobe epilepsy, 12 patients (70.5%) showed Engel class I, seizure-free, 4 Engel class II (23.5%), and 1 Engel class III (6%). CONCLUSIONS: These results confirm that most patients with drug-resistant epilepsy may benefit from surgical treatment without submitting to preoperative invasive explorations. This finding should help develop epilepsy surgery widely in Africa.

Prevalence of epilepsy in Morocco: A population-based study.

OBJECTIVE: In Morocco, there was a lack of data related to the epidemiology of epilepsy. This data serves as a useful basis for the development of any national intervention or action program against epilepsy in Morocco. Through this study, we aimed to estimate the active and lifetime prevalence of epilepsy in Morocco. METHODS: We collected data from eight out of 12 Moroccan regions in two steps: In the screening step, we first used a nationwide telephone diagnosis questionnaire and in the second stage, a team of physicians under the direction of an epileptologist conducted a confirmative survey for suspected cases. We fixed the confidence interval at α = 5% and the precision at 0.02. RESULTS: Up to 3184 responded positively to our invitation to participate in this study and were able to answer the questions of the first diagnostic questionnaire. In the diagnostic phase, physicians in neurology reinterviewed all 86 suspected cases using a confirmative diagnosis questionnaire, and 63 persons were confirmed as having lifetime epilepsy and 56 with active epilepsy. The mean age (Mean ± SD) of persons with epilepsy was 35.53 years (±21.36). The prevalence of lifetime and active epilepsy were 19.8 (19.6-20.0) and 17.6 (17.5-17.8) per 1000 (95% confidence interval), respectively. SIGNIFICANCE: This is the first study to estimate the active and lifetime prevalence of epilepsy in Morocco according to the international recommendations of the ILAE. The prevalence of lifetime and active epilepsy were 19.8 (15-24.6) and 17.6 (13.3-22.8) per 1000, respectively. We included both children and elderly subjects. The rates of active and lifetime population epilepsy prevalence in Morocco ranged between Asian and sub-Saharan Africa low- and middle-income countries.

The validity of the upper limb neurodynamic test 2A in women with a clinical diagnosis of carpal tunnel syndrome: a prospective diagnostic accuracy study.

Introduction: the validity of the upper limb neurodynamic tests and especially the upper limb neurodynamic test 1 for diagnosing carpal tunnel syndrome has been the subject of several previous studies. However, the upper limb neurodynamic test 2A, which is also a test designated to assess the mechanosensitivity of the median nerve, has not been sufficiently studied, particularly for the diagnosis of carpal tunnel syndrome. Methods: we used the upper limb neurodynamic test 2A as the index test and nerve conduction studies as the reference standard. We considered the upper limb neurodynamic test 2A positive according to Nee et al. criteria. Sensitivity, specificity, positive likelihood, and negative likelihood were calculated. In addition, a receiver operating characteristics analysis was carried out. Results: ninety-four women (188 hands) suspected of carpal tunnel syndrome with a mean age of 48.87 years and SD of 12.09 participated in the study. The sensitivity of the upper limb neurodynamic test 2A was estimated at 73.4%, the specificity at 47%, the positive likelihood ratio was 1.38, the negative likelihood ratio was 0.57, and the Kappa agreement was 20.3%, and the area under the curve 60.1%. Conclusion: the upper limb neurodynamic test 2A does not seem to have value in the diagnosis of carpal tunnel syndrome when compared to nerve conduction studies. It could be alternatively used to detect an increased mechanosensitivity of the median nerve when the upper limb neurodynamic test 1 cannot be performed in case of a range of motion limitation of the shoulder abduction.

Epilepsy in Morocco: Realities, pitfalls and prospects.

The World Health Organization (WHO) estimates that about 50 million people of all ages have epilepsy and nearly 85% of whom live in low- and middle-income (LMICs) countries. In Morocco, epilepsy is one of the major neurological health conditions, with an estimated prevalence of 1.1%. The management of patients is difficult due to multiple factors. The lack of neurologists whose number is currently 180, the uneven distribution of neurologists who are concentrated in large cities, 43% of whom are in Rabat and Casablanca alone; the low involvement of general practitioners in the management of epilepsy; the frequent consultation of traditional healers; and the low coverage of social security all contribute to the treatment gap. The management of epilepsy has advanced considerably since the early nineties. Several factors contributed to this progress: the increasing number of neurologists compared to previous years, the creation of well-equipped new academic centers, and small units of general neurology, in addition to the disuse of several antiepileptic drugs. However, much work remains to be done against the use of many forms of traditional practices and the low involvement of general practitioners in the management of epilepsy. This is the first study on epilepsy conducted in Morocco.

Sleep quality and mental health in the context of COVID-19 pandemic and lockdown in Morocco.

BACKGROUND: The lockdown of COVID-19 (Coronavirus Disease 2019) is associated with several stressful factors that can negatively affect peoples' sleep quality and mental health. OBJECTIVES: We conducted this study to evaluate sleep disorders and psychological impact associated with the spread of the COVID-19 and the lockdown on the Moroccan population. We also aimed to study the effects of respondents' beliefs and attitudes about sleep on sleep disorders, anxiety-related symptoms, and depressive symptoms. MATERIAL AND METHODS: We used a questionnaire enclosing respondents' sociodemographic information, five psychological and behavioral tests including Dysfunctional Beliefs and Attitudes about Sleep (DBAS-16), Athens Insomnia Scale (AIS), Epworth Sleepiness Scale (ESS), Hamilton Anxiety Rating Scale (HARS) and Beck Depression Inventory (BDI) test. RESULTS: Our results highlighted widespread false beliefs about sleep and the prevalence of sleep disorders, anxiety, and depression-related symptoms within the Moroccan population. Nearly 82.3% of respondents revealed false beliefs about sleep. Furthermore, we confirmed a strong positive correlation between knowledge and attitudes about sleep and the prevalence of sleep disorders, anxiety, and depression-related symptoms. However, we found no significant difference in the prevalence of sleep and psychological disorders, between healthcare workers and other professions workers. CONCLUSION: Our study revealed a high prevalence of sleep disorders, anxiety, and depressive symptoms in the Moroccan population during the COVID-19 lockdown period. Moreover, false beliefs on sleep understanding were prevalent and were presenting a risk factor leading to sleep disorders, anxiety, and depressive symptoms.

Clinical aspects, neuroimaging, and electroencephalography of 35 cases of hemiconvulsion-hemiplegia syndrome.

INTRODUCTION: The hemiconvulsion-hemiplegia-epilepsy (HHE) syndrome is a rare consequence of febrile seizures during childhood. It is characterized by the presence of prolonged unilateral clonic seizures occurring during febrile illness in a child less than 4years of age. Then, a flaccid unilateral hemiplegia with variable duration occurs. OBJECTIVES: The objective of the study was to describe the clinical, electroencephalogram (EEG), and neuroimaging treatment and outcome of series of cases of HHE syndrome followed for 10years in our clinical neurophysiology department of the specialty hospital of Rabat. PATIENTS AND METHODS: We report a retrospective study of 35 patients followed up for HHE syndrome from January 2005 to December 2015. All patients included in the study met the definition criteria for HHE syndrome. RESULTS: The age of onset ranged from 1 to 10years. Hemiplegia or spastic hemiparesis of the ipsilateral side to the convulsion was present in all patients. Abnormal brain magnetic resonance imaging (MRI) was found in all patients. All patients developed drug-resistant focal epilepsy during the course of the disease. CONCLUSIONS: The management of HHE syndrome constitutes a real public health problem in developing countries like Morocco. The neurological morbidity and the severe sequels are of high impact in these young kids. On the one hand, authors highlight the need for improving emergency care of status epilepticus. On the other hand, in our context, the prophylaxis of febrile seizures seems to be the corner stone of the prevention of HHE Syndrome.

Loss of Function of GALNT2 Lowers High-Density Lipoproteins in Humans, Nonhuman Primates, and Rodents.

Human genetics studies have implicated GALNT2, encoding GalNAc-T2, as a regulator of high-density lipoprotein cholesterol (HDL-C) metabolism, but the mechanisms relating GALNT2 to HDL-C remain unclear. We investigated the impact of homozygous GALNT2 deficiency on HDL-C in humans and mammalian models. We identified two humans homozygous for loss-of-function mutations in GALNT2 who demonstrated low HDL-C. We also found that GALNT2 loss of function in mice, rats, and nonhuman primates decreased HDL-C. O-glycoproteomics studies of a human GALNT2-deficient subject validated ANGPTL3 and ApoC-III as GalNAc-T2 targets. Additional glycoproteomics in rodents identified targets influencing HDL-C, including phospholipid transfer protein (PLTP). GALNT2 deficiency reduced plasma PLTP activity in humans and rodents, and in mice this was rescued by reconstitution of hepatic Galnt2. We also found that GALNT2 GWAS SNPs associated with reduced HDL-C also correlate with lower hepatic GALNT2 expression. These results posit GALNT2 as a direct modulator of HDL metabolism across mammals.

Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia.

Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed, suggesting that other genetic causes of HSP are still to be identified. HSP can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked manner. In the current study, we performed whole-exome sequencing to analyze a total of nine affected individuals in three families with autosomal-recessive HSP. Rare homozygous and compound-heterozygous nonsense, missense, frameshift, and splice-site mutations in CAPN1 were identified in all affected individuals, and sequencing in additional family members confirmed the segregation of these mutations with the disease (spastic paraplegia 76 [SPG76]). CAPN1 encodes calpain 1, a protease that is widely present in the CNS. Calpain 1 is involved in synaptic plasticity, synaptic restructuring, and axon maturation and maintenance. Three models of calpain 1 deficiency were further studied. In Caenorhabditis elegans, loss of calpain 1 function resulted in neuronal and axonal dysfunction and degeneration. Similarly, loss-of-function of the Drosophila melanogaster ortholog calpain B caused locomotor defects and axonal anomalies. Knockdown of calpain 1a, a CAPN1 ortholog in Danio rerio, resulted in abnormal branchiomotor neuron migration and disorganized acetylated-tubulin axonal networks in the brain. The identification of mutations in CAPN1 in HSP expands our understanding of the disease causes and potential mechanisms.

Cerebral Hemispheric Lateralization Associated with Hippocampal Sclerosis May Affect Interictal Cardiovascular Autonomic Functions in Temporal Lobe Epilepsy.

It is well established that the temporal lobe epilepsy (TLE) is linked to the autonomic nervous system dysfunctions. Seizures alter the function of different systems such as the respiratory, cardiovascular, gastrointestinal, and urogenital systems. The aim of this work was to evaluate the possible factors which may be involved in interictal cardiovascular autonomic function in temporal lobe epilepsy with complex partial seizures, and with particular attention to hippocampal sclerosis. The study was conducted in 30 patients with intractable temporal lobe epilepsy (19 with left hippocampal sclerosis, 11 with right hippocampal sclerosis). All subjects underwent four tests of cardiac autonomic function: heart rate changes in response to deep breathing, heart rate, and blood pressure variations throughout resting activity and during hand grip, mental stress, and orthostatic tests. Our results show that the right cerebral hemisphere predominantly modulates sympathetic activity, while the left cerebral hemisphere mainly modulates parasympathetic activity, which mediated tachycardia and excessive bradycardia counterregulation, both of which might be involved as a mechanism of sudden unexpected death in epilepsy patients (SUDEP).

A homozygous loss-of-function variant in MYH11 in a case with megacystis-microcolon-intestinal hypoperistalsis syndrome.

Megacystis-microcolon-intestinal hypoperistalsis syndrome (MMIHS) is characterized by marked dilatation of the bladder and microcolon and decreased intestinal peristalsis. Recent studies indicate that heterozygous variants in ACTG2, which codes for a smooth muscle actin, cause MMIHS. However, such variants do not explain MMIHS cases that show an autosomal recessive mode of inheritance. We performed exome sequencing in a newborn with MMIHS and prune belly phenotype whose parents are consanguineous and identified a homozygous variant (c.3598A>T: p.Lys1200Ter) in MYH11, which codes for the smooth muscle myosin heavy chain. Previous studies showed that loss of Myh11 function in mice causes a bladder and intestinal phenotype that is highly reminiscent of MMIHS. All together, these observations strongly suggest that loss-of-function variants in MYH11 cause MMIHS. The documentation of variants in ACTG2 and MYH11 thus points to the involvement of the contractile apparatus of the smooth muscle in MMIHS. Interestingly, dominant-negative variants in MYH11 have previously been shown to cause thoracic aortic aneurism and dilatation. Different mechanisms of MYH11 disruption may thus lead to distinct patterns of smooth muscle dysfunction.

Role of the phosphoinositide phosphatase FIG4 gene in familial epilepsy with polymicrogyria.

OBJECTIVE: The aim of this study was to identify the causal gene in a consanguineous Moroccan family with temporo-occipital polymicrogyria, psychiatric manifestations, and epilepsy, previously mapped to the 6q16-q22 region. METHODS: We used exome sequencing and analyzed candidate variants in the 6q16-q22 locus, as well as a rescue assay in Fig4-null mouse fibroblasts and immunohistochemistry of Fig4-null mouse brains. RESULTS: A homozygous missense mutation (p.Asp783Val) in the phosphoinositide phosphatase gene FIG4 was identified. Pathogenicity of the variant was supported by impaired rescue of the enlarged vacuoles in transfected fibroblasts from Fig4-deficient mice. Histologic examination of Fig4-null mouse brain revealed neurodevelopmental impairment in the hippocampus, cortex, and cerebellum as well as impaired cerebellar gyration/foliation reminiscent of human cortical malformations. CONCLUSIONS: This study extends the spectrum of phenotypes associated with FIG4 mutations to include cortical malformation associated with seizures and psychiatric manifestations, in addition to the previously described Charcot-Marie-Tooth disease type 4J and Yunis-Varón syndrome.

Bilateral brachial plexus injury following acute carbon monoxide poisoning.

BACKGROUND: Carbon monoxide (CO) intoxication is a leading cause of severe neuropsychological impairments. Peripheral nerve injury has rarely been reported. It consists usually in a demyelinating polyneuropathy or mononeuropathy affecting mainly the lower limbs. Isolated involvement of both upper extremities has been described in only 4 patients related to root damage. We report the first case of bilateral brachial plexus injury following CO poisoning and review all previous CO-induced neuropathy described in literature. CASE PRESENTATION: After being unconscious for three hours, a 42 years old man experienced bilateral brachial weakness associated with edema of the face and the upper limbs. Neurological examination showed a brachial diplegia, distal vibratory, thermic and algic hypoesthesia, deep tendon areflexia in upper limbs. There was no sensory or motor deficit in lower extremities. No cognitive disturbances were detected. Creatine kinase was elevated. Electroneuromyogram patterns were compatible with the diagnosis of bilateral C5 D1 brachial axonal plexus injury predominant on the left side. Clinical course after hyperbaric oxygen therapy was marked by a complete recovery of neurological disorders. CONCLUSION: Peripheral neuropathy is an unusual complication of CO intoxication. Bilateral brachial plexus impairment is exceptional. Various mechanisms have been implicated including nerve compression secondary to rhabdomyolysis, nerve ischemia due to hypoxia and direct nerve toxicity of carbon monoxide. Prognosis is commonly excellent without any sequelae.

Carboxypeptidase A6 gene (CPA6) mutations in a recessive familial form of febrile seizures and temporal lobe epilepsy and in sporadic temporal lobe epilepsy.

Febrile seizures (FS) and temporal lobe epilepsy (TLE) were found in four of the seven siblings born to healthy Moroccan consanguineous parents. We hypothesized autosomal recessive (AR) inheritance. Combined linkage analysis and autozygosity mapping of a genome-wide single nucleotide polymorphism genotyping identified a unique identical by descent (IBD) locus of 9.6 Mb on human chromosome 8q12.1-q13.2. Sequencing of the 38 genes mapped within the linked interval revealed a homozygous missense mutation c.809C>T (p.Ala270Val) in the carboxypeptidase A6 gene (CPA6). Screening all exons of CPA6 in unrelated patients with partial epilepsy (n = 195) and FS (n = 145) revealed a new heterozygous missense mutation c.799G>A (p.Gly267Arg) in three TLE patients. Structural modeling of CPA6 indicated that both mutations are located near the enzyme's active site. In contrast to wild-type CPA6, which is secreted and binds to the extracellular matrix where it is enzymatically active, Ala270Val CPA6 was secreted at about 40% of the level of the wild-type CPA6 and was fully active, while Gly267Arg CPA6 was not detected in the medium or extracellular matrix. This study suggests that CPA6 is genetically linked to an AR familial form of FS and TLE, and is associated with sporadic TLE cases.

A locus for bilateral occipital polymicrogyria maps to chromosome 6q16-q22.

We describe the clinical, radiographic, and genetic features of a large consanguineous Moroccan family in which bilateral occipital polymicrogyria segregated as an autosomal recessive trait. Six affected members of the family had partial complex seizures often associated with behavioral abnormalities. On MRI, three patients had a thickened irregular cortex in the lateral occipital lobes with small gyri. A high-density genome-wide scan with 10,000 SNPs established linkage by homozygosity mapping to a 14-Mb region on chromosome 6q16-q22. Candidate genes by function (TUBE1, GRIK2, GPRC6A, GPR6, NR2E1, MICAL1, and MARCKS) in this locus were screened for mutations.

A novel GDAP1 mutation P78L responsible for CMT4A disease in three Moroccan families.

BACKGROUND: The gene encoding the ganglioside-induced-differentiation-associated protein 1 (GDAP1) has been associated with both axonal and demyelinating neuropathy. Up to date, 25 mutations in the GDAP1 gene have been reported in patients from different origins. METHODS: Three Moroccan families with early onset ARCMT1 and autosomal recessive inheritance were genotyped to test linkage to 8q21.3 and their GDAP1 gene coding exons screened for mutations. RESULTS: A novel C233T transversion at codon 78 (P78L) was detected in 6 patients from 3 unrelated families. The mutation was found to be homozygous in two families and compound heterozygous in association with the already reported S194X mutation in one family. The P78L mutation was associated with a common haplotype suggesting a Moroccan founder mutation. The patients had symptoms within the two first years of life and developed common phenotype of CMT4A with evident hoarse-voice in two cases with the longer disease duration. CONCLUSION: P78L mutation was associated with a common haplotype suggesting a common ancestor.

Autosomal recessive axonal Charcot-Marie-Tooth disease (ARCMT2): phenotype-genotype correlations in 13 Moroccan families.

Charcot-Marie-Tooth disease is a genetically heterogeneous group of hereditary motor and sensory neuropathies. Three loci for the axonal autosomal recessive subgroup (ARCMT2) have been reported in 1q21 (CMT2B1, LMNA), 8q21 (CMT4A and CMT2K, GDAP1) and 19q13 (CMT2B2). We report here a clinical, electrophysiological, pathological and genetic study in 13 Moroccan families with ARCMT2 phenotypes. Clinical and electrophysiological examinations were performed in all index cases and 64 'at-risk' relatives. Thirty-one patients were clinically affected. A peroneal nerve biopsy was obtained from three patients. Four families were linked to the 1q21 locus, all had the LMNA R298C mutation. Six families were linked to the 8q21 locus, all had the GDAP1 S194X mutation. Founder effects for both mutations were suggested by the analysis of microsatellite markers close to the genes. The three remaining families were excluded from the three known loci. The electrophysiological findings were consistent with an axonal neuropathy. The clinical data show that in CMT2B1 the disease began most often in the second decade and progressed gradually from distal to proximal muscles. Three of our patients with the longest disease durations (>24 years) had also severe impairment in the scapular muscles. Reported here for the first time, this might be a hallmark of CMT2B1. Patients with CMT4A/2K had onset most often before the age of 2 years. Most had severe clubfoot from the beginning, one of the hallmarks of CMT4A/2K. None of our patients with CMT4A/2K had vocal cord paralysis. The clinical phenotype of the three families that are not linked to the three known loci presented some particularities that were not seen in those with known genetic defects. One family was characterized by late onset of the disease (>20 years) or a mild neuropathy that was diagnosed only when the family was examined. In a second family, dorsal scoliosis was the most prominent symptom. In the third family, symptoms began in the second decade with a moderate neuropathy associated with a pronounced scoliosis. These families illustrate the extent of clinical and genetic heterogeneity in ARCMT2.

Autosomal recessive mutilating sensory neuropathy with spastic paraplegia maps to chromosome 5p15.31-14.1.

Autosomal recessive ulcero-mutilating neuropathy with spastic paraplegia is a very rare disease since only few cases were described up to date. We report in this study a consanguineous Moroccan family with four affected males with this syndrome. The disease onset was in early infancy, with spastic paraplegia and sensory loss leading to mutilating acropathy. Electrophysiological studies revealed a severe axonal sensory neuropathy, magnetic resonance imaging ruled out compression of spinal cord and biological investigations showed decreased levels of Apo B, total cholesterol and triglycerides. A genomewide search was conducted in this family and linkage was found to chromosome 5p. Analysis of recombination events and LOD score calculation map the responsible gene in a 25 cM genetic interval between markers D5S2054 and D5S648. A maximum LOD score value of 3.92 was obtained for all markers located in this candidate interval. This study establishes the presence of a locus for autosomal recessive mutilating sensory neuropathy with spastic paraplegia on chromosome 5p15.31-14.1.

Phenotypical features of a Moroccan family with autosomal recessive Charcot-Marie-Tooth disease associated with the S194X mutation in the GDAP1 gene.

BACKGROUND: The first locus for demyelinating autosomal recessive Charcot-Marie-Tooth (ARCMT) disease was identified in 8q13, where mutations in GDAP1 have been found. Mutations in the same gene have been detected in families with axonal ARCMT disease. OBJECTIVE: To determine the clinical, electrophysiologic, and morphologic characteristics of a consanguineous Moroccan family with ARCMT disease associated with the S194X mutation in the GDAP1 gene. METHODS: Four patients from a consanguineous Moroccan family were examined clinically and electrophysiologically. In one patient, a morphometric and ultrastructural study of a peroneal nerve biopsy sample was performed. Mutation in the coding region of the GDAP1 gene was identified by direct sequencing. RESULTS: Neuropathy was evident early in childhood, walking was delayed in one patient, and onset of symptoms occurred before 18 months in the others. The phenotype was severe: foot deformities and disabilities involving the hands and feet developed toward the end of the first decade, followed by involvement of proximal muscles in the lower limbs, leading to loss of autonomy. Electrophysiologic findings were consistent with an axonal form of CMT disease: motor nerve conduction velocities, recordable in one patient only, were greater than 40 m/sec. Sensory nerve action potentials were either abolished or substantially reduced in amplitude. The morphologic data supported the diagnosis of axonal neuropathy, showing a marked reduction in myelinated fibers and signs of axonal regeneration, including frequent pseudo-onion bulb formations. The 4 patients in this family were homozygous for the S194X mutation in the GDAP1 gene. CONCLUSION: Electrophysiologic and pathological findings support the hypothesis of an axonal disorder in this ARCMT family with the S194X mutation in the GDAP1 gene.

Haplotype study of West European and North African Unverricht-Lundborg chromosomes: evidence for a few founder mutations.

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.