Abdulaziz Al-Semari

Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome.

Hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome (also referenced as Woodhouse-Sakati syndrome) is a rare autosomal recessive multisystemic disorder. We have identified a founder mutation consisting of a single base-pair deletion in C2orf37 in eight families of Saudi origin. Three other loss-of-function mutations were subsequently discovered in patients of different ethnicities. The gene encodes a nucleolar protein of unknown function, and the cellular phenotype observed in patient lymphoblasts implicates a role for the nucleolus in the pathogenesis of this disease. Our findings expand the list of human disorders linked to the nucleolus and further highlight the developmental and/or maintenance functions of this organelle.

Autosomal-recessive syndrome with alopecia, hypogonadism, progressive extra-pyramidal disorder, white matter disease, sensory neural deafness, diabetes mellitus, and low IGF1

We explored the manifestations of an autosomal‐recessive multisystemic disorder in several Saudi families. Recognized causes of progressive extra‐pyramidal disorder and white matter disease were excluded and the neurological, imaging, endocrine, and skin manifestations of this syndrome described. The onset of these symptoms in these patients began in early adolescence and progressed more rapidly in males. All affected patients had total or partial alopecia, clinical and chemical evidence of hypogonadism (low levels of estradiol and testosterone); females had clear evidence of hypogonadism (streak or absent ovaries), and some patients had diabetes mellitus and/or sensorineural deafness. The constant biochemical abnormality was the low IGF‐1. The neurological manifestations included moderate to severe intellectual decline and abnormality of muscle tone and posture with choreo‐athetoid and dystonic movements resulting in gait difficulty, dysarthria, difficulty swallowing, and scoliosis. The MRI of brain demonstrated white matter involving cerebellum, brain stem, and cerebral structures, as well as abnormal decreased signal intensity in the basal ganglia with involvement of the substantia nigra. We conclude that the association of hypogonadism, alopecia, and persistent low IGF‐1 is a significant autosomal recessive syndrome; it is prevalent in Saudi Arabia. We also demonstrate that the progressive extra‐pyramidal disorder, white matter disease, and abnormal signals of the basal ganglia are common features of this syndrome. Sensorineural deafness and diabetes mellitus were recognized features.

Rift Valley fever encephalitis.

To the Editor: Rift Valley fever (RVF) is an undifferentiated febrile illness caused by Rift Valley fever virus (RVFV). Several human outbreaks occurred in Africa, resulting in tens of thousands of infections (1,2). During fall 2000, an outbreak of RVF in the Arabian Peninsula (the first recorded outside of Africa) resulted in many human and animal fatalities (3,4). Severe and frequently fatal encephalitis thought to be directly related to viral invasion of the central nervous system develops in <1% of patients (5). Encephalitis complicating RVF is poorly described in the literature, which offers no detailed description of the clinical findings, results of cerebrospinal fluid (CSF) studies, or imaging. We describe a case of RVF encephalitis associated with retinitis, including CSF findings, viral culture results, and neuroradiology findings An 18-year-old woman from Jazan (southwest of Saudi Arabia) had a 3-day history of confusion, fever, and blurred vision at the time an RVF outbreak was peaking in Jazan. Philadelphia-chromosome–positive chronic myeloid leukemia (CML) had been diagnosed in her several months before (leukocyte count 108 x 109/L). She responded well to hydroxyurea, and she had been in stable-phase CML for a few months. At the time of her visit, her temperature was 39.2°C, blood pressure 110/70 mm Hg, pulse 120 beats/min, respiratory rate 22/min. She had no lymphadenopathy, pallor, or jaundice. Results of her head, neck, and throat examinations were normal. Her chest was clear, and her abdomen was soft and nontender. Her spleen was 3 cm below the left costal margin. She was conscious and oriented. No meningeal signs could be elicited. Pupils were equally reactive to light with normal extraocular movements. Extremities had normal tone, power, sensation, and reflexes. Plantar reflex was flexor bilaterally. She had ataxic gait and bilateral retinal hemorrhages. She was unable to count fingers. Hemoglobin was 100 g/L, leukocyte count 5.1 x 109/L, and platelets 373 x 109/L. Renal and liver function tests were normal. Contrast-enhanced computed tomography (CT) scan of the brain was normal. Urine analysis and malaria smear were negative. CSF was clear. CSF glucose was 3.9 mmol/L (serum 5.8), protein 455 mg/L. CSF leukocyte count was 323 x 106/L, 58% lymphocytes, and 38% polynuclearleukocytes. Tests for hepatitis B surface antigen, antibodies to hepatitis C virus, HIV, cytomegalovirus antigenemia, rheumatoid factor, and antinuclear antibodies were negative. Cultures from blood, CSF, and urine were negative for bacteria. CSF viral culture was negative. Polymerase chain reaction for herpes simplex virus and enterovirus from CSF was negative. Tests for serum anti-RVF virus immunoglobulin M were positive. No other tests for RVFV were performed. Bone marrow on admission day was consistent with CML in remission. Prednisone was started on admission for 7 days. On hospital day 5, the patient was noted to be agitated, confused, and unresponsive to commands. She was transferred to the intensive care unit after her level of consciousness decreased; she was moving all four limbs but did not respond to verbal commands or painful stimuli. Pupils were 5 mm equal bilaterally with a sluggish reaction to light. Corneal reflexes were reactive bilaterally. Gag reflex was present, and tone was increased in all four limbs with brisk reflexes and extensor planter responses. The next day, her condition deteriorated, and she became unresponsive to painful stimuli. Repeated CT scan of the brain showed no pathologic changes. Electroencephalogram showed generalized continuous rhythmic sharp and spike wave activity consistent with nonconvulsive status epilepticus. Magnetic resonance imaging (MRI) of the brain showed bilateral frontoparietal high signal intensity on T2-weighted images and evidence of subtle right posterior thalamic hyperintensity with no corresponding abnormalities in T1-weighted images. The axial diffusion MRI images were more elaborative, showing multiple bilateral asymmetrical cortical hyperintense areas consistent with an ischemic or inflammatory process. Phenytoin was started. The next day, the patient was able to open her eyes and responded to painful stimuli, corneal reflexes were present bilaterally, oculocephalic reflex was present, and planters were flexors bilaterally. Repeat CSF studies on day 30 showed glucose of 3.8 mmol/L, protein 431 mg/L, leukocyte count of 12 x 106/L, and 68% polynuclearleukocytes. Repeat CT scan of the brain showed new bilateral temporo-occipital hypodensity more on the left side and a probable right middle cerebellar and left thalamic internal capsule infarct. There was no intracranial hemorrhage or hydrocephalus. She was discharged home awake, blind, quadreparetic, and incontinent, on anticonvulsants. After 1 year, her neurologic condition had not changed. Encephalitis and retinitis are severe complications of RVF, developing 1 or 2 weeks into the course of diseases. By that time, RVFV antigen assay is negative. Our patient met the definition of an RVF case during the outbreak (3). In one outbreak in Mauritania, 4.9% of observed infections had encephalitis (6), although the true frequency of encephalitis in RVF may be overestimated because infection can go unrecognized. The literature contains limited clinical description of this syndrome (6–8). Detailed neuroimaging findings, including MRI and flow studies, have not been previously reported. These findings, along with the patient’s clinical signs and symptoms, suggest cerebral vasculitis; however, no angiogram was performed, and markers of vasculitis were negative. A more likely cause would be direct viral parenchymal invasion. The pathogenesis of RVF encephalitis in humans is not clear. Animal studies indicate that active viral replication and necrotizing encephalitis with diffuse perivascular infiltrates of lymphocytes and macrophages occur in cerebral parenchyma (9,10). Postmortem histopathologic examination of brains of fatally infected rhesus monkeys have shown a mild, nonsuppurative, multifocal, perivascular encephalitis in the cerebral cortex, primarily of lymphoplasmacytic cells and nodular aggregates of neutrophils in association with mild necrotic changes of neurons (11). In one patient who died of meningoencephalitis in South Africa, brain pathologic findings showed perivascular cuffing and round-cell infiltration (2). In humans, we are not aware of positive RVFV cultures from CSF, blood, or brain during encephalitis. We have no reason to suspect CML to influence disease manifestations in this patient. CML was in stable phase for several months and should not have affected immune response of the patient towards RVFV.

Novel FGD1 mutation underlying Aarskog-Scott syndrome with myopathy and distal arthropathy.

In this report, we describe a kindred consisting of five affected males presenting with many of the well-recognized features of Aarskog–Scott syndrome. The diagnosis, which was confirmed by the identification of a novel nonsense mutation of FGD1, was associated with the presence of a symmetric distal arthropathy with electromyographic signs of myopathy. These features should be considered in the evaluation of future patients.

Natural course of epilepsy concomitant with CNS tuberculomas

BACKGROUND Epilepsy is relatively common in CNS tuberculomas, but its natural course is unclear. AIM To determine the prevalence and prognosis of epilepsy in patients with seizures related to CNS tuberculomas. METHODS We retrospectively reviewed the charts of patients with CNS tuberculomas who presented at our institution between 1983 and 2001. RESULTS Seizures occurred in 22 of 93 (23.6%) of the patients with CNS tuberculomas. These patients were treated with standard antituberculous therapy for a period varying between 6 and 20 months. Sixty-three out of 93 patients were cured of tuberculosis, and 21 of the 63 (33%) who had concomitant epilepsy became seizure-free. TB recurred in 3 patients, and 1 out of 22 who had concomitant epilepsy continued to have seizures; 3 died and 24 were lost to follow-up. Anti-epileptic medications were discontinued after completion of the anti-TB course. CONCLUSION Seizures are commonly associated with CNS tuberculomas and most often resolve after successful treatment of the underlying CNS tuberculosis.

Recessive VARS2 mutation underlies a novel syndrome with epilepsy, mental retardation, short stature, growth hormone deficiency, and hypogonadism

BackgroundMost mitochondrial and cytoplasmic aminoacyl-tRNA synthetases (aaRSs) are encoded by nuclear genes. Syndromic disorders resulting from mutation of aaRSs genes display significant phenotypic heterogeneity. We expand aaRSs-related phenotypes through characterization of the clinical and molecular basis of a novel autosomal-recessive syndrome manifesting severe mental retardation, ataxia, speech impairment, epilepsy, short stature, microcephaly, hypogonadism, and growth hormone deficiency.ResultsA G>A variant in exon 29 of VARS2 (c.3650G>A) (NM_006295) was identified in the index case. This homozygous variant was confirmed by Sanger sequencing and segregated with disease in the family studied. The c.3650G>A change results in alteration of arginine to histidine at residue 1217 (R1217H) of the mature protein and is predicted to be pathogenic.ConclusionsThese findings contribute to a growing list of aaRSs disorders, broadens the spectrum of phenotypes attributable to VARS2 mutations, and provides new insight into genotype-phenotype correlations among the mitochondrial synthetase genes.

Ictal kissing with subdural EEG recording.

Purpose Ictal kissing has been described in the literature. Five cases were reported and associated with temporal lobe epilepsy lateralizing to the nondominant hemisphere. Methods A case of ictal kissing was identified. The aim was to demonstrate the clinical, clinical and electrophysiological features (as recorded by subdural electrodes). The surgical procedure, histopathology, and imaging data were reviewed and correlated with the literature. Results A 29-year-old right-handed female, who presented with ictal right hand left arm dystonic posturing, and lip smacking, was studied. The automatism was usually followed by prolonged emotional gestures and by hugging and kissing her relative and/or attendant nurse. Magnetic resonance imaging of the brain showed right small cortical and subcortical lesions of the right inferior frontal lobe with gliosis but without mass effect and normal-sized hippocampi. The PET scan showed hypometabolism of the right temporal lobe. Neuropsychological evaluation showed deficit in her nonverbal memory. The subdural electrodes showed high amplitude spikes over right mesial temporal lobe strips. The offsite of the ictal discharges was usually at the right frontal strips. Right standard temporal lobectomy with amygdalohippocampectomy and right inferior frontal lesionectomy were performed. The patient continued to be seizure-free for one year postoperatively. Conclusion Our case report supports with subdural EEG recording the findings of the few reported cases of ictal kissing behavior lateralized to the nondominant hemisphere. However, the affectionate kissing behavior was associated with spread of the epileptic discharges to the right frontal lobe.

Intraoperative direct cortical stimulation motor evoked potentials: Stimulus parameter recommendations based on rheobase and chronaxie

OBJECTIVE To determine optimal interstimulus interval (ISI) and pulse duration (D) for direct cortical stimulation (DCS) motor evoked potentials (MEPs) based on rheobase and chronaxie derived with two techniques. METHODS In 20 patients under propofol/remifentanil anesthesia, 5-pulse DCS thenar MEP rheobase and chronaxie with 2, 3, 4 and 5ms ISI were measured by linear regression of five charge thresholds at 0.05, 0.1, 0.2, 0.5 and 1msD, and estimated from two charge thresholds at 0.1 and 1msD using simple arithmetic. Optimal parameters were defined by minimum threshold energy: the ISI with lowest rheobase2×chronaxie, and D at its chronaxie. Near-optimal was defined as threshold energy <25% above minimum. RESULTS The optimal ISI was 3 or 4 (n=7 each), 2 (n=4), or 5ms (n=2), but only 4ms was always either optimal or near-optimal. The optimal D was ∼0.2 (n=12), ∼0.1 (n=7) or ∼0.3ms (n=1). Two-point estimates closely approximated five-point measurements. CONCLUSIONS Optimal ISI/D varies, with 4ms/0.2ms being most consistently optimal or near-optimal. Two-point estimation is sufficiently accurate. SIGNIFICANCE The results endorse 4ms ISI and 0.2msD for general use. Two-point estimation could enable quick individual optimization.

Response of ictal asystole to pacemaker implantation documented by video-EEG/ECG.

CASE A 30-year-old left-handed male computer operator suffering from clinically diagnosed dyscognitive (complex partial) seizures with secondary generalization since age 24 was admitted for epilepsy monitoring. His attacks consisted of an aura of “flashes from past memory” followed by loss of awareness with amnesia and often progressed to generalized tonic-clonic motor activity. They continued in clusters of four to five attacks about every two weeks despite phenytoin and carbamazepine therapy as well as trials of topiramate and levetiracetam. He reported a closed head injury with loss of consciousness while playing soccer at age ten. There was no history of other risk factors or febrile convulsions. Past health, functional enquiry and family history were unremarkable. In particular, there were no other neurologic or cardiac symptoms and there was no family history of epilepsy or heart disease. Neurological examination was normal. A routine outpatient EEG had shown bilateral intermittent slow activity maximal in the left temporal region. Magnetic resonance imaging (MRI) disclosed right inferior frontal lobe atrophy and gliosis suspected to be an old traumatic lesion; no temporal lobe abnormalities were evident. Positron emission tomography suggested right inferior frontal and bilateral mesial temporal hypometabolism. Neuropsychologic testing suggested mild non-dominant frontal and bitemporal deficits. Video-EEG/ECG monitoring disclosed occasional left temporal spikes or sharp waves and rare independent right temporal sharp waves. Nine seizures were captured and all began with a left temporal delta frequency seizure pattern. Two produced aura followed by motionlessness and amnesia with bradycardia but no asystole. Seven showed bradycardia rapidly progressing to asystole several seconds after EEG onset. Two of these occurred during sleep and produced less than eight second asystole with no clinical signs. The other five occurred during wakefulness and produced symptomatic asystole of 8-21 seconds duration. Each began with a left temporal seizure pattern followed by aura, motionlessness and then asystole. After a few seconds of asystole the patient collapsed unconscious with brief clonic jerking and then tonic neck and limb extension (Figure 1). Response of Ictal Asystole to Pacemaker Implantation Documented by Video-EEG/ECG