Neuronal ceroid lipofuscinosis

Neuronal ceroid lipofuscinosis
Other names	NCL
Confocal image of a spinal motor neuron showing stained lipofuscin granules in blue and yellow.
Specialty	Endocrinology

Neuronal ceroid lipofuscinosis is the general name for a family of at least eight genetically separate

Signs and symptoms

The classic characterization of the group of neurodegenerative,

In the early infantile variant of NCL (also called INCL or Santavuori-Haltia), probands appear normal at birth, but early visual loss leading to complete retinal blindness by the age of 2 years is the first indicator of the disease; by 3 years of age, a vegetative state is reached, and by 4 years, isoelectric encephalograms confirm brain death. Late infantile variant usually manifests between 2 and 4 years of age with seizures and deterioration of vision. The maximum age before death for late infantile variant is 10–12 years.^[5][6][7][8] 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.^[9] 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.^[1]

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.^{[citation needed]}

Genetics

Childhood NCLs are generally

Many authorities refer to the NCLs collectively as Batten disease.[10]

Diagnosis

Because vision loss is often an early sign, NCL may be first suspected during an eye exam. An eye doctor can detect a loss of cells within the eye that occurs in the three childhood forms of NCL. However, because such cell loss occurs in other eye diseases, the disorder cannot be diagnosed by this sign alone. Often, an eye specialist or other physician who suspects NCL may refer the child to a neurologist, a doctor who specializes in disease of the brain and nervous system. To diagnose NCL, the neurologist needs the patient's medical history and information from various laboratory tests.^{[citation needed]}

Diagnostic tests used for NCLs include:

• Skin or tissue sampling: The doctor can examine a small piece of tissue under a microscope to spot typical NCL deposits. These deposits are found in many different tissues, including
  curvilinear profiles, fingerprint profiles, and mixed-type inclusions are typically found in LINCL, JNCL, and ANCL, respectively.^{[citation needed}
  ]
• seizures.^{[citation needed}
  ]
• Electrical studies of the eyes: These tests, which include
  visual-evoked responses and electroretinograms, can detect various eye problems common in childhood NCLs.^{[citation needed}
  ]
• Brain scans: Imaging can help doctors look for changes in the brain's appearance. The most commonly used imaging technique is
  computed tomography (CT), which uses x-rays and a computer to create a sophisticated picture of the brain's tissues and structures. A CT scan may reveal brain areas that are decaying in NCL patients. An increasingly common tool is magnetic resonance imaging, which uses a combination of magnetic fields and radio waves, instead of radiation, to create a picture of the brain.^{[citation needed}
  ]
• Enzyme assay: A recent development in diagnosis of NCL is the use of enzyme assays that look for specific missing lysosomal enzymes for infantile and late infantile versions only. This is a quick and easy diagnostic test.^{[citation needed]}

Types

The older classification of NCL divided the condition into four types (CLN1, CLN2, CLN3, and CLN4) based upon age of onset, while newer classifications divide it by the associated gene.^[11][12]

CLN4 (unlike CLN1, CLN2, and CLN3) has not been mapped to a specific gene.

Mutations

Infantile form

Nonsense and frameshift mutations in the CLN1 gene (located at 1p32

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.^{[citation needed]}

Two independent families have been shown to have mutations in the DNAJC5 gene – one with a transversion and the other with a deletion mutation.^[23] 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.^[24]

Treatment

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.^{[citation needed]} Several experimental treatments are under investigation.^{[citation needed]}

Cystagon

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.^{[citation needed]}

Gene therapy

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.^[25] The trial was conducted by Weill Medical College of Cornell University^[25] and sponsored by the Nathan's Battle Foundation.^[26] 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"^[27] and "suggested that higher doses and a better delivery system may provide greater benefit".^[28]

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.^[28] Animal models of late infantile NCL showed that the AAVrh.10 delivery system "was much more effective, giving better spread of the gene product and improving survival greatly".^[28]

A third gene therapy trial, using the same AAVrh.10 delivery system, began in 2011 and has been expanded to include late infantile NCL patients with moderate tosevere impairment or uncommon genotypes, and uses a novel administration method that reduces general anesthesia time by 50% to minimize potential adverse side effects.^[29]

Flupirtine

A painkiller available in several European countries, flupirtine, has been suggested to possibly slow down the progress of NCL,^[30] 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.^{[citation needed]}

Stem cells

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.^[31]

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.^{[citation needed]}

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.^[32]

Immunosuppressants

In late 2007, Dr. David Pearce et al. reported that

On April 27, 2017, the U.S. FDA approved cerliponase alfa as the first specific treatment for NCL.[21]

Epidemiology

Incidence can vary greatly from type-to-type, and from country-to-country.^[34]

In Germany, one study reported an incidence of 1.28 per 100,000.^[35]

A study in Italy reported an incidence of 0.56 per 100,000.^[36]

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.^[37]

History

19th century

The first probable instances of this condition were reported in 1826 in a Norwegian medical journal by Dr. Christian Stengel,

In 1913–14, Max Bielschowsky delineated the late infantile form of NCL.^[45] 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.^[46]

1950 to today

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.^[47] Simultaneously, Terry and Korey^[48] and Svennerholm^[49] 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.^{[citation needed]}

Subsequently, Santavuori and Haltia showed that an infantile form of NCL exists,^[50] which Zeman and Dyken had included with the Jansky Bielschowsky type.^{[citation needed]}

References