title: The neurology of carbonic anhydrase type II deficiency syndrome.
abstract: Carbonic anhydrase type II deficiency syndrome is an uncommon autosomal recessive disease with cardinal features including osteopetrosis, renal tubular acidosis and brain calcifications. We describe the neurological, neuro-ophthalmological and neuroradiological features of 23 individuals (10 males, 13 females; ages at final examination 2-29 years) from 10 unrelated consanguineous families with carbonic anhydrase type II deficiency syndrome due to homozygous intron 2 splice site mutation (the 'Arabic mutation'). All patients had osteopetrosis, renal tubular acidosis, developmental delay, short stature and craniofacial disproportion with large cranial vault and broad forehead. Mental retardation was present in approximately two-thirds and varied from mild to severe. General neurological examinations were unremarkable except for one patient with brisk deep tendon reflexes and two with severe mental retardation and spastic quadriparesis. Globes and retinae were normal, but optic nerve involvement was present in 23/46 eyes and was variable in severity, random in occurrence and statistically correlated with degree of optic canal narrowing. Ocular motility was full except for partial ductional limitations in two individuals. Saccadic abnormalities were present in two, while half of these patients had sensory or accommodative strabismus, and seven had congenital nystagmus. These abnormalities were most commonly associated with afferent disturbances, but a minor brainstem component to this disorder remains possible. All internal auditory canals were normal in size, and no patient had clinically significant hearing loss. Neuroimaging was performed in 18 patients and repeated over as long as 10 years. Brain calcification was generally progressive and followed a distinct distribution, involving predominantly basal ganglia and thalami and grey-white matter junction in frontal regions more than posterior regions. At least one child had no brain calcification at age 9 years, indicating that brain calcification may not always be present in carbonic anhydrase type II deficiency syndrome during childhood. Variability of brain calcification, cognitive disturbance and optic nerve involvement may imply additional genetic or epigenetic influences affecting the course of the disease. However, the overall phenotype of the disorder in this group of patients was somewhat less severe than reported previously, raising the possibility that early treatment of systemic acidosis with bicarbonate may be crucial in the outcome of this uncommon autosomal recessive problem.
authors: Department of Ophthalmology and Paediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
authors: Thomas M
authors: TM
authors: Bosley
authors: Mustafa A
authors: MA
authors: Salih
authors: Ibrahim A
authors: IA
authors: Alorainy
authors: M Zahidul
authors: MZ
authors: Islam
authors: Darren T
authors: DT
authors: Oystreck
authors: Omer S M
authors: OS
authors: Suliman
authors: Salem
authors: S
authors: al Malki
authors: Adel H
authors: AH
authors: Suhaibani
authors: Hattan
authors: H
authors: Khiari
authors: Sigri
authors: S
authors: Beckers
authors: Liesbeth
authors: L
authors: van Wesenbeeck
authors: Bram
authors: B
authors: Perdu
authors: Abdulmajeed
authors: A
authors: AlDrees
authors: Salah A
authors: SA
authors: Elmalik
authors: Wim
authors: W
authors: Van Hul
authors: Khaled K
authors: KK
authors: Abu-Amero
mesh_terms: D000141:Acidosis, Renal Tubular / Q000235:genetics / Q000503:physiopathology*; D000293:Adolescent; D000328:Adult; D001921:Brain / Q000503:physiopathology*; D002114:Calcinosis / Q000235:genetics / Q000503:physiopathology; D024402:Carbonic Anhydrase II / Q000172:deficiency* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000235:genetics / Q000503:physiopathology*; D005260:Female; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000503:physiopathology*; D008297:Male; D059906:Neuroimaging; D010022:Osteopetrosis / Q000235:genetics / Q000503:physiopathology*; D010375:Pedigree; D013577:Syndrome
chemical_list: D024402:Carbonic Anhydrase II