Approach

The lysosomal storage diseases (LSDs) are a clinically diverse group of disorders and the differential diagnosis is vast. The different LSDs are easily confused with each other; consultant referral at an early stage is important.

Treatment is now available for many LSDs, and hence there is an increasing emphasis on the need for early diagnosis and intervention before significant organ damage has occurred.

Delay in diagnosis is a significant issue for all LSDs. A diagnosis of an LSD should be considered in cases with relevant clinical features indicative of an LSD.

LSDs are inherited disorders and, therefore, a detailed family history should be taken. The help of a clinical geneticist should be sought if family screening is to be undertaken.

History and examination

Clinical and laboratory diagnosis should be integrated and the possibility of an LSD should be considered in cases with relevant clinical features indicative of an LSD.

Gaucher disease

  • Type 1 Gaucher disease typically presents in adults with thrombocytopenia and/or splenomegaly.[30] Fatigue and hepatomegaly are frequent symptoms.[30] It is more common in Ashkenazi Jews.[10][11]

  • Gaucher disease (severe type 2, acute neuronopathic) presents in neonates with failure to thrive, feeding difficulty, hepatosplenomegaly, abnormal skin, seizures, and gross central nervous system disease; these patients typically die in the first few months of life.[30]

  • Type 3 (chronic neuronopathic) presents mostly between the ages of 10 and 20 years with an eye movement disorder, hepatosplenomegaly, and bone pain. Seizures, cataracts, cardiac valve disease, joint contractures, and depression may also occur.[41][42][Figure caption and citation for the preceding image starts]: Skeletal magnetic resonance imaging in type 1 Gaucher's disease showing widespread skeletal deposition of substrate with associated necrosis and bony infarction. There is avascular necrosis of the head of the femur (arrow)From the personal collection of Professor Atul B. Mehta [Citation ends].com.bmj.content.model.Caption@70f2a108

  • Parkinsonism can occur in association with adult Gaucher disease.[30]

  • There may be a non-specific history of recurrent respiratory tract infections.

  • Eye movement disorders, such as delayed initiation of horizontal saccades, are common in infantile disease.[43]

Fabry disease

  • Fabry disease is often missed in childhood.[38]

  • Typical presenting features include burning limb pain, fever, abdominal pain, and diarrhoea.[16][17][44]​​​​ It may present in adulthood with transient ischaemic attack or stroke, cardiac enlargement (hypertrophic cardiomyopathy), and chronic renal failure.[31]

  • Corneal clouding, cataracts, hypertension, hypothyroidism, valvular cardiac disease, hearing impairments/sudden deafness, and depression may occur.[12]

  • Cutaneous lesions are also seen.[31] Examples include angiokeratoma and telangiectasia. [Figure caption and citation for the preceding image starts]: Cutaneous lesions in Fabry's disease: (A) flank, (B) genitals, (C) umbilicus, (D) lower back, (E) toesOrteu CH, Jansen T, Lidove O, et al. Fabry disease and the skin: data from FOS, the Fabry Outcome Survey. Br J Dermatol. 2007 Aug;157(2):331-7; used with permission [Citation ends].com.bmj.content.model.Caption@5d6dbafc[Figure caption and citation for the preceding image starts]: Cutaneous lesions in Fabry's disease: (A) palms, (B) lips, (C) labial mucosaOrteu CH, Jansen T, Lidove O, et al. Fabry disease and the skin: data from FOS, the Fabry Outcome Survey. Br J Dermatol. 2007 Aug;157(2):331-7; used with permission [Citation ends].com.bmj.content.model.Caption@656ee29

  • Oral symptoms include dental agenesis, supernumerary teeth, and hyposalivation.[45]

  • Heterozygous females are frequently (>75% of cases) symptomatic.[36][37][38][39][40]

Mucopolysaccharidosis (severe forms of MPS I, II, and others)

  • MPS typically presents in the neonatal period or in infancy/early childhood with abnormal facies, large head circumference, hydrocephalus, enlargement of the tongue, hepatosplenomegaly, dysostosis and spinal malformation (including gibbus), corneal clouding, neurodevelopmental delay, joint deformity, and failure to thrive.[5][46]

  • Cardiac valve abnormalities, shortness of breath, difficulties in breathing and swallowing also occur.[47] Cognitive impairment is common.

  • Children with MPS III may present with symptoms of autism spectrum disorder, including language delay and impaired social communication. Symptoms typically emerge at an older age than idiopathic autism spectrum disorder, following a period of normal development.[48]

  • MPS can also present as recurrent non-immune hydrops fetalis.[1]

  • There may be a non-specific history of recurrent respiratory tract infections.[49]

  • Attenuated variants present later (typically age 5 to 15 years), but could present in patients >30 years old with joint deformity, carpal tunnel syndrome, hepatosplenomegaly, compression neuropathy, heart and lung disease, and hearing impairment/sudden deafness.

Pompe disease

  • Also known as glycogen storage disease type II, the classic infantile form presents in the first few weeks or months of life as feeding difficulties, failure to thrive, hypotonia, and cardiac enlargement with abnormal ECG and echocardiographic changes of hypertrophic cardiomyopathy.[35][50][51]

  • Tongue enlargement, hepatomegaly, and hearing impairment may occur.[45]

  • Death usually occurs within the first year of life without specific therapy.

  • Classic feature of Pompe disease is fatigability, found at all ages (e.g., feeding difficulties in infancy, poor sporting performance in childhood, respiratory difficulties, falls, difficulty climbing stairs in adulthood).

  • There may be a non-specific history of recurrent respiratory tract infections.[52]

  • Later-onset attenuated variants present aged 10 to 20 years (may be as late as >30 years) with symptoms of skeletal muscle dysfunction: difficulty climbing stairs, rising from a sitting/lying position, respiratory difficulty, fatigue, joint contracture, and depression.[53]

Niemann-Pick disease

  • Presentation will depend on type: hepatosplenomegaly in types A, B, and C; neurodevelopmental delay in type A; and progressive dementia, ataxia or gait disturbance, or hearing problems in type C.[54][55]

  • Psychiatric symptoms precede physical symptoms in 75% of patients with type C. Cognitive, memory, and instrumental impairments are the most common psychiatric symptoms, followed by psychosis, altered behaviour, and mood disorders.[55]

  • Eye movement disorders such as vertical gaze palsies are common in type C.[54]

  • Type A is more common in Ashkenazi Jews.

Tay-Sachs disease

  • In the infantile form, this presents with hyperacusis and a macular 'cherry red spot'.[56]

  • The juvenile form presents with optic atrophy (retinitis pigmentosa), progressive dementia and ataxia or gait disturbance, failure to thrive, joint contracture, and depression.

  • Psychosis, ataxia, dystonia, and cataplexy in young adults may be presenting features of neurodegeneration.[57][58]

  • Eye movement disorders such as vertical gaze palsies are common.

  • It is more common in Ashkenazi Jews.

Confirmatory diagnosis is by testing the activity of the specific enzyme, or by requesting gene sequence and family studies. It is generally appropriate for generalists to consider the diagnosis and to screen for it; however, early consultant referral is recommended to define the specific diagnosis or to exclude LSDs if there is any doubt.

Enzyme assay

This is the key investigation for most LSDs. It may be appropriate to request assay of a single enzyme (e.g., glucocerebrosidase if Gaucher disease is suspected), or of a group of enzymes (e.g., requesting leukocyte enzyme assay as a screen for MPS disorders). In the X-linked LSDs (e.g., Fabry, MPS II), heterozygous females can often have values that are borderline, as about half of their cells will be normal.

It is also important to request plasma enzyme activity as well as leukocyte activity, as some mutations are associated with disturbed export of enzyme leading to lowered plasma activity with normal leukocyte activity.

Consultant and accredited laboratories should be used as the assays are technically complex and refinements are constantly being made (e.g., to improve diagnosis of Pompe disease).[59] Guidelines for the laboratory diagnosis of MPS VI are now available.[60] These guidelines recommend caution in using urinary glycosaminoglycan (GAG) analysis alone in confirming the diagnosis of MPS VI, and acknowledge enzyme activity analysis as a critical component of diagnosis.

Substrate levels

Increased levels of the appropriate substrate will be detectable in the presence of an enzyme deficiency. Thus, urinary GAGs are elevated in the MPS disorders, and urinary oligosaccharides are elevated in GM1 and GM2 gangliosidosis.[61] Urinary levels of globotriaosylceramide (Gb3) are elevated in Fabry disease. Urinary glucose tetrasaccharide (Glc4) and plasma glucose tetrasaccharide (Hex4) levels are increased in patients with Pompe disease.[62] Plasma levels of glucosylceramide are elevated in Gaucher disease.

DNA analysis

Genetic studies can provide confirmation of the diagnosis for most LSDs.

In Gaucher disease, there are 6 common mutations seen among Ashkenazi Jews, and a small number of other recurrent mutations occur such that diagnostic kits are available allowing detection of common mutations by polymerase chain reaction (PCR).[63][64] Often only one mutant allele is detected; therefore, clinical manifestations should be considered in differentiating carriers from sufferers.

In Fabry disease, most classically affected males have 'private' mutations (rare mutations typically found only in small populations) that are typically null (associated with absent enzyme).[31]

In Pompe disease, the MPS disorders, and most other LSDs, a large number of mutations are reported for each disease, but there are recurrent mutations that are typically more common in some communities than in others.

The DNA result needs to be considered in light of detailed clinical information and data on enzyme activity.

Some mutations are polymorphisms and may not be associated with disease. Many PCR tests only screen for common mutations; 'private' mutations are only detected by sequence analysis in research laboratories.

Denaturing high-pressure liquid chromatography is a method for rapid screening for single-base mutations.

Carrier detection in X-linked disorders can only be reliably achieved by DNA analysis.

Not all mutations have been analysed and some disorders will only be diagnosed in consultant laboratories; it is essential that specialist centres are consulted in the design and implementation of the diagnostic strategy for these rare diseases.

Full blood count

Anaemia may be multifactorial due to chronic disease, renal impairment, feeding difficulties, or marrow replacement.

Leukopenia is typically due to splenomegaly. Abnormal inclusions may be seen in leukocytes: for example, periodic acid-Schiff-positive lymphocytes in Pompe disease; abnormal leukocyte appearances in blood/marrow in Tay-Sachs.[65]

Thrombocytopenia is typically due to splenomegaly, although there may be disturbed platelet function in, for example, Hermansky-Pudlak syndrome.[66]

ECG and echocardiogram

These are essential for cardiac assessment in infantile Pompe, adult Fabry, and many neonatal MPS disorders.[67][68] Findings may indicate enlarged cardiac chambers, abnormal valves, and functional defects in these patients.

Pulmonary function tests

These are critical in Niemann-Pick types A and B for assessing severity. Abnormal lung function with deficient gas transfer will be detected in these patients.[69]

Ophthalmic examination

Macular 'cherry spot' and optic atrophy or retinitis pigmentosa are seen in Tay-Sachs.[56] Corneal clouding is seen in MPS disorders, Fabry disease, and some Gaucher disease.[43] Characteristic cataract seen in Fabry disease with tortuous retinal vessels.[56] Cataracts are also seen in Gaucher disease, MPS disorders, and other LSDs.

Biopsy of affected tissue

This should only be considered after less invasive tests have been undertaken. Tissue biopsy of an organ that is enlarged and/or has disordered function (e.g., liver, kidney, heart) can be done to demonstrate increased levels of substrate, often associated with cellular engorgement.

Bone marrow biopsy is often undertaken in the investigation of hepatosplenomegaly and may reveal characteristic storage cells such as substrate-laden macrophages in Gaucher disease.[70] Electron microscopy of affected tissue may show characteristic changes of lysosomal damage. Muscle biopsy is of diagnostic utility in many LSDs (e.g., late-onset Pompe; however, appearances may be normal); skin biopsy is often favoured as it is relatively non-invasive and cultured skin fibroblasts are useful for enzyme assay.[71][72][73] The decision of the appropriate biopsy tissue will be undertaken by the consultant.[Figure caption and citation for the preceding image starts]: Bone marrow aspirate showing a typical Gaucher's cell. This is a macrophage that has ingested cellular material; the undegraded substrate (glucosyl ceramide) accumulates within lysosomesFrom the personal collection of Professor Atul B. Mehta [Citation ends].com.bmj.content.model.Caption@6e14f427[Figure caption and citation for the preceding image starts]: Electron microscope image of biopsy of pulmonary epithelial cells in Fabry's disease showing the characteristic deposits of substrate in lysosomes, forming 'zebra bodies': (A) magnification x8000, (B) magnification x62,500Kelly MM, Leigh R, McKenzie R, et al. Induced sputum examination: diagnosis of pulmonary involvement in Fabry's disease. Thorax. 2000 Aug;55(8):720-1; used with permission [Citation ends].com.bmj.content.model.Caption@5ebcd899

Imaging

LSDs are diverse multisystem disorders and many different forms of imaging are important and relevant. Examples are computed tomography (CT) and magnetic resonance imaging (MRI) to measure organ volumes and to assess the skeleton in Gaucher disease; echocardiogram, ultrasound, or MRI to assess heart, kidneys, and brain in Fabry disease; and CT and x-ray to assess communicating hydrocephalus, atlanto-axial dysplasia, and spinal/vertebral anomalies in MPS disorders.[42][74][75][76][77][Figure caption and citation for the preceding image starts]: Skeletal magnetic resonance imaging in type 1 Gaucher's disease showing widespread skeletal deposition of substrate with associated necrosis and bony infarction. There is avascular necrosis of the head of the femur (arrow)From the personal collection of Professor Atul B. Mehta [Citation ends].com.bmj.content.model.Caption@55df2645

Significance of negative test results

Early consultant referral is necessary. The clinician should liaise closely with the laboratory and ensure that samples reach the laboratory quickly, to avoid decay and possible false negative interpretation. Some assays are being refined (e.g., for Pompe disease); some DNA/enzyme tests may only be available through consultant referral to international research laboratories.[78] Deficiency of a sphingolipid activator protein or saposin may result in a clinical phenotype that resembles an LSD and may underlie Gaucher disease and metachromatic leukodystrophy.[1]

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