[Oculopharyngeal muscular dystrophy: study of patients from seven Spanish families with different GCG expansions in PABP2 gene]. / Distrofia muscular oculofaríngea: estudio de pacientes pertenecientes a siete familias españolas con diferentes expansiones GCG en el gen PABP2.

INTRODUCTION: Autosomal dominant oculopharyngeal muscular dystrophy (OPMD), with late onset due to ptosis and/or dysphagia, is caused by short (GCG)8-13 triplet-repeat expansions in the polyadenylation binding protein 2 (PABP2) gene, which is localized in chromosome 14q11. The severity of the dominant OPMD as well as the number of expansions that cause the disease are variable. (GCG)9 is mentioned as the most frequent and the genotype/phenotype has still not been well-determined. OBJECTIVE: To describe the type of expansions (GCG)n found in Spanish families with OPMD, establishing if there is variability of them and the possible geno-phenotypical correlations. METHODS: Clinicopathological and molecular studies have been performed in 15 consecutive patients, belonging to seven Spanish families with OPMD. The muscular biopsy study under electronmicroscopy shows intranuclear inclusions (INIs) in all the examined patients (one patient per family). The genetic findings confirm the cause of the disease in all the affected members and in one clinically asymptomatic member of one recently examined family: three families (six, one and one studied members, respectively) present the (GCG)9 expansion, two families (one studied member each one) present the (GCG)10 expansion and two families (one and four studied members respectively) present the (GCG)11 expansion. In these 15 patients with a short GCG expansion causing OPMD, clinical tests for OPMD and a follow-up study of their clinical course have been carefully assessed: in patients with the (GCG)9 expansion major abnormalities appeared in extrinsic ocular mobility and more precocious presentation of limb girld (lumbopelvic preferentially) weakness leading to a great disability before the seventh decade of life under the seventies in some patients and sometimes leading to death. In patients with (GCG)10 and (GCG)11 expansions, eye movements are always preserved and the limb girld muscles weakness did not appear before the seventh decade. No correlation seems to exist between age of onset of the ptosis or dysphagia and the different (GCG)n expansions and the surgical treatment of ptosis, performed in eight patients, showed good results independently of the (GCG)n mutation. CONCLUSIONS: Although further clinical and genetic studies are necessary to establish a strict genotype/phenotype correlation in OPMD, we concluded that the (GCG)9 expansion involve more severe phenotypes than those related to the (GCG)10 or (GCG)11 expansions. Therefore, genetic testing could benefit prognosis in asymptomatic individuals.

SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I.

Hereditary sensory neuropathy type I (HSN I) is an autosomal dominant ulceromutilating disorder of the peripheral nervous system characterized by progressive sensory loss. HSN I locus maps to chromosome 9q22.1-22.3 and is caused by mutations in the gene coding for serine palmitoyltransferase long-chain base subunit 1 (SPTLC1). A novel missense mutation in exon 13 of the SPTLC1 gene (c.1160G-->C; p.G387A) in twin sisters with a severe HSN I phenotype is reported.

[Crazy laughter: first manifestation of a pontine tumour]. / "Risa loca": primera manifestación de un tumor protuberancial.

Crazy laughter (<>) was first described in 1903 as a prodromic symptom of an ischemic stroke and was later associated with brain lesions having a different location and etiology. We describe the case of a patient with a poorly differenciated pulmonary carcinoma who presented a centropontine image consistent with metastasis, whose initial manifestation was involuntary, persistent and unmotivated laughter that preceded other clinical manifestations. We revised, on the one hand, previous cases described in the literature of pathological laughter in relationship to structural lesions, of vascular or neoplastic etiology, and, on the other, the nervous centers and pathways that control the laughter mechanism.

[Hereditary neuropathy with liability to pressure palsies: study of six Spanish families]. / Neuropathies héréditaires sensibles à la pression: étude de six familles espagnoles.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant inherited demyelinating neuropathy typically characterized by recurrent episodes of acute painless peripheral nerve palsies often preceded by minor trauma or compression at entrapment sites. However, less classical phenotypes have been reported. A 1.5 Mb deletion in chromosome 17 p11.2 has been shown to be the genetic basis of the disease in the majority of HNPP patients. The few families without this deletion harbored a mutation in the PMP22 gene. We performed a clinical, neurophysiological and molecular genetic study of 6 Spanish HNPP families. Five families (22 individuals) showed the classical chromosome 17 p11.2 deletion and one family (3 individuals) had a novel 3'splice-site mutation in PMP22. Neurophysiological abnormalities were detected in all symptomatic (n=21) and asymptomatic (n=4) deletion or mutation carriers, even in childhood. In addition to the typical presentation we observed other phenotypes: recurrent focal short-term sensory symptoms, a progressive mononeuropathy, a Charcot-Marie-Tooth (CMT) disease-like chronic progressive polyneuropathy, a chronic sensory polyneuropathy and a chronic inflammatory demyelinating polyneuropathy. We report new or very rare phenotypesThese atypical clinical aspects and intrafamilial heterogeneity are present in families with the HNPP deletion as well as in the family with the PMP22 mutation. However, the CMT disease-like chronic polyneuropathy was more common in the PMP22 mutation family. Intrafamilial heterogeneity also seemed to be more pronounced in this kinship. Patients in this family had a mild chronic motor and sensory polyneuropathy neurophysiologically characterized by delayed distal latencies, reduced nerve conduction velocities (NCV) within the demyelinating range, mildly decreased amplitudes of motor and sensory evoked potentials and absence of conduction blocks. In contrast, patients with the common HNPP deletion, regardless of their phenotype, had a diffuse increase in distal motor latencies contrasting with moderately reduced motor NCVs, preserved sensory nerve action potentials, slowing of NCVs at the common entrapment sites and occasionally conduction blocks. In this study we confirm the clinical and molecular heterogeneity of HNPP, emphasizing the need for a mutation analysis of the PMP22 gene when the common 17p11.2 deletion is not found in clinically suspected HNPP patients. We conclude that the 3'splice-site mutation in PMP22 and the common HNPP deletion have largely the same functional consequences although some clinical and neurophysiological differences were observed.

[Familial myopathy with desmin storage seen as a granulo-filamentar, electron-dense material without mutation of the alphabeta-crystallin gene]. / Miopatía familiar con sobrecarga de desmina, bajo forma de material granulofilamentoso denso en microscopia electrónica, sin mutación en el gen de la alphabeta-cristalina.

BACKGROUND: Desmin-related myopathy is a familial myopathy and cardiomyopathy. Three subgroups have been outlined, an autosomal dominant (AD) granulofilamentous type with cardiomyopathy, an AD cytoplasmic/spheroid inclusion body type and an autosomic recessive Mallory body-like inclusion type. Recently, in one family belonging to the first group it has been identified a mutation within a gene coding for a chaperone protein, alphabeta-crystallin (CRYAB gene). OBJECTIVE: To describe a Spanish family with a desmin-related myopathy, an AD granulofilamentous type with cardiomyopathy, with a molecular study that does not express any point mutation in the CRYAB gene. PATIENTS, METHODS AND RESULTS: This report concerns a family from southern Spain in which 2 sisters (37 and 44 and 36 years old respectively) present an involvement of skeletal (distal more than proximal) and velo-pharyngeal muscles with onset at the third decade of life and with a rather severe progression, leading soon to bilateral foot drops. The mode of transmission is autosomal dominant. Two other members, the mother and one brother _the latter with hypertrophic cardiomyopathy, atrioventricular block and severe heart failure_, have already died. The electrophysiological study carried out in the sisters shows myogenic patterns with abundant spontaneous activity but not genuine myotonic discharges. Muscle biopsy, also purchased in both sisters, shows myopathic changes, a few rimmed vacuoles in one of them, and several "rubbed-out" fibers or fibers "effacées" visible within the intramyofibrilary network on the enzymatic stainings. The ultrastructural findings in both biopsies reveal a similar pattern of structural damage: an intrasarcoplasmic (specially subsarcolemmal) accumulation of an electro-dense filamentous material arising from the Z-bands and a focal disruption of the myofibrils. Immunohistochemically the subsarcolemmal material stained positively for the intermediate filament protein desmin but other proteins as ubiquitin, tropomyosine and actin were found overexpressed. Genetic studies have excluded myotonic dystrophy, any point mutation in the CRYAB gene, and different markers failled to express linkage to any loci on chromosome 12. The possible mutations in desmin gene are to be studied. CONCLUSION: The distinct intrafamilial phenotype observed in this family confirms the multisystemic character of the desmin-related myopathyies. The genetic results also support the genetic heterogeneity of these myopathies and reinforce the concept that mutations in the desmin gene must be investigated as a cause of the disease.

A novel 3'-splice site mutation in peripheral myelin protein 22 causing hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant, demyelinating peripheral neuropathy. Clinical hallmarks are recurrent painless focal neuropathies mostly preceded by minor trauma or compression at entrapment sites of peripheral nerves. In the majority of the patients, HNPP is caused by a 1.5 Mb deletion on chromosome 17p11.2-p12 containing the peripheral myelin protein 22 (PMP22) gene. Point mutations within this gene are reported in only a few families. We report a novel mutation in the PMP22 gene in a Spanish family with HNPP. The mutation is a 3' splice-site mutation, preceding coding exon 3 (c.179-1 G>C), causing a mild HNPP phenotype.

[Acquired dysimmune neuropathies. Clinical symptoms and classification]. / Neuropatías disinmunes adquiridas. Sintomatología clínica y clasificación.

INTRODUCTION: The neuropathies caused by dysimmunity have seen great changes in recent years. The different forms of clinical presentation, electrophysiological expression, associated anomalies seen on analytical tests, particularly the presence of antibodies to the various antigens of myelin are becoming better understood. This confirms their dysimmune nature and also offers unforeseen possibilities for the comprehension of etiopathogenic mechanisms and possible classifications of specific etiopathogenic factors. DEVELOPMENT: Based mainly on our own experience, in this paper we review current concepts of the three main dysimmune polyneuropathies, the Guillain-Barré syndrome, chronic inflammatory demyelinating polyradiculoneuritis or CIDP and the motor multifocal neuropathies (MMN) with block-conduction or Lewis-Summer syndrome. Regarding the first condition, we particularly emphasize the convenience of establishing the broad classification needed by the variation in its clinical presentation, with regional and functional variants: among the latter we consider particularly the pure motor forms which in most cases are axonal forms with an etiopathogenic basis which is fairly well established and almost constantly associated with the presence of specific antibodies in the serum of patients with this condition. With reference to CIDP, we discuss the existence of atypical forms and the frequency of the relapsing form concerning the evolution. The MMN are the most recently discovered dysimmune neuropathies, according to both the literature and personal experience. We try to establish the difference between pure motor forms and those which also have sensory involvement (or MADSAM) and are called the Lewis-Sumner syndrome.

[Acute posterior cord lesions in multiple sclerosis. An MRI study of the clinical course in 20 cases]. / Lésions cordonales postérieures aiguës dans la sclérose en plaques.Etude clinico-évolutive et par IRM de 20 cas.

Twenty patients with multiple sclerosis (MS), 19 women and 1 man, with acute proprioceptive sensory disturbances related to the presence of plaques on the posterior columns (posterior column syndrome) at the cervical or thoracic levels of the spinal cord, were selected among 138 new patients with MS assisted in our neurological unit over the past five years. In 17 of these patients, the acute posterior cordonal syndrome was responsible for the first clinical manifestations of the disease. The other 3 patients had a history suggestive of MS. These 20 patients were followed with a minute analysis of neurological function with repeated clinical evaluation combined with repeated MRI study of the spinal cord. Brain MRI (strongly suggestive of MS in 15 patients), evoked potentials (EP) and cerebrospinal fluid electrophoresis analysis (with oligoclonal bands present in all patients were it was performed) were also obtained at least once in each patient. Spinal cord MRI demonstrated more lesions in the cervical region (90 p.100) than in the thoracic regions (10 p.100). Eighty percent of the cervical lesions were located high, between C1 and C4. The most characteristic clinical expression was the deafferentation of one upper limb, preferentially the "useless hand" (Oppenheim) or even a pseudoathetosic or dystonic limb. Propioceptive ataxia or spontaneous cervical or brachial pain were other forms of clinical expression. No major motor deficit or sphincter disorders were noted at any time in the clinical course in any of the patients. There was a good correlation between localization and morphology of the plaques detected by spinal cord MRI and clinical signs. Intrinsic medullary lesions were seen as high intensity signals on T2-weighted images which were enlarged more than the same lesion visualized on T1-weighted images after injection of paramagnetic contrast agents. This reflected the presence of edema extending beyond the main inflammatory lesion. There was also a good correlation between improvement of clinical symptoms and total or, mor frequently, partial reduction of the plaques, analyzed morphologically by successive spinal cord MRI series. The diagnosis of MS was clinically definitive in 60 p.100 of cases and laboratory-supported definitive in 40 p.100. During the follow-up period (average 36 months), 15 patients (75 p.100) presented one or more exacerbations, all of them presenting a favorable course: at last follow-up, 9 patients were asymptomatic, EDSS was 1 in 6 patients, 1.5 in 4 patients and 2 in 1 patient. This study confirms the contribution of serial spinal cord MR studies to understanding the natural history and pathophysiology of medullary forms of MS presenting as a cordonal posterior syndrome. It also shows a good relationship between the clinical manifestations and course of this form of MS and the localization and variable morphology of plaques. Finally, our results suggest the predictive benign course for this medullary form of MS that seems to be almost exclusively restricted to the female gender.

Genetic refinement of the hereditary neuralgic amyotrophy (HNA) locus at chromosome 17q25.

Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant, recurrent focal neuropathy. HNA is characterised by episodes of painful brachial plexus neuropathy with muscle weakness and atrophy, as well as sensory disturbances. Single episodes are commonly preceded by non-specific infections, immunisations or parturition. Mild dysmorphic features and short stature are present in some HNA families, but absolute co-segregation with HNA has not been described. To refine the previously described HNA locus on chromosome 17q25, we performed a genetic linkage study in five HNA families with different geographic origins. Significant linkage was obtained with chromosome 17q24-q25 short tandem repeat (STR) markers in three HNA families and suggestive linkage was found in the other two HNA families. Analysis of the informative recombinations in affected individuals allowed us to reduce the HNA linkage interval to a candidate region of 3.5 cM.

[Bilateral intra-axial involvement of the common oculomotor nerve (III): 2 cases]. / Atteinte bilatérale intra-axiale du nerf moteur oculaire commun (III): deux cas.

Bilateral palsy of the common ocular motornerve (III) was observed in two patients with an intra-axial lesion due ti hemorrhage in one and ischemia in the other. The lesions involved the cerebral peduncle in the periaqueductal region and the nuclear complex of the III in the first case. Bilateral infarct of the thalamus was seen in the second. Clinical manifestations were transitory except for the oculomotor impairment. In the first patient, oculomotricity was dissociated as intrinsic mortricity was spared. These exceptional cases demonstrate a syndrome with unique oculomotor expression resulting from intra-axial oculomotor lesions. Prognosis varies and is related to the ischemic or hemorrhagic nature of the causal lesion and its localization.

[Natural evolution of neurocutaneous syndrome in adults]. / Evolución natural de las facomatosis en la edad adulta.

Neurofibromatoses (NF1 and NF2) are genetic diseases with an extremely wide range of manifestations, particularly NF1. In order to gain insight into their prognosis, we have conducted a follow-up study of 100 patients with neurofibromatoses, 89 NF1 patients and 11 NF2 patients all of them presenting neurological manifestations. Four deaths occurred in the NF1 group (3 neurofibrosarcomas) and two in the NF2 group (after neurosurgery). We describe a series of NF1 brainstem tumors as being pilocytic astrocytomas, much less aggressive than non-NF1 brainstem tumors but more symptomatic than brainstem UBOs ('unidentified bright objects') in NF1. The series of optic nerve tumors also demonstrate the poor and non-progressive evolution of tumors with the same histopatological estructure. Hydrocephalus related to aqueductal stenosis is a frequent and tratable manifestation in NF1 patients. Data are presented which suggest that a severe form of NF2 is much more frequent than a mild form but it is rule that number and progressivity of tumors render the prognosis always severe in NF2 patients. A long term follow-up study has been carried among 20 patients with tuberous sclerosis: patients who presented seizures before the age of 5 years have mental retardation in spite of disappearing, often spontaneously, the seizures. The initial symptoms in Von Hippel-Lindau patients depend often on the hemangioblastoma of the spinal cord and a strict control is proposed for patients with risk of suffering spinal-cerebello-retino hemangioblastomatosis. Other phakomatoses are also being considered in their general prognosis.

[Painful bilateral lumbar radiculoplexopathy associated with Epstein-Barr virus infection]. / Radiculoplexopathie lombaire douloureuse bilatérale associée à une infection par le virus d'Epstein-Barr.

We report a case of polyneuropathy caused by primary Epstein Barr virus (EBV) infection in a 57-year-old patient. The primary EBV infection was confirmed by serology tests and EBNA (Epstein-Barr nuclear antigen) seroconversion. The main clinical sign was a highly painful subacute, bilateral lumbar radiculoplexopathy with amyotrophy which responded to corticosteroids and complement treatment within a few months. The association of left facial paralysis, neurophysiological signs of polyradiculopathy and elevated protein levels in the cerebrospinal fluid demonstrate the variability of peripheral neurological involvement in the same subject with EBV infection. This case also demonstrates the poorly limits of dysimmune polyneuropathies, including lumbar radiculoplexopathy which can be considered as an exceptional variant.

[Deletion of 17p11.2 chromosome in Spanish families with hereditary neuropathy and abnormal sensitivity to pressure]. / Deleción del cromosoma 17p11.2 en familias españolas con neuropatía hereditaria por vulnerabilidad excesiva a la presión.

Hereditary neuropathy with abnormal liability to pressure palsies (HNPP) is a dominant autosomally transmitted disease that gives rise to foci of peripheral nerve myelination, reducing conduction and leading to episodes of palsy and sensory changes that are all linked to sensitivity to pressure and traction on the affected nerve roots. The molecular basis of HNPP has been identified as a submicroscopic deletion of the 17p11.2 chromosome in exactly the same region that it is duplicated in Charcot-Marie-Tooth disease, type 1A (CMT1A). We report genetic analyses of 13 patients (belonging to 3 families) diagnosed of HNPP by means of physical examination and electrophysiologic and morphologic tests (the last in 3 cases only). Inter- and intrafamilial variation in symptomatology was studied. Some patients presented the usual clinical signs, such as recidivating brachial plexus palsy, permanent sensory polyneuropathy, foot deformities and others that might also be found in patients with CMT1A. All the patients showed electrophysiologic signs of underlying demyelinating polyneuropathy. Genetic study centered on detecting the deletion of 17p11.2 by segregation analysis with the polymorphic markers VAW409R3a (D17S122) and EW401HE (D17S61). Our results confirmed deletion at the CTM1A location of chromosome 17p11.2 in all 13 patients examined. These data suggest that the deletion of 17p11.2 plays a causal role in HNPP and that it is the most prevalent mutation in this disease; our findings constitute new evidence of the importance of the CMT1A/HNPP locus in the formation and control of peripheral myelin and in the ultimate functioning of peripheral nerves.

[Spinal cord ischemia indicating aneurysm of the abdominal aorta. Report of three cases]. / Isquemia medular reveladora de un aneurisma de aorta abdominal. Estudio de tres casos.

We report 3 cases of dorsal ischemic myelopathy indicative of aneurysm of the abdominal aorta. In 2 cases the aneurysm was dissecting and in all patients medullary symptoms were preceded by sudden lumbar or abdominal pain. Neurological symptoms were slightly different in each case. One patient experienced 3 episodes of acute paraparesis and rapid regression evoking transitory medullary ischemic accidents (intermittent medullary claudication). Another patient suffered progressive asymmetric paraparesis which first stabilized and later improved partially after surgical treatment of the aneurysm. The third suffered acute paraplegia related to irreversible ischemia of the anterior 2/3 of the medulla. The great variety of clinical manifestations of spinal cord ischemia related to aneurysms of the descending aorta can be explained by the topography of the aneurysm, pecularities of medullary vascularization and, especially, by the diversity of etiopathogenetic mechanisms that give rise to ischemia. We conclude that in the face of symptoms suggesting dorsal ischemic myelopathy, the possibility that an aneurysm of the abdominal aorta may be the cause must be considered, whether or not pain has been experienced prior to signs of medullary involvement.

[Isolated angiitis of the central nervous system. Clinical and neuropathological study of 2 cases]. / Angéite isolée du système nerveux central. Etude clinique et neuropathologique de deux cas.

Isolated angiitis of the central nervous system (IAC) is an idiopatic, recurrent vasculitis confined to the CNS involving small blood vessels. We describe the clinical, angiographic, and neuropathological data in two patients with IAC and delineate the main clinical and neuropathological features in both cases as well as the importance of a complete autopsy for discovering subclinical vasculitic lesions outside the CNS. Patient 1 concerned a 40 year-old-man that evolved for the last three years, initially with focal seizures, headache, and neurological focal deficits, later on the left sided hemihyposthesia and preferentially left parieto-occipital dysfunctions. He presented an oligoclonal band in CSF with slight hyperproteinorraquia and 25 lymphocytes. A cerebral angiography was compatible with angiitis and a leptomeningeal/cerebral biopsy showed lymphocytic vasculitis in the leptomeningeal and intraparenchymatous cerebral small vessels. These results lead to start a treatment with Cyclophosphamide associated to high dose of steroids. The patient clearly improved and now is almost asymptomatic. Patient 2 concerned a 67 year-old-man that evolved for 4 years with encephalic ischemic lesions distributed and confined throughout the brain stem and cerebellum, temporary remissions occurred and the patient required high-dose steroids and Cyclophosphamide to improve. Conventional and MRI angiographies only suggested the diagnosis that was confirmed at autopsy. The patient died after a massive pulmonary thromboembolism and a complete necropsic study showed abundant lymphocytic infiltrates, without granulomatous lesions, in the intraparenchymatous and leptomeningeal cerebral small vessels specially at the brain stem and cerebellar level where many demyelinated greyish areas and few infarctions were to be seen. The inflammatory cells were, in both cases, predominantly CD4+ T lymphocytes.(ABSTRACT TRUNCATED AT 250 WORDS)