A Rare Variant in PGAP2 Causes Autosomal Recessive Hyperphosphatasia with Mental Retardation Syndrome, with a Mild Phenotype in Heterozygous Carriers

Table 1

Patients’ clinical data.

Patient	Hx	Physical exam	Lab measurements	Imaging + EEG
Patient 1; 25-year-old male; sibling; IV-3	Mild mental retardation; Mood problems, depression; Speech difficulties; Past history of febrile convulsions	No organ anomaly; No signs of dysmorphism; Normal cranial, motor, sensory, gait, and cerebellar exam	Elevated alkaline phosphatase: 499 IU/L at 23 yrs of age	Normal brain CTA; Normal EEG
Patient 2; 18-year-old male sibling; IV-5	Developmental delay; Moderate mental retardation; Behavioral problems- aggression; Past history of seizures without fever	No organ anomaly; No signs of dysmorphism; Normal cranial, motor, sensory, gait, and cerebellar exam	Elevated alkaline phosphatase: 673 IU/L at 17 yrs of age	Normal brain MRI; EEG: normal background activity; Generalized spike and wave interictal epileptiform discharges
Patient 3; 15-year-old female; sibling; IV-6	Mild mental retardation; Mood problems- depression; Speech difficulties	No organ anomaly; No signs of dysmorphism	Elevated alkaline phosphatase: >1000 IU/L at 10 yrs of age
Patient 4; 11-year-old female; sibling; IV-7	Developmental delay; Mild mental retardation; Speech difficulties; Enuresis	No organ anomaly; No signs of dysmorphism; Normal cranial, motor, sensory, gait, and cerebellar exam	Elevated alkaline phosphatase: 1318 IU/L at 10 yrs of age	Normal spinal MRI
Carrier 1; 22-year-old male; sibling; IV-1	Reported Learning disabilities without mental retardation	No organ anomaly; No signs of dysmorphism; Normal cranial, motor, sensory, gait, and cerebellar exam	Mildly elevated alkaline phosphatase: 122 IU/L at 20 yrs of age	Normal brain CT scan
Carrier 2; 19-year-old female; sibling; IV-4	Reported learning disabilities without mental retardation	No organ anomaly; No signs of dysmorphism; Normal cranial, motor, sensory, gait, and cerebellar exam	Mildly elevated alkaline phosphatase: 134 IU/L at 18 yrs of age	—
Homozygous; wild-type; 24-year-old female; sibling; IV-2	High academic performance	No organ anomaly; No signs of dysmorphism; Normal cranial, motor, sensory, gait, and cerebellar exam	Normal alkaline phosphatase: 84 IU/L at 23 yrs of age	Normal brain CT

Patients IDs correspond with pedigree in Figure 1(a). Hx = medical history; IU/L = international units per liter.