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1.
Int J Mol Sci ; 20(15)2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31344879

RESUMO

Rett syndrome (RTT) is a neurodevelopmental disorder, affecting 1 in 10,000 girls. Intellectual disability, loss of speech and hand skills with stereotypies, seizures and ataxia are recurrent features. Stringent diagnostic criteria distinguish classical Rett, caused by a MECP2 pathogenic variant in 95% of cases, from atypical girls, 40-73% carrying MECP2 variants, and rarely CDKL5 and FOXG1 alterations. A large fraction of atypical and RTT-like patients remain without genetic cause. Next Generation Sequencing (NGS) targeted to multigene panels/Whole Exome Sequencing (WES) in 137 girls suspected for RTT led to the identification of a de novo variant in STXBP1 gene in four atypical RTT and two RTT-like girls. De novo pathogenic variants-one in GABRB2 and, for first time, one in GABRG2-were disclosed in classic and atypical RTT patients. Interestingly, the GABRG2 variant occurred at low rate percentage in blood and buccal swabs, reinforcing the relevance of mosaicism in neurological disorders. We confirm the role of STXBP1 in atypical RTT/RTT-like patients if early psychomotor delay and epilepsy before 2 years of age are observed, indicating its inclusion in the RTT diagnostic panel. Lastly, we report pathogenic variants in Gamma-aminobutyric acid-A (GABAa) receptors as a cause of atypical/classic RTT phenotype, in accordance with the deregulation of GABAergic pathway observed in MECP2 defective in vitro and in vivo models.

2.
Acta Neurol Scand ; 140(3): 184-193, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31102535

RESUMO

OBJECTIVES: To determine the prevalence of epilepsy in children with early-onset mitochondrial diseases (MDs) and to evaluate the epileptic phenotypes and associated features. MATERIALS AND METHODS: Children affected by MD with onset during the first year of life were enrolled. Patients were classified according to their mitochondrial phenotype, and all findings in patients with epilepsy versus patients without were compared. The epileptic features were analyzed. RESULTS: The series includes 129 patients (70 females) with median age at disease onset of 3 months. The median time of follow-up was 5 years. Non-syndromic mitochondrial encephalopathy and pyruvate dehydrogenase complex deficiency were the main mitochondrial diseases associated with epilepsy (P < 0.05). Seizures occurred in 48%, and the presence of epilepsy was significantly associated with earlier age at disease onset, presence of perinatal manifestations, and early detection of developmental delay and regression (P < 0.001). Epileptic encephalopathy (EE) with spasms and EE with prominent focal seizures were the most detected epileptic syndromes (37% and 27.4%). Several seizure types were recorded in 53.2%, with the unusual association of generalized and focal epileptic pattern. Disabling epilepsy was detected in 63% and was associated with early seizure onset, presence of several seizure types, epileptic syndrome featuring EE, and the recurrence of episodes of status epilepticus and epilepsia partialis continua (P < 0.05). CONCLUSIONS: Epilepsy in children with early-onset MD may be a presenting or a prominent symptom in a multisystemic clinical presentation. Epilepsy-related factors could determine a worst seizure outcome, leading to a more severe burned of the disease.

3.
Neuromuscul Disord ; 29(5): 376-380, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31040037

RESUMO

LAMA2 mutations cause the most frequent congenital muscular dystrophy subtype MDC1A and a variety of milder phenotypes, characterized by total or partial laminin-α2 deficiency. In both severe and milder cases brain MRI invariably shows abnormal white matter signal intensity. We report clinical, histopathological, imaging and genetic data on two siblings with very subtle, and at first undetected, reduction in laminin-α2 expression, and brain MRI showing minor non-specific abnormalities. Clinical features in the female proband were characterized by muscle weakness involving neck and axial muscles, and pelvic girdle and distal lower limb muscles, reduced tendon reflexes and pes cavus. Clinical features in a younger brother were similar, and remained stable in both siblings during the follow up. Whole exome sequencing (WES) detected two heterozygous truncating LAMA2 mutations. Brain MRI in combination with laminin-α2 immunohistochemistry might not be sufficient and WES might be the only means to reach a diagnosis.

4.
Muscle Nerve ; 60(3): 242-249, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31026080

RESUMO

INTRODUCTION: Balance impairment contributes to gait dysfunction, falls, and reduced quality of life in adults with Charcot-Marie-Tooth disease (CMT) but has been minimally examined in pediatric CMT. METHODS: The CMT Pediatric Scale (CMTPedS) was administered to 520 children with CMT. Associations between balance function (Bruininks-Oseretsky Test of Motor Proficiency [BOT-2]) and sensorimotor and gait impairments were investigated. RESULTS: Daily trips/falls were reported by 42.3% of participants. Balance (BOT-2) varied by CMT subtype, was impaired in 42% of 4-year-olds, and declined with age (P < 0.001). Vibration (P < 0.001), pinprick (P < 0.004), ankle dorsiflexion strength (P < 0.001), and foot alignment (P < 0.004) were associated with BOT-2 balance (adjusted R2 = 0.28). The visual dependence of balance increased with age. DISCUSSION: Balance impairment occurs from a young age in children with CMT. Balance intervention studies are required in pediatric CMT and should consider the degree of sensorimotor impairment, foot malalignment, and visual dependence. Muscle Nerve, 2019.

5.
Mol Genet Metab ; 126(4): 489-494, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30826161

RESUMO

BACKGROUND: Aicardi-Goutières syndrome (AGS) is a rare genetic leukoencephalopathy related to inappropriate activation of type I interferon. Neuroradiological findings are typically characterized by white matter abnormalities, cerebral atrophy and cerebral calcification. The disease usually manifests itself during the first year of life in the form of an initial "encephalitic-like" phase followed by a chronic phase of stabilization of the neurological signs. Recently new therapeutic strategies have been proposed aimed at blocking the abnormal activation of the interferon cascade. MATERIALS AND METHODS: We reviewed clinical and MRI findings in three young RNASEH2B-mutated patients studied with serial CT and MRI studies. RESULTS: All three patients presented clinical and MRI features consistent with AGS but, very unexpectedly, an improving neuroradiological course. In patient 1, the MRI improvement was noted some months after treatment with high-dose steroid and IVIg treatment; in patients 2 and 3 it occurred spontaneously. Patient 2 did not show cerebral calcification on CT images. CONCLUSIONS: Our series highlights the possibility of spontaneous neuroradiological improvement in AGS2 patients, as well as the possibility of absence of cerebral calcification in AGS. The study underlines the need for extreme caution when using MRI as an outcome measure in therapeutic trials specific for this disease. MRI follow-up studies in larger series are necessary to describe the natural course of AGS.


Assuntos
Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Calcinose , Malformações do Sistema Nervoso/diagnóstico por imagem , Doenças Autoimunes do Sistema Nervoso/genética , Encéfalo/patologia , Pré-Escolar , Feminino , Seguimentos , Humanos , Imagem por Ressonância Magnética , Masculino , Mutação , Malformações do Sistema Nervoso/genética , Neuroimagem , Ribonuclease H/genética , Tomografia Computadorizada por Raios X
6.
Hum Mutat ; 40(5): 601-618, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30801875

RESUMO

Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family, responsible for fission of mitochondria, and having a role in the division of peroxisomes, as well. DRP1 impairment is implicated in several neurological disorders and associated with either de novo dominant or compound heterozygous mutations. In five patients presenting with severe epileptic encephalopathy, we identified five de novo dominant DNM1L variants, the pathogenicity of which was validated in a yeast model. Fluorescence microscopy revealed abnormally elongated mitochondria and aberrant peroxisomes in mutant fibroblasts, indicating impaired fission of these organelles. Moreover, a very peculiar finding in our cohort of patients was the presence, in muscle biopsy, of core like areas with oxidative enzyme alterations, suggesting an abnormal distribution of mitochondria in the muscle tissue.

8.
Eur J Med Genet ; : 103596, 2018 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-30528446

RESUMO

OBJECTIVE OF THE STUDY: To give a full overview of the clinical presentation of PTEN mutations in pediatric patients and to propose a pediatric follow-up protocol. METHODS: Recruitment of 16 PTEN mutated children (age 6 months-11 years) from two pediatric centers in Milan (Italy) between 2006 and 2017. All the patients underwent clinical and neurologic evaluations, cognitive and behavioral tests, and brain MRI; they are currently following an oncologic follow-up. RESULTS: Extreme macrocephaly is present in all the patients (69% HC above +4 SD). Neuropsychiatric issues have high prevalence, with 56% of patients showing developmental delay and 25% showing autism spectrum disorder. Brain MRI reveals in 75% of the patients at least one of the following: enlarged perivascular spaces, white matter anomalies, and/or downward displacement of the cerebellar tonsils through the foramen magnum, resulting in Chiari I malformation in two patients. Vascular malformations have a prevalence of 19%, with further evidence that complex cardiovascular malformations may be related to PTEN mutations; 31% of patients present hamartomas. None of our patients have so far experienced any oncologic complication. CONCLUSIONS: We suggest to screen for PTEN mutations all children presenting macrocephaly and one of the following: neurodevelopmental issues, one of the three major brain MRI anomalies, cutaneous lesions, vascular malformations, family history positive for PTEN related malignancies; or also with macrocephaly alone when exceeding +3 SD. Basing on our cohort results and further recent studies on the condition, we recommend a follow-up protocol that includes annual clinical and dermatological examination, thyroid and abdominal US, and Fecal Occult Blood test plus neurodevelopmental evaluation, heart US (to exclude congenital heart malformations), and brain MRI (to exclude Chiari I malformation) at diagnosis.

9.
Brain ; 141(12): 3319-3330, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30476010

RESUMO

Many genetic subtypes of Charcot-Marie-Tooth disease (CMT) show signs of symptomatic disease during the earliest years of life. This might be the ideal time to intervene before progression of clinical sequelae due to demyelination and axonal loss. In the absence of disease-specific clinical trial outcome measures for CMT during infancy and early childhood the aim of this study was to develop and validate a functional measure of disease severity, known as the Charcot-Marie-Tooth disease Infant Scale (CMTInfS). Development projects involved identification of a preliminary pool of 31 items representing the range of disability in affected patients aged 0-4 years from a systematic review of the literature, peer review by 12 expert clinicians and researchers in the field, design of a scoring algorithm and pilot testing in 22 participants. Subsequently, a series of validation projects were conducted based on 128 assessments of: 26 confirmed cases of inherited neuropathy (17 CMT1A, one CMT1B, one CMT1D, one CMT2C, one CMT2S, two CMT4C, one CMTX3, one Riboflavin Transporter Deficiency Type 2, and one unidentified mutation); seven 'at risk' cases and 95 unaffected healthy controls recruited through the NIH-funded Inherited Neuropathies Consortium. Validation projects included: Item, Factor and Rasch analysis, intra- and inter-rater reliability, discriminant ability and convergent validity with the CMT Pediatric Scale (CMTPedS) for children aged 3-4 years. Development and validation projects produced a psychometrically robust 15-item scale. Rasch analysis supported the viability of the CMTInfS as a unidimensional measure of disease severity and showed good overall model fit, no evidence of misfitting items or persons and was well targeted for affected children. The CMTInfS demonstrated high intra-rater reliability [intraclass correlation coefficient (ICC)3,1 0.999, 95% confidence interval 0.996-1.000) and inter-rater reliability (ICC2,1 0.997, 95% confidence interval 0.992-0.999). The CMTInfS was able to discriminate between the CMT group and controls (P = 0.006), and convergent validity demonstrated good agreement between CMTInfS and CMTPedS scores (r = 0.76, P = 0.01). The final version of the CMTInfS requires 20 min to administer and is a reliable and sensitive functional outcome measure for early onset CMT and related neuropathies.10.1093/brain/awy280_video1awy280media15970672819001.

10.
Orphanet J Rare Dis ; 13(1): 135, 2018 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-30111349

RESUMO

BACKGROUND: We present a group of patients affected by a paediatric onset genetic encephalopathy with cerebral calcification of unknown aetiology studied with Next Generation Sequencing (NGS) genetic analyses. METHODS: We collected all clinical and radiological data. DNA samples were tested by means of a customized gene panel including fifty-nine genes associated with known genetic diseases with cerebral calcification. RESULTS: We collected a series of fifty patients. All patients displayed complex and heterogeneous phenotypes mostly including developmental delay and pyramidal signs and less frequently movement disorder and epilepsy. Signs of cerebellar and peripheral nervous system involvement were occasionally present. The most frequent MRI abnormality, beside calcification, was the presence of white matter alterations; calcification was localized in basal ganglia and cerebral white matter in the majority of cases. Sixteen out of fifty patients tested positive for mutations in one of the fifty-nine genes analyzed. In fourteen cases the analyses led to a definite genetic diagnosis while results were controversial in the remaining two. CONCLUSIONS: Genetic encephalopathies with cerebral calcification are usually associated to complex phenotypes. In our series, a molecular diagnosis was achieved in 32% of cases, suggesting that the molecular bases of a large number of disorders are still to be elucidated. Our results confirm that cerebral calcification is a good criterion to collect homogeneous groups of patients to be studied by exome or whole genome sequencing; only a very close collaboration between clinicians, neuroradiologists and geneticists can provide better results from these new generation molecular techniques.

11.
Am J Med Genet B Neuropsychiatr Genet ; 177(6): 557-562, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30105822

RESUMO

The presence of redundant copy number variants (CNVs) in groups of patients with neurological diseases suggests that these variants could have pathogenic effect. We have collected array comparative genomic hybridization (CGH) data of about 2,500 patients affected by neurocognitive disorders and we observed that CNVs in 2p16.3 locus were as frequent as those in 15q11.2, being both the most frequent unbalances in our cohort of patients. Focusing to 2p16.3 region, unbalances involving NRXN1 coding region have been already associated with neuropsychiatric disorders, although with incomplete penetrance, but little is known about CNVs located proximal to the gene, in the long noncoding RNA AK127244. We found that, in our cohort of patients with neuropsychiatric disorders, the frequency of CNVs involving AK127244 was comparable to that of NRXN1 gene. Patients carrying 2p16.3 unbalances shared some common clinical characteristics regardless NRXN1 and AK127244 CNVs localization, suggesting that the AK127244 long noncoding RNA could be involved in neurocognitive disease with the same effect of NRXN1 unbalances. AK127244 as well as NRXN1 unbalances seem to have a particular influence on language development, behavior or mood, according with the topographic correlation between NRXN1 expression and prefrontal cortex functions.

12.
Orphanet J Rare Dis ; 13(1): 120, 2018 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-30025539

RESUMO

BACKGROUND: Mitochondrial acyl-CoA dehydrogenase family member 9 (ACAD9) is essential for the assembly of mitochondrial respiratory chain complex I. Disease causing biallelic variants in ACAD9 have been reported in individuals presenting with lactic acidosis and cardiomyopathy. RESULTS: We describe the genetic, clinical and biochemical findings in a cohort of 70 patients, of whom 29 previously unpublished. We found 34 known and 18 previously unreported variants in ACAD9. No patients harbored biallelic loss of function mutations, indicating that this combination is unlikely to be compatible with life. Causal pathogenic variants were distributed throughout the entire gene, and there was no obvious genotype-phenotype correlation. Most of the patients presented in the first year of life. For this subgroup the survival was poor (50% not surviving the first 2 years) comparing to patients with a later presentation (more than 90% surviving 10 years). The most common clinical findings were cardiomyopathy (85%), muscular weakness (75%) and exercise intolerance (72%). Interestingly, severe intellectual deficits were only reported in one patient and severe developmental delays in four patients. More than 70% of the patients were able to perform the same activities of daily living when compared to peers. CONCLUSIONS: Our data show that riboflavin treatment improves complex I activity in the majority of patient-derived fibroblasts tested. This effect was also reported for most of the treated patients and is mirrored in the survival data. In the patient group with disease-onset below 1 year of age, we observed a statistically-significant better survival for patients treated with riboflavin.

13.
Orphanet J Rare Dis ; 13(1): 45, 2018 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-29615062

RESUMO

BACKGROUND: KARS encodes lysyl- transfer ribonucleic acid (tRNA) synthetase, which catalyzes the aminoacylation of tRNA-Lys in the cytoplasm and mitochondria. Eleven families/sporadic patients and 16 different mutations in KARS have been reported to date. The associated clinical phenotype is heterogeneous ranging from early onset encephalopathy to isolated peripheral neuropathy or nonsyndromic hearing impairment. Recently additional presentations including leukoencephalopathy as predominant cerebral involvement or cardiomyopathy, isolated or associated with muscular and cerebral involvement, have been reported. A progressive Leukoencephalopathy with brainstem and spinal cord calcifications was previously described in a singleton patient and in two siblings, without the identification of the genetic cause. We reported here about a new severe phenotype associated with biallelic KARS mutations and sharing some common points with the other already reported phenotypes, but with a distinct clinical and neuroimaging picture. Review of KARS mutant patients published to date will be also discussed. RESULTS: Herein, we report the clinical, biochemical and molecular findings of 2 unreported Italian patients affected by developmental delay, acquired microcephaly, spastic tetraparesis, epilepsy, sensory-neural hypoacusia, visual impairment, microcytic hypochromic anaemia and signs of hepatic dysfunction. MRI pattern in our patients was characterized by progressive diffuse leukoencephalopathy and calcifications extending in cerebral, brainstem and cerebellar white matter, with spinal cord involvement. Genetic analysis performed on these 2 patients and in one subject previously described with similar MRI pattern revealed the presence of biallelic mutations in KARS in all 3 subjects. CONCLUSIONS: With our report we define the molecular basis of the previously described Leukoencephalopathy with Brainstem and Spinal cord Calcification widening the spectrum of KARS related disorders, particularly in childhood onset disease suggestive for mitochondrial impairment. The review of previous cases does not suggest a strict and univocal genotype/phenotype correlation for this highly heterogeneous entity. Moreover, our cases confirm the usefulness of search for common brain and spine MR imaging pattern and of broad genetic screening, in syndromes clinically resembling mitochondrial disorders in spite of normal biochemical assay.

14.
Gait Posture ; 62: 497-504, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29679921

RESUMO

BACKGROUND: Charcot-Marie-Tooth (CMT) is a slowly progressive disease characterized by muscular weakness and wasting with a length-dependent pattern. Mildly affected CMT subjects showed slight alteration of walking compared to healthy subjects (HS). RESEARCH QUESTION: To investigate the biomechanics of step negotiation, a task that requires greater muscle strength and balance control compared to level walking, in CMT subjects without primary locomotor deficits (foot drop and push off deficit) during walking. METHODS: We collected data (kinematic, kinetic, and surface electromyographic) during walking on level ground and step negotiation, from 98 CMT subjects with mild-to-moderate impairment. Twenty-one CMT subjects (CMT-NLW, normal-like-walkers) were selected for analysis, as they showed values of normalized ROM during swing and produced work at push-off at ankle joint comparable to those of 31 HS. Step negotiation tasks consisted in climbing and descending a two-step stair. Only the first step provided the ground reaction force data. To assess muscle activity, each EMG profile was integrated over 100% of task duration and the activation percentage was computed in four phases that constitute the step negotiation tasks. RESULTS: In both tasks, CMT-NLW showed distal muscle hypoactivation. In addition, during step-ascending CMT-NLW subjects had relevant lower activities of vastus medialis and rectus femoris than HS in weight-acceptance, and, on the opposite, a greater activation as compared to HS in forward-continuance. During step-descending, CMT-NLW showed a reduced activity of tibialis anterior during controlled-lowering phase. SIGNIFICANCE: Step negotiation revealed adaptive motor strategies related to muscle weakness due to disease in CMT subjects without any clinically apparent locomotor deficit during level walking. In addition, this study provided results useful for tailored rehabilitation of CMT patients.


Assuntos
Doença de Charcot-Marie-Tooth/fisiopatologia , Eletromiografia , Músculo Esquelético/fisiopatologia , Caminhada/fisiologia , Adulto , Fenômenos Biomecânicos , Feminino , Marcha/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Debilidade Muscular/fisiopatologia
15.
J Hum Genet ; 63(5): 563-568, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29531337

RESUMO

Biallelic mutations in NDUFAF6 have been identified as responsible for cases of autosomal recessive Leigh syndrome associated with mitochondrial complex I deficiency. Here we report two siblings and two unrelated subjects with Leigh syndrome, in which we found the same compound heterozygous missense (c.532G>C:p.A178P) and deep intronic (c.420+784C>T) variants in NDUFAF6. We demonstrated that the identified intronic variant creates an alternative splice site, leading to the production of an aberrant transcript. A detailed analysis of whole-exome sequencing data together with the functional validation based on mRNA analysis may reveal pathogenic variants even in non-exonic regions.


Assuntos
Heterozigoto , Íntrons , Doença de Leigh/diagnóstico , Doença de Leigh/genética , Mutação de Sentido Incorreto , RNA Mensageiro/genética , Sequenciamento Completo do Exoma , Alelos , Criança , Pré-Escolar , Feminino , Fibroblastos/metabolismo , Expressão Gênica , Haplótipos , Humanos , Lactente , Linfócitos/metabolismo , Imagem por Ressonância Magnética/métodos , Masculino , Proteínas Mitocondriais , Linhagem , Fenótipo
16.
Hum Mutat ; 39(4): 563-578, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29314548

RESUMO

In recent years, an increasing number of mitochondrial disorders have been associated with mutations in mitochondrial aminoacyl-tRNA synthetases (mt-aaRSs), which are key enzymes of mitochondrial protein synthesis. Bi-allelic functional variants in VARS2, encoding the mitochondrial valyl tRNA-synthetase, were first reported in a patient with psychomotor delay and epilepsia partialis continua associated with an oxidative phosphorylation (OXPHOS) Complex I defect, before being described in a patient with a neonatal form of encephalocardiomyopathy. Here we provide a detailed genetic, clinical, and biochemical description of 13 patients, from nine unrelated families, harboring VARS2 mutations. All patients except one, who manifested with a less severe disease course, presented at birth exhibiting severe encephalomyopathy and cardiomyopathy. Features included hypotonia, psychomotor delay, seizures, feeding difficulty, abnormal cranial MRI, and elevated lactate. The biochemical phenotype comprised a combined Complex I and Complex IV OXPHOS defect in muscle, with patient fibroblasts displaying normal OXPHOS activity. Homology modeling supported the pathogenicity of VARS2 missense variants. The detailed description of this cohort further delineates our understanding of the clinical presentation associated with pathogenic VARS2 variants and we recommend that this gene should be considered in early-onset mitochondrial encephalomyopathies or encephalocardiomyopathies.

17.
JAMA Neurol ; 75(1): 105-113, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29181510

RESUMO

Importance: Neurologic disorders with isolated symptoms or complex syndromes are relatively frequent among mitochondrial inherited diseases. Recessive RTN4IP1 gene mutations have been shown to cause isolated and syndromic optic neuropathies. Objective: To define the spectrum of clinical phenotypes associated with mutations in RTN4IP1 encoding a mitochondrial quinone oxidoreductase. Design, Setting, and Participants: This study involved 12 individuals from 11 families with severe central nervous system diseases and optic atrophy. Targeted and whole-exome sequencing were performed-at Hospital Angers (France), Institute of Neurology Milan (Italy), Imagine Institute Paris (France), Helmoltz Zentrum of Munich (Germany), and Beijing Genomics Institute (China)-to clarify the molecular diagnosis of patients. Each patient's neurologic, ophthalmologic, magnetic resonance imaging, and biochemical features were investigated. This study was conducted from May 1, 2014, to June 30, 2016. Main Outcomes and Measures: Recessive mutations in RTN4IP1 were identified. Clinical presentations ranged from isolated optic atrophy to severe encephalopathies. Results: Of the 12 individuals in the study, 6 (50%) were male and 6 (50%) were female. They ranged in age from 5 months to 32 years. Of the 11 families, 6 (5 of whom were consanguineous) had a member or members who presented isolated optic atrophy with the already reported p.Arg103His or the novel p.Ile362Phe, p.Met43Ile, and p.Tyr51Cys amino acid changes. The 5 other families had a member or members who presented severe neurologic syndromes with a common core of symptoms, including optic atrophy, seizure, intellectual disability, growth retardation, and elevated lactate levels. Additional clinical features of those affected were deafness, abnormalities on magnetic resonance images of the brain, stridor, and abnormal electroencephalographic patterns, all of which eventually led to death before age 3 years. In these patients, novel and very rare homozygous and compound heterozygous mutations were identified that led to the absence of the protein and complex I disassembly as well as mild mitochondrial network fragmentation. Conclusions and Relevance: A broad clinical spectrum of neurologic features, ranging from isolated optic atrophy to severe early-onset encephalopathies, is associated with RTN4IP1 biallelic mutations and should prompt RTN4IP1 screening in both syndromic neurologic presentations and nonsyndromic recessive optic neuropathies.

18.
Eur J Paediatr Neurol ; 22(2): 332-335, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29287834

RESUMO

Encephalopathies with neostriatal involvement constitute a heterogeneous group of acquired and genetically inherited conditions that include Bilateral Striatal Necrosis (BSN) and other Striatal Lesions (SL) (Tonduti et al). We describe two new patients suffering from BSN due to biallelic SLC19A3 mutations. In the first patient vitamin supplementation was started early on, resulting in the remission of the clinical picture, and an almost complete normalization of the neuroradiological findings. In the second one treatment was started late, compliance was irregular and the resulting clinical outcome was poor. The clinical outcome of our two patients confirms and further stresses the importance of the early administration of vitamin supplementation in all patients presenting with neostriatal lesions, or clear bilateral striatal necrosis. Patient 2 didn't present any additional episode of acute decompensation after the age of 20 years despite having completely stopped treatment. This suggests the existence of an age dependency of thiamin requirement in humans.


Assuntos
Encefalopatias Metabólicas Congênitas/tratamento farmacológico , Encefalopatias Metabólicas Congênitas/genética , Proteínas de Membrana Transportadoras/genética , Neostriado/patologia , Tiamina/uso terapêutico , Adulto , Encefalopatias Metabólicas Congênitas/patologia , Pré-Escolar , Feminino , Humanos , Masculino , Necrose , Complexo Vitamínico B/uso terapêutico
19.
Neuromuscul Disord ; 27(11): 1029-1037, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28844614

RESUMO

Detection of worsening in the slowly progressive Charcot-Marie-Tooth disease (CMT) is difficult. As previous clinical scales showed low responsiveness, novel outcome measures are under study, including innovative approaches such as quantitative muscle MRI and instrumented movement analysis. Since gait analysis proved able to reliably quantify CMT locomotor deficits, we aimed to explore whether it can be a sensitive-to-change outcome measure in CMT studies. Clinical and biomechanical evaluations were performed in 71 CMT subjects at baseline and after a mean (±sd) of 28.9 ± 9.5 months. Locomotor tasks included natural walking, ascending and descending steps. Instrumented analysis of such tasks provided indexes related to muscle strength (kinetic parameters) and joint movement (kinematic parameters). Parameter responsiveness was expressed as Standardized Response Mean (SRM). Considering the whole CMT group, several parameters showed moderate responsiveness; subgrouping subjects according to disease severity allowed reaching high responsiveness (SRM >0.80). CMT Examination Score showed moderate responsiveness (SRM 0.53) in the minimally affected group; kinematic parameters were more responsive in this group, whereas kinetic parameters in the most severely affected one. Biomechanical parameters can represent suitable outcome measures for CMT by showing moderate-to-high responsiveness. These data suggest that appropriate selection of patient population and outcome measures is crucial for clinical trials' design.


Assuntos
Doença de Charcot-Marie-Tooth/diagnóstico , Doença de Charcot-Marie-Tooth/fisiopatologia , Marcha , Adulto , Fenômenos Biomecânicos , Ensaios Clínicos como Assunto , Estudos de Coortes , Progressão da Doença , Feminino , Marcha/fisiologia , Humanos , Extremidade Inferior/fisiopatologia , Masculino , Força Muscular , Índice de Gravidade de Doença
20.
Ann Neurol ; 82(3): 353-359, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28796392

RESUMO

OBJECTIVE: To determine the rate of disease progression in a longitudinal natural history study of children with Charcot-Marie-Tooth (CMT) disease. METHODS: Two hundred six (103 female) participants aged 3 to 20 years enrolled in the Inherited Neuropathies Consortium were assessed at baseline and 2 years. Demographic, anthropometric, and diagnostic information were collected. Disease progression was assessed with the CMT Pediatric Scale (CMTPedS), a reliable Rasch-built linearly weighted disability scale evaluating fine and gross motor function, strength, sensation, and balance. RESULTS: On average, CMTPedS Total scores progressed at a rate of 2.4 ± 4.9 over 2 years (14% change from baseline; p < 0.001). There was no difference between males and females (mean difference, 0.5; 95% confidence interval [CI], -0.9 to 1.9; p = 0.49). The most responsive CMTPedS items were dorsiflexion strength (z-score change, -0.3; 95% CI, -0.6 to -0.05; p = 0.02), balance (z-score change, -1.0; 95% CI, -1.9 to -0.09; p = 0.03), and long jump (z-score change, -0.4; 95% CI, -0.7 to -0.02; p = 0.04). Of the most common genetic subtypes, 111 participants with CMT1A/PMP22 duplication progressed by 1.8 ± 4.2 (12% change from baseline; p < 0.001), 9 participants with CMT1B/MPZ mutation progressed by 2.2 ± 5.1 (11% change), 6 participants with CMT2A/MFN2 mutation progressed by 6.2 ± 7.9 (23% change), and 7 participants with CMT4C/SH3TC2 mutations progressed by 3.0 ± 4.5 (12% change). Participants with CMT2A progressed faster than CMT1A (mean difference, -4.4; 95% CI, -8.1 to -0.8; p = 0.02). Children with CMT1A progressed consistently through early childhood (3-10 years) and adolescence (11-20 years; mean difference, 1.1; 95% CI, -0.6 to 2.7; p = 0.19), whereas CMT2A appeared to progress faster during early childhood than adolescence (mean difference, 10.0; 95% CI, -2.2 to 22.2; p = 0.08). INTERPRETATION: Using the CMTPedS as an outcome measure of disease severity, children with CMT progress at a significant rate over 2 years. Understanding the rate at which children with CMT deteriorate is essential for adequately powering trials of disease-modifying interventions. Ann Neurol 2017;82:353-359.


Assuntos
Doença de Charcot-Marie-Tooth/patologia , Adolescente , Doença de Charcot-Marie-Tooth/genética , Criança , Pré-Escolar , Progressão da Doença , Feminino , Humanos , Estudos Longitudinais , Masculino , Mutação , Proteínas da Mielina/genética , Adulto Jovem
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