Gaucher Disease

The cytoplasm in Gaucher Disease has wrinkled tissue paper
appearance,  which results from an accumulation of
glucosylcerebroside. (Image source)
Gaucher disease is a lipid storage disease characterized by the deposition of glucocerebroside in cells of the macrophage-monocyte system. The disorder results from the deficiency of a specific lysosomal hydrolase, glucocerebrosidase (also termed acid beta-glucosidase, glucosylceramidase). The disease is characterized by a continuum of phenotypes. The severity widely varies; some patients present in childhood with virtually all the complications of Gaucher disease, whereas others remain asymptomatic into the eighth decade of life.

Gaucher disease has traditionally been divided into the following 3 clinical subtypes, delineated by the absence or presence of neurologic involvement and its progression:

- Type 1 - Nonneuronopathic form
- Type 2 - Acute neuronopathic form
- Type 3 - Chronic neuronopathic form

However, some cases do not fit precisely into one of these categories. All forms of Gaucher disease are autosomal recessively inherited.

Type 1 Gaucher disease is more common among Jewish people of Eastern European origin; the carrier frequency in these individuals is approximately 1 per 15 population, whereas the disease frequency is 1 per 855 population. Gaucher disease is rare in the non-Jewish population, with an estimated frequency of 1 per 40,000 population.

As many as 60% of patients of Ashkenazi origin are estimated to be homozygous for the mild N370S mutation, which accounts for 75% of disease alleles in this population. Many individuals with this genotype never seek medical attention, contributing to an underestimation of the disease frequency. Type 3 disease is more common in the Norrbottnian region of Sweden (1 per 50,000 population), which has been traced to a common founder in the 17th century.

Mortality and morbidity varies with the different types.Type 1 Gaucher disease often presents in childhood with hepatosplenomegaly, pancytopenia, and skeletal disease, although striking clinical variability occurs in disease severity. Type 2 Gaucher disease causes rapidly progressive neurovisceral storage disease and death during infancy or during the first years of life. A subset of this type, associated with congenital ichthyosis and hydrops fetalis, is described as neonatal lethal and results in perinatal or in utero death. Type 3 Gaucher disease is often a less rapidly progressive neurovisceral storage disease. Various associated clinical courses have been reported, some of which cause death in childhood or early adulthood.

Type 1 Gaucher disease

Computerized tomography of hepatomegaly, often seen in
Gaucher Disease.
(Image source)
At onset, patients with type 1 Gaucher disease commonly present with painless splenomegaly, anemia, or thrombocytopenia. They may also have chronic fatigue, hepatomegaly (with or without abnormal liver function test findings), bone pain, or pathologic fractures and may bruise easily because of thrombocytopenia. Bleeding secondary to thrombocytopenia may manifest as nosebleeds, bruising, or both. In symptomatic patients, splenomegaly is progressive and can become massive. Children with massive splenomegaly may be short in stature because of the energy expenditure required by the enlarged organ.

Most patients with type 1 Gaucher disease have radiologic evidence of skeletal involvement, including an Erlenmeyer flask deformity of the distal femur, which is an early skeletal change. Clinically apparent bony involvement, which occurs in more than 20% of patients with Gaucher disease, can present as bone pain or pathologic fractures. In patients with symptomatic bone disease, lytic lesions can develop in the long bones, ribs, and pelvis, and osteosclerosis or osteopenia may be evident at an early age. Bone crises with severe pain and swelling can occur in individuals with type 1 Gaucher disease and are frequently mistaken for synovitis or osteomyelitis until other symptoms become apparent.
Occasional patients with type 1 Gaucher disease develop pulmonary involvement, parkinsonism, multiple myeloma, or portal hypertension. Patients with milder presentations of Gaucher disease are diagnosed later in life during evaluations for hematologic or skeletal problems or are found to have splenomegaly during routine examinations. Some patients are overtly asymptomatic, and a diagnosis is made incidentally after evaluation for other medical problems.

Type 2 Gaucher disease

Type 2 disease is rare and is characterized by a rapid neurodegenerative course with extensive visceral involvement and death within the first 2 years of life. Patients with this type may present at birth or during infancy with increased tone, seizures, strabismus, and organomegaly. Disruption of the epidermal layers of the skin, observed on skin biopsy findings, may manifest before the onset of neurological symptoms, but this may not always be clinically apparent.
Failure to thrive, swallowing abnormalities, oculomotor apraxia, hepatosplenomegaly, and stridor due to laryngospasm are typical in infants with type 2 disease. The progressive psychomotor degeneration and brain stem involvement leads to death, usually caused by aspiration and respiratory compromise.
A severe neonatal form can present in utero or perinatally with hydrops fetalis, congenital ichthyosis, or both.

Type 3 Gaucher disease

This form of Gaucher disease widely varies and can present in infancy or childhood. In addition to organomegaly and bony involvement, individuals with type 3 disease have neurologic involvement. The slowing of the horizontal saccades, an oculomotor finding, is often the sole neurologic manifestation. Some patients develop myoclonic epilepsy, exhibit learning disabilities, or develop dementia.
One rare subgroup of patients with type 3 Gaucher disease present with oculomotor findings, calcifications of the mitral and aortic valves, and corneal opacities. The phenotype is associated with homozygosity for the D409H mutant allele.
Another rare subgroup of patients with type 3 Gaucher disease is a genetic isolate from the Norrbottnian region of Sweden, homozygous for the L444P mutation. These individuals present in early childhood with visceral and skeletal involvement and oculomotor abnormalities and may develop seizures, cognitive disabilities, and dementia.
Some specific learning disabilities are common in children with type 3 Gaucher disease.

Type 2-3 intermediate Gaucher disease

Some patients present with severe neurovisceral manifestations in infancy or early childhood but survive past the second year of life, with death occurring in mid childhood (age 3-7 y). These patients are considered to fall within the phenotypic continuum between types 2 and 3.


All 3 forms of Gaucher disease are caused by glucocerebrosidase activity deficiency due to mutations in GBA1, the structural gene that encodes the enzyme. Widespread accumulation of glucosylceramide-laden macrophages results from the enzyme deficiency.
More than 300 different mutant GBA1 alleles have been identified in patients with Gaucher disease. Screening for the 6 most common GBA1 mutations in patients of Ashkenazi Jewish descent has enabled the identification of 90%-95% of the mutant alleles in this population, but a large number of other mutations have been described in other populations, making screening impractical.
Progressive “Norrbottnian like” phenotype in a male patient who
 was splenectomized at approximately 2 years. Characteristic
 initial and progressively severe kyphosis is present. The patient
 also has supranuclear gaze palsy and a mask-like facies as the
 predominant neurologic manifestation beginning at
 approximately 5 years of age. The patient's age in the various
 images is the inset number. He is homozygous for an L444P
encoding alleles that has several intronic polymorphic changes.
(Image source)
Some mutations derive from recombination with the glucocerebrosidase pseudogene, a sequence 15 kb downstream that shares 96% sequence homology to glucocerebrosidase. Complex alleles with regions of pseudogene sequence, in which simple polymerase chain reaction (PCR)–based mutation detection screening is inadequate, have been identified in some patients.
Genotype and phenotype correlations have been noted in some specific Gaucher presentations. For example, patients with type 1 Gaucher disease who are homozygous for the N370S mutation tend to have a later onset and a relatively mild course, and patients with type 3 Gaucher disease who are homozygous for the D409H mutation exhibit a rare phenotype that involves cardiac calcifications, oculomotor abnormalities, and corneal opacities. However, clinical presentation in patients with Gaucher disease widely varies and frequently cannot be fully explained by the underlying mutations because severity can vary even among siblings who have identical genotypes.
Similarly, the amount of residual enzymatic activity does not accurately predict disease subtype and severity, with the exception that many of the mutations identified in patients with severe type 2 Gaucher disease express little, if any, enzymatic activity in vitro. These are frequently nonsense, frame-shift, or recombinant alleles that cannot form a complete protein and are essentially null alleles.
These resources address the diagnosis or management of Gaucher disease and may include treatment providers.
For questions regarding the disease, please contact The National Gaucher Foundation.