Genetic epidemiology of NLSD, Chanarin Dorfman (NLSD-I) and Neutral Lipid Storage with Myopathy (NLSD-M). A retrospective review

Neutral Lipid Storage Disease (NLSD) refers to a group of rare, inherited metabolic disorders characterized by the defective degradation of cytoplasmic triglycerides, leading to their accumulation in various tissues. A classic finding in both disorders is Jordan’s anomaly, which consists of lipid-filled vacuoles within neutrophils and other leukocytes on a peripheral blood smear; this phenomenon frequently serves as a critical diagnostic clue.

The genetic epidemiology of NLSD is characterized by autosomal recessive transmission, a strong association with consanguinity, and two distinct genetic aetiologies corresponding to different clinical subtypes. However, this epidemiology has not yet been fully investigated.

Chanarin-Dorfman Syndrome (CDS) is inherited as an autosomal recessive disorder. It is extremely rare, with approximately 186 cases reported worldwide. The major findings of CDS are non-bolluos congenital ichthyosiform erythroderma (NCIE), hepatomegaly, and liver steatosis. CDS is most frequently described in populations from Turkey, Mediterranean countries, the Middle East, North Africa, Pakistan, and neighboring regions. A higher prevalence is consistently associated with consanguineous marriages, which increase the likelihood of inheriting two pathogenic ABHD5 gene variants.

Similarly, Neutral Lipid Storage Disease with Myopathy (NLSDM) is instead inherited as an autosomal recessive disorder, though it is considered even rarer than CDS, with only 142 cases reported globally. To date, cases of NLSDM have been reported across Europe (particularly in Italy), China, Japan, and Middle Eastern populations. Unlike CDS, many NLSDM patients present during adulthood – typically in their 20s to 40s – manifesting with progressive muscle weakness and significantly elevated serum creatine kinase (CK) levels. Furthermore, cardiomyopathy represents a major cause of morbidity in this specific cohort.