Retinitis pigmentosa is one of the leading causes of loss of vision in children and is characterised by progressive retinal degeneration resulting in severe bilateral visual impairment. It may be caused by different ocular and/or systemic disorders, chief of which are Bardet-Biedl syndrome (BBS) and neuronal ceroid lipofuscinosis (NCL).1,2

Bardet-Biedl syndrome and NCL are autosomal recessive genetic disorders manifesting with bilateral retinal degeneration. In addition, BBS manifests with intellectual disability, hypogonadism, obesity, renal abnormalities, spastic paraparesis and dysmorphic extremities, and NCL with progressive encephalopathy with an early onset (ages 2–11 years), epilepsy and intellectual and impaired cognitive and motor skills.3,4

The diagnosis of 2 genetic disorders in a single patient is rare, and consanguinity is the main risk factor for this outcome.5

We present the case of a boy with healthy nonconsanguineous parents and a healthy older brother. The patient had congenital polydactyly with a full supernumerary digit emerging from the first phalanx of the 5th toe of the left foot, which was surgically removed at age 2 years, and early-onset vision abnormalities. At age 3 years, the patient received a diagnosis of retinitis pigmentosa with bilateral total blindness and underwent microarray-based genotyping (Asper Biotech®) for screening of 347 mutations in 16 genes involved in syndromic retinal dystrophy (BBS1-BBS13, PHF6, ALMS1, GNAS1). The results revealed the presence of the homozygous variant c.1169 T > G (p.Met390Arg) in gene BBS1, described as pathogenic in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/). Since the variant was found in both alleles, it was disease-causing.

During the follow-up, the patient exhibited psychomotor retardation and cognitive impairment, predominantly in language. At age 8 years, he experienced regression of motor skills accompanied by impaired balance, ataxic gait and loss of muscle tone. Concurrently, the patient developed myoclonic seizures in the context of progressive myoclonic epilepsy. The clinical picture was consistent with neurodegenerative disease, which led to performance of molecular tests for identification of lysosomal storage diseases.

Massive sequencing of the main genes involved in lysosomal storage diseases (Table 1) was performed using the Ion S5 system (Ion Torrent®). Sequencing evinced the presence in heterozygosis of the following variants in the CLN5 gene associated with NCL: point variant c.335 G > C (p.Arg112Pro), described as a pathogenic variant in ClinVar; point variant c.835 G > A (p.Asp279Asn) described as possibly pathogenic in ClinVar; and frameshift insertion c.291_292insC (p.Ser98fs) that is likely pathogenic.

Neuronal ceroid lipofuscinosis has an autosomal recessive pattern of inheritance, so heterozygous variants do not cause disease unless they are found in both alleles, a pattern known as compound heterozygosity. Parental testing was performed, since confirming compound heterozygosis requires detection of one of the variants in the maternal allele and another in the paternal allele. Variants c.835 G > A (p.Asp279Asn) and c.335 G > C (p.Arg112Pro) were found in heterozygosis in the mother and insertion c.291_292insC (p.Ser98fs) in heterozygosis in the father. Parental testing confirmed the compound heterozygous pattern, as the parental variants in the CLN5 gene affected both alleles in the proband. Both heterozygous variants detected in the mother were also detected in the proband, proving that both were located in the same allele and ruling out compound heterozygosis in the mother. The brother of the proband also underwent testing that revealed the presence of insertion c.291_292insC (p.Ser98fs) in heterozygosis (Table 2).

These results led to the conclusion that this patient, previously given a diagnosis of BBS on account of the homozygous variant c.1169 T > G (p.Met390Arg) in the BBS1 gene, also had the compound heterozygous variants c.335 G > C (p.Arg112Pro), c.835 G > A (p.Asp279Asn) and c.291_292insC (p.Ser98fs) in the CLN5 gene, which accounted for the molecular aetiology of NCL. The mother, father and brother were each carriers of at least one of these variants.

The presence of early-onset severe retinal dystrophy combined with the development of manifestations characteristic of neurodegenerative disease was not explain in full by the diagnosis of BBS in isolation, which led to the performance of additional molecular tests and diagnosis of NCL, diseases with overlapping phenotypes. The association of BBS and NCL in a single patient is an exceptional finding and is the first such case to be described in the medical literature.