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Background: Genetic mutations have been reported in a number of bone disorders with or without extra-skeletal manifestations. The purpose of the present study was to investigate the genetic cause in a middle-aged woman with osteoporosis, recurrent fractures and extraskeletal manifestations. Methods: A 56-year-old Indian woman presented to the clinic with complaints of difficulty in walking, recurrent fractures, limb bending, progressive skeletal deformities, and poor overall health. At the age of 37, she had experienced severe anemia with diarrhea, significant weight loss, knuckle pigmentation, and a significant loss of scalp hair. She had received multiple blood transfusions and parenteral iron supplementation with normalization of hemoglobin. Subsequently, she had premature menopause at the age of 37. She died at the age of 61 due to liver failure. Exome sequencing followed by Sanger sequencing were undertaken to identify the potential pathogenic mutations. Results: Genetic investigation identified likely pathogenic mutations in the LRP5 and LGR4 genes. Out of the two mutations, the heterozygous mutation (c.1199C>T) in the LRP5 gene resulted in a non-synonymous substitution of alanine with valine at the 400th position, and the second mutation (c.1403A>C) in the LGR4 gene led to a non-synonymous substitution of tyrosine with serine at the 468th residue of the protein. The minor allele frequencies of the c.1199C>T (LRP5) substitution in the 1000 genomes and IndiGenomes databases are 0.0003 and 0.001, while the c.1403A>C (LGR4) substitution has not been reported in these databases. Various in silico prediction tools suggested LGR4 mutation to be pathogenic and LRP5 mutation to be likely pathogenic. Conclusion: Heterozygous mutations in the LRP5 and LGR4 genes had additive deteriorative effects on BMD, resulting in recurrent fractures and bone deformities, and extended the effect to extraskeletal sites, contributing to the poor overall health in this patient. [ABSTRACT FROM AUTHOR]

Objectives: Genetics have been shown to have a substantial impact on amyotrophic lateral sclerosis (ALS). The ALS process involves defects in axonal transport and cytoskeletal dynamics. It has been identified that KIF1A, responsible for encoding a kinesin-3 motor protein that carries synaptic vesicles, is considered a genetic predisposing factor for ALS. Methods: The analysis of whole-exome sequencing data from 1,068 patients was conducted to examine the genetic link between ALS and KIF1A. For patients with KIF1A gene mutations and a family history, we extended the analysis to their families and reanalyzed them using Sanger sequencing for cosegregation analysis. Results: In our cohort, the KIF1A mutation frequency was 1.31% (14/1,068). Thirteen nonsynonymous variants were detected in 14 ALS patients. Consistent with the connection between KIF1A and ALS, the missense mutation p.A1083T (c.3247G>A) was shown to cosegregate with disease. The mutations related to ALS in our study were primarily located in the cargo-binding region at the C-terminal, as opposed to the mutations of motor domain at the N-terminal of KIF1A which were linked to hereditary peripheral neuropathy and spastic paraplegia. We observed high clinical heterogeneity in ALS patients with missense mutations in the KIF1A gene. KIF5A is a more frequent determinant of ALS in the European population, while KIF1A accounts for a similar proportion of ALS in both the European and Chinese populations. Conclusion: Our investigation revealed that mutations in the C-terminus of KIF1A could increase the risk of ALS, support the pathogenic role of KIF1A in ALS and expand the phenotypic and genetic spectrum of KIF1A-related ALS. [ABSTRACT FROM AUTHOR]

Mutations in the SACS gene are associated with autosomal recessive spastic ataxia of Charlevoix-Saguenay disease (ARSACS) or complex clinical phenotypes of Charcot-Marie-Tooth disease (CMT). This study aimed to identify SACS mutations in a Korean CMT cohort with cerebellar ataxia and spasticity by whole exome sequencing (WES). As a result, eight pathogenic SACS mutations in four families were identified as the underlying causes of these complex phenotypes. The prevalence of CMT families with SACS mutations was determined to be 0.3%. All the patients showed sensory, motor, and gait disturbances with increased deep tendon reflexes. Lower limb magnetic resonance imaging (MRI) was performed in four patients and all had fatty replacements. Of note, they all had similar fatty infiltrations between the proximal and distal lower limb muscles, different from the neuromuscular imaging feature in most CMT patients without SACS mutations who had distal dominant fatty involvement. Therefore, these findings were considered a characteristic feature in CMT patients with SACS mutations. Although further studies with more cases are needed, our results highlight lower extremity MRI findings in CMT patients with SACS mutations and broaden the clinical spectrum. We suggest screening for SACS in recessive CMT patients with complex phenotypes of ataxia and spasticity. [ABSTRACT FROM AUTHOR]

Lymphedema is a disorder that leads to excessive swelling due to lymphatic insufficiency, resulting in the accumulation of protein-rich interstitial fluid. Primary lymphedema predominantly impacts the lower extremities and is frequently linked to hereditary factors. This condition is known to be associated with variants in several genes, such as FOXC2, FLT4, and SOX18. However, many cases remain unexplained, suggesting undiscovered gene associations. This study describes a novel mutation in the hepatocyte growth factor (HGF) gene, a previously hypothesized candidate for lymphedema pathogenesis. This mutation was identified in affected members of a multigenerational family presenting with primary leg lymphedema, consistent with an autosomal dominant inheritance pattern. [ABSTRACT FROM AUTHOR]

Autosomal recessive Nonaka distal myopathy is a rare autosomal recessive genetic disease characterized by progressive degeneration of the distal muscles, causing muscle weakness and decreased grip strength. It is primarily associated with mutations in the GNE gene, which encodes a key enzyme of sialic acid biosynthesis (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase). This study was performed to find GNE mutations in six independent distal myopathy patients with or without peripheral neuropathy using whole-exome sequencing (WES). In silico pathogenic prediction and simulation of 3D structural changes were performed for the mutant GNE proteins. As a result, we identified five pathogenic or likely pathogenic missense variants: c.86T>C (p.Met29Thr), c.527A>T (p.Asp176Val), c.782T>C (p.Met261Thr), c.1714G>C (p.Val572Leu), and c.1771G>A (p.Ala591Thr). Five affected individuals showed compound heterozygous mutations, while only one patient revealed a homozygous mutation. Two patients revealed unreported combinations of combined heterozygous mutations. We observed some specific clinical features, such as complex phenotypes of distal myopathy with distal hereditary peripheral neuropathy, an earlier onset of weakness in legs than that of hands, and clinical heterogeneity between two patients with the same set of compound heterozygous mutations. Our findings on these genetic causes expand the clinical spectrum associated with the GNE mutations and can help prepare therapeutic strategies. [ABSTRACT FROM AUTHOR]

The article focuses on a rare case of Donnai–Barrow syndrome (DBS) presenting with spastic paraparesis, a feature not previously documented in the literature. Topics include the unique neurological manifestation of spastic paraparesis in DBS, the importance of reporting atypical symptoms for early diagnosis and genetic counseling, and the use of whole exome sequencing to confirm the diagnosis.

Background: Oculocutaneous albinism (OCA) is a group of rare genetic disorders characterized by a reduced or complete lack of melanin in the skin, hair, and eyes. Patients present with colorless retina, pale pink iris, and pupil, and fear of light. The skin, eyebrows, hair, and other body hair are white or yellowish-white. These conditions are caused by mutations in specific genes necessary for the production of melanin. OCA is divided into eight clinical types (OCA1-8), each with different clinical phenotypes and potential genetic factors. This study aimed to identify the genetic causes of non-syndromic OCA in a Chinese Han family. Methods: We performed a comprehensive clinical examination of family members, screened for mutation loci using whole exome sequencing (WES) technology, and predicted mutations using In silico tools. Results: The patient's clinical manifestations were white skin, yellow hair, a few freckles on the cheeks and bridge of the nose, decreased vision, blue iris, poorly defined optic disk borders, pigmentation of the fundus being insufficient, and significant vascular exposure. The WES test results indicate that the patient has compound heterozygous mutations in the OCA2 gene (c.1258G > A (p.G420R), c.1441G > A (p.A481T), and c.2267-2 A > C), respectively, originating from her parents. Among them, c.1258G > A (p.G420R) is a de novo mutation with pathogenic. Our analysis suggests that compound heterozygous mutations in the OCA2 gene are the primary cause of the disease in this patient. Conclusions: The widespread application of next-generation sequencing technologies such as WES in clinical practice can effectively replace conventional detection methods and assist in the diagnosis of clinical diseases more quickly and accurately. The newly discovered c.1258G > A (p.G420R) mutation can update and expand the gene mutation spectrum of OCA2-type albinism. [ABSTRACT FROM AUTHOR]

Mutations of the SCN1A gene, which encodes the voltage-dependent Na+ channel's α subunit, are associated with diverse epileptic syndromes ranging in severity, even intra-family, from febrile seizures to epileptic encephalopathy. The underlying cause of this variability is unknown, suggesting the involvement of additional factors. The aim of our study was to describe the properties of mutated channels and investigate genetic causes for clinical syndromes' variability in the family of five SCN1A gene p.Arg1596Cys mutation carriers. The analysis of additional genetic factors influencing SCN1A-associated phenotypes was conducted through exome sequencing (WES). To assess the impact of mutations, we used patch clamp analysis of mutated channels expressed in HEK cells and in vivo neural excitability studies (NESs). In cells expressing the mutant channel, sodium currents were reduced. NESs indicated increased excitability of peripheral motor neurons in mutation carriers. WES showed the absence of non-SCA1 pathogenic variants that could be causative of disease in the family. Variants of uncertain significance in three genes, as potential modifiers of the most severe phenotype, were identified. The p.Arg1596Cys substitution inhibits channel function, affecting steady-state inactivation kinetics. Its clinical manifestations involve not only epileptic symptoms but also increased excitability of peripheral motor fibers. The role of Nav1.1 in excitatory neurons cannot be ruled out as a significant factor of the clinical phenotype. [ABSTRACT FROM AUTHOR]

Congenital myasthenic syndromes (CMS) are a clinically and genetically heterogeneous group of rare diseases due to mutations in neuromuscular junction (NMJ) protein-coding genes. Until now, many mutations encoding postsynaptic proteins as Agrin, MuSK and LRP4 have been identified as responsible for increasingly complex CMS phenotypes. The majority of mutations identified in LRP4 gene causes bone diseases including CLS and sclerosteosis-2 and rare cases of CMS with mutations in LRP4 gene has been described so far. In the French cohort of CMS patients, we identified a novel LRP4 homozygous missense mutation (c.1820A > G; p.Thy607Cys) within the β1 propeller domain in a patient presenting CMS symptoms, including muscle weakness, fluctuating fatigability and a decrement in compound muscle action potential in spinal accessory nerves, associated with congenital agenesis of the hands and feet and renal malformation. Mechanistic expression studies show a significant decrease of AChR aggregation in cultured patient myotubes, as well as altered in vitro binding of agrin and Wnt11 ligands to the mutated β1 propeller domain of LRP4 explaining the dual phenotype characterized clinically and electoneuromyographically in the patient. These results expand the LRP4 mutations spectrum associated with a previously undescribed clinical association involving impaired neuromuscular transmission and limb deformities and highlighting the critical role of a yet poorly described domain of LRP4 at the NMJ. This study raises the question of the frequency of this rare neuromuscular form and the future diagnosis and management of these cases. [ABSTRACT FROM AUTHOR]

Spastic paraplegia type 76 (SPG76) is a subtype of hereditary spastic paraplegia (HSP) caused by calpain-1 (CAPN1) mutations. Our study described the phenotypic and genetic characteristics of three families with spastic ataxia due to various CAPN1 mutations and further explored the pathogenesis of the two novel mutations. The three patients were 48, 39, and 48 years old, respectively. Patients 1 and 3 were from consanguineous families, while patient 2 was sporadic. Physical examination showed hypertonia, hyperreflexia, and Babinski signs in the lower limbs. Patients 2 and 3 additionally had dysarthria and depression. CAPN1 mutations were identified by whole-exome sequencing, followed by Sanger sequencing and co-segregation analysis within the family. Functional examination of the newly identified mutations was further explored. Two homozygous mutations were detected in patient 1 (c.213dupG, p.D72Gfs*95) and patient 3 (c.1729+1G>A) with HSP, respectively. Patient 2 had compound heterozygous mutations c.853C>T (p.R285X) and c.1324G>A (p.G442S). Western blotting revealed the p.D72Gfs*95 with a smaller molecular weight than WT and p.G442S. In vitro, the wild-type calpain-1 is mostly located in the cytoplasm and colocalized with tubulin by immunostaining. However, p.D72Gfs*95 and p.G442S abnormally formed intracellular aggregation, with little colocalization with tubulin. In this study, we identified three cases with SPG76, due to four various CAPN1 mutations, presenting lower limb spasticity and ataxia, with or without bulbar involvement and emotional disorder. Among these, c.213dupG and c.1324G>A are first identified in this paper. The genotype-phenotype correlation of the SPG76 cases reported worldwide was further summarized. [ABSTRACT FROM AUTHOR]

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases with genetic and clinical heterogeneity characterized by spasticity and weakness of the lower limbs. It includes four genetic inheritance forms: autosomal dominant inheritance (AD), autosomal recessive inheritance (AR), X-linked inheritance, and mitochondrial inheritance. To date, more than 82 gene loci have been found to cause HSP, and SPG15 (ZFYVE26) is one of the most common autosomal recessive hereditary spastic paraplegias (ARHSPs) with a thin corpus callosum (TCC), presents with early cognitive impairment and slowly progressive leg weakness. Here, we reported a homozygous pathogenic variant in ZFYVE26. A 19-year-old Chinese girl was admitted to our hospital presenting with a 2-year progressive bilateral leg spasticity and weakness; early cognitive impairment; corpus callosum dysplasia; chronic neurogenic injury of the medulla oblongata supplied muscles; and bilateral upper and lower limbs on electromyogram (EMG). Based on these clinical and electrophysiological features, HSP was suspected. Exome sequencing of the family was performed by high-throughput sequencing, and an analysis of the patient showed a ZFYVE26 NM_015346: c.7111dupA p.(M2371Nfs*51) homozygous mutation. This case reported a new ZFYVE26 pathogenic variant, which was different from the SPG15 gene mutation reported earlier. [ABSTRACT FROM AUTHOR]

Objective: Hereditary 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. Methods: Mutational 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. Results: SPG54 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. Interpretation: SPG54 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. [ABSTRACT FROM AUTHOR]

Schwartz–Jampel syndrome type 1 (SJS1) is a rare autosomal recessive musculoskeletal disorder caused by various mutations in the HSPG2 gene encoding the protein perlecan, a major component of basement membranes. We report a novel splice mutation HSPG2(NM_005529.7):c.3888 + 1G > A and a known point mutation HSPG2(NM_005529.7):c.8464G > A, leading to the skipping of exon 31 and 64 in mRNA, respectively, in a Moroccan child with clinical features suggestive of SJS1 and carrying two compound heterozygous mutations in the HSPG2 gene detected by next-generation sequencing. Both parents harboured one mutation. Real-time and immunostaining analysis revealed down-regulation of the HSPG2 gene and a mild reduction in the protein in the muscle, respectively. We reviewed all genetically characterized SJS1 cases reported in literature, confirming the clinical hallmarks and unspecific instrumental data in our case. The genotype–phenotype correlation is very challenging in SJS1. Therapy is mainly focused on symptom management and several drugs have been administered with different efficacy.Here, we report the second case with spontaneous improvement. [ABSTRACT FROM AUTHOR]

Introduction: Von Hippel Lindau (VHL) syndrome is caused by an autosomal dominant hereditary or sporadic germline mutation of the VHL gene with more than five hundred pathogenic mutations identified. Pheochromocytomas and rarely paragangliomas occur in 10-50% of patients with VHL syndrome usually around 30 years of age and exceptionally before the age of 10. Case presentation: Wediagnoseda 9-year-oldgirlofnormal appearance andsevere refractory hypertension, with a norepinephrine-secreting pheochromocytoma related to VHL syndrome due to a known familial germline heterozygous mutation ofVHLgene(c.414A>G), alsopresent in threemembers ofher family. At age 13, apelvic tumor and a left adrenal pheochromocytoma that showed to be multi-metastatic to both lungs were discovered in the patient leading to left adrenalectomy and pelvic tumor resection. In addition to the germline VHL gene mutation, blood analysis using Next Generation Sequencing identified a novel heterozygous germline mutation of the KIF1B gene (c.3331_3332del; p.Asn1111Glnfs*21), which is only present in the girl and not the other family members. The patient is currently under steroid substitution therapy and leads a normal life. Discussion: This family is notable by the early age of onset of multiple neural crest tumors associated with a high propensity for malignancy and metastatic spread. Most reports in the literature associated the VHL mutation with a later onset in adulthood and a benign course, which contrast with our findings and question the role of this mutation in the phenotype expressed in this kindred. Also, the presence of concomitant mutations in two susceptibility genes for neural crest tumors poses the question of their respective roles in the development of tumors in this family. Our familial case description illustrates the potential for systematic use of targeted Next Generation Sequencing with multi-gene panels in patients with neural crest tumors to confirm the role of known susceptibility genes as well as identifying new ones, but also to contribute to comprehensive databases on gene variants and their phenotypic counterparts in this specific area of medicine. [ABSTRACT FROM AUTHOR]

Background: Oral clefts and ectrodactyly are common, heterogeneous birth defects. We performed whole‐exome sequencing (WES) analysis in a Syrian family. The proband presented with both orofacial clefting and ectrodactyly but not ectodermal dysplasia as typically seen in ectrodactyly, ectodermal dysplasia, and cleft lip/palate syndrome‐3. A paternal uncle with only an oral cleft was deceased and unavailable for analysis. Methods: Variant annotation, Mendelian inconsistencies, and novel variants in known cleft genes were examined. Candidate variants were validated using Sanger sequencing, and pathogenicity assessed by knocking out the tp63 gene in zebrafish to evaluate its role during zebrafish development. Results: Twenty‐eight candidate de novo events were identified, one of which is in a known oral cleft and ectrodactyly gene, TP63 (c.956G > T, p.Arg319Leu), and confirmed by Sanger sequencing. Conclusion: TP63 mutations are associated with multiple autosomal dominant orofacial clefting and limb malformation disorders. The p.Arg319Leu mutation seen in this patient is de novo but also novel. Two known mutations in the same codon (c.956G > A, p.(Arg319His; rs121908839, c.955C > T), p.Arg319Cys) cause ectrodactyly, providing evidence that mutating this codon is deleterious. While this TP63 mutation is the best candidate for the patient's clinical presentation, whether it is responsible for the entire phenotype is unclear. Generation and characterization of tp63 knockout zebrafish showed necrosis and rupture of the head at 3 days post‐fertilization (dpf). The embryonic phenotype could not be rescued by injection of zebrafish or human messenger RNA (mRNA). Further functional analysis is needed to determine what proportion of the phenotype is due to this mutation. [ABSTRACT FROM AUTHOR]

27060254 7 Barca E, Musumeci O, Montagnese F, Marino S, Granata F, Nunnari D. Cerebellar ataxia and severe muscle CoQ10 deficiency in a patient with a novel mutation in ADCK3. Whereas, based on the results of haplotype analysis, the p.(Leu111Pro) mutation in I COQ7 i may be a founder mutation in the Iranian population that results in a distinct phenotype such as HSP or HSP-like disease [[1]]. [Extracted from the article]

Background: Congenital myopathies are a group of clinically, genetically, and histologically heterogeneous diseases caused by mutations in a large group of genes. One of these is CACNA1S, which is recognized as the cause of Dihydropyridine Receptor Congenital Myopathy. Methods: To better characterize the phenotypic spectrum of CACNA1S myopathy, we conducted a systematic review of cases in the literature through three electronic databases following the PRISMA guidelines. We selected nine articles describing 23 patients with heterozygous, homozygous, or compound heterozygous mutations in CACNA1S and we added one patient with a compound heterozygous mutation in CACNA1S (c.1394-2A>G; c.1724T>C, p.L575P) followed at our Institute. We collected clinical and genetic data, muscle biopsies, and muscle MRIs when available. Results: The phenotype of this myopathy is heterogeneous, ranging from more severe forms with a lethal early onset and mild–moderate forms with a better clinical course. Conclusions: Our patient presented a phenotype compatible with the mild–moderate form, although she presented peculiar features such as a short stature, myopia, mild sensorineural hearing loss, psychiatric symptoms, and posterior-anterior impairment gradient on thigh muscle MRI. [ABSTRACT FROM AUTHOR]

We report a 49-year-old patient suffering from spastic paraplegia with a novel heterozygous mutation and analyzed the levels of heat shock proteins (hsp)-27, dopamine (DA), and its metabolites in their cerebrospinal fluid (CSF). The hsp27 protein concentration in the patient's CSF was assayed by an ELISA kit, while DA levels and its metabolites in the CSF, 3,4-dihydroxyphenylacetic acid (DOPAC), Cys-DA, and Cys-DOPA were measured by HPLC. Whole exome sequencing demonstrated SPG-11 c.1951C>T and novel SYNJ1 c.2614G>T mutations, both heterozygous recessive. The patient's DA and DOPAC levels in their CSF were significantly decreased (53.0 ± 6.92 and 473.3 ± 72.19, p < 0.05, respectively) while no differences were found in their Cys-DA. Nonetheless, Cys-DA/DOPAC ratio (0.213 ± 0.024, p < 0.05) and hsp27 levels (1073.0 ± 136.4, p < 0.05) were significantly higher. To the best of our knowledge, the c.2614G>T SYNJ1 mutation has not been previously reported. Our patient does not produce fully functional spatacsin and synaptojanin-1 proteins. In this line, our results showed decreased DA and DOPAC levels in the patient's CSF, indicating loss of DAergic neurons. Many factors have been described as being responsible for the increased cys-DA/DOPAC ratio, such as MAO inhibition and decreased antioxidant activity in DAergic neurons which would increase catecholquinones and consequently cysteinyl-catechols. In conclusion, haploinsufficiency of spatacsin and synaptojanin-1 proteins might be the underlying cause of neurodegeneration produced by protein trafficking defects, DA vesicle trafficking/recycling processes, autophagy dysfunction, and cell death leading to hsp27 upregulation as a cellular mechanism of protection and/or to balance impaired protein trafficking. [ABSTRACT FROM AUTHOR]

A 24-year-old man presented with insidious onset progressive gait disturbance and was finally diagnosed with autosomal recessive hereditary spastic paraplegia. Two novel mutations, including a frameshift mutation (c.5687_5691del) and a non-sense mutation (c.751C>T), were identified in the SPG11 gene of the patient through whole genome sequencing. The frameshift mutation of c.5687_5691del leads to a change in amino acid synthesis beginning with amino acid No. 1896 arginine and terminating at the 8th amino acid after the change (p. Arg1896MetfsTer8). The non-sense mutation (c.751C>T) causes the conversion of codon 251st encoding the amino acid Gln into a stop codon (p. Gln251Ter), resulting in premature termination of peptide synthesis. Although confirmation of compound-heterozygosity could not be performed, our findings enriched the phenotypic spectrum of SPG11 mutations related to hereditary spastic paraplegia. [ABSTRACT FROM AUTHOR]

Objective: Spastic paraplegia type 2 (SPG2) is an X‐linked recessive (XLR) form of hereditary spastic paraplegia (HSP) caused by mutations in proteolipid protein 1 (PLP1) gene. We described the clinical and genetic features of three unrelated families with PLP1 mutations and reviewed PLP1‐related cases worldwide to summarize the genotype–phenotype correlations. Methods: The three probands were 23, 26, and 27 years old, respectively, with progressively aggravated walking difficulty as well as lower limb spasticity. Detailed physical examination showed elevated muscle tone, hyperreflexia, and Babinski signs in lower limbs. Brain MRI examinations were investigated for all cases. PLP1 mutations were identified by whole exome sequencing, followed by Sanger sequencing, family co‐segregation, and phenotypic reevaluation. Results: A total of eight patients with SPG2 were identified in these three families. The probands additionally had cognitive impairment, urinary or fecal incontinence, ataxia, and white matter lesions (WML) in periventricular regions, with or without kinetic tremor. Three hemizygous mutations in PLP1 were identified, including c.453+159G>A, c.834A>T (p.*278C), and c.434G>A (p.W145*), of which c.834A>T was first associated with HSP. Interpretation: We identified three families with complicated SPG2 due to three PLP1 mutations. Our study supports the clinically inter‐and intra‐family heterogeneity of SPG2. The periventricular region WML and cognitive impairment are the most common characteristics. The kinetic tremor in upper limbs was observed in 2/3 families, suggesting the spectrum of PLP1‐related disorders is still expanding. [ABSTRACT FROM AUTHOR]

Objective: NIPA1 mutations have been implicated in hereditary spastic paraplegia (HSP) as the cause of spastic paraplegia type 6 (SPG6). The aim of this study was to investigate the clinical and genetic features of SPG6 in a Taiwanese HSP cohort. Methods: We screened 242 unrelated Taiwanese patients with HSP for NIPA1 mutations. The clinical features of patients with a NIPA1 mutation were analyzed. Minigene‐based splicing assay, RT‐PCR analysis on the patients' RNA, and cell‐based protein expression study were utilized to assess the effects of the mutations on splicing and protein expression. Results: Two patients were identified to carry a different heterozygous NIPA1 mutation. The two mutations, c.316G>A and c.316G>C, are located in the 3′ end of NIPA1 exon 3 near the exon–intron boundary and putatively lead to the same amino acid substitution, p.G106R. The patient harboring NIPA1 c.316G>A manifested spastic paraplegia, epilepsy and schizophrenia since age 17 years, whereas the individual carrying NIPA1 c.316G>C had pure HSP since age 12 years. We reviewed literature and found that epilepsy was present in multiple individuals with NIPA1 c.316G>A but none with NIPA1 c.316G>C. Functional studies demonstrated that both mutations did not affect splicing, but only the c.316G>A mutation was associated with a significantly reduced NIPA1 protein expression. Interpretation: SPG6 accounted for 0.8% of HSP cases in the Taiwanese cohort. The NIPA1 c.316G>A and c.316G>C mutations are associated with adolescent‐onset complex and pure form HSP, respectively. The different effects on protein expression of the two mutations may be associated with their phenotypic discrepancy. [ABSTRACT FROM AUTHOR]

Valosin-containing protein (VCP) gene mutations have been associated with a rare autosomal dominant, adult-onset progressive disease known as multisystem proteinopathy 1 (MSP1), or inclusion body myopathy (IBM), Paget's disease of bone (PDB), frontotemporal dementia (FTD), (IBMPFD), and amyotrophic lateral sclerosis (ALS). We report the clinical and genetic analysis findings in five patients, three from the same family, with novel VCP gene variants: NM_007126.5 c.1106T>C (p.I369T), c.478G>A (p.A160T), and c.760A>T (p.I254F), associated with cardinal MSP1 manifestations including myopathy, PDB, and FTD. Our report adds to the spectrum of heterozygous pathogenic variants found in the VCP gene and the high degree of clinical heterogeneity. This case series prompts increased awareness and early consideration of MSP1 in the differential diagnosis of myopathies and/or PDB, dementia, or ALS to improve the diagnosis and early management of clinical symptoms. [ABSTRACT FROM AUTHOR]

Background: As a rare genetic disease, adrenomyeloneuropathy (AMN) is the most common adult phenotype of X-linked adrenoleukodystrophy (X-ALD). Mutations in the ABCD1 gene have been identified to cause AMN. Methods: We applied clinical evaluation, laboratory tests, and neuroimaging on three patients with progressive spastic paraparesis. In genetic analysis, we investigated ABCD1 gene mutations by whole-exome sequencing and Sanger sequencing. Bioinformatics tools were used to predict the eects of identified ABCD1 mutations on the protein. Results: All three patients were men with adult-onset disease, mainly characterized by progressive spastic paraparesis. Among them, two patients had peripheral neuropathy and one patient had signs of adrenal insufficiency. All three patients showed cerebral involvement on brain MRI, while two patients were found with diuse cord atrophy on spinal MRI. High-VLCFA levels in plasma, as well as C24:0/C22:0 and C26:0/C22:0 ratios, were found in all three patients. In addition, three dierent ABCD1 mutations were identified in three unrelated Chinese families, including one known mutation (c.1415_1416delAG) and two novel mutations (c.217C>T and c.160_170delACGCAGGAGGC). Based on the clinical assessment, radiographic, biochemical, and genetic testing, the final diagnosis was AMN in these patients with spastic paraparesis. Conclusion: This study reported three patients with AMN and identified two novel mutations in the ABCD1 in the Chinese population. Our finding emphasized that XALD is an important cause of adult-onset spastic paraplegia. Thus, neuroimaging, VLCFA testing, and especially the detection of the ABCD1 gene have important implications for the etiological diagnosis of adult patients with spastic paraplegia. [ABSTRACT FROM AUTHOR]

Amelogenesis imperfecta (AI) is a heterogeneous collection of hereditary enamel defects. The affected enamel can be classified as hypoplastic, hypomaturation, or hypocalcified in form. A better understanding of normal amelogenesis and improvements in our ability to diagnose AI through genetic testing can be realized through more complete knowledge of the genes and disease-causing variants that cause AI. In this study, mutational analysis was performed with whole exome sequencing (WES) to identify genetic etiology underlying the hypomaturation AI condition in affected families. Mutational analyses identified biallelic WDR72 mutations in four hypomaturation AI families. Novel mutations include a homozygous deletion and insertion mutation (NM_182758.4: c.2680_2699delinsACTATAGTT, p.(Ser894Thrfs*15)), compound heterozygous mutations (paternal c.2332dupA, p.(Met778Asnfs*4)) and (maternal c.1287_1289del, p.(Ile430del)) and a homozygous 3694 bp deletion that includes exon 14 (NG_017034.2:g.96472_100165del). A homozygous recurrent mutation variant (c.1467_1468delAT, p.(Val491Aspfs*8)) was also identified. Current ideas on WDR72 structure and function are discussed. These cases expand the mutational spectrum of WDR72 mutations causing hypomaturation AI and improve the possibility of genetic testing to accurately diagnose AI caused by WDR72 defects. [ABSTRACT FROM AUTHOR]

Objective: Mutations in protein O-mannosyltransferase 2 (POMT2) (MIM#607439) have been identified in severe congenital muscular dystrophy such as Walker-Warburg syndrome (WWS) and milder limb-girdle muscular dystrophy type 2N (LGMD2N). The aim of this study is to investigate the genetic causes in patients with LGMD2N. Methods: Three patients diagnosed with mild limb-girdle muscular dystrophy were recruited. The genetically pathogenic variant was identified by clinical exome sequencing, and healthy controls were verified by Sanger sequencing. Results: Novel compound heterozygous mutations c.800A > G and c.1074_1075delinsAT of POMT2 were revealed in one affected individual by clinical exome sequencing. There was no report of these two variants and predicted to be highly damaging to the function of the POMT2. Conclusion: The novel variants extend the spectrum of POMT2 mutations, which promotes the prognostic value of testing for POMT2 mutations in patients with LGMD2N. [ABSTRACT FROM AUTHOR]

Introduction: Spastic paraplegia type 54 (SPG54) is an autosomal recessive disorder caused by bi-allelic mutations in the DDHD-domain-containing protein 2 (DDHD2) gene. Worldwide, over 24 SPG54 families and 24 pathogenic variants have been reported. Our study aimed to describe the clinical and molecular findings of a pediatric patient from a consanguineous Iranian family with significant motor development delay, walking problems, paraplegia, and optic atrophy. Methods: The patient was a 7-year-old boy with severe neurodevelopmental and psychomotor problems. Neurological examinations, laboratory tests, electroencephalography, computed tomography scan, and brain magnetic resonance scan (MRI) were carried out for clinical evaluation. Whole-exome sequencing and in silico analysis were undertaken to identify the genetic cause of the disorder. Results: The neurological examination showed developmental delay, spasticity in the lower extremities, ataxia, foot contractures, and deep tendon reflexes in the extremities. The computed tomography scan was normal, but MRI revealed corpus callosum thinning with atrophic changes in the white matter. The genetic study reported a homozygous variant (c.856 C>T, p.Gln286Ter) in the DDHD2 gene. The homozygous state was confirmed by direct sequencing in the proband and his 5-year-old brother. This variant was not reported as a pathogenic variant in the literature or genetic databases and was predicted to affect the function of the DDHD2 protein. Conclusion: The clinical symptoms in our cases were similar to the previously reported phenotype of SPG54. Our results deepen the molecular and clinical spectrum of SPG54 to facilitate future diagnoses. [ABSTRACT FROM AUTHOR]

Background: Nephronophthisis type 12 (NPHP 12) is a rare cilia‐related cystic kidney disease, caused by TTC21B mutation, mainly involving the kidneys, which generally occurs in children. Our study aimed to illustrate its clinical, pathological and genetic characteristics by reporting an adult‐onset case of NPHP 12 caused by a single heterozygous nonsense mutation of TTC21B confirmed by renal histology and whole exome sequencing and reviewing related literature with a comparative analysis of the clinical features of each case. It will further increase the recognition of this rare kidney genetic disease, which sometimes can manifest as an adult disease. Results: A 33‐years‐old man showed a chronic disease course, and he exhibited slight renal dysfunction (CKD stage 3, eGFR = 49 ml/[min* 1.73 m2]) with renal tubular proteinuria, without any extrarenal manifestations, congenital malformation history of kidney disease, or family hereditary disease. Renal histological findings showed substantial interstitial fibrosis with some irregular and tortuous tubules with complex branches and segmental thickening and splitting of the tubular basement membrane. The patient was diagnosed with chronic interstitial nephritis for an unknown reason clinically. Further genetic analysis revealed a single heterozygous nonsense mutation in the TTC21B gene and NPHP 12 was diagnosed finally. Conclusion: A single heterozygous mutation in the TTC21B gene may cause atypical NPHP12, which had a relatively later onset and milder clinical symptoms without developmental abnormalities. Therefore, for unexplained adult‐onset chronic interstitial nephritis with unusual changes of renal tubules and interstitial fibrosis, even without a clear history of hereditary kidney disease, genetic testing is still recommended. The correct diagnosis of this rare adult‐onset hereditary nephropathy can avoid unnecessary treatment. [ABSTRACT FROM AUTHOR]

Hereditary spastic paraplegias are characterized by lower limb spasticity resulting from degeneration of long corticospinal axons. SPG11 is one of the most common autosomal recessive hereditary spastic paraplegias, and the SPG11 protein spatacsin forms a complex with the SPG15 protein spastizin and heterotetrameric AP5 adaptor protein complex, which includes the SPG48 protein AP5Z1. Using the integration-free episomal method, we established SPG11 patient-specific induced pluripotent stem cells (iPSCs) from patient fibroblasts. We differentiated SPG11 iPSCs, as well as SPG48 iPSCs previously established, into cortical projection neurons and examined protective effects by targeting mitochondrial dynamics using P110, a peptide that selectively inhibits mitochondrial fission GTPase Drp1. P110 treatment mitigates mitochondrial fragmentation, improves mitochondrial motility, and restores mitochondrial health and ATP levels in SPG11 and SPG48 neurons. Neurofilament aggregations are increased in SPG11 and SPG48 axons, and these are also suppressed by P110. Similarly, P110 mitigates neurofilament disruption in both SPG11 and SPG48 knockdown cortical projection neurons, confirming the contribution of hereditary spastic paraplegia gene deficiency to subsequent neurofilament and mitochondrial defects. Strikingly, neurofilament aggregations in SPG11 and SPG48 deficient neurons double stain with ubiquitin and autophagy related proteins, resembling the pathological hallmark observed in SPG11 autopsy brain sections. To confirm the cause-effect relationship between the SPG11 mutations and disease phenotypes, we knocked-in SPG11 disease mutations to human embryonic stem cells (hESCs) and differentiated these stem cells into cortical projection neurons. Reduced ATP levels and accumulated neurofilament aggregations along axons are observed, and both are mitigated by P110. Furthermore, rescue experiment with expression of wild-type SPG11 in cortical projection neurons derived from both SPG11 patient iPSCs and SPG11 disease mutation knock-in hESCs leads to rescue of mitochondrial dysfunction and neurofilament aggregations in these SPG11 neurons. Finally, in SPG11 and SPG48 long-term cultures, increased release of phosphoNF-H, a biomarker for nerve degeneration, is significantly reduced by inhibiting mitochondrial fission pharmacologically using P110 and genetically using Drp1 shRNA. Taken together, our results demonstrate that impaired mitochondrial dynamics underlie both cytoskeletal disorganization and axonal degeneration in SPG11 and SPG48 neurons, highlighting the importance of targeting these pathologies therapeutically. [ABSTRACT FROM AUTHOR]

SPTLC1 has been implicated in hereditary sensory and autonomic neuropathy type 1 (HSAN1) and macular telangiectasia type2. Recent studies have reported mutations in SPLTC1 may cause juvenile amyotrophic lateral sclerosis (JALS), especially in the first transmembrane domain of SPTLC1(exon 2). In this study, we identified a novel heterozygous variant in exon 2, c.113 T > C: p. Leu38Arg, of SPTLC1 in a 12-year-old girl with sporadic JALS who experienced early-childhood-onset lower extremity spasticity followed by slowly progressive lower motor weakness and atrophy without sensory symptoms or signs. SPLTC1 is the first monogenic lipid metabolic disturbance that has been linked to ALS. The variant in exon 2 may impact on negative regulation of sphingolipid biosynthesis. [ABSTRACT FROM AUTHOR]

Osteopetrosis (from the Greek "osteo": bone; "petrosis": stone) is a clinically and genetically heterogeneous group of rare diseases of the skeleton, sharing the same main characteristic of an abnormally increased bone density. Dense bones in radiological studies are considered the hallmark of these diseases, and the reason for the common term used: "Marble bone disease". Interestingly, a radiologist, Dr. Albers-Schonberg, described this disease for the first time in Germany in 1904. Indeed, radiology has a key role in the clinical diagnosis of osteopetrosis and is fundamental in assessing the disease severity and complications, as well as in follow-up controls and the evaluation of the response to treatment. Osteopetrosis includes a broad spectrum of genetic mutations with very different clinical symptoms, age onset, and prognosis (from mild to severe). This diversity translates into different imaging patterns related to specific mutations, and different disease severity. The main recognized types of osteopetrosis are the infantile malignant forms with autosomal recessive transmission (ARO—including the rarer X-linked recessive form); the intermediate autosomal recessive form (IAO); and the autosomal dominant ones ADO, type I, and type II, the latter being called 'Albers-Schonberg' disease. Imaging features may change among those distinct types with different patterns, severities, skeletal segment involvement, and speeds of progression. There are several classical and well-recognized radiological features related to osteopetrosis: increased bone density (all types with different degrees of severity assuming a 'Marble Bone Appearance' especially in the ARO type), different metaphyseal alterations/enlargement including the so-called 'Erlenmeyer flask deformity' (particularly of femoral bones, more frequent in ADO type 2, and less frequent in ARO and IAO), 'bone in bone' appearance (more frequent in ADO type 2, less frequent in ARO and IAO), and 'rugger-jersey spine' appearance (typical of ADO type 2). After conducting an overview of the epidemiological and clinical characteristic of the disease, this review article aims at summarizing the main radiological features found in different forms of osteopetrosis together with their inheritance pattern. [ABSTRACT FROM AUTHOR]

Congenital pseudarthrosis of the tibia (CPT) is a rare congenital bone malformation, which has a strong relationship with Neurofibromatosis type 1 (NF1). NF1 is an autosomal dominant disease leading to multisystem disorders. Here, we presented the genotypic and phenotypic characteristics of one unique case of a five-generation Chinese family. The proband was CPT accompanied with NF1 due to NF1 mutation. The proband developed severe early-onset CPT combined with NF1 after birth. Appearance photos and X-ray images of the left limb of the proband showed significant bone malformation. Slit-lamp examination showed Lisch nodules in both eyes of the proband. Wholeexome sequencing (WES) and Sanger sequencing confirmed the truncation variant of NF1 (c.871G>T, p. E291*). Sequence conservative and evolutionary conservation analysis indicated that the novel mutation (p.E291*) was highly conserved. The truncated mutation led to the loss of functional domains, including CSRD, GRD, TBD, SEC14-PH, CTD, and NLS. It may explain why the mutation led to a severe clinical feature. Our report expands the genotypic spectrum of NF1 mutations and the phenotypic spectrum of CPT combined with NF1. [ABSTRACT FROM AUTHOR]

The hereditary spastic paraplegias (HSP) are among the most genetically diverse of all Mendelian disorders. They comprise a large group of neurodegenerative diseases that may be divided into 'pure HSP' in forms of the disease primarily entailing progressive lower-limb weakness and spasticity, and 'complex HSP' when these features are accompanied by other neurological (or non-neurological) clinical signs. Here, we identified biallelic variants in the transmembrane protein 63C (TMEM63C) gene, encoding a predicted osmosensitive calcium-permeable cation channel, in individuals with hereditary spastic paraplegias associated with mild intellectual disability in some, but not all cases. Biochemical and microscopy analyses revealed that TMEM63C is an endoplasmic reticulum-localized protein, which is particularly enriched at mitochondria-endoplasmic reticulum contact sites. Functional in cellula studies indicate a role for TMEM63C in regulating both endoplasmic reticulum and mitochondrial morphologies. Together, these findings identify autosomal recessive TMEM63C variants as a cause of pure and complex HSP and add to the growing evidence of a fundamental pathomolecular role of perturbed mitochondrial-endoplasmic reticulum dynamics in motor neurone degenerative diseases. [ABSTRACT FROM AUTHOR]

Hereditary spastic paraplegia (HSP) is a group of neurodegenerative disorders with a predominant lesion of the pyramidal tract. The autosomal dominant form of SPG3A, associated with mutations in the ATL1 gene, is one of the most common forms of HSP in European populations. Analysis of the ATL1 gene was performed in 63 unrelated families with HSP from the Republic of Bashkortostan. Two pathogenic variants were identified: one patient had a duplication of the entire third exon, and seven patients from three unrelated families had a missense mutation c.1246C>T (p.Arg416Cys). The frequency of SPG3A among unrelated patients in Bashkortostan was 6.3%. In one of the examined families, the origin of the c.1246C>T de novo mutation was established. The clinical symptoms of the disease in most cases correspond to uncomplicated HSP occurring in a mild form. Intrafamilial differences in clinical manifestations of the disease, including in identical twins, were revealed. The age of manifestation in the majority of examined patients ranged from 10 to 50 years. [ABSTRACT FROM AUTHOR]

Complicated Hereditary Spastic Paraparesis (HSP) is a group of heterogenous neurodegenerative disease characterized by progressive spastic paraparesis with additional features like cognitive impairment, seizures, movement disorders, visual loss, deafness, peripheral neuropathy, and pes cavus. There have been few case series reported in literature from India. We herein report four cases of complicated HSP. Four (three females and 1 male) patients of genetically confirmed HSP with a mean age of onset 10.5 years were recruited. There was mean delay of 8 years in reaching diagnosis. MRI brain showed thinning of corpus callosum in three patients and Ear of lynx sign in two patients. Next Generation Clinical Exome Sequencing confirmed mutations in SPG11 gene in three patients and SLC2A1 in one patient. SPG11 gene mutations were the most frequent genetic abnormality with SLC2A1 gene mutation in single patient. Genetically confirmed diagnosis helps in prognostication and genetic counselling. [ABSTRACT FROM AUTHOR]

Background: Hereditary spastic paraplegias (HSPs) are a heterogeneous group of rare neurodegenerative disorders affecting the corticospinal tracts, and more than 80 HSP loci have been mapped to cause HSP. In this study, we aim to perform a genetic and clinical study of ten (6 male, 4 female) sporadic Chinese HSP patients.Methods: Next-generation sequencing (NGS) gene panels combined with multiplex ligation-dependent probe amplification assay (MLPA) analysis and the trinucleotide repeat dynamic mutation detection are available for the ten patients.Results: Among the 10 patients, one SPG7 patient, one SPG11 patient, and one pure SPG31 patient were detected. Two variants (deletion of exon 3-9 of SPG7 gene and the heterozygous mutation c.1861C > T/p.Q621* of SPG11 gene) were novel and three (c.1150_1150 + 1insCTAC/p.G384Afs*13 in SPG7 gene, c.3075dupA/p.E1026Rfs*4 in SPG11 gene, and c.478delA/p.R160Gfs*63 of REEP1 gene/SPG31) were previously reported. The SPG11 patient presented mild intellectual with peripheral neuropathy and thin corpus callosum (TCC) with no white matter abnormalities (WMA). The SPG7 patient detected in this study is the third SPG7 family reported in China; he manifested peripheral neuropathy, scoliosis, and polydactyly which expand the phenotype spectrum of SPG7.Conclusions: The AAO overlapped among each HSP subtype, which limited the ability to predict the subtype of HSP from AAO. Compared with non-Asian patients, the mutation frequency of SPG7 is relatively low in Asian populations. Considering the varieties of mutation types of HSP, we suggested targeted sequencing gene panels should be combined with MLPA for diagnosis of HSP. [ABSTRACT FROM AUTHOR]

Pathogenic variants in the ABCD1 gene on the X chromosome may result in widely heterogenous phenotypes, including adrenomyeloneuropathy (AMN). Affected males typically present in their third or fourth decade of life with progressive lower limb weakness and spasticity, and may develop signs and symptoms of adrenal insufficiency and/or cerebral demyelination. Heterozygous females may be asymptomatic, but may develop a later-onset and more slowly progressive spastic paraparesis. In this review, we describe the clinical presentation of AMN, as well as its diagnosis and management. The role of rehabilitative therapies and options for management of spasticity are highlighted. [ABSTRACT FROM AUTHOR]

Hereditary Spastic Paraplegia (HSP) is considered to be one of the common neurodegenerative diseases with marked genetic heterogeneity. Recently, the mutations in ubiquitin-associated protein 1 (UBAP1) have been described in patients with HSP, known as spastic paraplegias 80 (SPG80). Here, we reported a Chinese HSP family presenting a frameshift mutation in the UBAP1 gene leading to complex HSP. Their clinical features encompassed spastic paraparetic gait, exaggerated patellar tendon reflexes, bilateral Babinski signs, and hyperactive Achilles tendon reflex. The proband also had severe urinary incontinence and a dermoid cyst at the lumbar 4-5 spinal cord, which rarely occurs in HSP patients. Following whole-exome sequencing, a novel heterozygous mutation (c.437dupG, NM_016,525) was identified in the UBAP1 that segregated with the family's phenotype and resulted in truncating UBAP1 protein (p. Ser146ArgfsTer13). Moreover, we reviewed the genotypes of UBAP1 and the phenotypic variability in 90 HSP patients reported in the literature. We found that the age of onset in UBAP1-related patients was juvenile, and there were population differences in the age of onset. The main complications were lower extremity spasticity, hyperreflexia, and the Babinski sign. Exon 4 of UBAP1 was identified as a mutation hotspot region. Our study expands the knowledge of UBAP1 mutations, which will aid in HSP patient counseling. Further molecular biological research is needed to explore the genotype-phenotype correlations of UBAP1-related HSP. [ABSTRACT FROM AUTHOR]

• Identification and validation of a novel "de novo" missense heterozygous mutation of the KMT2D. • Evolutionary conservation and 2D structure of KMT2D prediction. • Haplotype construction and clone sequencing; the mother may be gonadal mosaicism. Here we reported a pedigree that gave birth to two characteristic clinical signs of Kabuki syndrome daughters. They had an intellectual disability with special facial features. Their eyebrows were relatively wide and the rear 1/3 of the eyebrows were light and sparse. Their eyes were long, narrow, valgus and strabismus. Their noses were broad at the root and flat at the tip. They also had skeletal dysplasia, mainly manifested in the short second knuckle of the little fingers of both hands. Genetic studies showed a novel de novo KMT2D variant (c.16343G > C; p.R5448P) as a cause of Kabuki syndrome. It was very unlikely that the same de novo mutation occurred in two members of a family. Gonadal mosaicism in one of the parents was suspected. Haplotype construction and clone sequencing were used for mutation source analysis. Finally, we inferred that the haplotype from the mother (Gdel-G-C-T-A) contained the pathogenic mutation. A gonadal mosaicism novel KMT2D mutation was identified in their mother. [ABSTRACT FROM AUTHOR]

Background: Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases characterized by lower-limb spastic paraplegia with highly genetic and clinical heterogeneity. However, the clinical sign of spastic paraplegia can also be seen in a variety of hereditary neurologic diseases with bilateral corticospinal tract impairment. The purpose of this study is to identify the disease spectrum of spastic paraplegia, and to broaden the coverage of genetic testing and recognize clinical, laboratorial, electrophysiological and radiological characteristics to increase the positive rate of diagnosis.Methods: Twenty-seven cases were screened out to have definite or suspected pathogenic variants from clinically suspected HSP pedigrees through HSP-associated sequencing and/or expanded genetic testing. One case was performed for enzyme detection of leukodystrophy without next-generation sequencing. In addition, detailed clinical, laboratorial, electrophysiological and radiological characteristics of the 28 patients were presented.Results: A total of five types of hereditary neurological disorders were identified in 28 patients, including HSP (15/28), leukodystrophy (5/28), hereditary ataxia (2/28), methylmalonic acidemia/methylenetetrahydrofolate reductase deficiency (5/28), and Charcot-Marie-tooth atrophy (1/28). Patients in the HSP group had chronic courses, most of whom were lower limbs spasticity, mainly with axonal neuropathy, and thinning corpus callosum, white matter lesions and cerebellar atrophy in brain MRI. In the non-HSP groups, upper and lower limbs both involvement was more common. Patients with homocysteine remethylation disorders or Krabbe's disease or autosomal recessive spastic ataxia of Charlevoix-Saguenay had diagnostic results in laboratory or imaging examination. A total of 12 new variants were obtained.Conclusions: HSP had widespread clinical and genetic heterogeneity, and leukodystrophy, hereditary ataxia, Charcot-Marie-Tooth atrophy and homocysteine remethylation disorders accounted for a significant proportion of the proposed HSP. These diseases had different characteristics in clinical, laboratorial, electrophysiological, and radiological aspects, which could help differential diagnosis. Genetic analysis could ultimately provide a clear diagnosis, and broadening the scope of genetic testing could improve the positive rate of diagnosis. [ABSTRACT FROM AUTHOR]

Background: Genetic factors play an important role in the pathogenesis of early-onset Parkinson's disease (EOPD). To date, more than 20 pathogenic genes associated with Parkinson's disease (PD) have been identified. This study aims to explore the mutation spectrum of EOPD and the clinical characteristics of mutation carriers in eastern China. Methods: We recruited 155 unrelated EOPD patients, including 8 familial and 147 sporadic EOPD (age at onset ≤ 50 years). Overall, 24 known PD-associated genes were detected by whole exome sequencing and multiplex ligation-dependent probe amplification (MLPA) from patient samples. The genetic and clinical characteristics of pathogenic/likely pathogenic (P/LP) loci in this cohort were analyzed. Results: Overall, 14 (9.03%) patients were detected with P/LP variants distributed in seven genes. The most frequent mutation occurred in PRKN (7/155, 4.52%), followed by LRRK2 (2/155, 1.29%), SNCA , CHCHD2 , TMEM230 , DNAJC13 and PLA2G6 (1/155, 0.64%, respectively). Exon rearrangement mutations accounted for 57.9% (11/19) of all mutations in PRKN. Four novel variants were detected: c.14T > C (p.M5T) in SNCA , c.297C > A (p.Y99X) in CHCHD2 , c.2578C > T (p.R860C) in DNAJC13 and c.4C > T (p.Q2X) in TMEM230. We found the first case of LRRK2 c.6055G > A (p.G2019S) mutation in Chinese population. The median onset age of patients with P/LP mutations in autosomal recessive genes (PRKN and PLA2G6) was about 18.0 years earlier than patients without mutation. The proportion of patients with mutations were 63.64%, 27.03% and 9.68% when patients were stratified according to the age of onset at ≤ 30, ≤ 40 and ≤ 50 years, respectively. Conclusion: Early-onset Parkinson's disease patients from eastern China present a regional specific mutation spectrum. Analysis of larger patient cohorts is required to support these findings, and mechanistic studies of the four novel missense/non-sense mutations will clarify their role in the pathogenicity of EOPD. [ABSTRACT FROM AUTHOR]

Background and Purpose: A variety of hereditary diseases overlap with neurological phenotypes or even share genes with hereditary spastic paraplegia (HSP). The aim of this study was to determine the clinical features and genetic spectrum of patients with clinically suspected HSPs. Methods: A total of 52 patients with clinically suspected HSPs were enrolled in this study. All the patients underwent next-generation sequencing (NGS) and triplet repeat primed PCR to screen for the dynamic mutations typical of spinocerebellar ataxia (SCA). Multiplex ligation-dependent probe amplification (MLPA) was further conducted in patients with no causative genetic mutations detected to examine for large deletions and duplications in genes of SPAST, ATL1, REEP1, PGN, and SPG11. Clinical characteristics and findings of brain MRI were analyzed in patients with definite diagnoses. Results: The mean age of the patients studied was 36.90 ± 14.57 years. 75% (39/52) of patients manifested a phenotype of complex form of HSPs. A genetic diagnosis was made in 51.9% (27/52) of patients, of whom 40.3% (21/52) of patients had mutations in HSPs genes (SPG4/SPG6/SPG8/SPG11/SPG15/SPG78/SPG5A) and 11.5% (6/52) of patients had mutations in SCAs genes (SCA3/SCA17/SCA28). SPG4 and SPG11 were the most common cause of pure form of HSPs (5/6, 83.3%) and complex form of HSPs (5/15, 33.3%), respectively. Gait disturbance was the most common initial symptom in both the patients with HSPs (15/21) and in patients with SCAs (5/6). Dysarthria and cerebellar ataxia were detected in 28.5% (6/21) and 23.8% (5/21) of patients with HSPs, respectively, and were the most common symptoms in addition to progressive weakness and spasticity of the lower limbs. Cerebellar atrophy was seen on the brain MRI of patients with SPG5A, SCA3, and SCA28. Conclusion: Causative genetic mutations were identified in 51.9% of patients with clinically suspected HSPs by NGS and triplet repeat primed PCR. A final diagnosis of HSPs or SCAs was made in 40.3% and 11.5% of patients, respectively. The clinical manifestations and neuroimaging findings overlapped between patients with HSPs and patients with SCAs. Dynamic mutations should be screened in patients with clinically suspected HSPs, especially in those with phenotypes of complex form of HSPs. [ABSTRACT FROM AUTHOR]

Background: Mutations in the NIPA1 gene cause hereditary spastic paraplegia (HSP) type 6 (SPG6), which is a rare type of HSP with a frequency of less than 1% in Europe. To date, less than 30 SPG6 families and limited NIPA1 mutations have been reported in different ethnic regions. The clinical features are variable. Methods: We screened for NIPA1 mutations by whole exome sequencing or next generation sequencing in 35 unrelated Chinese families with HSP. The clinical manifestations were evaluated. Results: Two variants of NIPA1 were identified in three index patients (3/35, 8.6%), two of whom carried a previously reported common variant c.316G > A (p.G106R), and the third patient harbored a novel likely pathogenic variant c.126C > G (p.N42K). Both variants were de novo in the three index patients. The phenotype was pure HSP in two patients and complicated HSP with epilepsy in the third one. Conclusion: NIPA1 -related HSP is more common in China than it in Europe. Both pure and complicated form of HSP can be found. The variant c.316G > A is a hotspot mutation, and the novel variant c.126C > G expands the mutational spectrum. The phenomenon of de novo mutations in NIPA1 emphasizes the need to consider autosomal dominant HSP-related genes in sporadic patients. [ABSTRACT FROM AUTHOR]

Background: Beckwith–Wiedemann syndrome (BWS) is an inherited disorder affecting 1 in 10,500 to 13,700 newborns worldwide. The disease is caused in a vast majority of patients by a molecular defect in the imprinted chromosome 11p15.5. Hereditary spherocytosis (HS) is a form of hemolytic anemia associated with a variety of mutations leading to congenital red blood cell (RBC) membrane defects. The prevalence of HS varies by geographic regions around the world, ranging from 1.2 in 100,000 in Asia to 1 in 2000 in Northern Europe. Methods and Results: Herein, we report for the first time a rare case diagnosed with co‐existing BWS and HS. Based on the classical presentations, including macroglossia, hepatosplenomegaly, and macrosomia, the patient was first suspected with BWS. MS‐MLPA confirmed the BWS diagnosis based on hypomethylation of maternal 11p15.5 (KCNQ1OT1), but no copy number variations in chromosome 11 was detected by CNV‐seq. Nevertheless, to scrutinize molecular causes of other symptoms of the patient, including anemia, hyperbilirubinemia, and jaundice, a whole exome sequencing (WES) was performed. We identified a novel and de novo mutation in ANK1 gene (c.520delC). This frameshift mutation of ANK1 gene results in a truncated protein without important functional domains and impaired membrane stability and structure of the resultant red blood cells (RBCs), leading to a definitive diagnosis of HS. Conclusion: The present case demonstrated that multiple genetic and epigenetic aberrations might co‐exist in the complex genetic diseases. For such kind of complicated cases, the different types of molecular tests, such as WES and MS‐MLPA, should be utilized in combination to reveal independent causal molecular events. The identifications from this study added new insights into the understanding of molecular mechanisms underlying the co‐existing HS and BWS. [ABSTRACT FROM AUTHOR]

Hereditary spherocytosis (HS) is the most frequently observed chronic non-immune hemolytic disorder caused by altered red cell membrane function. SPTB gene mutation is one of the most common causes of HS, but pathogenicity analyses and pathogenesis research on these mutations have not been widely conducted. In this study, a novel heterozygous mutation of the SPTB gene (c.1509_1518del; p.K503Nfs*67) was identified in a Chinese family with HS by whole-exome sequencing (WES) and was then confirmed by Sanger sequencing. Next, the pathogenicity and pathogenesis of this mutation were studied using peripheral blood. We found that this mutation disrupted the synthesis and localization of β-spectrin and weakened the interaction between β-spectrin and ankyrin, which may be caused by the nonsense-mediated mRNA degradation pathway. These changes lead to the transformation of discoid erythrocytes into spherocytes, resulting in hemolytic anemia. Therefore, we classified this novel mutation as a pathogenic mutation leading to loss-of-function of β-spectrin. It would be insightful to perform the same mutation test and to provide genetic counseling to other relatives of the proband. Our study increases the current understanding of the molecular mechanisms related to mutations in SPTB. [ABSTRACT FROM AUTHOR]

Krabbe disease (KD) is a rare autosomal recessive lipid storage leukodystrophy. It is caused by deficient enzyme activity resulting from mutations of the β-galactocerebrosidase (GALC) gene. KD is distinguished into subtypes based on the age of onset; these are early infantile, late infantile, juvenile, and adult-onset. We report a case of a 47-year-old Caucasian man with a 2-year history of muscle atrophy and weakness in both hands associated with pyramidal signs and mild spasticity in the lower limbs. An extensive work-up led this motor neuron disease-like disorder to be diagnosed as adult-onset KD. The patient was found to be compound heterozygous for two GALC mutations (p.G286D and p.Y490N). These two rare missense mutations have previously been reported with other heterozygous mutations. However, their co-occurrence in a KD patient is novel. From the perspective of this case, we review the current literature on compound heterozygous mutations in adult-onset KD and their phenotypic variability. [ABSTRACT FROM AUTHOR]

Hereditary spastic paraplegia (HSP) represents a group of rare inherited neurodegenerative conditions and is characterized by progressive lower limb spasticity. Ubiquitin-associated protein 1 (UBAP1)-related HSP is classified as spastic paraplegia-80 (SPG80), which is an autosomal-dominant (AD) juvenile-onset neurologic disorder and mainly affects the lower limbs. We described the clinical and genetic features of two patients in the same family caused by heterozygous mutation of the UBAP1 gene. The proband was a 34-year-old woman with progressive spasticity and hyperreflexia in the lower limbs for 26 years. Her mother also had similar symptoms since the age of 6. The proband and her mother only had motor dysfunctions, such as unsteady gait, hypertonia, and hyperreflexia of lower limbs. Other system functions (sensory, urinary, visual, and cognitive impairments) were not involved. WES disclosed a frameshift mutation (c.371dupT) in the UBAP1 gene, which was predicted to be "likely pathogenic" and was co-segregated in the pedigree. c.371dupT, encoding the truncated UBAP1 protein with 72.6% missing of the normal amino acid sequence, is responsible for the spastic paraplegia (SPG) in this family. In combination with clinical characteristics, genetic testing results, and co-segregation analysis, the diagnosis is considered to be pure spastic paraplegia-80 (SPG80), which is an AD disease. By retrospectively analyzing the documented cases, we comprehensively review the phenotypic features and summarize the genotype spectrum of SPG80 to enhance earlier recognition and therapeutic strategies. [ABSTRACT FROM AUTHOR]

Background: Hereditary spastic paraplegia 49 (HSP49) is an autosomal recessive genetic disease first discovered in 2012; and which the mutation primarily affects Bukharian Jewish patients.Case Presentation: The present case reports the first instance of HSP49 detected in China. The patient had normal mental development and good athletic ability before 10 years old and presented with instable temperature, mental retardation, spastic ataxia, and paroxysmal convulsions. Genetic diagnosis was based on detection of whole exons and two heterozygous variants in the exon region of the TECPR2 gene: c.1729C > T and c.4189G > A. Mutations at these two sites have not been previously reported.Conclusions: This case expands the gene mutation spectrum and clinical phenotypic characteristics of autosomal recessive HSP in China; moreover, it indicates differences in the clinical phenotype of HSP49 in different ethnicities. In addition, this reported provides further evidence regarding the effectiveness of targeted next-generation sequencing technology in improving the efficiency and diagnostic rate of genetic diagnosis of HSP. [ABSTRACT FROM AUTHOR]

Hereditary spastic paraplegias consist of a group of rare neurodegenerative diseases characterized by lower limb spasticity. These inherited Mendelian disorders show high genetic variability associated with wide clinical diversity. Pathophysiological investigations have suggested that mutations in genes affecting the same cellular pathway generally lead to similar clinical symptoms, highlighting the importance of genetic mutation in these diseases. However, phenotype-genotype correlations have failed to explain the observed large inter-individual variability linked to mutations in a single gene, suggesting that genetics alone is not sufficient to explain symptom diversity. The identification of biomarkers, such as neurofilament light chain, could fill the gap and predict disease evolution. • Genetics is the primary driver of disease in hereditary spastic paraplegias. • The identification of mutated genes is not sufficient to predict disease evolution. • Biomarkers may help to predict disease course. [ABSTRACT FROM AUTHOR]

We would like to thank the patient's family for supporting the research and providing information on their daughter's symptoms and assisting with sample acquisition. A TECPR2 band (140 kDa) was detected in the control human skeletal muscle sample but not in the patient skeletal muscle lysate (Figure 1b) suggesting that the truncated TECPR2 proteins are degraded. [Extracted from the article]