Lipid Storage Disorders

Updated: Jun 10, 2020
  • Author: Rubia Khalak, MD; Chief Editor: Luis O Rohena, MD, PhD, FAAP, FACMG  more...
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Lipid storage disorders are a family of diverse diseases related by their molecular pathology. In each disorder, a deficiency of a lysosomal hydrolase is inherited, which leads to lysosomal accumulation of the enzyme's specific sphingolipid substrate. [1, 2] Lipid substrates share a common structure, including a ceramide backbone (2-N-acyl-sphingosine), in which various sphingolipids are derived by substitution of hexoses, phosphorylcholine, or one or more sialic acid residues on terminal hydroxyl groups of the ceramide molecule.

Pathways of glycosphingolipid metabolism in both nervous tissue and visceral organs are elucidated, and for each catabolic step, a genetically determined metabolic derangement is identified. [3]

Examples of lipid storage disorders include GM1 gangliosidoses, [4] GM2 gangliosidoses, [4] Gaucher disease, sphingomyelinase deficiency or Niemann-Pick disease (NPD) types A and B, [5] Niemann-Pick disease type C, Fabry disease, fucosidosis, Schindler disease, metachromatic leukodystrophy (MLD), Krabbe disease, multiple sulfatase deficiency, Farber disease, Wolman disease, and cholesterol ester storage disease (CESD).

The biochemical basis of lipid storage disorders is well characterized and includes determining properties of enzymatic activities and various storage products. Research has led to development of diagnostic assays for identification of affected individuals, which usually rely on measurement of specific enzymatic activity in isolated leukocytes or cultured fibroblasts. In some cases, screening tests, such as urine metabolite analysis for mucopolysaccharidoses, can be helpful. [6] For most disorders, carrier identification and prenatal diagnosis are available as well. Making a specific diagnosis in an affected individual is essential in order to provide accurate genetic counseling.

More recently, investigators have focused efforts on determining the molecular basis of each of these disorders. These studies have resulted in identifying specific disease-causing mutations and have led to improved clinical and laboratory diagnosis, prenatal diagnosis, and carrier identification. In addition, for some disorders (eg, Gaucher disease), making genotype-phenotype correlations that predict disease severity and allow more accurate genetic risk counseling is possible. Advances in understanding the molecular and biochemical basis include cloning and characterization of most genes that encode specific enzymes required for sphingolipid metabolism. These investigations permit development of improved therapeutic options, such as recombinant enzyme replacement therapy. Dietary restriction has shown promise for disorders such as lysosomal acid lipase deficiency (Wolman disease), as has incorporation of lipid-lowering drugs in the regimen along with sebelipase alpha, a recombinant enzyme replacement therapy. [7] Other therapeutic options, such as gene therapy and bone marrow transplantation, for selected lipidoses may also result in improved prognosis.



Because glycosphingolipids are essential components of all cell membranes, inability to degrade these substances and their subsequent accumulation results in physiologic and morphologic alterations of specific tissues and organs that lead to characteristic clinical manifestations. The defective enzyme leads to lipid product accumulation, resulting in dysfunction of cellular organelles with a common storage place being the lysosome. [8] Progressive lysosomal accumulation of glycosphingolipids in the central nervous system can lead to a neurodegenerative course; whereas, storage in visceral cells can lead to organomegaly, skeletal abnormalities, bone marrow dysfunction, pulmonary infiltration, and other manifestations. Various disorders of lipid metabolism have characteristic patterns of organ involvement and clinical history, depending on the particular substrate that is stored. The lysosome is the cell’s recycling center, ridding the cell of unwanted waste; in individuals with an enzyme defect, accumulation occurs as noted above. One of the most common lysosomal storage disorders is Gaucher disease, discussed below.


Mode of Inheritance

All lipid storage disorders are inherited in an autosomal-recessive fashion, except for Fabry disease and mucopolysaccharidosis type II (Hunter disease), which are X-linked. Some disorders are more prevalent in certain geographic areas or among particular population groups; for example, Gaucher, Tay-Sachs, and Niemann-Pick type A are more common in Ashkenazi Jews, largely as a result of ancestral founder mutations. [9, 10, 11] For many diseases, such as Fabry disease, most kindreds have private mutations.




United States

Lipid storage disorders are rare disorders, although some have an ethnic predilection with more appreciable frequency.


Frequency is similar to that in the United States.


Infantile forms are usually fatal. Juvenile-onset and adult-onset disorders have variable survival rates that depend on particular manifestations.


Most lipid storage disorders are panethnic; however, an ethnic predilection has been noted for Tay-Sachs disease, type 1 Gaucher disease, and sphingomyelinase deficiency (NPD type A), which all occur at increased frequency in Ashkenazi Jews. Guidelines for carrier screening for genetic disorders in individuals of Ashkenazi Jewish descent have been established. [12]

Other important ethnic predilections include the following:

  • NPD type C1 has a high incidence in Acadians from Nova Scotia, individuals of Hispanic descent in parts of the southwestern United States, and a Bedouin group in Israel.

  • Late-onset form of Fabry disease is found in increased incidence in Italy (1 in 4,600).

  • Gaucher disease type 3 is more common in the Norrbottnian region of Sweden (1 in 50,000).

  • Tay-Sachs disease has an increased incidence in French Canadians (1 in 10,000), Cajuns from Louisiana, and Old Order Amish in Pennsylvania.

  • Metachromatic leukodystrophy has an increased incidence in the Habbanite Jewish in Israel (1 in 75), Israeli and Christian Israeli Arabs (1 in 10,000), and the western portion of the Navajo nation in the United States (1 in 2,500).


Each disorder is transmitted as an autosomal recessive trait, except Fabry disease and mucopolysaccharidosis type II (Hunter disease), which have X-linked recessive inheritance.


Congenital presentation

The perinatal lethal form of Gaucher disease is associated with nonimmune hydrops fetalis, arthrogryposis, ichthyosiform or collodion skin abnormalities, hepatosplenomegaly, and pancytopenia.

Perinatal forms of GM1 gangliosidosis, NPD type C, Wolman disease, and Farber disease are associated with nonimmune hydrops fetalis.

Presentation in infancy

In general, patients with type 1 Gaucher disease who present in childhood tend to have more pronounced visceral and bony disease manifestations than those who present in adulthood. [13] Patients with type 1 Gaucher disease can experience growth retardation, delayed puberty, leukopenia, impairment of pulmonary gas exchange, and destruction of vertebral bodies with secondary neurologic complications. They are at an increased risk of multiple myeloma and Parkinson disease. [14]

GM1 gangliosidosis type 1 and sphingomyelinase deficiency (NPD type A) usually appear in early infancy. GM2 gangliosidoses, which include Tay-Sachs disease and Sandhoff disease, have infantile forms.

The clinical phenotypes for MLD widely vary. Patients who are severely affected usually present in the first year of life with developmental delay and somatic features, similar to those of mucopolysaccharidoses. Late infantile forms of MLD, which is most common, usually present in infants aged 12-18 months with irritability, inability to walk, and hyperextension of the knee, causing genu-recurvatum.

Infantile forms of Krabbe disease are rapidly progressive and present early in infancy with irritability, spasms upon noise stimulation, recurrent episodes of unexplained fever, blindness, deafness, seizures, and hypertonia. [15] Optic atrophy is evident in the first year of life and mental development is severely impaired. A second, late infantile form of Krabbe disease is also observed and presents in children older than 2 years. Affected individuals have a disease course similar to early infantile form.

Wolman disease is a fatal disorder of infancy. Clinical features become apparent in the first week of life and include failure to thrive, relentless vomiting, abdominal distention, and hepatosplenomegaly.

Multiple sulfatase deficiency is typically diagnosed in infancy and childhood. Affected patients have ichthyosis, dysostosis multiplex, demyelination of the central and peripheral nervous systems, and symptoms of MLD due the deficient activity of several sulfatases.

The few reported cases of Farber disease describe the presence of irritability, hoarse cry, and nodular, erythematous swelling of the wrists during the first few weeks of life, with severe motor and mental retardation and death by 2 years of age.

Patients with Schindler disease type 1 have infantile onset of neuroaxonal dystrophy, developmental delay, and rapidly progressive psychomotor deterioration without organomegaly.

Sphingomyelinase deficiency (NPD type A) is a fatal disorder of infancy. Hepatosplenomegaly develops by 6 months of age and development does not progress beyond 12 months. A relentless neurodegenerative course then follows with death by 21 months of age. Other symptoms include impaired pulmonary function due to accumulation of sphingomyelin in reticuloendothelial and pulmonary tissues. With a few rare exceptions, cognition is spared. [16]

Presentation in childhood

GM1 and GM2 gangliosidoses type 2 are juvenile-onset forms.

Sphingomyelinase deficiency (NPD type B) has a variable age of presentation but frequently appears early in childhood when hepatosplenomegaly is detected.

Angiokeratomas that appear in Fabry disease usually occur in childhood and can lead to early diagnosis.

Juvenile forms of MLD have more indolent courses and onset can occur in persons as old as 20 years. This form presents with gait disturbances, mental deterioration, urinary incontinence, and emotional difficulties.

Gaucher disease types 2 and 3 (neuronopathic) and more severe cases of type 1 (non-neuronopathic) present during childhood.

Cholesterol ester storage disease (CESD) is the milder form of Wolman disease, with later onset in childhood, less severe symptoms, and lifespan into adulthood.

Schindler disease type III has milder neurologic manifestations and later onset in childhood.

Patients with classic NPD type C develop normally for the first 2 years of life, followed by the onset of ataxia, grand mal seizures, loss of speech, impaired vertical gaze, and other neurologic manifestations leading to death in mid to late childhood.

Patients with sphingomyelinase deficiency (NPD type B) primarily have visceral involvement, sometimes massive, without neurologic symptoms and often survive into adulthood.

Presentation in adulthood

Adult forms of MLD, which present after the second decade of life, are similar to juvenile forms in clinical manifestations, although emotional difficulties and psychosis are more prominent features. Late-onset and variant forms with onset or diagnosis in adulthood due to milder symptoms include Krabbe, NPD type C, Gaucher disease type 1, and Schindler disease type II (Kanzaki disease).

Type A Niemann-Pick disease is acute and affects children. Type B Niemann-Pick disease has a later onset and carries a better prognosis. Although rare in general and exceedingly rare in adults (6% of cases), Niemann-Pick disease is among the differential diagnoses for isolated splenomegaly and thrombocytopenia. [17]



Patients affected with infantile forms that include neurologic disease have an unrelenting course that leads to death, usually when patients are younger than 5 years.

Most patients with GM1 gangliosidosis are blind and deaf when younger than 2 years. They also have severe neurologic impairment characterized by decerebrate rigidity. Death usually occurs by age 3-4 years.

Infants with Tay-Sachs have a progressive course leading to death within 4 years. [6]

Gaucher disease type 2, which is much less common than type 1 disease, is characterized by a rapid neurodegenerative course with extensive visceral involvement and death within the first 2 years of life.

Gaucher disease type 3 presents with clinical manifestations intermediate to those in types 1 and 2. Patients present in childhood and death occurs by age 10-15 years. Neurologic involvement is present, but occurs later and with decreased severity compared to type 2. Type 3 is further classified into type 3a and 3b based on extent of neurologic involvement and presence of progressive myotonia and dementia (type 3a) or isolated supranuclear gaze palsy (type 3b).

For fucosidosis, Krabbe disease, and Schindler disease, the CNS storage results in a relentless neurodegenerative course with death in childhood.

In metachromatic leukodystrophy (MLD), nystagmus, myoclonic seizures, optic atrophy, and quadriparesis appear first. The disease continues to progress, resulting in death within the first decade of life. The juvenile form has a more indolent course with onset as late as age 20 years.

Clinical presentation and course of sphingomyelinase deficiency (NPD type A) is relatively uniform and characterized by normal appearance at birth with the occasional complication of prolonged jaundice. Hepatosplenomegaly, moderate lymphadenopathy, and psychomotor retardation are evident by age 6 months, followed by regression. With advancing age, loss of motor function and deterioration of intellectual capabilities result in progressive debilitation. In later stages, spasticity and rigidity are evident with affected infants experiencing complete loss of contact with their environment. Death occurs by age 5 years. In contrast to the stereotyped type A phenotype, clinical presentation and course of patients with type B disease are more variable. Most patients are diagnosed in infancy or childhood when enlargement of liver and spleen is detected during a routine physical examination. Survival to adulthood is typical.

Clinical manifestations of Gaucher disease type 1 have a variable age of onset from early childhood to late adulthood, with most symptomatic patients presenting by adolescence. Some patients who have a benign disease course may be discovered during evaluation for other conditions or as part of a routine examination. Patients who exhibit delays secondary to the effects of chronic disease may ultimately achieve normal development and intelligence, with the exception of children with severe growth retardation. Patients typically survive until adulthood.

Patients with Fabry disease have major morbid symptoms resulting from progressive involvement of vascular system. Gradual deterioration of renal function and development of azotemia occur in the second through fourth decades of life, and cardiovascular findings may include hypertension, left ventricular hypertrophy, anginal chest pain, myocardial ischemia or infarction, and congestive heart failure. Death most often results from uremia or vascular disease of heart or brain. Prior to hemodialysis or renal transplantation, mean age of death for affected men was 41 years.


Patient Education

Highly effective preconception carrier-screening programs for populations at risk for Tay-Sachs disease have been in place since 1971, [18] leading to a great reduction in the number of affected children born. Carrier screening of Ashkenazi Jews has been expanded to include several other hereditary disorders found at higher frequency in this group. [19]