A chorea-acanthocytosis patient with novel mutations in the VPS13A gene without acanthocyte.

Chorea-acanthocytosis (ChAc) is a rare clinical genetic disorder of the nervous system, which is characterized by choreiform movement disorder, cognitive decline, and psychiatric disorders. ChAc is mostly diagnosed based on its typical clinical manifestations and the increased number of acanthocytes in peripheral blood smears. Here, we report a patient, who has the characteristic clinical manifestations of ChAc with limb choreiform movements, involuntary lip and tongue bites, seizures, and emotional instability. However, her blood smear was negative for acanthocytes with scanning electron microscopy. We later identified two novel pathogenic mutations in the patient's vacuolar protein sorting homolog 13 A (VPS13A) on chromosome 9q21 by targeted gene sequencing, and she was definitively diagnosed with "ChAc." After treatment with carbamazepine, haloperidol, the patient's symptoms gradually improved. We consider that an acanthocyte negative blood smear cannot rule out ChAC diagnosis, and genetic testing is the "gold standard" for the diagnosis. Through a review of previous research, it is rare for a patient to have a clear diagnosis of ChAc by genetic testing, but whose blood smear is negative for acanthocytes with electron microscopy. In addition, in this report, we discovered two novel pathogenic mutations, which have not been reported previously, and extended the genetic characteristics of ChAc.

Free-Water Imaging in Friedreich Ataxia Using Multi-Compartment Models.

BACKGROUND: The neurological phenotype of Friedreich ataxia (FRDA) is characterized by neurodegeneration and neuroinflammation in the cerebellum and brainstem. Novel neuroimaging approaches quantifying brain free-water using diffusion magnetic resonance imaging (dMRI) are potentially more sensitive to these processes than standard imaging markers. OBJECTIVES: To quantify the extent of free-water and microstructural change in FRDA-relevant brain regions using neurite orientation dispersion and density imaging (NODDI), and bitensor diffusion tensor imaging (btDTI). METHOD: Multi-shell dMRI was acquired from 14 individuals with FRDA and 14 controls. Free-water measures from NODDI (FISO) and btDTI (FW) were compared between groups in the cerebellar cortex, dentate nuclei, cerebellar peduncles, and brainstem. The relative sensitivity of the free-water measures to group differences was compared to microstructural measures of NODDI intracellular volume, free-water corrected fractional anisotropy, and conventional uncorrected fractional anisotropy. RESULTS: In individuals with FRDA, FW was elevated in the cerebellar cortex, peduncles (excluding middle), dentate, and brainstem (P < 0.005). FISO was elevated primarily in the cerebellar lobules (P < 0.001). On average, FW effect sizes were larger than all other markers (mean ηρ 2 = 0.43), although microstructural measures also had very large effects in the superior and inferior cerebellar peduncles and brainstem (ηρ 2 > 0.37). Across all regions and metrics, effect sizes were largest in the superior cerebellar peduncles (ηρ 2 > 0.46). CONCLUSIONS: Multi-compartment diffusion measures of free-water and neurite integrity distinguish FRDA from controls with large effects. Free-water magnitude in the brainstem and cerebellum provided the greatest distinction between groups. This study supports further applications of multi-compartment diffusion modeling, and investigations of free-water as a measure of disease expression and progression in FRDA. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Febuxostat ameliorates muscle degeneration and movement disorder of the dystrophin mutant model in Caenorhabditis elegans.

Duchenne muscular dystrophy (DMD) is an inherited disorder with mutations in the dystrophin gene characterized by progressive muscle degeneration and weakness. Therapy such as administration of glucocorticoids, exon skipping of mutant genes and introduction of dystrophin mini-genes have been tried, but there is no radical therapy for DMD. In this study, we used C. elegans carrying mutations in the dys-1 gene as a model of DMD to examine the effects of febuxostat (FBX). We applied FBX to dys-1 mutant animals harboring a marker for muscle nuclei and mitochondria, and found that FBX ameliorates the muscle loss. We next used a severer model dys-1; unc-22 double mutant and found the dys-1 mutation causes a weakened muscle contraction. We applied FBX and other compounds to the double mutant animals and assayed the movement. We found that the administration of FBX in combination of uric acid has the best effects on the DMD model.

Mild Motor Signs in Healthy Aging Are Associated with Lower Synaptic Density in the Brain.

OBJECTIVE: To investigate whether mild motor signs (MMS) in old age correlate with synaptic density in the brain. BACKGROUND: Normal aging is associated with a decline in movement quality and quantity, commonly termed "mild parkinsonian signs" or more recently MMS. Whether MMS stem from global brain aging or pathology within motor circuits remains unresolved. The synaptic vesicle glycoprotein 2A positron emission tomography (PET) ligand 11 C-UCB-J allows the investigation of brain-motor associations at the synaptic level in vivo. METHOD: Fifty-eight healthy older adults (≥50 years) were included from two monocentric control cohorts. Brain magnetic resonance imaging and 11 C-UCB-J PET data were available in 54 participants. 11 C-UCB-J PET binding was quantified by standardized uptake value ratio (SUVR) values in grey matter (GM) volumes of interest (VOIs): caudate, putamen, globus pallidus, substantia nigra, thalamus, cerebellum, and the frontal, parietal, temporal, and occipital cortex. Multiple linear regression analyses were performed with Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score measuring MMS as the dependent variable and mean SUVR values in each VOI as the independent variable with age, Fazekas score (white matter lesion [WML] load), VOI and cohort as covariates. RESULTS: Participants (68 ± 7.5 years; 52% female) had an average MDS-UPDRS part III score of 3.3 ± 2.8. The MDS-UPDRS part III score was inversely associated with synaptic density, independently of WML load or GM volume, in the caudate, substantia nigra, thalamus, cerebellum, and parietal, occipital, temporal cortex. Cohen's f2 showed moderate effect sizes for subcortical (range, 0.30-0.35), cortical (0.28-0.35) and cerebellar VOIs (0.31). CONCLUSION: MMS in healthy aging are associated with lower synaptic density throughout the brain. © 2023 International Parkinson and Movement Disorder Society.

GNAO1-related movement disorder: An update on phenomenology, clinical course, and response to treatments.

AIM: To evaluate clinical phenotype and molecular findings of 157 cases with GNAO1 pathogenic or likely pathogenic variants delineating the clinical spectrum, course, and response to treatments. METHOD: Clinical phenotype, genetic data, and pharmacological and surgical treatment history of 11 novel cases and 146 previously published patients were analyzed. RESULTS: Complex hyperkinetic movement disorder (MD) characterizes 88% of GNAO1 patients. Severe hypotonia and prominent disturbance of postural control seem to be hallmarks in the early stages preceding the hyperkinetic MD. In a subgroup of patients, paroxysmal exacerbations became so severe as to require admission to intensive care units (ICU). Almost all patients had a good response to deep brain stimulation (DBS). Milder phenotypes with late-onset focal/segmental dystonia, mild to moderate intellectual disability, and other minor neurological signs (i.e., parkinsonism and myoclonus) are emerging. MRI, previously considered noncontributory to a diagnosis, can show recurrent findings (i.e., cerebral atrophy, myelination and/or basal ganglia abnormalities). Fifty-eight GNAO1 pathogenic variants, including missense changes and a few recurrent splice site defects, have been reported. Substitutions at residues Gly203, Arg209 and Glu246, together with the intronic c.724-8G > A change, account for more than 50% of cases. INTERPRETATION: Infantile or childhood-onset complex hyperkinetic MD (chorea and/or dystonia) with or without paroxysmal exacerbations, associated hypotonia, and developmental disorders should prompt research for GNAO1 mutations. DBS effectively controls and prevents severe exacerbations and should be considered early in patients with specific GNAO1 variants and refractory MD. Prospective and natural history studies are necessary to define genotype-phenotype correlations further and clarify neurological outcomes.

Movement disorders are linked to TDP-43 burden in the substantia nigra of FTLD-TDP brain donors.

Movement disorders (MD) have been linked to degeneration of the substantia nigra (SN) in Parkinson's disease and include bradykinesia, rigidity, and tremor. They are also present in frontotemporal dementia (FTD), where MD have been linked to frontotemporal lobar degeneration with tau pathology (FTLD-tau). Although MD can also occur in FTLD with TDP-43 pathology (FTLD-TDP), the local pathology in the SN of FTLD-TDP patients with MD is currently unexplored. The aims of this study are to characterize the frequency and the nature of MD in a cohort of FTLD-TDP brain donors and to investigate the relationship between the presence of MD, the nigral neuronal loss, and the TDP-43 burden in the SN. From our cohort of FTLD-TDP patients (n = 53), we included 13 donors who presented with MD (FTLD-MD+), and nine age-sex matched donors without MD (FTLD-MD-) for whom the SN was available. In these donors, the TDP-43 burden and the neuronal density in the SN were assessed with ImageJ and Qupath software. The results were compared between the two groups using T-test. We found that the TDP-43 burden in the SN was higher in FTLD-MD+ (mean 3,43%, SD ± 2,7) compared to FTLD-MD- (mean 1,21%, SD ± 0,67) (p = 0,04), while no significant difference in nigral neuronal density was found between the groups (p = 0,09). 17% of FTLD-TDP patients developed MD, which present as symmetric akinetic-rigid parkinsonism or CBS. Given the absence of a significant nigral neuronal cell loss, TDP-43 induced neuronal dysfunction could be sufficient to cause MD.

Neurodegeneration with brain iron accumulation: a case series highlighting phenotypic and genotypic diversity in 20 Indian families.

Neurodegeneration with brain iron accumulation (NBIA) is an umbrella term encompassing various inherited neurological disorders characterised by abnormal iron accumulation in basal ganglia. We aimed to study the clinical, radiological and molecular spectrum of disorders with NBIA. All molecular-proven cases of NBIA presented in the last 5 years at 2 tertiary care genetic centres were compiled. Demographic details and clinical and neuroimaging findings were collated. We describe 27 individuals from 20 unrelated Indian families with causative variants in 5 NBIA-associated genes. PLA2G6-associated neurodegeneration (PLAN) was the most common, observed in 13 individuals from 9 families. They mainly presented in infancy with neuroregression and hypotonia. A recurrent pathogenic variant in COASY was observed in two neonates with prenatal-onset severe neurodegeneration. Pathogenic bi-allelic variants in PANK2, FA2H and C19ORF12 genes were observed in the rest, and these individuals presented in late childhood and adolescence with gait abnormalities and extrapyramidal symptoms. No intrafamilial and interfamilial variability were observed. Iron deposition on neuroimaging was seen in only 6/17 (35.3%) patients. A total of 22 causative variants across 5 genes were detected including a multiexonic duplication in PLA2G6. The variants c.1799G > A and c.2370 T > G in PLA2G6 were observed in three unrelated families. In silico assessments of 8 amongst 9 novel variants were also performed. We present a comprehensive compilation of the phenotypic and genotypic spectrum of various subtypes of NBIA from the Indian subcontinent. Clinical presentation of NBIAs is varied and not restricted to extrapyramidal symptoms or iron accumulation on neuroimaging.

Neuronal intranuclear inclusion disease mimicking progressive supranuclear palsy.

BACKGROUND: Given the variable nature of clinical manifestations, neuronal intranuclear inclusion disease (NIID) is regarded as a heterogeneous disease which is challenging to diagnose early. To the present, progressive supranuclear palsy (PSP)-like symptoms have never been listed in the performance of NIID. CASE PRESENTATION: A 58-year-old man presented with progressive Parkinsonism and postural instability for 3 years. Initially, he was considered as probable PSP due to vertical supranuclear gaze palsy, postural instability, and hummingbird sign. No high-intensity signal on diffusion-weighted imaging (DWI) was revealed. Eventually, the diagnosis was revised to NIID by Notch 2 N-terminal like C (NOTCH2NLC) GGC repeat expansions and skin biopsy showing intranuclear eosinophilic inclusions in the vesicles and ductal epithelial cells of sweat glands. CONCLUSION: Even if the typical high-intensity along the corticomedullary junction (CMJ) on DWI is lacking, clinicians should be alert to the possibility of NIID when PSP-like symptoms develop. This case report offers new features of NIID and expands its clinical spectrum.

Dystonia-like Movement Disorders Ameliorated by Shear Force and Pressure Stimulation after Small Infarction in the Left Posterolateral Thalamus.

Focal dystonia (FD) can develop after thalamic lesions. Abnormal somatic sensations were argued to be responsible for FD. Our patient experienced FD-like movement disorders, agraphesthesia, and a reduced sense of shear force on the skin and pressure to deep tissues of the right upper limb following a small infarction in the left posterolateral thalamus. FD-like symptoms improved while the skin was being pulled or the deep tissue was being pushed in a manner proportional to the strength of muscle contractions. Therefore, the lack of these sensations was suggested to be related to FD-like symptoms.

Motor organization of unilateral polymicrogyria associated with ipsilateral brainstem atrophy - a case report.

BACKGROUND: Polymicrogyria refers to the disruption of normal cerebral cortical development late in neuronal migration or in early cortical organization. Although patients with polymicrogyria feature relatively favorable motor outcomes, polymicrogyric lesions accompanied by extensive unilateral hemispheric atrophy and ipsilateral brainstem atrophy may induce poorer motor outcomes. This study is the first to employ transcranial magnetic stimulation (TMS) and diffusion tensor imaging (DTI) to characterize changes to motor organization and white matter tracts induced by polymicrogyria. CASE PRESENTATION: We document a case of a 16-year-old female with left hemiplegic unilateral polymicrogyria associated with ipsilateral brainstem atrophy. Magnetic resonance imaging (MRI) of the brain revealed unilateral polymicrogyria to have affected anterior cortical areas, including the perisylvian region on the right side. The right halves of the brain and brainstem were significantly smaller than the left halves. Although our patient was found to exhibit cortical dysplasia of the right frontoparietal and sylvian fissure areas and a decreased number of fibers in the corticospinal tract (CST) of the affected side on DTI, the connectivity of the CST was preserved up to the motor cortex. We also measured the cross-sectional area of the CST at the level of the pons. In TMS, contralateral motor evoked potentials (MEPs) were evoked from both hands, but the ipsilateral MEPs were evoked only from the left hand. The left hand featured a long duration, polyphasic pattern of contralateral MEPs. DISCUSSION AND CONCLUSION: TMS revealed that the concurrent bilateral projections to the paretic hand from the affected and unaffected hemispheres and contralateral MEPs in the paretic hand were polyphasic, indicating delayed electrophysiological maturation or a pathologic condition of the corticospinal motor pathways. In DTI, the cross-sectional area of the CST at the level of the pons on the affected side was smaller than that on the unaffected side. These DTI findings reveal an inadequate CST volume. Despite extensive brain malformation and ipsilateral brainstem atrophy, our patient had less severe motor dysfunction and presented with involuntary mirror movements. Mirror movements in the paretic hand are considered to indicate ipsilateral corticospinal projections from the unaffected hemisphere and may suggest favorable motor outcomes in early brain injury.

A translational perspective on pathophysiological changes of oscillatory activity in dystonia and parkinsonism.

Intracerebral recordings from movement disorders patients undergoing deep brain stimulation have allowed the identification of pathophysiological patterns in oscillatory activity that correlate with symptom severity. Changes in oscillatory synchrony occur within and across brain areas, matching the classification of movement disorders as network disorders. However, the underlying mechanisms of oscillatory changes are difficult to assess in patients, as experimental interventions are technically limited and ethically problematic. This is why animal models play an important role in neurophysiological research of movement disorders. In this review, we highlight the contributions of translational research to the mechanistic understanding of pathological changes in oscillatory activity, with a focus on parkinsonism and dystonia, while addressing the limitations of current findings and proposing possible future directions.

Shivering and Stringhalt in horses.

Pelvic limb movement disorders unrelated to lameness or proprioceptive ataxia have been described in horses for centuries. The two best described are Shivering and Stringhalt. Shivering is unique in that it is primarily apparent when horses are asked to walk backward, without affecting forward gaits until quite advanced. Horses exhibit abduction and either hyperflexion or marked hyperextension of one or both pelvic limbs when walking backward, resulting in a pause at the peak of the stride cycle and reluctance to move backward. Generally, Stringhalt differs from Shivering in that it produces consistent hyperflexion without abduction in forward gaits including walk and trot. This review will focus on the two most common pelvic limb movement disorders, Shivering and Stringhalt, their clinical presentation, differential diagnosis, etiopathology, and treatment.

An Updated Overview of the Magnetic Resonance Imaging of Brain Iron in Movement Disorders.

Brain iron load is one of the most important neuropathological hallmarks in movement disorders. Specifically, the iron provides most of the paramagnetic metal signals in the brain and its accumulation seems to play a key role, although not completely explained, in the degeneration of the basal ganglia, as well as other brain structures. Moreover, iron distribution patterns have been implicated in depicting different movement disorders. This work reviewed current literature on Magnetic Resonance Imaging for Brain Iron Detection and Quantification (MRI-BIDQ) in neurodegenerative processes underlying movement disorders.

Juvenile-Onset Huntington Disease Pathophysiology and Neurodevelopment: A Review.

Huntington disease is an autosomal dominant inherited brain disorder that typically becomes manifest in adulthood. Juvenile-onset Huntington disease refers to approximately 5% of patients with symptom onset before the age of 21 years. The causal factor is a pathologically expanded CAG repeat in the Huntingtin gene. Age at onset is inversely correlated with CAG repeat length. Juvenile-onset patients have distinct symptoms and signs with more severe pathology of involved brain structures in comparison with disease onset in adulthood. The aim of this review is to compare clinical and pathological features in juvenile- and adult-onset Huntington disease and to explore which processes potentially contribute to the observed differences. A specific focus is placed on molecular mechanisms of mutant huntingtin in early neurodevelopment and the interaction of a neurodegenerative disease and postnatal brain maturation. The importance of a better understanding of pathophysiological differences between juvenile- and adult-onset Huntington disease lies in development and implementation of new therapeutic strategies. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Relation Between the Corticospinal Tract State and Activities of Daily Living in Patients With Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: We investigated the relation between the ipsilesional corticospinal tract (CST) state and activity of daily living independence in patients with chronic intracerebral hemorrhage. METHODS: Fifty-six consecutive patients with unilateral intracerebral hemorrhage and 38 healthy control subjects were recruited for this study. The Motricity index and the modified Barthel index were used to evaluate motor function of the affected extremities and activity of daily living independence, respectively. The diffusion tensor imaging parameter values for fractional anisotropy (FA) and voxel number (VN) of the CST were determined. Ratios of the ipsilesional to the contralesional CST measures were calculated and are presented as the CST-ratio (FA value and VN). RESULTS: The FA value and VN of the ipsilesional CST and the CST-ratio in the patient group were lower than those of the control group (P<0.05). There was a strong positive correlation between the Motricity index score of the affected extremities and the modified Barthel index score (P<0.05), while the FA value and VN of the ipsilesional CST and the CST-ratio showed moderate and strong positive correlations with the Motricity index and modified Barthel index scores, respectively (P<0.05). In addition, the VN of the ipsilesional CST showed excellent utility as a classifier, whereas the FA value of the ipsilesional CST and the FA value and VN of the CST-ratio showed good classifier utility (P<0.05). CONCLUSIONS: We demonstrated that impairment of activity of daily living independency was closely related to the injury severity of the ipsilesional CST in patients with chronic intracerebral hemorrhage. In addition, the injury severity of the ipsilesional CST can be used to classify the degree of activity of daily living independency. Registration: URL: http://www.e-irb.com/index.jsp; Unique identifier: 2021-03-014.

Experimental deep brain stimulation in rodent models of movement disorders.

Deep brain stimulation (DBS) is the preferred treatment for therapy-resistant movement disorders such as dystonia and Parkinson's disease (PD), mostly in advanced disease stages. Although DBS is already in clinical use for ~30 years and has improved patients' quality of life dramatically, there is still limited understanding of the underlying mechanisms of action. Rodent models of PD and dystonia are essential tools to elucidate the mode of action of DBS on behavioral and multiscale neurobiological levels. Advances have been made in identifying DBS effects on the central motor network, neuroprotection and neuroinflammation in DBS studies of PD rodent models. The phenotypic dtsz mutant hamster and the transgenic DYT-TOR1A (ΔETorA) rat proved as valuable models of dystonia for preclinical DBS research. In addition, continuous refinements of rodent DBS technologies are ongoing and have contributed to improvement of experimental quality. We here review the currently existing literature on experimental DBS in PD and dystonia models regarding the choice of models, experimental design, neurobiological readouts, as well as methodological implications. Moreover, we provide an overview of the technical stage of existing DBS devices for use in rodent studies.

Assembly of α-synuclein and neurodegeneration in the central nervous system of heterozygous M83 mice following the peripheral administration of α-synuclein seeds.

Peripheral administration (oral, intranasal, intraperitoneal, intravenous) of assembled A53T α-synuclein induced synucleinopathy in heterozygous mice transgenic for human mutant A53T α-synuclein (line M83). The same was the case when cerebellar extracts from a case of multiple system atrophy with type II α-synuclein filaments were administered intraperitoneally, intravenously or intramuscularly. We observed abundant immunoreactivity for pS129 α-synuclein in nerve cells and severe motor impairment, resulting in hindlimb paralysis and shortened lifespan. Filaments immunoreactive for pS129 α-synuclein were in evidence. A 70% loss of motor neurons was present five months after an intraperitoneal injection of assembled A53T α-synuclein or cerebellar extract with type II α-synuclein filaments from an individual with a neuropathologically confirmed diagnosis of multiple system atrophy. Microglial cells changed from a predominantly ramified to a dystrophic appearance. Taken together, these findings establish a close relationship between the formation of α-synuclein inclusions in nerve cells and neurodegeneration, accompanied by a shift in microglial cell morphology. Propagation of α-synuclein inclusions depended on the characteristics of both seeds and transgenically expressed protein.

Mitofusin 2: The missing link between mtDNA maintenance defects and neurotransmitter disorders.

Mitofusin (MFN) 2 belongs to the large family of mitochondrial transmembrane GTPases and has a role in dynamic mitochondrial remodeling process governed by fusion and fission. MFN2 pathogenic variants classically cause Charcot-Marie-Tooth disease type 2A (CMT2A), the most common axonal form of CMT, but patients with complex and unusual phenotypes involving the central and peripheral nervous system have been described, with mitochondrial dysfunction proposed as the underlying pathogenic mechanism. Here, we report the first description of a neurochemical pattern of secondary alterations in the metabolism of biogenic amines linked to the de novo presence of the hotspot MFN2 pathogenic variant p.Arg104Trp. The infant presented a very early onset choreic movement disorder associated with severe axial hypotonia and fluctuating dystonia of limbs. The relationship between mitochondrial DNA (mtDNA) maintenance defects and dopaminergic neurotransmitter disorders, governed by MFN2, is discussed.

White matter degeneration in remote brain areas of stroke patients with motor impairment due to basal ganglia lesions.

Diffusion tensor imaging (DTI) studies have revealed distinct white matter (WM) characteristics of the brain following diseases. Beyond the lesion-symptom maps, stroke is characterized by extensive structural and functional alterations of brain areas remote to local lesions. Here, we further investigated the structural changes over a global level by using DTI data of 10 ischemic stroke patients showing motor impairment due to basal ganglia lesions and 11 healthy controls. DTI data were processed to obtain fractional anisotropy (FA) maps, and multivariate pattern analysis was used to explore brain regions that play an important role in classification based on FA maps. The WM structural network was constructed by the deterministic fiber-tracking approach. In comparison with the controls, the stroke patients showed FA reductions in the perilesional basal ganglia, brainstem, and bilateral frontal lobes. Using network-based statistics, we found a significant reduction in the WM subnetwork in stroke patients. We identified the patterns of WM degeneration affecting brain areas remote to the lesions, revealing the abnormal organization of the structural network in stroke patients, which may be helpful in understanding of the neural mechanisms underlying hemiplegia.

Expanding the genotypic spectrum of PYCR2 and a common ancestry in Thai patients with hypomyelinating leukodystrophy 10.

PYCR2 pathogenic variants lead to an autosomal recessive hypomyelinating leukodystrophy 10 (HLD10), characterized by global developmental delay, microcephaly, facial dysmorphism, movement disorder, and hypomyelination. This study identified the first two unrelated Thai patients with HLD10. Patient 1 harbored the novel compound heterozygous variants, c.257T>G (p.Val86Gly) and c.400G>A (p.Val134Met), whereas patient 2 possessed the homozygous variant, c.400G>A (p.Val134Met), in PYCR2. Haplotype analysis revealed that the two families' members shared a 2.3 Mb region covering the c.400G>A variant, indicating a common ancestry. The variant was estimated to age 1450 years ago. Since the c.400G>A was detected in three out of four mutant alleles and with a common ancestry, this variant might be common in Thai patients. We also reviewed the phenotype and genotype of all 35 previously reported PYCR2 patients and found that majorities of cases were homozygous with a consanguineous family history, except patient 1 and another reported case who were compound heterozygous. All patients had microcephaly and developmental delay. Hypotonia and peripheral spasticity were common. Hypomyelination or delayed myelination was a typical radiographic feature. Here, we report the first two Thai patients with HLD10 with the novel PYCR2 variants expanding the genotypic spectrum and suggest that the c.400G>A might be a common mutation in Thai patients.