Clinical presentation of 13 children with alkaptonuria.

Until now, only a few studies have focused on the early onset of symptoms of alkaptonuria (AKU) in the pediatric population. This prospective, longitudinal study is a comprehensive approach to the assessment of children with recognized AKU during childhood. The study includes data from 32 visits of 13 patients (five males, eight females; age 4-17 years) with AKU. A clinical evaluation was performed with particular attention to eye, ear, and skin pigmentation, musculoskeletal complaints, magnetic resonance imaging (MRI), and ultrasound (US) imaging abnormalities. The cognitive functioning and adaptive abilities were examined. Molecular genetic analyses were performed. The most common symptoms observed were dark urine (13/13), followed by joint pain (6/13), and dark ear wax (6/13). In 4 of 13 patients the values obtained in the KOOS-child questionnaire were below the reference values. MRI and US did not show degenerative changes in knee cartilages. One child had nephrolithiasis. Almost half of the children with AKU (5/13) presented deficits in cognitive functioning and/or adaptive abilities. The most frequent HGD variants observed in the patients were c.481G>A (p.Gly161Arg) mutation and the c.240A>T (p.His80Gln) polymorphism. The newly described allele of the HGD gene (c.948G>T, p.Val316Phe) which is potentially pathogenic was identified.

Next-generation sequencing testing in children with epilepsy reveals novel clinical, diagnostic and therapeutic implications.

Introduction: Epilepsy is one of the commonest diseases in children, characterized by extensive phenotypic and genetic heterogeneity. This study was conducted to determine the diagnostic utility and to identify novel clinical and therapeutic implications of genetic testing in pediatric patients with epilepsy. Methods: Large multigene panel and/or exome sequencing was performed in 127 unrelated Polish and Ukrainian patients with suspected monogenic epilepsy. Diagnostic yields were presented for five phenotypic subgroups, distinguished by seizure type, electroencephalographic abnormalities, anti-seizure treatment response, and neurodevelopmental deficits. Results: A definite molecular diagnosis was established in 46 out of 127 cases (36%). Alterations in six genes were detected in more than one patient: SCN1A, MECP2, KCNT1, KCNA2, PCDH19, SLC6A1, STXBP1, and TPP1, accounting for 48% of positive cases. 4/46 cases (8.7%) were mosaic for the variant. Although the highest rates of positive diagnoses were identified in children with developmental delay and generalized seizures (17/41, 41%) and in developmental end epileptic encephalopathies (16/40, 40%), a monogenic etiology was also frequently detected in patients with solely focal seizures (10/28, 36%). Molecular diagnosis directly influenced anti-seizure management in 15/46 cases. Conclusion: This study demonstrates the high diagnostic and therapeutic utility of large panel testing in childhood epilepsies irrespective of seizure types. Copy number variations and somatic mosaic variants are important disease-causing factors, pointing the need for comprehensive genetic testing in all unexplained cases. Pleiotropy is a common phenomenon contributing to the growing phenotypic complexity of single-gene epilepsies.

Highly diverse phenotypes of mucopolysaccharidosis type IIIB sibling patients: effects of an additional mutation in the AUTS2 gene.

Mucopolysaccharidosis type IIIB (MPS IIIB or Sanfilippo syndrome type B) is an inherited metabolic disease caused by mutations in the NAGLU gene, encoding α-N-acetylglucosaminidase. Accumulation of undegraded heparan sulfate (one of glycosaminoglycans) arises from deficiency in this enzyme and leads to severe symptoms, especially related to dysfunctions of the central nervous system. Here, we describe a case of two siblings with highly diverse phenotypes, despite carrying the same mutations (c.1189 T > G/c.1211G > A (p.Phe397Val/p.Trp404Ter)) and similar residual activities of α-N-acetylglucosaminidase; the younger patient reveals more severe phenotype; thus, these differences cannot be explained by the age and progression of the disease. Surprisingly, the whole exome sequencing analysis indicated the presence of an additional mutation in one allele of the AUTS2 gene (c.157G > A (p.Ala53Thr)) in the younger patient but not in the older one. Since mutations in this gene are usually dominant and cause delayed development and intellectual disability, it is likely that the observed differences between the MPS IIIB siblings are due to the potentially pathogenic AUTS2 variant, present in one of them. This case confirms also that simultaneous occurrence of two ultra-rare diseases in one patient is actual, despite a low probability of such a combination. Moreover, it is worth noting that apart from the genotype-phenotype correlation and the importance of the residual activity of the deficient enzyme, efficiency of glycosaminoglycan synthesis and global secondary changes in expression of hundreds of genes may considerably modulate the course and severity of MPS, especially Sanfilippo disease.

Untypically mild phenotype of a patient suffering from Sanfilippo syndrome B with the c.638C>T/c.889C>T (p.Pro213Leu/p.Arg297Ter) mutations in the NAGLU gene.

BACKGROUND: Sanfilippo syndrome B (or mucopolysaccharidosis type IIIB [MPS IIIB]) is a severe inherited metabolic disorder caused by mutations in the NAGLU gene, encoding α-N-acetylglucosaminidase. Dysfunction of this enzyme results in impaired degradation of heparan sulfate, one of glycosaminoglycans, and accumulation of this complex carbohydrate in lysosomes. Severe symptoms occurring in this disease are related to progressive neurodegeneration and include extreme hyperactivity, sleeping problems, aggressive-like behavior, reduced fear, and progressive mental and cognitive deterioration. No cure is currently available for Sanfilippo disease. METHODS: Clinical characterization of the patient's symptoms has been performed. Biochemical analyses included glycosaminoglycan level determination and measurement of α-N-acetylglucosaminidase activity. Molecular analyses included exome sequencing and detailed analysis of the NAGLU gene. Psychological tests included assessment of attention, communication and behavior. RESULTS: We describe a patient with an untypically mild phenotype, who was diagnosed at the age of 13 years. Many cognitive, communication, and motoric functions were preserved in this patient, contrary to vast majority of those suffering from MPS IIIB. The patient is a compound heterozygote (c.638C>T/c.889C>T) in the NAGLU gene, and relatively high residual activity (about 25%) of α-N-acetylglucosaminidase was measured in serum (while no activity of this enzyme could be detected in dry blood spot). CONCLUSIONS: We suggest that the mild phenotype might arise from the partially preserved function of the mutant enzyme (p.Pro213Leu), suggesting the genotype-phenotype correlation in this case.