Birk-Landau-Perez Syndrome

A number sign (#) is used with this entry because of evidence that Birk-Landau-Perez syndrome (BILAPES) is caused by homozygous mutation in the SLC30A9 gene (604604) on chromosome 4p13. One such family has been described.

Clinical Features

Perez et al. (2017) reported a large multigenerational Bedouin kindred in which 6 patients had onset of different combinations of intellectual disability, muscle weakness, oculomotor apraxia, and nephropathy in early childhood. The patients had early normal development, but showed psychomotor regression by 1 to 2 years of age, manifest as loss of previously acquired skills, frequent falls, cognitive impairment resulting in profound intellectual disability, and progressive loss of speech. Motor disability included limb and truncal ataxia, poor neck and limb control, mild dyskinesia, choreoathetosis, or dystonia, axial hypotonia, increased limb muscle tone, and abnormal eye movements. The patients also had difficulty walking with camptocormia, or bent trunk postures. Ocular movement abnormalities included strabismus, wandering eye movements, saccadic pursuits, lack of fixation, and ptosis. Brain imaging showed no abnormalities. Four patients had renal insufficiency, which became apparent in 3 patients before age 2 years. Clinical manifestations included hyperkalemia, hypertension, and hyperechogenic kidneys without cysts on renal imaging. Renal biopsy of 1 patient showed tubulointerstitial nephritis. None of the patients had deterioration of renal function during childhood, and none reached end-stage renal failure.

Inheritance

The transmission pattern of BILAPES in the family reported by Perez et al. (2017) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 6 affected individuals from a highly consanguineous Bedouin kindred from Saudi Arabia with Birk-Landau-Perez syndrome, Perez et al. (2017) identified a homozygous in-frame 3-bp deletion in the SLC30A9 gene (Ala350del; 604604.0001). The mutation, which was found by a combination of homozygosity mapping and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. In vitro functional expression assays in human neuroblastoma cells showed that, compared to wildtype, the mutant protein localized similarly but caused a significant decrease in cytosolic free zinc levels. The findings were consistent with a defect in zinc homeostasis, which would likely have an effect on various cellular functions. WNT (see e.g., WNT3A, 606359) signaling was not affected by the mutation.