Spinocerebellar ataxia type 5 (SCA5), a dominant spinocerebellar ataxia is caused by spectrin beta nonerythrocytic 2 gene (SPTBN2) mutation. It typically consists of a slow progressive cerebellar ataxia with an onset principally in adulthood. Here, we report on the first Japanese patient with infantile-onset SCA5 associated with a novel heterozygous SPTBN2 mutation. The patient, a 6-year-old girl, developed delayed motor development and unsteady arm movement during infancy. She also showed gaze-evoked nystagmus, saccadic eye pursuit, dysarthria, dysmetria, intention tremor and mild intellectual disability. Brain MRI revealed moderate cerebellar atrophy and mild pontine atrophy. Comprehensive target capture sequencing to identify the causative gene identified a novel missense mutation in SPTBN2 (c.1309C<G, p.R437G), which was thought to be pathogenic. Two patients with infantile-onset SCA5 associated with another novel heterozygous SPTBN2 mutation have recently been reported; these SPTBN2 mutations, which may have a significant impact on protein function, were located in the second spectrin. Our findings indicate that SPTBN2 mutations may be associated with infantile-onset cerebellar ataxia accompanied with global developmental delay.

Objective: To explore the phenotype and genotype of mitochondrial DNA depletion syndromes (MDS) in Chinese children. Methods: The clinical and genetic data of 12 MDS patients (8 were boys and 4 were girls) diagnosed in the Department of Neurology in Beijing Children's Hospital, Capital Medical University from October 2010 to April 2018 were retrospectively collected and analyzed. Results: The developmental milestones were normal or mildly retardated before disease onset. The age of onset ranged from 0 to 2.9-year-old. Most cases developed postnatal or after infection. The most common initial symptoms were feeding difficulty, seizure, muscle weakness, psychomotor regression and hepatic dysfunction. At the last evaluation, all the patients had developmental retardation, failure to thrive, muscle weakness, and dysphagia. Other clinical features were weight loss (9 cases), hearing impairment (7 cases), ptosis (6 cases), seizure (5 cases), dyspnea (4 cases), visual impairment (1 case), hirsutism (1 case), lactic acidosis (7 cases), elevated hepatic enzymes (4 cases) and creatine kinase (2 cases), elevated protein in cerebrospinal fluid (3 cases), abnormalities on screening for inborn error of metabolism (10 cases) and brain magnetic resonance imaging (MRI) (10 cases), abnormal electromyogram (including neurogenic or myogenic injury) (5 cases). Five patients died of infection or multiple organ failure. A total of 18 novel mutations presented below were detected in these patients. Among the 6 cases of encephalomyopathy, there were 3 with SUCLG1 mutation (c. 916G>T, c. 619T>C, c. 980dupT were novel), 2 with SUCLA2 mutation (c. 851G>A, c.971G>A were novel), and one with RRM2B mutation (c.456-2A>G, c.212T>C were novel). All the cases of hepatic encephalopathy all had POLG mutations (c. 3151G>A, c. 2294C>T, c. 2858G>C, c. 680G>A and c. 150_158delGCAGCAGCA were novel). Two cases of infantile-onset spinocerebellar ataxia had TWNK mutations (c. 1163C>T, c. 1319T>C, c. 1388G>A and c. 257_258delAG were novel). One case of myopathy had TK2 mutations (c.557C>G and c.341A>T were novel). Conclusions: The clinical and genetic features of MDS were heterogeneous. Eighteen novel mutations in six MDS related genes were reported, which expanded the genetic spectrum of MDS in Chinese children. 目的： 分析线粒体DNA耗竭综合征（MDS）患儿的临床表型及基因型特点。 方法： 回顾性总结分析2010年10月至2018年4月首都医科大学附属北京儿童医院神经内科确诊的12例MDS患儿（男8例，女4例）的临床表现及基因检查结果。 结果： 12例MDS患儿起病前发育正常或落后，起病年龄为0~2.9岁，多为生后发病或感染后起病，首发症状为喂养困难、抽搐、肌无力、发育倒退或肝功能损害，所有患儿均出现发育迟缓、喂养困难、肌无力、吞咽困难，部分患儿逐渐出现消瘦（9例）、听力损害（7例）、眼睑下垂（6例）、抽搐（5例）、呼吸困难（4例）、视力损害（1例）、多毛（1例）、血乳酸升高（7例）、肝酶升高（4例）、心肌酶升高（2例）、脑脊液蛋白升高（3例）、血尿代谢筛查异常（10例）、头颅磁共振成像异常（10例）、肌电图示神经源性或肌源性损害（5例）。至2018年4月末次随访5例患儿因感染、全身器官功能衰竭死亡。脑肌病型6例，SUCLG1基因变异3例（其中c.916G>T，c.619T>C和c.980dupT为新变异）；SUCLA2基因变异2例（其中c.851G>A，c.971G>A为新变异）；RRM2B基因变异1例（其中c.456-2A>G，c.212T>C为新变异）。肝性脑病型3例均为POLG基因变异（其中c.3151G>A，c.2294C>T，c.2858G>C，c.680G>A，c.150_158delGCAGCAGCA为新变异），婴儿起病的脊髓小脑共济失调型2例，均为TWNK基因变异（其中c.1163C>T，c.1319T>C，c.257_258delAG，c.1388G>A为新变异），肌病型1例为TK2基因变异（其中c.557C>G，c.341A>T为新变异）。 结论： 儿童MDS临床表型及基因变异谱异质性强，本组共发现MDS 6种致病基因的18个新变异，丰富了中国儿童MDS的临床表型及基因型。.

The TWNK (C10orf2) gene encodes Twinkle, an essential helicase for mtDNA replication. Homozygous mutations in TWNK can lead to mitochondrial DNA depletion syndrome 7 (MTDPS7) that usually manifests as Infantile onset spinocerebellar ataxia (IOSCA). Here, we report a 15-year-old Iranian boy with three main symptoms; ataxia, sensorineural hearing loss and optic nerves atrophy which were accompanied by other symptoms including flexion contracture, dysarthric speech, nystagmus, dystonia and borderline intellectual disability. Whole exome sequencing (WES) revealed a homozygous mutation in his TWNK gene. The mutation was a transversion which replaced a C with A (NM_021830.4 (TWNK):c.874C>A). This nucleotide substitution results in replacing a Threonine with Proline in codon 292 of Twinkle protein (p.Pro292Thr). In silico analyses showed that this amino acid change in Twinkle could be deleterious and disease-causing; therefore, we attribute the symptoms of our patient to this mutation. Our study extended the homozygous mutation spectrum of the TWNK gene that leads to IOSCA.

Perrault syndrome is a rare autosomal recessive disorder that is characterized by the association of sensorineural hearing impairment and ovarian dysgenesis in females, whereas males have only hearing impairment. In some cases, patients present with a diversity of neurological signs. To date, mutations in six genes are known to cause Perrault syndrome, but they do not explain all clinically-diagnosed cases. In addition, the number of reported cases and the spectra of mutations are still small to establish conclusive genotype-phenotype correlations. Affected siblings from family SH19, who presented with features that were suggestive of Perrault syndrome, were subjected to audiological, neurological and gynecological examination. The genetic study included genotyping and haplotype analysis for microsatellite markers close to the genes involved in Perrault syndrome, whole-exome sequencing, and Sanger sequencing of the coding region of the TWNK gene. Three siblings from family SH19 shared similar clinical features: childhood-onset bilateral sensorineural hearing impairment, which progressed to profound deafness in the second decade of life; neurological signs (spinocerebellar ataxia, polyneuropathy), with onset in the fourth decade of life in the two females and at age 20 years in the male; gonadal dysfunction with early cessation of menses in the two females. The genetic study revealed two compound heterozygous pathogenic mutations in the TWNK gene in the three affected subjects: c.85C>T (p.Arg29*), previously reported in a case of hepatocerebral syndrome; and a novel missense mutation, c.1886C>T (p.Ser629Phe). Mutations segregated in the family according to an autosomal recessive inheritance pattern. Our results further illustrate the utility of genetic testing as a tool to confirm a tentative clinical diagnosis of Perrault syndrome. Studies on genotype-phenotype correlation from the hitherto reported cases indicate that patients with Perrault syndrome caused by TWNK mutations will manifest neurological signs in adulthood. Molecular and clinical characterization of novel cases of recessive disorders caused by TWNK mutations is strongly needed to get further insight into the genotype-phenotype correlations of a phenotypic continuum encompassing Perrault syndrome, infantile-onset spinocerebellar ataxia, and hepatocerebral syndrome.