Redefining the phenotype of alpha-methylacyl-CoA racemase (AMACR) deficiency.

IF 3.4 2区 医学 Q2 GENETICS & HEREDITY Orphanet Journal of Rare Diseases Pub Date : 2024-09-23 DOI:10.1186/s13023-024-03358-9
Femke C C Klouwer, Stefan D Roosendaal, Carla E M Hollak, Mirjam Langeveld, Bwee Tien Poll-The, Arlette J van Sorge, Nicole I Wolf, Marjo S van der Knaap, Marc Engelen
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Abstract

Background: Alpha-methylacyl-CoA racemase (AMACR) deficiency is a rare peroxisomal enzyme deficiency caused by biallelic variants in the AMACR gene. This deficiency leads to the accumulation of toxic bile acid intermediates (R)-trihydroxycholestenoic acid (THCA) and (R)-dihydroxycholestenoic acid (DHCA) and pristanic acid. With less than 20 patients described in literature, the phenotype of AMACR deficiency is poorly defined and no data on the natural history are available.

Results: Here we describe a cohort of 12 patients (9 adults and 3 children) with genetically confirmed AMACR deficiency (median age at diagnosis 56 years, range 3-69), followed for an average of 6 years (between 2015 and 2023). Five novel pathogenic variants are described. In 5/9 adult patients, retinitis pigmentosa was detected at a median age of 45 years (range 30-61). The median delay to diagnosis of AMACR deficiency after the diagnosis of retinitis pigmentosa was 24 years (range 0-33). All adult patients subsequently developed neurological signs and symptoms after the age of 40 years; most frequently neuropathy, ataxia and cognitive decline with prior normal cognitive functioning. One patient presented with a stroke-like episode. All adult patients showed a typical MRI pattern involving the thalami and gray matter structures of the pons and midbrain. One patient had a hepatocellular carcinoma at the time of the AMACR deficiency diagnosis and two patients suffered from gallstones. All three included children had elevated liver transaminases as single presenting sign and showed no brain MRI abnormalities.

Conclusion: AMACR deficiency can be considered as an adult slowly progressive disease with a predominant neurological phenotype. The main signs comprise retinitis pigmentosa, neuropathy, ataxia and cognitive decline; stroke-like episodes may occur. Recognition of typical MRI abnormalities may facilitate prompt diagnosis. In addition, there is a risk of liver fibrosis/cirrhosis and hepatocellular carcinoma in these patients, requiring active monitoring.

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重新定义α-甲基乙酰-CoA 消旋酶(AMACR)缺乏症的表型。
背景:α-甲基乙酰-CoA外消旋酶(AMACR)缺乏症是一种罕见的过氧化物酶体酶缺乏症,由AMACR基因的双叶变体引起。这种缺陷导致有毒胆汁酸中间产物(R)-三羟基胆甾烯酸(THCA)、(R)-二羟基胆甾烯酸(DHCA)和肉豆蔻酸的积累。文献中描述的患者不足 20 例,AMACR 缺乏症的表型尚不明确,也没有关于自然病史的数据:在此,我们描述了一个由 12 名经基因证实患有 AMACR 缺乏症的患者(9 名成人和 3 名儿童)组成的队列(诊断时的中位年龄为 56 岁,范围为 3-69 岁),平均随访 6 年(2015 年至 2023 年)。其中描述了五种新型致病变异。在 5/9 例成年患者中,发现视网膜色素变性的中位年龄为 45 岁(30-61 岁不等)。视网膜色素变性确诊后,AMACR 缺乏症的中位延迟诊断时间为 24 年(0-33 岁)。所有成年患者在 40 岁之后都出现了神经系统体征和症状,最常见的是神经病变、共济失调和认知功能下降,而之前的认知功能正常。一名患者出现了类似中风的症状。所有成年患者的磁共振成像均显示出典型的丘脑和脑桥及中脑灰质结构。一名患者在确诊AMACR缺乏症时患有肝细胞癌,两名患者患有胆结石。所有三名患儿均以肝脏转氨酶升高为单一表现,未出现脑磁共振成像异常:结论:AMACR 缺乏症可被视为一种以神经系统表型为主的成人缓慢进展性疾病。主要表现包括视网膜色素变性、神经病变、共济失调和认知能力下降;可能出现中风样发作。识别典型的磁共振成像异常有助于及时诊断。此外,这些患者有肝纤维化/肝硬化和肝细胞癌的风险,需要积极监测。
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来源期刊
Orphanet Journal of Rare Diseases
Orphanet Journal of Rare Diseases 医学-医学:研究与实验
CiteScore
6.30
自引率
8.10%
发文量
418
审稿时长
4-8 weeks
期刊介绍: Orphanet Journal of Rare Diseases is an open access, peer-reviewed journal that encompasses all aspects of rare diseases and orphan drugs. The journal publishes high-quality reviews on specific rare diseases. In addition, the journal may consider articles on clinical trial outcome reports, either positive or negative, and articles on public health issues in the field of rare diseases and orphan drugs. The journal does not accept case reports.
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