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Unusual Clinical Manifestations in a Mexican Patient with Sanfilippo B Syndrome.

ABSTRACT: We present an unusual Mexican patient affected with mucopolysaccharidosis type IIIB (MPS IIIB; also called Sanfilippo B syndrome, MIM #252920) bearing clinical features that have not previously been described for MPS IIIB (growth arrest, hypogonadotropic hypogonadism, and congenital heart disease). Chromosomal microarray analysis was useful in identifying runs of homozygosity at 17q11.1-q21.33 and supporting the diagnosis of an underlying autosomal recessive condition. Sanger sequencing of NAGLU (17q21.2, MIM*609701) allowed us to identify a pathogenic homozygous p.(Arg234Cys) genotype. This NAGLU allele could be related to that previously described in an Iberian MPS IIIB founder haplotype; results from the polymorphic marker D17S800 and rs2071046 led us to hypothesize that it may have been introduced to Mexico through the Spanish settlement. The analysis of a clinical exome sequencing ruled out other monogenic etiologies for the previously undescribed clinical MPS IIIB manifestations. Our findings contribute to further delineating the MPS IIIB phenotype and suggest possible phenotype-genotype correlations.

SUBMITTER: Fernandez-Hernandez L

PROVIDER: S-EPMC9140210 | biostudies-literature | 2022 May

REPOSITORIES: biostudies-literature

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Unusual Clinical Manifestations in a Mexican Patient with Sanfilippo B Syndrome.

Fernández-Hernández Liliana L Reyna-Fabián Miriam Erandi ME Alcántara-Ortigoza Miguel Angel MA Aláez-Verson Carmen C Flores-Lagunes Luis L LL Carrillo-Sánchez Karol K González-Del Angel Ariadna A

Diagnostics (Basel, Switzerland) 20220519 5

We present an unusual Mexican patient affected with mucopolysaccharidosis type IIIB (MPS IIIB; also called Sanfilippo B syndrome, MIM #252920) bearing clinical features that have not previously been described for MPS IIIB (growth arrest, hypogonadotropic hypogonadism, and congenital heart disease). Chromosomal microarray analysis was useful in identifying runs of homozygosity at 17q11.1-q21.33 and supporting the diagnosis of an underlying autosomal recessive condition. Sanger sequencing of <i>NA ...[more]

PMID: 35626423

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Project description:ObjectivesSanfilippo syndrome is a rare multisystem disease with no approved treatments. This study explores caregiver perspectives on the most impactful symptoms and patient-relevant clinical outcomes assessments. The pediatric onset and progressive neurodegenerative nature of Sanfilippo limits use of self-report in clinical research. This study obtains Sanfilippo caregiver data to support the selection of fit-for-purpose and patient-relevant clinical outcome assessments (COAs).MethodsWe conducted an asynchronous online focus group (n = 11) followed by individual interviews with caregivers (n = 19) of children with Sanfilippo syndrome. All participants reported on the impact of disease symptoms and level of unmet treatment need across Sanfilippo symptom domains. Focus group participants reviewed existing assessments relating to 8 symptom domains (15 total assessments) and provided feedback on meaningfulness and relevance. Focus group data were used to reduce the number of assessments included in subsequent interviews to 8 COAs across 7 symptom domains: communication, eating, sleep, mobility, pain, behavior and adapting. Interview respondents provided data on meaningfulness and relevance of assessments. Data were coded using an item-tracking matrix. Data summaries were analyzed by caregivers' responses regarding meaningfulness; relevance to Sanfilippo syndrome; and based on caregiver indication of missing or problematic subdomains and items.ResultsParticipants' children were 2-24 years in age and varied in disease progression. Caregivers reported communication and mobility as highly impactful domains with unmet treatment needs, followed closely by pain and sleep. Domains such as eating, adaptive skills, and behaviors were identified as impactful but with relatively less priority, by comparison. Participants endorsed the relevance of clinical outcome assessments associated with communication, eating, sleep, and pain, and identified them as highly favorable for use in a clinical trial. Participants specified some refinements in existing assessments to best reflect Sanfilippo symptoms and disease course.DiscussionThe identification of impactful symptoms to treat and relevant and meaningful clinical outcome assessments supports patient-focused drug development. Our results inform targets for drug development and the selection of primary and secondary outcome assessments with high meaningfulness and face validity to Sanfilippo syndrome caregivers. Assessments identified as less optimal might be refined, replaced, or remain if the clinical trial necessitates.

Project description:BackgroundMucopolysaccharidosis type III (MPS III), or Sanfilippo syndrome, is caused by a deficiency in one of the four enzymes involved in the lysosomal degradation of heparan sulphate. Four MPS III types have been recognized, characterized by a large phenotypic heterogeneity. This is the first Spanish study describing the natural history of Sanfilippo patients (MPSIIIA, MPSIIIB and MPSIIIC), representing an essential step for understanding patient prognosis and for the establishment and application of future therapies.MethodsThis retrospective study aimed to establish the natural history of MPS III in Spain based on an extensive chronological data survey involving physicians and parents of 55 Spanish MPSIII patients. In addition to clinical description we report biochemical and molecular analysis already performed in the majority of cases.ResultsThe most frequent subtype was MPS IIIA (62%). Symptoms before diagnosis were speech delay in 85%, followed by coarse facial features in 78%, and hyperactivity in 65% of cases at a mean age of 3 years old. The median age at clinical and biochemical diagnosis for each MPS III subtype were as follows: IIIA 4.4 years (1.2 - 16 years), IIIB 3.1 years (1-29 years), and IIIC 6.3 years (3.4-22 years).45% of patients developed epilepsy at a median age of 8.7 (2.5 - 37) years old.Age of death for MPS IIIA patients was 15 years (11.5 - 26 years).Molecular analysis of our cohort reveals, as alluded to above, a great allelic heterogeneity in the three subtypes without clear genotype-phenotype correlations in most cases.ConclusionMPS IIIA is the most frequent subtype in Spanish Sanfilippo patients. Diagnosing physicians should consider Sanfilippo syndrome in children with non-specific speech delay, behavioural abnormalities, and/or mild dysmorphic features. We stress the importance of establishing early diagnosis procedures as soon as possible so as to be able to determine future short-term enzymatic or gene therapy treatments that can change the prognosis of the disease.

Dataset Information

Unusual Clinical Manifestations in a Mexican Patient with Sanfilippo B Syndrome.

Publications

Unusual Clinical Manifestations in a Mexican Patient with Sanfilippo B Syndrome.

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