© Harris & Campbell

An Introduction to

Neuronopathic Gaucher Disease

by Chris Harris & Pauline Campbell

• What is Gaucher disease
• Phenotypes
• Genotypes
• Genotype - Phenotype Correlations
• Eye movement abnormalities
• Auditory abnormalities
• Diagnosis

The purpose of this page is to give a very broad overview of neuronopathic Gaucher disease. Gaucher disease is a very complex multi-system disease.  More detailed information about eye movement abnormalities and audiological dysfunction will be provided on other pages in due course.

Please read our disclaimer

What is Gaucher Disease?

Gaucher disease (GD) is a rare inherited metabolic disease (IMD) caused by a deficient production of the enzyme glucerebrosidase (b-glucosidase).This leads to an accumulation of the lipid (fat) cerebroside in cells in the spleen, liver, bone, lungs, and the brain in a few. When there is a direct (‘primary’) effect on the brain, the condition is usually called ‘neuronopathic’ Gaucher disease (nGD).

It is important to distinguish between the effects of the disease on the body and its organs (excluding the brain), which we call ‘systemic disease’, and the direct effects of the disease on the brain, which we call ‘neuronopathic disease’. All patients with neuronopathic disease have systemic disease, but only about 10% or less of patients with systemic disease also have neuronopathic disease (depending on ethnicity). Thus nGD is very rare. Occasionally, a patient with only systemic disease may get complications that lead to neurological problems. These complications are secondary, not primary neurological involvement, and do imply neuronopathic disease.

Our research (and this website) is concerned only with neuronopathic disease. Sensorimotor abnormalities including abnormal eye movements and audiology are the first signs of nGD. If you are only interested in systemic disease, then read no further. We do emphasize the need to exclude neuronopathic disease, and we suggest reading the recent consensus papers by Grabowski et al (2004) and Baldellou et al (2004). Opposite you will find a number of websites with information on support groups (mostly UK). Alternatively, search the internet for “Gaucher disease”, “lysosomal disorders”, or “sphingolipid disorders”.

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Phenotypes

Typical systemic manifestations in symptomatic GD patients (including nGD):

• splenomegaly (enlarged spleen)
• hepatomegaly (enlarged liver)
• anaemia
• thrombocytopenia
• growth retardation
• bone disease
• lung disease

Primary neurological abnormalities in nGD include:

• eye movement abnormalities
• auditory abnormalities
• myoclonus
• abnormal EEG/ seizures
• cognitive impairment
• progressive bulbar palsy

Historically and traditionally, Gaucher disease has been subdivided into 3 phenotypes:

• Type 1 (‘adult’) Gaucher disease (GD1) is non-neuronopathic. Patients with GD1 have only systemic disease (or rarely secondary neurological problems). The old-fashioned term ‘adult’ GD is especially misleading since the first signs of GD1 may occur in infancy.

• Type 2 (‘infantile’, ‘acute’) Gaucher disease (GD2) is a severe neuronopathic disease with onset before 6 months. The infant presents with severe systemic disease and rapid neurodegeneration. Death usually occurs by the 2nd year.

• Type 3 (‘juvenile’, ‘subacute’) Gaucher disease (GD3) is neuronopathic disease that is less severe than GD2. Systemic disease is always present, but often more severe than GD1. Neurological progression is slower than GD2 but quite variable, being rapid and fatal in early childhood or very slow and insidious into adulthood. The term ‘juvenile’ is misleading, as onset in many GD3 patients will be before the 2nd birthday. The subtlety of neurological abnormalities in the young GD3 child can lead to diagnostic difficulties.

More recently, a lethal perinatal phenotype associated with ichthyosis or collodion skin and hydrops fetalis has been found.

A ‘cardiovascular’ GD3 phenotype with calcification of the aortic and mitral valves in addition to the eye movement abnormalities has also been identified.

The question of whether the traditional subtypes are discrete non-overlapping phenotypes has often been raised. It seems likely that the distinction between GD2 and GD3 is blurred, with some affected toddlers having neuronopathic disease more severe than typical for GD3 but not as severe as GD2. However, GD3 and GD1 do seem to have genuinely separate phenotypes, at least when assessed by eye movements and audiology.

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Genotypes

The Gaucher gene is a large gene on chromosome 1q21. There is also a pseudogene downstream.  More than 150 GD mutations have been detected, but new mutations are being discovered. 

Genetic testing is available [see your Consultant; for more details click here ttp://www.genetests.org/query?dz=gaucher].

GD and its subtypes are autosomal recessively inherited, so that the affected patient inherits two mutations, one from each biological parent. If the mutations are the same, the patient is said to be ‘homozygous’ for the specified mutation. If they are different mutations then the patient is said to be ‘compound heterozygous’ with specified mutations, or simply ‘heterozygous’ (if we are talking about a patient already diagnosed with GD).

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Genotype – Phenotype Correlations

A hallmark of GD is phenotypic variablity (ie. variability in disease severity) with some patients not coming to medical attention at all, whilst being lethal in others. This makes it very difficult to make a prognosis based on the genotype. Nevertheless, there are some correlations. Patients who are homozygous for the N370S do not have neuronopathic disease. Patients who are homozygous for the L444P or the D409H mutations usually have neuronopathic disease. Patients hetrozygous with L444P/N370S or with D409H/N370S are usually type 1 (not neuronopathic).

It should be emphasised that precise eye movement measurements have not been carried out to confirm these correlations, or the possible rare exceptions. Indeed, it is sometimes forgotten in this 'genocentric' era, that genotype-phenotype correlations cannot be assessed without also precise measurement of the phenotype!

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Eye Movement Abnormalities

Eye movement abnormalities are a prominent feature of nGD. They are probably the first neurological sign of nGD. At present Gaucher-type eye movement abnormalities are diagnostic of nGD. This is particularly important for GD3 as abnormal eye movements may precede other more severe neurological problems by many years.

In general there are many different kinds of eye movement abnormalities, which can occur in association with a huge number of different disorders. Therefore we need to be specific to nGD. It is important to understand that these eye movement abnormalities are not diagnostic of Gaucher disease per se (although they maybe suggestive), but are diagnostic of neuronopathic Gaucher disease given that the patient has already been diagnosed (usually enzymatically) with GD (Harris et al. 1999).

Gaucher eye movement abnormalities are:

• Horizontal Saccade Initiation Failure (hSIF) (also known as ocular motor apraxia)
• Horizontal Saccade Slowing
• Vertical Saccade Initiation Failure (vSIF) (especially downward)
• Vertical Saccade slowing (especially downward)
• 6th nerve paresis (in some)
• Decreased gain of the vestibulo-ocular reflex (probably rare)

Please note that SIF is also known as ‘ocular motor apraxia’, ‘oculomotor apraxia’, ‘congenital ocular motor apraxia’, ‘looping’. SIF is an obligatory feature of nGD. Saccade slowing is also obligatory when saccades are made [in some GD2 infants no saccades can be made, so it is impossible to measure their speeds (Vivian et al 1993; Campbell et al 2003)].

Other eye movement abnormalities are not part of the nGD spectrum. For example, nGD children do not have nystagmus. Thus, alternative explanations would be needed to explain such a phenomenon in an GD child.

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Auditory Pathway Abnormalities

Hearing is a complicated process involving sound entering the inner ear (cochlea) with the signals being transmitted along the auditory pathway up to the brain (central auditory processing). The auditory brainstem response (ABR; also known as the BAEP or BAER) is a standard electrophysiological technique for assessing auditory function. It can be used at any age and requires no attention. In fact, it is best measured while the child is asleep. It measures the integrity of the brainstem auditory pathways, and we have shown that it can be used to detect neurological deficits in NGD disease (Bamiou et al., 2001, Campbell et al., 2003). Our recent data also reveal, for the first time, a clear deterioration in GD3 children who are undergoing ERT (Campbell et al 2004) which testifies to the sensitivity of ABRs and emphasises the need for new neurologically effective drugs.

Many of the abnormalities seen in nGD could be explained by problems in timing disparity. The ABR occurs within a few milliseconds of stimulation, and timing needs to be very precise in order to be recorded. Poor synchronization results in abnormal waveform morphology and plummeting of the ABR amplitude (Starr, 2001). These timing problems within the auditory nerve could also interfere with precise phonemic decoding and, consequently, with the perception of speech sounds and other auditory tasks particularly in background noise (Starr, 2001).

Other audiological abnormalities include:

• Peripheral hearing as assessed by pure tone audiometry (to assess hearing thresholds) is usually normal in nGD but there are sporadic reports of hearing loss (conductive and sensorineural) in some cases.

• Tympanometry, a method used to assess middle ear function, is usually normal but middle ear reflexes are absent or elevated.

• Otoacoustic emissions (to assess outer hair cell/cochlear function) are usually present but are suppressed/absent when recorded with contralateral noise (medial olivocochlear suppression).

• Hyperacusis (hypersensitivity to loud noise) has also been reported.   

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Diagnosing Neuronopathic Gaucher Disease

The diagnosis of nGD nearly always occurs after the diagnosis of GD has been made. Only rarely do the neurological signs preempt systemic signs (usually in some type 2 infants and in some rare forms of type 3 patients).

Unless there is a family history or some other clue, the usual course of events is that, first, Gaucher disease is diagnosed often after rather lengthy investigations for more likely disorders (such as a blood disorder). Eventually the diagnosis is confirmed by tests of cells from blood or the skin. Second (nowadays), a genotype is obtained by DNA analysis. Then the question of whether the child has neuronopathic disease is raised. Given that Gaucher disease has been confirmed, the diagnosis of neuronopathic disease is based partially on genotype and partially on phenotype.

It is currently accepted that, genetically, homozygosity for the N370S allele always indicates non-neuronopathic disease and neurological investigations are usually not pursued. Compound heterozygotes with the N370S allele are usually also assumed to be non-neuronopathic. In most centres, homozygosity for the L444P or the D409H alleles usually indicate neuronopathic disease. Other alleles are more difficult to evaluate a priori. Family history may also be included in the judgement.

Except in already advanced disease, the most accepted phenotypic indication of neuronopathic disease is the presence of specific eye movement abnormalities (see above). Horizontal saccade initiation failure (hSIF) ('ocular motor apraxia') is the most easily and most often tested. This is not without problems due to false negatives - it is easy to miss!

We recommend formal eye movement testing. This can detect SIF and eliminate false negatives. It can also confirm the absence of SIF, thus eliminating false positives, but also relieve any nagging doubts about a patient's phenotype. The speed of saccades can usually be measured as well to yield a base-line measure of neuronopathic disease. We can perform these tests in our laboratory on patients of any age, including infants (see Patient Info).

If eye movements are not measured, we strongly recommend that the procedure of manual spinning is used to assess the presence of SIF, as outlined in Cassidy et al (2000). The reason for this is that many nGD children with SIF do not exhibit the classic headthrusts that many clinicians believe should be present in SIF. We have winessed misdiagnoses and cannot emphasise this point too much - lack of headthrusts does not preclude SIF and hence nGD.

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