Abstract
Purpose :
LAMA1 encodes laminin subunit alpha 1, an essential intercellular adhesion molecule in embryonic development of the fetal kidney, retina, and brain. Pathogenic variants causing LAMA1 loss of function are associated with Poretti-Boltshauser syndrome (PBS), an autosomal recessive disease characterized by neurologic and ophthalmic manifestations including cerebellar dysplasia with cysts, delayed developmental milestones, oculomotor apraxia, high myopia, retinal dystrophy, and retinal vascular abnormalities. To date, only two prior reports have described the multimodal ophthalmic imaging features of this disease. We present a retrospective, multi-center case series of patients with LAMA1 variants demonstrating a spectrum of neurologic and ophthalmic findings.
Methods :
Patients underwent complete eye examinations along with multimodal ophthalmic imaging and electrophysiologic testing including optical coherence tomography, fundus photography, kinetic visual field evaluation, and full-field electroretinography (ERG). Neurologic imaging and clinical documentation were reviewed when available.
Results :
Seven patients, including two siblings within the same family, were identified. Two unrelated patients reported a family history of consanguinity, one of whom also was found to have a homozygous ABCA4 variant. Diagnoses prior to genetic testing included Joubert or Joubert-like syndrome (2/7), Stickler syndrome (1/7) and pathologic myopia with maculopathy (1/7). The most frequent ophthalmic features identified included high myopia (5/7), reduced best-corrected visual acuity (4/7), atrophic macular changes with retinal thinning and focal outer retinal loss (4/7), retinal vascular anomalies including vessel dragging and/or peripheral nonperfusion (2/7), ERG abnormalities (2/4), and strabismus or oculomotor apraxia (3/7). Neurologically, the most common findings were cerebellar hypoplasia and cysts (4/7) and developmental delay (2/7).
Conclusions :
PBS is an extremely rare genetic disease characterized by variable neurologic and ophthalmic manifestations. It is likely currently underdiagnosed, most often masquerading as Joubert syndrome (which features a “molar tooth sign” on MRI). This series highlights the importance of a multi-disciplinary approach to diagnosis, in combination with genetic testing and further detailed clinical follow up to define the natural history of PBS.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.