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 15months. Delayed motor skills were the initial symptom when the disease began before 12months of age, and ataxia was the first sign when the disease began later. Cognitive decline, which is described between 12 and 18months of age, occurred from 16 to 20months 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 3years of age. Myoclonic jerks occurred after 24months 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.
► INCL is characterized by motor impairment, cognitive decline and autistic features. ► Epilepsy can appear at any time during the course of the disease. ► The V181M mutation is clinically associated with the most severe INCL phenotype. ► Knowing chronological evolution is helpful to identify patients with INCL.
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.
