Lipid Storage Disorders Clinical Presentation

Updated: Jun 10, 2020
  • Author: Rubia Khalak, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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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.



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. [20] . Retinoblastoma has been noted in an infant with Gaucher disease. [21]

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. [22]

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.


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. [20]

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. [20]

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. [20]

Multiple sulfatase deficiency

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


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.



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). [23]

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.


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).


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.



Myoclonic jerks, developmental regression, vision loss, macrocephaly, seizures, and spasticity are potential complications of Tay-Sachs disease. [6]

Neurodegeneration, hypertonia, fevers of unknown etiology, seizures, vision loss, and developmental regression are all potential complications of Krabbe disease. [6]

Anemia, thrombocytopenia, splenic rupture, hepatosplenomegaly, and bone pain are all potential complications of Gaucher disease. In addition, while the brain is not notably affected, an association between Parkinson disease and Gaucher disease has been demonstrated. [6]

Splenic rupture is a potential complication of sphingomyelinase deficiency (NPD types A and B).

Aspiration that results in neurologic deficits is possible in individuals with infantile forms of lipid storage disorders.

If untreated, Pompe disease can lead to complications such as respiratory insufficiency and heart failure. [6]

Acroparesthesias, stroke, and renal failure may result from Fabry disease. [6]