Childhood-Onset Myopathy With Preserved Ambulation Caused by a Recurrent ADSSL1 Missense Variant.

IF 3 3区 医学 Q2 CLINICAL NEUROLOGY
Neurology-Genetics Pub Date : 2024-01-03 eCollection Date: 2024-02-01 DOI:10.1212/NXG.0000000000200122
Dipti Baskar, Kiran Polavarapu, Veeramani Preethish-Kumar, Seena Vengalil, Saraswati Nashi, Ana Töpf, Aneesha Thomas, Sai Bhargava Sanka, Deepak Menon, Kosha Srivastava, Gautham Arunachal, Bevinahalli N Nandeesh, Hanns Lochmüller, Atchayaram Nalini
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引用次数: 0

Abstract

Background and objectives: Distal myopathies are a heterogeneous group of primary muscle disorders with recessive or dominant inheritance. ADSSL1 is a muscle-specific adenylosuccinate synthase isoform involved in adenine nucleotide synthesis. Recessive pathogenic variants in the ADSSL1 gene located in chromosome 14q32.33 cause a distal myopathy phenotype. In this study, we present the clinical and genetic attributes of 6 Indian patients with this myopathy.

Methods: This was a retrospective study describing on Indian patients with genetically confirmed ADSSL1 myopathy. Details were obtained from the medical records.

Results: All patients presented in their first or early second decade. All had onset in the first decade with a mean age at presentation being 17.7 ± 8.4 years (range: 3-27 years) and M:F ratio being 1:2. The mean disease duration was 9.3 ± 5.2 years ranging from 2 to 15 years. All patients were ambulant with wheelchair bound state in 1 patient due to respiratory involvement. The median serum creatine kinase (CK) level was 185.5 IU/L (range: 123-1564 IU/L). In addition to salient features of ptosis, cardiac involvement, bulbar weakness, and proximo-distal limb weakness with fatigue, there were significant seasonal fluctuations and decremental response to repetitive nerve stimulation, which have not been previously reported. Muscle histopathology was heterogenous with the presence of rimmed vacuoles, nemaline rods, intracellular lipid droplets along with chronic myopathic changes. Subtle response to pyridostigmine treatment was reported. While 5 of 6 patients had homozygous c.781G>A (p.Asp261Asn) variation, 1 had homozygous c.794G>A (p.Gly265Glu) in ADSSL1 gene.

Discussion: This study expands the phenotypic spectrum and variability of ADSSL1 myopathy with unusual manifestations in this rare disorder. Because the variant c.781G>A (p.Asp261Asn) is the most common mutation among Indian patients similar to other Asian cohorts, this finding could be useful for genetic screening of suspected patients.

由复发性 ADSSL1 错义变异引起的保留活动能力的儿童期肌病
背景和目的:远端肌病是一组隐性或显性遗传的原发性肌肉疾病。ADSSL1 是一种肌肉特异性腺苷酸合成酶同工酶,参与腺嘌呤核苷酸的合成。位于染色体14q32.33的ADSSL1基因的隐性致病变体会导致远端肌病表型。在本研究中,我们介绍了 6 名印度肌病患者的临床和遗传特征:这是一项回顾性研究,描述了经基因证实患有 ADSSL1 肌病的印度患者。详细资料来自医疗记录:结果:所有患者均在第一个或第二个十年初期发病。所有患者均在第一个十年发病,平均发病年龄为(17.7 ± 8.4)岁(3-27 岁),男女比例为 1:2。平均病程为 9.3 ± 5.2 年,从 2 年到 15 年不等。所有患者均能行走,只有一名患者因呼吸系统受累而需要坐轮椅。血清肌酸激酶(CK)水平中位数为 185.5 IU/L(范围:123-1564 IU/L)。除了上睑下垂、心脏受累、球结膜无力和伴有疲劳的近端-远端肢体无力等显著特征外,患者的病情还有明显的季节性波动和对重复性神经刺激的反应减弱,这在以前的报告中从未出现过。肌肉组织病理学表现不一,存在边缘空泡、神经氨酸棒、细胞内脂滴以及慢性肌病变。据报道,患者对吡啶斯的明治疗有微弱的反应。6 名患者中有 5 人的 ADSSL1 基因出现同源 c.781G>A(p.Asp261Asn)变异,1 人的 ADSSL1 基因出现同源 c.794G>A(p.Gly265Glu)变异:本研究扩展了ADSSL1肌病的表型谱和变异性,发现了这种罕见疾病的不寻常表现。由于c.781G>A (p.Asp261Asn)变异是印度患者中最常见的变异,与其他亚洲队列相似,因此这一发现有助于对疑似患者进行基因筛查。
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来源期刊
Neurology-Genetics
Neurology-Genetics Medicine-Neurology (clinical)
CiteScore
6.30
自引率
3.20%
发文量
107
审稿时长
15 weeks
期刊介绍: Neurology: Genetics is an online open access journal publishing peer-reviewed reports in the field of neurogenetics. Original articles in all areas of neurogenetics will be published including rare and common genetic variation, genotype-phenotype correlations, outlier phenotypes as a result of mutations in known disease-genes, and genetic variations with a putative link to diseases. This will include studies reporting on genetic disease risk and pharmacogenomics. In addition, Neurology: Genetics will publish results of gene-based clinical trials (viral, ASO, etc.). Genetically engineered model systems are not a primary focus of Neurology: Genetics, but studies using model systems for treatment trials are welcome, including well-powered studies reporting negative results.
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