Saudi Journal of Kidney Diseases and Transplantation

: 2013  |  Volume : 24  |  Issue : 3  |  Page : 561--565

Cerebral calcification, osteopetrosis and renal tubular acidosis: is it carbonic anhydrase-II deficiency?

Ala A Sh. Ali1, Sarmad A Al-Mashta2,  
1 Department of Nephrology, Dialysis and Renal Transplantation, Baghdad Teaching Hospital, The Medical City Complex, Baghdad, Iraq
2 Department of Neurology, Baghdad Teaching Hospital, The Medical City Complex, Baghdad, Iraq

Correspondence Address:
Ala A Sh. Ali
Internist and Nephrologist, Baghdad Teaching Hospital, P. O. Box 53205, Bab Al-mudhum, Baghdad


Carbonic anhydrase-II deficiency is an autosomal recessive disorder with a triad of cerebral calcification, osteopetrosis and renal tubular acidosis (often combined proximal and distal). Mental retardation, growth failure, complications of osteopetrosis and other features were all recorded in this syndrome. We present a case of an Iraqi male with all these features and a positive family history.

How to cite this article:
Sh. Ali AA, Al-Mashta SA. Cerebral calcification, osteopetrosis and renal tubular acidosis: is it carbonic anhydrase-II deficiency?.Saudi J Kidney Dis Transpl 2013;24:561-565

How to cite this URL:
Sh. Ali AA, Al-Mashta SA. Cerebral calcification, osteopetrosis and renal tubular acidosis: is it carbonic anhydrase-II deficiency?. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2021 Sep 22 ];24:561-565
Available from:

Full Text


Carbonic anhydrase-II (CA-II) is a zinc me­tallo-enzyme that catalyzes the reversible hy­dration of carbon dioxide to form carbonic acid (H 2 CO 3 ). CA-II has a wide tissue distri­bution, being found in bone, kidney (proximal tubules and collecting duct), erythrocytes and glial cells, with osteoclasts being particularly rich in CA-II. Deficiency of CA-II impairs the production of H + by the osteoclasts and, thus, bone resorption is blocked, leading to the de­velopment of osteopetrosis.

The CA gene has been defined and is located on chromosome 8. It is a point mutation of histidine residue mapped to 8q22. The renal tubular acidosis (RTA) may be of mixed pro­ximal and distal type, but either distal or pro­ximal RTA may predominate. In common with osteopetrosis due to CA-II deficiency, a defect in acidification appears to be the common basis of disease. It has also been documented that different allelic variants may give rise to auto­somal dominant (as well as recessive) forms of osteopetrosis. Mutations in the low-density lipoprotein receptor 5 (LRP5) have been iden­tified in other families with autosomal domi­nant osteopetrosis. CA-II deficiency is most common in the Arab Gulf region, with what is known as an Arabic mutation, and it is also recorded in Japan; also, American as well as Belgian mutations have been detected. [1]

 Case Report

A 27-year old male presented with muscle aches, contractions, fever and disturbed beha­vior of one week' duration. His story dated back to childhood, at the age of about three years, when he started to experience recurrent attacks of weakness involving the upper and, to a lesser extent, the lower limbs that did not occur in a stereotyped fashion and resolved spontaneously or with certain medications.

In the last month, these episodes became more frequent and occurred with a prolonged duration, interfering with his already poor quality life induced by this long illness. All these were precipitated by febrile illness.

The patient was admitted to a local hospital and investigated. A diagnosis of space-occu­pying lesion of the brain was made for which the patient received one course of chemothe­rapy that led to greater deterioration in his general condition, with increasing fever and bloody diarrhea. For this reason, he was re­ferred to our hospital.

At admission, the patient had dry cough, breathlessness, decreased appetite, nausea, vo­miting and diarrhea. There was no cyanosis, no urinary symptoms and no skin rash. There was decreased hearing as well as decreased visual acuity. The patient had generalized malaise, muscle contraction mainly involving the hands and bone and muscle pain; there were no seizures. There was no history of fractures. His past medical history consisted mainly of similar attacks in addition to deaf­ness and impaired vision. Drug history was remarkable for the recent addition of carbamazepine for treating recurrent seizures. His surgical history was unremarkable.

He was a product of uneventful pregnancy, born at term with average weight and from closely related parents of the same tribe. He was the fourth sibling among four brothers and two sisters. Sadly, the two sisters died at the age of seven and 14 years of poorly diagnosed neurological disease precipitated by febrile illnesses. He did not attend school and showed delayed mental and motor development, but, surprisingly, he was eager for potassium-rich foods like dates.

On clinical examination, we encountered a male with stunted growth, thin physique, apa­thetic and dysmorphic features of head posing, peaked nose, thin upper lip, mal-occluded teeth, dehydrated with sunken eyes, acidotic, deaf and with minimal visual acuity. Vital signs revealed a febrile patient with a pulse rate of 110 beats per minute and respiratory rate of 20/ min. His blood pressure was 110/70 mmHg with no postural drop. His height was 135 cm, which is about 3 SD below the mean for his age. Cardiac examination revealed normal first heart sound and loud second heart sound with a hemic murmur. Chest examination revealed coarse rales in the lower zones bilaterally. The abdomen was soft with no organomegaly. Neurological examination revealed nearly intact muscle bulk with carpopedal spasm. Muscle power grade was 4/5 and decreased deep tendon reflexes were noted. Apart from bilateral optic atrophy and hearing defect, there were no other cranial nerve lesions. Sensation was intact.

A number of laboratory investigations were performed and are shown in [Table 1]. Imaging studies were also performed. Computerized tomography (CT) scan of the brain revealed diffuse intra-cerebral calcifications [Figure 1]. Abdominal ultrasound revealed normal-sized kidneys with no evidence of nephrolithiasis or nephrocalcinosis. X-ray films of the femur, arm bones and vertebral column revealed in­creased bone density [Figure 2].{Figure 1}{Figure 2}{Table 1}

Unfortunately, neither proper genetic testing nor erythrocyte lysate test are available in our center, and a clinical diagnosis of CA-II defi­ciency was made. Multiple opinions were sought for confirmation of our provisional diagnosis to be recorded as the first case in our country.

During the stay in the hospital, the patient received intravenous fluid support mainly of normal saline and ringer lactate with 10% calcium gluconate and potassium chloride, 60 meq/day, as infusion followed by sodium bi­carbonate in a dose of 2 mmol/kg/day, along with antibiotic therapy. His level of conscious­ness and hydration status improved as also his temperature. His renal indices and acid-base status improved with the correction of dehy­dration and electrolyte disturbances. The pa­tient was discharged on potassium citrate and oral calcium and vitamin D supplementation.


CA-II deficiency or marble brain disease is a clinical diagnosis based on the presence of the triad of cerebral calcification, osteopetrosis and renal tubular acidosis. It is an autosomal recessive disease, although autosomal domi­nant cases have also been reported. [1],[2]

The presence of such a triad in a male with positive family history, from an area near the Arab Gulf (the patient is from the southern part of Iraq), increased our index of suspicion about the diagnosis. The other differential diag­nosis that came to mind is Sanjad-Sakati syndrome, which is an autosomal recessive dis­order and shares some of the phenotypic fea­tures as well as the geographic distribution of CA-II deficiency; this was excluded with a finding of normal parathyroid hormone levels in our patient. [3] The absence of fractures and the presence of mental retardation and high creatine phosphokinase (CPK) are suggestive of the peculiar Arabic variant of CA-II defi­ciency rather than other types of mutation. [4] All patients have increased density of axial ske­leton, long bones and skull along with wide­ning of metaphysis of long bones. [5] Intracranial calcifications in CA-II deficiency are not present at birth and they usually deve­lop by 2-5 years of age. The reason for such calcifications is still unclear. Cranial nerve entrapments leading to blindness and deafness are rare in CA-II deficiency. [5] The periods of weakness can be explained by hypokalemia to­gether with acidosis, both of which cause such apathy and chronic ill health. Three unrelated Japanese families were reported to have recur­rent episodes of muscle paralysis attributed to hypokalemia. [6] The carpopedal spasm was due to hypocalcemia, which may occur on an acute basis due to renal impairment and malnu­trition and on a chronic basis due to hypoalbuminemia.

In most cases of CA-II deficiency, combined renal tubular acidosis occurs but, clinically, one of them dominates the clinical picture. In our patient, the distal component seems to be the prevailing one as evident by the presence of non-anion gap metabolic acidosis, positive urine anion gap and positive urine pH of +4. [4]

Conflict of interest: None


1Cotter M, Connell T, Colhoun E, Smith OP, McMahon C. Carbonic Anhydrase II Deficiency. A rare autosomal recessive disorder of osteopetrosis, renal tubular acidosis, and cerebral calcification. J Pediatr Hematol Oncol 2005; 27:115-7.
2Sly WS, Hewett-Emmett D, Whyte MP, Yu Y-SL, Tashian RE. Carbonic anhydrase II deficiency identified as the Primary defect in the autosomal recessive syndrome of osteoporosis with renal tubular acidosis and cerebral calcifi­cation. Proc Nat Acad Sci USA 1983;80:2752-6.
3Sanjad SS, Sakati N, Abu-Osba YK. Conge­nital hypoparathyroidism with dysmorphic features: A new syndrome. Pediatr Res 1988; 23:A419.
4Al-Ibrahim A, Al-Harbi M, Al-Musallam S. Paralysis episodes in Carbonic Anhydrase II Deficiency. Saudi J Kidney Dis Transpl 2003; 14:70-4.
5Nampoothiri S, Anikster Y. Carbonic Anhydrase II Deficiency: A Novel Mutation. Indian Pediatr 2009;46:532-4.
6Aramaki S, Yoshida I, Yoshino M, et al. Carbonic Anhydrase II deficiency in three unrelated Japanese patients. J Inherit Metab Dis 1993;16:982-90.