Neuronopathic Gaucher diseaseE75.2

Gaucher disease is caused by the lack of activity of a lysosomal enzyme, beta-glucocerebrosidase (also called glucosylceramidase or acid beta-glucosidase).

Type 2 Gaucher disease is a rare, autosomal recessive neurologically accentuated form of the disease and accounts for only 1% of all cases. Symptoms usually begin in infancy, during the first 3 to 6 months of life, with hepatosplenomegaly and a severe neurologic syndrome. The first signs of the disease are oculomotor paralysis or bilateral fixed strabismus, bulbar signs, especially in the form of dysphagia, and progressive spasticity and dystonic movements. Later, cerebral convulsions occur in the form of myoclonic epilepsy that does not respond to anticonvulsants.

Prevalence: <1 / 1 000 000

The cause is mutations in the GBA gene in chromosomal region 1q21.

Tsuji et al (1987) identified a homozygous mutation in the GBA gene (L444P; 606463.0001) in patients with Gaucher type II disease.

Grace et al (1990) used site-directed mutagenesis and characterization of the expressed beta-glucosidase mutant to understand the molecular basis of phenotypic differences between type II and type III Gaucher disease. The results suggest that the presence of at least one nonfunctional GBA allele in type II patients may provide a molecular basis for the different phenotypes of types II and III.

Infancy

Although patients with Gaucher disease type II typically have acute neurologic progression and patients with type III have slow progression, Goker-Alpan et al. (2003) described nine children with an intermediate phenotype characterized by delayed age of onset, rapid progression of neurologic disease with refractory seizures, and oculomotor abnormalities.

Filocamo et al (2005) reported a 25-month-old girl with an atypical form of neuronopathic Gaucher disease between types II and III caused by a homozygous double mutation in the GBA gene (606463.0047). The first symptoms appeared at 5 months of age with hepatosplenomegaly. A few months later, she developed neurologic features, including spasticity with persistent retroflexion of the neck, convergent strabismus, oculomotor apraxia, and abnormal MRI changes. At 25 months of age, she showed slow progression of symptoms and was able to sit alone, walk with assistance, and pronounce some words.

In a clinical review of Gaucher disease, Daykin et al (2021) noted that GD2 in the neonatal period may be associated with congenital ichthyosis, hepatosplenomegaly, biliary atresia, facial dysmorphology, arthrogryposis, congenital thrombocytopenia, and/or growth abnormalities.

Note: Ichthyosis may result from increased glucosylceramide concentration in the stratum corneum, leading to an abnormal histologic appearance of the skin on microscopic examination.

Diagnosis is confirmed by determination of glucocerebrosidase activity in leukocytes of peripheral blood. Prenatal testing in pregnancies after a child with Gaucher disease type 2 is performed by measuring the activity of glucocerebrosidase, either in chorionic villus sampling (10th-12th week after the last menstrual period) or in cultured amniocytes (16th week n.d.l.r.). in chromosomal region 1q21. The diagnosis is confirmed by glucocerebrosidase activity determination in leukocytes of peripheral blood. Prenatal testing in pregnancies after a child with Gaucher disease type 2 is performed by measuring the activity of glucocerebrosidase, either in chorionic villus sampling (10th-12th week after the last menstrual period) or in cultured amniocytes (16th week n.d.l.R.).

None of the neurological symptoms are amenable to therapy, and patients with type 2 Gaucher disease can only be treated symptomatically.

Prognosis is poor, with most patients dying before reaching their second birthday.

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