Neonatal vocal cord paralysis-an early presentation of hereditary neuralgic amyotrophy due to a mutation in the SEPT9 gene.

Hereditary neuralgic amyotrophy is a rare autosomal dominant disorder involving recurrent episodes of painful brachial plexus neuropathies. Involvement of other nerves has been described in some families. The age of onset is from infancy to adulthood. Mutations in the SEPT9 gene were identified in approximately half of the hereditary neuralgic amyotrophy families. We evaluated a family with six affected members from three generations with a point mutation in the SEPT9 gene. One of the patients presented in the neonatal period with vocal cord paralysis necessitating intubation and prolonged ventilation. The neonatal presentation of vocal cord paralysis broadens the phenotypic spectrum of hereditary neuralgic amyotrophy. The identification of a SEPT9 mutation in a neonate with respiratory distress due to vocal cord paralysis expands the differential diagnosis in these patients.

Neuropsychological aspects of benign childhood epilepsy with centrotemporal spikes.

PURPOSE: To establish whether the disability in benign epilepsy with centrotemporal spikes (BECTS) is the result of the number of seizures, the anti-epileptic therapy or is an inherent characteristic of the syndrome itself. METHODS: Thirty-six children with BECTS were tested for cognitive functions prior to commencing treatment with anti-epileptic drugs, and the findings were compared with those in 15 children with normal electroencephalograms, performed for unrelated reasons. The data in the study group were further correlated with the laterality of the epileptic focus and the number of seizures. RESULTS: Scores for verbal functioning on neuropsychological tests were significantly lower in the study group than the control group. There was no relationship between the neuropsychological scores in the patients and either lateralization of the epileptic focus or number of seizures. DISCUSSION: Children with BECTS have an impaired ability to process verbal information. The deficiency is apparently a result of the pathological electrical discharges that are part of the syndrome and are not dependent on the epileptic focus laterality, the number of seizures, or the anti-epileptic treatment.

Treatment of status epilepticus and acute repetitive seizures with i.v. valproic acid vs phenytoin.

OBJECTIVE: To evaluate the efficacy and tolerability of the treatment with valproic acid (VPA) in patients with status epilepticus (SE) or acute repetitive seizures (ARS) comparing it with phenytoin (PHT) treatment. MATERIALS AND METHODS: Patients with SE or ARS were treated in a consecutive manner with either VPA or PHT intravenously. The primary endpoint was defined as clinical seizure cessation; the secondary endpoint was evaluation of drug tolerability. RESULTS: Seventy-four adult patients with SE or ARS participated in the study, 49 with VPA i.v. and 25 PHT i.v. In 43 (87.8%) of the VPA patients, the seizures discontinued, and no rescue medication was needed. Similar results were found in the PHT group in which seizures of 22 (88%) patients were well controlled. Side effects were found in 12% of the PHT group, and in none of the VPA group. CONCLUSIONS: VPA i.v. seems to be effective and well tolerated in adult patients with SE or ARS.

A defect in the thymidine kinase 2 gene causing isolated mitochondrial myopathy without mtDNA depletion.

Isolated mitochondrial myopathies (IMM) are either due to primary defects in mtDNA, in nuclear genes that control mtDNA abundance and structure such as thymidine kinase 2 (TK2), or due to CoQ deficiency. Defects in the TK2 gene have been found to be associated with mtDNA depletion attributed to a depleted mitochondrial dNTP pool in non-dividing cells. We report an unusual case of IMM, homozygous for the H90N mutation in the TK2 gene but unlike other cases with the same mutation, does not demonstrate mtDNA depletion. The patient's clinical course is relatively mild and a muscle biopsy showed ragged red muscle fibers with a mild decrease in complexes I and an increase in complexes IV and II activities. This report extends the phenotypic expression of TK2 defects and suggests that all patients who present with an IMM even with normal quantities of mtDNA should be screened for TK2 mutations.

Minocycline treatment in acute stroke: an open-label, evaluator-blinded study.

BACKGROUND: Ischemic animal model studies have shown a neuroprotective effect of minocycline. OBJECTIVE: To analyze the effect of minocycline treatment in human acute ischemic stroke. METHODS: We performed an open-label, evaluator-blinded study. Minocycline at a dosage of 200 mg was administered orally for 5 days. The therapeutic window of time was 6 to 24 hours after onset of stroke. Data from NIH Stroke Scale (NIHSS), modified Rankin Scale (mRS), and Barthel Index (BI) were evaluated. The primary objective was to compare changes from baseline to day 90 in NIHSS in the minocycline group vs placebo. RESULTS: One hundred fifty-two patients were included in the study. Seventy-four patients received minocycline treatment, and 77 received placebo. NIHSS and mRS were significantly lower and BI scores were significantly higher in minocycline-treated patients. This pattern was already apparent on day 7 and day 30 of follow-up. Deaths, myocardial infarctions, recurrent strokes, and hemorrhagic transformations during follow-up did not differ by treatment group. CONCLUSIONS: Patients with acute stroke had significantly better outcome with minocycline treatment compared with placebo. The findings suggest a potential benefit of minocycline in acute ischemic stroke.

Dysferlinopathy in the Jews of the Caucasus: a frequent mutation in the dysferlin gene.

Dysferlin encoding gene (DYS) is mutated in the autosomal recessive disorders Miyoshi myopathy, Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and distal anterior compartment myopathy, causing dysferlin deficiency in muscle biopsy. Three ethnic clusters have previously been described in Dysferlinopathy: the Libyan Jewish population originating in the area of Tripoli, Italian and Spanish populations. We report another cluster of this muscular dystrophy in Israel among Jews of the Caucasus region. A genomic analysis of the dysferlin coding sequence performed in patients from this ethnic group, who demonstrated an absence of dysferlin expression in muscle biopsy, revealed a homozygous frameshift mutation of G deletion at codon 927 (2779delG) predicting a truncated protein and a complete loss of functional protein. The possible existence of a founder effect is strengthened by our finding of a 4% carrier frequency in this community. These findings are important for genetic counseling and also enable a molecular diagnosis of LGMD2B in Jews of the Caucasus region.

Cervical paraspinal electromyography: normal values in 100 control subjects.

The normal electromyographic values and the significance of spontaneous activity, when examining the cervical paraspinal muscles, has been studied rarely, and there are very few studies concerning this issue. To obtain muscle unit potential (MUP) reference values for cervical paraspinal muscles, we examined 100 volunteers. Spontaneous activity and the analysis of 20 MUPs in every individual were checked by the automated MUP analysis program. In those individuals ages 20 to 40 years, no spontaneous activity was observed, and in the ones ages 40 to 60 years and 60 years or older, fibrillations and/or positive sharp waves were seen in 8% and 92%, respectively. MUP values were found to be close to those of upper limb muscles. Age has no significant effect on MUP values, except for mean amplitude that was increased in individuals ages 60 to 80 years.Our findings suggest that fibrillations and positive sharp waves do not have much electrodiagnostic value in the study of cervical paraspinal muscles of middle-aged and elderly subjects, when it is an isolated finding, and there is a need for an extended electromyographic examination, including other muscles, to exclude radiculopathy. Automated MUP analysis is easily performed, and our results may serve as reference values.

Skin biopsy for assessment of autonomic denervation in Parkinson's disease.

Autonomic dysfunction in Parkinson's disease (PD) is considered a late complication of the disease or an adverse effect of anti-parkinsonian medications. Morphological changes are demonstrated only by postmortem examination. The study objective was to evaluate peripheral autonomic neural involvement in PD using punch skin biopsy. The study sample included 22 patients (mean age 50 +/- 7.7 years, mean disease duration 5.3 +/- 3.8 years) and 19 controls. Four-millimeter skin biopsies were immunohistochemically stained with anti-PGP 9.5 antibody. Autonomic innervation of the blood vessels, sweat glands, and erector pili muscles was assessed and rated from 0 (normal) to 2 (severe). Cutaneous autonomic innervation was decreased in patients compared to controls. Semi quantitative analysis demonstrated reduced autonomic innervation of the blood vessels (1.0 +/- 0.8 vs. 0.42 +/- 0.8 in controls; p < 0.02), of sweat glands (0.95 +/- 0.67 vs. 0.47 +/- 0.61; p < 0.02) and of the erector pili muscles (1.06 +/- 0.55 vs 0.21 +/- 0.42; p < 0.001). This method demonstrates that the peripheral autonomic system is affected in PD at early stage of the disease and that autonomic involvement in PD may be more prevalent than previously thought.

Annexin V SPECT imaging of phosphatidylserine expression in patients with dementia.

The authors sought to use radiolabeled annexin V, a marker of phosphatidylserine expression, to image Alzheimer dementia (AD). Four of five patients with AD had multifocal cortical annexin V uptake, whereas all seven non-AD and six control patients had normal SPECT. The mean cortex/cerebellar activity in patients with AD (1.4 +/- 0.6) was higher than that of non-AD dementia patients (0.7 +/- 0.2; p = 0.02). Radiolabeled annexin V may be useful for imaging AD.

Transient global amnesia -- not always a benign process.

OBJECTIVES: Transient global amnesia (TGA) is an episodic dysfunction of declarative memory, which is assumed to be a benign disorder. Brain perfusion single photon emission computed tomography (SPECT) was shown to be abnormal during the acute stage and to become normal with normalization of memory function. No data are known about the brain perfusion pattern among these patients with recurrent TGA. MATERIAL AND METHODS: Sixteen patients with TGA were studied with an initial brain imaging during the acute stages of their attack, and a second imaging was performed after 3 months. In the event of a patients having a second abnormal brain perfusion HMPAO SPECT, a third imaging was performed after 1 year. RESULTS: Hypofusion perfusion was demonstrated in all cases during the acute stage. In all patients who had a first TGA, a normal SPECT was demonstrated after 3 months. In three patients with recurrent TGA, the brain perfusion remained abnormal after 3 months and after 1 year. CONCLUSIONS: A normal perfusion in TGA after 3 months can be expected in a patient with a first attack. In patients with recurrent TGA attacks, a persistent focal hypoperfusion can be expected. This subgroup of patients may demonstrate a non-benign type of TGA, eventually due to a different etiology of event.

Clinical presentations of mitochondrial cardiomyopathies.

UNLABELLED: To determine the clinical manifestations and interfamilial variability of patients diagnosed with a mitochondrial cardiomyopathy, we reviewed the charts of 14 patients with cardiomyopathy out of 59 patients with mitochondrial disorders who attended the mitochondrial disease clinic at Wolfson Medical Center from 1996 to 2001. All patients underwent a metabolic evaluation including blood lactate, pyruvate, carnitine, and amino acids and urine organic acids. Respiratory chain enzymes were assessed in 10 patients. The mitochondrial DNA (mtDNA) was assessed for mutations. The age at presentation ranged between 6 months and 24 years. Six of the patients died, 5 from heart failure. The cardiomyopathy was hypertrophic in 10 and dilated in 4. Conduction and rhythm abnormalities were present in 6. Eleven patients had family members with mitochondrial disorders. All the patients had additional involvement of one or more systems. Seven patients exhibited a deficiency of a respiratory chain enzyme in the muscle. The MELAS mtDNA point mutation (3243) was found in one patient. Blood lactic acid levels were increased in 5. Brain MRI abnormalities were observed in 4. CONCLUSIONS: Mitochondrial dysfunction frequently affects the heart and may cause both hypertrophic and dilated cardiomyopathy. The cardiomyopathy is usually a part of a multisystem involvement and may rarely be isolated. The course may be stable for many years, but rapid deterioration may occur. Understanding the biochemical and genetic features of these diseases will enable us to comprehend the clinical heterogeneity of these disorders.

Hereditary inclusion body myopathy: the Middle Eastern genetic cluster.

BACKGROUND: Recessively inherited hereditary inclusion body myopathy (HIBM) with quadriceps sparing was initially described only in Jews originating from the region of Persia. The recent identification of the gene responsible for this myopathy and the common "Persian Jewish mutation" (M712T) enabled the re-evaluation of atypical phenotypes and the epidemiology of HIBM in various communities in the Middle East. OBJECTIVE: To test for the M712T mutation in the DNA from HIBM patients in the Middle East. METHODS: DNA from all suspected HIBM patients was tested for the M712T mutation. Unaffected members of families with genetically proven HIBM were studied too. In the majority of families, haplotype construction with markers spanning the 700-kb region of the HIBM gene was performed. RESULTS: One hundred twenty-nine HIBM patients of 55 families (Middle Eastern Jews, Karaites, and Arab Muslims of Palestinian and Bedouin origin) were homozygous for the M712T mutation, and all carried the same haplotype. Five clinically unaffected subjects were also homozygous for the common mutation and haplotype, including two older adults (ages 50 and 68 years). Atypical features with this same mutation were marked quadriceps weakness in five patients, proximal weakness only in two patients, facial weakness in three patients, and a muscle biopsy showing perivascular inflammation in one patient. CONCLUSIONS: The phenotypic spectrum of recessive HIBM is wider than previously described, and the diagnostic criteria for this myopathy must be changed. The Middle Eastern cluster is the result of a founder mutation, with incomplete penetrance, that is approximately 1,300 years old and is not limited to Jews.

Optic neuritis complicating west nile virus meningitis in a young adult.

A case of West Nile virus (WNV) infection with meningitis and optic neuritis in a 28-year-old man is presented. The patient had a number of unusual clinical and laboratory findings that broadened the differential diagnosis. The emergence of WNV infection in southern Europe and North America calls for increased awareness of physicians to this clinical entity.

Establishment of the genomic structure and identification of thirteen single-nucleotide polymorphisms in the human RECK gene.

The human RECK gene, mapped at 9p13-->p12, is known as a tumor suppressor gene and as a key regulator of extracellular matrix integrity and angiogenesis. We have established the entire genomic structure of this gene, which spans more than 87 kb and consists of 21 exons and 20 introns, and identified thirteen single nucleotide polymorphisms (SNPs). Four SNPs were identified in the coding region of the gene (exons 1, 9, 13 and 15), and the remaining nine in introns 5, 8, 10, 12, 15 and 17. The availability of the genomic organization of the RECK gene and the identification of polymorphisms throughout its entire genome will facilitate the evaluation of its role in several disorders and also contribute to the assignment of genes to the several diseases mapped to this chromosomal region.

Serum leptin level in women with idiopathic intracranial hypertension.

Leptin is a protein secreted by adipose cells which influences regulation of energy balance and body weight. Idiopathic intracranial hypertension (IIH) is recognised as a neurological disorder mainly affecting obese females. The aim of this study was to evaluate the association between IIH and serum leptin level in 15 obese patients and compare the results with those for 16 obese and 15 non-obese women. A significantly higher serum leptin level was found in patients with IIH than in controls (p<0.0001), and this did not correlate with body mass index (BMI). Serum leptin levels were significantly associated with BMI in both control groups (p<0.0006). Additional factors must therefore be involved in the phenomenon of serum leptin increase beyond weight gain. The cause can only be hypothesised, but it seems that the origin is central, probably hypothalamic.

Cerebrovascular reactivity in patients under long-term acetazolamide treatment.

BACKGROUND AND PURPOSE: The acetazolamide (AZA) test is a well-accepted method for measuring the vascular reactivity of the cerebral arteries. In order to investigate the nature of this reactivity after long-term daily AZA treatment, the cerebral blood velocity (CBV) was measured using transcranial Doppler in patients under continuous AZA treatment after a single AZA 1 g intravenous (IV) dose. METHODS: Thirteen patients (eight women, five men) on long-term daily AZA (750 mg/day, mean treatment duration 68 +/- 12+ months) were included in the study. The CBV of the middle cerebral artery (MCA) and the basilar artery (BA), including the values of peak velocity, mean velocity and pulsatility index (PI) were measured. The examination was performed twice - with the initial IV administration of AZA and 20 min later. The results were compared with those of 10 age matched volunteers. RESULTS: A consistent significant increase of CBV in the right and left MCA (P < 0.001 for both arteries) was found in all study participants. A highly significant decrease of peak CBV in the BA (P < 0.001) was found in the post-AZA velocities of the patient's group. In the control group, a consistent significant increase in all post-AZA tests was demonstrated (P < 0.001). CONCLUSIONS: A mild elevation of blood velocity in the MCAs concomitant with a highly significant decrease of velocity in the BA was present in all examined patients. These patterns of CBV changes indicate the presence of a 'steal phenomenon' from the posterior to the anterior circulation and stress the necessity for caution when evaluating the indications for performance of the AZA test in patients under continuous AZA therapy.

Three novel COLQ mutations and variation of phenotypic expressivity due to G240X.

OBJECTIVE: To determine the molecular basis and consequences of endplate (EP) acetylcholinesterase (AChE) deficiency. BACKGROUND: The EP species AChE is an asymmetric enzyme consisting of a tail subunit composed of three collagenic strands (ColQ), each attached to a tetramer of catalytic subunits. The tail subunit is essential for insertion of AChE into the synaptic basal lamina. Human EP AChE deficiency is caused by mutations in COLQ. The authors report three novel COLQ mutations in eight kinships. METHODS: Immunocytochemistry, electron microscopy, microelectrode recordings, mutation analysis, and expression studies in COS cells were employed. RESULTS: Two mutations (275insC and Q211X) were heterozygous in one patient. EP studies in this patient revealed no EP AChE, small nerve terminals, reduced presynaptic membrane length, as well as abnormally low-evoked quantal release. The third mutation (G240X) was homozygous in six Palestinian Arab families of the same tribe and in an Iraqi Jewish patient. Expression studies of the three mutations in COS cells indicate that each abrogates formation of insertion competent asymmetric AChE. Although the three mutations have identical predicted consequences at the EP, their phenotypic expressivity varies as regards age at onset, rate of progression, and severity of symptoms. CONCLUSIONS: 1) After mutations in the AChR epsilon subunit, mutations in COLQ are emerging as second most common cause of congenital myasthenic syndromes. 2) A founder effect is likely for G240X in the Palestinian Arab families. 3) That mutations predicting total absence of AChE from the EP have variable phenotypic expressivity suggests that modifying genes or environmental factors can partially compensate for EP AChE deficiency.

Quantitative anal sphincter EMG in multisystem atrophy and 100 controls.

OBJECTIVE: To evaluate data of quantitative anal sphincter EMG in normal controls and to compare them with patients with multiple system atrophy (MSA). METHODS: Quantitative anal sphincter EMG were performed on 100 normal controls and 11 patients with MSA to characterise EMG data in these two groups. RESULTS: In the normal controls, there was a trend for increased motor unit potential (MUP) amplitude, duration, area, and polyphasicity with advancing age. Patients with MSA exhibited similar MUP size and fibre density. Significant differences were found only in parameters of the recruitment pattern, which were reduced in MSA, with a diminution in the number of active MUPs during rest. CONCLUSIONS: These results may reflect either decreased number of motor cells in Onuf's nucleus without significant consequential reinnervation, or upper motor neuron involvement affecting the anal sphincter in MSA. They further underline the importance of comparative data for age matched controls.

The UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase gene is mutated in recessive hereditary inclusion body myopathy.

Hereditary inclusion body myopathy (HIBM; OMIM 600737) is a unique group of neuromuscular disorders characterized by adult onset, slowly progressive distal and proximal weakness and a typical muscle pathology including rimmed vacuoles and filamentous inclusions. The autosomal recessive form described in Jews of Persian descent is the HIBM prototype. This myopathy affects mainly leg muscles, but with an unusual distribution that spares the quadriceps. This particular pattern of weakness distribution, termed quadriceps-sparing myopathy (QSM), was later found in Jews originating from other Middle Eastern countries as well as in non-Jews. We previously localized the gene causing HIBM in Middle Eastern Jews on chromosome 9p12-13 (ref. 5) within a genomic interval of about 700 kb (ref. 6). Haplotype analysis around the HIBM gene region of 104 affected people from 47 Middle Eastern families indicates one unique ancestral founder chromosome in this community. By contrast, single non-Jewish families from India, Georgia (USA) and the Bahamas, with QSM and linkage to the same 9p12-13 region, show three distinct haplotypes. After excluding other potential candidate genes, we eventually identified mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase (GNE) gene in the HIBM families: all patients from Middle Eastern descent shared a single homozygous missense mutation, whereas distinct compound heterozygotes were identified in affected individuals of families of other ethnic origins. Our findings indicate that GNE is the gene responsible for recessive HIBM.