Disorder

Onset

Gene

Enzyme deficiency

Worldwide incidence

Alpha-mannosidosis

Prenatal (type III) Infancy (type I) Juvenile/Adult (type II)

MAN2B1

Alpha-mannosidase

1:500,000

Phenotype: continuum of clinical features ranging from severe and rapidly progressive disease to a milder and more slowly progressive course. Prenatal onset (type III) manifests as prenatal loss or early death from progressive neurodegeneration. Infantile onset (type I) is characterized by rapidly progressive mental retardation, hepatosplenomegaly, and severe dysostosis multiplex. Type II is milder and slower progressing with survival into adulthood.

Beta-mannosidosis

Infancy to juvenile

MANBA

Beta-mannosidase

<100 patients described

Phenotype: clinical features vary in severity and may include intellectual disability, respiratory infections, hearing loss, hypotonia, peripheral neuropathy, and behavioral issues.

Aspartylglucosaminuria

Early childhood

AGA

Aspartylglucosaminidase

1:2,000,000 higher incidence in Finland approx 1:17,000

Phenotype: normal appearing at birth followed by progressive neurodegeneration at 2-4 years, frequent respiratory infections, coarse features, thick calvarium, and osteoporosis. Slowly progressive mental decline into adulthood.

Alpha-fucosidosis

Infancy to early childhood

FUCA1

Alpha-fucosidase

<100 patients described

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

Infancy (type I)

Early childhood (type III)

Adult (type II)

NAGA

Alpha-N-acetyl-galactosaminidase

<30 patients described

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 rapidly progressive neurodegeneration. Type II is adult onset characterized by angiokeratoma and mild cognitive impairment, and type III is an intermediate and variable form ranging from seizures and psychomotor delay to milder autistic features.

GM1 gangliosidosis

Infancy (type I)

Late infantile/juvenile (type II)

Adult (type III)

GLB1

Beta-galactosidase (Beta-Gal)

1:200,000

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.

GM2 gangliosidosis variant 0

(Sandhoff disease)

Early infancy to juvenile or adult

HEXB

Beta-hexosaminidase A and B

1:400,000

Phenotype: infantile onset is characterized by rapidly progressive neurodegeneration, exaggerated startle reflex, "cherry red spot". Milder later-adult onset forms of the disease exist presenting with neurological problems such as ataxia, dystonia, spinocerebellar degeneration, and behavior changes.

Sialidosis (ML I)

Early adulthood (type I)

Earlier for congenital, infantile, and juvenile forms (type II)

NEU1

Alpha-neuraminidase (Neu)

<30 patients described

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

Early infancy, late infancy or early adult

CTSA

Cathepsin A causing secondary deficiencies in Beta-Gal and Neu

<30 patients described

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. The majority of patients have milder presentations, which include ataxia, myoclonus, angiokeratoma, cognitive and neurologic decline.

Mucolipidosis II-alpha/-beta (I-cell)

Mucolipidosis III-alpha/-beta and III-gamma (pseudo-Hurler Polydystrophy)

Early infancy

Early childhood, may live well into adulthood 

GNPTAB(alpha/beta)

GNPTG (gamma)

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

1:300,000

Phenotype: I-cell resembles Hurler with short stature and skeletal anomalies, but presents earlier, is more severe, and can include cardiomyopathy and coronary artery disease. Pseudo-Hurler polydystrophy is milder and later presenting.

Mucopolysaccharidosis IVB (Morquio B)

Infancy to adult

GLB1

Beta-Gal

1:75,000

N. Ireland

1:640,000

W. Australia

Phenotype: progressive condition that largely affects the skeletal system. Features include short-trunk dwarfism, skeletal (spondyloepiphyseal) dysplasia, fine corneal deposits, and preservation of intelligence.

Pompe disease (glycogen storage disease type II)

Early infancy

Late onset (childhood-adult)

GAA

Alpha-glucosidase

1:40,000

Phenotype: infantile onset is characterized by prominent cardiomegaly, hepatomegaly, hypotonia, and weakness. Later onset forms present with proximal muscle weakness and respiratory insufficiency.