Child Neurology: Type 1 sialidosis due to a novel mutation in NEU1 gene

Abstract

A 39-year-old man of Ecuadorian descent presented with a history of seizures, visual impairment, and ataxia. He had a normal birth and early developmental history. His first seizure was a generalized tonic-clonic seizure (GTCS) at 16 years old. Around the same time, he also started experiencing 1-2 myoclonic jerks per day. The myoclonic jerks progressively worsened over a period of 20 years to 15-20 episodes per day. GTCS continued to occur 1-2 times a year until the age of 24 years. EEG revealed multiple brief myoclonic seizures and generalized slow spike/polyspike wave complexes consistent with primary generalized epilepsy. Despite valproic acid, zonisamide, and clonazepam, his seizure control remained poor. When he was 30 years old, he began to have blurring of his vision; ophthalmologic evaluation at that time revealed bilateral cherry-red spots. Optical coherence tomography showed hyperreflectivity in the superficial layers of the retina at the posterior pole consistent with abnormal storage in the ganglion cells. An electroretinogram showed normal rod and cone responses. Flash visual evoked responses demonstrated a delay in the P100 response consistent with dysfunction of the visual pathways. His medical and family history was otherwise noncontributory. Gross physical examination was within normal limits. Neurologic examination demonstrated severe myoclonus of the face interrupting his speech, frequent myoclonus of the arms, truncal and appendicular ataxia, and broad-based ataxic gait. MRI of the brain with and without gadolinium was normal. Chromosome single nucleotide polymorphism microarray revealed long contiguous regions of allele homozygosity (>10 MB) in multiple chromosomes. A query of the regions of homozygosity that was subsequently narrowed down using his clinical presentation identified NEU1 as a candidate gene. Sequencing of NEU1 revealed a homozygous missense mutation c.629C>T (p.Pro210Leu). Enzymatic testing in fibroblasts showed sialidase activity to be deficient (0 nmol/h/mg; ref: 23-74). β-Galactosidase activity was within normal limits.

Conventional and Unconventional Therapeutic Strategies for Sialidosis Type I

“…A list of the NEU1 mutations identified in these patients and their position in the primary structure of the protein are given in Figure 1A,B. For six of the patients, the mutations have been reported earlier [8,[16][17][18][19]. The remaining six patients, not described in the literature, carry novel All patients' fibroblasts expressed different levels of NEU1 mRNA, as determined by quantitative real-time PCR analysis, some even higher than wild-type (WT) levels ( Figure 1C).…”

Sialidosis type 1 without cherry-red spots: a case report and literature review

“…Studies by Kivlin et al suggest that these spots may appear early and disappear later,8 while Qun Wang et al summarise that these spots could disappear as the disease progresses or appear 20 years after onset 9. Given the presence of cherry-red spots in the fundus, type I sialidosis is also known as cherry-red spot myoclonus syndrome 3. However, Bou Ghannam AS et al reported a case where no cherry-red spots were observed in the fundus 10.…”

“…However, it is necessary to avoid drugs such as carbamazepine, phenytoin, gabapentin and vigabatrin, which can exacerbate myoclonus. Lamotrigine can be used cautiously because it can worsen myoclonus in some patients 3. Some studies have shown that dietary supplementation with betaine, a natural amino acid derivative, may benefit the treatment of type I sialic acid poisoning by serving as a histone deacetylase inhibitor, inducing a sustained increase in the residual activity of mutated NEU1 in patient primary fibroblasts 11 18…”

“…The cherry-red spot in the retina is a hallmark of sialidosis type I and was once referred to as the cherry-red spot myoclonus syndrome. 3 However, previous case reports suggest that not all patients with sialidosis type I present with a cherry-red spot. 4 This observation may carry significant clinical implications for the diagnosis and understanding of the disease, as overemphasis on the cherry-red spot could mislead clinicians and delay diagnosis.…”

“…Additionally, the symptoms of this disease can resemble those of more common conditions, potentially leading to misdiagnosis as other diseases, such as psychiatric disorders, and consequently delayed diagnosis. The cherry-red spot in the retina is a hallmark of sialidosis type I and was once referred to as the cherry-red spot myoclonus syndrome 3. However, previous case reports suggest that not all patients with sialidosis type I present with a cherry-red spot 4.…”