Table 4.

Genetic Disorders of Interest in the Differential Diagnosis of Type I (Infantile) GM1 Gangliosidosis

Gene(s)DiffDx Disorder 1Features of DiffDx Disorder
Cherry-
red spot (≤12 mos)		Onset of
neurologic
regression		Other features /
Comment		Distinguishing it from
type I (infantile) GM1
gangliosidosis
ASPA Canavan disease –≤6 mosMacrocephaly, head lag, hypotonia, seizuresLeukoencephalopathy,
↑ N-acetyl aspartate in CSF
CLN5
CLN6
CLN8
CTSD
MFSD8
PPT1
TPP1 		Neuronal ceroid lipofuscinoses, infantile & late-infantile (OMIM PS256730)–≤6 mosVisual deficits, seizuresAbnormal ERG
CTSA Galactosialidosis 2 (OMIM 256540)+≤6 mosSeizuresCorneal clouding
GALC Krabbe disease –≤6 mosSeizuresLeukodystrophy, peripheral neuropathy, irritability
GBA1 (GBA)Gaucher disease type 2–≤6 mosSeizures in some personsOculomotor abnormalities, hypertonia, opisthotonos
GFAP Alexander disease, infantile form–≤6 mosMacrocephaly, seizuresLeukodystrophy
GM2A Activator-deficient TSD 3 (GM2 gangliosidosis, AB variant) (See GM2 Activator Deficiency.)+≤6 mosPhenotype identical to classic TSD; 4 extremely rare disorderLack of coarse features & skeletal disease
GNPTAB Mucolipidosis II (I-cell disease) (See GNPTAB Disorders.)–≤12 mosAbsence of seizures
HEXA Tay-Sachs disease (See HEXA Disorders.)+≤6 mosMacrocephaly, head lag, hypotonia, seizuresLack of skeletal disease
HEXB Sandhoff disease 5+≤6 mosSeizuresLack of skeletal disease
NEU1 Sialidosis type II 6 (neuraminidase deficiency) (OMIM 256550)+≤12 mosSeizuresHydrops fetalis, epiphyseal stippling, facial edema
SMPD1 Niemann-Pick disease type A (See Acid Sphingomyelinase Deficiency.)+≤12 mosFeeding difficulties, severe failure to thrive, xanthomas, absence of seizures

CSF = cerebrospinal fluid; DiffDx = differential diagnosis; ERG = electroretinogram; TSD = Tay-Sachs disease

1.

The disorders included in Table 4 are inherited in an autosomal recessive manner, with the exception of Alexander disease, which is an autosomal dominant disorder.

2.

Galactosialidosis and sialidosis are caused by deficiencies in enzymes that form a complex with beta-galactosidase. This high molecular-weight complex includes beta-galactosidase (GM1 gangliosidosis), cathepsin A encoded by CTSA (galactosialidosis), and neuramidase 1 encoded by NEU1 (sialidosis/mucolipidosis I). Note that in galactosialidosis the activity of the enzymes beta-galactosidase and neuramidase 1 is reduced, respectively, to about 15% and less than 1% of normal values secondary to a primary deficiency of the protective protein/cathepsin A. Therefore, the activity of cathepsin A and of neuraminidase 1 in fibroblasts should be measured to definitively rule out galactosialidosis in an individual with partial deficiency of beta-galactosidase.

3.

In activator-deficient TSD, enzymatic activity of both beta-hexosaminidase (HEX A) and hexosaminidase B (HEX B) is normal, but GM2 ganglioside accumulation occurs because of a deficit of the intralysosomal glycoprotein ("GM2 activator") that is required for the degradation of GM2 ganglioside.

4.

Progressive weakness and loss of motor skills between ages six and 12 months, associated with an increased startle response, a cherry-red spot of the macula of the retina, and normal-size liver and spleen

5.

In Sandhoff disease, the activity of HEX A is deficient, as is the activity of HEX B, since both enzymes lack the common beta subunit.

6.

The features of sialidosis II more closely resemble GM1 gangliosidosis than sialidosis I. Sialidosis type I is also known as cherry-red spot myoclonus syndrome. Onset is in the teens and twenties. Gait disturbances and reduced visual acuity are the most common presenting symptoms. With time, myoclonus, ataxia, and reduced vision worsen, but are not life threatening. Intellect is normal.

From: GLB1-Related Disorders

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