Perinatal Lethal Gaucher Disease: A Distinct Phenotype Along the Neuronopathic Continuum

Abstract

Gaucher disease, the inherited deficiency of glucocerebrosidase, is characterized by significant genetic and phenotypic heterogeneity. At the extreme end of the phenotypic continuum is the perinatal lethal variant, typically presenting in utero or during the neonatal period as hydrops and/orcongenital ichthyosis, with severe and progressive neurological involvement. Insights from the null-allele Gaucher mouse model contributed to the identification of this distinct phenotype, which has unique epidermal involvement. While multiple mutations are encountered, many affected infants are homozygous for recombinant alleles. The diagnosis is often missed due to the early lethality and the failure to recognize the association between lysosomal disorders and hydrops fetalis. The incidence of severe perinatal Gaucher disease may prove more common than currently appreciated with greater physician awareness of the disorder.

In utero administration of Ad5 and AAV pseudotypes to the fetal brain leads to efficient, widespread and long-term gene expression

“…Acute neuronopathic type II Gaucher disease is such an example; irreversible disease pathology is present in the patient's brain during gestation 2,19,20 and death usually occurs before 2 years of age. 21 The delivery of therapeutic genes to the brains of mouse models of such diseases during gestation could provide vital information; is in utero intervention required to prevent irreversible brain damage and whether lifespan can be enhanced?…”

A Newborn with a Blueberry Muffin Rash, Hepatosplenomegaly, Thrombocytopenia and Severe Cholestatic Jaundice at Birth

“…Anemia is associated with hydrops, but is neither profound nor frequent enough to explain it. Fetal cases are reported with skin abnormalities and a peculiar facial appearance with low-set ears, small nose with flat bridge and anteverted nares and, less frequently, hypertelorism, microstomia, eversed lips, microretrognathia and microcephaly [12]. Our case did not present with neurological signs until age 3 months when he was irritable and had difficulty swallowing.…”

“…Three clinical forms of Gaucher disease have been described: type 1, or non-neuronopathic; type 2, or acute neuronopathic; and type 3, or subacute neuronopathic [12].…”

“…Perinatal type 2 GD is a severe and uncommon variant [4,12] characterized by hepatosplenomegaly, thrombocytopenia, secondary to hypersplenism [4] and bone marrow infiltration, and anemia. In its most severe and lethal form, it can present in utero as non-immune hydrops fetalis and congenital icthyosis in the newborn [12].…”

“…In its most severe and lethal form, it can present in utero as non-immune hydrops fetalis and congenital icthyosis in the newborn [12].…”