Advances in Gaucher Disease 11 Table 2. Minimum clinical protocol for neurological follow-up in GD 1. Clinical examination • Neurological eximination: every 3 months during year 1, every 6 months thereafter. Neurological examination to include scoring as defined in the Severity Scoring Tool for NGD (Davies et al 2007b) to monitor changes. In adolescent and adult patient who are stable, neurological examination once a year may be sufficient. • If eye movements were considered to be normal at the time of initial assessment or if the result was equivocal (often the case with very young or sick children), such testing should be repeated. • Additional neuro-ophthalmological investigations: only if clinically indicated, e.g. development of sixth-nerve palsy. • Peripheral hearing (audiometry or electro-acoustical emissions depending on age, as stated above): evaluating trends every 2 or 3 years. 2. Brain imaging • Only if clinically indicated. The risk of anaesthesia should be considered. An exception to this may be made in patients who have the D409H allele. Such patients may be at risk of hydrocephalus (Inui et al 2001; Shiihara et al 2000), and may therefore need to be scanned on a regular basis. 3. Neurophysiology • EEG: only if clinically indicated, e.g. by presence of seizures. If myoclonus is suspected, telemetry may be needed. • Nerve conduction velocity: only if clinically indicated with reported symptoms of tingling, numbness, pins and needles. 4. Neuropsychometry • Annual assessments are probably not necessary as they are time consuming. We suggest the following: assessment at school entry, then at trasition from primary to secondary school, then when transitioning to college/adult education. Age-appropriate scales should be used. • Convergent strabismus and bulbar dysfunction were found in 22% and 37%. • 54% of patients had evidence of oppositional defiant disorder. • 30% developed seizures while on ERT for 1-9 years. Among those, 15% died suddenly and unexpectedly at a mean age of 6.7 years. Sudden death was usually associated with a seizure disorder or terminal seizure, even though 7 of 12 patients had a normal EEG earlier. • 11% had background slowing or epileptogenic activity on EEG without clinical seizures. Sudden unexpected death occurred in 3 familial cases. The interest in this study is partly due to its design: This was a large and genetically homogeneous group that shared the most common genotype. The cohort showed the entire clinical spectrum of this genotype, including normal neurologic phenotype to severe neurologic manifestations. The study included only pa- tients on ERT. The authors note that general health and initial cognitive function in GD3 patients is influenced by the visceral disease. The remarkable observation in this study is that the severity of the phenotype in this patient population in Egypt was markedly greater than what has been observed for the same genotype in other countries. Highlighting differences in the disease between countries, the authors point to other reports in which GD3 patients in China and Japan seem to have more severe neurologic disease than patients in Europe and the United States.13,14 The study also examines data on epilepsy with an observation that, in most cases, deaths occurred shortly after an epileptic seizure. There is an important caveat: although epilepsy in GD3 is associated with a risk for sudden unexpected death, a normal EEG does not rule out the possibility of sudden death. Because the lowest incidence of sudden unexpected death was in patients with well-controlled epilep-sy or epilepsy in remission, seizure control appears to be the optimal way of directly preventing such death. There is no answer yet as to why these patients in Egypt have such a unique phenotype—behavioral abnormalities, bulbar dysfunction, epilepsy, and sudden unexpected death. One possible explanation is modifier gene variants and the authors speculate that glutamate receptors may underlie the phenotypic expression of neuronopathic GD (see below). Additionally, there may be other unconfirmed explanations such as a cardiovascular risk factors not yet identified. It is intriguing to consider the implications of this Egyptian report. We need continued long-term follow-up of these patients because further evaluation may yield insights useful for the development and assessment of therapy and for identifying genetic modifiers. The overall management plan, for example, could include prophylactic antiepileptic strategies or other disease-altering agents not currently investigated. Characterizing Cognitive Outcomes in Neuronopathic GD Significant progress over the last 2 decades has been made with therapeutic interventions, including hematopoietic stem cell transplantation (HSCT) and ERT for some lysosomal storage disorders. Although ERT has reduced the frequency of systemic complications in patients with GD3 with consequent improvement in some measures of quality of life, there is no clear evidence that neurologic outcomes in neuronopathic GD have been improved.11,12 Additionally, information is emerging on the spectrum and prevalence of cognitive deficits among children with GD3 who previously received ERT or HSCT. The focus on systemic disease in children means that developmental and learning problems have not been adequately investigated. A retrospective study done by Goker-Alpan et al15 provided perspectives on 32 children whose neurologic assessments showed a wide spectrum of full-scale IQ scores ranging from 39 to 124 (mean 75). The key findings from this study: • Verbal abilities were within the average age for most pa-
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