Charles-Antoine Haenggeli

Non-invasive epileptic focus localization using EEG-triggered functional MRI and electromagnetic tomography

We present a new approach for non-invasive localization of focal epileptogenic discharges in patients considered for surgical treatment. EEG-triggered functional MR imaging (fMRI) and 3D EEG source localization were combined to map the primary electrical source with high spatial resolution. The method is illustrated by the case of a patient with medically intractable frontal lobe epilepsy. EEG obtained in the MRI system allowed triggering of the fMRI acquisition by the patients habitual epileptogenic discharges. fMRI revealed multiple areas of signal enhancement. Three-dimensional EEG source localization identified the same active areas and provided evidence of onset in the left frontal lobe. Subsequent electrocorticography from subdural electrodes confirmed spike and seizure onset over this region. This approach, i.e. the combination of EEG-triggered fMRI and 3D EEG source analysis, represents a promising additional tool for presurgical epilepsy evaluation allowing precise non-invasive identification of the epileptic foci.

A recessive form of central core disease, transiently presenting as multi-minicore disease, is associated with a homozygous mutation in the ryanodine receptor type 1 gene

Multi‐minicore disease is an autosomal recessive congenital myopathy characterized by the presence of multiple, short‐length core lesions (minicores) in both muscle fiber types. These lesions being nonspecific and the clinical phenotype being heterogeneous, multi‐minicore disease boundaries remain unclear. To identify its genetic basis, we performed a genome‐wide screening in a consanguineous Algerian family in which three children presented in infancy with moderate weakness predominant in axial muscles, pelvic girdle and hands, joint hyperlaxity (hand involvement phenotype), and multiple minicores. We mapped the disease to chromosome 19q13 in this family and, subsequently, in three additional families showing a similar phenotype, with a maximum LOD score of 5.19 for D19S570. This locus was excluded in 16 other multi‐minicore disease families with predominantly axial weakness, scoliosis, and respiratory insufficiency (“classical” phenotype). In the Algerian family, we identified a novel homozygous missense mutation (P3527S) in the ryanodine receptor type 1 gene, a positional candidate gene responsible for the autosomal dominant congenital myopathy central core disease. New muscle biopsies from the three patients at adulthood demonstrated typical central core disease with rods; no cores were found in the healthy parents. This subgroup of families linked to 19q13 represents the first variant of central core disease with genetically proven recessive inheritance and transient presentation as multi‐minicore disease.

Multi-minicore disease--searching for boundaries: phenotype analysis of 38 cases

Multi‐minicore disease (MmD) is a congenital myopathy morphologically defined by the presence of multiple small zones of sarcomeric disorganization and lack of oxidative activity (“minicores”) in muscle fibers. The clinical expression of MmD is considered to be greatly variable, and the morphological lesions are nonspecific; therefore, its boundaries are poorly defined, and its molecular bases are not known. To better define the phenotypic characteristics of MmD, we analyzed a large series of 38 patients with multiple minicores in muscle fibers in the absence of any other potential cause. According to clinical features, 4 subgroups were identified. Most patients (30 cases) shared a common highly consistent phenotype marked by the axial predominance of muscle weakness and a high occurrence of severe respiratory insufficiency and scoliosis (“classical” form). Other forms were characterized by pharyngolaryngeal involvement and total lack of head control (2 cases), antenatal onset with arthrogryposis (3 cases), and slowly progressive weakness with marked hand amyotrophy (3 cases). Type 1 fiber predominance and hypotrophy as well as centrally located nuclei were found in every subgroup. MmD is thus phenotypically heterogeneous, but a typical recognizable phenotype does exist. This phenotype classification should be helpful when undertaking research into the molecular defects that cause MmD. Ann Neurol 2000;48:745–757

Plant-induced seizures: reappearance of an old problem.

Abstract Several plant-derived essential oils have been known for over a century to have epileptogenic properties. We report three healthy patients, two adults and one child, who suffered from an isolated generalized tonic-clonic seizure and a generalized tonic status, respectively, related to the absorption of several of these oils for therapeutic purposes. No other cause of epilepsy was found, and outcome was good in the two adult cases, but the course has been less favorable in the child. A survey of the literature shows essential oils of 11 plants to be powerful convulsants (eucalyptus, fennel, hyssop, pennyroyal, rosemary, sage, savin, tansy, thuja, turpentine, and wormwood) due to their content of highly reactive monoterpene ketones, such as camphor, pinocamphone, thujone, cineole, pulegone, sabinylacetate, and fenchone. Our three cases strongly support the concept of plant-related toxic seizure. Nowadays the wide use of these compounds in certain unconventional medicines makes this severe complication again possible.

PCR based mutation screening of the laminin alpha2 chain gene (LAMA2): application to prenatal diagnosis and search for founder effects in congenital muscular dystrophy.

Classical congenital muscular dystrophy with merosin deficiency is caused by mutations in the laminin alpha2 chain gene (LAMA2). Extended sequencing of the introns flanking the 64 LAMA2 exons was carried out and, based on these sequences, oligonucleotide primers were designed to amplify the coding region of each exon separately. By PCR-SSCP analysis, we identified eight new mutations in nine families originating from various countries. All induced a premature truncation of the protein, either in the short arm or in the globular C-terminal domain. A 2 bp deletion in exon 13, 2098delAG, was found in three French non-consanguineous families and a nonsense mutation of exon 20, Cys967stop, in two other non-consanguineous families originating from Italy. Determination of rare intragenic polymorphisms permitted us to show evidence of founder effects for these two mutations suggesting a remote degree of consanguinity between the families. Other, more frequent polymorphisms, G to A 1905 (exon 12), A to G 2848 (exon 19), A to G 5551 (exon 37), and G to A 6286 (exon 42), were used as intragenic markers for prenatal diagnosis. This study provides valuable methods for determining the molecular defects in LAMA2 causing merosin deficient congenital muscular dystrophy.

Severe childhood encephalopathy with dyskinesia and prolonged cognitive disturbances: evidence for anti-N-methyl-d-aspartate receptor encephalitis

Aim  We report four cases of acquired severe encephalopathy with massive hyperkinesia, marked neurological and cognitive regression, sleep disturbance, prolonged mutism, and a remarkably delayed recovery (time to full recovery between 5 and 18mo) with an overall good outcome, and its association with anti‐N‐methyl‐d‐aspartate (anti‐NMDA) receptor antibodies.

Contribution of a non-inactivating potassium current to the resting membrane potential of fusion-competent human myoblasts

1. Using the patch‐clamp technique, a new non‐inactivating voltage‐gated potassium current, IK(ni), was studied in cultured fusion‐competent human myoblasts. 2. IK(ni) is activated at voltages above ‐50 mV and its conductance reaches its maximum around +50 mV. Once activated, the current remains at a steady level for minutes. 3. Reversal potential measurements at various extracellular potassium concentrations indicate that potassium ions are the major charge carriers of IK(ni). 4. IK(ni) is insensitive to potassium channel blockers such as charybdotoxin, dendrotoxins, mast cell degranulating (MCD) peptide, 4‐aminopyridine (4‐AP), 3,4‐diaminopyridine (3,4‐DAP) and apamin, but can be blocked by high concentrations of TEA and by Ba2+. 5. A potassium channel of small conductance (8.4 pS at +40 mV) with potential dependence and pharmacological properties corresponding to those of IK(ni) in whole‐cell recording is described. 6. IK(ni) participates in the control of the resting potential of fusion‐competent myoblasts, suggesting that it may play a key role in the process of myoblast fusion.

Early onset and rapidly progressive subacute sclerosing panencephalitis after congenital measles infection

Abstract. We report an 18-month-old girl with rapidly progressive subacute sclerosing panencephalitis, whose non immunised mother had measles at the time of delivery. The patient presented with repetitive episodes of myoclonic jerks of the head and arms, followed by a drop of head and trunk with frequent falls. EEG, CSF studies and MRI confirmed the diagnosis. Despite therapy with isoprinosine and valproate, seizure activity continued and she became vegetative within 2 months, with severe spasticity and swallowing difficulties, and died at the age of 28 months. Early age of onset and rapid progression were most likely related to haematogenous in utero acquisition of the measles virus prior to delivery, as well as immaturity of neuronal and immune systems. Conclusion: this case emphasises the importance of a high measles vaccine coverage in the population in order to prevent the risk of disease in general and, in particular, gestational measles.

Association of multiple vertebral hemangiomas and severe paraparesis in a patient with a PTEN hamartoma tumor syndrome. Case report.

The PTEN hamartoma tumor syndrome, manifestations of which include Cowden disease and Bannayan-Riley-Ruvalcaba syndrome, is caused by various mutations of the PTEN gene located at 10q23. Its major criteria are macrocephaly and a propensity to develop breast and thyroid cancers as well as endometrial carcinoma. Minor diagnostic criteria include hamartomatous intestinal polyps, lipomas, fibrocystic disease of the breasts, and fibromas. Mutations of PTEN can also be found in patients with Lhermitte-Duclos disease (dysplastic gangliocytoma of the cerebellum). The authors report the case of a 17-year-old girl who had a severe cyanotic cardiac malformation for which surgery was not advised and a heterozygous missense mutation (c.406T>C) in exon 5 of PTEN resulting in the substitution of cysteine for arginine (p.Cysl36Arg) in the protein, which was also found in her mother and sister. The patient presented in the pediatric emergency department with severe spastic paraparesis. A magnetic resonance imaging study of the spine showed vertebral hemangiomas at multiple levels, but stenosis and compression were maximal at level T5-6. An emergency T5-6 laminectomy was performed. The decompression was extremely hemorrhagic because the rapid onset of paraparesis necessitated prompt treatment, and there was no time to perform preoperative embolization. The patients postoperative course was uneventful with gradual recovery. This represents the first report of an association of a PTEN mutation and multiple vertebral angiomas. The authors did not treat the remaining angiomas because surgical treatment was contraindicated without previous embolization, which in itself would present considerable risk in this patient with congenital cyanotic heart disease.

MEHMO, a novel syndrome: assignment of disease locus to Xp21.1-p22.13. Mental retardation, epileptic seizures, hypogonadism and genitalism, microcephaly, obesity

We read with interest the article by Steinmüller et al entitled MEHMO (mental retardation, epileptic seizures, hypogonadism and genitalism, microcephaly, obesity), a novel syndrome: assignment of disease locus to Xp21.1–p22.13. We believe, however, that this is not a novel disorder, but the same syndrome we described in a French-language publication in 1989. The clinical similarities between the patients of Steinmüller et al and our own – particularly the facies, obesity, severe developmental delay and peculiar neurological status – are so striking that one can hardly doubt that these boys all suffer from the same syndrome (Figure 1). Their patients appear, however, to be more severely affected than were ours, attested to by shorter life spans and epilepsy. The patients described by Steinmüller et al died between 2 months and 2 years of age; one of our brothers died at age 4 1 2 years, but the second is alive, at age 14. According to his parents there has been absolutely no developmental progress since we last saw him at age 3 1 2, as he does not even sit or vocalise more than sounds, remains extremely hypertonic and irritable and has gained in weight but not in length (30 kilos for 96 cm at age 14). The patients we described did not have overt epilepsy, although EEGs were highly abnormal (VD’s were described as nearly flat); their neurological status was characterised by hypertonia (the typical posture being the same as that seen in Steinmüller’s patient IV/2, Figure 1a) and hyperreflexia, nystagmus and an extremely agitated and irritable behavioral pattern. Such variability in clinical presentation between two families (with allelic mutations?) is not surprising, given the small number of patients described to date. The differential diagnosis which we considered at that time was similar to that discussed by Steinmüller et al. The disorder which seemed the most similar among those described then was the Borjeson-ForssmanLehmann syndrome, which does not have the severe growth retardation nor the short life span described by Steinmüller et al and by ourselves. Clinical characteristics of the three patients they described in detail are compared with those of our two patients (Table 1). We would point out that if one searches the London Dysmorphology Database using, for example, the search terms ‘mental retardation, seizures/abnormal EEG, microcephaly, generalized obesity and hypogonadism’, only two syndrome are suggested, one being the disorder we described 10 years ago. The brothers we reported on lived in a small town in the south of Italy; as there was no autopsy after the death of the first and we have no DNA sample from him, it is impossible to investigate a potential Xp localisation. The mother does not have a brother and