An Essay by Parveen Monga

“Hope is the thing with feathers that perches in the soul, and sings the tune without the words, and never stops at all.”

Emily Dickinson wrote this many years ago, but it is still applicable to the families that have children suffering from Niemann-Pick Type C disease. We take simple tasks like walking, talking, eating, and breathing for granted each day, not realizing that these are so essential for our frail bodies to survive. For example, can you imagine, having a child born to you healthy and smiling, calling out to you “Mom! Dad!” being able to sing and eat and play and then slowly these things are snatched away until he or she is bedridden with seizures, complications from aspiration and eventually dies a most cruel death. This is what Niemann-Pick Type C disease does. It is a rare disease caused by an inherited condition involving lipid metabolism that affects not only children but some adults as well, and it tries to take away all hope.

Albert Niemann is a German Pediatrician who first described a young child with an enlarged spleen and liver, along with having brain and nervous system impairment in the year 1914. Additionally, Ludwick Pick studied the tissues of after the death of such children in 1920 to provide evidence of this new and rare disorder. That is how the name Niemann-Pick came about for the disease. There are three variants in Niemann-Pick Disease; Type A, Type B and Type C.

However, Type C is inherited in an autosomal recessive pattern, which typically means two copies of the gene must be altered for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of Niemann-Pick.

Mutations in either the NPC1 or NPC2 gene cause Niemann-Pick disease, Type C. The NPC1 gene produces a protein that is located in membranes inside the cell and is involved in the movement of cholesterol and lipids within cells. A deficiency of this protein leads to the abnormal build up of lipids and cholesterol within cell membranes. Accumulation of these fats disrupts cell function, leading to severe physical and neurological deterioration, including the loss of the ability to walk, speak and swallow. NPC always is ultimately fatal.

Even though children and adults with Type C Niemann-Pick show normal development for two or more years prior to diagnosis, the disease progresses by a slow loss of speech and other nervous system skills. The disease progresses with symptoms of increased clumsiness and lack of coordination, and eventually seizures, and a gradual failure of physical and mental function. Type C, is characterized by an onset of childhood, although infant and adult onsets are possible. Other signs include severe liver disease, breathing difficulties, developmental delay, seizures, increased muscle tone (dystonia), lack of coordination, problems with feeding, and an inability to move the eyes vertically. However, people with this disorder can survive into adulthood. The incidence of Niemann-Pick disease, Type C, is estimated to be 1 in 150,000 people. The disease occurs more frequently in people of French-Acadian descent in Nova Scotia.
Patients gradually develop neurologic abnormalities which are initially manifested by ataxia, grand mal seizures, and loss of previously learned speech. Spasticity is striking and seizures, particularly myoclonic jerks, are common. Other features include dystonia, vertical supranuclear gaze palsy, dementia, and psychiatric manifestations. In general, hepatosplenomegaly is less striking than in Types A and B, although it can be lethal in some. Cholestatic jaundice occurs in some patients. Foamy Niemann-Pick cells and 'sea-blue' histiocytes with distinctive histochemical and ultrastructural appearances are found in the bone marrow. Most children with Type C die between the ages of 5 and 15 years.

Therefore, the National Niemann-Pick Disease Foundation (NNPDF) was established in 1992 to fund family support services and research into Niemann-Pick Disease. Since then, the foundation's membership has grown to over 350 families, and over $4.3 million has been applied toward research. As a result of this research, the genes responsible for Niemann-Pick Disease have been identified, and research continues, seeking treatments and a cure for Niemann-Pick Disease.

At the age of eight both Aaditya, a boy in India and Sawson, a girl in Lebanon, were diagnosed with NPC-1 and were the first ever to receive an intracranial stem cell transplant for the rare and destructive illness for which there is no conventional treatment. Stem cells are cells that can, when provided the right stimulus, change themselves into specialised cells and, thus, develop into and replace malfunctioning or damaged body organs. The operation was carried out at the BGS Global Hospital, Bangalore, by Dr N.K. Venkataramana, Vice Chairman & Chief Neurosurgeon of the hospital.

Another experimental and more popular treatment in the West is Zavesca. Actelion, the makers of Zavesca, indicated that the company remains committed to moving forward in working for FDA approval of Zavesca for patients with NPC. Zavesca is not a cure for NPC, but it has shown promise in treating symptoms related to this neurodegenerative disease and is slowing its progression for some patients. Zavesca has been prescribed in the U.S. since 2003 for treatment of patients with Type 1 Gaucher's disease, the most common of the lysosomal storage disorders. As a result of the FDA's Tuesday announcement, U.S. physicians must continue to prescribe Zavesca "off-label" for NPC.

More recently another unconventional treatment had been researched by a mother of twins, Addi and Cassi, who were both diagnosed with NPC. She studied about cyclodextrin for months when she attended the June 2008 meeting in Tucson, Ariz., of the Ara Parseghian Medical Research Foundation, set up by the family of the legendary football coach who lost three grandchildren to NP-C disease. The foundation was providing some funding for cyclodextrin studies in the rare disease, and the latest data was presented there. In an email sent after the meeting, Ms. Hempel wrote to the NP-C researchers that, based on the data she heard, she and her husband, Hugh, planned to seek FDA approval to give the girls cyclodextrin infusions. "I feel very strongly that we must try this to help save Addi and Cassi from this horrible disease," she wrote.

She had already put together a three-inch binder of research studies about cyclodextrin. Working with three other families whose children have NP-C disease, they hired a scientist who began writing a request to the FDA for the Hempel children to receive cyclodextrin infusions. But Ms. Hempel knew that she needed more human data if she was going to persuade the FDA that the drug was safe enough to use in her children.

The search for a cure may be not be far with families putting not only their money and time but their whole lives at stake for their children.

This patient with Niemann-Pick disease was a 12 y/o boy with progressively worsening splenomegaly causing respiratory difficulty and anorexia. The splenectomy specimen showed firm, pale, red-brown parenchyma. Low-power view shows aggregates of foamy histiocytes throughout the spleen

In conclusion, we can say, there is no effective treatment for NPC. Bone marrow transplantation has been performed on a few patients with no positive results. Researchers continue to study possible treatments, including enzyme replacement therapy and gene therapy. There is no specific treatment for Type C and D. A healthy, low-cholesterol diet is recommended. Although research into low-cholesterol diets and cholesterol-lowering drugs does not show that these methods stop the disease from getting worse or change how cells break down cholesterol. However, medicines are available to control or relieve many symptoms, such as cataplexy and seizures. Perhaps hope and prayers can be the best remedies till researchers find new discoveries for this disease. “Let us pray for all those suffering from this fatal disease and come together to find a cure” says one desperate aunt.


Works Cited

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Niemann-Pick Disease

Niemann-Pick disease is an inherited condition involving lipid metabolism (the breakdown and use of fats and cholesterol in the body) in which harmful amounts of lipids accumulate in the spleen, liver, lungs, bone marrow, and brain.

There are three variants of Niemann-Pick disease based on the genetic cause and the symptoms exhibited by the patient. All variants are inherited in an autosomal recessive pattern.

Mutations in the NPC1, NPC2, and SMPD1 genes cause Niemann-Pick disease.

This condition is inherited in an autosomal recessive pattern, which means two copies of the gene must be altered for a person to be affected by the disorder. Most often, the parents of a child with an autosomal recessive disorder are not affected but are carriers of one copy of the altered gene. If both parents are carriers, there is a one in four, or 25%, chance with each pregnancy for an affected child. Genetic counseling and genetic testing is recommended for families who may be carriers of Niemann-Pick.

Type C is characterized by onset in childhood, although infant and adult onsets are possible. Other signs include severe liver disease, breathing difficulties, developmental delay, seizures, increased muscle tone (dystonia), lack of coordination, problems with feeding, and an inability to move the eyes vertically. People with this disorder can survive into adulthood. The incidence of Niemann-Pick disease, type C is estimated to be 1 in 150,000 people. The disease occurs more frequently in people of French-Acadian descent in Nova Scotia.

Mutations in either the NPC1 or NPC2 gene cause Niemann-Pick disease, type C. The NPC1 gene produces a protein that is located in membranes inside the cell and is involved in the movement of cholesterol and lipids within cells. A deficiency of this protein leads to the abnormal build up of lipids and cholesterol within cell membranes.

The molecular basis for this disease is extremely complex due to the role that endosome formation has on affected patients. Recently, three theories have attempted to explain the buildup of cholesterol in the lysosomes of affected patients of Niemann-Pick Disease Type C due to the malfunction of the protein NPC-1.

* The contention by Neufel et al is that the buildup of mannose 6-phosphate receptors (MPRs) in the late endosome suggests that the retrograde breakdown of cholesterol via the Trans Golgi Network cannot occur.[1]

* Another theory suggests that the blockage of retrograde cholesterol breakdown in the late endosome is due to decreased membrane elasticity and thus the return vesicles of cholesterol to the Trans Golgi Network cannot bud and form.

The support of these theories has considerable evidence using mutant proteins in vitro to determine the buildup of cholesterol in the lysosomes. Researchers have also discovered that the NPC-1 protein may function as a pump of cholesterol.[2]

The overall effect of a malfunction in NPC-1 is that low levels or an absence of the protein lead to the abnormal accumulation of lipids and cholesterol in the cells of people with this condition.


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