Department of Ophthalmology and Paediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
Brain. 2011 Dec;134(Pt 12):3502-15. doi: 10.1093/brain/awr302. Epub 2011 Nov 26.
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.
碳酸酐酶 II 缺乏综合征是一种罕见的常染色体隐性疾病，其主要特征包括骨硬化症、肾小管酸中毒和脑钙化。我们描述了 23 名（男性 10 名，女性 13 名；最终检查时年龄 2-29 岁）来自 10 个无关近亲家庭的患者的神经学、神经眼科和神经影像学特征，这些患者均患有碳酸酐酶 II 缺乏综合征，病因是同源性内含子 2 剪接位点突变（“阿拉伯突变”）。所有患者均患有骨硬化症、肾小管酸中毒、发育迟缓、身材矮小和颅面不成比例，表现为巨大的颅腔和宽阔的额头。大约三分之二的患者存在智力障碍，从轻度到重度不等。除了一名患者深腱反射活跃、两名患者严重智力障碍和痉挛性四肢瘫痪外，一般神经检查均无明显异常。眼球和视网膜正常，但 46 只眼中有 23 只存在视神经受累，其严重程度不同，发生无规律，与视神经管狭窄程度呈统计学相关。眼球运动完全，仅有 2 人存在部分内收限制。2 人存在扫视异常，一半患者存在感觉性或调节性斜视，7 人存在先天性眼球震颤。这些异常通常与传入干扰有关，但这种疾病的脑干成分较小仍有可能。所有内听道大小正常，无患者存在有临床意义的听力损失。18 名患者进行了神经影像学检查，最长随访 10 年。脑钙化通常呈进行性，具有特定的分布，主要累及基底节、丘脑和额区的灰白质交界区，后区较前区受累轻。至少有 1 名患儿 9 岁时无脑钙化，提示儿童期的碳酸酐酶 II 缺乏综合征并非总是存在脑钙化。脑钙化、认知障碍和视神经受累的变异性可能意味着其他遗传或表观遗传因素影响疾病的病程。然而，本组患者的疾病总体表型比之前报道的稍轻，这提示早期用碳酸氢盐治疗系统性酸中毒对这种罕见的常染色体隐性疾病的结局可能至关重要。
