Atypical Symptoms Delay Sanfilippo Type B Diagnosis in Mexican Youth
Lack of access to enzymatic activity assays also hampered diagnosis
The case of a Mexican youth with Sanfilippo syndrome type B who presented with atypical symptoms of the disease, including growth arrest, sex hormone deficiencies, and a heart defect has been reported by researchers.
These previously undescribed manifestations, along with lack of access in Mexico to enzymatic confirmatory tests for Sanfilippo type B, contributed to a delayed diagnosis, which genetic testing ultimately confirmed.
Further genetic analyses failed to identify a single-gene cause for the symptoms, underscoring the need for further studies to clarify whether they were caused by Sanfilippo type B or were a result of multiple, unrelated genetic variants.
The case study, “Unusual Clinical Manifestations in a Mexican Patient with Sanfilippo B Syndrome,” was published in Diagnostics.
Mucopolysaccharidoses (MPS) comprise a group of inherited lysosomal storage diseases caused by the toxic accumulation of complex sugar molecules inside lysosomes due to deficiencies in the enzymes that break them down. Lysosomes are cells’ recycling centers.
Also known as MPS type III, Sanfilippo is caused by the absence or reduced activity of one of four enzymes involved in breaking down heparan sulfate, whose accumulation leads to progressive and severe neurodegeneration.
Sanfilippo type B is the result of low or no activity of the alpha-N-acetylglucosaminidase (NAGLU) enzyme due to mutations in the NAGLU gene. More than 150 disease-causing NAGLU mutations have been reported to date.
Its diagnosis is typically based on analyzing NAGLU enzymatic activity in cell samples from blood or skin and is confirmed with genetic testing.
Children with this type commonly show developmental delays in the first years of life, followed by behavioral problems, sleep disturbances, and seizures. They also have a mildly enlarged liver and spleen, “a normal or slightly below average height and mild musculoskeletal abnormalities,” the researchers wrote. At later stages, they usually lose their mobility and, in some cases, may develop heart abnormalities.
Researchers in Mexico described the case of a youth, 21, with Sanfilippo type B who showed arrested growth, sex hormone deficiencies, and a congenital heart defect — none of which had been reported previously.
The youth was born of healthy and endogamic parents of a small community in Mexico. Endogamy refers to marriage within a specific social group, religious denomination, caste, or ethnic group. He had three healthy younger siblings.
He was referred to the hospital at age 9 due to delayed speech and language development and the loss of some acquired skills after showing normal development up to age 4. His weight, and especially his height, were below the median for his age. He also had a smaller head and exhibited coarse facial features, a droopy left eyelid, and limited range of motion in both elbows.
Further imaging tests showed no evidence of enlarged organs or bone problems, but a birth defect was present in one of the walls of the heart. It didn’t affect blood flow or need medical or surgical management.
The youth also had higher-than-normal urine levels of uronic acid, a sugar molecule reported to accumulate in MPS patients.
Enzyme testing specific for MPS type II (Hunter syndrome) and type IV (Morquio syndrome) came back normal.
“Unfortunately, the enzymatic activity assays needed to confirm a MPS IIIA or MPS IIIB diagnosis were not available in our country,” the researchers wrote.
At age 10, his growth stopped completely, despite having normal levels of growth hormone. Four years later, he started having seizures and showed no signs of puberty, with lab tests showing deficient levels of sex hormones. Metabolic testing was normal, but brain imaging showed some volume abnormalities.
A genetic test called chromosomal microarray analysis pointed to a region containing the NAGLU gene, which — combined with the youth’s clinical features and the physician’s initial suspicions — supported a Sanfilippo type B diagnosis.
Targeted analysis of the NAGLU gene revealed a previously reported disease-causing mutation (c.700C>T; p.Arg234Cys) in both copies of the gene, each inherited from each parent.
This mutation accounts for 32% of disease-causing NAGLU mutations in Spanish and Portuguese patients and the youth also carried other NAGLU variants detected in these cases.
This and because his parents were from a small, endogamic community suggested this mutational profile of the NAGLU gene “may have been introduced to Mexico through the Spanish settlement,” the researchers wrote.
Additional tests looking for mutations in single genes known to be associated with growth arrest, lack of puberty, and congenital heart disease came back negative, meaning the cause of these atypical symptoms remains unclear. Mutations in several genes may be behind them and the heart defect may be a coincidence, the researchers noted.
The diagnostic delay “was attributed to the patient’s atypical clinical manifestations and lack of access to enzymatic and molecular MPS IIIB confirmatory analyses in Mexico,” the researchers wrote. The findings contribute to further delineating Sanfilippo type B’s clinical profile and suggest some associations between genetics and a clinical profile.
About the Author
