Multigene panel next generation sequencing in a patient with cherry red macular spot: Identification of two novel mutations in NEU1 gene causing sialidosis type I associated with mild to unspecific biochemical and enzymatic findings

Ulrike Mütze; Friederike Bürger; Jessica Hoffmann; Helmut Tegetmeyer; Jens Heichel; Petra Nickel; Johannes R Lemke; Steffen Syrbe; Skadi Beblo

doi:10.1016/j.ymgmr.2016.11.004

Multigene panel next generation sequencing in a patient with cherry red macular spot: Identification of two novel mutations in NEU1 gene causing sialidosis type I associated with mild to unspecific biochemical and enzymatic findings

Mol Genet Metab Rep. 2016 Dec 1:10:1-4. doi: 10.1016/j.ymgmr.2016.11.004. eCollection 2017 Mar.

Authors

Ulrike Mütze¹, Friederike Bürger², Jessica Hoffmann³, Helmut Tegetmeyer⁴, Jens Heichel⁵, Petra Nickel⁶, Johannes R Lemke⁷, Steffen Syrbe¹, Skadi Beblo⁶

Affiliations

¹ Department of General Pediatrics, Division of Neuropediatrics and Inherited Metabolic Diseases, University Children's Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany; Hospital for Children and Adolescents, Centre for Pediatric Research Leipzig (CPL), Department of Women and Child Health, University Hospitals, University of Leipzig, Liebigstraße 20 a, 04103 Leipzig, Germany.
² Center for Pediatric Metabolic Medicine, Department of General Pediatrics, University Children's Hospital Heidelberg, Im Neuenheimer Feld 669, 69120 Heidelberg, Germany.
³ Center for Human Genetics, Paul-Ehrlich-Straße 23, Tübingen, Germany.
⁴ University Eye Hospital, Department of Head and Dental Health, University Hospitals, University of Leipzig, Liebigstr. 10-14, 04103 Leipzig, Germany.
⁵ Department of Ophthalmology, University Hospital of Martin Luther University Halle-Wittenberg, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany.
⁶ Hospital for Children and Adolescents, Centre for Pediatric Research Leipzig (CPL), Department of Women and Child Health, University Hospitals, University of Leipzig, Liebigstraße 20 a, 04103 Leipzig, Germany.
⁷ Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.

Abstract

Background: Lysosomal storage diseases (LSD) often manifest with cherry red macular spots. Diagnosis is based on clinical features and specific biochemical and enzymatic patterns. In uncertain cases, genetic testing with next generation sequencing can establish a diagnosis, especially in milder or atypical phenotypes. We report on the diagnostic work-up in a boy with sialidosis type I, presenting initially with marked cherry red macular spots but non-specific urinary oligosaccharide patterns and unusually mild excretion of bound sialic acid.

Methods: Biochemical, enzymatic and genetic tests were performed in the patient. The clinical and electrophysiological data was reviewed and a genotype-phenotype analysis was performed. In addition a systematic literature review was carried out.

Case report and results: Cherry red macular spots were first noted at 6 years of age after routine screening myopia. Physical examination, psychometric testing, laboratory investigations as well as cerebral MRI were unremarkable at 9 years of age. So far no clinical myoclonic seizures occurred, but EEG displays generalized epileptic discharges and visual evoked potentials are prolonged bilaterally. Urine thin layer chromatography showed an oligosaccharide pattern compatible with different LSD including sialidosis, galactosialidosis, GM1 gangliosidosis or mucopolysaccharidosis type IV B. Urinary bound sialic acid excretion was mildly elevated in spontaneous and 24 h urine samples. In cultured fibroblasts, α-sialidase activity was markedly decreased to < 1%; however, bound and free sialic acid were within normal range. Diagnosis was eventually established by multigene panel next generation sequencing of genes associated to LSD, identifying two novel, compound heterozygous variants in NEU1 gene (c.699C > A, p.S233R in exon 4 and c.803A > G; p.Y268C in Exon 5 in NEU1 transcript NM_000434.3), leading to amino acid changes predicted to impair protein function.

Discussion: Sialidosis should be suspected in patients with cherry red macular spots, even with non-significant urinary sialic acid excretion. Multigene panel next generation sequencing can establish a definite diagnosis, allowing for counseling of the patient and family.

Keywords: DNA, deoxyribonucleic acid; EEG, electroencephalography; Lysosomal storage disease; Multigene panel next generation sequencing; NEU1 gene; Sialidosis; c.699C > A (p.S233R); c.803A > G (p.Y268C).