Uncovering Lysosomal Storage Diseases Beyond Newborn Screening

Jaden was a 4-year-old who presented to his PCP’s office with a persistent cough following an upper respiratory infection. Parents reported Jaden also had easy bruising, a symptom they had also noted after he had started walking. After labs revealed transaminitis, he was referred to gastroenterology. Repeat testing was notable for transaminitis along with fasting hypercholesterolemia and hypertriglyceridemia. Abdominal ultrasound showed massive splenomegaly with hepatomegaly. Given the provider’s suspicion, Jaden was referred to CHOP’s Lysosomal Storage Disease (LSD) Program to rule out Gaucher disease. Further enzymatic and genetic testing revealed the patient had acid sphingomyelinase deficiency (ASMD), another lysosomal storage disease similar to Gaucher disease.

Lysosomal storage diseases are a group of more than 70 different, rare metabolic diseases caused by genetic mutations that affect the function of the cell’s lysosomes as a result of a deficiency or absence of an enzyme. Without adequate enzymatic activity, toxic waste products build up in the cell which can adversely affect many different organ systems. Signs and symptoms can vary greatly among each LSD based on the enzyme and organs affected. Findings can include, but are not limited to, hepatosplenomegaly, thrombocytopenia, hyperlipidemia, bone pain, pain in the extremities (acroparesthesias), rash (angiokeratomas), hypotonia, joint contractures, hernias, frequent upper respiratory or ear infections, cardiac disease, intellectual disability, and developmental delay.

Difficult to diagnose

Given the rarity of these LSDs and nonspecific symptoms, they can be difficult to diagnosis, often sending patients on a long diagnostic odyssey. With the inclusion of some LSDs on the newborn screen (Gaucher, Fabry, MPS I, Pompe, Niemann-Pick, and Krabbe), it’s possible to establish a diagnosis early and monitor the patient from birth, initiating treatment as soon as signs or symptoms of disease progression appear. For older patients or those with a disease not covered by the newborn screen, it requires a keen eye and high level of suspicion to send them in the right diagnostic direction.

The Lysosomal Storage Disease Program through the Division of Human Genetics at CHOP offers both initial evaluations for individuals with a suspected diagnosis as well as comprehensive care for those with a confirmed LSD diagnosis. Through the program, patients of all ages work with physicians, APPs, genetic counselors, and others to diagnosis and manage these diseases throughout their lives.

Aside from seeing patients in the general LSD clinic, the program also offers 2 multidisciplinary clinics with Developmental Pediatrics and Physical Therapy to best provide care for patients with a MPS disease or Pompe disease. As needed, patients are referred to other subspecialists based on symptom presentation and disease monitoring. Although there is no cure for LSDs, current available treatment such as enzyme replacement therapy (ERT) is aimed at slowing disease progression. Ongoing research is directed at developing better therapeutics, including new ERT (such as that for acid sphingomyelinase deficiency) and even those targeting cures, such as gene therapy.