Spinocerebellar ataxia, autosomal recessive 2 (SCAR2) [MIM:213200] is a rare autosomal recessive disease of spinocerebellar ataxia associated with degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCAR2 is characterized by onset of impaired motor development and ataxic gait in early childhood. Recently, several PMPCA gene variants have been reported in SCAR2 patients with mild and non-progressive symptoms. PMPCA codes frataxin, which is crucial for iron biosynthesis in cells. We report a case of a 15-year-old Japanese girl with infancy-onset, very severe and progressive developmental delay, cerebellar ataxia, and extrapyramidal symptoms. Brain magnetic resonance imaging showed cerebellar atrophy and excessive brain iron accumulation in the bilateral globus pallidi and substantia nigra. Based on the clinical phenotypes and imaging, neurodegeneration with brain iron accumulation was suspected. Whole-exome sequencing on the proband and her parents revealed novel compound heterozygous variants at c.667C > T (p.Arg223Cys) and c.853del (p.Asp285llefs*16) in PMPCA. Thus, her disease was diagnosed as SCAR2. Phenotype in our case was different from ones previously reported for SCARs in the points of much severer clinical presentations with extrapyramidal signs and imaging suspected iron accumulation, and might overlap neurodegeneration with brain iron accumulation or NBIA subtypes. Our case might provide a new insight into PMPCA gene-related disorders and expand the disease concept.

中文翻译：

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与新的 PMPCA 变异相关的一种严重的常染色体隐性遗传脊髓小脑共济失调


脊髓小脑共济失调，常染色体隐性 2 (SCAR2) [MIM:213200] 是一种罕见的脊髓小脑共济失调常染色体隐性遗传疾病，与小脑变性相关，并伴有不同程度的脑干和脊髓受累。 SCAR2 的特点是在儿童早期出现运动发育受损和共济失调步态。最近，在具有轻度和非进展性症状的 SCAR2 患者中报道了几种 PMPCA 基因变异。 PMPCA 编码 frataxin，这对于细胞中铁的生物合成至关重要。我们报道了一名 15 岁日本女孩的病例，该女孩患有婴儿期发病、非常严重且进行性发育迟缓、小脑性共济失调和锥体外系症状。脑磁共振成像显示小脑萎缩，双侧苍白球和黑质脑铁积聚过多。根据临床表型和影像学检查，怀疑伴有脑铁积累的神经退行性变。先证者及其父母的全外显子组测序揭示了 PMPCA 中 c.667C > T (p.Arg223Cys) 和 c.853del (p.Asp285llefs*16) 的新型复合杂合变异。因此，她的疾病被诊断为SCAR2。我们病例的表型与之前报道的 SCAR 的表型不同，其临床表现更为严重，包括锥体外系体征和影像学疑似铁积累，并且可能与脑铁积累或 NBIA 亚型的神经退行性病变重叠。我们的案例可能为 PMPCA 基因相关疾病提供新的见解并扩展疾病概念。