CORSO DI LAUREA IN SCIENZE E TECNICHE PSICOLOGICHE NIEMANN-PICK DISEASE TRANSLATION PRACTICE

1. Introduction In 1914 the German paediatrician Albert Niemann described a Jewish child with damage to the brain and nervous system. Subsequently in 1927 Ludwig Pick analyzed the tissues from deceased children and provided evidence of a new storage disease, not previously described. Currently, the term Niemann-Pick Disease (NPD) refers to a group of genetic diseases of the metabolism, characterized by lipid storage and autosomal recessive inheritance. Alan Crocker, in 1958, was the first to propose a classification of this series of metabolic disorders, based on biochemical and clinical features. Types A and B of Niemann-Pick disease (NPD-A and NPD-B) are due too a lack of acid sphingomyelinase (A-SMase) activity, a lysosomal enzyme encoded by the SMPD1 gene (sphingomyelin phosphodiesterase 1) located on chromosome 11. The enzyme defect results in a pathological accumulation of sphingomyelin (SM) and other lipids, particularly within the tissues of the reticulo-endothelial system (RES) including the spleen, lymph nodes, bone marrow, thymus and mononuclear phagocytes which along with the liver and lungs, is deeply affected by the disease. Niemann-Pick disease type C (NPD-C) is a chronic neuropathy, with clinical, biochemical and molecular features distinct from those of NPD-A and B (primary sphingolipidosis). Common symptoms are hepatosplenomegaly and neurodegeneration, resulting in progressive motor dysfunction, cognitive decay and psychicdisorders. NPD-C is divided into 3 subgroups according to the age of clinical onset and the respective phenotype: childhood presentation, late-childhood presentation and adolescent and adult presentation. (253 words)

2. Clinical features

NPD-A phenotype

Clinical features and progression of the disease are relatively uniform. Pregnancy, labour and childbirth are regular and affected babies appear as normal at birth. Sometimes the neonatal period may be characterized by jaundice. Typically, in the first months, or less frequently at 4-6 months of age, the abdomen becomes globose and hepaspenomegaly may be evident; also, a mild lymphadenopathy can be observed. Examination of the bone marrow reveals the presence of typical Niemann-Pick foam cells. Later, during disease progression, a mild microcytic anemia may occur which normally responds to iron supplementation along with a decrease in platelet count. Early neurological symptoms include weakness and muscle hyptonia, which manifest themselves in feeding difficulty. Vomiting and chronic constipation are frequent. As a consequence of feeding difficulty and of splenomegaly, affected infants show delayed growth. The cardiac function is normal. Most babies with NPD-A have mild breathing difficulty during the first year of age, with the exception of repeated episodes of bronchitis and pneumonia, intercurrent or caused by foreign bodies. However, chest X-rays show alveolar infiltration, which appears as uniform, widely reticular or finely nodular in the lungs. At about 6 months of age, psychomotor retardation becomes evident. As the baby becomes weaker and hypotonic, there is a regression with respect to the acquired stages of development (e.g. The child is no longer able to sit.) An examination of the eyes, during the first or second year of age, highlights a cherry-red spot on macula in approximately 50% of affected children. (248 words)

3. Gene therapy Another important study has tested the effect, on ASMKO mice, of a combined treatment, both systemic and on nervous tissues, based on the use of A-SMase-expressing AAV vectors. The animals, treated with this combined therapy, show high levels of A-SMase protein in brain and other organs and an almost complete reversion of the pathological phenotype. This remission is evident also through recovery of normal weight, higher levels of cognitive and motor skills, and longer survival compared to untreated controls and to animals treated with either brain or systemic injections. In addition, the animals treated with combined therapy do not generate antibodies against recombinant A-SMase, which demonstrates that tolerance induced by the first systemic injections improves the efficacy of subsequent brain injections.These data show that combined therapyis a promising approach for the treatment of those pathological disorders involving visceral organs and the central nervous system. Despite this optimistic perspective, many issues still need to be addressed before gene therapy can be employed. In particular, in order to slow down or, even better, stop the progression of the disease, the safety of viral vectors should be further improved, as well as the uptake and targeting of genetically-modified viruses and finally, the efficiency of recombinant gene expression. Moreover, it must be pointed out that this therapy can be effective only if employed on the nervous system at the onset of the first neurological systems, as these are mostly irreversible. (236 words) 4. Psychological Support for Adult Sufferers of NPD-C In this psychological treatise we have chosen to consider patients affected with NPD-C and, in particular, those who discover their illness in the period from adolescence to adulthood. These are people more often than not capable of a deep awareness of what is happening and who, due to the chronic and debilitating nature of the disease, may find themselves living the last years of life with serious cognitive, behavioural, emotive and motor disturbances. Adolescent or adult NPD patients necessitate not only physiological assistance but also moral and psychological help, which must be recognized by caregivers in order for an efficient therapeutic approach: the necessity of receiving information on the diagnosis and treatment; the desire for emotional closeness; the necessity to express the feelings connected to their disease, to keep a satisfying level of communication with their own family circle, and with relations to face uncertainty, insecurity and lack of self-control; the need to maintain a continuity in their daily activities and their planning ability, to preserve their own cognitive abilities as long as possible. The aim of psychological support are directly correlated to the described needs, including the following: to communicate the information concerning the diagnosis and other medical aspects related to assistance; to help the patient to comprehend and accept his/her disease; to ensure an emotional restriction of anguish and depression; to support and motivate the patient so that he/she might play an active role, attending to needs on his/her own, compatibly with his/her residual potentialities; to ease the patients loneliness through the last phase of his/her life. (259 words)