Journal of Pediatric Ophthalmology and Strabismus

Short Subjects 

Five Year Follow-Up of Two Sisters With Type II Sialidosis: Systemic and Ophthalmic Findings Including OCT Analysis

Rémi Rosenberg, MD; Emmanuel Halimi, MD; Karine Mention-Mulliez, MD; Jean-Marie Cuisset, MD; Muriel Holder, MD; Sabine Defoort-Dhellemmes, MD

Abstract

The authors report a 5-year follow-up examination of two sisters diagnosed as having a juvenile form of type II sialidosis. Diagnosis occurred during a routine ophthalmic examination when the girls were 5 and 3 years old after bilateral macular cherry-red spots were revealed. Main clinical findings were hypotonia, hepatosplenomegaly, hearing loss, dysostosis, and respiratory distress. Ophthalmic symptoms were low visual acuity and nystagmus. Spectral-domain optical coherence tomography examination showed increased reflectivity of the retinal ganglion cells. Sialidosis may present as a mild form with slow progression. The cherry-red spots may be the first clue for proper diagnosis of storage disease. Spectral-domain optical coherence tomography examination unveiled the accumulation of sialic acid in the retinal ganglion cells and could potentially be used to monitor the progression of storage diseases. [J Pediatr Ophthalmol Strabismus 2013;50:e33–e36.]

From the Service d’Exploration Fonctionnelle de la Vision et Neuro Ophtalmologie, Hopital Roger Salengro, Lille, France (RR, EH); the Centre de Référence des Maladies Héréditaires du Métabolisme, Clinique de Pédiatrie, Hopital Jeanne de Flandre, Lille, France (KM-M, MH); Service de Neuropédiatrie, Clinique de Pédiatrie, Hopital Roger Salengro, Lille, France (J-MC); and Service d’Exploration Fonctionnelle de la Vision et Neuro Ophtalmologie, Hopital Roger Salengro, Lille, France (SD-D).

The authors have no financial or proprietary interest in the materials presented herein.

Correspondence: Rémi Rosenberg, MD, 4 Rue de Panama, 75018, Paris, France. E-mail: remi.rosenberg@gmail.com

Received: July 17, 2012
Accepted: May 02, 2013
Posted Online: July 02, 2013

Abstract

The authors report a 5-year follow-up examination of two sisters diagnosed as having a juvenile form of type II sialidosis. Diagnosis occurred during a routine ophthalmic examination when the girls were 5 and 3 years old after bilateral macular cherry-red spots were revealed. Main clinical findings were hypotonia, hepatosplenomegaly, hearing loss, dysostosis, and respiratory distress. Ophthalmic symptoms were low visual acuity and nystagmus. Spectral-domain optical coherence tomography examination showed increased reflectivity of the retinal ganglion cells. Sialidosis may present as a mild form with slow progression. The cherry-red spots may be the first clue for proper diagnosis of storage disease. Spectral-domain optical coherence tomography examination unveiled the accumulation of sialic acid in the retinal ganglion cells and could potentially be used to monitor the progression of storage diseases. [J Pediatr Ophthalmol Strabismus 2013;50:e33–e36.]

From the Service d’Exploration Fonctionnelle de la Vision et Neuro Ophtalmologie, Hopital Roger Salengro, Lille, France (RR, EH); the Centre de Référence des Maladies Héréditaires du Métabolisme, Clinique de Pédiatrie, Hopital Jeanne de Flandre, Lille, France (KM-M, MH); Service de Neuropédiatrie, Clinique de Pédiatrie, Hopital Roger Salengro, Lille, France (J-MC); and Service d’Exploration Fonctionnelle de la Vision et Neuro Ophtalmologie, Hopital Roger Salengro, Lille, France (SD-D).

The authors have no financial or proprietary interest in the materials presented herein.

Correspondence: Rémi Rosenberg, MD, 4 Rue de Panama, 75018, Paris, France. E-mail: remi.rosenberg@gmail.com

Received: July 17, 2012
Accepted: May 02, 2013
Posted Online: July 02, 2013

Introduction

Sialidosis is a rare, inherited lysosomal storage disease resulting from a deficiency of the sialidase enzyme. Two clinical variants are described according to the severity of the phenotype. Type I, also known as cherry-red spot myoclonus syndrome, is the mildest form. Type II is divided into congenital, infantile, and juvenile forms and is characterized by dysmorphic features, early onset, and shorter life expectancy.

We report a 5-year ophthalmologic and pediatric follow-up examination of two sisters diagnosed as having sialidosis after a routine examination unveiled bilateral macular cherry-red spots. Clinical findings led to classifying this diagnosis into type II infantile sialidosis.

Our objective is to report complete ophthalmic features and underline the relevance of spectral-domain optical coherence tomography (SD-OCT) examination in the diagnostic process.

Case Reports

Family History

Both parents were healthy, unrelated, and had no family history suggestive of medical problems or an inherited disorder. The parents were free from metabolic, neurological, or ophthalmic pathologies.

Case 1

The first patient, the elder of two children, was a girl born at term. Weight, height, and head circumference measurements were normal and no abnormal features were reported at birth.

We first saw her at the age of 5 years old. She had been referred by an ophthalmologist for specialized ophthalmic examination after low visual acuity and macular cherry-red spots were identified during a routine examination. In her medical history, we noted a nystagmus diagnosed 2 years earlier and not yet investigated, and ear tubes (myringotomy) for chronic otitis media. No other particular clinical events were reported.

The ophthalmic examination showed best-corrected visual acuity at 20/63 in the right eye and 20/80 in the left eye, with mild myopia. We observed a vertical downbeat nystagmus that increased on downward gaze and decreased on upward gaze. During the upward gaze, the head was bent forward in a torticollis-like position. In both eyes, peripheral evaluation of the visual field, slit-lamp examination, and visual evoked potentials were normal. The dilated fundus examination unveiled typical bilateral macular cherry-red spots (Figure ). The peripheral retina and optic nerve heads were normal. SD-OCT (Cirrus; Carl Zeiss Meditec, Inc., Dublin, CA) revealed increased reflectivity from the inner retinal layer (Figure ). These clinical findings were suggestive of a lysosomal storage disease. The child was then referred to the pediatric department for further examinations.

 
Right eye fundus examination of case 1 showing a cherry-red spot. 

Figure 1. Right eye fundus examination of case 1 showing a cherry-red spot.

 
Right eye spectral-domain optical coherence tomography of case 1 showing increased reflectivity of the inner retinal layers. 

Figure 2. Right eye spectral-domain optical coherence tomography of case 1 showing increased reflectivity of the inner retinal layers.

Pediatric examination showed normal weight (0 standard deviation [SD]), height (−1 SD), and head circumference (+1 SD), and coarse facial features. Neurological examination revealed a slight hypotonia. Orthopedic examination showed bilateral genu valgum and flat feet with a valgus deformity. There was no psychomotor delay but we noted slightly impaired executive functions. The abdominal sonogram revealed a hepatosplenomegaly. Full blood count showed 8% of vacuolated lymphocytes.

Myelography showed numerous large histiocytes with cytoplasm filled with unstained vacuoles. Urinalysis showed a high rate of sialylated oligosaccharides, suggesting glycoproteinosis. Enzymatic studies on cultured skin fibroblasts revealed normal β-galactosidase activity and low α-D-neuraminidase activity, confirming the diagnosis of sialidosis.

Results from other investigations, including brain magnetic resonance imaging (MRI), cardiac ultrasound, respiratory function (with lung x-rays, pulmonary function tests, and measurements of nocturnal oxygen saturation), and skeletal x-rays were normal. These clinical and biological findings were compatible with a diagnosis of type II infantile-onset sialidosis.

The child has been observed every 3 months for pediatric clinical examination and annual complete inpatient clinical and imaging review.

At the age of 6 years, the child developed a sleeping disorder associated with anxiety that was treated with amitriptyline. Mild changes to the white matter were observed on the MRI and have remained stable since. At the age of 7 years old, she exhibited joint stiffness and a scoliosis-like posture, which were treated by physiotherapy. Lung examination revealed mild obstructive pulmonary disease not requiring treatment. At the age of 8 years, a skeletal survey showed disc degeneration at T12-L1, which has remained stable. At the age of 9 years, we noted mild conductive hearing loss on the left side due to otosclerosis and bone fusion.

At the 5-year follow-up there was no psychomotor delay and weight had regularly increased (+2 SD) but height was below −2 SD. Ophthalmic examination showed improvement in visual acuity (20/25 in the right eye and 20/32 in the left eye at the last follow-up examination), but the nystagmus remained. The dilated fundus and SD-OCT examination results remained identical to those of the initial examination, with the typical macular spot and increased reflectivity from the inner retinal layer. At the last follow-up examination, visual field testing showed decreased global sensitivity with a paracentral scotoma on the right eye and a central scotoma on the left eye.

Case 2

After discovering the typical macular cherry-red spot in our index patient, we conducted an ophthalmic examination of her 3-year-old sister, who had an uneventful medical history apart from chronic serous otitis media.

Her visual acuity was 20/80 in the right eye and 20/63 in the left eye with mild myopia. We noted no abnormal eye movements. Peripheral evaluation of the visual field, slit-lamp examination, and visual evoked potentials were normal. The dilated fundus examination showed bilateral macular cherry-red spots. The peripheral retina and optic nerve heads were normal. The SD-OCT examination unveiled the same findings as in case 1.

Pediatric examination reported the same clinical features as in case 1 except for excessive weight.

Case 2 was also been classified as type II infantile-onset sialidosis. The 3-year-old girl had the same medical follow-up as her sister.

During the 5-year follow-up examination, vertical downbeat nystagmus, multiple ear, nose, and throat infections that required tonsillectomy and adenoidectomy, severe perceptive and conductive hearing loss, mild changes to the white matter on brain MRI, sleeping disorder, anarchic vertebral body ossification, cerebellar syndrome with walking instability, and mild psychomotor delay were reported.

Ophthalmic examination showed an improved visual acuity (20/32 in the right eye and 20/32 in the left eye with mild myopia at the last follow-up examination), and results of dilated fundus and SD-OCT examinations remained the same. At the last follow-up examination, visual field testing showed decreased global sensitivity with bilateral central scotoma and impaired upper peripheral visual field.

Discussion

Sialidosis is a rare inherited lysosomal storage disease, first reported as a distinct clinical entity by Spranger and Wiedemann in 1968. It is caused by intracellular accumulation of sialic acid resulting in α-N-acetyl neuraminidase-1 deficiency. Various mutations have been reported in the causative gene NEU1.2,3  There is some genotype-phenotype correlation.

Sialidosis is divided into two types, which are distinguished by the age of onset and severity of symptoms. Type I is the mildest form. Clinical features are constant macular cherry-red spot, myoclonus, and cerebral ataxia. Type II exhibits a severe phenotype with multisystem involvement including ophthalmic abnormalities (macular cherry-red spots are the most frequent, but corneal clouding, cataract, optic atrophy, strabismus, and nystagmus have also been described). Type II sialidosis is also further divided into congenital, infantile, and juvenile forms, ranging respectively from the most severe congenital onset form where children die early on to a slowly progressive form with juvenile onset where affected individuals can survive into their 20s.

The relevance of this report is to present a 5-year follow-up of two sisters with type II infantile sialidosis. The girls were aged 5 and 3 years when typical macular cherry-red spots were detected during dilated fundus examination. At that time, the other clinical symptoms of lysosomal storage disease were so mild that they had not come to medical attention. Clinical presentation and progression were similar for both sisters with hypotonia, hepatosplenomegaly, nystagmus, and decreased visual sensitivity with visual field scotomas, hearing loss, dysostosis, and respiratory distress. Case 2 also developed cerebellar syndrome with mild psychomotor delay.

Those two cases may also be classified as the juvenile form, but clinical presentation is particularly mild and the progression of their systemic symptoms is slow.

Another relevant element in this study was the use of SD-OCT for identifying macular cherry-red spots in sialidosis. To our knowledge, no studies have focused on the pathological retina in sialidosis, but neuropathological studies have described an accumulation of terminal sialic acid at the non-reducing end of the sugar chain in the lysosomes of motor neurons, dorsal root ganglia, cerebellar dentate neurons, and some neurons in the thalamus and nucleus basalis of Meynert.7,8 

In both cases, SD-OCT showed increased reflectivity of the inner retinal layers including ganglionic and nerve fiber layers as first described by Heroman et al. It probably corresponds to the accumulation of sialic acid in the lysosomes of ganglion cells. In other storage diseases, such as GM2 gangliosidosis, this accumulation has been validated in the same location in ophthalmic pathological studies.10  This accumulation is also responsible for the cherry-red spots. In our two cases we noted that this increased reflectivity has remained stable since the first SD-OCT performed 5 years ago.

Ophthalmologists should think of storage diseases when fundus examination reveals bilateral macular cherry-red spots in children. It may be the first clue to the diagnosis, especially in milder forms.

We considered the increased reflectivity of the inner retinal layers to be secondary to accumulated sialic acid in retinal ganglion cells, which was also responsible for the macular cherry-red spot. SD-OCT is an easy-to-conduct method for observing the accumulation of stored oligosaccharides, which can appear earlier than any brain findings on the MRI. SD-OCT examinations have remained stable over the 5-year follow-up in cases of slowly progressing sialidosis, but it would be interesting to conduct SD-OCT in forms that progress more quickly and in other storage diseases such as Tay-Sachs or Niemann-Pick disease. This could potentially be used to monitor the evolution of storage diseases or effectiveness of a potential treatment in the future.

References

     
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10.3928/01913913-20130625-02

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