Neuronal Ceroid Lipofuscinosis (NCL) is one of the most common progressive encephalopathy of childhood. This class of diseases, for which is charac-teristic common etiology as well as clinical and pathological manifestations, is caused by different mutations in one of the 14 genes. From a pathological point of view, NCL is characterized by lysosomal storage disorder and by excessive accumulation of storage materials with various biochemical compo-sitions and histological characteristics in the tissues of the organism, especially in neurons and in many organs, including the liver, spleen, myocardium and kidney, which determines the symptoms of the disease. The histopathological signs of lysosomal lipopigments which are visible in the brain and other types of tissue using electronic microscopy present a characteristic ultrastructural pattern. The molecular mechanisms that cause the progressive neurodegeneration in NCL as well as the common molecular pathways that determine the expression of genes are largely unknown. NCL can manifest in all age groups, and may be inherited by autosomal recessive disorder, and there are also recognized autosomal dominant forms. NCL are associated with variable and progressive symptoms, including seizures, deterioration of motor and cognitive functions and often psychiatric disorders, i. e., dementia, visual loss and/or cerebral atrophy. Prenatal diagnosis may be possible in a family with an affected child, depending on the type of NCL. Infantile and juvenile forms are the most common and are characterized by visual disturbances progressing to blindness, behavioral problems, development of seizures, and loss of cognitive and motor functions, i. e., developmental regression, and eventual death. The onset and progression of the NCL clinical manifestations can be quite heterogeneous, even within families. Recent progress of molecular genetic can promote the understanding of the molecular background of the NCL, ensuring important prerequisites for the understanding, recognition and treatment of NCL and associated disorders. For diagnostic purposes, in the present work we are described here a clinically studied case.
Keywords: Neuronal ceroid lipofuscinosis (NCL), progressive disorders, diagnosis.
Juvenile Neuronal ceroid lipofuscinosis (NCL) also known as Batten disease, belongs to rare diseases, which are underrecognized, presenting a neurobiological disabling disorder, affecting both children and adults . The diagnosing of the disease is determined by comprehensive clinical and laboratory testing. However, diagnosis can be made using by cerebral imaging. Diagnosis can be confirmed by molecular genetic analysis. The starting point in the diagnosis of NCL is determined by the clinical progressive symptoms, i. e., visual loss to blindness, behavioral problems, development of seizures, loss of cognitive and motor functions, i. e., developmental regression and, finally, eventual death. Recent progress in molecular genetics can improve the understanding of changes occurring at the molecular level in patients with NCL, ensuring a great potential in the understanding, recognition and treatment of NCL, as well as related disorders . Presented case studies are important to comprehensive understanding the full impact of the NCL gene mutations and their influence on the destruction of cellular proteins.
SCOPE OF THE STUDY
Is to study the clinical and laboratory aspects of NCL in children based on literature as well as studying the clinical and genetic manifestations in a child with NCL.
MATERIALS AND METHODS
The study was based on historical and clinical examinations, neurophysiological evaluation as well as on cerebral imaging and genetic testing of a child with NCL.
Was carried out analysis of clinical and paraclinical data of a child with suspected NCL. Date about child: Boy DB at the age of 5 years, admitted with following symptoms noted by mother: polymorph seizures, prominent developmental and verbal regress, coordination disorders, ataxia, aggression, sleep disturbances, irritability, tearfulness, lack of effect on previously administered treatment. History of life: non-complicated pregnancy, born at 40 weeks by an urgent Caesarean section, with an Apgar score 7/8 points, weight 4050 kg, cranial perimeter
– 35 cm, non-complicated neonatal period, following neuropsychical and motor development corresponds with age standards, i. e., walking from 10 months, verbal development from 1.5 – 2 years, parents are healthy, age of mother was 30 years, age of father was 38 years, parents of mixed nationality, i. e., mother was Russian and Ucranian, and father was Azerbaijan or Crimean Karaite, without consanguinity. The child has been vaccinated according to the plan. For the first time the child became ill at the age of 3 years, when polymorph seizures were developed, with oral cavity muscles involvement, chewing and tonic clonic unilateral seizures. Electrophysiologic investigation showed EEG recording characteristic for epileptic like generalized features in the frontal central temporal symmetric regions, and since May 2014, the treatment with Leviteracetam (60 mg/kg/ day) was administered. In September 2014, the child’s condition continued to worsen, i. e., epileptic seizures were repeated with frequency 3 – 5 per week, and to the treatment schedule the Convulex (50 mg/kg/day) was added. The seizures continued with the frequency of 3 – 4 per week. In July 2015 Leviteracetam was cancelled and Sabril (1000 mg/day) was added. Since April 2015 appeared gait instability, clumsiness, ataxia, frequent falls. Since August 2015 the patient could not walk and sit, the speech was stopped. Seizures are repeated 3 – 4 times/day, from 2 to 5 minutes duration. Dexamethasone was added in dose of 4 mg/day. For 6 months, develops severe cognitive and motor regression. Since 21.09.2015 Sabril was cancelled, was initiated the treatment with Felabamate (600 mg b. i. d.) and Frizium (10 mg b.i.d.). However, the EEG recording showed epileptic like changes (29.06.2017), (Fig. 1).
The results of the electrolyte, biochemical and immunological profile have not found any pathological changes. Ophthalmoscopy from 25.08.2014 – venous stasis; 27.06.2017 – atrophy of optic nerve, retinal degeneration. USG of internal organs (25.08.2014)
– without the signs of pathology; 27.06.2017 – hepatosplenomegaly. ECG (20.09.2014) – aneurism of atrial septum. EMG (04.09.2015) – without the pathological changes. Cerebral MRI (12.06.2014): Cerebellar hypoplasia. Signs of perinatal hypoxic ischemic lesion. MRI (21.09.2014) – cerebral generalized parenchymatous atrophy, including cerebellum, ventricular enlargement; structural aggravation: result from 10.09.2015 (Fig. 2), structural aggravation: result from 28.06.2017 – cerebral generalized atrophy, including cerebellum, frontal intracerebral post hemorrhagic cyst on right, ventricular enlargement. Shall continue to be indicated: genetic investigations, i.e., chromosomal, molecular, exome scan etc., metabolic parameters, visualization. Visualization data from 10.09.2015 are present below (Fig. 2). Repetitive molecular analysis allow to detect (from 29.02.2016) gene transcriptTPP-1 (NM_000391.3); nucleotide substitutions c.622C>T(p.Arg.208), c.833A>C (p.Gln278Pro); the frequency of recessive allele 0,00017, described by Sleat et al. (1997) and Ju et al. (2002). These data are suggestive for NCL type 2 (AR, 2014500).
Evolution of the diagnosis:
- Symptomatic focal epilepsy. Autistic behavior. (18.06.2014).
- Generalized epilepsy. Megalencephalic leukoencephalopathy or Van der Knaap disease. Regress of psychomotor development (22.02.2015).
- Generalized epilepsy with myoclonic component. Regress of psychomotor development (21.09.2015).
- Progressive neurodegenerative disorder with cerebral and cerebellar atrophy. Generalized epilepsy with myoclonic component. Regress of psychomotor development (22.12.2015).
- NCL type 2. Structural epilepsy with polymorph seizures. Severe psychomotor and verbal regress. Visual loss (29.02.2016).
In present the patient’s condition is very severe. There are polymorph seizures, resistant to treatment, combined with severe developmental disorders, i. e., motor, cognitive, sensorial, speech and language. The prognosis is unfavorable. Discussion. The first clinical descriptions suggestive of a probable type of NCL were made in 1826 in a Norwegian medical journal by Dr. Otto Christian Stengel, through the systematic clinical observation of 4 children (siblings), two boys and two girls, from seemingly healthy parents. In evolution, the disease led to blindness, progressive mental deterioration, loss of speech and epileptic seizures . Clinical descriptions fully substantiated the diagnosis . Later, Batten (1903)  and Heinrich Vogt (1905) , made various fundamental observations and clinical pathological studies on many families. Later Spielmeyer reported studies on three siblings  who suffered from the juvenile type of pathology, i. e., Spielmeyer-Sjogren. Later, it was delineated the late infantile form of NCL , which was clinically and genetically documented. Once was the period of time when the disease was erroneously associated with the Tay-Sachs disease. In the present studies continue with research at the level of chemical pathology and intracellular microstructures, as well as histological and genetic studies, which allowed to separate NCL from other types of neurodegenerative diseases. NCL types were systematized according to clinical descriptions and genetic characteristics .
Definition. NCL represents a group of progressive degenerative brain diseases, with autosomal recessive inheritance, resulting from the intracellular excessive storage of a fluorescent lipopigment, ceroid lipofuscin, in the tissues of the organism, in particular in neurons of the brain and retina, with lipofuscin and ceroide and variable enzyme deficiency, depending on the type of disease, which is clinically characterized by neurological disorders, i. e., decreased mental functions and other skills, as well as the development of epilepsy and loss of vision [1, 2, 9].
NCL was initially defined according to age, onset of disease and clinical symptoms. However, later this disease was reclassified on the basis of newer molecular discoveries, which provided evidence for various genetic variants, compared with clinical phenotypes .
From an epidemiological standpoint, NCL is one of the most common progressive lysosomal diseases as a type of neurodegenerative disorders in children . The exact prevalence and incidence of this group of disorders is unknown. Some studies indicate that the incidence may vary depending on the type of disease and from country to country. A prevalence of 1:12500 was recently found in some populations . According to some German authors, was reported an incidence of 1.28:100000 , and in Italy 0.56:100000 population . The incidence of the late infantile NCL is reported by 9.0:100000 . However, other studies note the prevalence of 1:100000 live births worldwide .
Experimental biochemical studies have allowed the confirmation of cytosomes compromise, largely in proteins [4, 14]. In most types of NCL in animals and humans was identified the lipid subunit of binding of mitochondrial ATP-synthase in storage proteins, with the same terminal sequence NH2 [4, 15]. Furthermore, other authors appreciated a high level of protein contents in the storage cytosomes (sphingolipids or saposin A and D). They constitute a major portion of the protein stored in the infantile type of human NCL , which then found in other types of human and animal NCL. The authors of an experimental study analyzed the proteomics changes in the brain of a CLN1 type model in different stages of disease: presymptomatic, symptomatic and advanced. Observations have highlighted the following features at presymptomatic stage: changes in metabolic processes and inhibition of various neural functions (neurogenesis); at the symptomatic stage: the deregulation of mitochondrial functions, the transport of synaptic vesicles, proteomics of myelin and signaling cascade; at the advanced stage: breakdown of the myelin sheath on protein levels, network disturbances, etc. .
Despite to the large number of finished studies, the pathogenetic mechanisms of NCL remain unclear. Several studies attempts to establish a correlation of oxidative stress with lysosomal storage disorders, in which neurodegeneration is a devastating manifestation. Despite the fact, there is no known precise mechanism to clarify these interactions. A perspective in this area is provided by a study on animals that appreciates the influence of oxidative stress on the suppression of agrin-22 production, which determines the inhibition of Ca2+ current, following with synaptic dysfunction. These results can be suggestive to perform correction treatments of agrin-22 levels . Furthermore, some authors showed correlation of neuroinflammation with the progression of the disease. It was determined that the T lymphocytes CD8+ contribute to the axonal disturbance and the loss of neurons in the CNS in mice as a model of with a model of NCL type 1. And the increase in Sn marker expression in microglia or macrophages contributes to neural disturbance in two distinct models of NCL type 1 and 3 .
From a morphopathological standpoint, in NCL takes place accumulation of storage material or ceroid, i. e., lipofuscin, in lysosomes, progressive neural degeneration and activation of glia . Lipofuscin belongs to lipopigments that contains of fats and proteins, which are seen as yellow-greenish matter under ultraviolet light microscopy and have a special ultrastructural pattern under electronic microscopy. Lipofuscin accumulates in neurons and in many organs, including liver, spleen, myocardium and kidney. NCL is characterized by diffuse cerebral atrophy which affect grey as well as white matter in brain, cerebellum, brainstem, spinal cord and accumulation of ceroid pigment in the retina, with loss of the ganglion cells and lesion of rods and cones . Were observed deposits of ceroid/lipofuscin in ganglia of gastrointestinal tract and in the macrophages of the spleen, lymph nodes and lungs .
On the current classification of NCL it should be note the principle of classification on the basis of predominance of protein storage in two main chemical entities, namely, C subunit and storage of sphingolipids activator A and D . The older classification has based on the age of first manifestations of NCL and divide of four types of the disease, namely, CLN1, CLN2, CLN3 and CLN4, while newer classifications divide it by the associated gene. CLN4 was not attributed to a particular gene .
The clinical manifestations of NCL are characterized by early onset, and treatment options are limited to symptomatic and palliative care . The classical characterization of this group of neurodegenerative disorders is determined by progressive and permanent loss of motor and psychological capacity, which correlates with the degree of prominent intracellular accumulation of lipofuscin . From a clinical standpoint, based on the age of onset, these diseases are categorized in the following types: infantile, late infantile, juvenile and adult. Although the phenotypes of the disease may vary by age and the order of appearance of symptoms, the clinical picture usually include progressive visual deterioration and blindness, cognitive impairment, motor deficits and seizures . All the mutations that were associated with NCL were related to the genes involved in the metabolism of neural synapses. At present there are known pathogenic variants in thirteen genes – CLN1/PPT1, CLN2/TPP1, CLN3, CLN4/DNAJC5, CLN5, CLN6, CLN7/ MFSD8, CLN8, CLN9, CLN10/CTSD, CLN11/ GRN, CLN12/ATP13A2, CLN13/CTSF, CLN14/ KCTD7 . Infantile NCL are the most common and have rapid progression. The following infantile types are described:
Type 1 – NCL1 or INCL (early infantile NCL), begins between 6 months and 2 years of age and progresses rapidly with the delay in psychomotor development and with progressive deterioration, seizures, early visual loss with blindness by the age of 2 years, microcephaly, typical muscle contractions, i. e., myoclonic jerks, by 3 years of age a vegetative state is reached and by 4 years isoelectric encephalograms confirm brain death . This disease is associated with the mutation in the CLN1 gene, which encodes an lysosomal enzyme, the protein Palmitoyl-protein thioesterase 1 (PPT1). It is disturbed the maturation of the enzyme, which produces a major lysosomal degradation of the CD protein that has a common pathogenic association with two of the most lethal neurological disorders, INCL and CNCL, i. e., congenital type .
Type 2 – LINCL (late infantile NCL) usually begins with loss of muscle coordination and seizures along with progressive mental and visual deterioration between ages 2 and 4. Sometimes before other symptoms occur, the disease can manifest with speech disorders. This form progresses rapidly and ends in death between ages 8 and 12 [4, 24, 26]. The mutation of the Tripeptidyl peptidase I gene (TPP1), which is mapped to the short arm of chromosome 11 (locus 11p15), which determines different rates of global cortical atrophy in various cortical regions .
Other late NCLI types have been identified in Germany, Serbia, Finland and in other countries.
Type 10 – CNL10, i. e., congenital cathepsin D deficiency, CTSD, usually begins with signs and symptoms of affection of the nervous system immediately after birth, including muscle stiffness, respiratory failure and prolonged episodes of status epilepticus, and microcephaly. Some affected patients may also manifest seizures before birth. Children with CLN10 die a few weeks after birth. There are possible late onset types with problems of balance and coordination, speech loss and progressive cognitive disorder and visual loss. Associated gene is CTSD . It has been established that this type of NCL is determined by implication of neuroecodermal cells and, as neurodegeneration progress, a loss of thymocytes and an atrophy of the intestinal mucosa may be present .
In the diagnosis and genetic counseling of NCL has been attained progress for the affected families . To diagnose NCL, it is necessary to address the neurologist, to obtain detailed medical history and to carry out comprehensive laboratory work. It is known that often the first sign of NCL is visual loss. The ophthalmologist is often the first to contact with a patient. Recognizing of the NCL individual clinical forms in childhood is based on invasive investigations by electronic microscopy, as well as molecular diagnosis. While the distinct genetic forms of NCL have been known for a long time, recent genetic progress has considerably widened the genotype and phenotype spectrum of NCL, highlighting a significant overlap with other neurodegenerative diseases. Prenatal diagnosis may be possible in a family with an affected child, depending on the type NCL, by determining the gene mutations or by haplotype analysis . At present, the following diagnostic tests of NCL are used: examination of tissues, i. e., blood, skin, muscle, conjunctiva, rectal mucosa etc. using electronic microscopy, which can visualize characteristic deposits in dependence of the type of disease .
Thus, over the last two decades, more than ten genes have been identified that can carry more than 430 mutations and 13 candidate genes in affected patients . Recently have been identified the 14th gene responsible for NCL, i. e., ADNC5/CLN4 . Within the direction of studying the social amoeba Dictyostelium were studied the functions of normal proteins related to human neurological disorders . At the same time, a new genetic variant associated with NCL was described in a dog species . However, many aspects of NCL remain unclear, and there are types of this pathology where associated genes are unknown .
From the results of the studies it is clear that the infantile and late infantile types of NCL are the most severe and are characterized by visual loss leading to complete blindness, behavioral problems, seizures, loss of cognitive and motor functions and to eventual death. These processes we are described also at presented work. Since NCL beginning is often non-specific, progression of clinical manifestations may suggest the development of the disease.
Brain imaging using magnetic resonance imaging (MRI) is a method of choice in NCL. MRI findings show cerebral and cerebellar atrophy, dilation of all cerebral ventricles, atrophy of intermediate mass of thalamus, etc. . MRI is indicated in all children suspected for a NCL. In the case described the revealed findings are important.
There are currently no accepted treatment programs that delay or stop progression of the disease or improve NCL symptoms. However, the current management of the disease is mainly oriented towards controlling the clinical symptoms of NCL rather than to “cure” the disease. For example, seizures can be controlled or improved using antiepileptic medicines. Some studies provide prospects for developing the strategies of immune-regulating treatments . Several therapeutic strategies, including replacement of enzymes, gene therapy, stem cell therapy and small molecule drugs, have resulted in minimal improvements in the model associated with the PPT1 deficiency. However, more recent studies have shown more promising results, in some cases, more than doubling the life span of mice with PPT1 deficiency. These combined therapies aimed at different pathogenic mechanisms can provide the hope of treating this profound neurodegenerative disorder . Several attempts are being made to understand the cause of gene damage and the methods of correction of the disrupted pathways in NCL. Various experimental treatments are being researched. Important implications for the supply of histologic correction therapies oriented brain – and spinal cord – oriented in INCL, are promoted . It provides evidence of potential drug targets for thioesterase deficiency diseases, such as INCL, using N-(tert-Butyl) hydroxylamine (NtBuHA) . Some studies describe how future research will be able to test new hypotheses (at Dictyostelium level) that will eventually lead to effective therapeutic options for this devastating and currently untreatable neurological disorder .
NCL are the most common neurodegenerative diseases encountered in childhood. The medical challenge in this case will be determined by the early diagnosis of NCL, which will improve the effectiveness of treatments and patient care. It is therefore important for specialists to recognize in time the clinical signs of NCL to propose advanced laboratory tests or to address the patient to a specialized centre for better management. The atypical forms of NCL must be considered in any of the patients presenting either psychomotor decline or progressive visual loss. Early imaging results can be significant for a leucodystrophy, and ophthalmological testing can be normal. The electronic microscopy of peripheral blood lymphocytes and the analysis of the enzymes implicated in NCL can facilitate early diagnosis. Recent genetic progress broadens the understanding of the molecular base of NCL, serving great potential in understanding, recognizing and treating NCL and related disorders.
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