SIL1-negative Marinesco-Sjögren syndrome: First report of two sibs from India.

Dear Sir,

Marinesco-Sjögren syndrome is a rare genetically heterogeneous, autosomal recessive disorder characterized by cerebellar ataxia, congenital cataracts, intellectual disability and short stature.[1] It was first described by Marinesco in 1931 in four Romanian siblings.[1] The syndrome has been mapped to chromosome 5q31, and loss-of-function mutations in the SIL1 gene have been identified as the primary pathology in about 60% of cases with a typical Marinesco-Sjögren syndrome phenotype.[234] Here, we present the first report of two sibs with SIL1 mutation negative Marinesco-Sjögren syndrome from India.

These two girl siblings were born to nonconsanguineous parents. After an uneventful perinatal period they presented with early onset bilateral cataract, developmental delay, and cerebellar ataxia. The younger sib presented at 11 months of age with bilateral cataract (first reported at the age of 4 months), motor delay, truncal swaying, titubation, nystagmus, esotropia, abnormally small head (head circumference at −2 standard deviations [SD]), brisk deep tendon reflexes, hypotonia, pes valgus and short stature. The elder sister aged 4 years had bilateral cataracts noted at her first birthday. She also had microcephaly (head circumference < −2 SD), short stature, pes valgus, esotropia, swaying and uncoordinated hand movements from 2 years of age and spastic paraparesis. Seizures were a recent development over the last 6 months. They did not have dysmorphic features, microcornea, muscle weakness, abnormal fat distribution, inverted nipples, ocular or renal involvement. Magnetic resonance imaging of the brain in both the siblings revealed marked cerebellar atrophy predominantly affecting the vermian region with preservation of the supratentorial structures [Figures 1 and 2]. Metabolic and biochemical workup such as serum ammonia, arterial lactate, liver and kidney functions, creatine kinase level, lipid profile, coagulation profile, tandem mass spectrometry of blood, and gas chromatography-mass spectrometry of urine were within normal limits. Nerve conduction studies did not show any evidence of neuropathy. SIL1 gene sequencing was performed at the Institute for Neuropathology, Aachen, Germany, in both the siblings and parents, but no mutation was found. Mitochondrial DNA analysis was not performed.

Figure 1

Magnetic resonance imaging of the brain of younger sib (11 months) on (a) T1 coronal and (b) T2 axial image showing cerebellar vermian and hemispheric atrophy

Figure 2

Magnetic resonance imaging of the brain of elder sib (4 years) on (a) T1 axial and (b) T2 sagittal image showing cerebellar vermian and hemispheric atrophy

Mutations that disrupt the function of SIL1 protein have been identified as a cause of Marinesco-Sjögren syndrome. However, previous studies have found SIL1 mutation in only about 60% of cases.[24] The sibs manifested the cardinal clinico-radiological features of Marinesco-Sjögren syndrome [Table 1], but did not exhibit a mutation in the SIL1 gene, suggesting a possible role of another gene in these cases. Our observation provides further evidence for clinical and genetic heterogeneity of this syndrome.[24]

Table 1

Clinicoradiological features of Marinesco-Sjögren syndrome

This sibling pair is the first report of SIL1 negative Marinesco-Sjögren syndrome from India. Pediatricians and neurologists need to be aware of this entity, which forms an important differential diagnosis of developmental delay, ataxia, and early onset cataract. Other possible entities with similar presentation such as congenital cataracts facial dysmorphism, neuropathy, carbohydrate deficient glycoprotein syndromes, lowe syndrome, and mitochondrial diseases were excluded based on clinical profile and laboratory investigations. In cases like ours without identified SIL1 mutation, the diagnosis of Marinesco-Sjögren syndrome stills rests on the clinical picture and radiological evidence of cerebellar atrophy.