Childhood-Onset Ataxia

Childhood presentations of ataxia can often be challenging to diagnose. Recognising ataxia is especially difficult in young children, the most frequent reason for consultation is walking instability and loss of balance. Clinical presentations tend to be heterogeneous; key considerations may vary based on the age of onset, time course, and associated manifestations. Ataxias can be acute, intermittent, chronic non-progressive, or chronic progressive conditions. Acute ataxias are mostly acquired conditions (post-infectious or immune-mediated). Intermittent ataxias may be secondary to genetic channelopathies or metabolic diseases. Non-progressive chronic ataxias are mostly related to cerebellar malformations and progressive chronic ataxias are usually secondary to genetic variants, which in children are usually autosomal recessive conditions. A complete medical history and a detailed physical examination are essential for an adequate approach. Treatment of a child with ataxia depends on the aetiology. One of the most important challenges is to identify the treatable causes

Estudio clínico genético en pacientes con complejo de esclerosis tuberosa

Introduction: Tuberous sclerosis complex (TSC) is a multisystem autosomal dominant disease caused by mutations in the tumor suppressor genes TSC1 or TSC2. Objective: To characterize clinically and genetically patients diagnosed with TSC. Patients and method: Descriptive study of clinical records from a pediatric neuropsychiatry department of 42 patients diagnosed with TSC and genetic study of 21 of them. The exon 15 of the TSC1 gene and exons 33, 36 and 37 of the TSC2 gene were amplified by polymerase chain reaction and sequenced. The relationship between the mutations found with the severity and clinical evolution were analyzed. Results: In 61.9% of the patients the symptoms began before 6 months of age. The most frequent initial manifestations of TSC were new onset of seizures (73.8%) and the detection of cardiac rhabdomyomas (16.6%). During the evolution of the disease all patients had neurological involvement; 92.9% had epilepsy. All patients presented hypomelanotic spots, 47.6% facial angiofibromas, 23.8% Shagreen patch, 47.6 heart rhabdomyomas and 35.7% retinal hamartomas. In the genetic study of 21 patients, two heterozygous pathogenic mutations in TSC1 and one in TSC2 genes were identified. The latter had a more severe clinical phenotype. Conclusions: Neurological and dermatological were the most frequent manifestations in patients with TSC. Two pathogenic mutations in TSC1 and one in TSC2 genes were identified. The patient with TSC2 mutation manifested a more severe clinical phenotype.Seed Project of the Chilean Society of Pediatrics (Proyecto Semilla de la Sociedad Chilena de Pediatría)

Lesch-Nyhan disease in two families from Chiloe island with mutations in the HPRT1 gene

Lesch-Nyhan disease (LND) is a rare X-linked inherited neurogenetic disorder of purine metabolism in which the enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGprt) is defective. The authors report two independent point mutations leading to splicing errors: IVS 2 +1G>A, c.134 +1G>A, and IVS 3 +1G>A, c.318 +1G>A in the hypoxanthine-phosphoribosyltransferase1 (HPRT1) gene which result in exclusion of exon 2 and exon 3 respectively, in the HGprt enzyme protein from different members of two Chiloe Island families. Molecular analysis has revealed the heterogeneity of genetic mutation of the HPRT1 gene responsible for the HGprt deficiency. It allows fast, accurate carrier detection and genetic counseling.Lesch-Nyhan Syndrome Children's Research Foundation / Harold A. and Madeline R. Jacobs Fund at The San Diego Foundatio

A novel ITPA variant causes epileptic encephalopathy with multiple-organ dysfunction

Inborn errors of metabolism can cause epileptic encephalopathies. Biallelic loss-of-function variants in the ITPA gene, encoding inosine triphosphate pyrophosphatase (ITPase), have been reported in epileptic encephalopathies with lack of myelination of the posterior limb of the internal capsule, brainstem tracts, and tracts to the primary visual and motor cortices (MIM:616647). ITPase plays an important role in purine metabolism. In this study, we identified two novel homozygous ITPA variants, c.264-1 G > A and c.489-1 G > A, in two unrelated consanguineous families. The probands had epilepsy, microcephaly with characteristic magnetic resonance imaging findings (T2 hyperintensity signals in the pyramidal tracts of the internal capsule, delayed myelination, and thin corpus callosum), hypotonia, and developmental delay; both died in early infancy. Our report expands the knowledge of clinical consequences of biallelic ITPA variants.AMED JP19ek0109280 JP19dm0107090 JP19ek0109301 JP19ek0109348 JP18kk020501 Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT) Japan Society for the Promotion of Science Grants-in-Aid for Scientific Research (KAKENHI) JP17H01539 JP19H03621 Ministry of Health, Labour and Welfare, Japan Takeda Science Foundation (TSF

The clinical and biochemical hallmarks generally associated with GLUT1DS may be caused by defects in genes other than SLC2A1

Glucose transporter 1 deficiency syndrome (GLUT1DS) is a neurometabolic disorder caused by haploinsufficiency of the GLUT1 glucose transporter (encoded by SLC2A1) leading to defective glucose transport across the blood–brain barrier. This work describes the genetic analysis of 56 patients with clinical or biochemical GLUT1DS hallmarks. 55.4% of these patients had a pathogenic variant of SLC2A1, and 23.2% had a variant in one of 13 different genes. No pathogenic variant was identified for the remaining patients. Expression analysis of SLC2A1 indicated a reduction in SLC2A1 mRNA in patients with pathogenic variants of this gene, as well as in one patient with a pathogenic variant in SLC9A6, and in three for whom no candidate variant was identified. Thus, the clinical and biochemical hallmarks generally associated with GLUT1DS may be caused by defects in genes other than SLC2A1Carlos III Institute (ISCIII), European Regional Development Funds (PI19/01155); CIBERER (ERTRLE0I1); Consejería de Educacion, Juventud y Deporte, Comunidad de Madrid (B2017/BMD3721); Fundacion Isabel Gemio, the Fundacion La Caixa (LCF/PR/ PR16/11110018

Classic and Atypical Late Infantile Neuronal Ceroid Lipofuscinosis in Latin America: Clinical and Genetic Aspects, and Treatment Outcome with Cerliponase Alfa

Introduction: Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), is a neurodegenerative autosomal recessive disease caused by TPP1 gene variants, with a spectrum of classic and atypical phenotypes. The aim of treatment is to slow functional decline as early as possible in an attempt to improve quality of life and survival. This study describes the clinical characteristics as well as the response to treatment with cerliponase alfa. Materials and methods: A retrospective study was conducted in five Latin-American countries, using clinical records from patients with CLN2. Clinical follow-up and treatment variables are described. A descriptive and bivariate statistical analysis was performed. Results: A total of 36 patients were observed (range of follow-up of 61–110 weeks post-treatment). At presentation, patients with the classic phenotype (n = 16) exhibited regression in language (90%), while seizures were the predominant symptom (87%) in patients with the atypical phenotype (n = 20). Median age of symptom onset and time to first specialized consultation was 3 (classical) and 7 (atypical) years, while the median time interval between onset of symptoms and treatment initiation was 4 years (classical) and 7.5 (atypical). The most frequent variant was c.827 A > T in 17/72 alleles, followed by c.622C > T in 6/72 alleles. All patients were treated with cerliponase alfa, and either remained functionally stable or had a loss of 1 point on the CLN2 scale, or up to 2 points on the Wells Cornel and Hamburg scales, when compared to pretreatment values. Discussion and conclusion: This study reports the largest number of patients with CLN2 currently on treatment with cerliponase alfa in the world. Data show a higher frequency of patients with atypical phenotypes and a high allelic proportion of intron variants in our region. There was evidence of long intervals until first specialized consultation, diagnosis, and enzyme replacement therapy. Follow-up after the initiation of cerliponase alfa showed slower progression or stabilization of the disease, associated with adequate clinical outcomes and stable functional scores. These improvements were consistent in both clinical phenotypes