Niemann Pick disease – What is it?

There are three recognised forms of Niemann-Pick Disease, Niemann-Pick Type A, B and C. Niemann-Pick Type A and B are caused by an enzyme deficiency, causing a build up of toxic materials in the body’s cells. Niemann-Pick Type C is not caused by an enzyme deficiency, but the end result is the same; an accumulation of materials (cholesterol and other fatty acids) in the body’s cells.

In Niemann-Pick Type A this accumulation occurs very quickly, an affected child will usually die before reaching three years of age.

Niemann-Pick Type B does not affect the brain and, although growth may be slow, those affected will survive into adolescence or early adulthood, with many being able to lead a full and normal life.

In Niemann-Pick Type C, the brain and other organs are affected, leading to progressive intellectual decline, loss of motor skills, seizures and dementia. Speech can become slurred and swallowing problems may develop. The rate at which the disease progresses varies greatly between patients; children who develop neurological symptoms in early childhood are thought to have a more aggressive form of the disease, others may remain symptom free for many years.

If you or someone you know has been diagnosed as having, or suspected as having Niemann-Pick disease, it is likely that you are feeling overwhelmed with emotion and greatly confused as to what the disease is and how it has been acquired. The information provided on this website is intended to assist you and your family with understanding what the disease is and, hopefully, this will help in a small way in dealing with the distress that you inevitably feel and must face.

Why is it called Niemann-Pick?

The Niemann-Pick diseases are quite separate in terms of the fundamental cause but the similarities in clinical presentation have resulted in the naming of the diseases as Niemann-Pick, after two doctors who described the symptoms in the early part of the 20th century.

In 1914, a German paediatrician, Dr Albert Niemann, described the clinical presentation of children with the disease, but at that time little was known regarding the cellular or molecular explanation. Then, in the 1920′s, the studies of Luddwick Pick provided evidence of a new disorder, one distinct from storage disorders previously described. Further investigations using cells taken from the tissues of affected individuals in the mid and latter years of the century, resulted in an improved understanding of the diseases and their cause. Since then there has been a considerable amount of investigation into these and other inherited diseases of metabolism.

It was not until 1958 that the disease presentations were classified into type A, B and C. In 1966 types A and B were identified with a lysosomal enzyme, acid sphingomyelinase. Type C, which in turn was further sub classified into types D, E and possibly others, remained the subject of investigation, mainly by the National Institute of Health near Washington, USA. Although NPC could be diagnosed through clinical, histological and biochemical means, it was not until 1997 that the genetic link was made which accounted for most of the NPC cases and is identified as NPC1. Subsequently, a further link was made with a second gene, NPC2, which accounted for most of the remainder. Some patients diagnosed with the disease remain to be accounted for. All known types of Niemann-Pick disease are acquired through autosomal recessive inheritance.

What causes Niemann-Pick disease?

In order to appreciate the cause of the disease, some basic understanding of the biology of the cell is needed. This is a complicated subject but it is worth investing a little time to learn about the basic components of the cell and gain a general understanding into how inheritance works. For those unfamiliar with the science, click here for an introduction to cell operations and the role of DNA (deoxyribonucleic acid) in inherited disease.

How does one become affected by Niemann-Pick disease?

Niemann-Pick is an inherited disease. It is inherited in an autosomal recessive manner. In simple terms, this means that both parents have to be carriers of the faulty gene. In each pregnancy of a carrier couple, there is a 25% chance that they will pass on this gene mutation to their child.

Autosomes are the non-sex related chromosomes, and recessive indicates that the effects of possessing a single copy of a disease-causing gene are hidden. With a recessive condition, a person may be a carrier of a disease gene, but with no noticeable affect in their everyday lives and health. All types of NPD are autosomal recessive.

A positive diagnosis of say Niemann-Pick Type C disease in a child means that each of the parents is a carrier of a disease causing mutation on this gene. The mutations may be identical from each parent and the child will be referred to as homozygous for this mutation. In other instances the parental mutations will be different but disease causing and, the child will be referred to as heterozygous for the mutations.

The homozygous condition may arise through intermarriage although this may not be obvious over many generations. Interbreeding may occur as a result of the isolation of a community possibly through geographic necessity or because of religious or cultural tradition.

Examples of the geographical isolation may be found in the USA and Canada and are due to a situation described as the founder effect. Communities of immigrants from Europe made their home in remote places on the American continent and had little contact with the outside world for many years. Unfortunately one or more of their members carried a recessive defective gene. This circulated down through the generations and gained in frequency as the population grew.

The Ashkenazi Jewish population is known to be at risk of higher than normal from certain inherited diseases such as Tay-Sachs and Niemann-Pick Type A. The reason for this is the cultural and religious practice of marrying within their own community. This tends to concentrate the disease gene frequency rather than dilute it. Communities with known problems are at least able to plan for carrier testing and take preventative measures. For the general population this cannot be done at present.

If a family is affected by Niemann-Pick disease apparently out of the blue, there is no way they could have prepared for the shock and no measure of prevention, which could have been planned. The tragedy is often compounded by the delayed disease onset. Children may not show symptoms for many years and diagnosis may itself take a number of years. Other children may have been born in this period and will each have a 25% risk of having the disease. There are, sadly, too many instances of families with more than one child affected. Further complications may arise where symptoms and diagnosis of the disease in an individual are delayed to adulthood and they have families of their own. The affect is that of a time bomb. Once a diagnosis has been obtained in a family then they will be acutely aware that they are at risk in terms of having further children. In addition other members of the family will be concerned and wonder if they too, could be affected.

Niemann-Pick diseases are Lysosomal disorders, of which there are approximately 40 different types. Most of the identified diseases are either named after the doctor who first described the clinical symptoms or the cellular/molecular basis or, the scientific name that is most appropriate. In the latter case most of the names are unpronounceable without practice. The incidence of each disease ranges from one in a few hundred to one in many thousands or even millions. Individually each of the diseases is classified as rare by medical authorities but taken as a whole, they are epidemic proportions. It has been observed that there seems to be a lot of rare diseases. The miracle is that any of us function at all!

More about Niemann-Pick Type C disease

Niemann-Pick disease type C (NPC) is an extremely rare genetic disorder arising from build up of glycosphingolipids particularly in the Central Nervous System.  These build up in toxic quantities as unesterified cholesterol, causing structural and functional damage in cells and tissues.   NPC is pan-ethnic and arises at irregular intervals across populations, regardless of race, although genetic isolates (clusters) have been identified in Nova Scotia, Colorado, and New Mexico. It is believed that NPC arises in 1 case per every 150,000 births. However, it is considered highly likely that this is an underestimate due to a mixture of factors – chiefly, failure to recognise the clinical characteristics and a previous lack of definitive diagnostic tests.

Based on molecular genetic testing, NPC is now divided into two subtypes − NPC1 and NPC2 − as each is caused by a different gene mutation. These names are currently preferred, as they relate back to the mutated genes responsible for the clinical phenotype. Niemann-Pick disease type D (NPD), previously and still sometimes used to describe the genetic isolate from Nova Scotia, should no longer be considered as a separate condition as it is biochemically and clinically indistinguishable from NPC, and is now known to result from mutations in the NPC1 gene.   NPC has an extremely varied clinical presentation, but is characterised by a range of progressive neurological problems that become severe and limiting at late stages of the disease.  It can present, either with or without associated hepatosplenomegaly (enlarged liver and spleen) in infants, children or adults, and is characterized by eye movement abnormalities, dysphagia (difficulty in swallowing) and dysarthria (slurred, irregular speech), ataxia (lack of muscle control) and progressive cognitive dysfunction (progressive intellectual decline) leading to dementia.

When does Niemann-Pick Type C become apparent?

NPC is present in an individual from the moment of conception but is not necessarily apparent.  The symptoms are often related to the age when the disease takes hold and, this is in itself an extremely variable factor ranging from birth to old age.  It is possible that babies have died prior to birth and been undiagnosed or diagnosed in a ‘blanket’ manner, eg liver disease.

Similarly, people with very late onset may be incorrectly diagnosed with a disease such as Alzheimer’s.  Since awareness of the disease has increased and diagnosis has been improved, the age profile of the disease is beginning to look different to that of a few years ago.  What was once considered to be a childhood disease is now, equally, beginning to look like a disease of adults.  Information on numbers of people affected, age of onset and progression has been collected in a number of countries and this will help to provide a better picture in due course.

How is Niemann-Pick Type C diagnosed?

If NPC is suspected clinically a skin biopsy is taken and grown in a sterile environment which takes about 6 weeks.  When sufficient tissue is available it is stained with filipin which causes the lipid filled lysosomes to fluoresce in affected cells   A second test to look at the rate of cholesterol esterification (how the cell processes the cholesterol) is also done.  The whole process usually takes about 12 weeks.  Meanwhile, a blood test to check for raised chitotriosidase levels may be done as this is raised in most (but not all) NPC patients.

Symptoms of NPCD

Symptoms vary with age of onset and may include:

  • jaundice at (or shortly after) birth
  • an enlarged spleen and/or liver (hepatosplenamegaly)
  • difficulty with upward and downward eye movements (Vertical Supranuclear Gaze Palsy).
  • unsteadiness of gait, clumsiness, problems in walking (ataxia)
  • difficulty in posturing of limbs (dystonia)
  • slurred, irregular speech (dysarthria)
  • learning difficulties and progressive intellectual decline (Cognitive dysfunction – “dementia”)
  • sudden loss of muscle tone which may lead to falls (cataplexy)
  • tremors accompanying movement and, in some cases, seizures

Type C is the most variable form of the disease.  Symptoms may appear and then disappear. Some symptoms may never appear. The rate of progression of the disease is different from person to person.  The rate of progress for an individual will change over time.

Type C is often incorrectly diagnosed. Some of the common errors are:

  • Attention Deficit Disorder (ADD)
  • Learning Disability
  • Retardation
  • Delayed Development

Vertical Supranuclear Gaze Palsy (VSGP or VGP) is highly suggestive of Type C.  VSGP is the inability to move the eyes up and down.  Parents often notice this when their child walks up and down stairs, watches TV while sitting on the floor, or in similar situations – the child tilts their head to see instead of moving their eyes. Liver or spleen problems in the first few months after birth are also highly suggestive of Type C.