Man Faced Delay of Nearly 3 Decades for Sanfilippo Type A Diagnosis

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by Marta Figueiredo, PhD |

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Complications shortly after birth and a slow disease progression — combined with poor disease awareness — delayed a correct diagnosis of Sanfilippo syndrome type A for more than two decades in a 28-year-old man in Germany, a study says.

While this type is associated with a faster progression, the man was found to carry a mix of severe and milder disease-causing mutations that was previously linked to milder forms of the disease.

This case report points out some of the factors that may delay even further the diagnosis of this rare disease with non-specific neuropsychiatric symptoms, and highlights the need for greater awareness among physicians for metabolic diseases such as Sanfilippo.

The case study, “A case report of Sanfilippo syndrome – the long way to diagnosis,” was published in the journal BMC Neurology.

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Sanfilippo type A, also known as mucopolysaccharidosis type IIIA (MPS IIIA), is the most common and severe form of Sanfilippo syndrome, typically characterized by an earlier symptom onset, faster progression, and shorter life expectancy.

It is caused by the absence or reduced activity of heparan N-sulfatase — an enzyme involved in the breakdown of a complex sugar molecule called heparan sulfate — due to mutations in both copies of the SGSH gene.

Heparan N-sulfatase deficiency leads to the molecule’s toxic accumulation inside cells, which is particularly damaging for nerve cells, which die as a consequence.

People with Sanfilippo type A usually show “early nonspecific neuropsychiatric symptoms, followed by progressive neurocognitive impairment in combination with only mild [physical] features,” the researchers wrote.

While these non-specific and non-obvious disease features already challenge timely diagnosis of Sanfilippo type A, some SGSH mutations have been associated with slower disease progression, which may prolong even more a patient’s journey to a correct diagnosis.

Now, a team of researchers at the University Hospital of Wuerzburg and its Center for Rare Diseases, in Germany, described the case of a man with a slowly progressive form of Sanfilippo type A that was correctly diagnosed when he was 28 years of age.

The patient’s parents contacted the center to obtain a diagnosis for the severe progressive developmental regression that their son experienced. He was the couple’s first child, and had two healthy siblings.

He was delivered through an emergency c-section at 41 weeks of gestation due to presence of his stool within the womb, which may cause distress and affect breathing. He had to be ventilated for one day and treated for sudden acute kidney failure, whose cause remains unknown.

While motor development was normal in the first year, fine motor skills, or movements using the small muscles of the hands and wrists, were always impaired. Mental and speech development was delayed and he was diagnosed with global developmental delay at age 2.

One year later, lab tests showed normal results for molecules associated with some metabolic diseases, but there was no evidence that the urinary levels of heparan or other glycosaminoglycans — a common diagnostic test for Sanfilippo — were evaluated.

Regression of motor skills, speech, and cognitive abilities started after the age of 12 years, when he was able to walk or ride a bike unaided. Psychiatric evaluation at 14 showed behavioral abnormalities, restlessness, excessive involuntary movements, repetitive movements or sounds, and mental retardation.

He lost the ability to walk independently at 16 and to speak at 18, and severe hearing and visual impairment was reported since he was 24. At 28, when he admitted to the center, he was “fully dependent on assistance for all activities of daily living,” the researchers wrote.

An examination found no distinct facial features, and brain magnetic resonance imaging scans revealed pronounced brain shrinkage.

Genetic testing of blood samples from the man and his parents showed the patient carried two SGSH mutations — p.R245H and p.S298P — one from each parent. Both mutations were previously reported to be disease-causative, confirming a diagnosis of Sanfilippo type A.

The p.R245H mutation, the most common disease-causing mutation within the SGSH gene in northern Europe, leads to a nearly complete loss of heparan N-sulfatase activity and when present in both copies of the gene is associated with rapid and severe disease progression.

In turn, the p.S298P mutation has been linked to “a milder course of the disease,” the team wrote, adding that the presence of both variants (one in each gene copy) has been previously associated with a mild clinical course similar to that of their patient.

“Diagnosis of patients with a slowly progressive course of the disease was on average [five years] later than in patients with rapid progression,” they added.

“The history of complications during delivery and in early [infant] life may have contributed to the delayed recognition of MPS IIIa in our patient,” as “developmental delay was initially seen as a consequence of [oxygen deficiency immediately before and after birth],” the researchers wrote.

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They also noted that children with slowly progressing Sanfilippo may have less contact with specialized pediatricians, which may reduce their chances to be seen by one highly familiarized with the broad field of metabolic diseases that include Sanfilippo.

In adulthood, when regression of previously acquired skills is more obvious, “diagnostic delay may thus be due to a limited awareness of metabolic disorder spectrum in adult patients,” the team wrote.

Sanfilippo “is a diagnostic challenge, particularly in the early stages and in patients with an attenuated course of the disease, due to a variable course, nonspecific early neuropsychiatric symptoms and the lack of obvious [bodily/physical] features,” the researchers wrote.

“The possibility of a metabolic disorder should be kept in mind in young children with developmental and/or speech delay in combination with behavioral abnormalities and/or sleeping difficulties and in adults, especially when pre-existing health conditions may obscure the clinical picture,” they added.