Lipid Storage Disorders 

Updated: Sep 12, 2017
Author: Tamam N Mohamad, MD, FACC, FSCAI, RVPI; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG 

Overview

Background

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. 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. Other therapeutic options, such as gene therapy and bone marrow transplantation, for selected lipidoses may also result in improved prognosis.

Pathophysiology

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. In particular, 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. In general, storage of any particular substrate in a specific tissue is dependent on the normal distribution of the compound in the body. Thus, various disorders of lipid metabolism have characteristic patterns of organ involvement and clinical history, depending on the particular substrate that is stored.

Mode of Inheritance

All lipid storage disorders are inherited in an autosomal-recessive fashion, except for Fabry disease, which is 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.[6, 7, 8] For many diseases, such as Fabry disease, most kindreds have private mutations.

Epidemiology

Frequency

United States

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

International

Frequency is similar to that in the United States.

Mortality/Morbidity

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

Race

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.[9]

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).

Sex

Each disorder is transmitted as an autosomal recessive trait, except Fabry disease, which is an X-linked recessive trait.

Age

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.[10] 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.[11]

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.[12] 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.[13]

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).

Patient Education

Highly effective preconception carrier-screening programs for populations at risk for Tay-Sachs disease have been in place since 1971,[14] 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.[15]

 

Presentation

History

Progressive lysosomal accumulation of glycosphingolipids results in clinical symptoms in patients with lipid storage disorders.

Storage in CNS can lead to a neurodegenerative course, with loss of skills or failure to attain developmental milestones. Loss of milestones, in any infant or child, should prompt an evaluation for presence of a storage disorder.

Storage in visceral cells can lead to organomegaly, skeletal abnormalities, bone marrow dysfunction, pulmonary infiltration, and other manifestations.

Patterns of abnormalities and clinical history vary among different lipidoses. Symptoms depend on the underlying enzymatic deficiency and the particular substrate that is accumulated.

Physical

Neurologic findings

Accumulation of lipid substrates in CNS leads to neurodegeneration, which frequently manifests as loss of previously attained milestones in an infant or young child. Neurodegeneration is characteristic of many lipidoses.

GM1 gangliosidoses type 1

Infantile forms in newborns present with hepatosplenomegaly, edema, and skin eruptions. They also can present within the first 6 months of life, with developmental arrest followed by progressive psychomotor retardation and tonic-clonic seizures. As many as 50% of affected infants have a cherry-red spot in the macula.

By the end of the first year of life, most patients are blind and deaf, with severe neurologic impairment characterized by decerebrate rigidity. Death usually occurs by age 3-4 years.

GM2 gangliosidoses type 2

These include Tay-Sachs disease and Sandhoff disease. Each results from deficiency of hexosaminidase activity and lysosomal accumulation, particularly in the CNS. Both disorders have been classified into infantile, juvenile, and adult onset.

Patients with infantile forms of Tay-Sachs disease present in infancy with loss of motor skills, increased startle reaction, and presence of a cherry-red spot on slit lamp examination.

Affected infants usually develop normally until about age 5 months, when decreased eye contact and exaggerated startle response to noise is noted. Macrocephaly may develop but is not associated with hydrocephalus. In the second year of life, seizures usually develop and require anticonvulsant therapy. Neurodegeneration is relentless, death occurs by age of 4-5 years.

Juvenile-onset disease presents with ataxia and dysarthria and is not associated with a cherry-red spot of the macula. Clinical manifestations of Sandhoff disease are similar to Tay-Sachs disease. Juvenile forms present with ataxia, dysarthria, and mental deterioration but without visceral enlargement or a macular cherry-red spot.

Gaucher disease type 1

Gaucher disease type 1 is less severe than type 2.

Patients who present in childhood tend to have more pronounced visceral and bony disease manifestations than those who present in adulthood.

Physical findings include growth retardation, delayed puberty, leukopenia, impairment of pulmonary gas exchange, and destruction of vertebral bodies with secondary neurologic complications.[16]

Gaucher disease type 2

This condition is characterized by a rapid neurodegenerative course with extensive visceral involvement and death within first 2 years of life. It presents in infancy with increased tone, strabismus and organomegaly. Failure to thrive and stridor due to laryngospasm are typical.

After several years of psychomotor retrogression, death usually occurs secondary to respiratory compromise.

Sphingomyelinase deficiency (NPD type A)

Clinical presentation and course are relatively uniform and characterized by normal appearance at birth. Hepatosplenomegaly and psychomotor retardation are evident by age 6 months, followed by regression.

With advancing age, loss of motor function and deterioration of intellectual capabilities are progressively debilitating. In later stages, spasticity and rigidity are evident, with affected infants experiencing complete loss of contact with environment.

Sphingomyelinase deficiency (NPD type B)

Patients usually have normal neurologic findings and intelligence, although some have reported cherry-red maculae or haloes and subtle neurologic symptoms (eg, peripheral neuropathy). Skeletal involvement is more prevalent than previously recognized.[17]

NPD type C

The clinical presentation and course is relatively uniform and characterized by normal appearance at birth, hepatosplenomegaly and psychomotor retardation by age 6 months, followed by regression and progressive debilitation. In later stages, spasticity and rigidity are evident, with affected infants experiencing complete loss of contact with the surrounding environment.

Fucosidosis

Wide variability is observed, with severely affected patients presenting in the first year of life. Developmental delay and somatic features are similar to those for mucopolysaccharidoses. These include frontal bossing, hepatosplenomegaly, coarse facial features, and macroglossia.

CNS storage results in a relentless neurodegenerative course with death in childhood.

Fabry disease

The typical presentation is acute, episodic pain crises followed by chronic acroparesthesias.[16]

Schindler disease type 1

This disease is an infantile-onset neuroaxonal dystrophy. Affected infants have normal development for the first months of life, followed by a rapid neurodegenerative course that results in severe psychomotor retardation, cortical blindness, and frequent myoclonic seizures.

Metachromatic leukodystrophy (MLD)

Late infantile forms are most common. Patients usually present when aged 12-18 months with irritability, inability to walk, and hyperextension of knee, causing genu-recurvatum. Deep tendon reflexes are diminished or absent. Gradual muscle wasting, weakness, and hypotonia become evident and lead to a debilitated state. As disease progresses, nystagmus, myoclonic seizures, optic atrophy, and quadriparesis appear. Death occurs within the first decade of life.

Krabbe disease

The infantile form is rapidly progressive and presents in early infancy with irritability, seizures, and hypertonia.

Optic atrophy is evident in the first year of life, and mental development is severely impaired. As disease progresses, optic atrophy and severe developmental delay become apparent.

Death typically occurs within the first 2 years of life because of respiratory complications.[16]

Niemann-Pick disease

Type A: Hypotonia at age 7 months, cognitive progression up to 8 months, cognitive stagnation and regression, loss of deep tendon reflexes, eventual loss of interaction with environment, dysphagia, and aspiration.[16]

Multiple sulfatase deficiency

Affected individuals may display developmental delay and ataxia. Some patients develop rapid neurologic deterioration.

Organomegaly

Organomegaly is caused by storage of lipid substrates in visceral cells and development of symptoms of hypersplenism, which include anemia, leukopenia, and thrombocytopenia.

Splenomegaly can be massive and life threatening; however, removal of spleen should be delayed as long as possible because patients frequently have exacerbation of other symptoms due to loss of the spleen as a reservoir for substrate storage.

Organomegaly is a feature of the infantile form of GM1 gangliosidosis, Sandhoff disease, but not Tay-Sachs disease, Gaucher disease, sphingomyelinase deficiency (NPD types A and B), or fucosidosis. For example, patients with NPD type B disease who undergo splenectomy frequently have worsening of pulmonary symptoms. Hepatosplenomegaly is prominent in childhood, but with increasing linear growth, abdominal protuberance decreases and becomes less conspicuous. In mildly affected patients, splenomegaly may not be noted until adulthood and disease manifestations may be minimal.

In Gaucher disease, splenomegaly is progressive and can become massive.

Skeletal abnormalities

These result from substrate accumulation and are present in several lipidoses.

In GM1 gangliosidosis, skeletal abnormalities are similar to those of mucopolysaccharidoses. There is anterior beaking of vertebrae, enlargement of sella turcica, and thickening of calvaria.

Clinical manifestations of Gaucher disease type 1 include clinically apparent bony involvement. It occurs in more than 20% of patients and can present as bone pain or pathologic fractures. More than half of patients have radiological evidence of skeletal involvement, including an Erlenmeyer flask deformity of the distal femur. In patients with symptomatic bone disease, lytic lesions can develop in long bones including the femur, ribs, and pelvis, and osteosclerosis occurs at an early age. Bone crises with severe pain and swelling can occur.

Patients with Farber disease develop nodular, erythematous swelling of the wrists and at other sites of trauma.

Pulmonary infiltration

Accumulation of substrate in pulmonary tissue occurs in several lipidoses.

Occasionally, patients with Gaucher disease type 1 have pulmonary involvement at time of presentation.

At diagnosis, most patients with sphingomyelinase deficiency (NPD type B) also have evidence of mild pulmonary involvement, usually detected as a diffuse reticular or finely nodular infiltration on chest roentgenogram. In most type B patients, decreased pulmonary diffusion, due to alveolar infiltration, becomes evident in late childhood and progresses with age. Severely affected individuals may experience significant pulmonary compromise by age 15-20 years. Such patients have low pO2 values and dyspnea on exertion. Life-threatening bronchopneumonias may occur and cor pulmonale is described.

Dermatologic findings

Findings include presence of edema and skin eruptions in infantile forms of GM1 gangliosidosis.

Patients with Fabry disease have angiokeratomas that usually appear in childhood and lead to early diagnosis. They increase in size and number with age and range from barely visible to several millimeters in diameter. Lesions are punctate, dark red to blue-black, and flat or slightly raised. They do not blanch with pressure and larger ones may show slight hyperkeratosis. Lesions are most dense between umbilicus and knees, in "bathing trunk area," but may occur anywhere, including oral mucosa. Hips, thighs, buttocks, umbilicus, lower abdomen, scrotum, and glans penis are common sites, and there is a tendency toward bilateral symmetry. Variants without skin lesions are described.

Angiokeratoma are also found in patients with Schindler disease, fucosidosis, and GM1 gangliosidosis.

Ichthyosis and dry, scaly, itchy skin occurs in patients with multiple sulfatase deficiency and the congenital form of Gaucher disease.

Painful crises

Pain is the most debilitating symptom of Fabry disease in childhood and adolescence. Fabry crises last from minutes to several days. They consist of agonizing, burning pain in hands, feet, and proximal extremities. Pains are usually associated with exercise, fatigue, and fever. Painful acroparesthesias usually become less frequent in the third to fourth decades of life, although in some men they may become more frequent and severe. Attacks of abdominal or flank pain may simulate appendicitis or renal colic.

Vascular disease

With increasing age, major morbid symptoms of Fabry disease result from progressive involvement of vascular system. Early in disease, casts, red cells, and lipid inclusions, with characteristic birefringent "Maltese crosses," appear in urinary sediment.

Proteinuria, isosthenuria, gradual deterioration of renal function, and development of azotemia occur in the second through fourth decades of life. Cardiovascular findings may include hypertension, left ventricular hypertrophy, anginal chest pain, myocardial ischemia or infarction, and congestive heart failure. Mitral insufficiency is the most common valvular lesion. Abnormal electrocardiographic and echocardiographic findings are common. Cerebrovascular manifestations result primarily from multifocal small vessel involvement.

Other features are chronic bronchitis and dyspnea, lymphedema of legs without hypoproteinemia, episodic diarrhea, osteoporosis, retarded growth, and delayed puberty. Death 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.

Atypical male variants with residual alpha -galactosidase A activity that are asymptomatic or produce mild symptoms have been described. More recently, several patients with late-onset, isolated cardiac or cardiopulmonary disease have been reported. These patients do not have early classic manifestations. These cardiac variants include cardiomegaly, usually involving left ventricular wall, interventricular septum and electrocardiographic abnormalities consistent with a cardiomyopathy. Others have had hypertrophic cardiomyopathy and myocardial infarction.

Abdominal examination

This examination may reveal hepatosplenomegaly. Marked splenomegaly is sometimes overlooked when the spleen edge is in the pelvis, and abdominal contour also should be assessed. Hepatosplenomegaly may be evident at birth in neonates with GM1 gangliosidosis, sphingomyelinase deficiency (NPD type A), and Sandhoff disease.

Ophthalmologic examination

Ophthalmologic examination reveals findings in several lipidoses. A cherry-red macula can be identified by slit lamp examination in patients with GM1 gangliosidosis, GM2 gangliosidosis (Tay-Sachs disease and Sandhoff disease), Farber disease, and sphingomyelinase deficiency (NPD types A and B). The cherry red spot is the only normal part of the retina and is accentuated by the deposition of gangliosides in the surrounding retinal ganglion cells.

Neurologic examination

Neurologic examination documents presence and extent of neuropathology.

Causes

Each disorder results from deficiency of a specific enzymatic activity. With exception of Fabry disease, which is X-linked, each is inherited in an autosomal recessive fashion (see the image below).

Autosomal recessive inheritance pattern. Autosomal recessive inheritance pattern.

GM1 gangliosidoses

Type 1 disease frequently presents in early infancy, but patients with type 2 have been described with juvenile onset.

Both forms result from deficient activity of beta-galactosidase, a lysosomal enzyme encoded on chromosome 3 (band 3p21.33).

Although it is characterized by pathologic accumulation of GM1 gangliosides in the lysosomes of both neural and visceral cells, its accumulation is most marked in the brain. In addition, keratan sulfate, a mucopolysaccharide, accumulates in liver and is excreted in urine.

GM2 gangliosidoses

Tay-Sachs disease and Sandhoff disease both result from deficiency of hexosaminidase activity and lysosomal accumulation of GM2 gangliosides, particularly in central nervous system.

Both disorders have been classified into infantile, juvenile, and adult onset, with chronic forms based on age of onset and clinical features.

Hexosaminidase occurs as two isozymes, hexosaminidase A, which is composed of a and b subunits, and hexosaminidase B, which has two b subunits. Hexosaminidase A deficiency results from mutations in the a subunit and causes Tay-Sachs disease; mutations in the b subunit gene result in deficiency of both hexosaminidase A and B and cause Sandhoff disease.

Complementary DNA (cDNA) for both a and b subunits of hexosaminidase have been isolated and genes cloned. The a subunit is encoded by the HEXA gene on 15q23-q24 and the b subunit by the HEXB gene on 15q13. To date, more than 50 mutations have been identified, most associated with infantile forms of the disease. Three mutations account for more than 95% of mutant alleles among Ashkenazi Jewish carriers of Tay-Sachs disease, including 1 allele associated with the adult-onset form. Mutations that cause the subacute or chronic forms are associated with higher residual enzymatic activity levels, which correlate with decreased severity of symptoms.

A small number of patients accumulate GM2 gangliosides despite the presence of increased amounts of hexosaminidase A and B activity. These patients demonstrate complete absence of GM2 activator protein, which is encoded by the GM2A gene on 5q31.3-q33.1, and is necessary for the interaction of lipid substrates with the water-soluble enzyme hexosaminidase A.

Gaucher disease

Three clinical subtypes are delineated by the presence and progression of neurologic manifestations. All three subtypes are inherited as autosomal recessive traits

  • Type 1 - Adult, non-neuronopathic form
  • Type 2 - Infantile, acute neuronopathic form
  • Type 3 - Juvenile, Norrbotten form

Type 1, which accounts for 99% of cases, has a striking Ashkenazi Jewish predilection with an incidence of about 1 in 1000 and a carrier frequency of 1 in 18.

Gaucher disease results from deficient activity of lysosomal hydrolase, acid beta-glucosidase, which is encoded by a gene on chromosome 1 (q21 to q31). Enzymatic defects result in accumulation of undegraded glycolipid substrates, particularly glucosylceramide, in cells of reticuloendothelial system. This progressive deposition results in infiltration of bone marrow, progressive hepatosplenomegaly, and skeletal complications.

Acid beta-glucosidase cDNA has been cloned and mutant alleles have been identified including missense, insertion, and deletion mutations. Four of these mutations, N370S, L444P, 84insG, and IVS2, account for 90-95% of mutant alleles among Ashkenazi Jewish patients permitting screening for this disorder in this population.

Genotype-phenotype correlations have been noted, providing molecular basis for clinical heterogeneity seen in Gaucher disease type 1, which has a wide range of severity and age of onset. For example, patients who are homozygous for N370S mutations tend to have later onset of disease manifestations with a more indolent course than patients with one copy of N370S and another common allele.

Sphingomyelinase deficiency (NPD types A and B)

These disorders result from deficient activity of sphingomyelinase, a lysosomal enzyme encoded by a gene located on chromosome 11 (11p15.1 to p15.4). Enzymatic defects result in pathologic accumulation of sphingomyelin, a ceramide phospholipid, and other lipids in monocyte-macrophage systems, the primary site of pathology.

Progressive deposition of sphingomyelin in central nervous system results in a neurodegenerative course, seen in type A and in systemic disease manifestations of type B, including progressive lung disease. Complete sphingomyelinase genomic regions have been isolated and sequenced, and a number of mutations that cause NPD types A and B are identified, including single base substitutions and small deletions.

NPD type C

This disorder results from the egress of lipids, and particularly cholesterol, from late endosomes or lysosomes. Most cases of NPD type C result from mutations in the NPC1 gene on 18q11-q12. A small number of cases result from mutations in the NPC2 gene on chromosome 14q24.3. The NPC1 and NPC2 genes provide instructions for producing protein that are involved in the movement of cholesterol and lipids within cells. The term Niemann-Pick disease type D is no longer used; it describes the Nova Scotian variant which results from mutations of the NPC1 gene. Fabry disease

This disorder results from deficient activity of alpha-galactosidase A, a lysosomal enzyme encoded by a gene located on long arm of chromosome X (Xq22).[18]

Enzymatic defects lead to systemic accumulation of neutral glycosphingolipids, primarily globotriaosylceramide (GL-3), particularly in plasma and lysosomes of vascular endothelial and smooth muscle cells.

Progressive vascular glycosphingolipid deposition in affected males results in ischemia and infarction, which leads to major disease manifestations. Affected males who have type B or AB blood have a more severe disease course, since blood group B substance also accumulates, as it is normally degraded by alpha-galactosidase A.

Both cDNA and genomic sequences, encoding alpha-galactosidase A, are isolated and characterized. Molecular studies have identified a variety of different mutations in alpha-galactosidase A gene that are responsible for this lysosomal storage disease, including amino acid substitutions, gene rearrangements and messenger RNA (mRNA) splicing defects.

Fucosidosis

This rare, autosomal recessive disorder results from deficient activity of alpha-fucosidase and accumulation of fucose containing glycosphingolipids, glycoproteins, and oligosaccharides in lysosomes of the liver, brain, and other organs.

The alpha-fucosidase gene is localized to chromosome 1 (band 1p24), and specific mutations are been identified.

Schindler disease

This autosomal recessive neurodegenerative disorder results from deficient activity of alpha-N -acetylgalactosaminidase, and accumulation of sialylated, asialio-glycopeptides, and oligosaccharides.

The gene for the enzyme is cloned and mapped to chromosome 22 (bands 22q13.1-13.2).

MLD

This is an autosomal recessive white matter disease caused by deficiency of arylsulfatase A (ASA), which is required for hydrolysis of sulfated glycosphingolipids. Another form is caused by a deficiency of a sphingolipid activator protein (SAP-1), a protein required for formation of substrate-enzyme complex.

Deficiency of enzymatic activity results in white matter storage of sulfated glycosphingolipids, which then leads to demyelination and a neurodegenerative course.

The ASA gene is localized to chromosome band (22q13.31-qter) and specific mutations are identified. They fall into two groups, which correlate with disease severity.

Multiple sulfatase deficiency

This is an autosomal recessive disorder resulting from mutations in the sulfatase-modifying factor-1 gene (SUMF1) localized to chromosome 3p26. The activities of all sulfatases are impaired due to a defect in their post-translational modification by the protein encoded by SUMF1.

Sulfatides, mucopolysaccharides, steroid sulfates, and gangliosides accumulate in cerebral cortex and visceral tissues. This results in a clinical phenotype with features of leukodystrophy and mucopolysaccharidoses.

Krabbe disease

This autosomal recessive, fatal disorder of infancy is also known as globoid cell leukodystrophy.

It results from deficiency of enzymatic activity, galactocerebroside, and white matter accumulation of galactosylceramide, which is normally found exclusively in myelin sheath.

The galactocerebroside gene is localized to chromosome 14 (band14q31) and specific disease-causing mutations have been identified.

Farber disease

This autosomal recessive disorder results from deficiency of lysosomal enzyme, ceramidase, and accumulation of ceramide in various tissues, especially the joints.

Ceramidase is encoded by the gene ASAH localized to chromosome 8p22-p21.3.

Schindler disease

The 3 forms of Schindler disease result from deficiency in the alpha-N-acetylgalactosaminidase encoded by the NAGA gene on 22q11.

Wolman disease and CESD both result from deficiency of lysosomal acid lipase, an acid cholesteryl ester hydrolase encoded by the LIPA gene on chromosome 10q24-q25. Wolman patients have no enzyme activity, and patients with the milder CESD demonstrate residual enzyme activity.

 

DDx

Differential Diagnoses

 

Workup

Laboratory Studies

Diagnosis of lipid storage disorders depends on demonstration of specific enzymatic deficiency in peripheral blood leukocytes or cultured fibroblasts.

Imaging Studies

Brain imaging

Brain imaging studies are frequently obtained during evaluation of infants and children with developmental delay or retrogression. However, they are not essential to diagnosis, which depends on demonstration of specific enzymatic deficiency in peripheral blood leukocytes or cultured fibroblasts.

Findings vary with different disorders.

Skeletal radiography

In GM1 gangliosidosis, skeletal abnormalities are similar to those associated with mucopolysaccharidoses. They include anterior beaking of vertebrae, enlargement of sella-turcica and thickening of calvaria.

In Gaucher disease type 1, more than half of patients have radiological evidence of skeletal involvement including an Erlenmeyer flask deformity of the distal femur.

In patients with symptomatic bone disease, lytic lesions can develop in long bones like the femur, ribs, and pelvis. Osteosclerosis may be evident at an early age.

Chest radiography

Patients with sphingomyelinase deficiency (NPD types A and B) typically have fine reticular-nodular infiltrates.

Findings are not associated with clinical pulmonary disease in young patients but can be accompanied by pulmonary dysfunction later in life.

Abdominal radiography

Patients with Wolman disease typically have calcification of the adrenal noted on abdominal radiograph.

Other Tests

Genetic testing

For most disorders, carrier identification and prenatal diagnosis are available. Making a specific diagnosis in an affected child is important in order to provide genetic counseling.

More recently, investigators have focused efforts on determining molecular basis. These studies have resulted in identification of specific disease-causing mutations, allowing for improved diagnosis, prenatal diagnosis and carrier identification.

For some disorders (eg, Gaucher disease), it is possible to make genotype-phenotype correlations that predict disease severity and allow more precise genetic counseling. Thus, determination of genotype is recommended when possible.[19]

Disease-specific molecular analysis

Fabry disease

Most pathogenic GLA mutations are “private” and nonrecurrent; more than 300 mutations have been described. In general, mutations that result in prematurely truncated α-gal A, which are approximately 45% of those reported, result in a classic Fabry phenotype in a hemizygote.[20] Missense mutations that result in very low leukocyte α-gal A levels also result in a classic phenotype.

Gaucher disease

Sequencing of the GBA gene is the definitive method in the diagnosis of Gaucher disease. Within the Ashkenazi Jewish population, four common mutations (p.N370S, p.L444P, c.84insG, and c.IVS2 1) account for 90% of the disease-causing alleles; these same mutations account for 50%-60% of disease-causing alleles in non-Jewish patients.[21]

Krabbe disease

The diagnosis can be confirmed via molecular analysis of the GALC gene.[22] Genotype-phenotype correlation is limited and may be possible only if the clinical impact of a particular genotype is known in a larger set of patients with Krabbe disease.

Metachromatic leukodystrophy

The diagnosis of MLD can also be confirmed with molecular genetic analysis of the ARSA gene. To date, more than 140 disease-relevant mutations have been identified. Several recurrent mutations account for up to 60% of disease-relevant alleles in certain populations.[23, 24] ARSA mutations characterized in more detail have been divided into two groups: (1) “null alleles” such as c.459 1g>a (25% of disease alleles) and c.1204 1g>a, which result in complete loss of enzymatic activity, and (2) “R alleles” such as p.P426L (25% of disease alleles) and p.I179S (12.5% of disease alleles), which allow the synthesis of ARSA enzyme with residual catalytic activity of up to 5% of normal.[25]

Niemann-Pick disease, types A and B

Sequencing of the SMPD1 gene is the most reliable method to confirm a diagnosis of NPD. In the Ashkenazi Jewish population, three founder mutations, p.R496L, p.L302P, and fsP330, account for more than 95% of mutant alleles and are associated with the NPA phenotype.[26]

Histologic Findings

Examination of tissues reveals pathologic storage of substrate in many tissues including liver, bone marrow and, for some disorders, the brain.

Gaucher disease has a pathologic hallmark, which is the Gaucher cell in the reticuloendothelial system, particularly in bone marrow. Cells, which are 20-100 µm in diameter, have a wrinkled-paper appearance resulting from presence of intracytoplasmic inclusions of substrate. Cytoplasm reacts strongly positive with periodic acid-Schiff stain. Presence in bone marrow and organ tissue specimens is highly suggestive of Gaucher disease, although it can be found in patients with granulocytic leukemia and myeloma.

Sphingomyelinase deficiency (NPD types A and B) and NPD type C have a pathological hallmark, which is histochemically lipid-laden foam cells, often called Niemann-Pick cells.[5] These cells can be readily distinguished from Gaucher cells by their histologic and histochemical characteristics. They are not pathognomonic for NPD because histologically similar cells are found in patients with Wolman disease, cholesterol ester storage disease, lipoprotein lipase deficiency, and GM1 gangliosidosis type 2.

 

Treatment

Medical Care

Except for Gaucher and Fabry disease, treatment options are limited in patients with lipid storage disorders. Primarily, treatment is directed at symptomatic relief. No specific treatment is available for either form of GM1 gangliosidosis, Tay-Sachs disease, Sandhoff disease, fucosidosis, Krabbe disease or Schindler disease. These disorders pursue a relentless course, leading to death.

Gaucher disease

When possible, patients with Gaucher disease should be managed by a multidisciplinary team at a comprehensive Gaucher Center.

Enzyme replacement therapy (ERT) with recombinant beta-glucocerebrosidase (Cerezyme, Genzyme, Cambridge, Mass; VPRIV, Shire, Cambridge, Mass) is available for the treatment of symptomatic patients with Gaucher disease type 1.[27]

Regular intravenous infusions of recombinant enzyme have been shown to clear the stored substrate GL1, and thus reverse hematologic and liver/spleen involvement. Although skeletal disease is slower to respond, early treatment may be efficacious in normalizing linear growth and bone morphology in affected children.

Although enzyme replacement does not alter the neurologic progression of patients with Gaucher disease types 2 and 3, it has been used in selected patients as a palliative measure, particularly in patients with severe visceral involvement. Individuals with severe visceral symptoms due to Gaucher disease type 3 often benefit from bone marrow transplantation. In some individuals, a combination approach using both enzyme replacement therapy and bone marrow transplant has been used. However, the use of bone marrow transplant is limited due to the associated morbidity and mortality.

Substrate reduction therapy (SRT) is a new approach in which glycolipid accumulation is counteracted, not by replacing the deficient enzyme, but by reducing the substrate level to better balance residual activity of the deficient enzyme.

​Miglustat was approved in 2003 as a second-line monotherapy in adults with mild-to-moderate type 1 Gaucher disease for whom enzyme replacement therapy is not a therapeutic option.

Eliglustat was approved in August 2014 as first-line treatment for the long-term treatment of adults with Gaucher disease type 1. The dose of eliglustat is determined by establishing the patient’s CYP2D6 phenotype (ie, extensive metabolizers [EM], intermediate metabolizers [IM], or poor metabolizers [PM]). Approval was based on efficacy data from 2 positive phase 3 studies involving 199 patients. One study involved patients new to therapy (trial 1), and the other involved patients switching from approved enzyme replacement therapies (trial 2). Efficacy data from 4 years of the Cerdelga phase 2 study also contributed to the approval. Improvements in study participants were observed in spleen size, platelet levels, hemoglobin levels, and liver volume, and noninferiority to enzyme replacement therapy (imiglucerase) was established in trial 2.[28]

SRT was shown to be effective concerning hepatosplenomegaly, anemia, and thrombocytopenia; by contrast, improvements of bone disease were delayed and limited.[16]

Studies are currently underway to investigate the use of miglustat for the treatment of infantile-onset GM2 gangliosidosis and childhood Niemann-Pick type C.

A case study of combined ERT and SRT revealed improvement of neurological signs in symptomatic patients with Gaucher disease type 3 and, over a 3-year observation period, demonstrated prevention of further neurological manifestations in a young child whose only initial manifestation was disturbed saccadic eye movements[16]

Fabry disease

Until recently, treatment for Fabry disease has been nonspecific and limited to supportive care. These measures included the use of phenytoin and carbamazepine, which have been shown to decrease the frequency and severity of the chronic acroparesthesias and the periodic crises of excruciating pain. Renal transplantation and long-term hemodialysis also have become life-saving procedures for patients with renal failure. Statins and aspirin have been used to reduce thromboembolic risk factors. Angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers have been used to treat proteinuria and hypertension.

Enzyme replacement therapy with recombinant alpha-galactosidase A (Replagal, TKT Corporation, Cambridge, Mass; Fabrazyme, Genzyme Corporation, Cambridge, Mass) is available. Fabrazyme is the only ERT for Fabry disease approved by the FDA.[27] Data from clinical trials show a decrease in GL-3 levels following enzyme replacement therapy, reversal in lipid tissue storage, and stabilized or improved renal and cardiac function. Subjective reduction or relief from neuropathic pain has been documented, in addition to a decrease in the long-term use of neuropathic pain medication.

Recent advances in recombinant enzyme replacement, bone marrow transplantation, gene transfer, substrate reduction, and chaperone-mediated therapy provide great hope in potentially treating other lipid storage disorders.

Consultations

Patients thought to have a lipidosis should have an evaluation with a clinical geneticist.

Neurologic consultation also is indicated.

Patients with Fabry disease should have a cardiac evaluation.

Patients with Gaucher disease type 1 and sphingomyelinase deficiency (NPD type B) should have pulmonary consultations.

Diet

No specific dietary manipulations have an effect on the disease course. In particular, restriction of lipids is of no benefit.

Patients with sphingomyelinase deficiency (NPD) have elevated total cholesterol, although effects of dietary restriction of cholesterol have not been demonstrated.

Activity

Gaucher disease and patients with sphingomyelinase deficiency (NPD types A and B) with organomegaly should avoid contact sports and seek immediate medical attention for trauma. If their platelet counts drop precipitously secondary to hypersplenism, they are at risk for both splenic rupture and intracranial bleeding.

 

Guidelines

Guidelines Summary

Family-based studies and new technologies for newborn screening have enabled the diagnosis of lysosomal storage disorders (LSDs) in presymptomatic individuals. Although significant limitations were faced in composing the guidelines, they still provide a framework for the initial evaluation and management of several disorders.

LSDs are rare and complex. Natural history data for most conditions are limited, and scant long-term follow-up data are available on the efficacy of different therapeutic approaches. The evidence bases for these rare disorders are poorly organized and statistically weak. Efforts to capture diagnostic and long-term follow-up data to improve understanding are urgently needed. Biospecimen repositories are needed for future research studies of biomarkers and modifier genes. In this regard, the creation of ACMG/NIH Newborn Screening Translational Research Network301 is timely and will play an important role in improving the knowledge base in the coming years.

Patients with LSDs often need multidisciplinary care that should ideally be provided through a team approach, including medical geneticists, hematologists, cardiologists, neurologists, ophthalmologists, and anesthesiologists, among other specialists. As newborn screening for LSDs becomes more widespread, there will be an increasing need for physicians trained in the care of these patients, particularly biochemical geneticists.

Laboratories used for enzymology and molecular diagnostics should be experienced and of high quality as evidenced by participation in quality assurance and proficiency testing programs. They should be capable of providing rapid turn-around of results (local laboratories are desirable).[16]

 

Medication

Medication Summary

Recombinant enzymes may be used to treat Gaucher and Fabry disease. Glucosylceramide synthase inhibitors are used for adults with type 1 Gaucher disease. For more information, see the Medscape Reference articles Gaucher Disease and Fabry Disease.

Enzyme replacement therapies

Class Summary

Specific recombinant enzymes are available to treat Gaucher and Fabry Disease.

Imiglucerase is approved for children aged 2 years or older for Gaucher disease. Velaglucerase and taliglucerase are both approved for children aged 4 years or older for Gaucher disease.

Imiglucerase (Cerezyme)

A recombinant-derived analog of beta-glucocerebrosidase. It is an enzyme used for replacement therapy in type 1 Gaucher disease. Catalyzes hydrolytic cleavage of glucocerebroside (a glycoprotein) to glucose and ceramide within the lysosomes of phagocytic cells in the reticuloendothelial system. This normally is a catabolic pathway of membrane lipids derived from hematologic cell turnover. A deficiency of this enzyme results in accumulation of glucocerebroside within tissue macrophages, which become engorged with the glycolipid. Treatment improves anemia and thrombocytopenia, reduces spleen and liver size, and decreases cachexia.

Velaglucerase alfa (VPRIV)

Hydrolytic lysosomal glucocerebroside-specific enzyme indicated for long-term enzyme replacement therapy for type 1 Gaucher disease. Improves symptoms associated with the disease, including anemia, thrombocytopenia, increased spleen and liver size, and cachexia.

Taliglucerase alfa (Elelyso)

Taliglucerase is a plant-based recombinant enzyme for type I Gaucher disease. It catalyzes the hydrolysis of glucocerebroside to glucose and ceramide, which results in reduced spleen and liver enlargement and increased RBCs and platelets.

Agalsidase alfa (Fabrazyme, Replagal)

Recombinant form of the human enzyme alpha-galactosidase A, levels of which are deficient in Fabry disease. Data from clinical trials show a decrease in GL-3 levels following enzyme replacement, reversal in lipid tissue storage, stabilized or improved renal and cardiac function, and reduced or relief from neuropathic pain. Following enzyme replacement, the long-term use of neuropathic pain medication has been reduced.

Both agalsidase beta and alpha forms are designated as orphan drugs. Agalsidase beta (Fabrazyme) is manufactured by Genzyme Corporation (Cambridge, Mass) and is based on expression of the human GLA gene in CHO cells.

Agalsidase alfa (Replagal) is manufactured by Transkaryotic Therapies, Inc (Cambridge, Mass) and is based on activation of the human GLA gene expression in human (skin) fibroblasts.

Glucosylceramide Synthase Inhibitors

Class Summary

These agents are indicated for type 1 Gaucher disease. These agents inhibit the enzyme glucosylceramide synthase, the initial enzyme in a series of reactions that result in the synthesis of most glycosphingolipids, including glucocerebroside. The goal of treatment is to reduce the rate of glucocerebroside biosynthesis so that the amount is reduced to a level that allows the residual activity of the deficient glucocerebrosidase enzyme to be more effective (substrate reduction therapy).

Eliglustat (Cerdelga)

Eliglustat is a specific inhibitor of glucosylceramide synthase, thereby reducing production of glucosylceramide. It is indicated for the long-term treatment of adults with Gaucher disease type 1 who are CYP2D6 extensive metabolizers (EM), intermediate metabolizers (IM), or poor metabolizers (PM) as detected by an FDA-cleared test for phenotype. Dosage is based on establishing the patient's CYP2D6 metabolizer status.

Miglustat (Zavesca)

Indicated for type 1 Gaucher disease in patients in whom ERT is not a therapeutic option. Reduces GSL production by inhibiting glucosylceramide synthase. Reduces spleen and liver volume and increases hemoglobin and platelet counts.

 

Follow-up

Further Outpatient Care

Fabry disease

Baseline diagnostic studies (electrocardiography, echocardiogram, ophthalmologic examination, renal function tests, plasma and/or urine GL-3) should be obtained. Affected family members identified during screening should also undergo identical evaluations; adults should also undergo additional testing as recommended.

Infants with Fabry disease should be seen by a metabolic specialist at 6-month intervals and monitored for the onset of Fabry symptoms.[16]

Gaucher disease

Evaluations for anemia/thrombocytopenia, hepatosplenomegaly, and bony involvement should be performed.

In patients who are predicted to have neuronopathic Gaucher disease and in patients whose genotype cannot accurately predict the phenotype, the degree of neurological impairment should also be assessed.

Gaucher biomarker and anti-GBA antibody levels should be measured before initiation of ERT.

Infants should be monitored at regular intervals (at least quarterly) to assess response to treatment and development.[16]

Niemann-Pick disease

Infants with Niemann-Pick disease should undergo dilated funduscopic examination performed by an ophthalmologist.

Plain chest radiography abdominal ultrasonography should be performed at regular intervals to document the extent of pulmonary involvement and hepatosplenomegaly.

The metabolic physician should evaluate the infant on a monthly basis, documenting weight gain, linear growth, pulse oximetry, and developmental progression.

Infants need evaluation and regular follow-up by a neurologist and pulmonologist as the disorder progresses. Because no curative treatment currently exists, only symptomatic and supportive care can be provided.

Lipid-lowering drugs (eg, statins) are ineffective.[16]

Complications

Potential complications are as follows:

  • Splenic rupture in Gaucher disease and sphingomyelinase deficiency (NPD types A and B)
  • Aspiration that results in neurologic deficits possible in patients affected with infantile forms of lipid storage disorders
  • Renal failure in Fabry disease

Prognosis

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 with death at age 4-5 years.

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.