patients were followed prospectively on the international collaborative gaucher group gaucher registry , clinicaltrials.gov study number nct00358943 , and enrolled in the neurological outcomes subregistry . all patients with gaucher disease type 3 and neurologically asymptomatic patients with the l444p / l444p gba1 genotype ( c.1448t > c ) who were on ert were included in this study . all patients were diagnosed by glucocerebrosidase deficiency followed by gba1 genotyping . analysis for common mutations was performed by pcr followed by sanger sequencing . in addition , for some patients , a strip hybridization  based assay for gaucher disease was used for the detection of 8 commonly reported mutations in the gba gene ( c.84dupg ( 84gg ) , c.115 + 1g > a ( ivs2 + 1g > a ) , c.1226a > g ( p.n370s ) , c.1297g > t ( p.v394l ) , c.1342g > c ( p.d409h ) , c.1448t > c ( p.l444p ) , c.1504c > t ( p.r463c ) , and c.1604g > a ( p.r496h ) ) and 2 recombinant alleles ( recnci - l and rectl ) according to manufacturer 's protocol ( viennalab diagnostics , vienna , austria ) . however , gba1 genotyping was not performed in some patients ( designated as unknown in tables e-1 and e-2 at neurology.org/ng ) . neurologic evaluation included performing 21-channel standard eeg and iq testing when the patient 's overall health was sufficiently improved to permit meaningful measurement . assessment varied according to age ; vineland adaptive behavioral scale was used for children < 4 years and wechsler intelligence scales were used for preschool , school - age , and adult groups . neurocognitive impairment is mild if iq is 5570 , moderate if iq is 3555 , and severe if iq is < 35 . ert dose ranged from 20 to 60 iu / kg of body weight every 2 weeks . some patients were given a trial of higher ert doses when possible to better control their symptoms ( table e-1 ) . summary statistics for continuous and categorical variables are reported with mean (  sd ) and percentages , respectively . time - to - event analyses were conducted using kaplan - meier survival curves with hall - wellner 95% confidence intervals . patients were followed prospectively on the international collaborative gaucher group gaucher registry , clinicaltrials.gov study number nct00358943 , and enrolled in the neurological outcomes subregistry . all patients with gaucher disease type 3 and neurologically asymptomatic patients with the l444p / l444p gba1 genotype ( c.1448t > c ) who were on ert were included in this study . all patients were diagnosed by glucocerebrosidase deficiency followed by gba1 genotyping . analysis for common mutations was performed by pcr followed by sanger sequencing . in addition , for some patients , a strip hybridization  based assay for gaucher disease was used for the detection of 8 commonly reported mutations in the gba gene ( c.84dupg ( 84gg ) , c.115 + 1g > a ( ivs2 + 1g > a ) , c.1226a > g ( p.n370s ) , c.1297g > t ( p.v394l ) , c.1342g > c ( p.d409h ) , c.1448t > c ( p.l444p ) , c.1504c > t ( p.r463c ) , and c.1604g > a ( p.r496h ) ) and 2 recombinant alleles ( recnci - l and rectl ) according to manufacturer 's protocol ( viennalab diagnostics , vienna , austria ) . however , gba1 genotyping was not performed in some patients ( designated as unknown in tables e-1 and e-2 at neurology.org/ng ) . neurologic evaluation included performing 21-channel standard eeg and iq testing when the patient 's overall health was sufficiently improved to permit meaningful measurement . assessment varied according to age ; vineland adaptive behavioral scale was used for children < 4 years and wechsler intelligence scales were used for preschool , school - age , and adult groups . neurocognitive impairment is mild if iq is 5570 , moderate if iq is 3555 , and severe if iq is < 35 . ert dose ranged from 20 to 60 iu / kg of body weight every 2 weeks . some patients were given a trial of higher ert doses when possible to better control their symptoms ( table e-1 ) . summary statistics for continuous and categorical variables are reported with mean (  sd ) and percentages , respectively . time - to - event analyses were conducted using kaplan - meier survival curves with hall - wellner 95% confidence intervals . their mean  sd age when last examined was 9.5  5.5 years ( range , 1.522.5 ) . twenty - three patients developed seizures ( table e-1 ) , 9 patients had eeg abnormalities without clinical seizures ( table e-1 ) , and 46 patients had no eeg abnormality or seizures ( table e-2 ) . patients , their genotype , and clinical characteristics are presented in tables e-1 and e-2 . in the group with seizures , all but 3 patients were l444p homozygous : 1 patient was d409h homozygous , and the mutations in the other 2 were unknown . in the group without seizures and with normal eeg , 2 patients with d409h / d409h had aortic root and valvular calcifications and regurgitation , whereas 1 patient ( patient 6 ) had a newly observed anomaly consisting of ectatic proximal coronaries . these patients had increased reflectivity of the cornea and asymptomatic hydrocephalus . in the group with eeg abnormalities , 6 patients were l444p homozygous and 3 were unknown . among those with no eeg abnormalities or seizures , 31 patients were l444p homozygous and the genotype in 9 was unknown . there was considerable intrafamilial heterogeneity , and siblings often had discordant neurologic and systemic disease severity ( tables e-1 and e-2 ) . seven patients , all in the normal eeg and no seizures group , had no neurologic abnormalities on clinical examination , including normal horizontal saccades . six of them were homozygous for l444p and 1 was l444p / d409h ; 3 patients had a splenectomy at a very early age . the other 71 patients all had supranuclear gaze palsy in isolation or in combination with variable developmental delay but often had improved motor skills over time . patients with seizures ( table e-1 ) had lower cognitive function than those with no seizures and normal eeg ( table e-2 ) . if one imputes an iq of 100 to those with clearly normal cognitive function , the full - scale iq of the former group was 68  15 and that of the latter group was 85  13 ( p < 0.0001 ) . convergent strabismus was noted in 22% overall ( 11% without and 37% with seizures or eeg abnormalities ) . bulbar dysfunction was reported in 37% overall ( 28% without and 50% with seizures or eeg abnormalities ) ( tables e-1 and e-2 ) . features of oppositional defiant disorder were observed in 54% overall ( 48% without and 62% with eeg abnormalities ) . eeg abnormalities consisted of a persistent generalized slow and disorganized background , often seen in diffuse encephalopathies ( table e-1 ) . eeg abnormality was not always associated with clinical seizures ; on the other hand , no epileptogenic activity was detected with surface eeg in some patients with seizures . seizures were reported in about 30% of patients with gaucher disease type 3 who were on ert ( table e-1 ) , and their cumulative incidence is presented in figure 1 . patients with a chronic seizure disorder were treated with valproic acid at a dose of up to 60 mg / kg / day , with variable results ( table e-1 ) . twelve patients died unexpectedly at a mean age of 6.7  5.0 years ( range 1.518 ) . the cumulative incidence of sudden death in patients with seizures , in those with seizures and eeg abnormalities , and in the overall study population is presented in figure 2 . of note , 7 of the 12 patients who died suddenly had a preceding normal eeg ( table e-1 ) . patients were followed for a total of 476 years , which is an incidence of sudden death of 25 per 1,000 patient - years in this population of patients with gaucher disease . there was no clear relationship between sudden unexpected death and the severity of the systemic disease , ert dose , or cognitive level . there were 3 cases in which sudden unexpected death occurred in 2 affected siblings in a family  patients 6 and 7 ; the identical twin and cousin of patient 21 died suddenly with seizures ; and patient 22 and his sibling both died suddenly after seizure . cumulative incidence of sudden death ( a ) in patients with seizures , ( b ) in those with seizures and eeg abnormalities , and ( c ) in the overall study population . their mean  sd age when last examined was 9.5  5.5 years ( range , 1.522.5 ) . twenty - three patients developed seizures ( table e-1 ) , 9 patients had eeg abnormalities without clinical seizures ( table e-1 ) , and 46 patients had no eeg abnormality or seizures ( table e-2 ) . patients , their genotype , and clinical characteristics are presented in tables e-1 and e-2 . in the group with seizures , all but 3 patients were l444p homozygous : 1 patient was d409h homozygous , and the mutations in the other 2 were unknown . in the group without seizures and with normal eeg , 2 patients with d409h / d409h had aortic root and valvular calcifications and regurgitation , whereas 1 patient ( patient 6 ) had a newly observed anomaly consisting of ectatic proximal coronaries . these patients had increased reflectivity of the cornea and asymptomatic hydrocephalus . in the group with eeg abnormalities , 6 patients were l444p homozygous and 3 were unknown . among those with no eeg abnormalities or seizures , 31 patients were l444p homozygous and the genotype in 9 was unknown . there was considerable intrafamilial heterogeneity , and siblings often had discordant neurologic and systemic disease severity ( tables e-1 and e-2 ) . seven patients , all in the normal eeg and no seizures group , had no neurologic abnormalities on clinical examination , including normal horizontal saccades . six of them were homozygous for l444p and 1 was l444p / d409h ; 3 patients had a splenectomy at a very early age . the other 71 patients all had supranuclear gaze palsy in isolation or in combination with variable developmental delay but often had improved motor skills over time . patients with seizures ( table e-1 ) had lower cognitive function than those with no seizures and normal eeg ( table e-2 ) . if one imputes an iq of 100 to those with clearly normal cognitive function , the full - scale iq of the former group was 68  15 and that of the latter group was 85  13 ( p < 0.0001 ) . convergent strabismus was noted in 22% overall ( 11% without and 37% with seizures or eeg abnormalities ) . bulbar dysfunction was reported in 37% overall ( 28% without and 50% with seizures or eeg abnormalities ) ( tables e-1 and e-2 ) . features of oppositional defiant disorder were observed in 54% overall ( 48% without and 62% with eeg abnormalities ) . eeg abnormalities consisted of a persistent generalized slow and disorganized background , often seen in diffuse encephalopathies ( table e-1 ) . eeg abnormality was not always associated with clinical seizures ; on the other hand , no epileptogenic activity was detected with surface eeg in some patients with seizures . seizures were reported in about 30% of patients with gaucher disease type 3 who were on ert ( table e-1 ) , and their cumulative incidence is presented in figure 1 . patients with a chronic seizure disorder were treated with valproic acid at a dose of up to 60 mg / kg / day , with variable results ( table e-1 ) . twelve patients died unexpectedly at a mean age of 6.7  5.0 years ( range 1.518 ) . the cumulative incidence of sudden death in patients with seizures , in those with seizures and eeg abnormalities , and in the overall study population is presented in figure 2 . of note , 7 of the 12 patients who died suddenly had a preceding normal eeg ( table e-1 ) . patients were followed for a total of 476 years , which is an incidence of sudden death of 25 per 1,000 patient - years in this population of patients with gaucher disease . there was no clear relationship between sudden unexpected death and the severity of the systemic disease , ert dose , or cognitive level . there were 3 cases in which sudden unexpected death occurred in 2 affected siblings in a family  patients 6 and 7 ; the identical twin and cousin of patient 21 died suddenly with seizures ; and patient 22 and his sibling both died suddenly after seizure . cumulative incidence of sudden death ( a ) in patients with seizures , ( b ) in those with seizures and eeg abnormalities , and ( c ) in the overall study population . here we present a large and genetically homogeneous patient cohort with gaucher disease type 3 , most of whom ( about 80% ) had the common neuronopathic gaucher genotype l444p / l444p . this cohort shows the entire clinical spectrum of this genotype  from normal neurologic phenotype to severe neurologic manifestations . we included only patients on ert in this study because general health and cognitive performance in patients with gaucher disease type 3 are known to be influenced by the visceral disease . therefore , the neurologic outcome of patients with gaucher disease type 3 on long - term ert reflects only their intrinsic cerebral dysfunction . the phenotype observed in our patients consisted of marked behavioral abnormalities ; common bulbar dysfunction ( dysarthria , dysphagia , or stridor ) ; epilepsy ; and frequent sudden unexpected death , usually with epilepsy or an isolated seizure , in the face of stable cognitive function in most patients . remarkably , their phenotype was more severe and different from that described for the same genotype in other countries . it should be noted that 31% of patients in the study analyzing the neurological outcomes subregistry of the international collaborative gaucher group gaucher registry as of june 1 , 2007 , were from egypt , but their phenotype was not specifically described . patients with gaucher disease type 3 in china and japan seem to have more severe neurologic disease than patients in europe and the united states . however , none of these studies have described sudden death , even in patients receiving long - term ert . behavioral problems have not been described in patients with gaucher disease type 3 . a 17-year - old arab israeli female patient with the l444p / l444p genotype developed epilepsy that devolved into myoclonic seizures and a more rapid cognitive decline . the causes of death of our patients are unknown , but in most cases death occurred shortly after an epileptic seizure . in these cases , sudden unexpected death in epilepsy ( sudep ) can be invoked . the incidence of sudep in our study population is much higher than that described in various epilepsy populations ( 0.359.3 per 1,000 person - years ) . the epileptic seizures in many cases were phenotypically partial complex , with possible temporal lobe epileptogenic foci in some patients . involvement of the temporal lobes in neuronopathic gaucher disease is not surprising because a specific pattern of hippocampal neuropathologic abnormalities has been described . our data suggest that epilepsy in gaucher disease type 3 is associated with a risk for sudden unexpected death , but a normal eeg does not preclude sudden death . in the general population , the lowest incidence of sudep is in patients with well - controlled epilepsy or patients in remission . therefore , seizure control is likely to be the most direct way of preventing sudep in this population of patients with gaucher disease . it remains to be seen whether prophylactic use of certain antiepileptic medications can decrease the likelihood of sudep in this patient population . the reason for such a unique gaucher disease type 3 phenotype , which includes behavioral abnormalities , frequent bulbar dysfunction , epilepsy , and sudden unexpected death , in patients in egypt is unknown . it is likely that modifier gene variants common in this population contribute to this phenotype . these may include ion channels that are directly or indirectly influenced by cellular levels of glucosylceramide . increased sensitivity of hippocampal neurons to glutamate - induced neurotoxicity has been described . the higher the level of glucosylceramide in neurons , the greater the toxicity . therefore , certain glutamate receptors may play a role in the phenotypic expression of neuronopathic gaucher disease . defective calcium homeostasis mediated by overactivity of the ryanodine receptor that correlated with glucosylceramide levels was also described . therefore , this calcium receptor may also be a potential phenotype modulator in neuronopathic gaucher disease . a yet - unidentified cardiovascular risk factor may be an important contributor to sudep in egyptian patients with gaucher disease type 3 . the detailed clinical spectrum and long - term follow - up of gaucher disease type 3 in egypt presented here should be useful for the development and assessment of primary therapy for this disease and for identifying genetic modifiers . such genetic variants may help identify the best antiepileptic medications or other medical interventions to either use or omit in this condition . it may also lead to using other disease - altering agents that are not currently under consideration . m.a . recruited and studied the patients and gathered all data , interpreted and analyzed the data , and edited the manuscript . r.s . has served on scientific advisory boards and received funding for travel and/or speaker honoraria from protalix biotherapeutics and amicus therapeutics ; has applied for and/or holds patents for triheptanoin diet for adult polyglucosan body disease treatment , use of tetrahydrobiopterin as a marker and a therapeutic agent for fabry disease , use of tetrahydrobiopterin as a marker and a therapeutic agent for fabry disease ( europe ) , urinary triaosylceramide ( gb3 ) as a marker of cardiac disease ( europe ) , and gene encoding a new trp channel is mutated in mucolipidosis ; has consulted for gerson lehrman group councils guidepoint global ; has served on speakers ' bureaus for genzyme corporation ; and has received research support from protalix biotherapeutics , amicus therapeutics , and baylor research foundation .
objective : to describe the long - term follow - up and distinct phenotype of a large cohort of patients with gaucher disease type 3 on enzyme replacement therapy ( ert ) in egypt.methods:a prospective cohort study of 78 patients on ert who were followed for up to 9 years with yearly evaluations that included eeg and cognitive testing.results:of the patients , 73% were homozygous for the l444p gba1 mutation ; all but 7 were neurologically symptomatic . 
 supranuclear gaze palsy with variable but stable cognitive function was present in 91% of patients . 
 convergent strabismus and bulbar dysfunction were noted in 22% and 37% , respectively . 
 features of oppositional defiant disorder were present in 54% of patients . 
 twenty - three patients ( 30% ) developed seizures while on ert for 19 years . 
 of those , 12 patients ( 15% ) died suddenly and unexpectedly at a mean age of 6.7  5.0 years ( range 1.518 ) . 
 sudden death was usually associated with a seizure disorder or a terminal seizure , but 7 of 12 patients had a preceding normal eeg . 
 an additional 11% had background slowing or epileptogenic activity on eeg without clinical seizures . 
 there were 3 familial cases of sudden unexpected death.conclusions:despite having the most common gba1 genotype known to be associated with neuronopathic gaucher disease , patients with gaucher disease type 3 in egypt have a phenotype and a clinical outcome on ert that are very different from those observed in other populations . identifying putative modifying genes of this ethnic group is likely to lead to better therapy for neuronopathic gaucher disease generally .