Clinical presentation and outcome in infantile Sandhoff disease: a case series of 25 patients from Iranian neurometabolic bioregistry with five novel mutations

Lysosomal storage disorders (LSDs) are a specific group of inborn errors of metabolism including more than fifthy different diseases caused by a structural defect or deficiency of lysosomal enzymes [1]. GM2 gangliosidosis is one group of LSDs that is classified into three types: Sandhoff (0 variant), Tay-Sachs (B variant) and GM2 activator deficiency (GM2A-AB variant). Mutations in HEXA, HEXB and GM2A genes that are inherited by autosomal recessive pattern lead to defective β-Hexosaminidase activity and accumulation of GM2 ganglioside in the intracellular organelles of visceral and neural cells [2]. Sandhoff disease (SD, OMIM 26880) due to a deficiency of β-Hexosaminidase activity (A and B units) was first described by Warren Tay in 1881 [3, 4]. The clinical manifestations of Tay-Sachs (OMIM 606869) and Sandhoff disease are the same and have been classified clinically into three forms of infantile, juvenile and adult. The clinical severity and age at disease onset are related to residual enzyme activity. Infantile SD presents with truncal hypotonia, muscle weakness, hyperacusis, developmental delay and regression, seizure and cherry red spots in ophthalmologic exam around 6 months of age. Hepatosplenomegaly, coarse facies and bone abnormality are less seen than Tay-Sachs disease. Death occurs by 3 years of age due to intractable seizure and aspiration pneumonia. The juvenile form of SD present between 2 and 10 years of age with dysarthria, ataxia, mental deterioration and seizures. Organomegaly and cherry red spots are uncommon. Adult form of SD is characterized by movement disorder, pyramidal and extra pyramidal signs and symptoms of lower motor neuron disease and supraneuclear ophtalmoplegia [2]. Molecular analysis and enzyme activity assessment are necessary to confirm the diagnosis of SD. There is no specific treatment for GM2 gangliosidosis but chaperone therapy with ketogenic diet and miglustat has been able to increase the cardiac function and reduce the frequency of seizures [3]. Due to the broad spectrum of clinical signs and symptoms of the disease and variety of mutations in the HEXB among the different races, herein we report the spectrum of clinical manifestations, clinical course and outcome of 25 cases of infantile SD presenting five novel mutations.

We stablished a bioregistry system in our hospital Children’s Medical Center hospital, Tehran, Iran in 2010. During 7 years clinical and laboratory data of more than 270 patients with different types of neurometabolic disorders has been registered. Twenty five enzymatically and genetically proven cases of SD were extracted from the Iranian Neurometabolic Registry (INMR) from December 2010 to December 2017. Early diagnosis was carried out according to clinical manifestations, physical and neurologic examinations, neuro-imaging findings followed by assessment of hexosaminidase enzyme activity in peripheral blood leukocyte. The diagnosis of SD was confirmed by molecular study in some patients. All parents entered the study with informed consent (Fig. 1).

SD constitutes 7% of GM2 gangliosidosis with an incidence of 1 in 384,000 live births that is associated with decrease of β-hexosaminidase activity [1]. In this study, we reviewed the most common presenting symptoms, clinical course and outcome of 25 cases of infantile-onset Sandhoff disease. Although the clinical features of infantile SD are non-specific in most patients, our experience showed motor and cognitive milestones delay and regression as the most common and the earliest features of the disease [2, 8]. The mean age at presentation in our cases of 6.4 months and a delay of diagnosis of 7.8 months were similar to other reports [2, 9]. As we previously mentioned clinical symptoms of the infantile SD, organomegaly was detected in only 2 patients over the time and follow-up of the patients for at least 1 year, so, unlike other GM2 gangliosidosis the lack of organomegaly could not preclude the presence of infantile SD [8, 10, 11]. Cherry-red spots are a characteristic ocular and physical sign of the infantile SD and can be used for early detection of suspected patients to this disease [2, 8]. In present study as other reports association between diffuse Mongolian spots with some lysosomal storage diseases and SD has been showed that may be a clue for diagnosis of lysosomal storage disorders including infantile SD [12, 13]. Accumulation of calcium associated with collection of GM2 ganglioside leads to gliosis and loss of myelin and axon in the cortical neurons. These evolutions give rise some earliest findings on T2-weighted images of brain MRI including bilateral thalamic hypotensity and hypomylination that are characteristic of brain involvement in the infantile SD disease which also were detected in our patients [14, 15]. SD is caused by mutation in HEXB gene is about 40 kb in length and located on 5q13 with 14 exons [6]. So far, 51 mutations have been identified in HEXB, the most of which are missense/nonsense (the human gene mutation database). Although there is no correlation between genotype and phenotype in SD but knowledge about mutations will facilitate genetic counseling and prenatal diagnosis in affected families [16]. Genetic study is important to make definitive diagnosis and to help family planning and prenatal diagnosis in the affected families. The presence of various and novel mutations in our patients may indicate heterogeneity in mutations in infantile SD among the Iranian population [17, 18]. We expect these mutations lead to partial or complete loss of protein, because the activity of HEXB enzyme were lesser than normal.

Infantile SD should be considered for each child presented with neurologic regression especially during the first of life and presence of cherry red spots in ophthalmic examination. Absence of organomegaly cannot rule out the disease. Molecular analysis is important for definitive and prenatal diagnosis.