Lysosomal storage diseases are a group of inherited metabolic disorders that occur as a consequence of a deficiency in a single key enzyme required for either lipid, glycoprotein or mucopolysaccharide metabolism, affecting several organs. The key symptoms of lysosomal storage disease include developmental delays, movement disorders, seizures and/or even dementia, deafness or blindness. Some patients have hepatomegaly or splenomegaly as well as pulmonary or cardiac problems or bones that grow abnormally. The severity and type of symptoms depend on the precise enzyme that is deficient.
Dr. Kiran Kartheek Veeranki, a leading paediatrician practising at Sravani Hospital at Guntur in Andhra Pradesh, was presented with five-year-old Ravi (name changed), who was showing behaviour abnormalities and delayed milestones. The boy’s gross motor skills were limited to walking and climbing stairs and his fine motor skills limited to drawing straight lines. He was also delayed in speech and continued to have stranger anxiety. His parents also complained of loose stools and abdominal distention since the child was one year old. On examination, Dr. Kiran observed that the child had coarse facies, short stature, and hepatomegaly. Based on these clinical observations, he suspected the child to have a lysosomal storage disorder. Several primary tests were performed to rule out liver problems and infections. Liver function tests like total bilirubin, aspartate aminotransferase and alanine aminotransferase were normal, as were blood counts and stool culture. To confirm the diagnosis and identify the type of lysosomal storage disease, the child’s blood sample was sent for genetic testing. Genetic testing is critical in confirming the diagnosis, which, in turn, dictates the treatment regimen. The results showed that the patient had a mutation in the NAGLU gene, which causes mucopolysaccharidosis type IIIB, also known as Sanfilippo syndrome B.
Sanfilippo syndrome B is a type of rare, autosomal recessive lysosomal storage disease caused due to a deficiency in enzymes required to metabolise glycosaminoglycan heparan sulfate. Glycosaminoglycans are unbranched polysaccharides that are attached to proteoglycans in the extracellular matrix and the cell membrane. Several enzymes are important for metabolism of glycosaminoglycan heparan sulfate – heparin N-sulfatase, N-acetyl-alpha-D-glucosaminidase, acetyl-CoA:alpha-glucosaminide N-acetyltransferase, and N-acetylglucosamine-6-sulfatase. The NAGLU gene encodes alpha-N-acetylglucosaminidase, which is required for breaking the glycosaminoglycans. A deficiency in this enzyme results in an accumulation of glycosaminoglycan molecules, which produces progressive cellular damage and multisystemic disease.
Clinically, children are initially symptom-free, and usually present with a slowing of development as seen for Ravi. Sanfilippo syndrome is a progressive disorder, presenting first with mild developmental and behavioural problems and a progressive intellectual decline followed by increasing behavioural disturbances, hyperactivity and destructiveness. It is easily misdiagnosed as attention-deficit/hyperactivity disorder and/or autism spectrum disorders. Doctors must take a step back and view the entire presentation in case of a progressive decline in behavioural and cognitive function associated with skeletal abnormalities. These symptoms may later progress to seizures and/or dementia.
Currently, there is no cure for this disease. Bone marrow transplantation has been shown to be beneficial if the diagnosis is made early on but does not prevent neurological deterioration. Intravenous injections of a recombinant enzyme can be administered; however, the enzyme is unable to cross the blood-brain barrier and consequently cannot treat the neurological manifestations. Substrate reduction therapy using small molecules that can inhibit glycosaminoglycan synthesis is a potential therapy option that is being explored, having shown promising results in animal studies and in preliminary human studies. Gene therapy is another promising option; clinical trials are currently in progress and may offer a suitable treatment option in the near future.
Ideally, patients’ families should be screened for carrier status and pre-natal testing should be counselled in case the parents are planning another child. However, in this case, the family was unable to afford genetic testing and Dr. Kiran had to convince them that it was absolutely necessary at least for Ravi.
Unfortunately for Ravi, there is no current treatment other than supportive care and conservative management. He was given loperamide to decrease bowel movement along with zinc supplements for recovering epithelial damage caused due to diarrhea. This treatment has not resolved Ravi’s symptoms. In spite of this, Ravi’s parents are happy that their son’s condition has been accurately diagnosed and they are mentally prepared for what awaits Ravi in the future.