gaucher disease ( gd ) is an autosomal recessive lysosomal glycolipid storage disorder characterized by the accumulation of glucocerebroside ( glucosylceramide ) in reticuloendothelial cells .
the gene coding for the deficient enzyme glucocerebrosidase ( acid beta - glucosidase ) is located on chromosome 1q21 .three phenotypes are traditionally recognized based on the absence ( type 1 ) or presence and severity ( types 2 and 3 ) of cns involvement .
specific mutations in the beta - glucocerebrosidase gene are associated with specific clinical presentations , for example , the l444p mutation produces neurologic involvement . the liver , the spleen , and long bones are the primary organs affected by the storage of glucosylceramide , mainly derived from the normal turnover of leukocytes and erythrocytes . the highly cytotoxic substance glucosylsphingosine ( the nonacyl derivative of glucosylceramide ) is also stored in excess in the viscera and in the brain , leading to cell death .
such neuronal destruction involves mainly the brain stem and deep cerebellar nuclei , but the thalamus , basal ganglia , and spinal cord are also affected .
type 3 ( gd3 ) represents the subacute , juvenile neuronopathic form , with onset in the teenage years and a chronic course .
the severity of gd3 is intermediate between type 1 ( gd1 ) and type 2 ( gd2 ) with milder neurological features .
the first symptoms are due to the massive visceral involvement , and disorders of eye movements are the usual presenting signs .
adult patients [ 4 , 5 ] in whom symptoms had begun in late childhood , adolescence , or early adult years present myoclonic epilepsy   and a distinctive supranuclear eye movement disorder affecting primarily horizontal gaze and only occasionally vertical gaze [ 79 ] .
the early defect in horizontal gaze involves the saccadic system , and the disorder mimics closely congenital ocular motor apraxia .
ocular motor abnormalities include horizontal saccadic initiation failure ( sif ) , with blinking , strabismus , slow horizontal and downward saccades , and an abnormal vestibulo - ocular reflex .
horizontal sif is the most consistent finding and is frequently the first sign of neurological involvement .
vertical sif usually indicates a progression of the disease , even if one case with vertical without horizontal sif has been pointed out .
both quick phases of optokinetic nystagmus   and voluntary saccades   can be used to early detect and follow the neurological involvement .
the phenotypic continuity between nonneuronopathic and severe acute neuronopathic forms of gaucher disease ( gd ) is emerging from the literature [ 1416 ] , contrary to a clear - cut distinction among the classical gd1 , gd2 , and gd3 types . in a large series of french patients ,
the clinical characteristics suggest that the three forms of gd each involves a different profile of neurological manifestations .
gd1 is treatable with appropriate amounts of exogenous enzyme ( imiglucerase ) replacement therapy ( ert ) , whose safety and efficacy have been clearly documented .
ert is however unable to stop the progression of the neurological involvement . due to the fact that infusion of glucocerebrosidase increases enzyme activity in the cns
if a dosage of 120  u / kg body weight or higher is given , the role of such high - dose ert in neuronopathic cases was studied : it was concluded that   the latter is not able to stabilize neurological disease . to protect the brain of gd patients ,
substrate reduction therapy ( srt ) performed by n - butyldeoxynojirimycin ( miglustat ) could be an alternative .
the formation of glycosphingolipids is decreased to amounts that may be metabolised by the residual enzyme . in patients with visceral gd ,
the efficacy of srt with miglustat has been demonstrated , while the benefit of miglustat also for patients with neuronopathic gd is not proved , given the contrasting results obtained [ 23 , 24 ] . in this paper ,
the clinical history of two gd sisters , initially treated with ert , is described .
one of them developed saccadic eye movement alterations that   disappeared after two years of miglustat therapy .
two sisters ( f. i. and a. i. ) , out of 7 siblings ( 5 females , 2 males ) , offspring to second cousin parents , presenting the same genotype ( r353g / r353 g ) , were gd diagnosed in 1983 and both submitted to splenectomy in the same year . during adolescence , they presented epilepsy responsive to barbiturate : generalized tonic - clonic seizures ( patient f. i. ) and partial complex seizures ( patient a. i. ) .
a first saccadic eye movements recording was carried out in both patients in year 2000 , during their annual clinical control .
f. i. , born in 1961 and suffering from hepatosplenomegaly , anemia , thrombocytopenia , and bilateral necrosis of the femoral epiphysis at the moment of diagnosis , began ert in 1995 ( alglucerase / imiglucerase : 30  u / kg every 2 weeks ) . at that time she showed liver cirrhosis without signs of liver insufficiency ; focal spike activity at eeg ( left temporal region ) ; normal visual evoked potentials ( vep ) and auditory brain responses ( abr ) ; increased threshold intensity and reduced amplitude at upper limb motor - evoked potentials .
the 2005 control brought out that in the previous 5 years ert therapy had been performed without continuity ; therefore , treatment was changed to srt miglustat ( 200  mg , 3 t.i.d ) oral therapy .
the barbiturate therapy continued . at the 2007 control , liver volume remained stable , no bone fracture was reported or detected , and the eeg proved unchanged ( infrequent focal paroxysmal discharges ) .
the miglustat treatment was confirmed owing to the absence of adverse events ( gastrointestinal disturbances ) in the two years of oral treatment .
a. i. , born in 1967 and suffering from splenomegaly , anemia and thrombocytopenia at the moment of diagnosis , began ert in 2002 ( regularly performed ) because of a hepatic involvement ( imiglucerase : 15  u / kg every 2 weeks ) . at that time she did not manifest neurological signs and had normal eeg and abr , so that the barbiturate therapy was stopped .
she changed the treatment to srt miglustat ( 100  mg , 3 t.i.d . ) too , oral therapy , that was confirmed at the 2007 control , thanks to   the tolerability of the oral treatment .
saccadic movements of both eyes were recorded by means of the infrared limbus tracking technique ( a very accurate technique in cooperative patients ) , with the subject looking at a target ( a red light spot ) in random horizontal motion , in a visual range of 15  deg with amplitudes of 5 , 10 , 15 , and 20  deg .
the ophthalmic and orthoptic examinations , performed before each saccadic test , showed the absence of relevant ocular and/or oculomotor disturbances .
for each identified saccade , the amplitude ( a ) , duration ( d ) , latency , and peak velocity ( vp ) were calculated .
a / d and a / vp relationships ( main sequence ) were evaluated and best fitted . for the a / d relation a linear regression
( d = m*a + q ) was used , while for the a / vp relation the fitting curve was derived from the function vp = 1/( + /a ) . the k ( mean velocity / peak velocity ratio ) and skewness ( saccadic rise time / duration ratio ) parameters , able to provide a description of velocity responses , were also evaluated [ 25 , 26 ] , and their relationships with the amplitude ( a / k , a / skewness )
were examined by linear best fitting ( k = mk*a + qk ; skewness = ms*a + qs ) . at a first examination of the acquired traces ,
a worsening was evident in the second test performed by f. i. , with some sif tracts and frequent blinks ; a recovery was instead evident in the last recording .
the saccadic parameters , resulting from all the six registrations , are summarized in table 1 , where the normal values ( obtained from a sample of 10 normal adult subjects performing the same test ) are also indicated .
while a. i. presents normal values in the three tests , f. i. shows a significant alteration of the main sequence at the second test , characterized by saccadic slowing ( lower 1/ values in the a / vp relationship , p < .05 ) with duration increase ( greater m slope in the a / d relationship , p < .01 ) and a subsequent improvement after miglustat therapy .
moreover , from 2000 to 2007 she presents a large reduction in mk slope and an increase in ms slope in the a / k and a / skewness relationships , respectively , even though their values appear within the normal confidence interval ( table 1 ) .
the two patients were initially treated with an ert dosage for gd1 , because epilepsy was considered a casual event not correlated to the cns glycolipid storage observed in gd3 , and the barbiturate therapy was effective .
in fact , even if it is known that barbiturate treatment could affect eye movements , in f. i. the therapy was always the same ; therefore , it is unlikely that the eye movement changes could be due to barbiturate . in f. i. , with more important visceral symptoms ,
ert was started more precociously , but during the 20002005 period it was performed with considerable discontinuity because of the   unaccepted administration route . at the second eye movement recording control ( 2005 ) ,
the presence of oculomotor abnormalities is a sufficient condition to change the classification from nonneuronopathic to neuronophatic illness type , as indicated by harris et al .   and accardo et al .
her r353g / r353 g genotype , already proposed as a neurological type   because of the presence of epilepsy , is confirmed as neurological owing to the onset of the new oculomotor alterations .
we underline that in spite of the gd1 ert dosage therapy , till about 40 years of age no evidence of neurological involvement ( if we exclude epilepsy ) was present ; this indicates a low grade of neurological aggressiveness of this genotype .
after two years of miglustat therapy , the oculomotor signs disappeared , showing the efficacy of srt to improve ( even by itself and not only if combined with ert [ 23 , 24 ] ) some neurological symptoms .
a positive result in one gd3 patient with myoclonic epilepsy was reported by capablo et al .   using a combined ert and srt therapy . in our case
srt therapy alone did not influence the course of epilepsy , while it normalized saccades . on the contrary , a controlled trial in 30 gd3 patients , where miglustat was used in addition to ert , did not show significant differences in the neurological signs ( included saccadic eye movement characteristics ) in a 24-month period , while a positive effect on systemic disease ( pulmonary function and chitotriosidase activity ) was observed .
the vertical and horizontal saccadic velocities were significantly different between the gd patients and 10 age - matched control subjects at the starting point , but the standard deviation in the gd group was very large , therefore including cases with low velocities and other cases with normal ones .
our case presented a clear peak velocity reduction , only 259  deg / s , which became   851  deg / s after two years of therapy ( srt alone ) , a very large variation ( confirmed by two tests ) . to compare our results to other clinical cases
, it would be interesting to know whether gd patients with the lowest saccadic velocities in the schiffmann et al .
series   clearly improved their ocular motor ability after miglustat therapy ( together to ert ) . in a. i.
, the clinical picture appears unchanged in the 2005 and 2007 controls : the eye movements were normal as in 2000 . in spite of the low dosage therapy and of the neurological genotype r353g / r353 g , at an age of 38 years she did not yet show other neurological signs ( in addition to the temporary epilepsy ) .
perhaps , the change of therapy ( from ert to srt ) did not permit any further mild neurological manifestation .
concerning the presence of epilepsy , it was initially considered as a casual event in the two patients .
after the appearance , in f. i. , of new ocular motor pathological signs , it seemed more probable that epilepsy was part of the neurological picture of some gd3 patients .
however , the inefficacy of the srt therapy on eeg paroxysmal , with the necessity to maintain the barbiturate therapy , seems to indicate a low grade of brain activity of srt , probably able to recover from only light and initial neurological manifestations .
considering the clinical course in the two siblings , it can be hypothesised   that the r353 g homozygote genotype corresponds to a low - aggressiveness and late - onset gd3 illness . in f. i. , eye movement analysis permitted to point out the new slight neurological worsening , showing once more the value of this instrumental examination in   monitoring the neurological situation , including the efficacy of therapy . in gd patients , beside eye movement examination , it is suitable to execute other exams able to investigate the brain - stem reticular formation , particularly those regarding the auditory pathways .
in fact , ocular motility is not the only neurological aspect showing up at the beginning of gd3 , even if it is the most precocious .
thus we recommend the convenience to exam periodically ocular motility in gd patients with risks genotypes to develop neurological symptoms .
it was previously reported that some gd1 patients present some slight eye movement alterations , related to saccadic velocity profiles , or evident neurological symptoms , bringing forward the concept of a phenotypic continuum from gd1 to gd3 classification .
this concept is similar to the one that was already proposed by goker et al .   for the heavy neurological involvements : a continuum between gd2 and gd3 classification .
the results of the present study seem to be in agreement with this new approach to the evaluation of gd patients .
 in gaucher disease ( gd ) the enzyme ( imiglucerase ) replacement therapy ( ert ) is not able to stop the progression of the neurological involvement , while the substrate reduction therapy ( srt ) , performed by n - butyldeoxynojirimycin ( miglustat ) , is an alternative that should be evaluated . 
 
 two sisters , presenting the same genotype ( r353g / r353 g ) , were diagnosed as suffering from gd ; one of them later developed neurological alterations identified by quantitative saccadic eye movements analysis . 
 the aim of the study was to quantitatively measure the miglustat effects in this gd neurological patient . 
 eye movement analysis during subsequent controls was performed by estimating the characteristic parameters of saccadic main sequence . 
 the study demonstrates that the srt alone can be effective in gd3 . 
 moreover , it confirms that quantitative eye movement analysis is able to precociously identify also slight neurological alterations , permitting more accurate gd classification . 
 
1. Introduction
2. Case Report
3. Discussion