From: Sphingolipid lysosomal storage diseases: from bench to bedside
LSD | Defective enzyme | Mutated gene | Major accumulating SL(s) | Onset | Symptoms and neurological manifestations | Refs. |
---|---|---|---|---|---|---|
GM1 Gangliosidosis | β-gal | GLB1 | GM1 | Type I: First year Premature death at age 2-3 | • Developmental arrest • Seizures • Disintegration in the nervous system • Stiffening of joints • Hepatosplenomegaly • Edema • Gum hypertrophy • Skeletal abnormalities • Cherry-red spot (50% of the population) • Corneal cloudiness followed by blindness and deafness | |
Type II-late infantile: 7 months-3 years | • Developmental delay • Subsequent dementia • Cerebellar pyramidal, and extrapyramidal signs • Possible late loss of vision • No skeletal dysplasia | |||||
Type III:3-30 years | • Dysarthia and gait disturbances • Dystonia in the neck and extremities • Extrapyramidal signs • Cardiomyopathy | |||||
Sandhoff (Variant B) | α-subunit of β-Hexoseaminidase | HEXA | GM2, lyso-GM2 | Infantile (Tay-Sachs): 3-6 months | • Loss of skills • General weakness • Seizures • Bone abnormalities • Cherry-red spot • Startle response • Demyelination and swelling of neuronal cells • Reduction of consciousness, vision, and hearing. • Eventual spasticity and death. | |
Juvenile: 2-6 years with death at 10-15 years | • Progressive spasticity • Loss of speech and vision • Progressive dementia • Infertility | |||||
Chronic: 2-5 years but patients can reach their fourth decade | • Chronic: Gait disturbances • Posture abnormalities, followed by distinct neurological symptoms. • No sensory or intellectual impairment • Adult: has heterogeneous symptoms with intact mental and visual capabilities. • Bipolar psychosis may develop | |||||
Sandhoff (Variant O) | β-subunit of β-Hexoseaminidase | HEXB | GM2, lyso-GM2, uncharged glycolipids like GA2 | Infantile: 6 months | • Same as Tay-Sachs with fewer bone deformities, and organomegaly. | |
Juvenile: 2-10 years | • Cerebellar ataxia • Slurred speech • Psychomotor retardation followed by gradual mental retardation • Spasticity | |||||
Adult: in late adult life | • Pyramidal and extrapyramidal signs and symptoms of lower motor neurons • Supranuclear ophthalmoplegia • Movement problems | |||||
Sandhoff (Variant AB) | GM2A protein | GM2A | GM2, GA2 | 3-6 months | • Muscle weakening. • Loss of motor skills (crawling and sitting) • Startle reaction to noises • Seizures • Loss of vision and hearing • Intellectual disability • Paralysis | |
Gaucher Disease | GCase | GBA1 | GlcCer, GlcSph | Type I (Non-neuronopathic): Infancy to late adulthood | • Massive abdominal distension • Anemia and thrombocytopenia • Defective platelet function (abnormal coagulation) • Organomegaly • Poor development and delayed puberty • Bone diseases • Hepatopulmonary syndrome • No neurologic symptoms | |
Type II: 3-6 months with death at ~2 years | • Collodion skin • Visceral and bone marrow involvement • More severe neurological manifestations: Strabismus • Fast eye movement. • Bulbar palsy or paresis. • Severe hypertonia, rigidity, arching, swallowing impairment. • Seizures. • Progressive dementia. • Ataxia | |||||
Type III: 2-5 years | • Visceral and bone marrow involvement • Less severe neurological manifestations with slower progression | |||||
Niemann Pick A, B | aSMase | SMPD1 | SM | NPD-A: early onset premature death at the age of 3 | • Lymphadenopathy • Hepatosplenomegaly Hypotonia • Muscular weakness leading to feeding difficulties, followed by decreased platelet count, microcytic anemia • Osteoporosis • Cherry-red spots in the eye • Brownish-yellow color of skin • After six months of age, psychomotor retardation is observed • Loss of contact with the surroundings | |
NPD-B: chronic ranges from infancy-adulthood | • Slowly progressive systemic symptoms • No neurodegeneration • Hepatosplenomegaly • Anemia • Thrombocytopenia • Liver dysfunction • Lung and bone diseases. | |||||
Farber Disease | Acid Ceramidase | ASAH1 | Cer | Type I: Early-onset premature death at age 2-3 years | • Hepatosplenomegaly • Joint contractures • Voice hoarseness • Inflammation of subcutaneous nodules, along with other neurological manifestations | |
Type II: intermediate | • Decreased neurological inflammation-related symptoms • Longer lifespan | |||||
Type III: mild | ||||||
Type IV: Neonatal-visceral | • Organomegaly and visceral manifestations | |||||
Type V: Neurological-Progressive | • Progressive neurodegeneration and seizures | |||||
Type VI | • Combined Farber and Sandhoff diseases and associated symptoms | |||||
Fabry Disease | α-GAL | GLA | Gb3, lyso-Gb3 | Males: During childhood or adolescence | • Corneal dystrophy • Acroparesthesia • Angiokeratomas, and hypohidrosis, followed by progressive multi-system involvement leading to kidney failure, cerebrovascular disease, and hypertrophic cardiomyopathy in affected males • Females range from having no symptoms to severe ones. | |
Females: Heterozygous Mild late-onset disease (adult-onset) or severe disease. Homozygous Similar onset as males | ||||||
Krabbe Disease | GALC | GALC | psychosine | Infantile: 3-6 months. premature death between 2-5 years of age | • Motor dysfunction • Seizures • Cognitive decline | |
Juvenile & adult: few years- 73 years | • Dementia • Blindness, Psychomotor retardation • Spastic paraparesis | |||||
Metachromatic Leukodystrophy | ASA | ASA | sulfatide | Late infantile: Before 30 months | • Hypotonia • Mental regression, Unsteady gait, followed by loss of speech • Incontinence • Blindness • Seizures • Peripheral neuropathy • Complete loss of motor function • Loss of contact with the surroundings is observed before reaching 40 months of age | |
Juvenile: 2.5-16 years | • Later in onset but once the ability of walking is lost, the disease progresses as seen in the infantile form • Infertile | |||||
Adult: After puberty | • Variable progression | |||||
Niemann Pick C1 | NPC1 | NPC1 | Chol and other SLs | Perinatal (up to 2 months) | Systemic: • Mild thrombocytopenia (newborns or toddlers) • Prolonged neonatal cholestatic jaundice (in perinatal) • Hepatomegaly/ Splenomegaly Neurological: • Vertical supranuclear • Gaze palsy • Gelastic cataplexy • Ataxia • Dystonia • Dysarthria • Dysphagia • Hypotonia • Clumsiness • Delayed developmental milestones • Seizures • Hearing loss Psychiatric • Psychosis • Cognitive decline • Developmental delay | |
Niemann Pick C2 | NPC2 | NPC2 | ||||
Early-infantile (2 months–2 years of age) | ||||||
Late-infantile (2–6 years of age) | ||||||
Juvenile (6–12 years of age) | ||||||
Adolescent/adult (>12 years of age) | ||||||
Sialidosis | Sialidase (Neuraminidase) | NEU1 | sialyloligosaccharides | Sialidosis type I: Second to third decade | • Macular cherry-red spot • Gait abnormalities • Decreased visual acuity • Normal to slightly impaired intelligence • Action myoclonus • Intentional tremors • Cerebellar ataxia • Hyperreflexia • Hypotonia may occur • Cerebellar atrophy in advanced stages | [100] |
Sialidosis type II-congenital hydropic: in utero | • Hydrops fetalis: Ascites, Edema • Hepatosplenomegaly • Course features • Stillbirths or death at a very early age • Inguinal hernia • Cardiac Abnormalities • Renal Abnormalities • Respiratory distress • Psychomotor retardation • Hydrocephalus • Seizures • Corneal clouding • Dysostosis multiplex | |||||
 |  |  |  | Sialidosis type II-infantile: 0–12 months | • Coarse features • Hepatosplenomegaly • DysostosisMultiplex • Cherry red spot • Corneal Clouding • Cataract • Hearing loss • Inguinal hernia • Umbilical hernia • Hypotonia | |
 |  |  |  | Sialidosis type II- juvenile: 2–20 years | • Psychomotor delay • Seizures • myoclonic jerks • Ataxia • Myoclonic epilepsy |