Clinical and genetic spectrum of hereditary spastic paraplegia in Chinese children

Wang, Jiaping; Fang, Fang; Ding, Changhong; Li, Jiuwei; Wu, Yun; Zhang, Weihua; Bao, Xinhua; Lv, Jialin; Wang, Xiaohui; Ren, Xiaotun; Zhao, Jianbo; Wang, Hongmei

doi:10.1111/dmcn.15385

Cited by 5 publications

(10 citation statements)

References 30 publications

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“…9,34 However, in pediatric-onset HSP cohorts, SPG54 was responsible for approximately 2% of HSP cases, which indicated that SPG54 more frequently caused HSP symptoms in early childhood. 13,14,35 Concordant to the results observed in other ethnic groups, SPG54 accounted for only 1.2% (3 out of 242) of all patients with HSP and 2% (3 out of 147) of patients with AR or apparently sporadic HSP in our Taiwanese cohort. These findings suggest that SPG54 is a rare HSP subtype and should be considered only in patients with AR or apparently sporadic HSP.…”

Section: Discussionsupporting

confidence: 90%

“…[7][8][9][10][11][12][13][14] Most of the variants result in loss-of-function of the protein product (pLoF variants), including nonsense or frameshift truncating mutations, and a minor group of variants are missense mutations, including p.Y56C, p.W103R, p.R112Q, p.T186M, p.G197R, p.V220F, pR242C, pR242H, p.P269L, p.P339S, p.Q487H, p.F502S, pG510E, p.D660H, p.C683S, and p.Y699C. [7][8][9][10][11][12][13][14] Among these mutations, only p.R287* and p.D660H have been identified in more than two families. 8,15,16 Most SPG54 patients have early-onset disease, with symptoms presenting in the first decade of life.…”

Section: Introductionmentioning

confidence: 99%

“…Spastic paraplegia type 54 (SPG54; MIM# 615033) is a rare AR complex HSP caused by biallelic mutations in the DDHD2 gene. Thirty‐four variants of DDHD2 mutations have been reported in SPG54 patients 7–14 . Most of the variants result in loss‐of‐function of the protein product (pLoF variants), including nonsense or frameshift truncating mutations, and a minor group of variants are missense mutations, including p.Y56C, p.W103R, p.R112Q, p.T186M, p.G197R, p.V220F, pR242C, pR242H, p.P269L, p.P339S, p.Q487H, p.F502S, pG510E, p.D660H, p.C683S, and p.Y699C 7–14 .…”

Section: Introductionmentioning

confidence: 99%

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Biallelic DDHD2 mutations in patients with adult‐onset complex hereditary spastic paraplegia

Chou

Hsu

Tsai

et al. 2023

Ann Clin Transl Neurol

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ObjectiveHereditary spastic paraplegias (HSPs) are a group of inherited neurodegenerative disorders characterized by slowly progressive lower limb spasticity and weakness. HSP type 54 (SPG54) is autosomal recessively inherited and caused by mutations in the DDHD2 gene. This study investigated the clinical characteristics and molecular features of DDHD2 mutations in a cohort of Taiwanese patients with HSP.MethodsMutational analysis of DDHD2 was performed for 242 unrelated Taiwanese patients with HSP. The clinical, neuroimaging, and genetic features of the patients with biallelic DDHD2 mutations were characterized. A cell‐based study was performed to assess the effects of the DDHD2 mutations on protein expression.ResultsSPG54 was diagnosed in three patients. Among them, two patients carried compound heterozygous DDHD2 mutations, p.[R112Q];[Y606*] and p.[R112Q];[p.D660H], and the other one was homozygous for the DDHD2 p.R112Q mutation. DDHD2 p.Y606* is a novel mutation, whereas DDHD2 p.D660H and p.R112Q have been reported in the literature. All three patients manifested adult onset complex HSP with additional cerebellar ataxia, polyneuropathy, or cognitive impairment. Brain proton magnetic resonance spectroscopy revealed an abnormal lipid peak in thalamus of all three patients. In vitro studies demonstrated that all the three DDHD2 mutations were associated with a considerably lower DDHD2 protein level.InterpretationSPG54 was detected in approximately 1.2% (3 of 242) of the Taiwanese HSP cohort. This study expands the known mutational spectrum of DDHD2, provides molecular evidence of the pathogenicity of the DDHD2 mutations, and underlines the importance of considering SPG54 as a potential diagnosis of adult‐onset HSP.

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Section: Discussionsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Biallelic DDHD2 mutations in patients with adult‐onset complex hereditary spastic paraplegia

Chou

Hsu

Tsai

et al. 2023

Ann Clin Transl Neurol

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“…In this regard, two CPT1C variants have been identified to date as the genetic cause of a pure adult‐onset autosomal dominant form of the disease, known as hereditary spastic paraplegia 73 (SPG73), which leads to a loss of independent ambulation 10–15 years after the onset of the symptoms in both men and women (Boutry et al., 2019; Hong et al., 2019; Rinaldi et al., 2015). Moreover, two other CPT1C mutations have also been detected in paediatric patients with complicated forms of HSP, one of them causing delay of speech, cortical dysplasia, seizures and hearing impairments (Wang et al., 2023). However, none of these subjects exhibited cognitive alterations.…”

Section: Introductionmentioning

confidence: 99%

CPT1C is required for synaptic plasticity and oscillatory activity that supports motor, associative and non‐associative learning

Iborra‐Lázaro,

Djebari,

Sánchez‐Rodríguez

et al. 2023

The Journal of Physiology

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Carnitine palmitoyltransferase 1c (CPT1C) is a neuron‐specific protein widely distributed throughout the CNS and highly expressed in discrete brain areas including the hypothalamus, hippocampus, amygdala and different motor regions. Its deficiency has recently been shown to disrupt dendritic spine maturation and AMPA receptor synthesis and trafficking in the hippocampus, but its contribution to synaptic plasticity and cognitive learning and memory processes remains mostly unknown. Here, we aimed to explore the molecular, synaptic, neural network and behavioural role of CPT1C in cognition‐related functions by using CPT1C knockout (KO) mice. CPT1C‐deficient mice showed extensive learning and memory deficits. The CPT1C KO animals exhibited impaired motor and instrumental learning that seemed to be related, in part, to locomotor deficits and muscle weakness but not to mood alterations. In addition, CPT1C KO mice showed detrimental hippocampus‐dependent spatial and habituation memory, most probably attributable to inefficient dendritic spine maturation, impairments in long‐term plasticity at the CA3–CA1 synapse and aberrant cortical oscillatory activity. In conclusion, our results reveal that CPT1C is not only crucial for motor function, coordination and energy homeostasis, but also has a crucial role in the maintenance of learning and memory cognitive functions. imageKey points CPT1C, a neuron‐specific interactor protein involved in AMPA receptor synthesis and trafficking, was found to be highly expressed in the hippocampus, amygdala and various motor regions. CPT1C‐deficient animals exhibited energy deficits and impaired locomotion, but no mood changes were found. CPT1C deficiency disrupts hippocampal dendritic spine maturation and long‐term synaptic plasticity and reduces cortical γ oscillations. CPT1C was found to be crucial for motor, associative and non‐associative learning and memory.

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“…Several years ago, Schiavoni et al 3 reported a retrospective cohort study of 47 Italian patients with HSP onset as children. Now, Wang et al 4 present a retrospective cohort study of 45 Chinese patients with a clinical diagnosis of childhood onset HSP. In the Wang et al 4 study, a genetic etiology was identified in 35 of these individuals (78%), a percentage exceeding that of many similar studies.…”

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confidence: 99%

Importance of genetic testing for childhood‐onset hereditary spastic paraplegia

Blackstone

2022

Develop Med Child Neuro

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Clinical and genetic spectrum of hereditary spastic paraplegia in Chinese children

Cited by 5 publications

References 30 publications

Biallelic DDHD2 mutations in patients with adult‐onset complex hereditary spastic paraplegia

Biallelic DDHD2 mutations in patients with adult‐onset complex hereditary spastic paraplegia

CPT1C is required for synaptic plasticity and oscillatory activity that supports motor, associative and non‐associative learning

Importance of genetic testing for childhood‐onset hereditary spastic paraplegia

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