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Background: Asparagine synthetase deficiency (OMIM# 615574) is a very rare newly described neurometabolic disorder characterized by congenital microcephaly and severe global developmental delay, associated with intractable seizures or hyperekplexia. Brain MRI typically shows cerebral atrophy with simplified gyral pattern and delayed myelination. Only 12 cases have been described to date. The disease is caused by homozygous or compound heterozygous mutations in the ASNS gene on chromosome 7q21., Case Presentation: Family 1 is a multiplex consanguineous family with five affected members, while Family 2 is simplex. One affected from each family was available for detailed phenotyping. Both patients (Patients 1 and 2) presented at birth with microcephaly and severe hyperekplexia, and were found to have gross brain malformation characterized by simplified gyral pattern, and hypoplastic cerebellum and pons. EEG showed no epileptiform discharge in Patient 2 but multifocal discharges in patient 1. Patient 2 is currently four years old with severe neurodevelopmental delay, quadriplegia and cortical blindness. Whole exome sequencing (WES) revealed a novel homozygous mutation in ASNS (NM_001178076.1) in each patient (c.970C > T:p.(Arg324*) and c.944A > G:p.(Tyr315Cys))., Conclusion: Our results expand the mutational spectrum of the recently described asparagine synthetase deficiency and show a remarkable clinical homogeneity among affected individuals, which should facilitate its recognition and molecular confirmation for pertinent and timely genetic counseling.

Pallido-pyramidal syndromes combine dystonia with or without parkinsonism and spasticity as part of a mixed neurodegenerative disorder. Several causative genes have been shown to lead to pallido-pyramidal syndromes, including FBXO7, ATP13A2, PLA2G6, PRKN and SPG11. Among these, ATP13A2 and PLA2G6 are inconsistently associated with brain iron deposition. Using homozygosity mapping and direct sequencing in a multiplex consanguineous Saudi Arabian family with a pallido-pyramidal syndrome, iron deposition and cerebellar atrophy, we identified a homozygous p.G53R mutation in C19orf12. Our findings add to the phenotypic spectrum associated with C19orf12 mutations., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Objective: To identify a genetic cause for migrating partial seizures in infancy (MPSI)., Methods: We characterized a consanguineous pedigree with MPSI and obtained DNA from affected and unaffected family members. We analyzed single nucleotide polymorphism 500K data to identify regions with evidence of linkage. We performed whole exome sequencing and analyzed homozygous variants in regions of linkage to identify a candidate gene and performed functional studies of the candidate gene SLC25A22., Results: In a consanguineous pedigree with 2 individuals with MPSI, we identified 2 regions of linkage, chromosome 4p16.1-p16.3 and chromosome 11p15.4-pter. Using whole exome sequencing, we identified 8 novel homozygous variants in genes in these regions. Only 1 variant, SLC25A22 c.G328C, results in a change of a highly conserved amino acid (p.G110R) and was not present in control samples. SLC25A22 encodes a glutamate transporter with strong expression in the developing brain. We show that the specific G110R mutation, located in a transmembrane domain of the protein, disrupts mitochondrial glutamate transport., Interpretation: We have shown that MPSI can be inherited and have identified a novel homozygous mutation in SLC25A22 in the affected individuals. Our data strongly suggest that SLC25A22 is responsible for MPSI, a severe condition with few known etiologies. We have demonstrated that a combination of linkage analysis and whole exome sequencing can be used for disease gene discovery. Finally, as SLC25A22 had been implicated in the distinct syndrome of neonatal epilepsy with suppression bursts on electroencephalogram, we have expanded the phenotypic spectrum associated with SLC25A22.

Mutations in PLA2G6 gene have variable phenotypic outcome including infantile neuroaxonal dystrophy, atypical neuroaxonal dystrophy, idiopathic neurodegeneration with brain iron accumulation and Karak syndrome. The cause of this phenotypic variation is so far unknown which impairs both genetic diagnosis and appropriate family counseling. We report detailed clinical, electrophysiological, neuroimaging, histologic, biochemical and genetic characterization of 11 patients, from 6 consanguineous families, who were followed for a period of up to 17 years. Cerebellar atrophy was constant and the earliest feature of the disease preceding brain iron accumulation, leading to the provisional diagnosis of a recessive progressive ataxia in these patients. Ultrastructural characterization of patients' muscle biopsies revealed focal accumulation of granular and membranous material possibly resulting from defective membrane homeostasis caused by disrupted PLA2G6 function. Enzyme studies in one of these muscle biopsies provided evidence for a relatively low mitochondrial content, which is compatible with the structural mitochondrial alterations seen by electron microscopy. Genetic characterization of 11 patients led to the identification of six underlying PLA2G6 gene mutations, five of which are novel. Importantly, by combining clinical and genetic data we have observed that while the phenotype of neurodegeneration associated with PLA2G6 mutations is variable in this cohort of patients belonging to the same ethnic background, it is partially influenced by the genotype, considering the age at onset and the functional disability criteria. Molecular testing for PLA2G6 mutations is, therefore, indicated in childhood-onset ataxia syndromes, if neuroimaging shows cerebellar atrophy with or without evidence of iron accumulation.

Hereditary spastic paraplegia (HSP) is considered one of the most heterogeneous groups of neurological disorders, both clinically and genetically. The disease comprises pure and complex forms that clinically include slowly progressive lower-limb spasticity resulting from degeneration of the corticospinal tract. At least 48 loci accounting for these diseases have been mapped to date, and mutations have been identified in 22 genes, most of which play a role in intracellular trafficking. Here, we identified mutations in two functionally related genes (DDHD1 and CYP2U1) in individuals with autosomal-recessive forms of HSP by using either the classical positional cloning or a combination of whole-genome linkage mapping and next-generation sequencing. Interestingly, three subjects with CYP2U1 mutations presented with a thin corpus callosum, white-matter abnormalities, and/or calcification of the basal ganglia. These genes code for two enzymes involved in fatty-acid metabolism, and we have demonstrated in human cells that the HSP pathophysiology includes alteration of mitochondrial architecture and bioenergetics with increased oxidative stress. Our combined results focus attention on lipid metabolism as a critical HSP pathway with a deleterious impact on mitochondrial bioenergetic function., (Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

We have identified a novel form of recessive ataxia that segregates in three children of a large consanguineous Saudi Arabian family. The three patients presented with childhood onset gait and limb ataxia, dysarthria and had limited walking without aid into their teenage years. Two patients developed epilepsy at 7 months without relapse after treatment, and mental retardation. Linkage studies allowed us to identify a single locus that segregated with the disease on chromosome 3q28-qter. Mutation screening of all coding sequences revealed a single nucleotide deletion, 2927delC, in exon 19 of the KIAA0226 gene, which results in a frame shift of the C-terminal domain (p.Ala943ValfsX146). The KIAA0226 gene encodes a protein that we named rundataxin, with two conserved domains: an N-terminal RUN domain and a C-terminal domain containing a diacylglycerol binding-like motif. The closest paralogue of rundataxin, the plekstrin homology domain family member M1, has been shown to colocalize with Rab7, a small GTPase associated with late endosomes/lysosomes, suggesting that rundataxin may also be associated with vesicular trafficking and signalling pathways through its RUN and diacylglycerol binding-like domains. The rundataxin pathway appears therefore distinct from the ataxia pathways involving deficiency in mitochondrial or nuclear proteins and broadens the range of mechanisms leading to recessive ataxias.

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COLQ) cause synaptic basal-lamina associated CMS with end-plate AChE deficiency. Here we present the clinical and molecular genetic findings of 22 COLQ-mutant CMS patients, carrying a total of 20 different COLQ mutations, 11 of them had not previously been reported. Typically, patients with esterase deficiency suffer from a severe, progressive weakness with onset at birth or in early infancy. In addition, patients with a late onset showing a mild course of disease are described. AChE inhibitor therapy, beneficial for other forms of CMS, is of no effect in cases of esterase deficiency. The large cohort of COLQ patients studied here enabled us to define additional clinical presentations associated with COLQ mutations that differ from the 'classical' phenotypes: several patients with disease onset at birth or in early infancy presented an unexpected, mild disease course without significant progression of weakness. Moreover, many patients had clinical features reminiscent of limb-girdle CMS with mutations in the recently discovered DOK7 gene, including sparing of eye movements and a predominantly proximal muscle weakness. There was no long-term objective benefit from esterase inhibitors treatment in COLQ patients. Surprisingly, a short-term beneficial effect was observed in four patients and a Tensilon test was positive in two. Treatment with ephedrine was efficient in all five cases where it was administered. The variability of phenotypes caused by COLQ mutations, the divergence from the previously published classical clinical features and an initial positive response to esterase inhibitors in some patients may obscure AChE deficiency as the molecular cause of the disease and delay the start of appropriate therapy. Moreover, overlap with other CMS subtypes and potentially absence of a repetitive compound muscle action potential should be considered in the diagnosis of COLQ-mutated patients.

Objectives: To describe the epidemiology and clinical features of stroke in a prospective and retrospective cohort of Saudi children and ascertain the causes, pathogenesis, and risk factors., Methods: The Retrospective Study Group (RSG) included children with stroke who were evaluated at the Division of Pediatric Neurology, or admitted to King Khalid University Hospital, College of Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia during the period July 1992 to February 2001. The Prospective Study Group (PSG) included those seen between February 2001 and March 2003., Results: During the combined study periods of 10 years and 7 months, 117 children (61 males and 56 females, aged one month-12 years) were evaluated; the majority (89%) of these were Saudis. The calculated annual hospital frequency rate of stroke was 27.1/100,000 of the pediatric (1 month-12 years) population. The mean age at onset of the initial stroke in the 104 Saudi children was 27.1 months (SD = 39.3 months) and median was 6 months. Ischemic strokes accounted for the majority of cases (76%). Large-vessel infarcts (LVI, 51.9%) were more common than small-vessel lacunar lesions (SVLL, 19.2%). Five patients (4.8%) had combined LVI and SVLL. Intracranial hemorrhage was less common (18.2%), whereas sinovenous thrombosis was diagnosed in 6 (5.8%) patients. A major risk factor was identified in 94 of 104 (89.4%) Saudi children. Significantly more hematologic disorders and coagulopathies were identified in the PSG compared to the RSG (p=0.001), reflecting a better yield following introduction of more comprehensive hematologic and coagulation laboratory tests during the prospective study period. Hematologic disorders were the most common risk factor (46.2%), presumed perinatal ischemic cerebral injury was a risk factor in 23 children (22.1%) and infectious and inflammatory disorders of the circulatory system in 18 (17.3%). Congenital and genetic cerebrovascular anomalies were the underlying cause in 7 patients (6.7%) and cardiac diseases in 6 (5.8%). Six patients (5.8%) had moyamoya syndrome, which was associated with another disease in all of them. Inherited metabolic disorders (3.8%) included 3 children with Leigh syndrome and a 29-month-old girl with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Systemic vascular disease was a risk factor in 3 children (2.9%) including 2 who had hypernatremic dehydration; and post-traumatic arterial dissection was causative in 3 cases (2.9%). Several patients had multiple risk factors, whereas no risk factor could be identified in 11 (10.6%)., Conclusion: Due to the high prevalence and importance of multiple risk factors, a comprehensive investigation, including hematologic, neuroimaging and metabolic studies should be considered in every child with stroke.

Objective: To assess the value of brainstem auditory evoked potentials and event related evoked potential (3rd positive component of evoked related potentials with latency of 300 millisecond, in evaluating cognitive dysfunction in patients with chronic respiratory failure., Methods: Thirty-two patients with chronic obstructive pulmonary disease and respiratory failure of mild to moderate severity, were assessed regarding their mental function, utilizing mini-mental state examination, arterial blood gases including PH, partial pressure of carbon dioxide, partial pressure of oxygen, and both brainstem auditory evoked potentials and event related evoked potential response. Twenty-five normal subjects, matched for age and sex, were also studied as a control group. The study was carried out during the year 1999 to 2000 in 3 hospitals; King Khalid University Hospital, King AbdulAziz University Hospital and Sahara Hospital, Riyadh, Kingdom of Saudi Arabia., Results: There were significant delay of event related evoked potential response in patients compared with controls (P<0.05). No significant difference was noted for brainstem auditory evoked potentials and mini-mental state examination scores were within normal limits in 78% of patients. When event related evoked potential were analyzed in comparison with blood gases and mini-mental state examination, there was a clear moderate correlation with severity of hypoxemia (r = -0.697). Correlation was also noted, but to a lesser degree with partial pressure of carbon dioxide (r = 0.52) and PH (r = 0.53). There was no correlation with mini-mental state examination., Conclusion: The significant delay of event related evoked potential, which is considered the neuro-physiological correlate of cognition, points clearly to the presence of a certain degree of mental dysfunction in many of these patients, namely sub-clinical encephalopathy. These subtle changes commonly evade detection by conventional bed side test (mini-mental state examination), while detailed neuropsychological assessment is cumbersome and time consuming. So, event related evoked potential measurement may be an objective and practical test of subtle cognitive dysfunction in mild respiratory failure. Unfortunately, absolute event related evoked potential values may not be useful in individual patients, in view of its wide range. However, it is probably very helpful in the assessment of a group of subjects, such as trials of a new therapeutic modality. A follow-up study utilizing a larger group of patients, and formal neuropsychological mental assessment, will be expected to confirm and expand the present study`s conclusions.

Objective: To compare nerve conduction parameters in asymptomatic diabetic patients and with no clinical signs of neuropathy and in control subjects., Methods: Forty-eight diabetic Saudi subjects (20 males, 28 females) and 48 age-and-sex-matched control subjects were studied. The mean age of patients +/- standard deviation was 45.6+/-11.7 years. The mean duration of diabetes from time of diagnosis was 10.8+/-3.1 years, and their mean fasting plasma glucose was 8.5+/-0.9 mmol/l. Nerve conduction studies were performed on the right lower limb., Results: In diabetic patients the tibial and peroneal nerve conduction velocity values were 48.6+/-4.7 and 46.3+/-5.2 m/s. They were not significantly different from controls (p>0.01). The tibial and peroneal distal motor latency values were 5.1+/-0.6 and 4.7+/-0.9 ms, and not significantly different from controls (p>0.01). The sural nerve distal sensory latency in patients was 3.2+/-0.7 ms and the sural sensory nerve action potential amplitude was 4.9+/-2.5 uV. These values were significantly different from controls (p<0.01). The tibial and peroneal minimal F-wave latency values in patients were 32.5+/-1.9 ms/m and 32.9+/-1.6 ms/m, and were significantly different from controls (p<0.001). The F-wave average duration values in patients were 11.8+/-1.5 ms for the tibial nerve and 9.0+/-1.4 ms for the peroneal nerve. These were significantly different from control (p<0.001)., Conclusion: The peroneal and tibial minimal F-latency and average F-duration provide the most sensitive nerve conduction; indicators for the diagnosis of subclinical neuropathy in diabetes.

Phrenic nerve conduction study and measurements of static lung volumes such as functional residual capacity (FRC), total lung capacity (TLC) and residual volumes (RV) using body plethysmography were carried out in 31 normal healthy male subjects (31 +/- 8 years). The objective was to correlate changes in latency, amplitude, duration and area of diaphragmatic compound muscle action potential (DCMAPs) with lung volumes and changes in them with changes in postures. The mean phrenic nerve latency did not show any significant change with lung volumes or postures, but the latency and height of the subject had a significant correlationship (r = 0.68). The peak to peak amplitude of DCMAP showed a significant relationship with the quantitative lung volumes (r = 0.65). The amplitude was significantly higher and duration reduced (p < 0.001) at TLC as compared with those at measured FRC and RV in both sitting and supine postures. The area under the curve did not change significantly. Similarly, amplitudes and latency did not show any significant relation with other anthropometric parameters. The study evaluates a new quantitative relationship between DCMAPs amplitude and lung volumes. This may be carefully used along with other clinical parameters in critically ill patients for an early weaning from ventilator. Posture exerts minimal influence on DCMAPs amplitude; since DCMAPs amplitudes depends on the position of the diaphragm which in turn depends on dipolic potential, its electromagnetic fields and its moving angle subtends at the recording electrode, one can confidently use it to predict lung volume in respiratory failure due to neuromuscular diseases where subjective lung function assessment is impossible. However, a further study is in process in the critical care unit to confirm its utility.

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We determined the motor terminal latency index (MTLI) of the median nerve across the carpal tunnel in 41 upper extremities of 31 patients with carpal tunnel syndrome. Changes in motor nerve conduction velocity (MNCV), motor terminal latency (MTL), sensory action potential and the amplitude of the compound muscle action potential recorded from the abductor pollicis brevis muscle were all suggestive of proximal and distal segment involvement of the nerve across the carpal tunnel. There was no correlation between forearm MNCV and MTL (r = 0.40), although MTLI was correlated with MTL (r = 0.67) but not with MNCV, indicating a disproportionate conduction across the carpal tunnel.

A review of 36 interictal EEGs compatible with the diagnosis of benign childhood epilepsy with centro-temporal spikes (BECTS) was made in this study. These children constituted 31% of the children with focal epileptic EEG activity observed in the same period. The dipolic spikes occurred either as a single focus (78%) or as two independent foci with a greater preponderance to the right (22%). The onset of seizures before the age of 5 years (Group I) is 53% and between 6 and 10 years (Group II) is 47%. Clinical evaluation showed that 60% of the patients in Group I and 75% in Group II had lateralized seizures, although all of them were initially diagnosed as nocturnal generalized tonic-clonic seizures. A follow-up study showed 31% complete recovery, 47% seizure-free under medications, 8% occasional seizures, 8% frequent seizures, and the rest 6% had a single seizure without medication. It is therefore concluded that the syndrome is common in Saudi Arabia and is usually unrecognized by the general physicians. The follow-up of our patients so far confirms the excellent prognosis.

We evaluated the clinical characteristics and the electroencephalographic (EEG) findings by long video-EEG monitoring in 64 successive patients with definite nocturnal seizures. Mental state, neurological examination, neuroimaging and EEG background were normal in all patients. Classification of epilepsies was possible in 42 out of 64 (66%) patients according to the revised Classification of Epilepsies and Epileptic Syndromes by the Commission on Classification and Terminology of International League Against Epilepsy (1989). Out of those 42 patients, 33 (79%) had partial epilepsies, while 9 (21%) had generalized epilepsies. Response to antiepileptic drugs was excellent and only 4 (6%) patients had one seizure attack per year, two of them were on two antiepileptic drugs while the others were free of seizure on a single drug during the 2 years of follow-up. It seems that nocturnal seizures in adults form a new distinctive partial epileptic syndrome of a benign entity.

Evoked potential audiometry and brain-stem auditory evoked potentials were evaluated in 15 patients with systemic brucellosis in whom brucella meningitis was suspected clinically. In 8 patients cerebrospinal fluid (CSF) was abnormal with high brucella titre, and evoked potentials were abnormal in all of them. In 7 patients the CSF was normal and evoked potentials were also normal. Brain-stem auditory evoked potential abnormalities were categorised into 4 types: (1) abnormal wave I, (2) abnormal wave V, both irreversible, (3) prolonged I-III interpeak latencies, and (4) prolonged I-V interpeak latencies, both reversible. These findings are of important diagnostic value and correlate well with the clinical features, aetiopathogenesis and final outcome.

Maximum expiratory flow-volume (MEFV) curves recorded before and after salbutamol inhalation on 100 patients with various lung diseases were studied. Improvement was found to occur more frequently in MEF50, FEF25-75, FVC and MEF25, than in FEV1, FEV1/FVC%, or MTT. If improvement in only one of the first four parameters was taken as a measure of reversibility of airways obstruction, many cases showing improvement in the others were missed. Improvement in any of the last three parameters was rarely missed if improvement in any of the first four was present. It was concluded that there is no single best measurement for assessment of bronchodilator response. FVC, FEF25-75, MEF50 and MEF25 should all be measured. A flow-volume record of forced expiration from which all these measurements can be derived would therefore be preferable for this purpose to the time-volume spirometer record from which only FVC and FEF25-75 can be determined.