GAUCHER DISEASE

Dr.mazin M.kadhim

Nelson textbook of paediatrics 20TH EDITION

This disease is a multisystemic lipidosis characterized by hematologic abnormalities, organomegaly, and skeletal involvement, the latter usually manifesting as bone pain and pathologic fractures . It is one of the most common lysosomal storage diseases and the most prevalent genetic defect among Ashkenazi Jews.

There are 3 clinical subtypes delineated by the absence or presence and progression of neurologic manifestations: type 1 or the adult, nonneuronopathic form; type 2, the infantile or acute neuronopathic form; andtype 3, the juvenile or subacute neuronopathic form. All are autosomal recessive traits.

Clinical manifestations Gaucher Diz. type 1

•Thrombocytopenia & its manifestation•Anemia & its manifestation• Hepatomegaly with or without elevated liver function test results•Splenomegaly•Bone pain. •Pulmonary involvement •Growth retardation

Erlenmeyer flask deformity of the distal femur

Gaucher disease type 2

is a rare form and does not have an ethnic predilection. It is characterized by a rapid neurodegenerative course with extensive visceral involvement and death within the first years of life.

It presents in infancy with

• increased tone• strabismus•organomegaly• Failure to thrive• stridor caused by laryngospasm•psychomotor regression•death typically occurs secondary to respiratory

compromise.

Gaucher disease type 3

presents with clinical manifestations that are intermediate to those seen in types 1 and 2, with presentation in childhood and death by age 10-15 yr. It has a predilection for the Swedish Norrbottnian population, among whom the incidence is approximately 1 in 50,000.

Neurologic involvement is present. Type 3 disease is further classified as types 3a and 3b based on the extent of neurologic involvement and whether there is progressive myotonia and dementia (type 3a) or isolated supranuclear gaze palsy (type 3b).

Gaucher disease should be considered in the differential diagnosis of

patients with unexplained organomegaly, who bruise easily, have bone pain, or have a combination of these conditions

The pathologic hallmark of Gaucher disease is the Gaucher cell in the reticuloendothelial system, particularly in the bone marrow. The presence of this cell in bone marrow and tissue specimens is highlysuggestive of Gaucher disease, although it also may be found in patients with granulocytic leukemia and myeloma.

Prenatal diagnosis

is available by determination of enzyme activity and/or the specific family mutations in chorionic villi or cultured amniotic fluid cells.

Treatment of patients with Gaucher disease type 1

includes enzyme replacement therapy. The efficacy of enzyme replacement therapy with mannose-terminated recombinant human acid β-glucosidase has definitively been demonstrated.

Most symptoms (organomegaly, hematologic indices, bone pain) are reversed by enzyme replacement therapy (60 IU/kg) administered by intravenous infusion every other week and the bone involvement can be stabilized or improved.

A two additional enzyme preparations are approved by the FDA for the treatment of type 1 Gaucher disease, including velaglucerase alfa (VPRIV, Shire HGT), which is produced in human fibrosarcoma cells, and taliglucerase alfa (Uplyso, Protalix Biotherapeutics), which is produced in carrot cells.

Treatment of patients with Gaucher disease type 2 & 3

Although enzyme replacement does not alter the neurologic progression of patients with Gaucher disease types 2 and 3, it has been used in selected patients as a palliative measure, particularly in type 3 patients with severe visceral involvement.

Alternative treatments, including the use of oral substrate reduction agents designed todecrease the synthesis of glucosylceramide by chemical inhibition of glucosylceramide synthase (e.g., miglustat), also are available.

A small number of patients have undergone bone marrow transplantation (BMT), which is curative but is associated with significant morbidity and mortality from the procedure, limiting the selection of appropriate candidates.