Three unrelated families on three continents had children with severe multi-organ syndrome

Clinical synopsis. (a–c) Patient 4 at the age of 9 years. There is a marked spinal deformity with forward tilting of the pelvis (because of bilateral hip joint dislocation), exaggerated lumbar lordosis, and dorsal kyphosis with scoliosis. Features are identical to those of patient 5 (Fig. 2 in Liberfarb et al., 1986).17 (d) Ocular fundus examination of patient 1 at age 9 years showing optic disc pallor, generalized mottling of the retinal pigment epithelium (RPE) with areas of atrophy interspersed with pigmentary changes, and “bone spicules” identified in the macula and the midperiphery. Vascular caliber was reduced, with peripheral areas being avascular with remaining ghost vessels. (e) Fundus of patient 2 at age 6 years showing atrophy of the optic disc, extremely thin vessels, atrophic central macular area with pigment clumping. (f–k) Skeletal features including bilateral hip dislocation with femoral head dysplasia (patient 3, age 7 years), dislocation of ulna and radial head at the elbow (patient 5, age 15 years), severe epiphyseal dysplasia with striations of metaphyses (patient 3, age 7 years), delay in carpal and phalangeal ossification but no marked dysplasia (patient 3, age 2 years), platyspondyly but no spinal deformity at age 2 months, and extremely severe spinal deformity at adult age (patient 5).

Three unrelated families on three continents (from continental Portugal, the United States and Brazil), all with healthy ancestors, had children with a very rare multi-organ condition that causes early-onset retinal degeneration, sensorineural hearing loss, microcephaly, intellectual disability, and skeletal dysplasia with scoliosis and short stature.

Genetic analysis by a team led by Carlo Rivolta, group head for genetic ophthalmology at IOB, and Prof. Andrea Superti-Furga, head of the division of genetic medicine at Lausanne University Hospital, has revealed that the disease traces back to a common founder variant, possibly originating from a healthy carrier of the mutation living in Portugal approximately 125 years ago.

“In 1986, the ophthalmologist Ruth Liberfarb and her co-workers first described the condition in a patient originating from the Azores but residing in the U.S. at time of diagnosis.

We could show in our study that the molecular cause of disease is the same in all patients.

Therefore, Andrea Superti-Furga had the idea we could suggest calling it Liberfarb syndrome,” says Carlo Rivolta.

Hope for future therapies

The research team is particularly pleased that their work did not only document the likely migration of a rare genetic mutation from Portugal to two continents, but also highlights the link between phospholipid metabolism and bone formation, sensory defects, and cerebral development, while raising the possibility of therapeutic phospholipid replacement for future patients.

Credit: Institute of Molecular and Clinical Ophthalmology Basel (IOB)

Liberfarb syndrome

Liberfarb syndrome is caused by a homozygous recessive defect in phosphatidylserine decarboxylase (PISD).

PISD is particularly enriched in mitochondrial membranes and required for viability.

Affected individuals examined in this study shared a 3.36 Mb region of autozygosity on chromosome 22q12.2, including a 10-bp deletion (NM_014338.3:c.904-12_904-3delCTATCACCAC), immediately upstream of the last exon of the PISD gene.

Sequencing ofPISDfrom paraffin-embedded tissue from the 1986 case revealed the identical homozygous variant, which likely does not completely abolish phosphatidylserine decarboxylase activity, but results in a severe disease.

Individuals carrying other mutations in PISD show quite divergent clinical phenotypes, possibly related to the severity of the variants detected.

They are ranging from apparently isolated skeletal dysplasia to multi-systemic conditions affecting brain, ear, eye, connective tissue, and bone.

More information: Virginie G. Peter et al. The Liberfarb syndrome, a multisystem disorder affecting eye, ear, bone, and brain development, is caused by a founder pathogenic variant in the PISD gene, Genetics in Medicine (2019). DOI: 10.1038/s41436-019-0595-x

Journal information: Genetics in Medicine
Provided by Institute of Molecular and Clinical Ophthalmology Basel (IOB)


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