History and exam

Key diagnostic factors

common

Family history

These are inherited disorders and should be assessed after appropriate consultation with a clinical geneticist. Occasionally patients do not have a family history, either because the families are small (these are mainly autosomal-recessive disorders and carriers are generally asymptomatic), or because it may be a new mutation. Family history in the extended pedigree is common in X-linked lysosomal storage diseases (Fabry, mucopolysaccharidosis [MPS] II, and Danon).

onset in childhood (MPS, Pompe, Gaucher, Fabry, Niemann-Pick type A)

Age <1 year: the severe forms of the mucopolysaccharidosis (MPS) disorders, classic Pompe disease, and neuronopathic forms of Gaucher disease present in early infancy.[30][35][46][50][80] Early age of onset is a strong indicator of a severe long-term course, and is often associated with low residual enzyme activity.

Age 1 to 10 years: most MPS disorders (including attenuated variants) and Niemann Pick type A will present by this age.[81] Most males with classic Fabry disease will have had some symptoms, although the average age of diagnosis in males is older.[38]

onset in adolescence (Fabry, Pompe, Gaucher types 1, 3, mucopolysaccharidosis, Niemann-Pick types B, C)

Age 10 to 20 years: most type 3 Gaucher disease; most of the more severe type 1 Gaucher disease but not all; most classic Fabry disease; and most Pompe, including adult onset, will be symptomatic, although not all diagnosed at these ages. Niemann-Pick types B and C are variable; severe phenotypes present earlier, milder phenotypes present later. Attenuated forms of mucopolysaccharidosis disorders are also highly variable.

onset in adulthood (Fabry, Gaucher type 1, Pompe)

Age 20 to 50 years: typical age of onset for most patients with type 1 Gaucher disease, and the age that patients with classic Fabry disease develop clinical problems.

Age >50 years: lysosomal storage diseases are unlikely to present in older age; exceptions are milder forms of type 1 Gaucher disease, atypical Fabry disease, and some patients with milder Pompe disease.

hepatomegaly and/or splenomegaly

Hepatomegaly is seen in type 2 and 3 Gaucher, mucopolysaccharidosis disorders, Pompe, and Niemann-Pick diseases.[5][30][46][49][54]

Splenomegaly is seen in type 2 and 3 Gaucher, mucopolysaccharidosis disorders, and Niemann-Pick disease.[5][30][46][49][54]

Hepatosplenomegaly is common in mucopolysaccharidosis disorders, Gaucher disease, and Niemann-Pick types A, B, and C.[5][30][46][49][54]

hyperacusis

Characteristic of Tay-Sachs disease.[82]

history of renal failure

Found in adult Fabry disease.[31]

skin rash/cutaneous lesions

Found in Fabry disease; other lysosomal storage diseases.[31][Figure caption and citation for the preceding image starts]: Cutaneous lesions in Fabry 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@613abbfe[Figure caption and citation for the preceding image starts]: Cutaneous lesions in Fabry 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@459986ca

large head circumference

Found in mucopolysaccharidosis disorders.[49][83]

macular "cherry red spot" on ophthalmoscopy

The choroid viewed through the fovea centralis appears as a red circular area surrounded by gray-white retina. Classical finding in infantile Tay-Sachs disease.[56]

optic atrophy or retinitis pigmentosa on ophthalmoscopy

Optic atrophy or retinitis pigmentosa are seen in juvenile form of Tay-Sachs disease.

corneal clouding on ophthalmoscopy

Seen in mucopolysaccharidosis disorders, Fabry disease, and some Gaucher disease.[12][49][56]

fatigue

Classic feature of Pompe disease, found at all ages (e.g., feeding difficulties in infancy, poor sporting performance in childhood, respiratory difficulties, falls, difficulty climbing stairs in adulthood).[84][85]

Other diagnostic factors

common

neurodevelopmental delay

Frequent in childhood forms of lysosomal storage diseases (mucopolysaccharidosis disorders, Niemann-Pick type A, type 2 and 3 Gaucher diseases).[30][41][49]

hearing impairment/sudden deafness

Found in Fabry disease, mucopolysaccharidosis disorders.[49]

cataract on ophthalmoscopy

Characteristic cataract seen in Fabry disease with tortuous retinal vessels. Cataracts are also seen in Gaucher disease, mucopolysaccharidosis disorders, and other lysosomal storage diseases.[56]

eye movement disorder

Eye movement disorders, such as horizontal saccades, are common in infantile Gaucher disease, Niemann-Pick type C, Tay-Sachs.[30][54]

progressive dementia and ataxia or gait disturbance

Seen in several juvenile and adult-onset lysosomal storage diseases, often accompanied by ataxia or gait disturbance (e.g., juvenile and chronic Tay-Sachs disease, Niemann-Pick type C).[54]

failure to thrive

Found in mucopolysaccharidosis disorders, Gaucher, Pompe, and Tay-Sachs diseases.[30][49]

joint contracture

Found in mucopolysaccharidosis disorders, Gaucher, Pompe, and Tay-Sachs diseases.[41][42]

depression

Very common in adults with Fabry disease.[12] Also found in Gaucher, Pompe, and Tay-Sachs diseases.

skeletal abnormalities including spinal gibbus

Frequent early sign in mucopolysaccharidosis disorders.[49]

hydrocephalus

Frequent early sign in mucopolysaccharidosis disorders.[49]

history of recurrent respiratory tract infections

Nonspecific but very common in mucopolysaccharidosis disorders, Pompe disease, infantile Gaucher disease.[49][52]

psychosis

Nonspecific; but psychosis in young adults may be the presenting feature of neurodegeneration in several lysosomal storage diseases (e.g., Niemann-Pick type C, Tay-Sachs).[54][58]

movement disorders

Nonspecific; but ataxia, dystonia, and cataplexy are all presenting features of neurodegeneration in lysosomal storage diseases (e.g., Niemann-Pick type C, Tay-Sachs) and parkinsonism can occur in association with adult Gaucher disease.[30][54]

uncommon

premature stroke/transient ischemic attack

Seen in Fabry disease (frequently posterior circulation).[31]

cardiomegaly

Seen in infantile Pompe and adult Fabry diseases.[35][50]

valvular cardiac disease

Seen in mucopolysaccharidosis disorders and in some patients with Gaucher and Fabry diseases.[12][30][47][49]

Risk factors

strong

male sex (mucopolysaccharidosis [MPS] II, Fabry disease)

MPS II is an X-linked trait; manifestations are exceedingly uncommon in females.

Fabry disease is also X-linked, but heterozygous females typically (>75%) do have symptoms, although less severe, more variable in expression, and at a later age of onset.[36][37][38][39][40]

Ashkenazi ethnicity

Carrier rate among Ashkenazi Jews is about 1 in 15 for Gaucher disease, 1 in 30 for Tay-Sachs, and 1 in 80 to 1 in 100 for Niemann-Pick type A.[11]

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