ABSTRACT
Introducción. Las lipofuscinosis neuronales ceroideas (LNC) se clasifican, según la edad de inicio de la sintomatología, en cuatro formas clínicas principales en la infancia: infantil, infantil tardía, juvenil y congénita (CLN1, CLN2, CLN3 y CLN10).Las formas variantes infantiles tardías (CLN5, CLN6, CLN7 y CLN8) se caracterizan por una gran variabilidad fenotípica y la mayoría de los pacientes proceden de Finlandia y Turquía (variante finlandesa, CLN5, y turca, CLN7). Casos clínicos. Se describen tres pacientes con la variante finlandesa y un cuarto paciente con la variante turca, procedentes de diferentes familias. Se propone un algoritmo que facilite el diagnóstico de este grupo de enfermedades poco prevalentes. Las pacientes con la variante finlandesa iniciaron un trastorno de conducta entre los 2,6 y 4,6 años seguido de dificultades de aprendizaje y déficit visual a los 6 años de edad. Las crisis epilépticas generalizadas y mioclonoatónicas aparecieron a los 7 años con sacudidas mioclónicas posteriormente. Las pacientes desarrollaron ataxia y ceguera a los 9años, y manifestaron una importante discapacidad a los 11 años de edad. El paciente con la variante turca presentó epilepsia refractaria desde los 2 años de edad seguido de un rápido deterioro con ataxia, pérdida de la deambulación en los dos a tres años siguientes y estado vegetativo a los 11 años.Conclusiones. El espectro de las formas variantes de LNC presenta una distribución geográfica cada vez más amplia. Nuestro estudio aporta tres nuevas mutaciones en el gen CLN5 y propone un protocolo de diagnóstico que facilite los estudios de correlación genotipo-fenotipo (AU)
Introduction. The neuronal ceroid lipofuscinosis are classified based on age at onset into four main clinical forms in childhood: infantile, late infantile, juvenile and congenital (CLN1, CLN2, CLN3 and CLN10). The variant late infantile forms (CLN5, CLN6, CLN7 and CLN8) are characterized by a wide variability of the clinical phenotypes and the most patients are originated from Finland and Turkey (Finnish, CLN5, and Turkish, CLN7 variants). Case reports. We describe three unrelated patients with Finnish variant and another patient with Turkish variant. We describe an algorithm to facility the diagnosis of these low prevalence diseases. Patients with Finnish variant started withbehaviour disorder between 2.6 and 4.6 years of age followed by learning difficulties and visual failure at an age of 6 years. Generalised tonic-clonic and myoclonic seizures were observed at 7 years of age with myoclonic jerks later on. Patients developed ataxia and blindness within 9 years and increasingly disability at 11 years of age. The patient with Turkish variant started with refractory epilepsy at age of 2, followed by a severe neurodegeneration manifested by ataxia,loss of walking ability within 2-3 years and vegetative state at 11 years of age.Conclusions. The clinical spectrum of the variant late infantile forms shows a wide geographical distribution. We report three novel mutations in the CLN5 gene and a diagnostic algorithm to facility the correlation genotype-phenotype studies (AU)
Subject(s)
Humans , Female , Child , Neuronal Ceroid-Lipofuscinoses/diagnosis , Algorithms , Neuronal Ceroid-Lipofuscinoses/classification , Genotype , Phenotype , Learning Disabilities/etiology , Child Behavior Disorders/etiologyABSTRACT
INTRODUCTION: The neuronal ceroid lipofuscinosis are classified based on age at onset into four main clinical forms in child-hood: infantile, late infantile, juvenile and congenital (CLN1, CLN2, CLN3 and CLN10). The variant late infantile forms (CLN5, CLN6, CLN7 and CLN8) are characterized by a wide variability of the clinical phenotypes and the most patients are originated from Finland and Turkey (Finnish, CLN5, and Turkish, CLN7 variants). CASE REPORTS: We describe three unrelated patients with Finnish variant and another patient with Turkish variant. We describe an algorithm to facility the diagnosis of these low prevalence diseases. Patients with Finnish variant started with behaviour disorder between 2.6 and 4.6 years of age followed by learning difficulties and visual failure at an age of 6 years. Generalised tonic-clonic and myoclonic seizures were observed at 7 years of age with myoclonic jerks later on. Patients developed ataxia and blindness within 9 years and increasingly disability at 11 years of age. The patient with Turkish variant started with refractory epilepsy at age of 2, followed by a severe neurodegeneration manifested by ataxia, loss of walking ability within 2-3 years and vegetative state at 11 years of age. CONCLUSIONS: The clinical spectrum of the variant late infantile forms shows a wide geographical distribution. We report three novel mutations in the CLN5 gene and a diagnostic algorithm to facility the correlation genotype-phenotype studies.
Subject(s)
Algorithms , Neuronal Ceroid-Lipofuscinoses/diagnosis , Child , Child, Preschool , Female , Finland , Humans , Male , Neuronal Ceroid-Lipofuscinoses/classification , Tripeptidyl-Peptidase 1 , TurkeyABSTRACT
Infantile neuronal ceroid lipofuscinosis (INCL; NCL1, Haltia-Santavuori disease) is caused by mutations in the CLN1/PPT gene which are associated with an early onset INCL phenotype. The most detailed descriptions of INCL have come from Finland and a few series have been reported from southern European countries. Clinical course and follow-up of six Spanish patients with INCL are reported with the aim of assessing the chronological evolution and severity of this disease. The age at disease onset ranged from 8 to 15 months. Delayed motor skills were the initial symptom when the disease began before 12 months of age, and ataxia was the first sign when the disease began later. Cognitive decline, which is described between 12 and 18 months of age, occurred from 16 to 20 months of age. In our series early stage is characterized by motor impairment, cognitive decline and autistic features. Visual failure may appear simultaneously with the neurological symptoms, leading quickly to blindness. As reported, psychomotor regression appeared between 2 and 3 years of age. Myoclonic jerks occurred after 24 months of age and epilepsy was the last symptom of the disease. We report two novel mutations in a patient without epilepsy to date and describe the features of two siblings homozygous for the V181M (c.541G>A) mutation, associated with the most severe INCL phenotype. The clinical evolution might be helpful to identify patients affected by this rare disease. Early diagnosis is essential in order to provide genetic counselling to affected families. Our series may contribute to the study of the genotype-phenotype INCL correlation in the Mediterranean countries.
Subject(s)
Neuronal Ceroid-Lipofuscinoses/genetics , Neuronal Ceroid-Lipofuscinoses/physiopathology , Brain/pathology , Child , Child, Preschool , DNA Mutational Analysis , Female , Follow-Up Studies , Humans , Male , Neuronal Ceroid-Lipofuscinoses/diagnosis , Neuronal Ceroid-Lipofuscinoses/pathology , Thiolester Hydrolases/geneticsABSTRACT
BACKGROUND: Juvenile neuronal ceroid lipofuscinosis (JNCL, NCL3, Batten disease) is usually caused by a 1.02-kb deletion in the CLN3 gene. Mutations in the CLN1 gene may be associated with a variant form of JNCL (vJNCL). We report the clinical course and molecular studies in 24 patients with JNCL collected from 1975 to 2010 with the aim of assessing the natural history of the disorder and phenotype/genotype correlations. PATIENTS AND METHODS: Patients were classified into the groups of vJNCL with mutations in the CLN1 gene and/or granular osmiophilic deposit (GROD) inclusion bodies (n = 11) and classic JNCL (cJNCL) with mutations in the CLN3 gene and/or fingerprint (FP) profiles (n = 13). Psychomotor impairment included regression of acquired skills, cognitive decline, and clinical manifestations of the disease. We used Kaplan-Meier analyses to estimate the age of onset of psychomotor impairment. RESULTS: Patients with vJNCL showed learning delay at an earlier age (median 4 years, 95% confidence interval [CI] 3.1-4.8) than those in the cJNCL group (median 8 years, 95% CI 6.2-9.7) (P = 0.001) and regression of acquired skills at a younger age. Patients with vJNCL showed a more severe and progressive clinical course than those with cJNCL. There may be a Gypsy ancestry for V181L missense mutation in the CLN1 gene. CONCLUSIONS: The rate of disease progression may be useful to diagnose vJNCL or cJNCL, which should be confirmed by molecular studies in CLN1/CLN3 genes. Further studies of genotype/phenotype correlation will be helpful for understanding the pathogenesis of this disease.
