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1.
Cerebellum ; 2024 Sep 23.
Article in English | MEDLINE | ID: mdl-39312122

ABSTRACT

Bi-allelic pathogenic variants in GRID2 have been initially associated to an autosomal recessive form of spinocerebellar ataxia, namely SCAR18. Subsequently, few monoallelic cases have been described. Here we present a new subject harboring a novel de novo heterozygous GRID2 missense variant presenting with progressive ataxia together with cerebellar atrophy and, for the first time, alpha-fetoprotein (AFP) elevation. We retrospectively collected data of the patient followed at our clinic. Genetic analysis was performed through clinical exome sequencing with an in-house in-silico ataxia-related genes panel. Variant effect prediction was performed through in silico modeling. The patient had normal psychomotor development except for mild fine and gross motor impairment. In adolescence, he started presenting dysarthria and progressive ataxia. Blood tests showed significant AFP elevation. Brain MRI showed cerebellar atrophy mainly involving the vermis. The novel de novo heterozygous GRID2 (c.1954C>A; p.Leu652Ile) missense variant was disclosed. This variant is located within a highly conserved site with low tolerance to variation and it is predicted to cause protein structure destabilization. GRID2 expression appears to be influenced by other genes related with ataxia and AFP elevation, like ATM and APTX, suggesting a possible shared mechanism. This additional patient increases the scarce literature and genotypic spectrum of the GRID2-related ataxia and evidences a fairly homogeneous phenotype of ataxia with oculomotor abnormalities for the autosomal-dominant form. Alfa-fetoprotein elevation is a novel finding in this condition and this data must be confirmed in larger case-series to definitively state that GRID2-related ataxia can be included among ataxias with AFP increase.

2.
Genet Med ; : 101251, 2024 Sep 10.
Article in English | MEDLINE | ID: mdl-39275948

ABSTRACT

PURPOSE: This study aims to comprehensively delineate the phenotypic spectrum of ACTL6B-related disorders, previously associated with both autosomal recessive and autosomal dominant neurodevelopmental disorders. Molecularly, the role of the nucleolar protein ACTL6B in contributing to the disease has remained unclear. METHODS: We identified 105 affected individuals, including 39 previously reported cases, and systematically analysed detailed clinical and genetic data for all individuals. Additionally, we conducted knockdown experiments in neuronal cells to investigate the role of ACTL6B in ribosome biogenesis. RESULTS: Biallelic variants in ACTL6B are associated with severe-to-profound global developmental delay/intellectual disability (GDD/ID), infantile intractable seizures, absent speech, autistic features, dystonia, and increased lethality. De novo monoallelic variants result in moderate-to-severe GDD/ID, absent speech, and autistic features, while seizures and dystonia were less frequently observed. Dysmorphic facial features and brain abnormalities, including hypoplastic corpus callosum, parenchymal volume loss/atrophy, are common findings in both groups. We reveal that in the nucleolus, ACTL6B plays a crucial role in ribosome biogenesis, in particular in pre-rRNA processing. CONCLUSION: This study provides a comprehensive characterization of the clinical spectrum of both autosomal recessive and dominant forms of ACTL6B-associated disorders. It offers a comparative analysis of their respective phenotypes provides a plausible molecular explanation and suggests their inclusion within the expanding category of 'ribosomopathies'.

3.
Eur J Paediatr Neurol ; 52: 10-19, 2024 Sep.
Article in English | MEDLINE | ID: mdl-38970889

ABSTRACT

AIM: This exploratory study evaluates rating scale usage by experts from the European Reference Network for Rare Neurological Diseases (ERN-RND) for paediatric MD, considering factors like diagnosis, intellectual disability, age, and transition to adult care. The aim is to propose a preliminary framework for consistent application. METHODS: A multicentre survey among 25 ERN-RND experts from 10 European countries examined rating scale usage in paediatric MD, categorizing MD into acute, non-progressive, and neurodegenerative types. Factors influencing scale choice and the transition to adult care practices were analysed. A comprehensive literature search was conducted to identify the earliest age of application of these scales in paediatric patients. RESULTS: The study identifies various rating scales and establishes their usage frequencies for different MDs. Experts highlighted the need for standardized scales and proposed preliminary evaluation strategies based on clinical contexts. Challenges in applying scales to young, non-cooperative patients were acknowledged. INTERPRETATION: The study recommends developing standardized rating scales for paediatric MDs to improve evaluations and data collection. It suggests potential scales for specific clinical scenarios to better evaluate disease progression. Comprehensive, patient-centred care remains crucial during the transition to adult care, despite the identified challenges. This exploratory approach aims to enhance patient outcomes and care.


Subject(s)
Movement Disorders , Humans , Movement Disorders/therapy , Movement Disorders/diagnosis , Child , Europe , Transition to Adult Care/standards , Pediatrics/standards , Pediatrics/methods , Severity of Illness Index , Adolescent
4.
Am J Hum Genet ; 111(3): 594-613, 2024 03 07.
Article in English | MEDLINE | ID: mdl-38423010

ABSTRACT

The endosomal sorting complex required for transport (ESCRT) machinery is essential for membrane remodeling and autophagy and it comprises three multi-subunit complexes (ESCRT I-III). We report nine individuals from six families presenting with a spectrum of neurodevelopmental/neurodegenerative features caused by bi-allelic variants in SNF8 (GenBank: NM_007241.4), encoding the ESCRT-II subunit SNF8. The phenotypic spectrum included four individuals with severe developmental and epileptic encephalopathy, massive reduction of white matter, hypo-/aplasia of the corpus callosum, neurodevelopmental arrest, and early death. A second cohort shows a milder phenotype with intellectual disability, childhood-onset optic atrophy, or ataxia. All mildly affected individuals shared the same hypomorphic variant, c.304G>A (p.Val102Ile). In patient-derived fibroblasts, bi-allelic SNF8 variants cause loss of ESCRT-II subunits. Snf8 loss of function in zebrafish results in global developmental delay and altered embryo morphology, impaired optic nerve development, and reduced forebrain size. In vivo experiments corroborated the pathogenicity of the tested SNF8 variants and their variable impact on embryo development, validating the observed clinical heterogeneity. Taken together, we conclude that loss of ESCRT-II due to bi-allelic SNF8 variants is associated with a spectrum of neurodevelopmental/neurodegenerative phenotypes mediated likely via impairment of the autophagic flux.


Subject(s)
Epilepsy, Generalized , Optic Atrophy , Animals , Humans , Child , Zebrafish/genetics , Optic Atrophy/genetics , Phenotype , Endosomal Sorting Complexes Required for Transport/genetics
5.
Neurol Sci ; 45(3): 1007-1016, 2024 Mar.
Article in English | MEDLINE | ID: mdl-37853291

ABSTRACT

BACKGROUND: Transition from child-centered to adult-centered healthcare is a gradual process that addresses the medical, psychological, and educational needs of young people in the management of their autonomy in making decisions about their health and their future clinical assistance. This transfer is challenging across all chronic diseases but can be particularly arduous in rare neurological conditions. AIM: To describe the current practice on the transition process for young patients in centers participating in the European Reference Network for Rare Neurological Diseases (ERN-RND). METHODS: Members of the ERN-RND working group developed a questionnaire considering child-to-adult transition issues and procedures in current clinical practice. The questionnaire included 20 questions and was sent to members of the health care providers (HCPs) participating in the network. RESULTS: Twenty ERN-RND members (75% adult neurologists; 25% pediatricians; 5% nurses or study coordinators) responded to the survey, representing 10 European countries. Transition usually occurs between 16 and 18 years of age, but 55% of pediatric HCPs continue to care for their patients until they reach 40 years of age or older. In 5/20 ERN-RND centers, a standardized procedure managing transition is currently adopted, whereas in the remaining centers, the transition from youth to adult service is usually assisted by pediatricians as part of their clinical practice. CONCLUSIONS: This survey demonstrated significant variations in clinical practice between different centers within the ERN-RND network. It provided valuable data on existing transition programs and highlighted key challenges in managing transitions for patients with rare neurological disorders.


Subject(s)
Delivery of Health Care , Nervous System Diseases , Adult , Adolescent , Humans , Child , Surveys and Questionnaires , Europe , Nervous System Diseases/diagnosis , Nervous System Diseases/therapy , Rare Diseases/diagnosis , Rare Diseases/therapy
6.
Cerebellum ; 2023 Nov 13.
Article in English | MEDLINE | ID: mdl-37955812

ABSTRACT

With disease-modifying drugs on the horizon for degenerative ataxias, ecologically valid, finely granulated, digital health measures are highly warranted to augment clinical and patient-reported outcome measures. Gait and balance disturbances most often present as the first signs of degenerative cerebellar ataxia and are the most reported disabling features in disease progression. Thus, digital gait and balance measures constitute promising and relevant performance outcomes for clinical trials.This narrative review with embedded consensus will describe evidence for the sensitivity of digital gait and balance measures for evaluating ataxia severity and progression, propose a consensus protocol for establishing gait and balance metrics in natural history studies and clinical trials, and discuss relevant issues for their use as performance outcomes.

7.
Cerebellum ; 2023 Oct 28.
Article in English | MEDLINE | ID: mdl-37897626

ABSTRACT

Dysarthria is a common and debilitating symptom of many neurodegenerative diseases, including those resulting in ataxia. Changes to speech lead to significant reductions in quality of life, impacting the speaker in most daily activities. Recognition of its importance as an objective outcome measure in clinical trials for ataxia is growing. Its viability as an endpoint across the disease spectrum (i.e. pre-symptomatic onwards) means that trials can recruit ambulant individuals and later-stage individuals who are often excluded because of difficulty completing lower limb tasks. Here we discuss the key considerations for speech testing in clinical trials including hardware selection, suitability of tasks and their role in protocols for trials and propose a core set of tasks for speech testing in clinical trials. Test batteries could include forms suitable for remote short, sensitive and easy to use, with norms available in several languages. The use of artificial intelligence also could improve accuracy and automaticity of analytical pipelines in clinic and trials.

8.
J Neurol ; 270(12): 5784-5792, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37578488

ABSTRACT

BACKGROUND AND OBJECTIVES: Hereditary spastic paraplegias (HSPs) are heterogenous genetic disorders characterized by progressive pyramidal tract involvement. SPG76 is a recently identified form of HSP, caused by biallelic calpain-1 (CAPN1) variants. The most frequently described MRI abnormality in SPG76 is mild cerebellar atrophy and non-specific white matter abnormalities were reported in only one case. Following the identification of prominent white matter abnormalities in a subject with CAPN1 variants, which delayed the diagnosis, we aimed to verify the presence of MRI patterns of white matter involvement specific to this HSP. METHODS: We performed a retrospective radiological qualitative analysis of 15 subjects with SPG76 (4 previously unreported) initially screened for white matter involvement. Moreover, we performed quantitative analyses in our proband with available longitudinal studies. RESULTS: We observed bilateral, periventricular white matter involvement in 12 subjects (80%), associated with multifocal subcortical abnormalities in 5 of them (33.3%). Three subjects (20%) presented only multifocal subcortical involvement. Longitudinal quantitative analyses of our proband revealed increase in multifocal white matter lesion count and increased area of periventricular white matter involvement over time. DISCUSSION: SPG76 should be added to the list of HSPs with associated white matter abnormalities. We identified periventricular white matter involvement in subjects with SPG76, variably associated with multifocal subcortical white matter abnormalities. These findings, in the presence of progressive spastic paraparesis, can mislead the diagnostic process towards an acquired white matter disorder.


Subject(s)
Paraparesis, Spastic , Spastic Paraplegia, Hereditary , White Matter , Humans , White Matter/diagnostic imaging , White Matter/pathology , Retrospective Studies , Spastic Paraplegia, Hereditary/diagnostic imaging , Spastic Paraplegia, Hereditary/genetics , Magnetic Resonance Imaging
9.
Minerva Pediatr (Torino) ; 75(1): 117-123, 2023 Feb.
Article in English | MEDLINE | ID: mdl-33820410

ABSTRACT

Friedreich ataxia (FRDA) is the most common form of ataxia in late childhood. Neurological manifestations often precede cardiac involvement, presenting mainly as hypertrophic cardiomyopathy. We describe a toddler with apparently isolated severe heart failure, successfully managed with heart transplant (HT). Although well described in adolescents and adults, onset of FRDA is very uncommon in toddlers and neurological ataxic features are predominant. The presenting symptom of cardiomyopathy is very rare. Similar history is rarely reported in literature, that we described, including an aggressive cardiomyopathy in children younger than 5 years-old. RESULTS: Our patient was diagnosed with FRDA at a postoperative stage due to minimal neurological manifestations. Moreover, the novelty of this study lies in demonstrating a major DNA triplet repeat expansion in skeletal muscle compared to DNA from peripheral blood leukocytes. These results support the concept that triplet repeat expansion is variable among different tissues in FRDA, and in our case it was more expanded in the post mitotic muscular tissue than in blood cells. We believe on the importance of taking in consideration this rare condition even in a toddler with apparently isolated cardiomyopathy and especially when conventional investigations give negative results. We discuss potential trigger effect of HT as a precipitating factor in manifesting neurological symptoms. This observation corresponds to our experience and relates to three patients described so far (the third patient died suddenly). Early onset cardiomyopathy with FRDA should increase awareness of this rare condition and we highlight HT successful outcome. Further reports are needed to delineate this rare condition in youngsters.


Subject(s)
Cardiomyopathies , Cardiomyopathy, Hypertrophic , Friedreich Ataxia , Child , Adult , Adolescent , Humans , Child, Preschool , Friedreich Ataxia/complications , Friedreich Ataxia/diagnosis , Friedreich Ataxia/genetics , Cardiomyopathy, Hypertrophic/complications , Cardiomyopathy, Hypertrophic/diagnosis , Cardiomyopathies/etiology , Cardiomyopathies/genetics , Trinucleotide Repeat Expansion , DNA
10.
Antioxidants (Basel) ; 11(11)2022 Oct 28.
Article in English | MEDLINE | ID: mdl-36358497

ABSTRACT

Redox imbalance, mitochondrial dysfunction, and inflammation play a major role in the pathophysiology of X-linked adrenoleukodystrophy (X-ALD), an inherited neurodegenerative disease caused by mutations in the ABCD1 gene, encoding the protein responsible for peroxisomal import and degradation of very long chain fatty acids (VLCFAs). Therefore, VLCFAs accumulate in tissues and plasma, constituting a pathognomonic biomarker for diagnosis. However, the precise role of VLCFA accumulation on the diverse clinical phenotypes of X-ALD and the pathogenic link between VLCFAs and oxidative stress remain currently unclear. This study proposes ferroptosis as a crucial contributor to the disease development and progression. The expression profiles of "GPX4-glutathione" and "NQO1-CoQ10" ferroptosis pathways have been analyzed in fibroblasts of one patient with AMN, the late onset and slowly progressive form of X-ALD, and in two patients with cALD, the cerebral inflammatory demyelinating form of early childhood. Furthermore, as no effective treatments are currently available, especially for the rapidly progressing form of X-ALD (cALD), the efficacy of NAC treatment has also been evaluated to open the way toward novel combined therapies. Our findings demonstrate that lipid peroxides accumulate in X-ALD fibroblasts and ferroptosis-counteracting enzymes are dysregulated, highlighting a different antioxidant response in patients with AMN and cALD.

11.
Front Hum Neurosci ; 16: 797282, 2022.
Article in English | MEDLINE | ID: mdl-35992946

ABSTRACT

Background: Gait Analysis of healthy people, imitating pathological conditions while walking, has increased our understanding of biomechanical factors. The influence of the pelvis as a biomechanical constraint during gait is not specifically studied. How could mimicking a pelvic attitude influence the dynamic mechanical interaction of the body segments? We proposed an investigation of the pelvic attitude role on the gait pattern of typically developed people when they mimicked pelvic anteversion and posteroversion. Materials and methods: Seventeen healthy volunteers were enrolled in this study (mean age 24.4 ± 5.5). They simulated a pelvic anteversion and posteroversion during walking, exaggerating these postures as much as possible. 3D gait analysis was conducted using an optoelectronic system with eight cameras (Vicon MX, Oxford, United Kingdom) and two force plates (AMTI, Or-6, Watertown, MA, United States). The kinematic, kinetic, and spatio-temporal parameters were compared between the three walking conditions (anteversion, posteroversion, and normal gait). Results: In Pelvic Anteversion gait (PA) we found: increased hip flexion (p < 0.0001), increased knee flexion during stance (p = 0.02), and reduction of ankle flexion-extension Range of Motion (RoM) compared with Pelvic Normal gait (PN). In Pelvic Posteroversion gait (PP) compared with PN, we found: decreased hip flexion-extension RoM (p < 0.01) with a tendency to hip extension, decreased knee maximum extension in stance (p = 0.033), and increased ankle maximum dorsiflexion in stance (p = 0.002). Conclusion: The configuration of PA contains gait similarities and differences when compared with pathologic gait where there is an anteversion as seen in children with Cerebral Palsy (CP) or Duchenne Muscular Dystrophy (DMD). Similarly, attitudes of PP have been described in patients with Charcot-Marie-Tooth Syndrome (CMT) or patients who have undergone Pelvic Osteotomy (PO). Understanding the dynamic biomechanical constraints is essential to the assessment of pathological behavior. The central nervous system adapts motor behavior in interaction with body constraints and available resources.

12.
Neuroepidemiology ; 56(3): 212-218, 2022.
Article in English | MEDLINE | ID: mdl-35636410

ABSTRACT

OBJECTIVE: The aim of this study was to estimate the Friedreich's ataxia (FRDA) prevalence in a highly populated region of Italy (previous studies in small geographic areas gave a largely variable prevalence) and to define the patients' molecular and clinical characteristics. METHODS: For the point-prevalence study, we considered patients belonging to families with a molecular diagnosis of FRDA and resident in Latium on 1 January 2019. The crude prevalence of FRDA, specific for age and sex, was calculated and standardized for age using the Italian population. Moreover, we investigated possible correlations among patients' genetic profile, symptoms, and age of onset. RESULTS: We identified 63 FRDA patients; the crude prevalence for total, males, and females were 1.07 (95% CI: 0.81-1.37), 0.81 (95% CI: 0.54-1.22), and 1.32 (95% CI: 0.97-1.79), per 100,000 inhabitants. We divided FRDA patients by three age-at-onset groups (early-EOFA 73%; late-LOFA 11.1%; very late-VLOFA 15.9%) and found significant differences in the scale for the assessment and rating of ataxia (SARA; p = 0.001), a biased distribution of the shorter allele (p = 0.001), an excess of scoliosis and cardiomyopathy (p = 0.001) in EOFA. To determine the contribution of patients' molecular and clinical characteristics to the annual rate of progression, we performed a multivariate regression analysis that gave an R2 value of 45.3%. CONCLUSIONS: We estimated the crude and standardized prevalence of FRDA in Latium. A clinical classification (EOFA, LOFA, VLOFA) gave significant correlations. This epidemiological estimate allows monitoring disease prevalence over time in cohort studies and/or for developing disease registry.


Subject(s)
Friedreich Ataxia , Cohort Studies , Cross-Sectional Studies , Female , Friedreich Ataxia/diagnosis , Friedreich Ataxia/epidemiology , Friedreich Ataxia/genetics , Humans , Italy/epidemiology , Male , Prevalence
13.
Front Hum Neurosci ; 16: 822205, 2022.
Article in English | MEDLINE | ID: mdl-35422690

ABSTRACT

Background and Objective: Absolute angle represents the inclination of a body segment relative to a fixed reference in space. This work compares the absolute and relative angles for exploring biomechanical gait constraints. Methods: Gait patterns of different neuromotor conditions were analyzed using 3D gait analysis: normal gait (healthy, H), Cerebral Palsy (CP), Charcot Marie Tooth (CMT) and Duchenne Muscular Dystrophy (DMD), representing central and peripheral nervous system and muscular disorders, respectively. Forty-two children underwent gait analysis: 10 children affected by CP, 10 children by CMT, 10 children by DMD and 12 healthy children. The kinematic and kinetic parameters were collected to describe the biomechanical pattern of participants' lower limbs. The absolute angles of thigh, leg and foot were calculated using the trigonometric relationship of the tangent. For each absolute series, the mean, range, maximum, minimum and initial contact were calculated. Kinematic and kinetic gait data were studied, and the results were compared with the literature. Results: Statistical analysis of the absolute angles showed how, at the local level, the single segments (thigh, leg and foot) behave differently depending on the pathology. However, if the lower limb is studied globally (sum of the kinematics of the three segments: thigh, leg and foot), a biomechanical constraint emerges. Conclusion: Each segment compensates separately for the disease deficit so as to maintain a global biomechanical invariance. Using a model of inter-joint co-variation could improve the interpretation of the clinical gait pattern.

14.
J Clin Med ; 11(4)2022 Feb 18.
Article in English | MEDLINE | ID: mdl-35207341

ABSTRACT

BACKGROUND: Children with ataxia experience balance and movement coordination difficulties and needs intensive physical intervention to maintain functional abilities and counteract the disorder. Exergaming represents a valuable strategy to provide engaging physical intervention to children with ataxia, sustaining their motivation to perform the intervention. This paper aims to describe the effect of a home-conducted exergame-based exercise training for upper body movements control of children with ataxia on their ataxic symptoms, walking ability, and hand dexterity. METHODS: Eighteen children with ataxia were randomly divided into intervention and control groups. Participants in the intervention group were asked to follow a 12-week motor activity program at home using the Niurion® exergame. Blind assessments of participants' ataxic symptoms, dominant and non-dominant hand dexterity, and walking ability were conducted. RESULTS: On average, the participants performed the intervention for 61.5% of the expected time. At the end of the training, participants in the intervention group showed improved hand dexterity that worsened in the control group. CONCLUSION: The presented exergame enhanced the participants' hand dexterity. However, there is a need for exergames capable of maintaining a high level of players' motivation in playing. It is advisable to plan a mixed intervention to take care of the multiple aspects of the disorder.

15.
Hum Mutat ; 43(1): 67-73, 2022 01.
Article in English | MEDLINE | ID: mdl-34747546

ABSTRACT

Biallelic mutations in the BRAT1 gene, encoding BRCA1-associated ATM activator 1, result in variable phenotypes, from rigidity and multifocal seizure syndrome, lethal neonatal to neurodevelopmental disorder, and cerebellar atrophy with or without seizures, without obvious genotype-phenotype associations. We describe two families at the mildest end of the spectrum, differing in clinical presentation despite a common genotype at the BRAT1 locus. Two siblings displayed nonprogressive congenital ataxia and shrunken cerebellum on magnetic resonance imaging. A third unrelated patient showed normal neurodevelopment, adolescence-onset seizures, and ataxia, shrunken cerebellum, and ultrastructural abnormalities on skin biopsy, representing the mildest form of NEDCAS hitherto described. Exome sequencing identified the c.638dup and the novel c.1395G>A BRAT1 variants, the latter causing exon 10 skippings. The p53-MCL test revealed normal ATM kinase activity. Our findings broaden the allelic and clinical spectrum of BRAT1-related disease, which should be suspected in presence of nonprogressive cerebellar signs, even without a neurodevelopmental disorder.


Subject(s)
Nuclear Proteins , Seizures , Genetic Association Studies , Genotype , Humans , Mutation , Nuclear Proteins/genetics , Phenotype , Seizures/genetics
16.
J Med Genet ; 59(9): 878-887, 2022 Sep.
Article in English | MEDLINE | ID: mdl-34656997

ABSTRACT

BACKGROUND: Human coenzyme Q4 (COQ4) is essential for coenzyme Q10 (CoQ10) biosynthesis. Pathogenic variants in COQ4 cause childhood-onset neurodegeneration. We aimed to delineate the clinical spectrum and the cellular consequences of COQ4 deficiency. METHODS: Clinical course and neuroradiological findings in a large cohort of paediatric patients with COQ4 deficiency were analysed. Functional studies in patient-derived cell lines were performed. RESULTS: We characterised 44 individuals from 36 families with COQ4 deficiency (16 newly described). A total of 23 different variants were identified, including four novel variants in COQ4. Correlation analyses of clinical and neuroimaging findings revealed three disease patterns: type 1: early-onset phenotype with neonatal brain anomalies and epileptic encephalopathy; type 2: intermediate phenotype with distinct stroke-like lesions; and type 3: moderate phenotype with non-specific brain pathology and a stable disease course. The functional relevance of COQ4 variants was supported by in vitro studies using patient-derived fibroblast lines. Experiments revealed significantly decreased COQ4 protein levels, reduced levels of cellular CoQ10 and elevated levels of the metabolic intermediate 6-demethoxyubiquinone. CONCLUSION: Our study describes the heterogeneous clinical presentation of COQ4 deficiency and identifies phenotypic subtypes. Cell-based studies support the pathogenic characteristics of COQ4 variants. Due to the insufficient clinical response to oral CoQ10 supplementation, alternative treatment strategies are warranted.


Subject(s)
Mitochondrial Proteins , Ubiquinone , Cell Line , Child , Humans , Infant, Newborn , Mitochondrial Proteins/genetics , Neuroimaging , Phenotype , Ubiquinone/genetics , Ubiquinone/metabolism
17.
J Med Genet ; 59(9): 888-894, 2022 Sep.
Article in English | MEDLINE | ID: mdl-34675124

ABSTRACT

BACKGROUND: Joubert syndrome (JS) is a recessively inherited ciliopathy characterised by congenital ocular motor apraxia (COMA), developmental delay (DD), intellectual disability, ataxia, multiorgan involvement, and a unique cerebellar and brainstem malformation. Over 40 JS-associated genes are known with a diagnostic yield of 60%-75%.In 2018, we reported homozygous hypomorphic missense variants of the SUFU gene in two families with mild JS. Recently, heterozygous truncating SUFU variants were identified in families with dominantly inherited COMA, occasionally associated with mild DD and subtle cerebellar anomalies. METHODS: We reanalysed next generation sequencing (NGS) data in two cohorts comprising 1097 probands referred for genetic testing of JS genes. RESULTS: Heterozygous truncating and splice-site SUFU variants were detected in 22 patients from 17 families (1.5%) with strong male prevalence (86%), and in 8 asymptomatic parents. Patients presented with COMA, hypotonia, ataxia and mild DD, and only a third manifested intellectual disability of variable severity. Brain MRI showed consistent findings characterised by vermis hypoplasia, superior cerebellar dysplasia and subtle-to-mild abnormalities of the superior cerebellar peduncles. The same pattern was observed in two out of three tested asymptomatic parents. CONCLUSION: Heterozygous truncating or splice-site SUFU variants cause a novel neurodevelopmental syndrome encompassing COMA and mild JS, which likely represent overlapping entities. Variants can arise de novo or be inherited from a healthy parent, representing the first cause of JS with dominant inheritance and reduced penetrance. Awareness of this condition will increase the diagnostic yield of JS genetic testing, and allow appropriate counselling about prognosis, medical monitoring and recurrence risk.


Subject(s)
Abnormalities, Multiple , Cerebellar Ataxia , Eye Abnormalities , Intellectual Disability , Kidney Diseases, Cystic , Abnormalities, Multiple/genetics , Cerebellar Ataxia/genetics , Cerebellum/abnormalities , Cerebellum/diagnostic imaging , Eye Abnormalities/genetics , Haploinsufficiency/genetics , Humans , Intellectual Disability/genetics , Kidney Diseases, Cystic/diagnosis , Kidney Diseases, Cystic/genetics , Male , Phenotype , Repressor Proteins/genetics , Retina/abnormalities
18.
Neurol Genet ; 7(2): e559, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33977142

ABSTRACT

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 DARS2, encoding mitochondrial aspartyl-tRNA synthetase (mtAspRS). DARS2 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. We noticed highly unusual MRI presentations in 15 cases diagnosed by WES. We examined these cases to determine whether they represent consistent novel LBSL phenotypes. METHODS: We reviewed clinical features, MRI abnormalities, and gene variants and investigated the variants' impact on mtAspRS structure and mitochondrial function. RESULTS: We found 2 MRI phenotypes: early severe cerebral hypoplasia/atrophy (9 patients, group 1) and white matter abnormalities without long tract involvement (6 patients, group 2). With antenatal onset, microcephaly, and arrested development, group 1 patients were most severely affected. DARS2 variants were severer than for classic LBSL and severer for group 1 than group 2. All missense variants hit mtAspRS regions involved in tRNAAsp binding, aspartyl-adenosine-5'-monophosphate binding, and/or homodimerization. Missense variants expressed in the yeast DARS2 ortholog showed severely affected mitochondrial function. CONCLUSIONS: DARS2 variants are associated with highly heterogeneous phenotypes. New MRI presentations are profound cerebral hypoplasia/atrophy and white matter abnormalities without long tract involvement. Our findings have implications for diagnosis and understanding disease mechanisms, pointing at dominant neuronal/axonal involvement in severe cases. In line with this conclusion, activation of biallelic DARS2 null alleles in conditional transgenic mice leads to massive neuronal apoptosis.

19.
Cerebellum Ataxias ; 8(1): 4, 2021 Jan 06.
Article in English | MEDLINE | ID: mdl-33407890

ABSTRACT

COVID-19 outbreak profoundly impacted on daily-life of patients with neurodegenerative diseases, including those with ataxia. Effects on interventional trials have been recently described. Conversely, changes in physical activity programs, which are crucial in care of ataxic patients, have not been assessed yet.Here we used a structured electronic survey to interview twenty patients with Friedreich ataxia (FA) on changes in physical activity during the lockdown in Italy.Regular physiotherapy was interrupted for most patients and up to 60% of them referred a substantial worsening of self-perceived global health. However, FA patients (especially those mildly affected) adopted voluntarily home-based training strategies and, in 30% of cases, used technology-based tools (TBTs) for exercise.COVID-19 crisis thus disclosed the urgent need to support ataxic patients improving systems for remote physical activity and technology-based assistance.

20.
Brain Sci ; 11(1)2021 Jan 13.
Article in English | MEDLINE | ID: mdl-33450882

ABSTRACT

The PLP1 gene, located on chromosome Xq22, encodes the proteolipid protein 1 and its isoform DM20. Mutations in PLP1 cause a spectrum of white matter disorders of variable severity. Here we report on four additional HEMS patients from three families harboring three novel PLP1 mutations in exon 3B detected by targeted next-generation sequencing. Patients experienced psychomotor delay or nystagmus in the first year of age and then developed ataxic-spastic or ataxic syndrome, compatible with a phenotype of intermediate severity in the spectrum of PLP1-related disorders. Regression occurred at the beginning of the third decade of the eldest patient. Extrapyramidal involvement was rarely observed. Brain MRI confirmed the involvement of structures that physiologically myelinate early, although the pattern of abnormalities may differ depending on the age at which the study is performed. These new cases contribute to expanding the phenotypic and genotypic spectrum of HEMS. Additional studies, especially enriched by systematic functional evaluations and long-term follow-up, are welcome to better delineate the natural history of this rare hypomyelinating leukodystrophy.

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