Sly et al. (1972) described 3 sisters, aged 22, 17, and 15 years, born to normal unrelated North American parents, with a form of osteopetrosis distinct from both the malignant form (see OPTB1, 259700) and the benign autosomal ... Sly et al. (1972) described 3 sisters, aged 22, 17, and 15 years, born to normal unrelated North American parents, with a form of osteopetrosis distinct from both the malignant form (see OPTB1, 259700) and the benign autosomal dominant form (see OPTA1, 607634). The disorder was manifest in the first 2 years because of fractures. Other features were short stature, mental retardation, dental malocclusion, and visual impairment from optic nerve compression. Mild anemia in infancy improved later and radiographic features of osteopetrosis improved some at puberty. Serum acid phosphatase was elevated and electrolyte changes suggested mild tubular acidosis. Whyte et al. (1980) provided a definitive report of these sibs. During adolescence basal ganglion calcification developed in 2. Renal tubular acidosis (type I) was diagnosed in each in early adulthood. Electron microscopy of bone suggested that osteoclasts failed to form 'ruffled membranes' characteristic of active bone resorbing cells. Chronic systemic acidosis may have ameliorated the skeletal manifestations. Guibaud et al. (1972) described 2 brothers with renal tubular acidosis and mild osteopetrosis. The unaffected parents, from North Africa, were cousins. Ohlsson et al. (1980) observed the syndrome, which they referred to as marble brain disease, in children of 3 Saudi families. They had striking facial similarities and cerebral calcifications. Bourke et al. (1981) observed this syndrome in 2 Kuwaiti Bedouin sibs. One sib showed basal ganglion calcification and mental subnormality. The major clinical manifestation in both was periodic hypokalemic paresis. Consanguinity was present in 9 of 12 pedigrees reported by Sly et al. (1985). More than half the known cases have been in families from Kuwait, Saudi Arabia, and North Africa. Ohlsson et al. (1986) described the findings in 4 new Saudi Arabian cases from 2 families, including the first description in a neonate. They reviewed the 17 previously reported cases. Cochat et al. (1987) added a case and reviewed the findings in 30 reported patients. Al Rajeh et al. (1988) described 2 affected sisters in a Saudi Arabian family. Strisciuglio et al. (1990) described 3 affected Italian sibs, the offspring of first cousins once removed. They had osteopetrosis with fractures and severe mental retardation. Whereas most previous patients had a mixed (proximal and distal) renal tubular acidosis, these patients had only proximal tubular acidosis. Aramaki et al. (1993) reported in detail the findings in 3 unrelated Japanese patients with CA II deficiency. Two of the 3 were born of first-cousin parents. All exhibited poor activity and poor appetite in the neonatal period and then developed psychomotor retardation. Two of them were diagnosed as having osteopetrosis at 10 months and 36 years of age, respectively, and the third as having osteomalacia at 28 years of age. All 3 had recurrent episodes of muscle weakness. Their parents exhibited approximately 50% normal levels of CA II activity in protein. The development of osteomalacia was considered to be related to the renal tubular acidosis.
Venta et al. (1990, 1991) sequenced the CA2 gene in a patient with osteopetrosis and renal tubular acidosis from the consanguineous Belgian family first described by Vainsel et al. (1972) and identified homozygosity for a missense mutation (H107Y; ... Venta et al. (1990, 1991) sequenced the CA2 gene in a patient with osteopetrosis and renal tubular acidosis from the consanguineous Belgian family first described by Vainsel et al. (1972) and identified homozygosity for a missense mutation (H107Y; 611492.0004). Roth et al. (1992) analyzed the molecular basis of carbonic anhydrase II deficiency in the American family in which the association of CA2 deficiency with a clinical syndrome was first recognized by Sly et al. (1972). The 3 affected sisters were found to be compound heterozygotes for a maternally inherited H107Y mutation (611492.0004) and a paternally inherited splice site mutation (611492.0005). Roth et al. (1992) suggested that residual activity of the H107Y mutant enzyme, demonstrated in expression studies in bacteria, might explain the absence of mental retardation and relatively mild phenotype in affected members of this family. Hu et al. (1992) pointed out that of the 39 reported cases of carbonic anhydrase deficiency syndrome, 72% were patients from North Africa and the Middle East countries, most, if not all, of whom were of Arabic descent. They showed that members of 6 unrelated Arabic kindreds were in 5 instances homozygous and in 1 instance heterozygous for a splice site mutation in intron 3 of the CA2 gene (611492.0006). Called the 'Arabic mutation,' it introduces a new Sau3A1 restriction site useful in PCR-based diagnosis, carrier detection, and prenatal diagnosis. The presence of mental retardation and relative infrequency of skeletal fractures distinguish the clinical course of patients with the Arabic mutation from that of American and Belgian patients with the H107Y mutation. In a 23-year-old Japanese woman previously reported by Aramaki et al. (1993) ('patient 1' of pedigree A) with carbonic anhydrase II deficiency, osteopetrosis, renal tubular acidosis, symmetrical cerebral calcification, and mental retardation, Soda et al. (1995) found a Y40X mutation in exon 2 of the CA2 gene resulting from a TAT-to-TAG transversion. Soda et al. (1996) identified the H107Y mutation in 2 unrelated Japanese patients previously described by Aramaki et al. (1993), both born of consanguineous parents, who had osteopetrosis and renal tubular acidosis as well as severe mental retardation. The authors stated that the basis for the more severe expression of the H107Y mutation, including mental retardation, in Japanese patients was unclear. Hu et al. (1997) identified 7 novel mutations in the CA2 gene in patients with osteopetrosis and mental retardation or developmental delay. All but 1 pair of Mexican sibs had renal tubular acidosis also. Borthwick et al. (2003) described 2 consanguineous Turkish kindreds with distal RTA and osteopetrosis. In affected members of 1 kindred, the authors identified homozygosity for a frameshift mutation in the CA2 gene (611492.0008). The authors excluded defects in CA2 in the other kindred, in which the proband had RTA and osteopetrosis but his sister manifested only RTA with sensorineural hearing loss and never developed osteopetrosis. In this kindred, Borthwick et al. (2003) found that the osteopetrosis (259700) was the result of a homozygous deletion in the TCIRG1 gene (604592.0007), whereas the distal RTA with hearing loss (267300) was the result of a homozygous mutation in the ATP6V1B1 gene (192132.0005). Borthwick et al. (2003) concluded that coinheritance of these 2 rare recessive disorders created a phenocopy of CA2A deficiency in this kindred, and commented that this case illustrates the importance of clinical characterization of all affected members of a kindred.
Fathallah et al. (1997) traced the origin of this disorder in 24 Tunisian families with CA II deficiency. All were descended from a common ancestor who emigrated from the Arabic Peninsula to North Africa in the 10th century. ... Fathallah et al. (1997) traced the origin of this disorder in 24 Tunisian families with CA II deficiency. All were descended from a common ancestor who emigrated from the Arabic Peninsula to North Africa in the 10th century.