Нейрональное цероидное липофусциноз: обзор и классификация.

Neuronal ceroid lipofuscinosis is the general name for a family of at least eight genetically separate neurodegenerative lysosomal storage diseases that result from excessive accumulation of lipopigments (lipofuscin) in the body's tissues. with the United States and Northern European populations having slightly higher frequency with an occurrence of one in 10,000. Four classic diagnoses have received the most attention from researchers and the medical field, differentiated from one another by age of symptomatic onset, duration, early onset manifestations such as blindness or seizures, and the forms which lipofuscin accumulation takes. Juvenile NCL (JNCL, Batten disease, or Spielmeyer Vogt), with a prevalence of one in 100,000, usually arises between 4 and 10 years of age; the first symptoms include considerable vision loss due to retinal dystrophy, with seizures, psychological degeneration, and eventual death in the mid to late 20s or 30s ensuing. Adult variant NCL (ANCL or Kuf's disease) is less understood and generally manifests milder symptoms; however, while symptoms typically appear around 30 years of age, death usually occurs 10 years later. All the mutations that have been associated with this disease have been linked to genes involved with the neural synapses metabolism – most commonly with the reuse of vesicle proteins.

Childhood NCLs are generally autosomal recessive disorders; that is, they occur only when a child inherits two copies of the defective gene, one from each parent. When both parents carry one defective gene, each of their children faces a one in four chance of developing NCL. At the same time, each child also faces a one in two chance of inheriting just one copy of the defective gene. Individuals who have only one defective gene are known as carriers, meaning they do not develop the disease, but they can pass the gene on to their own children. The most commonly identified mutations are in the CLN3 gene, which is located on the short arm of chromosome 16 (16p12.1). The normal function of the gene is not presently known, but results in a transmembrane protein. Adult NCL may be inherited as an autosomal recessive (Kufs), or less often, as an autosomal dominant (Parry's) disorder. In autosomal dominant inheritance, all people who inherit a single copy of the disease gene develop the disease. As a result, no carriers of the gene are unaffected. Many authorities refer to the NCLs collectively as Batten disease.

All mutations resulting in the juvenile variant of NCL have been shown to occur at the CLN3 gene on 16p12; Only recently have studies of human patients shown deficiency of lysosomal aspartyl proteinase cathepsin D.

Between 1.3 and 10% of cases are of the adult form. The age at onset is variable (6–62 yr). Two main clinical subtypes have been described: progressive myoclonus epilepsy (type A) and dementia with motor disturbances, such as cerebellar, extrapyramidal signs and dyskinesia (type B). Unlike the other NCLs, retinal degeneration is absent. Pathologically, the ceroid lipofuscin accumulates mainly in neurons and contains subunit C of the mitochondrial ATP synthase. Two independent families have been shown to have mutations in the DNAJC5 gene – one with a transversion and the other with a deletion mutation. The mutations occur in a cysteine string domain, which is required for membrane targeting/binding, palmitoylation, and oligomerization of the encoded protein cysteine string protein alpha (CSPα). The mutations dramatically decrease the affinity of CSPα for the membrane. A second report has also located this disease to this gene.

Currently, no widely accepted treatment can cure, slow down, or halt the symptoms in the great majority of patients with NCL, but seizures may be controlled or reduced with use of antiepileptic drugs. Additionally, physical, speech, and occupational therapies may help affected patients retain functioning for as long as possible. Several experimental treatments are under investigation.

In 2001, a drug used to treat cystinosis, a rare genetic disease that can cause kidney failure if not treated, was reported to be useful in treating the infantile form of NCL. Preliminary results report the drug has completely cleared away storage material from the white blood cells of the first six patients, as well as slowing down the rapid neurodegeneration of infantile NCL. Currently, two drug trials are underway for infantile NCL, both using Cystagon.

A gene therapy trial using an adenoassociated virus vector called AAV2CUhCLN2 began in June 2004 in an attempt to treat the manifestations of late infantile NCL. The trial was conducted by Weill Medical College of Cornell University In May 2008, the gene therapy given to the recipients reportedly was "safe, and that, on average, it significantly slowed the disease's progression during the 18 month follow up period" and "suggested that higher doses and a better delivery system may provide greater benefit". A second gene therapy trial for late infantile NCL using an adenoassociated virus derived from the rhesus macaque (a species of Old World monkey) called AAVrh.10 began in August 2010, and is once again being conducted by Weill Medical College of Cornell University.

A painkiller available in several European countries, flupirtine, has been suggested to possibly slow down the progress of NCL, particularly in the juvenile and late infantile forms. No trial has been officially supported in this venue, however. Currently, the drug is available to NCL families either from Germany, Duke University Medical Center in Durham, North Carolina, or the Hospital for Sick Children in Toronto.

On October 20, 2005, the Food and Drug Administration approved a phase I clinical trial of neural stem cells to treat infantile and late infantile Batten disease. Subsequent approval from an independent review board also approved the stem cell therapy in early March 2006. This treatment will be the first transplant of fetal stem cells performed on humans. The therapy is being developed by Stem Cells Inc and is estimated to have six patients. The treatment was to be carried out in Oregon. Juvenile NCL has recently been listed on the Federal Clinical Trials website to test the effectiveness of bone marrow or stem cell transplants for this condition. A bone marrow transplant has been attempted in the late infantile form of NCL with disappointing results; while the transplant may have slowed the onset of the disease, the child eventually developed the disease and died in 1998. Trials testing the effectiveness of bone marrow transplants for infantile NCL in Finland have also been disappointing, with only a slight slowing of disease reported.

In late 2007, Dr. David Pearce et al. reported that Cellcept, an immunosuppressant medication commonly used in bone marrow transplants, may be useful in slowing down the progress of juvenile NCL.

On April 27, 2017, the U. S. FDA approved cerliponase alfa as the first specific treatment for NCL. In Germany, one study reported an incidence of 1.28 per 100,000. A study in Italy reported an incidence of 0.56 per 100,000. A study in Norway reported an incidence of 3.9 per 100,000 using the years from 1978 to 1999, with a lower rate in earlier decades.

The first probable instances of this condition were reported in 1826 in a Norwegian medical journal by Dr. Christian Stengel, who described 4 affected siblings in a small mining community in Norway. Although no pathological studies were performed on these children the clinical descriptions are so succinct that the diagnosis of the Spielmeyer Sjogren (juvenile) type is fully justified.

More fundamental observations were reported by F. E. Batten in 1903, and by Heinrich Vogt in 1905, who performed extensive clinicopathological studies on several families. Retrospectively, these papers disclose that the authors grouped together different types of the syndrome. Furthermore, Batten, at least for some time, insisted that the condition that he described was distinctly different from Tay–Sachs disease, the prototype of a neuronal lysosomal disorder now identified as GM2 gangliosidosis type A. Around the same time, Walther Spielmeyer reported detailed studies on three siblings, who have the Spielmeyer Sjogren (juvenile) type, which led him to the very firm statement that this malady is not related to Tay–Sachs disease. Subsequently, however, the pathomorphological studies of Károly Schaffer made these authors change their minds to the extent that they reclassified their respective observations as variants of Tay–Sachs disease, which caused confusion lasting about 50 years. In 1913–14, Max Bielschowsky delineated the late infantile form of NCL. However, all forms were still thought to belong in the group of "familial amaurotic idiocies", of which Tay–Sachs was the prototype. In 1931, Torsten Sjögren, a Swedish psychiatrist and geneticist, presented 115 cases with extensive clinical and genetic documentation and came to the conclusion that the disease now called the Spielmeyer Sjogren (juvenile) type is genetically separate from Tay–Sachs.

Departing from the careful morphological observations of Spielmeyer, Hurst, and Sjovall and Ericsson, Zeman and Alpert made a determined effort to document the previously suggested pigmentary nature of the neuronal deposits in certain types of storage disorders. Simultaneously, Terry and Korey and Svennerholm demonstrated a specific ultrastructure and biochemistry for Tay–Sachs disease, and these developments led to the distinct identification and also separation of the NCLs from Tay–Sachs disease by Zeman and Donahue. At that time, it was proposed that the late infantile (Jansky–Bielschowsky), the juvenile (Spielmeyer–Vogt), and the adult form (Kufs) were quite different from Tay–Sachs disease with respect to chemical pathology and ultrastructure and also different from other forms of sphingolipidoses. Subsequently, Santavuori and Haltia showed that an infantile form of NCL exists, which Zeman and Dyken had included with the Jansky Bielschowsky type.