Neutral lipid storage disease with ichthyosis (ORPHA:98907)
A form of autosomal recessive neutral lipid storage disease characterized by the accumulation of lipid vacuoles in granulocytes (so-called Jordan's anomaly) and a variety of other cell types. Clinically, the skin symptoms with ichthyosiform erythroderma and scaling are initially in the foreground. Later, steatosis hepatis, hepatomegaly and muscle weakness develop. Other manifestations include growth delay, cataracts, sensorineural hearing loss, intellectual disability and bowel disease.
Epidemiology
The disease is very rare and the prevalence is unknown. Approximately 150 cases have been described in the literature.
Clinical description
The infants are often born with a collodion membrane and develop a pronounced generalized ichthyosiform erythroderma with mostly fine white scaling. In more than half of the cases, moderate myopathy and moderate hepatomegaly (or functional impairment of the liver) occur in adulthood. Other symptoms include intellectual deficits, eye abnormalities (cataracts, retinopathy) and hearing impairment, as well as neuropathy and short stature.
Etiology
Neutral lipid storage disease with ichthyiosis (NLSD-I) is caused by biallelic mutations in the gene ABHD5 which is located on chromosome 3p21. ABHD5 codes for an enzyme involved in the breakdown of triglycerides in the cell. The disruption of this process leads to an accumulation of lipid vacuoles in many cell types.
Diagnostic methods
A simple diagnostic method is a blood smear which reveals lipid droplets in peripheral leucocytes (Jordan's anomaly). The accumulation of lipid vacuoles can also be detected histologically, in biopsies from skin or muscle. Elevated liver and muscle enzyme levels can be detected in a blood test. The current standard procedure is next generation sequencing test of the ABDH5 gene to detect biallelic variants.
Differential diagnosis
Differential diagnoses include : congenital ichthyosiform erythroderma, other syndromic ichthyoses, neutral lipid storage disease with myopathy (mutations in ATGL/PNPLA2) and different mitochondrial diseases with accumulation of cytoplasmic triglycerides (e.g. deficiencies in carnitine, cartinine palmitoyl transferase or fatty acid oxidation enzymes).
Antenatal diagnosis
Prenatal diagnosis based on molecular genetic testing (after amniocentesis or chorionic villus sampling) is possible if the pathogenic variants in ABDH5 has previously been identified in a family member.
Genetic counseling
NLSD-I belongs to the syndromic ichthyoses spectrum and is inherited in an autosomal recessive manner. Couples at risk (both persons are carriers of a disease-causing mutation) should receive genetic counseling in which they are informed that there is a 25% risk of having an affected child with each pregnancy.
Management and treatment
A diet with high medium chain triglycerides/long chain triglycerides ratio can be beneficial. Retinoids (standard treatment for ichthyosis) should be used with caution due to the risk of liver toxicity.
Prognosis
In NLSD-I, the severity of the disease depends primarily on the severity of liver involvement and myopathy. Cases in which a liver transplant was necessary have been described. The development of the disease varies from patient to patient but is relatively slow; most patients do not have a significantly reduced life expectancy.

                            Last update: 
                            December 2023


                            - Expert reviewer(s): 
                            Pr Judith FISCHER | ERN-Skin*


                                * European Reference Network