Atypical pantothenate kinase-associated neurodegeneration with variable phenotypes in an Egyptian family.

Pantothenate kinase-associated neurodegeneration (PKAN) is a rare hereditary neurodegenerative disease characterized by an accumulation of iron within the brain. In the present report, we describe a family with 4 affected siblings presenting with variable clinical manifestations, e.g., parkinsonian features, dystonia and slow disease progression over 5 years. Exome sequencing revealed a causative variant in the pantothenate kinase 2 gene (PANK2). Variant NM_024960.6:c.710C > T was homozygous in all affected subjects. Our report describes the first genetically confirmed cases of PKAN in the Egyptian population. Studying genetics of neurodegenerative diseases in different ethnicities is very important for determining clinical phenotypes and understanding pathomechanisms of these diseases.

Evidence for pathogenicity of variant ATM Val1729Leu in a family with ataxia telangiectasia.

Ataxia telangiectasia is a rare autosomal recessive multisystem disorder caused by mutations in the gene of ATM serine/threonine kinase. It is characterized by neurodegeneration, leading to severe ataxia, immunodeficiency, increased cancer susceptibility, and telangiectasia. Here, we discovered a co-segregation of two ATM gene variants with ataxia telangiectasia in an Egyptian family. While one of these variants (NM_000051.4(ATM_i001):p.(Val128*)) has previously been reported as pathogenic, the other one (NM_000051.4(ATM_i001):p.(Val1729Leu)) is regarded as a variant of uncertain significance. Our findings in this family provide additional evidence for causality of the second variant and argue that its status should be changed to pathogenic.

Non-motor symptoms in essential tremor, akinetic rigid and tremor-dominant subtypes of Parkinson's disease.

OBJECTIVES: To compare non-motor symptoms (NMSs) among patients with essential tremor (ET), Parkinson's disease (PD) subtypes (akinetic-rigid type (ART) and tremor-dominant type (TDT)), and healthy controls. PATIENTS AND METHODS: This retrospective study included 129 participants, 72 PD (33 PD-ART, 33 PD-TDT, and 6 Mixed), 29 ET patients, and 28 controls. PD patients were assessed by the unified Parkinson's disease rating scale (UPDRS), Hoehn, and Yahr scale (H&Y), while ET patients were evaluated by the Fahn Tolosa Marin Tremor Rating Scale. All subjects were evaluated by non-motor symptoms scale (NMSS) for NMSs and Beck depression inventory (BDI) for depression. RESULTS: PD subtypes groups, ET, and controls were age and gender-matched. Compared to controls, all PD, PD subtypes, and ET showed significantly worse most of NMSs (p<0.001) and depression. Compared to ET, all PD and PD-ART had significantly worse gastrointestinal (p = 0.002), urinary symptoms (p = 0.001, p = 0.003) and depression (p = 0.002) and PD-TDT worse depression, while ET patients showed worse memory/attention than PD subtypes. Total NMSS of ET is highly correlated to depression and moderately to tremor severity and age of onset, while total of NMSS is highly correlated to depression, disease severity, and disability. CONCLUSION: The current study demonstrated several comparable domains of NMSs of PD subtypes and ET, except worse gastrointestinal and urinary symptoms among PD-ART. Identifying different NMSs profiles is important for predicting, better assessing, and tailoring management of ET and PD subtypes.

Clinical Profile of Non-Motor Symptoms in Patients with Essential Tremor: Impact on Quality of Life and Age-Related Differences.

Background: Identifying the clinical phenotypes of non-motor symptoms (NMSs) of essential tremor (ET) among different populations is necessary due to their impact on the quality of life (QoL). This study aimed to investigate the clinical phenotype and impact of NMSs on QoL in Egyptian patients with ET. Methods: Thirty ET patients were compared to 30 matched controls. Subjects were evaluated by the Fahn-Tolosa-Marin Tremor Rating Scale, Non-Motor Symptoms Scale (NMSS), Montreal Cognitive Assessment, Hamilton Anxiety Rating Scale, Beck Depression Inventory, Pittsburgh Sleep quality Index, and the Short Form 36 Health Survey Questionnaire. Both groups were divided into two subgroups of younger (<45 years, 14 patients) and older age (>45 years, 16 patients) groups, to investigate age-related differences. Results: ET patients showed significantly worse cognition, depression, anxiety, sleep and NMSS domains (p < 0.001), compared to controls, that negatively affected and predicted QoL. Older patients had more cognitive impairment (p = 0.003) and worse sleep/fatigue (p = 0.032) and sexual functions (p = 0.006), compared to younger group. Discussion: The study supports that NMSs are integral part of ET, negatively affect QoL, and similarly affect younger and older patients. Therefore, NMSs should be explored for proper care of ET patients.

Refractory Open Jaw Oromandibular Tardive Dystonia with a Sensory Trick, Treated with Botulinum Toxin: A Case Report.

Jaw-opening oromandibular dystonia (O-OMD) is a clinical subtype of OMD, commonly resistant to treatment. Here, we report a distinct case of tardive O-OMD with a characteristic sensory trick, successfully treated with high-dose botulinum toxin (BTX) injection. A 34-year-old male patient presented with involuntary jaw opening, tongue protrusion, dysarthria, and mild cervical dystonia. The patient reported improved abilities to talk and close his mouth after putting something, like a cigarette, between his teeth. After an unsuccessful treatment with anticholinergic medications, the patient received electromyography-guided BTX injection to the lateral pterygoids (through an extraoral approach), sternocleidomastoids, trapezius, tongue, and platysma muscles. Following the injection, the patient reported marked improvements in his ability to talk and close his mouth without using his sensory trick. One month later, we detected a 58.2% improvement in the Abnormal Involuntary Movement Scale score. Therefore, high-dose BTX injection may be an effective alternative in refractory O-OMD.

Urban Versus Rural Egypt: Stroke Risk Factors and Clinical Profile: Cross-Sectional Observational Study.

BACKGROUND: Egypt is a densely populated country with living habits and health care services that differ from urban to rural regions. We aimed to study how characteristics of stroke vary among these regions. METHODS: This is a cross-sectional observational study of ischemic stroke, thus hemorrhagic and venous strokes were excluded. A total of 1475 ischemic stroke patients were recruited for analysis from a tertiary hospital in Cairo representing urban area and from a secondary care hospital in Suhag representing rural region. RESULTS: Analysis was done for 1143 ischemic stroke patients from urban and 332 from rural area. Onset to door was shorter in urban. Urban patients showed an older age and higher prevalence of hypertension and diabetes (65.9%, 48.6% respectively), while rural patients were characterized by female preponderance (51.5%), more dyslipidemia, smoking 44.6%, stroke in young 20.5%, atrial fibrillation 23.8% % and recurrent stroke 44.3%. Rural cases showed a severer deficit at onset and poorer outcome. CONCLUSION: Vascular risk factors, stroke type, and presentation tend to differ in Egypt according to the geographic distribution whether urban or rural. Studying patterns of such difference may aid in planning specific targeted preventive and therapeutic strategies for stroke in urban and rural Egypt.

K-variant BCHE and pesticide exposure: Gene-environment interactions in a case-control study of Parkinson's disease in Egypt.

Pesticide exposure is associated with increased risk of Parkinson's disease (PD). We investigated in Egypt whether common variants in genes involved in pesticide detoxification or transport might modify the risk of PD evoked by pesticide exposure. We recruited 416 PD patients and 445 controls. Information on environmental factors was collected by questionnaire-based structured interviews. Candidate single-nucleotide polymorphisms (SNPs) in 15 pesticide-related genes were genotyped. We analyzed the influence of environmental factors and SNPs as well as the interaction of pesticide exposure and SNPs on the risk of PD. The risk of PD was reduced by coffee consumption [OR = 0.63, 95% CI: 0.43-0.90, P = 0.013] and increased by pesticide exposure [OR = 7.09, 95% CI: 1.12-44.01, P = 0.036]. The SNP rs1126680 in the butyrylcholinesterase gene BCHE reduced the risk of PD irrespective of pesticide exposure [OR = 0.38, 95% CI: 0.20-0.70, P = 0.002]. The SNP rs1803274, defining K-variant BCHE, interacted significantly with pesticide exposure (P = 0.007) and increased the risk of PD only in pesticide-exposed individuals [OR = 2.49, 95% CI: 1.50-4.19, P = 0.0005]. The K-variant BCHE reduces serum activity of butyrylcholinesterase, a known bioscavenger for pesticides. Individuals with K-variant BCHE appear to have an increased risk for PD when exposed to pesticides.

Non-Motor Symptoms as Predictors of Quality of Life in Egyptian Patients With Parkinson's Disease: A Cross-Sectional Study Using a Culturally Adapted 39-Item Parkinson's Disease Questionnaire.

OBJECTIVE: The prevalence of non-motor symptoms (NMSs) and their impact on health-related quality of life (HRQoL) in Parkinson's disease (PD) has been reported inconsistently among different populations. In this study, we aimed to investigate the NMSs and HRQoL profiles and their correlation in Egyptian PD patients, using a culturally adapted Arabic version of the 39-item Parkinson's disease questionnaire (PDQ-39). METHODS: Ninety-seven PD patients were rated using the unified Parkinson's disease rating scale (UPDRS), the non-motor symptoms scales (NMSS), Beck depression inventory (BDI), and the Arabic version of PDQ-39. We used the Spearman's rank correlation and multiple linear regression analyses to evaluate the relationship between NMSs domains and HRQoL dimensions. RESULTS: Fatigue/sleep (91.3%) and mood/cognitive disturbances (87%) were the most frequently and severely affected NMSS domains. Other common NMSs included urinary (75.9%), memory/attention (72.4%), gastrointestinal (67.8%), and cardiovascular problems (64.8%). The total NMSS scores were positively correlated with UPDRS I, II, and III scores. Depression was prevalent in 76.7% of PD patients. Moreover, all enrolled PD patients reported impairment in different HRQoL dimensions, especially mobility (98.9%), activities of daily living (97.8%), and emotional well-being (95.5%). The summary index of PDQ-39 was correlated to the total NMSS, UPDRS-I, UPDRS-II Off, UPDRS-III (Off and On states), and BDI scores. CONCLUSION: This study showed the high prevalence of NMSs and the value of NMSS and BDI scores as predictors of HRQoL in Egyptian PD patients. Therefore, characterizing the NMSs profile is essential for tailoring management strategies for PD patients.

c.207C>G mutation in sepiapterin reductase causes autosomal dominant dopa-responsive dystonia.

OBJECTIVE: To elucidate the genetic cause of an Egyptian family with dopa-responsive dystonia (DRD), a childhood-onset dystonia, responding therapeutically to levodopa, which is caused by mutations in various genes. METHODS: Rare variants in all coding exons of GCH1 were excluded by Sanger sequencing. Exome sequencing was applied for 1 unaffected and 2 affected family members. To investigate the functional consequences of detected genetic variants, urinary sepiapterin concentrations were determined by high-performance liquid chromatography. RESULTS: A heterozygous rare nonsynonymous variant in exon 1 of sepiapterin reductase (SPR, c.207C>G, p.Asp69Glu) was found in all affected family members. Urinary concentrations of sepiapterin were above the standard of normal controls in most SPR mutation carriers, suggesting functional biochemical consequences of the mutation. Variant filtering of all genes involved in the tetrahydrobiopterin pathway, required for levodopa synthesis, revealed an additional common variant in dihydrofolate reductase (DHFR, rs70991108). The presence of both variants was significantly stronger associated with the biochemical abnormality and the clinical disease state as opposed to 1 variant only. CONCLUSIONS: The rare SPR mutation can cause autosomal dominant DRD with incomplete penetrance. The common DHFR variant might have synergistic effects on production of tetrahydrobiopterin and levodopa, thereby increasing penetrance.

A Study of Extrapyramidal Manifestations Accompanying Decompensated Viral Hepatic Cirrhosis Patients.

BACKGROUND: Despite the high prevalence of viral hepatic cirrhosis all over the world, the characteristic motor features of related Parkinsonism (extrapyramidal manifestations) are not well described. The current study aimed to characterize such disorder in a sample of Egyptian patients with chronic viral liver disease (CLD), and their clinical correlates. METHODS: Ninety-six (96) patients with CLD were examined for the presence of extrapyramidal signs. Parkinsonism was assessed using the UPDRS-III scale and its sub scores. Ataxia and dystonia were also assessed by related scales. Patients with Parkinsonism were compared to other patients and correlations with clinical features of CLD were done. RESULTS: The clinical diagnosis of extrapyramidal manifestations was justified in 57 patients (59.4%) with predominant akinetic rigid syndrome (ARS) (87.7%). Bradykinesia and axial features were the most frequent signs (89.5% and 70.2%, respectively). 38.6% of patients had postural tremors, whereas only 3.5% had rest tremors. Gait and postural abnormalities were detected in 38.6% and 36.8% respectively. Parkinsonism was associated with advanced hepatic cirrhosis (p=0.02) and increased episodes of hepatic encephalopathy (HE) (p=0.006). Severity of parkinsonian features was correlated to patients' age, age of onset of CLD and rapid progression, while impaired speech and gait were rather correlated to a number of episodes of HE. CONCLUSION: Advanced viral cirrhosis is associated with high prevalence of parkinsonism that is characterized by symmetrical ARS with frequent axial features, postural tremor, gait and postural impairment. Severity of these signs is correlated to age, age of onset, rapid progression and frequency of HE.

Bee venom for the treatment of Parkinson's disease: How far is it possible?

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by progressive loss of dopaminergic neurons in the substantia nigra pars compacta leading to depletion of striatal dopamine and motor symptoms as bradykinesia, resting tremors, rigidity, and postural instability. Current therapeutic strategies for PD are mainly symptomatic and may cause motor complications, such as motor fluctuations and dyskinesia. Therefore, alternative medicine may offer an effective adjuvant treatment for PD. Bee venom therapy (BVT) has long been used as a traditional therapy for several conditions, such as rheumatoid arthritis, asthma, and skin diseases. Experimental and clinical studies showed that BVT could be an effective adjuvant treatment for PD. Several mechanisms were suggested for these findings including the ability of BVT to attenuate neuroinflammation, inhibit apoptosis of dopaminergic neurons, protect against glutamate-induced neurotoxicity, and restore normal dopamine levels in the nigrostriatal pathway. In this article, we reviewed and summarized the literature regarding the potential of BVT for the treatment of PD.

Restless legs syndrome in Egyptian medical students using a validated Arabic version of the Restless Legs Syndrome Rating Scale.

OBJECTIVE: Restless legs syndrome (RLS) is a common movement disorder that has a variable prevalence and impact reported from different countries and specific populations. The current study validated an Arabic version of the International Restless Legs Syndrome Study Group (IRLSSG) rating scale (IRLS) and investigated the prevalence and impact of RLS in medical students at Ain Shams University in Cairo. METHODS: Translation of IRLS was done according to standard recognized guidelines provided by the publisher. A total of 389 medical students (217 female and 172 male) participated in the study and answered four questions to detect RLS as proposed by the IRLSSG. Subjects who answered positively the first three questions were recruited for face-to-face interview to exclude RLS mimics and to answer the IRLS. RESULTS: A total of 46 subjects (11.8%; 27 female and 19 male) met the four criteria for RLS. Of these, 39 subjects (10%) had idiopathic RLS. Five subjects (1.3%) and two subjects (0.5%) reported association with history of anemia and diabetes mellitus respectively. Their mean total IRLS score was 16.33 ± 5.3, with moderate severity (11.62 ± 3.9) and low impact (3.1 ± 1.8). The prevalence of individuals who had two or more episodes of RLS of at least moderate severity per week was 5.9%. CONCLUSION: In this specific population of Egyptian medical students, a within-average prevalence of RLS was found with low impact on quality of life similar to worldwide reported populations. RLS sufferers were of high prevalence among this cohort. The Arabic version of IRLS is reliable and valid for further research in Arabic countries.

Arabic cross cultural adaptation and validation of the National Institutes of Health Stroke Scale.

INTRODUCTION: The National Institutes of Health Stroke Scale (NIHSS), the most commonly used tool to quantify neurological deficit in acute stroke, was initially developed in English. We present our experience in developing and validating an Arabic version of the NIHSS (arNIHSS). RESULTS: In 6months, 137 patients were recruited (mean age±standard deviation 62±12years; 48 women). For interrater agreement, weighted kappa value ranged from 0.36 to 0.66 and intraclass correlation coefficient (ICC) for the whole scale was excellent at 0.95 (95% confidence interval [CI] 0.94-0.97). For intrarater agreement, weighted kappa ranged from 0.52 to 1.0 and the ICC was 0.94 (95% CI 0.87-0.98). The construct validity of the arNIHSS is demonstrated by its correlation with the DWI-ASPECT and the 3months mRS score (Spearman correlation -0.46 and 0.58 respectively; P<0.001 for both). CONCLUSION: We developed and validated a culturally adapted Arabic version of the NIHSS. Further validation in other Arab countries is recommended.

Retinal changes in children and adolescents with sickle cell disease attending a paediatric hospital in Cairo, Egypt: risk factors and relation to ophthalmic and cerebral blood flow.

BACKGROUND: Sickle cell disease (SCD) is characterised by occlusion of small blood vessels. This study aimed to assess retinal changes in patients with SCD and its correlation with time-averaged mean flow velocity (TAMV) in middle cerebral arteries (MCA) and ophthalmic arteries (OA). METHODS: Sixty SCD patients (aged 3-18 years) attending a paediatric hospital in Cairo, Egypt, during March 2010 to November 2011, were compared with 30 healthy controls. All underwent clinical and fundus examination by indirect ophthalmoscopy, and assessment of TAMV in MCAs and OAs by transcranial Doppler, repeated 1 year later for those with conditional velocities. RESULTS: HbS/ß was diagnosed in 32 patients and HbSS in 28; 50 patients had normal fundus and 10 had bilateral non-proliferative retinopathy. Risk factors for retinopathy included HbSS, age, previous stroke, non-compliant hydroxyurea (HU) therapy, frequency of sickling crises and HbS level. TAMVs were increased in MCAs, but not in OAs, in sicklers. TAMVs in MCAs and OAs increased with non-compliant HU therapy, previous stroke, age, frequency of sickling crises and level of HbS. No significant interhemispheric difference was found. CONCLUSION: Sickle retinopathy was correlated with TAMV in MCAs but not in OAs. A significant difference was found between initial and follow-up TAMVs in the MCAs, after 1 year of regular HU and transfusion therapy, in those with conditional velocities.