Gaucher disease

Gaucher disease is a rare genetic neurometabolic disorder caused by deficiency of lysosomal glucocerebrosidase, resulting in accumulation of glucosylceramide and related substrates in cells and progressive multisystemic manifestations. It occurs as an inherited autosomal recessive genetic condition; absence of a relevant family history does not exclude the diagnosis because the parents of an affected individual are typically unaffected carriers. The major clinical phenotypes include non-neuronopathic Gaucher disease (type 1) and neuronopathic Gaucher disease (types 2 and 3), although there is substantial phenotypic variability and overlap. A distinctive presentation may include the combination of hepatosplenomegaly and hematologic abnormalities, bone disease, and progressive neuropsychiatric manifestations.

It can present with psychiatric features such as depression, anxiety, irritability, behavioural change, cognitive impairment, hallucinations, and psychosis. Psychiatric manifestations may become apparent or clinically significant during adolescence or adulthood, particularly in individuals with neurologic involvement, and may precede or accompany other neurologic manifestations.

Other characteristic features include hepatosplenomegaly, anemia and thrombocytopenia, bone disease, oculomotor abnormalities including impaired initiation of horizontal saccades or oculomotor apraxia, seizures, progressive myoclonic epilepsy, ataxia, spasticity, parkinsonism, peripheral neuropathy, and progressive cognitive impairment or dementia. Neuronopathic Gaucher disease, particularly type 3, may have a slowly progressive course extending into adulthood.

From a multisystemic lens perspective, clinical features in other body systems include (but are not limited to):

• Respiratory: pulmonary disease and, less commonly, pulmonary hypertension may occur.

• Hepatobiliary: hepatomegaly and gallstones may occur (splenomegaly is also a characteristic finding).

• Hematologic: anemia, thrombocytopenia, and leukopenia may occur as a result of bone marrow involvement and hypersplenism.

• Musculoskeletal: osteopenia, focal lytic or sclerotic bone lesions, bone pain, osteonecrosis, and pathologic fractures may occur.

Early diagnosis is important to recognize a potentially treatable cause of psychiatric and neurologic illness, identify and manage progressive neurologic disease and cognitive impairment, detect and treat potentially serious hematologic, hepatic, splenic, pulmonary, and skeletal complications, guide appropriate enzyme replacement or substrate reduction therapy, and enable genetic counselling and screening of at-risk relatives.