Table 1.

Summary of the Forms and Symptoms of Sphingolipidoses

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	[46, 48–52]
				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.	[46, 53–57]
				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.	[46, 58, 59]
				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	[60–63]
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	[46, 64–71]
				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	[46, 72, 73] [74–77]
				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	[46, 78–81]
				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.	[82–89]
				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	[46, 67, 90–92]
				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	[46, 93–95]
				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	[96–99]
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