Table 1.
Examples of lysosomal storage diseases (LSDs) where cognitive defects were observed.
| Disease | Defective gene | Signs and symptoms |
|---|---|---|
| Defects in glycoprotein degradation | ||
| Mucolipidosis I, Sialidosis | α-Sialidase | Cherry-red macules in the eyes. Coarse facial features. Skeletal malformation and mental delay. |
| Galactosialidosis | Cathepsin A | Difficulty coordinating movements. Muscle twitches. Seizures. Visual loss. Dark red spots on the skin. |
| α-Mannosidosis | α-Mannosidase | Intellectual disability, hearing loss, ataxia, skeletal abnormalities, and coarse facial features. |
| β-Mannosidosis | β-Mannosidase | Respiratory infections. Swallowing difficulties. Poor muscle tone. Hearing loss. Speech impairment. |
| Aspartylglucosa-minuria | Glycosylasparaginase | Recurrent infections. Diarrhea. Gradual coarsening of facial features. An enlarged tongue and liver. |
| Fucosidosis | α-Fucosidase | Seizures. Abnormal bone development and muscle stiffness. Dark red spots on the skin. |
| Schindler | α-N-Acetylglucosaminidase | Redness and development of clusters of wart-like discolorations on the skin. Intellectual impairment. |
| Defects in glycolipid degradation | ||
| GM1 gangliosidosis MPS IVB | β-Galactosidase | Poor muscle tone. Enlargement of liver and spleen. Skeletal abnormalities. Seizures. Visual impairment. |
| GM2 gangliosidosis Tay-Sachs/Sandhoff | β-Hexosaminidase (α) β-Hexosaminidase (β) GM2 activator protein | Feeding problems. Cherry red spots in the backs of the eyes. Severe and fatal mental and physical deterioration. |
| Gaucher disease | Glucocerebrosidase Saposin C | Spleen/liver enlargement. Blood and bone issues. Mental and motor problems. |
| Globoid cell leukodystrophy | β-Galactosylceramidase | Muscle weakness. Feeding difficulties. Severe seizures and fevers. Vision and hearing loss. |
| Metachromatic leukodystrophy | Arylsulfatase A Saposin B | Walking difficulties, marked spasticity, seizures, and profound mental retardation. |
| Multiple sulfatase deficiency | Formyl-Glycin generating enzyme | Abnormality of peripheral nerve conduction. Developmental delay. Enlarged liver. |
| Fabry | α-Galactosidase A | Severe burning pains in hands and feet. Distinctive skin rash on the legs. Kidney & heart failure. Strokes. |
| Defects in glycogen degradation | ||
| Pompe | α-Glucosidase | Heart enlargement and heart failure in infants. Respiratory problems and severe muscle weakness. |
| Defects in sphingomyelin degradation | ||
| Niemann Pick type A and B | Acid sphingomyelinase | Organ enlargement. Lung dysfunction and central nervous system damage for certain subtypes. |
| Farber lipogranulomatosis | Acid ceramidase | A hoarse voice & weak cry, small lumps of fat under the skin and tissues, swollen and painful joints. |
| Defects in triglycerides and cholesteryls esters degradation | ||
| Wolman/cholesteryl ester storage disease | Acid lipase | Anemia, vomiting and diarrhea. Developmental delay. Poor weight gain. Low muscle tone. |
| Defects in protein degradation | ||
| Pycnodystostosis | Cathepsin K | A large head and high forehead. Undeveloped facial bones. Short fingers and toes. Dental abnormalities. |
| Ceroid lipofuscinosis 2 Ceroid lipofuscinosis 1 | Tripeptidyl peptidase Palmitoyl-protein Thioesterase | Abnormally increased muscle tone or spasm. Vision problems. Dementia. Lack of muscle coordination. Intellectual disability. Loss of speech. Seizures. |
| Defects in lysosomal transporters | ||
| Cystinosis | Cystinosin (cystin transport) | Impaired kidney function. Increased sensitivity to light, and marked growth retardation. |
| Salla disease | Sialin (sialic acid transport) | Intellectual disability and seizures. Problems with movement and balance. Muscle tension. |
| Defects in lysosomal trafficking proteins | ||
| Mucolipidosis III (I-cell) | Phosphotransferase γ-subunit | Abnormal skeletal development. Delayed motor skills. Enlargement of liver, spleen, & heart valves. |
| Mucolipidosis IV | Mucolipin-1(cation channel) | Intellectual disability. Diminished muscle tone. Clouding (opacity) of the clear portion of the eyes. |
| Danon | LAMP-2 | Muscle problems. Delayed motor skills. Intellectual disability. Shortness of breath and visual complaints. |
| Niemann Pick type C | NPC1 | Organ enlargement. Lung dysfunction and central nervous system damage for certain subtypes. |
| Batten disease Ceroid lipofuscinosis 3, 6, 8 | CLN3- CLN 6- CLN 8 | Vision failure. Recurrent seizures. Neurological disturbances. Muscle rigidity. Impaired speech. |
| Chediak-Higashi | LYST | Sensitivity to light. Blond or light brown hair with a silvery tint. Damaged immune and nervous systems. |
| Griscelli Type 1 Griscelli Type 2 Griscelli Type 3 | MYOV RAB27A Melanophilin | Distinctive skin and hair coloring. Weak muscle tone. Delayed development. Intellectual disability. Vision issues. Liver enlargement. Immunodeficiency. |
| Hermansky Pudliak 2 | AP3 β-subunit HOPS complex: VPS11, VPS16, VPS18, VPS39, VPS41 and VPS33A BLOC complexes 1, 2, & 3 | Dysfunction of blood platelets leading to prolonged bleeding. Lack of skin, hair, and eye pigmentation. |
| Defects in glycosaminoglycan degradation | ||
| MPS II (Hunter) MPS 1 (Hurler, Scheie) MPS IVA (Morquio A) MPS IX MPS IIIa (Sanfilippo A) MPS IIIc (Sanfilippo C) MPS IIIb (Sanfilippo B) MPS IIId (Sanfilippo D) MPS VII (Sly) MPS VI | Iduronate sulfatase α-Iduronidase Galactose 6-sulfatase Hyaluronidase Heparan N-sulfatase Acetyl-CoA transferase N-acetyl-glucosaminidase N-acetyl glucosamine 6-sulfatase β-glucuronidase N-Acetylgalactosamine 4-sulfatase | Bone and joint deformity as well as interference with normal growth. Weight-bearing joints. |