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A, Patient 1 dysmorphic features: plagiocephaly, microcephaly, epicanthal folds, hypertelorism, flat nasal bridge, abnormal dentition, widely spaced teeth, micrognathia, low-set ears, hirsutism, spasticity, and crossing legs. B, Brain MRI (patient 1), T1-weighted image, and sagittal section showing abnormal shape of the corpus callosum with thinning. C, Brain MRI (patient 1), T2-weighted image, and axial section showing mild brain atrophy mainly in the frontal lobe. MRI indicates magnetic resonance imaging.
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PRUNE syndrome, or neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (OMIM#617481), is a new rare autosomal recessive neurodevelopmental disease that is caused by homozygous or compound heterozygous mutation in PRUNE1 on chromosome 1q21. Here, We report on 12-month-old and 30-month-old girls from 2 unrelated Sau...
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... she was referred to a genetics service at 16 months of age for further evaluation, where her examination showed the following growth parameters: weight 8.8 kg (À0.8 SD), length 46 cm (À0.6 SD), and head circumference 44.5 cm (À1 SD). She had dysmorphic features (plagiocephaly, microcephaly, epicanthal folds, hypertelorism, flat nasal bridge, abnormal dentition, widely spaced teeth, micrognathia, low-set ears, and hirsutism; Figure 1A). A neurological examination showed central hypotonia and spastic quadriplegia with hyperreflexia and clonus. ...
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... ophthalmology examination showed bilateral rudimentary iris strands. Brain magnetic resonance imaging (MRI) showed delayed myelination, slightly abnormal shape of the corpus callosum, and mild frontal cerebral atrophy ( Figure 1B and C). A skeletal survey and echocardiogram were unremarkable. ...
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... she was referred to a genetics service at 16 months of age for further evaluation, where her examina- tion showed the following growth parameters: weight 8.8 kg (À0.8 SD), length 46 cm (À0.6 SD), and head circumference 44.5 cm (À1 SD). She had dysmorphic features (plagioce- phaly, microcephaly, epicanthal folds, hypertelorism, flat nasal bridge, abnormal dentition, widely spaced teeth, micro- gnathia, low-set ears, and hirsutism; Figure 1A). A neurolo- gical examination showed central hypotonia and spastic quadriplegia with hyperreflexia and clonus. ...
Context 4
... ophthalmol- ogy examination showed bilateral rudimentary iris strands. Brain magnetic resonance imaging (MRI) showed delayed myelination, slightly abnormal shape of the corpus callosum, and mild frontal cerebral atrophy ( Figure 1B and C). A ske- letal survey and echocardiogram were unremarkable. ...
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Citations
... Autosomal recessive pathogenic variants of PRUNE1 have been associated with microcephaly, hypotonia, and variable brain anomalies (NMIHBA, MIM #617481) (1,12). In recent years, the clinicalradiological spectrum related to PRUNE1 has expanded to include craniofacial anomalies, skeletal muscle and articular impairment, neuropathy, profound global developmental delay, cortical and cerebellar atrophy, white matter disease, corpus callosum abnormalities, and seizures (3,(13)(14)(15)(16). ...
... Those described to date are missense, start-loss, nonsense, deletions, loss-offunction splicing, homozygous, and compound heterozygous, inherited in an autosomal recessive pattern. Interestingly, the expression of homozygous PRUNE1 variants was more pronounced in those populations with high rates of consanguineous marriages, and the majority of homozygous patients carried a missense variant, suggesting that PRUNE1-related disorders are mainly associated with hypomorphic alleles (1,13). Moreover, rare severe alleles from recent ancestors were associated with a relevant effect on PRUNE syndrome, greater than common variants reported in populations. ...
... In this context, the electroencephalogram (EEG) documents variable discharges, progressive development of hypsarrythmia, and/or slowed background activity as the epileptic encephalopathy worsens. Furthermore, vision problems such as optic atrophy, esotropia, cortical blindness, bilateral rudimentary iris strands, congenital cataracts, saccadic eye movements, and nystagmus have been reported and are often present after birth (1,8,13,19,20,23). Recently, gastrointestinal disorders such as dysphagia and gastrointestinal reflux have been described, usually followed by inadequate oral caloric intake and failure to thrive, requiring nasogastric tube feeding or gastrotomy tube placement (1,13,20). ...
Prune exopolyphosphatase 1 (PRUNE1) is a short-chain phosphatase that is part of the aspartic acid-histidine-histidine (DHH) family of proteins. PRUNE1 is highly expressed in the central nervous system and is crucially involved in neurodevelopment, cytoskeletal rearrangement, cell migration, and proliferation. Recently, biallelic PRUNE1 variants have been identified in patients with neurodevelopmental disorders, hypotonia, microcephaly, variable cerebral anomalies, and other features. PRUNE1 hypomorphic mutations mainly affect the DHH1 domain, leading to an impactful decrease in enzymatic activity with a loss-of-function mechanism. In this review, we explored both the clinical and radiological spectrum related to PRUNE1 pathogenic variants described to date. Specifically, we focused on neuroradiological findings that, together with clinical phenotypes and genetic data, allow us to best characterize affected children with diagnostic and potential prognostic implications.
... Furthermore, recessive mutations in PRUNE_1 locus (1q21.3) were also identified as candidate genetic causes of neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA; MIM #617481) (10,(12)(13)(14)(15)(16)(17)(18)(19)(20). Similarly, other genes responsible for microcephaly (MCPH) and mainly implicated in cell division mechanisms were also found both overexpressed in brain tumors (i.e., MB) and mutated in neurodevelopmental disorders (NDDs). ...
... Regarding the genotypic differences, among the variants identified in patients with PRUNE_1, the most representative was the homozygous c.G316A (p.D106N) variant that was found in 15 subjects: seven from Turkey (12,16,18), three from Italy (10,14), one from Sri Lanka (19), one from Caucasus (17), and three from Lebanon (16). The majority of homozygous mutations were found within the DHH domain of PRUNE_1, including c.G88A (p.D30N) in six patients from Oman (10) and one from Saudi Arabia (12), c.160C>A (p.P54T) in seven Iranian subjects (10), c.383G>A (p.R128Q) in two patients from Saudi Arabia (15), and c.515T>C (p.L172P) in three children from North Africa (16). Two types of homozygous mutations were also found within the DHHA2 domain: the missense variant c.C889T (p.R297W) in two patients from India (10) (17,20). ...
... In TNBC, AA7.1-mediated tumor inhibition occurred through the impairment of the TGF-b pathway, reduction of inflammatory cytokines (i.e., IL-17F) and the modulation of the protein content of extracellular vesicles (i.e., vimentin) (59). Importantly, this small molecule is not toxic, as suggested by the lack of acute toxicity measured in naive mice (Balb/C) that were intraperitoneally administered escalating doses (15,30, and 60 mg/kg) of AA7.1 daily for 1 week (11). The results showed no immediate acute toxicity of AA7.1 (in terms of hematological parameters, hepatotoxicity, or nephrotoxicity) in treated mice, as measured via glutamate-pyruvate transaminase 1, glutamic oxaloacetic transaminase, creatinine blood levels, and blood urea nitrogen (11). ...
We analyze the fundamental functions of Prune_1 in brain pathophysiology. We discuss the importance and maintenance of the function of Prune_1 and how its perturbation influences both brain pathological conditions, neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA; OMIM: 617481), and tumorigenesis of medulloblastoma (MB) with functional correlations to other tumors. A therapeutic view underlying recent discoveries identified small molecules and cell penetrating peptides to impair the interaction of Prune_1 with protein partners (e.g., Nm23-H1), thus further impairing intracellular and extracellular signaling (i.e., canonical Wnt and TGF-β pathways). Identifying the mechanism of action of Prune_1 as responsible for neurodevelopmental disorders (NDDs), we have recognized other genes which are found overexpressed in brain tumors (e.g., MB) with functional implications in neurodevelopmental processes, as mainly linked to changes in mitotic cell cycle processes. Thus, with Prune_1 being a significant target in NDDs, we discuss how its network of action can be dysregulated during brain development, thus generating cancer and metastatic dissemination.
... 2,3 Mutations involving PRUNE1 have been recently related to recessively transmitted neurodevelopmental disorders characterized by microcephaly, hypotonia, global developmental delay, various cerebral anomalies such as frontotemporal cortical, and cerebellar atrophy, thin or hypoplastic corpus callosum, and frequently occurring seizures (neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies, NMIHBA, MIM#617481). [4][5][6][7] Thus far, nearly 50 patients with biallelic PRUNE1 mutations have been reported in the literature. 1,2,[4][5][6][7][8][9][10][11][12] It has been debated if this disorder should be considered as a defect of normal development or a degenerative disease since it sometimes has prenatal onset with an appearance at birth. ...
... [4][5][6][7] Thus far, nearly 50 patients with biallelic PRUNE1 mutations have been reported in the literature. 1,2,[4][5][6][7][8][9][10][11][12] It has been debated if this disorder should be considered as a defect of normal development or a degenerative disease since it sometimes has prenatal onset with an appearance at birth. No specific signs of a constitutional disease might reveal from birth and brain imaging is usually unrevealing in the first stage of the disorder; however, a progressive worsening suggesting a neurodegenerative process is the rule in the natural history of the disease. ...
... 14,15 However, microcephaly does not seem by now a constant trait in PRUNE1-related encephalopathy and appears at this point to be a variable feature. 2,[4][5][6][7][8]10,11 Macrocephaly has been sometimes reported in patients with PRUNE1 deficiency, although this sign needs to be confirmed following up the patients' growth curves, since microcephaly is often acquired in advanced stages of the disease, as a supplementary sign of a progressive neurodegenerative process. 7,8,10 Indeed, an Oji-Cree male patient 5 presenting with macrocephaly at birth, became normocephalic at the age of 2 years, thus documenting a slowdown of the OFC values. ...
PRUNE1-related disorders manifest as severe neurodevelopmental conditions associated with neurodegeneration, implying a differential diagnosis at birth with static encephalopathies, and later with those manifesting progressive brain damage with the involvement of both the central and the peripheral nervous system.
Here we report on another patient with PRUNE1 (p.Asp106Asn) recurrent mutation, whose leukodystrophy, inferior olives hyperintensity, and macrocephaly led to the misleading clinical suspicion of Alexander disease. Clinical features, together with other recent descriptions, suggest avoiding the term “microcephaly” in defining this disorder that could be renamed “neurodevelopmental disorder with progressive encephalopathy, hypotonia, and variable brain anomalies” (NPEHBA).
... Recently, two unrelated Saudi families with PRUNE gene mutations reported by Alfadhel et al. 11 had psychomotor delay, progressive microcephaly, spasticity and dysmorphic features. However, neither clinical nor laboratory evidences suggesting spinal motor neuron involvement were mentioned in this report. ...
... However, neither clinical nor laboratory evidences suggesting spinal motor neuron involvement were mentioned in this report. 11 Zollo's study confirmed the interaction between PRUNE and tubulin, which was identified by mass spectrometry-based interaction screen. Tubulinopathies are severe neurodevelopmental and neurodegenerative disorders caused by the multiple mutations in the genes encoding tubulin proteins. ...
Okur D, Daimagüler HS, Ersen Danyeli A, Tekgül H, Wang H, Wunderlich G, Çırak S, Yiş U. Bi-allelic mutations in PRUNE lead to neurodegeneration with spinal motor neuron involvement and hyperCKaemia. Turk J Pediatr 2019; 61: 931-936. We aimed to systematically investigate the neuromuscular involvement of individuals with PRUNE mutations who may have a major spinal motor neuron involvement as part of the PRUNE-associated neurodegenerative phenotype. The complex neurological phenotypes associated with Prune mutations include microcephaly with brain abnormalities, spasticity, seizures, severe developmental delay and developmental regression. We used whole exome sequencing to identify the mutation and electrophysiological and muscle biopsy studies to evaluate the signs of spinal motor neuron involvement. The affected individuals carry homozygous PRUNE mutation (NM_021222.1, c.316G > A, p.D106N), showing the signs of spinal motor neuron involvement supported by electrophysiological and muscle biopsy findings and also persistent high creatine kinase levels. We confirm that individuals with PRUNE mutations may have a major spinal motor neuron involvement as part of the PRUNE-associated neurodegenerative phenotype. The PRUNE gene should be considered in all the individuals with non-5q spinal muscular atrophy. High creatine kinase values may be a part of PRUNE disease spectrum.
Background
Homozygous or compound heterozygous PRUNE1 mutations cause a neurodevelopmental disorder with microcephaly, hypotonia, and variable brain malformations (NMIHBA) (OMIM #617481). The PRUNE1 gene encodes a member of the phosphoesterase (DHH) protein superfamily that is involved in the regulation of cell migration. To date, most of the described mutations in the PRUNE1 gene are clustered in DHH domain.
Methods
We subjected 4 members (two affected and two healthy) of a consanguineous Iranian family in the study. The proband underwent whole-exome sequencing and a start loss identified variant was confirmed by Sanger sequencing. Co-segregation of the detected variant with the disease in family was confirmed.
Results
By whole-exome sequencing, we identified the a start loss variant, NM_021222.3:c.3G>A; p.(Met1?), in the PRUNE1 in two patients of a consanguineous Iranian family with spastic quadriplegic cerebral palsy (CP), hypotonia, developmental regression, and cerebellar atrophy. Sanger sequencing confirmed the segregation of the variant with the disease in the family. Protein structure analysis also revealed that the variant probably leads to the deletion of DHH (Asp-His-His) domain, the active site of the protein, and loss of PRUNE1 function.
Conclusion
We identified a start loss variant, NM_021222.3:c.3G>A; p.(Met1?) in the PRUNE1 gene in two affected members as a possible cause of NMIHBA in an Iranian family. We believe that the study adds a new pathogenic variant in spectrum of mutations in the PRUNE1 gene as a cause of PRUNE1-related syndrome.
Prune exopolyphosphatase‐1 (PRUNE1) encodes a member of the aspartic acid–histidine–histidine (DHH) phosphodiesterase superfamily that regulates cell migration and proliferation during brain development. In 2015, biallelic PRUNE1 loss‐of‐function variants were identified to cause the neurodevelopmental disorder with microcephaly, hypotonia, and variable brain abnormalities (NMIHBA, OMIM#617481). NMIHBA is characterized by the namesake features and structural brain anomalies including thinning of the corpus callosum, cerebral and cerebellar atrophy, and delayed myelination. To date, 47 individuals have been reported in the literature, but the phenotypic spectrum of PRUNE1‐related disorders and their causative variants remains to be characterized fully. Here, we report a novel homozygous PRUNE1 NM_021222.2:c.933G>A synonymous variant identified in a 6‐year‐old boy with intellectual and developmental disabilities, hypotonia, and spastic diplegia, but with the absence of microcephaly, brain anomalies, or seizures. Fibroblast RNA sequencing revealed that the PRUNE1 NM_021222.1:c.933G>A variant resulted in an in‐frame skipping of the penultimate exon 7, removing 53 amino acids from an important protein domain. This case represents the first synonymous variant and the third pathogenic variant known to date affecting the DHH‐associated domain (DHHA2 domain). These findings extend the genotypic and phenotypic spectrums in PRUNE1‐related disorders and highlight the importance of considering synonymous splice site variants in atypical presentations.
Background: Homozygous or compound heterozygous PRUNE1 mutations cause a neurodevelopmental disorder with microcephaly, hypotonia, and variable brain malformations (NMIHBA) (OMIM #617481). The PRUNE1 gene encodes a member of the phosphoesterase (DHH) protein superfamily that is involved in the regulation of cell migration. To date, most of the described mutations in the PRUNE1 gene are clustered in DHH domain.
Methods: We subjected 4 members (two affected and two healthy) of a consanguineous Iranian family in the study. The proband underwent whole-exome sequencing and a novel identified variant was confirmed by Sanger sequencing. Co-segregation of the detected variant with the disease in family was confirmed.
Results: By whole-exome sequencing, we identified the first start loss variant, NM_021222.3:c.3G>A; p.(Met1?), in the PRUNE1 in two patients of a consanguineous Iranian family with spastic quadriplegic cerebral palsy (CP), hypotonia, developmental regression, and cerebellar atrophy. Sanger sequencing confirmed the segregation of the variant with the disease in the family. Protein structure analysis also revealed that the variant probably leads to the deletion of DHH (Asp-His-His) domain, the active site of the protein, and loss of PRUNE1 function.
Conclusion: We identified a novel start loss variant, NM_021222.3:c.3G>A; p.(Met1?) in the PRUNE1 gene in two affected members as a possible cause of NMIHBA in an Iranian family. We believe that the study adds a new pathogenic variant in spectrum of mutations in the PRUNE1 gene as a cause of PRUNE1-related syndrome.
Neurodevelopmental disorder with microcephaly, hypotonia, and variable brain anomalies (NMIHBA) is an autosomal recessive neurodevelopmental and neurodegenerative disorder characterized by global developmental delay and severe intellectual disability. Microcephaly, progressive cortical atrophy, cerebellar hypoplasia and delayed myelination are neurological hallmarks in affected individuals. NMIHBA is caused by biallelic variants in PRUNE1 encoding prune exopolyphosphatase 1. We provide in-depth clinical description of two affected siblings harboring compound heterozygous variant alleles, c.383G > A (p.Arg128Gln), c.520G > T (p.Gly174*) in PRUNE1. To gain insights into disease biology, we biochemically characterized missense variants within the conserved N-terminal aspartic acid-histidine-histidine (DHH) motif and provide evidence that they result in the destabilization of protein structure and/or loss of exopolyphosphatase activity. Genetic ablation of Prune1 results in midgestational lethality in mice, associated with perturbations to embryonic growth and vascular development. Our findings suggest that NMIHBA results from hypomorphic variant alleles in humans and underscore the potential key role of PRUNE1 exopolyphoshatase activity in neurodevelopment.
Autosomal recessive PRUNE1 mutations on chromosome 1q21.3 are reported to cause a neurodevelopmental disorder with microcephaly, hypotonia, and variable brain malformations. Here, we report a Japanese case with a reported PRUNE1 mutation whose brain magnetic resonance imaging (MRI) showed specific imaging findings that have not been reported before. The patient was a 12-month-old girl, the first child of healthy and nonconsanguineous Japanese parents. She showed global developmental delay, intellectual disability, hypotonia, spastic quadriparesis, and hyperreflexia. Brain MRI showed cerebral and cerebellar atrophy, thin corpus callosum, white matter changes, and abnormal signal intensity of the brainstem, all of which were reported in the literature. In addition, we emphasize the three following imaging findings: a transient cerebral subcortical white matter lesion, atrophy of the midbrain and pontine tegmentum with a preserved pontine base, and abnormal signal intensity of the bilateral swelling putamina and medial portions of the thalami, which emerged after 4 years of age. The whole-exome sequencing (WES) analysis performed at the age of 4 years identified biallelic PRUNE1 variants, namely compound heterozygous mutations (c.[316G > A];[540 T > A],p.[Asp106Asn];[Cys180*]). Although the diagnosis of PRUNE1-related disorder requires WES, we think that these new characteristic MRI findings may help in the diagnosis of PRUNE1-related disorder.
Autosomal recessive PRUNE1 mutations are reported to cause a severe neurodevelopmental disorder with microcephaly, hypotonia, and brain malformations. We describe clinical and neuropathological features in a cohort of nine individuals of Cree descent who, because of a founder effect, are homozygous for the same PRUNE1 mutation. They follow the course of a combined neuromuscular and neurodegenerative disease, rather than a pure failure of normal development. This cohort presented in infancy with features of lower motor neuron disease, such as hypotonia, contractures, tongue fasciculations, and feeding difficulties in the absence of congenital brain anomalies and microcephaly. A neurodegenerative course followed with onset of seizures, spasticity, and respiratory insufficiency. Muscle biopsies showed denervation/reinnervation features, nonspecific atrophy and end‐stage atrophy. Autopsy findings in two patients are also described, suggesting length dependent central motor axon degeneration, peripheral motor axon degeneration, possible spinal motor neuron degeneration, and accumulation of beta amyloid precursor protein inclusions in select brainstem nuclei. Exome sequencing and homozygosity mapping identified a homozygous PRUNE1 mutation in a canonical splice site, which produces two abnormal PRUNE1 mRNA products. Based on our studies and the histopathology and phenotypic data, we provide further evidence that this disorder leads to a neurodegenerative disease affecting both the peripheral and central nervous systems and suggest that the pathogenic c.521‐2A>G mutation could lead to an altered effect on tubulin dynamics.
