Heterozygous variants disrupting the interaction of ERF with activated ERK1/2 cause microcephaly, developmental delay, and skeletal anomalies.

Heterozygous deleterious null alleles and specific missense variants in the DNA-binding domain of the ETS2 repressor factor (ERF) cause craniosynostosis, while the recurrent p.(Tyr89Cys) missense variant is associated with Chitayat syndrome. Exome and whole transcriptome sequencing revealed the ERF de novo in-frame indel c.

Leukoencephalopathy with spot-like calcifications caused by recessive COL4A2 variants.

Dominant COL4A1 and COL4A2 mutations cause a broad spectrum of cerebrovascular diseases, whose onset varies from fetal to adult life, mostly represented by prenatal-neonatal intracerebral hemorrhage with porencephaly and by periventricular leukomalacia with calcifications, corresponding clinical diagnoses of cerebral palsy mimics. Axenfeld-Rieger syndrome with leukoencephalopathy, HANAC syndrome, young- and late-onset stroke and malformation of cortical development are rarer presentations. Very recently, the existence of recessive COL4A1- and COL4A2-related forms has been documented.

Superior Cerebellar Atrophy: An Imaging Clue to Diagnose -Related Disorders.

The inositol 1,4,5-triphosphate receptor type 1 () gene encodes an InsP-gated calcium channel that modulates intracellular Ca release and is particularly expressed in cerebellar Purkinje cells. Pathogenic variants in the gene are associated with different types of autosomal dominant spinocerebellar ataxia: SCA15 (adult onset), SCA29 (early-onset), and Gillespie syndrome. Cerebellar atrophy/hypoplasia is invariably detected, but a recognizable neuroradiological pattern has not been identified yet.

"Atypical" Krabbe disease in two siblings harboring biallelic GALC mutations including a deep intronic variant.

Krabbe disease (KD) is a rare lysosomal storage disorder caused by biallelic pathogenic variants in GALC. Most patients manifest the severe classic early-infantile form, while a small percentage of cases have later-onset types. We present two siblings with atypical clinical and neuroimaging phenotypes, compared to the classification of KD, who were found to carry biallelic loss-of-function GALC variants, including a recurrent 30 kb deletion and a previously unreported deep intronic variant that was identified by mRNA sequencing.

Neuroimaging findings in leukoencephalopathy with calcifications and cysts: case report and review of the literature.

Leukoencephalopathy with cerebral calcifications and cysts (LCC) is a neurological disorder characterized by the radiological triad of white matter abnormalities, intracranial calcifications and cystic lesions variable in size resulting from a diffuse cerebral microangiopathy. Typically, progressive focal neurological deficits and seizures are the first clinical manifestation, but the severity of symptoms can vary according to the size and location of the cystic lesions holding compressive effects on the surrounding brain tissue. The most common histopathological finding is diffuse microangiopathy, which might be associated to pathogenic mutations in SNORD118 gene causing Labrune syndrome.

Expanded phenotype of AARS1-related white matter disease.

Purpose: Recent reports of individuals with cytoplasmic transfer RNA (tRNA) synthetase-related disorders have identified cases with phenotypic variability from the index presentations. We sought to assess phenotypic variability in individuals with AARS1-related disease.

Methods: A cross-sectional survey was performed on individuals with biallelic variants in AARS1.

Broadening the spectrum phenotype of TBCE-related neuron neurodegeneration.

Background: Severe loss of TBCE function has been related to two well-known dysmorphic syndromes, while TBCE hypomorphic variants have been linked to neurodegenerative conditions due to perturbed microtubule dynamics and homeostasis, with signs of central and peripheral nervous system involvement.

Method: We report on an Italian female originating from Southern Italy who presented early-onset regression and neurodegeneration, with neurological features of tetraparesis and signs of peripheral nervous system involvement. Her brain MRI revealed white matter involvement.

LBSL: Case Series and DARS2 Variant Analysis in Early Severe Forms With Unexpected Presentations.

Objective: Leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is regarded a relatively mild leukodystrophy, diagnosed by characteristic long tract abnormalities on MRI and biallelic variants in , encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). variants in LBSL are almost invariably compound heterozygous; in 95% of cases, 1 is a leaky splice site variant in intron 2. A few severely affected patients, still fulfilling the MRI criteria, have been described.

Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness.

Leukodystrophies are a heterogeneous group of rare inherited disorders that mostly involve the white matter of the CNS. These conditions are characterized by primary glial cell and myelin sheath pathology of variable aetiology, which causes secondary axonal degeneration, generally emerging with disease progression. Whole exome sequencing performed in five large consanguineous nuclear families allowed us to identify homozygosity for two recurrent missense variants affecting highly conserved residues of RNF220 as the causative event underlying a novel form of leukodystrophy with ataxia and sensorineural deafness.

Application of a Clinical Workflow May Lead to Increased Diagnostic Precision in Hereditary Spastic Paraplegias and Cerebellar Ataxias: A Single Center Experience.

The molecular characterization of Hereditary Spastic Paraplegias (HSP) and inherited cerebellar ataxias (CA) is challenged by their clinical and molecular heterogeneity. The recent application of Next Generation Sequencing (NGS) technologies is increasing the diagnostic rate, which can be influenced by patients' selection. To assess if a clinical diagnosis of CA/HSP received in a third-level reference center might impact the molecular diagnostic yield, we retrospectively evaluated the molecular diagnostic rate reached in our center on 192 unrelated families (90 HSP and 102 CA) (i) before NGS and (ii) with the use of NGS gene panels.

Expanding the Clinical and Mutational Spectrum of the -Related Hypomyelination of Early Myelinated Structures (HEMS).

The gene, located on chromosome Xq22, encodes the proteolipid protein 1 and its isoform DM20. Mutations in cause a spectrum of white matter disorders of variable severity. Here we report on four additional HEMS patients from three families harboring three novel mutations in exon 3B detected by targeted next-generation sequencing.

RARS1-related hypomyelinating leukodystrophy: Expanding the spectrum.

Objective: Biallelic variants in RARS1, encoding the cytoplasmic tRNA synthetase for arginine (ArgRS), cause a hypomyelinating leukodystrophy. This study aimed to investigate clinical, neuroradiological and genetic features of patients with RARS1-related disease, and to identify possible genotype-phenotype relationships.

Methods: We performed a multinational cross-sectional survey among 20 patients with biallelic RARS1 variants identified by next-generation sequencing techniques.

The impact of next-generation sequencing on the diagnosis of pediatric-onset hereditary spastic paraplegias: new genotype-phenotype correlations for rare HSP-related genes.

Hereditary spastic paraplegias (HSP) are clinical and genetic heterogeneous diseases with more than 80 disease genes identified thus far. Studies on large cohorts of HSP patients showed that, by means of current technologies, the percentage of genetically solved cases is close to 50%. Notably, the percentage of molecularly confirmed diagnoses decreases significantly in sporadic patients.

Sudden infant death syndrome: the role of multidisciplinary teams. Experience of the SIDS-ALTE Center of Liguria Region.

The aim of this paper was to highlight the importance of a multidisciplinary and multiprofessional management of SIDS for a complete approach to this tragic event. Both biomedical and psychosocial aspects are evaluated, focusing on the impact of SIDS diagnosis on the family. The paper describes the organization of our team, composed of a network of specialists involved in both prevention and management of SIDS.

Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy.

Hypomyelinating leukodystrophies are genetically heterogeneous disorders with overlapping clinical and neuroimaging features reflecting variable abnormalities in myelin formation. We report on the identification of biallelic inactivating mutations in NKX6-2, a gene encoding a transcription factor regulating multiple developmental processes with a main role in oligodendrocyte differentiation and regulation of myelin-specific gene expression, as the cause underlying a previously unrecognized severe variant of hypomyelinating leukodystrophy. Five affected subjects (three unrelated families) were documented to share biallelic inactivating mutations affecting the NKX6-2 homeobox domain.

Not only dominant, not only optic atrophy: expanding the clinical spectrum associated with OPA1 mutations.

Background: Heterozygous mutations in OPA1 are a common cause of autosomal dominant optic atrophy, sometimes associated with extra-ocular manifestations. Few cases harboring compound heterozygous OPA1 mutations have been described manifesting complex neurodegenerative disorders in addition to optic atrophy.

Results: We report here three patients: one boy showing an early-onset mitochondrial disorder with hypotonia, ataxia and neuropathy that was severely progressive, leading to early death because of multiorgan failure; two unrelated sporadic girls manifesting a spastic ataxic syndrome associated with peripheral neuropathy and, only in one, optic atrophy.

Clinical, neuroradiological and molecular characterization of cerebellar dysplasia with cysts (Poretti-Boltshauser syndrome).

Cerebellar dysplasia with cysts and abnormal shape of the fourth ventricle, in the absence of significant supratentorial anomalies and of muscular involvement, defines recessively inherited Poretti-Boltshauser syndrome (PBS). Clinical features comprise non-progressive cerebellar ataxia, intellectual disability of variable degree, language impairment, ocular motor apraxia and frequent occurrence of myopia or retinopathy. Recently, loss-of-function variants in the LAMA1 gene were identified in six probands with PBS.

TUBB4A-related hypomyelinating leukodystrophy: New insights from a series of 12 patients.

Background: Hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) was first described in 2002. After the recent identification of TUBB4A mutation as the genetic basis of the disease, the clinical and neuroimaging phenotype related to TUBB4A mutations expanded, ranging from primary dystonia type 4 with normal MRI to severe H-ABC cases.

Patients And Methods: The study included patients referred to us for an unclassified hypomyelinating leukodystrophy.