Gaucher Disease (GD) is a rare, inherited, autosomal recessive genetic disease affecting around 1 in 50,000 to 1 in 100,000 people in the general population. It is one of the most common Lysosomal Storage Disorders (LSD). More than 40 different types of LSDs have been recognized by the scientific community. They are progressive disorders; although there is variation in the level of severity, rate of progression and which organs are affected between disorders and within the different disorder subtypes.
GD is caused by a genetic mutation of the gene that codes for a lysosomal enzyme called ‘b-glucocerebrosidase’ (acid beta-glucosidase or GCase). This allows a macromolecule lipid (fatty substance) called glucocerebroside (also called glucosylceramide, which is a glycosphingolipid) to accumulate within the cells of the body – particularly the liver, spleen, brain (in Type 2 and 3) and bone marrow.
The signs and symptoms of GD (and other LSDs) can vary widely from patient to patient which can make diagnosis by physicians difficult. Some patients may have severe symptoms which start at an early age whilst others may have only a few symptoms which start much later in life, or indeed no signs or symptoms at all. Early treatment can help to reduce the signs and symptoms experienced by patients and prevent irreversible damage to body tissues.
“Gaucher cells” being present are characteristic of the disease. In GD, glucocerebroside accumulates in macrophage cells as the enzyme b-glucocerebrosidase (which is located within the lysosomes) fails to effectively break it down. When this occurs and the cells become full of the stored glucocerebroside the cells can swell, become misshapen and cease to function correctly. The cells are then known as Gaucher cells and these cells can accumulate within various tissues of the body, leading to the variety of signs and symptoms which can present.
Normally the GBA gene is involved in giving instructions for the production of b-glucocerebrosidase. Researchers have discovered over 200 genetic mutations linked to GD. Mutations within the GBA gene, which has been mapped to chromosome 1q21, are responsible for development of GD. The GBA gene mutations are numbered according to their position in the cDNA relative to the upstream ATG codon or identified on the basis of the amino acid position in the protein sequence [Complementary DNA (cDNA) is a DNA copy of a messenger RNA (mRNA) molecule produced by reverse transcriptase – the first ATG in an mRNA’s coding region is where translation into protein begins].
Some specific consequences linked to certain mutations are mentioned below:
Having 2 copies of the L444P mutation causes neurological symptoms and is related to Gaucher disease types 2 and 3.
Patients with 1 copy of an N370S mutations plus another mutation almost certainly will have Gaucher disease type 1.
Patients with 2 copies of the N370S mutation may have a milder form of Gaucher disease than people with just one N370S copy plus another mutation.
Type 1 GD is the most common form in the general population and individuals of all ages can be affected. This type of GD is known as non-neuronopathic as it does not affect the nervous system. Treatments may now include bone marrow transplantation, gene therapy and more commonly Substrate Reduction Therapy (SRT) as well as the most frequently used Enzyme Replacement Therapy (ERT).
Type 2 GD is a rapidly progressive and very rare form of the disease with patients not usually surviving past the age of 2. This type does affect the nervous system and as such is termed a neuronopathic form of GD. No specific treatment for Type 2 Gaucher disease is available. ERT is ineffective in Type 2.
Type 3 GD is a less severe form of Type 2 GD but is still very rare – it is neuronopathic but most patients have milder symptoms in childhood. The outlook for most patients has dramatically improved since the onset of enzyme replacement therapy.
Current recommendations from the EWGGD are that a diagnosis of GD is based upon histological or cytological examination of bone marrow specimens, a liver biopsy, or a surgically removed spleen; as its clinical manifestations may mimic lymphoma or other haematological diseases.
Gaucher disease is a rare, autosomal recessively inherited disorder caused by mutations of the GBA gene. This gene has been located to chromosome 1q21; it is encoded by a cDNA strand of about 2.5 kb and is comprised of 11 exons (7 kb) [an exon is a segment of a DNA or RNA molecule containing information coding for a protein sequence]. There are two upstream start codons (ATG) that are both utilized in translation [The start codon is the first codon of a messenger RNA (mRNA) transcript translated by a ribosome].
Mutations in the GBA gene leads to an abnormal production of the enzyme b-glucocerebrosidase. The enzyme normally breaks down a lipid called glucocerebroside into a sugar (glucose) and a simpler fat molecule (ceramide). When the activity of b-glucocerebrosidase is reduced or eliminated glucocerebroside can build up to toxic levels within cells. The abnormal accumulation and storage of glucocerebroside results in damage to tissues and organs, causing the characteristic features of GD.
Four mutant alleles [alternative forms of a gene that arise by mutation and are found at the same place on a chromosome] (N370S, L444P, 84GG, IVS2+1) account for the majority of disease-causing alleles. The common mutations have been associated with various clinical subtypes, although the presence of at least one N370S allele appears to prevent the development of neuronopathic involvement. Abnormal alleles identified include exonic missense and nonsense mutations, splice junction mutations, deletions or insertions of one or more nucleotides, and complex alleles resulting from gene conversion or recombination.
Gaucher’s disease is a pan-ethnic disorder that has had major focus in developed countries with populations of European origin.
The overall frequency of Gaucher’s disease variants is about one in 40,000 to one in 60,000 livebirths in the general population. However, there is a higher frequency of Gaucher’s disease type 1 in the Ashkenazi Jews, about one in 800 livebirths. This has led to characterisation of disease phenotypes mainly on the basis of that population.
However, the growing recognition of substantial populations with type 1 disease in Asia, South America, the Indian subcontinent, and other demographic areas is broadening our appreciation of the range of phenotypes in this variant.
Similarly, with the broader recognition of types 2 and 3, widespread variation and range of involvement from early onset has become increasingly evident.
The general frequencies of any of the variants in large populations of China, India, Indonesia, the Middle East, or Africa are unknown.
The management of GD type 1 follows the recommendation of the European Working Group on Gaucher Disease, an international GD Expert Group, who produced an expert consensus document for the management goals for type 1 Gaucher disease (Blood Cells, Molecules and Diseases 68 (2018) 203–208).
The consensus management goals are presented in Tables 1A, 1B and 2. Besides a subdivision into short-term and long-term goals, it was decided to apply an additional subdivision into goals that are ERT/ SRT related and goals that concern more general management of the disease.
In general, the consensus panel agreed that with regard to anaemia, bleeding tendency, bone disease, liver and spleen involvement and pulmonary complications, physicians should aim for (near) restoration of normal values, prevention of complications, and elimination or reduction of signs and symptoms.
Also, improvement in quality of life, reduction of fatigue and normal participation in school and work activities were considered important goals for which to strive.
The panel agreed that proper education of patients and their family members about the nature of GD and its treatment is important, although several experts indicated that they considered this not a goal as such but rather good clinical practice.
Consensus was reached on the statement on early detection of signs or symptoms of GD3; however, some indicated that patients at risk of GD3 are best identified by GBA1 analysis, and argued that monitoring of neurologic signs and symptoms of GD3 should be limited to those with GD3 related mutations.
Finally, consensus was achieved that early detection of malignancies, Parkinson disease/parkinsonism and (pre-) diabetes should be aimed for, since these conditions are likely to benefit from prompt initiation of appropriate additional care or treatment.