Publications by authors named "Ginevra Zanni"

66 Publications

Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders.

Genome Med 2021 Apr 19;13(1):63. Epub 2021 Apr 19.

The Atwal Clinic: Genomic & Personalized Medicine, Jacksonville, FL, USA.

Background: With the increasing number of genomic sequencing studies, hundreds of genes have been implicated in neurodevelopmental disorders (NDDs). The rate of gene discovery far outpaces our understanding of genotype-phenotype correlations, with clinical characterization remaining a bottleneck for understanding NDDs. Most disease-associated Mendelian genes are members of gene families, and we hypothesize that those with related molecular function share clinical presentations.

Methods: We tested our hypothesis by considering gene families that have multiple members with an enrichment of de novo variants among NDDs, as determined by previous meta-analyses. One of these gene families is the heterogeneous nuclear ribonucleoproteins (hnRNPs), which has 33 members, five of which have been recently identified as NDD genes (HNRNPK, HNRNPU, HNRNPH1, HNRNPH2, and HNRNPR) and two of which have significant enrichment in our previous meta-analysis of probands with NDDs (HNRNPU and SYNCRIP). Utilizing protein homology, mutation analyses, gene expression analyses, and phenotypic characterization, we provide evidence for variation in 12 HNRNP genes as candidates for NDDs. Seven are potentially novel while the remaining genes in the family likely do not significantly contribute to NDD risk.

Results: We report 119 new NDD cases (64 de novo variants) through sequencing and international collaborations and combined with published clinical case reports. We consider 235 cases with gene-disruptive single-nucleotide variants or indels and 15 cases with small copy number variants. Three hnRNP-encoding genes reach nominal or exome-wide significance for de novo variant enrichment, while nine are candidates for pathogenic mutations. Comparison of HNRNP gene expression shows a pattern consistent with a role in cerebral cortical development with enriched expression among radial glial progenitors. Clinical assessment of probands (n = 188-221) expands the phenotypes associated with HNRNP rare variants, and phenotypes associated with variation in the HNRNP genes distinguishes them as a subgroup of NDDs.

Conclusions: Overall, our novel approach of exploiting gene families in NDDs identifies new HNRNP-related disorders, expands the phenotypes of known HNRNP-related disorders, strongly implicates disruption of the hnRNPs as a whole in NDDs, and supports that NDD subtypes likely have shared molecular pathogenesis. To date, this is the first study to identify novel genetic disorders based on the presence of disorders in related genes. We also perform the first phenotypic analyses focusing on related genes. Finally, we show that radial glial expression of these genes is likely critical during neurodevelopment. This is important for diagnostics, as well as developing strategies to best study these genes for the development of therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13073-021-00870-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8056596PMC
April 2021

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

Brain Sci 2021 Feb 16;11(2). Epub 2021 Feb 16.

UOC Neurologia, Fondazione Policlinico Universitario 'A. Gemelli' IRCCS, 00168 Rome, Italy.

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. Overall, 46.3% of families received a genetic diagnosis by first-tier individual gene screening: 43.3% HSP and 50% spinocerebellar ataxias (SCA). The diagnostic rate was 56.7% in AD-HSP, 55.5% in AR-HSP, and 21.2% in sporadic HSP. On the other hand, 75% AD-, 52% AR- and 33% sporadic CA were diagnosed. So far, 32 patients (24 CA and 8 HSP) were further assessed by NGS gene panels, and 34.4% were diagnosed, including 29.2% CA and 50% HSP patients. Eleven novel gene variants classified as (likely) pathogenic were identified. Our results support the role of experienced clinicians in the diagnostic assessment and the clinical research of CA and HSP even in the next generation era.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/brainsci11020246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919782PMC
February 2021

CASK related disorder: Epilepsy and developmental outcome.

Eur J Paediatr Neurol 2021 Mar 19;31:61-69. Epub 2021 Feb 19.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genoa, Genova, Italy; Unit of Child Neuropsychiatry, ASST Fatebenefratelli Sacco, Milano, Italy.

Objective: CASK pathogenic variants are associated with variable features, as intellectual disability, optic atrophy, brainstem/cerebellar hypoplasia, and epileptic encephalopathy. Few studies describe the electroclinical features of epilepsy in patients with CASK pathogenic variants and their relationship with developmental delay.

Methods: this national multicentre cohort included genetically confirmed patients with different CASK pathogenic variants. Our findings were compared with cohorts reported in the literature.

Results: we collected 34 patients (29 females) showing from moderate (4 patients) to severe (22) and profound (8) developmental delay; all showed pontine and cerebellar hypoplasia, all except three with microcephaly. Seventeen out of 34 patients (50%) suffered from epileptic seizures, including spasms (11 patients, 32.3%), generalized (5) or focal seizures (1). In 8/17 individuals (47.1%), epilepsy started at or beyond the age of 24 months. Seven (3 males) out of the 11 children with spasms showed EEG features and a course supporting the diagnosis of a developmental and epileptic encephalopathy (DEE). Drug resistance was frequent in our cohort (52.9% of patients with epilepsy). EEG abnormalities included poorly organized background activity with diffuse or multifocal epileptiform abnormalities and sleep-activation, with possible appearance over the follow-up period. Developmental delay degree was not statistically different among patients with or without seizures but feeding difficulties were more frequent in patients with epilepsy.

Conclusions: epilepsy is a frequent comorbidity with a high incidence of spasms and drug resistance. Overall developmental disability does not seem to be more severe in the group of patients with epilepsy nor to be linked to specific epilepsy/EEG characteristics. A childhood onset of epilepsy is frequent, with possible worsening over time, so that serial and systematic monitoring is mandatory.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2021.02.006DOI Listing
March 2021

Photoparoxysmal response in ADCK3 autosomal recessive ataxia: a case report and literature review.

Epileptic Disord 2021 Feb;23(1):153-160

Unit of Child Neuropsychiatry, Epilepsy Centre, Department of Medical and Surgical Neuroscience and Rehabilitation, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Mutations in AarF domain-containing kinase 3 (ADCK3) are responsible for the most frequent form of hereditary coenzyme Q10 (CoQ10) deficiency (Q10 deficiency-4), which is mainly associated with autosomal recessive cerebellar ataxia type 2 (ARCA2). Clinical presentation is characterized by a variable degree of cerebellar atrophy and a broad spectrum of associated symptoms, including muscular involvement, movement disorders, neurosensory loss, cognitive impairment, psychiatric symptoms and epilepsy. In this report, we describe, for the first time, a case of photoparoxysmal response in a female patient with a mutation in ADCK3. Disease onset occurred in early childhood with gait ataxia, and mild-to-moderate degeneration. Seizures appeared at eight years and six months, occurring only during sleep. Photoparoxysmal response was observed at 14 years, almost concomitant with the genetic diagnosis (c.901C>T;c.589-3C>G) and the start of CoQ10 oral supplementation. A year later, disease progression slowed down, and photosensitivity was attenuated. A review of the literature is provided focusing on epileptic features of ADCK3-related disease as well as the physiopathology of photoparoxysmal response and supposed cerebellar involvement in photosensitivity. Moreover, the potential role of CoQ10 oral supplementation is discussed. Prospective studies on larger populations are needed to further understand these data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1684/epd.2021.1243DOI Listing
February 2021

Clinical phenotypes of infantile onset CACNA1A-related disorder.

Eur J Paediatr Neurol 2021 Jan 20;30:144-154. Epub 2020 Oct 20.

Pediatric Neurology Unit, Wolfson Medical Center, Holon, Israel; Pediatric Movement Disorders Service, Wolfson Medical Center, Holon, Israel; Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel. Electronic address:

Background: CACNA1A-related disorders present with persistent progressive and non-progressive cerebellar ataxia and paroxysmal events: epileptic seizures and non-epileptic attacks. These phenotypes overlap and co-exist in the majority of patients.

Objective: To describe phenotypes in infantile onset CACNA1A-related disorder and to explore intra-familial variations and genotype-phenotype correlations.

Material And Methods: This study was a multicenter international collaboration. A retrospective chart review of CACNA1A patients was performed. Clinical, radiological, and genetic data were collected and analyzed in 47 patients with infantile-onset disorder.

Results: Paroxysmal non-epileptic events (PNEE) were observed in 68% of infants, with paroxysmal tonic upward gaze (PTU) noticed in 47% of infants. Congenital cerebellar ataxia (CCA) was diagnosed in 51% of patients including four patients with developmental delay and only one neurological sign. PNEEs were found in 63% of patients at follow-up, with episodic ataxia (EA) in 40% of the sample. Cerebellar ataxia was found in 58% of the patients at follow-up. Four patients had epilepsy in infancy and nine in childhood. Seven infants had febrile convulsions, three of which developed epilepsy later; all three patients had CCA. Cognitive difficulties were demonstrated in 70% of the children. Cerebellar atrophy was found in only one infant but was depicted in 64% of MRIs after age two.

Conclusions: Nearly all of the infants had CCA, PNEE or both. Cognitive difficulties were frequent and appeared to be associated with CCA. Epilepsy was more frequent after age two. Febrile convulsions in association with CCA may indicate risk of epilepsy in later childhood. Brain MRI was normal in infancy. There were no genotype-phenotype correlations found.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2020.10.004DOI Listing
January 2021

7q11.23 Microduplication Syndrome: Clinical and Neurobehavioral Profiling.

Brain Sci 2020 Nov 11;10(11). Epub 2020 Nov 11.

Child and Adolescent Neuropsychiatry Unit, Department of Neurological and Psychiatric Science, Bambino Gesù Children's Hospital, IRCCS, 00165 Rome, Italy.

7q11.23 Microduplication (dup7q11.23) syndrome is a rare autosomal dominant disorder due to a recurring 1.5 to 1.8 Mb duplication of the Williams-Beuren Syndrome critical region. Dup7q11.23 has been associated with several neuro-behavioral characteristics such as low cognitive and adaptive functioning, expressive language impairment, anxiety problems and autistic features. In the present study, we analyze the clinical features of ten individuals in which array-CGH detected dup7q11.23, spanning from 1.4 to 2.1 Mb. The clinical characteristics associated with dup7q11.23 are discussed with respect to its reciprocal deletion. Consistent with previous studies, we confirm that individuals with dup7q11.23 syndrome do not have a homogeneous clinical profile, although some recurring dysmorphic features were found, including macrocephaly, prominent forehead, elongated palpebral fissures, thin lip vermilion and microstomia. Minor congenital malformations include patent ductus arteriosus, cryptorchidism and pes planus. A common finding is hypotonia and joint laxity, resulting in mild motor delay. Neuropsychological and psychodiagnostic assessment confirm that mild cognitive impairment, expressive language deficits and anxiety are recurring neurobehavioral features. New insights into adaptive, psychopathological and neurodevelopmental profiles are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/brainsci10110839DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697259PMC
November 2020

Heterozygous variants underlie a wide spectrum of neurodevelopmental and neurodegenerative disorders.

J Med Genet 2020 Jul 31. Epub 2020 Jul 31.

Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, Roma, Italy.

Background: Dominant and recessive variants in the gene on chromosome 2q37.3 are associated with several phenotypes, although only three syndromes are currently listed in the OMIM classification: hereditary sensory and autonomic neuropathy type 2 and spastic paraplegia type 30, both recessively inherited, and mental retardation type 9 with dominant inheritance.

Methods: In this retrospective multicentre study, we describe the clinical, neuroradiological and genetic features of 19 Caucasian patients (aged 3-65 years) harbouring heterozygous variants, and extensively review the available literature to improve current classification of -related disorders.

Results: Patients were divided into two groups. Group 1 comprised patients with a complex phenotype with prominent pyramidal signs, variably associated in all but one case with additional features (ie, epilepsy, ataxia, peripheral neuropathy, optic nerve atrophy); conversely, patients in group 2 presented an early onset or congenital ataxic phenotype. Fourteen different heterozygous missense variants were detected by next-generation sequencing screening, including three novel variants, most falling within the kinesin motor domain.

Conclusion: The present study further enlarges the clinical and mutational spectrum of -related disorders by describing a large series of patients with dominantly inherited pathogenic variants ranging from pure to complex forms of hereditary spastic paraparesis/paraplegias (HSP) and ataxic phenotypes in a lower proportion of cases. A comprehensive review of the literature indicates that screening should be implemented in HSP regardless of its mode of inheritance or presentations as well as in other complex neurodegenerative or neurodevelopmental disorders showing congenital or early onset ataxia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2020-107007DOI Listing
July 2020

Clinical and Genetic Overview of Paroxysmal Movement Disorders and Episodic Ataxias.

Int J Mol Sci 2020 May 20;21(10). Epub 2020 May 20.

Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, 00146 Rome, Italy.

Paroxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements. Two main categories of PMDs are recognized based on the phenomenology: Paroxysmal dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement disorders, while attacks of cerebellar dysfunction are the hallmark of episodic ataxias (EAs). From an etiological point of view, both primary (genetic) and secondary (acquired) causes of PMDs are known. Recognition and diagnosis of PMDs is based on personal and familial medical history, physical examination, detailed reconstruction of ictal phenomenology, neuroimaging, and genetic analysis. Neurophysiological or laboratory tests are reserved for selected cases. Genetic knowledge of PMDs has been largely incremented by the advent of next generation sequencing (NGS) methodologies. The wide number of genes involved in the pathogenesis of PMDs reflects a high complexity of molecular bases of neurotransmission in cerebellar and basal ganglia circuits. In consideration of the broad genetic and phenotypic heterogeneity, a NGS approach by targeted panel for movement disorders, clinical or whole exome sequencing should be preferred, whenever possible, to a single gene approach, in order to increase diagnostic rate. This review is focused on clinical and genetic features of PMDs with the aim to (1) help clinicians to recognize, diagnose and treat patients with PMDs as well as to (2) provide an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21103603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279391PMC
May 2020

Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients.

Ann Neurol 2020 08 10;88(2):251-263. Epub 2020 Jun 10.

Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.

Objective: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10).

Methods: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data.

Results: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%.

Interpretation: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251-263.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877690PMC
August 2020

Teaching Video NeuroImages: Palatal tremor associated with variants.

Neurology 2020 05 21;94(19):e2074-e2075. Epub 2020 Apr 21.

From the UOC Neurofisiopatologia (G.P., S.S.), Fondazione Policlinico Universitario A. Gemelli IRCCS; Istituto di Neurologia (G.P., S.S.), Università Cattolica del Sacro Cuore; and Unit of Neuromuscular and Neurodegenerative Disorders (G.Z., M.N.), Department of Neurosciences, IRCCS, Bambino Gesù Research Hospital, Rome, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000009409DOI Listing
May 2020

A wearable video-oculography based evaluation of saccades and respective clinical correlates in patients with early onset ataxia.

J Neurosci Methods 2020 05 20;338:108697. Epub 2020 Mar 20.

Department of Neuroscience - Unit of Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, Rome - Via Torre Di Palidoro s.n.c. 00050, Palidoro, Rome, Italy.

Background: Friedreich Ataxia (FRDA) and other inherited chronic ataxias (CAs) are common causes of early onset ataxias (EOA), a group of conditions still lacking effective therapies and biomarkers. Ocular saccades are considered a reliable paradigm of motor control, useful to track the functioning of underlying neural networks and serving as potential markers for neurological diseases.

New Method: A non-invasive video-oculography device (EyeSeeCam) was used to test saccadic parameters (latency, amplitude, duration, velocity) and peak velocity/amplitude ratio ("main sequence") in pediatric patients with FRDA, CAs and healthy controls, providing correlations with standard clinical scores.

Results: Pattern of saccadic features differed between CA and FRDA. The main sequence analysis was impaired respectively in vertical saccades in CA, and in horizontal saccades in FRDA. In CA, the amplitude of vertical saccades was reduced, and the size inversely correlated with the Scale for the assessment and rating of ataxia (SARA) score. In FRDA the amplitude of horizontal saccades directly correlated with SARA score.

Comparison With Existing Method: EyeSeeCam allowed testing saccades easily and quickly even in pediatric patients with EOA.

Conclusions: The pattern of saccadic impairment differed between FRDA and CAs, resulting a prominent involvement of vertical saccades in CA and of horizontal ones in FRDA, which respectively correlated with SARA score. Since such differences may reflect distinct pathophysiological substrates, saccades emerged as a potential source of biomarkers in EOAs. Availability of handy tools, such as EyeSeeCam, may facilitate future research in this field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jneumeth.2020.108697DOI Listing
May 2020

TUBB Variants Underlying Different Phenotypes Result in Altered Vesicle Trafficking and Microtubule Dynamics.

Int J Mol Sci 2020 Feb 18;21(4). Epub 2020 Feb 18.

Unit of Neuromuscular and Neurodegenerative Disorders, Department Neurosciences, Bambino Gesù Children's Hospital, IRCCS 00146 Rome, Italy.

Tubulinopathies are rare neurological disorders caused by alterations in tubulin structure and function, giving rise to a wide range of brain abnormalities involving neuronal proliferation, migration, differentiation and axon guidance. TUBB is one of the ten β-tubulin encoding genes present in the human genome and is broadly expressed in the developing central nervous system and the skin. Mutations in TUBB are responsible for two distinct pathological conditions: the first is characterized by microcephaly and complex structural brain malformations and the second, also known as "circumferential skin creases Kunze type" (CSC-KT), is associated to neurological features, excess skin folding and growth retardation. We used a combination of immunocytochemical and cellular approaches to explore, on patients' derived fibroblasts, the functional consequences of two TUBB variants: the novel mutation (p.N52S), associated with basal ganglia and cerebellar dysgenesis, and the previously reported variant (p.M73T), linked to microcephaly, corpus callosum agenesis and CSC-KT skin phenotype. Our results demonstrate that these variants impair microtubule (MT) function and dynamics. Most importantly, our studies show an altered epidermal growth factor (EGF) and transferrin (Tf) intracellular vesicle trafficking in both patients' fibroblasts, suggesting a specific role of TUBB in MT-dependent vesicular transport.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21041385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073044PMC
February 2020

Age and sex prevalence estimate of Joubert syndrome in Italy.

Neurology 2020 02 22;94(8):e797-e801. Epub 2020 Jan 22.

From the Neurogenetics Unit (S.N., M.G., E.M.V.), IRCCS Fondazione Santa Lucia, Rome; Department of Medicine and Surgery (S.N.), University of Salerno; National Center for Disease Prevention and Health Promotion (I.B., N.V.), National Institute of Health, Rome; Department of Molecular Medicine (M.G., A.C., V.S., E.M.V.), University of Pavia; IRCCS Stella Maris Foundation (R. Battini); Department of Clinical and Experimental Medicine (R. Battini), University of Pisa; Laboratory of Molecular Medicine (E.B., M.N., G.Z.), Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, and Laboratory of Medical Genetics (A.M.), IRCCS Bambino Gesù Children's Hospital, Rome; and Neuropsychiatry and Neurorehabilitation Unit (R. Borgatti, R.R.), Scientific Institute IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy.

Objective: To estimate the prevalence of Joubert syndrome (JS) in Italy applying standards of descriptive epidemiology and to provide a molecular characterization of the described patient cohort.

Methods: We enrolled all patients with a neuroradiologically confirmed diagnosis of JS who resided in Italy in 2018 and calculated age and sex prevalence, assuming a Poisson distribution. We also investigated the correlation between proband chronological age and age at diagnosis and performed next-generation sequencing (NGS) analysis on probands' DNA when available.

Results: We identified 284 patients with JS: the overall, female- and male-specific population-based prevalence rates were 0.47 (95% confidence interval [CI] 0.41-0.53), 0.41 (95% CI 0.32-0.49), and 0.53 (95% CI 0.45-0.61) per 100,000 population, respectively. When we considered only patients in the age range from 0 to 19 years, the corresponding population-based prevalence rates rose to 1.7 (95% CI 1.49-1.97), 1.62 (95% CI 1.31-1.99), and 1.80 (95% CI 1.49-2.18) per 100,000 population. NGS analysis allowed identifying the genetic cause in 131 of 219 screened probands. Age at diagnosis was available for 223 probands, with a mean of 6.67 ± 8.10 years, and showed a statistically significant linear relationship with chronological age ( = 0.79; < 0.001).

Conclusions: We estimated for the first time the age and sex prevalence of JS in Italy and investigated the patients' genetic profile. The obtained population-based prevalence rate was ≈10 times higher than that available in literature for children population.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000008996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136056PMC
February 2020

One-year outcome of coenzyme Q10 supplementation in ataxia (ARCA2).

Cerebellum Ataxias 2019 16;6:15. Epub 2019 Dec 16.

1Department of Neurosciences, Bambino Gesù Hospital, via della Torre di Palidoro, Fiumicino, Rome, Italy.

Background: The recessive ataxia ARCA2 is a rare disorder characterized by Coenzyme Q10 (CoQ10) deficiency due to biallelic mutations in gene. Despite the pathophysiological role, available data are not univocal on clinical efficacy of CoQ10 supplementation in ARCA2. Here we described the long-term motor outcome of 4 untreated ARCA2 patients prospectively followed-up for one year after starting CoQ10 oral supplementation (15 mg/kg/day).

Methods: Clinical rating scales (SARA; 9 holes peg test; 6 min walking test; Timed 25-Foot Walk) and videoelectronic gait analysis were performed at baseline and every 6 months (T0, T1, T2) to evaluate the motor performances. Since two patients discontinued the treatment at the 7th month, we could provide comparative analysis between longer and shorter supplementation.

Results: At T2, the gait speed (Timed 25-Foot Walk test) significantly differed between patients with long and short treatment; overall, the clinical condition tended to be better in patients continuing CoQ10.

Conclusions: Although preliminarily, this observation suggests that only prolonged and continuous CoQ10 supplementation may induce mild clinical effects on general motor features of ARCA2. Dedicated trials are now necessary to extend and validate such observation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40673-019-0109-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916514PMC
December 2019

Dystonia-Ataxia with early handwriting deterioration in COQ8A mutation carriers: A case series and literature review.

Parkinsonism Relat Disord 2019 11 28;68:8-16. Epub 2019 Sep 28.

Departments of Neurosciences and Pediatrics, University of California San Diego, San Diego, CA, USA; Division of Neurology Rady Children's Hospital, San Diego, CA, USA; Rady Children's Institute for Genomic Medicine, San Diego, CA, USA. Electronic address:

Cerebellar ataxia is a hallmark of coenzyme Q (CoQ) deficiency associated with COQ8A mutations. We present four patients, one with novel COQ8A pathogenic variants all with early, prominent handwriting impairment, dystonia and only mild ataxia. To better define the phenotypic spectrum and course of COQ8A disease, we review the clinical presentation and evolution in 47 reported cases. Individuals with COQ8A mutation display great clinical variability and unpredictable responses to CoQ supplementation. Onset is typically during infancy or childhood with ataxic features associated with developmental delay or regression. When disease onset is later in life, first symptoms can include: incoordination, epilepsy, tremor, and deterioration of writing. The natural history is characterized by a progression to a multisystem brain disease dominated by ataxia, with disease severity inversely correlated with age at onset. Six previously reported cases share with ours, a clinical phenotype characterized by slowly progressive or static writing difficulties, focal dystonia, and speech disorder, with only minimal ataxia. The combination of writing difficulty, dystonia and ataxia is a distinctive constellation that is reminiscent of a previously described clinical entity called Dystonia Ataxia Syndrome (DYTCA) and is an important clinical indicator of COQ8A mutations, even when ataxia is mild or absent.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.parkreldis.2019.09.015DOI Listing
November 2019

Defining the clinical-genetic and neuroradiological features in SPG54: description of eight additional cases and nine novel DDHD2 variants.

J Neurol 2019 Nov 13;266(11):2657-2664. Epub 2019 Jul 13.

Unit of Neuromuscular and Neurodegenerative Disorders, Department of Neurosciences, IRCCS, Bambino Gesù Research Hospital, Rome, Italy.

Recessive mutations in DDHD2 cause SPG54, a complex hereditary spastic paraplegia (HSP) with less than forty patients reported worldwide. In this retrospective, multicenter study we describe eight additional SPG54 cases harboring homozygous or compound heterozygous DDHD2 variants. Finally, we reviewed literature data on SPG54, with the aim to better define the phenotype and the brain magnetic resonance imaging (MRI) pattern as well as genotype-phenotype correlations. SPG54 is typically characterized by early-onset (i.e., congenital or, more frequently, infantile) delay in motor and cognitive milestones, coupled or followed by appearance of spasticity. Cognitive impairment is absent in adult-onset cases. Spasticity progresses over time. Abnormal eye movement, found in about 50% of cases, is the feature most frequently associated with spasticity and developmental delay. Cerebellar ataxia is a prominent sign in several patients, including one adult of this study, suggesting to include SPG54 in the differential diagnosis of spastic-ataxia syndromes. Brain MRI shows thin corpus callosum and non-specific periventricular white matter lesions in about 90% and 70% of cases, respectively. Brain MR spectroscopy reveals abnormal lipid peak in 90% of investigated patients. Twenty-one pathogenic changes have been reported so far, many of which are nonsense or small deletion/duplication. Most mutations appear to be private, with only two mutations recurring in three (i.e., R287*) or more families (i.e., D660H). The identification of nine novel variants expands the molecular spectrum of DDHD2-related HSP and corroborates the notion of a quite homogeneous clinical and neuroradiological phenotype in spite of different genotypes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00415-019-09466-yDOI Listing
November 2019

Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia.

Clin Genet 2019 08 5;96(2):169-175. Epub 2019 Jun 5.

Unit of Muscular and Neurodegenerative Diseases, Department of Neurosciences, Bambino Gesù Children's Hospital, Rome, Italy.

Heterozygous missense variants in the SPTBN2 gene, encoding the non-erythrocytic beta spectrin 2 subunit (beta-III spectrin), have been identified in autosomal dominant spinocerebellar ataxia type 5 (SCA5), a rare adult-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, whereas homozygous loss of function variants in SPTBN2 have been associated with early onset cerebellar ataxia and global developmental delay (SCAR14). Recently, heterozygous SPTBN2 missense variants have been identified in a few patients with an early-onset ataxic phenotype. We report five patients with non-progressive congenital ataxia and psychomotor delay, 4/5 harboring novel heterozygous missense variants in SPTBN2 and one patient with compound heterozygous SPTBN2 variants. With an overall prevalence of 5% in our cohort of unrelated patients screened by targeted next-generation sequencing (NGS) for congenital or early-onset cerebellar ataxia, this study indicates that both dominant and recessive mutations of SPTBN2 together with CACNA1A and ITPR1, are a frequent cause of early-onset/congenital non-progressive ataxia and that their screening should be implemented in this subgroup of disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13562DOI Listing
August 2019

Correction to: Biallelic Variants in the Nuclear Pore Complex Protein NUP93 Are Associated with Non-progressive Congenital Ataxia.

Cerebellum 2019 06;18(3):433-434

Institute of Biochemistry and Molecular Cell Biology, Medical School, RWTH Aachen University, 52074, Aachen, Germany.

The original version of this article unfortunately contained mistake in Fig. 3 image.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12311-019-01021-9DOI Listing
June 2019

Biallelic Variants in the Nuclear Pore Complex Protein NUP93 Are Associated with Non-progressive Congenital Ataxia.

Cerebellum 2019 Jun;18(3):422-432

Institute of Biochemistry and Molecular Cell Biology, Medical School, RWTH Aachen University, 52074, Aachen, Germany.

Nuclear pore complexes (NPCs) are the gateways of the nuclear envelope mediating transport between cytoplasm and nucleus. They form huge complexes of 125 MDa in vertebrates and consist of about 30 different nucleoporins present in multiple copies in each complex. Here, we describe pathogenic variants in the nucleoporin 93 (NUP93) associated with an autosomal recessive form of congenital ataxia. Two rare compound heterozygous variants of NUP93 were identified by whole exome sequencing in two brothers with isolated cerebellar atrophy: one missense variant (p.R537W) results in a protein which does not localize to NPCs and cannot functionally replace the wild type protein, whereas the variant (p.F699L) apparently supports NPC assembly. In addition to its recently described pathological role in steroid-resistant nephrotic syndrome, our work identifies NUP93 as a candidate gene for non-progressive congenital ataxia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12311-019-1010-5DOI Listing
June 2019

Impaired urinary concentration ability is a sensitive predictor of renal disease progression in Joubert syndrome.

Nephrol Dial Transplant 2020 07;35(7):1195-1202

Department of Nephrology and Urology, Unit of Nephrology and Dialysis, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

Background: Joubert syndrome (JS) is an inherited ciliopathy characterized by a complex midbrain-hindbrain malformation and multiorgan involvement. Renal disease, mainly juvenile nephronophthisis (NPH), was reported in 25-30% patients although only ∼18% had a confirmed diagnosis of chronic kidney disease (CKD). NPH often remains asymptomatic for many years, resulting in delayed diagnosis. The aim of the study was to identify a biomarker able to quantify the risk of progressive CKD in young children with JS.

Methods: Renal features were investigated in 93 Italian patients, including biochemical tests, ultrasound and 1-deamino-8D-arginine vasopressin test in children with reduced basal urine osmolality. A subset of patients was followed-up over time.

Results: At last examination, 27 of 93 subjects (29%) presented with CKD, ranging from isolated urinary concentration defect (UCD) to end-stage renal disease. Both normal and pathological urine osmolality levels remained stable over time, even when obtained at very early ages. Follow-up data showed that the probability of developing CKD can be modelled as a function of the urine osmolality value, exceeding 75% for levels <600 mOsm/kg H2O, and significantly increased in patients with an early diagnosis of isolated UCD.

Conclusions: We conclude that the frequency of CKD in JS increases with age and is higher than previously reported. Urine osmolality represents an early sensitive quantitative biomarker of the risk of CKD progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ndt/gfy333DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7417010PMC
July 2020

Nonprogressive congenital ataxias.

Handb Clin Neurol 2018 ;155:91-103

Department of Pediatric Neurology, University Children's Hospital, University of Zurich, Zurich, Switzerland.

The terminology of nonprogressive congenital ataxia (NPCA) refers to a clinically and genetically heterogeneous group of disorders characterized by congenital or early-onset ataxia, but no progression or even improvement on follow-up. Ataxia is preceded by muscular hypotonia and delayed motor (and usually language) milestones. We exclude children with prenatal, perinatal, and postnatal acquired diseases, malformations other than cerebellar hypoplasia, and defined syndromic disorders. Patients with NPCA have a high prevalence of cognitive and language impairments, in addition to increased occurrence of seizures, ocular signs (nystagmus, strabismus), behavior changes, and microcephaly. Neuroimaging is variable, ranging from normal cerebellar anatomy to reduced cerebellar volume (hypoplasia in the proper sense), and enlarged interfolial spaces, potentially mimicking atrophy. The latter appearance is often called "hypoplasia" as well, in view of the static clinical course. Some patients had progressive enlargement of cerebellar fissures, but a nonprogressive course. There is no imaging-clinical-genetic correlation. Dominant, recessive, and X-linked inheritance is documented for NPCA. Here, we focus on the still rather short list of dominant and recessive genes associated with NPCA, identified in the last few years. With future advances in genetics, we expect a rapid expansion of knowledge in this field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/B978-0-444-64189-2.00006-8DOI Listing
October 2018

X-linked ataxias.

Handb Clin Neurol 2018 ;155:175-189

Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesu' Children's Research Hospital, Rome, Italy.

X-linked cerebellar ataxias (XLCA) are an expanding group of genetically heterogeneous and clinically variable conditions characterized by cerebellar dysgenesis (hypoplasia, atrophy, or dysplasia) caused by gene mutations or genomic imbalances on the X chromosome. The neurologic features of XLCA include hypotonia, developmental delay, intellectual disability, ataxia, and other cerebellar signs. Normal cognitive development has also been reported. Cerebellar defects may be isolated or associated with other brain malformations or extraneurologic involvement. More than 20 genes on the X chromosome, mainly encoding for proteins involved in brain development and synaptic function that have been constantly or occasionally associated with a pathologic cerebellar phenotype, and several families with X-linked inheritance have been reported. Given the excess of males with ataxia, this group of conditions is probably underestimated and families of patients with neuroradiologic and clinical evidence of a cerebellar disorder should be counseled for high risk of X-linked inheritance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/B978-0-444-64189-2.00011-1DOI Listing
October 2018

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

Neurogenetics 2018 05 24;19(2):111-121. Epub 2018 Apr 24.

Unit of Neuromuscular and Neurodegenerative Disorders, Ospedale Pediatrico Bambino Gesù, Polo di Ricerca S. Paolo, V.le S. Paolo, 15, 00146, Rome, Italy.

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. To describe our diagnostic molecular genetic approach on patients with pediatric-onset pure and complex HSP, 47 subjects with HSP underwent molecular screening of 113 known and candidate disease genes by targeted capture and massively parallel sequencing. Negative cases were successively analyzed by multiplex ligation-dependent probe amplification (MLPA) analysis for the SPAST gene and high-resolution SNP array analysis for genome-wide CNV detection. Diagnosis was molecularly confirmed in 29 out of 47 (62%) patients, most of whom had clinical diagnosis of cHSP. Although SPG11 and SPG4 remain the most frequent cause of, respectively, complex and pure HSP, a large number of pathogenic variants were disclosed in POLR3A, FA2H, DDHD2, ATP2B4, ENTPD1, ERLIN2, CAPN1, ALS2, ADAR1, RNASEH2B, TUBB4A, ATL1, and KIF1A. In a subset of these disease genes, phenotypic expansion and novel genotype-phenotype correlations were recognized. Notably, SNP array analysis did not provide any significant contribution in increasing the diagnostic yield. Our findings document the high diagnostic yield of targeted sequencing for patients with pediatric-onset, complex, and pure HSP. MLPA for SPAST and SNP array should be limited to properly selected cases based on clinical suspicion.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10048-018-0545-9DOI Listing
May 2018

A V1143F mutation in the neuronal-enriched isoform 2 of the PMCA pump is linked with ataxia.

Neurobiol Dis 2018 07 12;115:157-166. Epub 2018 Apr 12.

Venetian Institute of Molecular Medicine, Padova, Italy. Electronic address:

The fine regulation of intracellular calcium is fundamental for all eukaryotic cells. In neurons, Ca oscillations govern the synaptic development, the release of neurotransmitters and the expression of several genes. Alterations of Ca homeostasis were found to play a pivotal role in neurodegenerative progression. The maintenance of proper Ca signaling in neurons demands the continuous activity of Ca pumps and exchangers to guarantee physiological cytosolic concentration of the cation. The plasma membrane CaATPases (PMCA pumps) play a key role in the regulation of Ca handling in selected sub-plasma membrane microdomains. Among the four basic PMCA pump isoforms existing in mammals, isoforms 2 and 3 are particularly enriched in the nervous system. In humans, genetic mutations in the PMCA2 gene in association with cadherin 23 mutations have been linked to hearing loss phenotypes, while those occurring in the PMCA3 gene were associated with X-linked congenital cerebellar ataxias. Here we describe a novel missense mutation (V1143F) in the calmodulin binding domain (CaM-BD) of the PMCA2 protein. The mutant pump was present in a patient showing congenital cerebellar ataxia but no overt signs of deafness, in line with the absence of mutations in the cadherin 23 gene. Biochemical and molecular dynamics studies on the mutated PMCA2 have revealed that the V1143F substitution alters the binding of calmodulin to the CaM-BD leading to impaired Ca ejection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.nbd.2018.04.009DOI Listing
July 2018

Defective kinesin binding of TUBB2A causes progressive spastic ataxia syndrome resembling sacsinopathy.

Hum Mol Genet 2018 06;27(11):1892-1904

Unit of Neuromuscular and Neurodegenerative Disorders, Department Neurosciences, Ospedale Pediatrico Bambino Gesù, 00146 Rome, Italy.

Microtubules participate in fundamental cellular processes, including chromosomal segregation and cell division, migration and intracellular trafficking. Their proper function is required for correct central nervous system development and operative preservation, and mutations in genes coding tubulins, the constituting units of microtubules, underlie a family of neurodevelopmental and neurodegenerative diseases, collectively known as 'tubulinopathies', characterized by a wide range of neuronal defects resulting from defective proliferation, migration and function. Here, we causally link a previously unreported missense mutation in TUBB2A (c.1249G>A, p.D417N), encoding one of the neuron-specific β-tubulin isotype II, to a disorder characterized by progressive spastic paraplegia, peripheral sensory-motor polyneuropathy and ataxia. Asp417 is a highly conserved solvent-exposed residue at the site mediating binding of kinesin superfamily motors. Impaired binding to KIF1A, a neuron-specific kinesin required for transport of synaptic vesicle precursors of the disease-associated TUBB2A mutant, was predicted by structural analyses and confirmed experimentally in vitro. We show that overexpression of TUBB2AD417N disrupts the mitotic spindle bipolarity and morphology and affects the M phase entry and length. Differently from the TUBB2AN247K and TUBB2AA248V, two mutants previously identified to affect neurodevelopment, TUBB2AD417N retains the ability to assemble into microtubules. Consistent with the differential clinical and structural impact, TUBB2AA248V does not drastically affect TUBB2A binding to KIF1A, nor mitotic spindle bipolarity. Overall, our data demonstrate a pathogenic role of the p.D417N substitution that is different from previously reported TUBB2A mutations and expand the phenotypic spectrum associated with mutations in this gene.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/hmg/ddy096DOI Listing
June 2018

Novel Homozygous KCNJ10 Mutation in a Patient with Non-syndromic Early-Onset Cerebellar Ataxia.

Cerebellum 2018 Aug;17(4):499-503

Department of Neurosciences, Unit of Neuromuscular and Neurodegenerative Disorders, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Mutations in KCNJ10, which encodes the inwardly rectifying potassium channel Kir4.1, a primary regulator of membrane excitability and potassium homeostasis, cause a complex syndrome characterized by seizures, sensorineural deafness, ataxia, intellectual disability, and electrolyte imbalance called SeSAME/EAST syndrome. We describe a 41-year-old patient with non-syndromic, slowly progressive, early-onset ataxia. Targeted next-generation sequencing identified a novel c.180 T > G (p.Ile60Met) missense homozygous mutation. The mutated residue Ile60Met likely impairs phosphatidylinositol 4, 5-bisphosphate (PIP2) binding which is known to play an essential role in channel gating. Our study expands the clinical and mutational spectrum of KCNJ10-related disorders and suggests that screening of this gene should be implemented in patients with early-onset ataxia, with or without syndromic features.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12311-018-0924-7DOI Listing
August 2018

Serum uric acid in Friedreich Ataxia.

Clin Biochem 2018 Apr 2;54:139-141. Epub 2018 Feb 2.

Department of Neurosciences and Neurorehabilitation, IRCCS Bambino Gesù Children Hospital, Rome, Italy.

Serum uric acid (UA) is a circulating antioxidant whose levels are typically lower in patients with idiopathic neurodegenerative diseases than healthy controls, reflecting a higher oxidative stress. Here we provided the first assessment of serum UA in Friedreich Ataxia (FRDA), an inherited neurodegenerative disorder, aimed at exploring novel disease biomarkers. Serum UA was measured in 19 FRDA patients and compared to 26 healthy controls (CTL). Multivariate analysis was conducted to eliminate main confounding factors (age, gender and BMI). Diagnostic accuracy was tested with ROC curve analysis and cut-off point calculation. Clinical predictive value was quantified by means Spearman's correlation with SARA score and other clinical parameters. Serum UA levels resulted significantly higher in FRDA than CTL (p = .016), independently from age, gender and BMI. At the cut-off value of 4.45 mg/dl, serum UA discriminates FRDA from CTL with >70% of sensitivity and >60% of specificity. No correlations emerged with clinical data. Contrarily to other neurodegenerative diseases, in FRDA, we observed an independent increase of serum UA content. Taking in account previous experimental findings, we hypothesize that such a finding may result from biochemical impairment induced by the genetic defect, acting as a sort of compensatory antioxidant defense although proper dedicated studies are mandatory. This preliminary report focuses UA as a potential biomarker for FRDA and encourages further studies on novel therapeutic strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinbiochem.2018.01.022DOI Listing
April 2018

A novel PMCA3 mutation in an ataxic patient with hypomorphic phosphomannomutase 2 (PMM2) heterozygote mutations: Biochemical characterization of the pump defect.

Biochim Biophys Acta Mol Basis Dis 2017 12 12;1863(12):3303-3312. Epub 2017 Aug 12.

Venetian Institute of Molecular Medicine, Padova, Italy. Electronic address:

The neuron-restricted isoform 3 of the plasma membrane Ca ATPase plays a major role in the regulation of Ca homeostasis in the brain, where the precise control of Ca signaling is a necessity. Several function-affecting genetic mutations in the PMCA3 pump associated to X-linked congenital cerebellar ataxias have indeed been described. Interestingly, the presence of co-occurring mutations in additional genes suggest their synergistic action in generating the neurological phenotype as digenic modulators of the role of PMCA3 in the pathologies. Here we report a novel PMCA3 mutation (G733R substitution) in the catalytic P-domain of the pump in a patient affected by non-progressive ataxia, muscular hypotonia, dysmetria and nystagmus. Biochemical studies of the pump have revealed impaired ability to control cellular Ca handling both under basal and under stimulated conditions. A combined analysis by homology modeling and molecular dynamics have revealed a role for the mutated residue in maintaining the correct 3D configuration of the local structure of the pump. Mutation analysis in the patient has revealed two additional function-impairing compound heterozygous missense mutations (R123Q and G214S substitution) in phosphomannomutase 2 (PMM2), a protein that catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate. These mutations are known to be associated with Type Ia congenital disorder of glycosylation (PMM2-CDG), the most common group of disorders of N-glycosylation. The findings highlight the association of PMCA3 mutations to cerebellar ataxia and strengthen the possibility that PMCAs act as digenic modulators in Ca-linked pathologies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbadis.2017.08.006DOI Listing
December 2017

A mild form of adenylosuccinate lyase deficiency in absence of typical brain MRI features diagnosed by whole exome sequencing.

Ital J Pediatr 2017 Aug 2;43(1):65. Epub 2017 Aug 2.

Genetics and Rare Diseases, Research Division, Bambino Gesù Children's Hospital, Piazza Sant'Onofrio 4, 00164, Rome, Italy.

Background: Adenylosuccinate lyase (ADSL) deficiency is a defect of purine metabolism affecting purinosome assembly and reducing metabolite fluxes through purine de novo synthesis and purine nucleotide recycling pathways. The disorder shows a wide spectrum of symptoms from slowly to rapidly progressing forms. The most severe form is characterized by neonatal encephalopathy, absence of spontaneous movement, respiratory failure, intractable seizures, and early death within the first weeks of life. More commonly, ADSL presents purely neurologic clinical picture characterized by severe psychomotor retardation, microcephaly, early onset of seizures, and autistic features (type I) or a more slowly progressing form with later onset, and major features including slight to moderate psychomotor retardation, and transient contact disturbances (type II). Diagnostic markers are the presence of succinylaminoimidazole carboxamide riboside (SAICAr) and succinyladenosine (SAdo) in extracellular fluids. ADSL is a rare disorder, although its prevalence remains unknown. Of note, the wide range of essentially nonspecific manifestations and lack of awareness of the condition often prevent diagnosis.

Case Presentation: We present here the case of particularly mild, late onset ADSL that has been unsuccessfully investigated until whole exome sequencing (WES) was performed.

Conclusions: Besides emphasizing the valuable diagnostic value of WES, this report provides new data further documenting the relatively wide clinical manifestation of ADSL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13052-017-0383-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5541734PMC
August 2017

Identification of novel and hotspot mutations in the channel domain of ITPR1 in two patients with Gillespie syndrome.

Gene 2017 Sep 8;628:141-145. Epub 2017 Jul 8.

Unit of Neuromuscular and Neurodegenerative Disorders, Laboratory of Molecular Medicine, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address:

ITPR1 encodes an intracellular receptor for inositol 1,4,5-trisphosphate (InsP3) which is highly expressed in the cerebellum and is involved in the regulation of Ca2+ homeostasis. Missense mutations in the InsP3-binding domain (IRBIT) of ITPR1 are frequently associated with early onset cerebellar atrophy. Gillespie syndrome is characterized by congenital ataxia, mild to moderate intellectual disability and iris hypoplasia. Dominant or recessive ITPR1 mutations have been recently associated with this form of syndromic ataxia. We performed next generation sequencing in two simplex families with Gillespie syndrome and identified de novo pathological mutations localized in the C-terminal channel domain of ITPR1 in both patients: a recurrent deletion (p.Lys2596del) and a novel missense mutation (p.Asn2576Ile) close to a point of constriction in the Ca pore. Our study expands the mutational spectrum of ITPR1 and confirms that ITPR1 screening should be implemented in patients with congenital cerebellar ataxia with or without iris hypoplasia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.gene.2017.07.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5607352PMC
September 2017