Disease

Gene

Enzyme deficiency

Alpha- mannosidosis

MAN2B1

Alpha-mannosidase

Phenotype: Considerably variable. Three clinical types have been suggested in untreated individuals. Type I Clinically recognized after age ten years, with myopathy, slow progression, and absence of skeletal abnormalities. Type 2 - Clinically recognized before age ten years, with myopathy, slow progression, and presence of skeletal abnormalities. Type 3 – Severe progression leading to early death from primary central nervous system involvement or infection. Enzyme replacement therapy is available for all forms.

Beta-mannosidosis

MANBA

Beta-mannosidase

Phenotype: Disease severity and progression is highly variable with onset from infancy to adulthood. Clinical features may include intellectual disability, respiratory infections, hearing loss, hypotonia, peripheral neuropathy, seizures, and behavioral problems.

Aspartylglucosaminuria

AGA

Aspartylglucosaminidase

Phenotype: Clinical features include developmental delay, intellectual disability, behavioral problems, recurrent infections, musculoskeletal features, and characteristic facial features. Clinical features worsen with age, and adults have progressive psychomotor decline.

Fucosidosis

FUCA1

Alpha-L-fucosidase

Phenotype: Continuum within a wide spectrum of severity; clinical features include neurodegeneration, coarse facial features, growth delay, recurrent infections, dysostosis multiplex, angiokeratoma, and elevated sweat chloride.

Schindler disease

NAGA

Alpha-N-acetyl-galactosaminidase

Phenotype: There are three types of Schindler diseases that differ in disease severity and age of onset. Type I is characterized by rapidly progressive neurodegeneration, typically by age 2 years. Type II is typically diagnosed in adulthood and characterized by angiokeratomas, mild cognitive impairment, and hearing loss.  Type III is an intermediate form that presents as a variety of symptoms that may include intellectual disability, seizures, and autism spectrum disorder.

GM1 gangliosidosis

GLB1

Beta-galactosidase

Phenotype: Continuum of clinical features ranging from severe and rapidly progressive disease to a milder and more slowly progressive course; infantile onset (type I) is characterized by early developmental delay/arrest followed by progressive neurodegeneration, skeletal dysplasia, facial coarseness, hepatosplenomegaly, and macular cherry red spot. Later onset forms (types II and III) are milder and observed as progressive neurologic disease and vertebral dysplasia. Adult onset presents mainly with dystonia.

Sandhoff disease

GM2 gangliosidosis, type II

HEXB

Beta-hexosaminidase A and B

Phenotype: Infantile onset is characterized by rapidly progressive neurodegeneration, exaggerated startle reflex, "cherry red spot". Juvenile and late-onset forms of the disease can present with developmental regression and/or neurological impairment, such as ataxia, dystonia, spinocerebellar degeneration, and behavior changes.

Sialidosis (ML I)

NEU1

Alpha-neuraminidase

Phenotype: Continuum of clinical features ranging from severe disease (type II) to a milder and more slowly progressive course (type I). Clinical features range from early developmental delay, coarse facial features, short stature, dysostosis multiplex, and hepatosplenomegaly to late onset cherry-red spot myoclonus syndrome. Seizures, hyperreflexia, and ataxia have been reported in more than 50% of later-onset patients. A congenital form of the disease has been reported in which patients present with fetal hydrops or neonatal ascites.

Galactosialidosis

CTSA

Cathepsin A causing secondary deficiencies in Beta-galactosidase and Alpha-neuraminidase

Phenotype: Continuum of clinical features ranging from severe and rapidly progressive disease to a milder and more slowly progressive course; clinical features of the early infantile type include fetal hydrops, edema, ascites, visceromegaly, dysostosis multiplex, coarse facies, and cherry red spot. Most patients have milder presentations, which include ataxia, myoclonus, angiokeratoma, cognitive and neurologic decline.

Mucolipidosis II/III alpha/beta (ML II/III a/ß)

Mucolipidosis III gamma (ML III?)

GNPTAB(alpha/beta)

GNPTG (gamma)

N-acetylglucosaminyl-1-phosphotransferase deficiency causing secondary intracellular deficiency of multiple enzyme activities

Phenotype: ML II is slowly progressive with features evident at birth. Common symptoms include skeletal abnormalities such as clubfeet, kyphosis, thoracic deformity, and deformed long bones, coarse facial features, gingival hyperplasia, and cardiovascular disease. ML III a/ß is slowly progressive with onset in early childhood presenting as slowed growth, short stature, and joint pain and stiffness. ML III? presents similarly to ML III a/ß but milder.

Mucopolysaccharidosis IVB (Morquio B)

GLB1

Beta-galactosidase

Phenotype: Progressive skeletal dysplasia with findings such as dysostosis multiplex, short stature, kyphoscoliosis, and genu/coxa valga. Corneal clouding is present in some individuals. Central nervous system dysfunction, course facial features, and organ enlargement are not typical.

Pompe disease (glycogen storage disease type II)

GAA

Alpha-glucosidase

Phenotype: Infantile onset is characterized by prominent cardiomegaly, hypotonia, respiratory distress, and weakness with onset before age 12 months. Later onset disease includes individuals with onset before age 12 months without cardiomyopathy and all individuals with onset after age 12 months and is characterized by proximal muscle weakness and respiratory insufficiency. Clinically significant cardiac involvement is uncommon with late onset.